A Randomized Phase II Study Comparing Single-Agent Olaparib, Single Agent Cediranib, and the Combinations of Cediranib/Olaparib, Olaparib/Durvalumab (MEDI4736), Cediranib/Durvalumab (MEDI4736), Olaparib/AZD5363 (Capivasertib) in Women With Recurrent, Persistent or Metastatic Endometrial Cancer.: A Platform Trial for Women With Recurrent or Persistent Endometrial Cancer
Phase: PHASE2
Conditions: Endometrial Adenocarcinoma, Endometrial Mixed Cell Adenocarcinoma, Endometrial Serous Adenocarcinoma, Endometrial Undifferentiated Carcinoma, Endometrioid Adenocarcinoma, Stage IV Uterine Corpus Carcinoma or Carcinosarcoma AJCC v8
Sponsor: National Cancer Institute (NCI)

NRG-GY012 
1              NCI Version Date: May 23, 2024 
 
For Protocol Amendment #8 to: NRG-GY012 
 
 
NCI Protocol #: NRG-GY012 
Local Protocol #: NRG-GY012 
 
NCI Protocol Version Date: May 23, 2024 
 
This amendment is being submitted in response to an RRA received by Dr. Helen Chen 
(helen.chen@nih.gov) received on May 9, 2024. 
 
 
Section 
Comment 
7.3.4 
• 
Added New Risk:    
• 
Less Likely: Cardiac troponin T increased  
• 
Rare but Serious: Endocrine disorders - Other (thyroiditis); 
Hypophysitis; Optic nerve disorder, Nervous system disorders - 
Other (non-infective encephalitis); Skin and subcutaneous tissue 
disorders - Other (pemphigoid) 
• 
Also Reported on Durvalumab Trials But With Insufficient 
Evidence for Attribution: Acidosis; Adult respiratory distress 
syndrome; Alkaline phosphatase increased; Aspiration; Cardiac 
disorders - Other (valvular vegitation); Cardiac troponin I 
increased; Cholecystitis; Chronic kidney disease;  Cognitive 
disturbance; Colonic obstruction; Colonic stenosis; Death NOS; 
Dry mouth; Dysphagia; Ejection fraction decreased; 
Electrocardiogram QT corrected interval prolonged; 
Encephalopathy; Esophagitis; Fall; Febrile neutropenia; 
Gastritis; General disorders and administration site conditions - 
Other (failure to thrive); General disorders and administration 
site conditions - Other (general physical health deterioration); 
Generalized muscle weakness; Hypocalcemia; Hypothermia; 
Ileal stenosis; Immune system disorders - Other (Giany cell 
arteritis syndrome); Injury, poisoning, and procedural 
complications - Other (radiation pneumonitis); Insomnia; 
Ischemia cerebrovascular; Laryngeal obstruction; Leukocytosis; 
Musculoskeletal and connective tissue disorder - Other 
(polymyalgia rheumatica); Myocardial infarction; Neck edema; 
Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other (increase in tumor mass); Nervous system 
disorders - Other (hypoesthesia); Nervous system disorders - 
Other (neuropathy peripheral); Pain in extremity; Palpitations; 
Proteinuria; Pulmonary edema; Pulmonary fistula; Respiratory, 
thoracic and mediastinal disorders - Other (asphyxia); 
Respiratory, thoracic and mediastinal disorders - Other (fungal 
pneumonia; Phialemonium spp.); Respiratory, thoracic and 
mediastinal disorders - Other (granulomatous changes in the 
lung); Sinus bradycardia; Stroke; Sudden death NOS; Syncope; 

NRG-GY012 
2              NCI Version Date: May 23, 2024 
 
Thromboembolic event; Transient ischemic attacks; Ventricular 
arrhythmia; Ventricular tachycardia 
  
• 
Increase in Risk Attribution:  
• 
Changed to Less Likely from Also Reported on Durvalumab 
Trials But With Insufficient Evidence for Attribution: Anemia; 
Back pain 
• 
Changed to Rare but Serious from Also Reported on 
Durvalumab Trials But With Insufficient Evidence for 
Attribution: Platelet count decreased 
 
• 
Deleted Risk:   
• 
 Also Reported on Durvalumab Trials But With Insufficient 
Evidence for Attribution: Tumor inflammation; Small intestinal 
obstruction 
 
ICD 
Please see the ICD for additional changes. 
 
 
Changes made in addition to RRA: 
 
Section 
Comment 
Title Page 
• NCI Version Date is now May 23, 2024 
• The Data Manager has been updated to Brianna Williams  
• Amendment 8 and version date have been added to the Document 
History box 
 
TOC 
• Page numbers have been updated 
8 
• CTSU language has been updated to agree with current template 
language 
8.1 
• CTSU language has been updated to agree with current template 
language 
8.2.1 
• CTSU language has been updated to agree with current template 
language 
12.1 
• CTSU language has been updated to agree with current template 
language 

NRG-GY012 
1              NCI Version Date: May 23, 2024 
 
NRG-GY012 
(ClinicalTrials.gov NCT # 03660826) 
A Randomized Phase II Study Comparing Single-Agent Olaparib, Single Agent Cediranib, and 
the Combinations of Cediranib/Olaparib, Olaparib/Durvalumab (MEDI4736), 
Cediranib/Durvalumab (MEDI4736), Olaparib/AZD5363 (Capivasertib) in Women with 
Recurrent, Persistent or Metastatic Endometrial Cancer. A Multi-Arm Trial for Women with 
Recurrent or Persistent Endometrial Cancer (24-MAY-2021) (08-NOV-2021) 
 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI). IND# 
 
Lead Organization: NRG / NRG Oncology 
 
 
 
 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020 
Philadelphia, PA 19103 
 
Study Team (24-MAY-2021)(27-APR-2022)(26-JUL-2023)(23-MAY-2024) 
Study Chair 
Study Co-Chair 
Helen Mackay, MD 
David Bender, MD 
Sunnybrook Cancer Centre 
University of Iowa 
275 Bayview Avenue 
Gyn/Onc Division 
Toronto, Ontario M4N 3M5 
200 Hawkins Drive, 4630-JCP 
Canada 
Iowa City, Iowa 52242 
(416) 946-2000/FAX: (416) 946-0100 
(319) 356-2015/FAX: (319) 353-8363 
helen.mackay@sunnybrook.ca 
david-bender@uiowa.edu 
 
 
Study Co-Chair 
Translational Science Co-Chair  
Shannon Westin, MD 
Elizabeth Swisher, MD 
UT MD Anderson Cancer Center 
Division of Gynecologic Oncology 
1155 Herman Pressler Drive  
Dept OB/GYN/UW Medicine 
Houston, TX 77030 
1959 NE Pacific Street, Box 356460 
(713) 794-4314/FAX: (713) 792-7586 
Seattle, WA 98195-6460 
swestin@mdanderson.org  
(206) 543-3669 
 
swishere@uw.edu  
 
 
Study Co-Chair 
Translational Scientist  
BJ Rimel, MD 
Heather Lankes, PhD, MPH 
Cedars-Sinai Medical Center 
 NRG Oncology-Philadelphia East 
Gynecologic Oncology 
Four Penn Center 
Participating Organizations  
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG 

NRG-GY012 
2              NCI Version Date: May 23, 2024 
 
8700 Beverly Blvd, Suite 290W 
1600 JFK Blvd., Suite 1020 
Los Angeles, CA 90048 
Philadelphia, PA 19103 
(310) 423-5800/FAX: (310) 423-9753 
215-854-0770/FAX: 215-854-0716 
Bobbie.rimel@cshs.org 
lankesh@nrgoncology.org 
 
 
Statistician 
Data Manager/Data Operations Ctr 
Danielle Enserro, PhD 
Brianna Williams 
NRG SDMC-Buffalo Office 
NRG SDMC-Pittsburgh Office 
Roswell Park Cancer Institute 
One Sterling Plaza 
Elm and Carlton Streets 
201 North Craig Street, Ste. 500 
Buffalo, NY 14263 
Pittsburgh, PA 15213 
(716) 845-5702/FAX: (716) 845-8393 
(412) 624-8576 
enserrod@nrgoncology.org 
williamsb@nrgoncology.org  
 
 
 
 
Protocol Coordinator 
Disease Site Chair 
Leah Madden 
Carol Aghajanian, MD 
NRG Oncology 
Memorial Sloan-Kettering Cancer Ctr  
Four Penn Center 
Dept. of Medical Oncology 
1600 JFK Blvd, Suite 1020 
1275 York Avenue 
Philadelphia, PA 19103 
New York, NY 10021 
(215) 854-0770/FAX: (215) 854-0716 
(646) 888-4217/FAX: (646) 888-4267 
maddenl@nrgoncology.org 
aghajanc@mskcc.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NRG-GY012 
3              NCI Version Date: May 23, 2024 
 
Protocol Agents (24-MAY-2021) 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Cediranib 
CTEP 
732208 
 
DCTD, NCI 
Olaparib 
CTEP 
747856 
 
DCTD, NCI 
Durvalumab 
(MEDI4736) 
CTEP 
778709 
 
DCTD, NCI 
AZD5363 
(capivasertib) 
CTEP 
782347 
 
DCTD, NCI 
 
 
 
 
 
Participating Sites (27-APR-2022) 
 U.S. 
 Canada 
 Approved International Member Sites 
 
Document History 
 
Version/Update Date 
Amendment 8 
May 23, 2024 
Amendment 7 
July 26, 2023 
Amendment 6 
April 27, 2022 
Amendment 5 
November 8, 2021 
Amendment 4 
August 27, 2021 
Amendment 3 
May 24, 2021 
Amendment 2 
June 11, 2019 
Amendment 1 
January 15, 2019 
Activation 
August 27, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NRG-GY012 
4              NCI Version Date: May 23, 2024 
 
 
Lead Organization: NRG / NRG Oncology (24-MAY-2021)(27-APR-2022)(26-JUL-2023) 
CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
 (Sign in at 
https://www.ctsu.org,            
and select the >Regulatory 
Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or email: 
1-866-651-CTSU (2878), or  
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) or 
CTSURegHelp@coccg.org for 
regulatory assistance. 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
by phone or email: 1-888-823-
5923 or ctsucontact@westat.com. 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions.  
 
. 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site (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 or the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.   
 
 
This protocol was designed and developed by NRG Oncology. It is intended to be used only 
in conjunction with institution-specific IRB approval for study entry.  No other use or 
reproduction is authorized by NRG Oncology nor does NRG Oncology assume any 
responsibility for unauthorized use of this protocol. 

NRG-GY012 
5              NCI Version Date: May 23, 2024 
 
TABLE OF CONTENTS (24-MAY-2021)(27-APR-2022)(26-JUL-2023)(23-MAY-2024) 
SCHEMA .........................................................................................................................................8 
1. 
OBJECTIVES ......................................................................................................................9 
1.1 
Primary Objective ....................................................................................................9 
1.2 
Secondary Objectives (24-MAY-2021) ...................................................................9 
1.3 
Exploratory Objectives ..........................................................................................10 
2. 
BACKGROUND ...............................................................................................................10 
2.1 
Endometrial Cancer (EC) .......................................................................................10 
2.2 
DNA Repair as a Potential Therapeutic Target in Endometrial Cancer 
(EC) ........................................................................................................................11 
2.3 
Olaparib and Endometrial cancer ...........................................................................13 
2.4 
Cediranib and Endometrial Cancer ........................................................................14 
2.5 
Combination of Olaparib and Cediranib ................................................................15 
2.6 
Future Combination Strategies ..............................................................................16 
2.7 
AZD 5363 (Capivasertib) and Endometrial Cancer...............................................16 
2.8 
Combination of Olaparib and AZD5363 (Capivasertib) .......................................17 
2.9 
Combination of Olaparib and Durvalumab (MEDI4736) ......................................17 
2.10 
Combination of Cediranib and Durvalumab (MEDI4736) ....................................18 
2.11 
Rationale for Trial Design (24-MAY-2021) ..........................................................20 
2.12 
Translational Science Background ........................................................................21 
2.13 
Inclusion of Women and Minorities ......................................................................23 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA .................23 
3.1 
Eligibility Criteria ..................................................................................................23 
3.2 
Ineligibility Criteria ...............................................................................................28 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..........32 
4.1 
Pre-treatment Assessments (24-MAY-2021)(27-APR-2022) ................................32 
4.2 
Assessments During Treatment (24-MAY-2021)(27-APR-2022) .........................33 
4.3 
Assessments After Treatment (27-APR-2022) ......................................................35 
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION (24-MAY-2021) ..............................35 
5.1 
Chemotherapy/Hormonal Therapy/Other Agent-Based Therapy 
(Amendments 1-2) .................................................................................................35 
5.2 
General Concomitant Medication and Supportive Care Guidelines (24-
MAY-2021)............................................................................................................37 
5.3 
Duration of Therapy ...............................................................................................42 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT (24-MAY-2021) .........................42 
6.1 
Potential dose modifications for each arm and drug are shown in Table 
6.1...........................................................................................................................42 
6.2 
Holding Study Medications ...................................................................................43 
6.3 
Dose Modifications for Hematologic Events, Neutropenia or 
Thrombocytopenia .................................................................................................43 

NRG-GY012 
6              NCI Version Date: May 23, 2024 
 
6.4 
Non-Hematologic Toxicity ....................................................................................46 
6.5 
Hypertension Related to Cediranib Arms 1 and 6 .................................................47 
6.6 
AZD5363 (capivasertib) Specific Toxicities (Arm 4) ...........................................56 
6.7 
Management of toxicities related to durvalumab (MEDI4736) Arms 5 and 
6..............................................................................................................................61 
Table 6.7 A: Durvalumab (MEDI4736) (ARMS 5 and 6) Dose Delays and 
Toxicity Management for imAEs ..........................................................................63 
6.8 
Adverse events of special interest (AESI) for durvalumab (MEDI4736) 
(24-MAY-2021) .....................................................................................................80 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................81 
7.1 
Protocol Agents ......................................................................................................81 
7.2 
Adverse Events and Serious Adverse Events ........................................................81 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for 
CTEP Study Agents ...............................................................................................81 
7.4 
Expedited Reporting of Adverse Events (27-APR-2022) ......................................93 
8. 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES ..............95 
8.1 
Cancer Trials Support Unit Registration Procedures (27-APR-2022)(26-
JUL-2023) ..............................................................................................................97 
8.2 
Patient Enrollment (26-JUL-2023) ......................................................................100 
9. 
DRUG INFORMATION .................................................................................................101 
9.1 
Cediranib (AZD2171, NSC 732208) (24-MAY-2021) .......................................101 
9.2 
Olaparib (AZD2281, NSC 747856) .....................................................................103 
9.3 
AZD5363 (capivasertib), (NSC 782347) (24-MAY-2021) .................................105 
9.4 
Durvalumab (MEDI4736) (NSC 778709) (24-MAY-2021)................................106 
9.5 
Agent Ordering, Accountability, Inventory, Investigator Brochures and 
Links (24-MAY-2021) .........................................................................................108 
9.6 
Blood Pressure Cuffs ...........................................................................................109 
10. 
PATHOLOGY/BIOSPECIMEN .....................................................................................109 
10.1 
Stained Pathology Slide Requirements for Central Review to Confirm 
Eligibility .............................................................................................................109 
10.2 
Biospecimen Selection for Integral Biomarker Testing .......................................109 
10.3 
Biospecimen Selection for Integrated Biomarker testing ....................................109 
10.4 
Biospecimen Submission Tables .........................................................................110 
10.5 
Banking Biospecimens for Future Research ........................................................111 
11. 
SPECIAL STUDIES (NON-TISSUE) .............................................................................112 
12. 
DATA AND RECORDS .................................................................................................112 
12.1 
Data Submission/Data Reporting .........................................................................112 
12.2 
Data Quality Portal ..............................................................................................113 
12.3 
Rave-CTEP-AERS Integration ............................................................................113 
12.4 
Global Reporting/Monitoring ..............................................................................115 
12.5 
Collaborative Agreements Language ...................................................................115 

NRG-GY012 
7              NCI Version Date: May 23, 2024 
 
13. 
STATISTICAL CONSIDERATIONS.............................................................................117 
13.1 
NRG-GY012 Governance (24-MAY-2021) ........................................................117 
13.2 
Study Design ........................................................................................................118 
13.3 
Study Endpoints (24-MAY-2021) .......................................................................118 
13.4 
Primary Objectives Study Design (24-MAY-2021) ............................................119 
13.5 
Study Monitoring of Primary Objectives .............................................................121 
13.6 
Accrual/Study Duration Considerations ..............................................................122 
13.7 
Dose Level Guidelines .........................................................................................122 
13.8 
Secondary or Exploratory Endpoints (Including Correlative Science 
Aims)(24-MAY-2021) .........................................................................................122 
13.9 
Exploratory Hypothesis and Endpoints (24-MAY-2021) ....................................124 
13.10 Gender/Ethnicity/Race Distribution (24-MAY-2021)(27-APR-2022) ................124 
14. 
EVALUATION CRITERIA ............................................................................................126 
14.1 
Definitions............................................................................................................126 
14.2 
Disease Parameters ..............................................................................................127 
14.3 
Methods for Evaluation of Measurable Disease ..................................................128 
15. 
REFERENCES (24-MAY-2021) .....................................................................................130 
APPENDIX I: TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES ....................138 
APPENDIX II: TRANSLATIONAL SCIENCE LABORATORY TESTING PROCEDURES 
(24-MAY-2021) ...............................................................................................................143 
APPENDIX III: ORAL ANTIHYPERTENSIVE MEDICATIONS ...........................................148 
APPENDIX IV: PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARDS .150 
APPENDIX V: PATIENT DRUG DIARIES (27-APR-2022) ....................................................156 
APPENDIX VI: PATIENT BLOOD PRESSURE DIARY .........................................................162 
APPENDIX VII: ACTIONS REQUIRED IN CASES OF INCREASE IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY’S LAW ............................................163 
 
 
 
 
 
 

NRG-GY012 
8              NCI Version Date: May 23, 2024 
 
 
SCHEMA  
 
  
Schema changes as of Amendment 3 (24-MAY-2021): 
 
 
 
 
            Original schema           Subsequent schema (Amendment 3) 
 
 

NRG-GY012 
9              NCI Version Date: May 23, 2024 
 
 
1. 
OBJECTIVES 
 
1.1 
Primary Objective 
To compare the efficacy of single-agent olaparib and the combination of olaparib and 
cediranib (and potentially other combination arms that may be added by subsequent 
amendment) versus single agent cediranib as measured by progression free survival 
(PFS), in patients with recurrent, persistent or metastatic endometrial cancer. 
 
To compare the efficacy of the combination of olaparib and AZD5363 (capivasertib), and 
the combination of olaparib and durvalumab (MEDI4736), and the combination of 
cediranib and durvalumab (MEDI4736) versus single agent cediranib as measured by 
progression free survival (PFS), in patients with recurrent, persistent or metastatic 
endometrial cancer. (24-MAY-2021) 
 
1.2 
Secondary Objectives (24-MAY-2021) 
 
1.2.1 To compare the efficacy of single-agent olaparib and the combination of olaparib and 
cediranib (and potentially other combination arms that may be added by subsequent 
amendment) versus single-agent cediranib as measured by overall survival (OS) in 
patients with recurrent, persistent or metastatic endometrial cancer.  
 
To compare the efficacy of the combination of olaparib and AZD5363 (capivasertib), and 
the combination of olaparib and durvalumab (MEDI4736), and the combination of 
cediranib and durvalumab (MEDI4736) versus single agent cediranib as measured by 
overall survival (OS), in patients with recurrent, persistent or metastatic endometrial 
cancer. 
 
1.2.2 To compare the efficacy of single-agent olaparib and the combination of olaparib and 
cediranib (and potentially other combination arms may be added by subsequent 
amendment versus single-agent cediranib as measured by response rate in patients with 
recurrent, persistent or metastatic endometrial cancer.  
 
To compare the efficacy of the combination of olaparib and AZD5363 (capivasertib), and 
the combination of olaparib and durvalumab (MEDI4736), and the combination of 
cediranib and durvalumab (MEDI4736) versus single agent cediranib as measured by 
response rate in patients with recurrent, persistent or metastatic endometrial cancer. 
 
1.2.3 To assess the safety and tolerability of single–agent cediranib, single-agent olaparib, and 
the combination of olaparib and cediranib (and potentially other combination arms may 
be added by subsequent amendment). 
 
To assess the safety and tolerability of the combination of olaparib and AZD5363 
(capivasertib), and the combination of olaparib and durvalumab (MEDI4736), and the 
combination of cediranib and durvalumab (MEDI4736). 
 

NRG-GY012 
10              NCI Version Date: May 23, 2024 
 
Secondary objectives 1.2.4 and 1.2.5 apply to the first three treatment arms only: 
cediranib alone, olaparib alone, and the combination of olaparib and cediranib.  
Biomarkers for added treatment arms require either amendment or correlative science 
proposal submission and secured funding.  
 
1.2.4 To assess if mutations in DNA Homologous Repair Genes (assayed prior to all treatment 
and prior to the study treatment) are predictive of response to olaparib alone or in 
combination with cediranib. (Integrated Biomarker)  
 
1.2.5 To assess if markers of angiogenesis in serial plasma samples are associated with 
response to cediranib alone or in combination with olaparib. (Integrated Biomarker) 
 
1.3 
Exploratory Objectives 
 
1.3.1   To compare the efficacy of the combination of olaparib and cediranib versus single agent 
olaparib as measured by PFS, response rate and OS, if and only if the combination is 
superior to the single-agent cediranib arm. 
 
 
2. 
BACKGROUND 
 
2.1 
Endometrial Cancer (EC) 
 
Endometrial cancer (EC) is the most common gynecologic malignancy in the developed 
world with 60,050 new cases and 10,470 deaths reported in the United States (US) in 
2016 [Siegel, 2016].  Furthermore, with an aging population and rising rates of obesity, 
the incidence of EC will continue to rise.  In the US, if current trends continue, there will 
be a doubling in the number of women diagnosed with EC by the year 2030 to 122,000 
cases per year [Rahib, 2014].  Although the majority of EC are diagnosed when disease is 
limited to the uterus, up to 25% of cases will recur.  For women with advanced or 
recurrent disease, therapeutic options are limited [Lheureux, 2014]. Frontline 
chemotherapy for recurrent or metastatic EC is platinum-based, with Protocol GOG-0209 
confirming the non-inferiority of carboplatin/paclitaxel (TC) compared to the more toxic 
doxorubicin-based regimen (doxorubicin, cisplatin, paclitaxel, TAP), where median 
overall survival (OS) was 32 vs. 38 months for the TC vs. TAP arms [Miller, 2012]. The 
value of second line chemotherapy is disputed with response rates in the order of 20% 
and progression free survival (PFS) in the order of months (Lheureux et al., 2014). For 
low grade tumors, endocrine therapy may be an option, but OS duration remains limited.  
 
The evaluation of a number of molecularly targeted agents in EC has demonstrated 
modest response rates with some evidence of prolonged disease stabilization Table 1 
[Lheureux, 2014]. Currently, activity has been insufficient to result in approval of any 
targeted agent for use in EC. 
 
 
 
 

NRG-GY012 
12              NCI Version Date: May 23, 2024 
 
 
Figure 1: Frequent alteration in DNA repair genes seen in endometrial cancer. [5] 
 
Additional genomic alterations that result in aberrations in the Homologous Recombination (HR) 
pathway are shown in Figure 2.  In 137 patients with EC, a higher “HR deficiency (HRD) score” 
was associated with a worse prognosis [Hansen, 2016].  
 
 
 Figure 2: Genomic aberrations in HR pathway in EC (48%) exclusive of PTEN.  

NRG-GY012 
13              NCI Version Date: May 23, 2024 
 
 
The incidence of molecular events in EC associated with DNA repair make targeting this 
an attractive therapeutic strategy to explore in this disease. 
 
2.3 
Olaparib and Endometrial cancer 
 
Olaparib is an orally active poly (ADP-ribose) polymerase inhibitor (PARPi) that has 
demonstrated efficacy and tolerability in a number of solid tumor types including 
prostate, pancreatic, and epithelial ovarian cancer (EOC) [Audeh, 2010; Kaufman, 2015; 
Ledermann, 2014; Mateo, 2015].  Extensive data exist on the safety of this drug in Phase 
I, II and III trials, and it has FDA approval for the treatment of recurrent EOC 
[Ledermann, 2012; Pujade-Lauraine, 2017].  Investigators should be familiar with the 
current olaparib (AZD2281) Investigator Brochure (IB). Treatment is generally well 
tolerated with the main side effects being anemia, decreased appetite, dizziness, 
headache, dysgeusia, vomiting, diarrhea, nausea, dyspepsia, and fatigue.  Health related 
quality of life remains high in patients despite long periods of treatment [Friedlander, 
2017]. Preclinical data is published, suggesting efficacy for olaparib in EC [Dedes, 2010; 
Shen, 2015].  These include data suggesting response to olaparib in EC cell lines and 
mouse models [Hansen, 2016; Miyasaka, 2014].  Clonogenic assays show sensitivity to 
olaparib varies among EC cell lines, with SF50 values ranging from 8 nM to 2,500 nM.  
The high ratio (25%) of sensitive cells with SF50 values <100 nM support the 
investigation of olaparib in women with EC.  
 
Dedes and colleagues documented increased PARP sensitivity in PTEN-deficient EC cell 
lines compared to cell lines with wild-type PTEN [Dedes, 2010], although subsequent 
data suggested response might be independent of PTEN status [Miyasaka, 2014].  
ARID1A is recruited to DNA breaks through interaction with ATR and is required for 
normal G2/M checkpoint inhibition; ARID1A loss of function impairs ATR activation by 
DNA double-strand breaks (DSBs), associated with sensitization to PARP inhibition 
[Shen, 2015] Figure 3.  Given the frequency of ARID1A mutation in EC, this suggests 
investigating olaparib would be a reasonable strategy.  Hansen et al reported a significant 
reduction in tumor weight following olaparib treatment in EC tumor bearing mice.  
Reduced proliferation and increased apoptosis were observed in cell lines with both a 
high and lower HRD score although response was most marked in the model with the 
higher HRD score [Hansen, 2016].  
 

NRG-GY012 
14              NCI Version Date: May 23, 2024 
 
 
 
Figure 3: Demonstrating ARID1A deficiency and impairment of HR repair 
 
2.4 
Cediranib and Endometrial Cancer  
 
Targeting angiogenesis has been extensively studied in EC [Lheureux, 2014]. A 48-
patient phase II study in an unrestricted EC patient population evaluated cediranib, a 
tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors 
(VEGFRs), platelet derived growth factor (PDGF) alpha and beta and fibroblast growth 
factor (FGF) receptor 1, in recurrent or metastatic EC has been completed.  This study 
included all histological subtypes.  A partial response was observed in 12.5% of patients 
and the six-month event free survival was 29%, meeting the protocol set efficacy 
objectives to warrant further investigation.  Response was seen across histological 
subgroups although the number of serous patients was low (11 patients).  Median PFS 
was 3.65 months with a median OS of 12.5 months.  Table 1, illustrates this in the 
context of other agents investigated in the GOG-0229 series of phase II trials.  Treatment 
was generally well tolerated with the most common grade 3 adverse events being: 
Hypertension (n=16), fatigue (10), and diarrhea (7) [Bender, 2015].  Cediranib is an oral 
agent, with an attractive mode of delivery compared to the intravenous route required for 
some other anti-angiogenic agents. Investigators should be familiar with the current 
cediranib (AZD2171) Investigator Brochure (IB). Single agent cediranib is included in 
this study to provide a comparator (reference arm) for the other study arms given the 
challenge of evaluating PFS against historical control.  Furthermore, this study includes 
patients who may have received prior anti-angiogenic therapy, a population who would 
not have been included in prior phase II studies.  
 

NRG-GY012 
15              NCI Version Date: May 23, 2024 
 
 
 
Figure 4: Augmenting DNA damage and repair: potential therapeutic directions [Ivy, 
2016]. 
 
2.5 
Combination of Olaparib and Cediranib 
 
Pre-clinical studies have indicated that angiogenesis inhibitors combined with PARPi can 
have supra-additive effects in some cell types.  In vivo anti-angiogenic effects have been 
observed with PARPi's and in PARP -1 knockout mice [Tentori, 2007].  In addition, 
down regulation of HR genes have been observed in hypoxic conditions (contextual 
synthetic lethality) with enhancement of PARPi sensitivity [Bindra, 2005], Figure 4.  
Pre-clinically cediranib and olaparib have shown potential synergistic activity in 
decreasing tumor cell invasion and blood vessel growth.  In a recent phase II study in 
women with platinum sensitive EOC the combination of the oral anti-angiogenic agent 
cediranib and olaparib exhibited greater efficacy than olaparib alone, and toxicity in this 
patient population was acceptable.  In the subset of patients that were BRCA non-
carrier/unknown the median PFS was 5.7 months with olaparib alone and 16.5 months 
with the combination (HR 0.32, 95% CI 0.14-0.74, p=0.008).  Olaparib and cediranib 
were well tolerated.  The most commonly reported grade 3 or 4 toxicities included fatigue 
27%, hypertension 41% and diarrhea 23% [Liu, 2014]. 
 
Although direct pre-clinical data is lacking for EC for the combination of olaparib and 
cediranib, based on data in other tumor types, on pre-clinical models suggesting targeting 
DNA repair in EC is a valid therapeutic direction and on evidence of efficacy for single 
agent cediranib, investigating this combination in women with EC is warranted.  
 

NRG-GY012 
16              NCI Version Date: May 23, 2024 
 
2.6 
Future Combination Strategies  
 
Augmenting DNA damage by targeting multiple parts of the DNA repair process is an 
attractive potential therapeutic strategy in EC. Whilst targeting angiogenesis in 
combination with PARP inhibition represents one approach other potential actionable 
opportunities exist   Figure 4.  Promising targets include ATM and ATR, and WEE1 and 
CHEK2 G2 checkpoint kinases [Ivy, 2017; Juvekar, 2012; Hu, 2016]. Other emerging 
strategies include combining PARP inhibition with anti-metabolic activity of agents such 
as the phosphor inositol 3 kinase inhibitors. The goal being to take advantage of clinical 
synthetic lethality resulting in selective tumor cell kill.  As this protocol evolves and data 
on combination strategies targeting DNA repair mature consideration will be given to 
amending the protocol to allow inclusion of new study arm(s). 
 
Sections 2.7-2.10 have been added as additional combinations of interest (24-MAY-
2021) 
 
2.7 
AZD 5363 (Capivasertib) and Endometrial Cancer 
 
More than 80% of endometrioid endometrial cancers have an aberration in PTEN, a tumor 
suppressor gene that encodes a pivotal phosphatase in the regulation of the PI3K-AKT-
mTOR pathway [Korets SB… CCR 2011]. Loss of PTEN function leads to cellular 
proliferation via upregulation of the pathway [Dedes KJ et al Sci Trans Med 2010]. PTEN 
is also involved in maintaining genomic stability, and PTEN mutations lead to defects in 
homologous recombination (responsible for repairing double-strand DNA breaks).  
 
AKT (also known as protein kinase B) is a key member of the PI3K pathway. Activation 
of AKT leads to cellular proliferation and survival through various downstream targets, 
including mTOR. Targeting AKT is an area of great interest for endometrial cancer 
secondary to the known molecular aberrations throughout this pathway.  In vitro and in 
vivo studies of AKT inhibitors have demonstrated activity against both ovarian and 
endometrial cancer [Wu…Cho CCR 2011, Engel…Perifosine Eur J Obst Gyn Repro 
2008]. The AKT inhibitor perifosine has demonstrated activity in phase I studies of solid 
tumors. Additionally, abbreviated versions of the planned clinical trials of the allosteric 
AKT inhibitor MK-2206 in women with operable breast cancer and another with 
platinum-resistant ovarian, primary peritoneal, or fallopian tube cancer were published 
[Kalinsky K Clin Transl Oncol 2018, Lee EK…Liu J Gyn Onc Reports 2020]. 
Unfortunately, both trials demonstrated higher than anticipated toxicity which resulted in 
premature termination. A phase II study of patients with PIK3CA mutated recurrent 
endometrial cancer did successfully complete its enrollment, but of note did have to to 
dose reduce during the study due to unacceptable toxicity [Myers AP Int J Cancer 2019]. 
 
AZD5363 (capivasertib) is a potent, orally bioavailable, selective inhibitor of the kinase 
activity of the serine/threonine kinase AKT/protein kinase B (PKB) that is being 
developed as a potential treatment for solid and hematological malignancies. Thus far, 
AZD5363 (capivasertib) appears to have good tolerability when administered in phase II 
combination trials of breast cancer patients [Turner NC Ann Oncol 2019, Jones RH 

NRG-GY012 
17              NCI Version Date: May 23, 2024 
 
Lancet Oncol 2020, Schmid P JCO 2020].  
 
2.8 
Combination of Olaparib and AZD5363 (Capivasertib) 
 
More than 80% of endometrioid EC have an aberration in PTEN, a tumor suppressor gene 
that encodes a pivotal phosphatase in the regulation of the PI3K-AKT-mTOR pathway 
[Korets 2011]. Loss of PTEN function leads to cellular proliferation via upregulation of 
the pathway [Dedes 2010]. PTEN is also involved in maintaining genomic stability and 
potentially in HRD as described above. 
 
Targeting the effects of PTEN loss in EC by inhibiting PI3K or exploitation of inadequate 
DNA repair, is an attractive therapeutic strategy. To date, this has met with limited success 
as the majority of agents investigated in EC have inhibited the pathway downstream at the 
mTOR complex. However, the majority of mTOR inhibitors evaluated in EC selectively 
inhibit only one of the two mTOR complexes, potentially resulting in cell survival via 
feedback activation of AKT [O'Reilly 2006]. AKT is a serine/threonine kinase also known 
as protein kinase B and is a key member of the PI3K pathway. Activation of AKT leads to 
cellular proliferation and survival through various downstream targets, including mTOR. 
Targeting AKT is therefore of interest in EC.  In vitro and in vivo studies of AKT inhibitors 
have demonstrated activity against both ovarian and endometrial cancer [Engel 2008, Wu 
2011]. AZD5363 (capivasertib) is a potent, orally bioavailable, selective inhibitor of the 
kinase activity of AKT/protein kinase B (PKB). AZD5363 (capivasertib) has shown 
activity against AKT 1 mutated tumors as part of the NCI-MATCH clinical trial. It has also 
been combined with paclitaxel without impact on tolerability (although it did not enhance 
efficacy) in metastatic breast cancer [Cancer Discov 2019, Turner 2019]. 
 
A recent Phase I study of the combination of olaparib and AZD5363 (capivasertib) 
demonstrated that the combination was safe and well-tolerated at olaparib 300mg BID 
and AZD5363 (capivasertib) 400 mg 4 day on/3 off schedule. Furthermore, in the 
endometrial cancer cohort, a 50% response rate among 8 evaluable patients was 
observed.  Importantly, response duration was durable lasting a median of 14 months 
[Westin 2017]. 
 
2.9 
Combination of Olaparib and Durvalumab (MEDI4736) 
 
The efficacy of immunotherapy in patients with MSI high EC is well documented based 
resulting in FDA approval for the PD-L1 inhibitor pembrolizumab [Marcus 2019]. 
Recently a novel mechanism of PARPi action was demonstrated by Shen et al. PARPi 
promoted accumulation of cytosolic DNA fragments because of unresolved DNA lesions 
[Shen 2019]. These free DNA fragments activated the DNA-sensing cGAS–STING 
pathway [Chen 2016] Activation of this pathway lead to stimulated production of type I 
IFNs to induce antitumor immunity [Shen 2019]. This process was independent of BRCA 
mutation status. These effects of PARPi were further enhanced by immune checkpoint 
blockade. Durvalumab (MEDI4736) is an FDA approved monoclonal antibody that blocks 
the interaction of PD-L1 with the PD-1 and CD80 molecules. 
 

NRG-GY012 
18              NCI Version Date: May 23, 2024 
 
A recent phase 1 study of the combination of olaparib and durvalumab (MEDI4736) in 
advanced ovarian malignancy was both safe and effective [Lee 2017]. At full doses of 
olaparib and durvalumab (MEDI4736) the combination demonstrated a disease control 
rate of 83/% with at least stable disease of >=4mo. While this study did not include 
advanced endometrial cancer patients, the preclinical data suggest that this strategy would 
be effective in endometrial cancer patients. 
 
2.10 
Combination of Cediranib and Durvalumab (MEDI4736) 
 
Angiogenesis and tumor neovascularization are critically linked to the functionality of the 
host’s immune system [Tartour 2011]. Angiogenic-related effects, seen in solid tumors, 
interfere with a functional immune response through a variety of mechanisms. Production 
of vascular endothelial growth factor (VEGF), the hypoxic tumor microenvironment, and 
proteins secreted by the tumor all lead to impaired immune function [Fukumura 2018]. The 
production and presence of VEGF has a negative impact on immune response.  Circulating 
VEGF leads to recruitment, proliferation, and increased activity of T regulatory cells 
[Wada 2009], tumor-associated macrophages [Maenhout 2014], and myeloid-derived 
suppressor cells [Huang 2007]; all of which contribute to an immunosuppressed state. The 
development and activation of cytotoxic T lymphocytes is directly inhibited by VEGF; 
decreased cytokine production by T-cells is observed as well as their ability to traffic to a 
solid tumor [Motz 2014,Voron 2015 ]. Similarly, dendritic cells lose their ability to mature 
and present antigens in the presence of VEGF [Gabrilovich 1998]. 
 
Tumor neovascularization, often the result of VEGF production, can be misleading, as the 
vascular supply to the tumor is typically poor leading to a hypoxic and acidotic 
microenvironment. Hypoxia and acidosis trigger activation of the PD-1/PD-L1 immune 
checkpoint pathway via T-regulatory cells, tumor-associated macrophages, dendritic cells, 
and endothelial cells [Barsoum 2014, Jain 2014]. The compromised function of the 
immune system and its various components, as seen during PD-1/PD-L1 activation, further 
enhances the tumor’s ability to evade the host’s immune system. Lastly, tumors secrete 
soluble mediators directly into the circulation subsequently inducing expression of 
immunosuppressive chemokines. Circulating VEGF, TGF-beta, and prostaglandin E2 
inhibit the activity of antigen presenting cells and ultimately reduce the anticancer response 
of the effector T-cells [Huang 2013, Li 2006, Raman 2007].   
 
A reasonable rationale exists for blocking both angiogenic and the immune checkpoint 
PD-1/PD-L1 pathways given their coordinated relationship and role in tumor growth. 
Preclinical data demonstrated a synergistic effect during the simultaneous blockade of 
PD-1/PD-L1 and VEGF pathways. Yasuda and colleagues treated a colorectal cancer 
murine model with an anti-VEGF receptor 2 monoclonal antibody and an anti-mouse PD-
1 blocking monoclonal antibody to show after three weeks of treatment a greater decrease 
was seen in tumor size compared to the decrease seen by either antibody alone [Yasuda 
2013].  Similar observations were made in a metastatic castration-resistant prostate 
cancer mouse model [Lu 2017]. 
 
The strategic combination of immune checkpoint inhibitors and antiangiogenic blockade 

NRG-GY012 
19              NCI Version Date: May 23, 2024 
 
has been studied in a variety of solid tumors and highlights the observation that response 
rates are considerably greater for the combination therapy compared to single agents 
[Atkins 2018, Hodi 2014, McDermott 2018]. Recently the FDA approved the 
combination of lenvatinib and pembrolizumab for MSS endometrial cancer and uterine 
serous carcinoma [Makker 2019] Lee and colleagues examined the specific combination 
of cediranib and durvalumab (MEDI4736) in ovarian, cervical and uterine tumors [Lee 
2017]. Their phase I study identified an optimal dosing regimen for each agent with 
acceptable toxicity.  
 
The recommended phase II dose from Lee et al [Lee 2017] for the combination was 
durvalumab (MEDI4736) 1500mg IV every 4 weeks and cediranib 20mg 5 days on 2 
days off.  This dosing strategy prevented excess accumulation of cediranib based on PK 
studies and provided sufficient washout based on the data gathered from the phase 1 
study.  Increased toxicity was noted with two patients in the continuous cediranib dosing 
arm having significant events (1 pulmonary hypertension, 1 colitis).  Based on these 
results, the intermittent dosing schedule is chosen for this study.  
 
Rationale for 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 durvalumab (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 
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 (Error! Reference source not found., 
Error! Reference source not found., Error! Reference source not found., Error! 
Reference source not found.). 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 (Error! Reference source not found.). 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, we considered it feasible to switch to fixed dosing regimens. Based on average 
body WT of 75 kg, a fixed dose of 1500 mg Q4W durvalumab (MEDI4736) (equivalent to 
20 mg/kg Q4W) is included in the current study. 
 
 

NRG-GY012 
20              NCI Version Date: May 23, 2024 
 
2.11 
Rationale for Trial Design (24-MAY-2021) 
 
The incidence of endometrial cancer (EC) is rising.  There is no effective second line 
therapy for EC and no new agents have been approved for the treatment of EC in the last 
two decades.  Well tolerated, effective therapies are urgently required.  
 
The TCGA (and others) identified genomic events across the spectrum of EC histologic 
sub types that suggest EC may be susceptible to DNA damaging agents.  There is 
therefore a strong rationale for targeting DNA repair across the histo-pathologic spectrum 
of EC.  The US National Cancer Institute (NCI) Gynecologic Cancer Steering Committee 
(GCSC) identified the integration of the emerging molecular and/or histologic 
stratification data into EC management as a top strategic priority in clinical trial planning 
and convened a group of experts.  In January 2016, the resulting Clinical Trials Planning 
Meeting, identified DNA repair as an actionable opportunity in EC and this trial concept 
emerged from that process [MacKay, 2017 (in press)]. We hypothesize that genomic 
events in EC effecting maintenance of genomic stability will pre-dispose EC to 
sensitivity to drugs, and drug combination strategies that prevent DNA repair and/or 
inhibit cell cycle checkpoint stop decisions.  
 
This study incorporates oral agents, an attractive option for patients, and to date both the 
single agents: cediranib, olaparib and their combination have demonstrated acceptable 
toxicity profiles in the patient populations where they have been explored.  As this study 
matures data may become available on other potentially attractive combinations targeting 
DNA repair and consideration will be given to amending the protocol to include 
additional arms.  
 
In order to accelerate the pace of discovery and explore a number of different strategies 
(underpinned by a strong scientific rationale) targeting DNA repair in a time and resource 
efficient manner this trial has been designed as a three-arm randomized phase II study 
with the potential to amend the study to include future arms containing drugs specific to 
the DNA damage repair pathway.  There is no standard of care for the second line 
treatment of EC, response rates are known to be low and comparisons of PFS with 
historical controls can be challenging.  This study has therefore been designed to compare 
2 (with the potential to include more by amendment) experimental arms versus cediranib, 
which has been previously shown to have promising activity in GOG-0229J [Bender, 
2015].  Women with recurrent, persistent, or metastatic EC who have previously received 
treatment with at least one prior line of platinum based chemotherapy will be randomized 
in a 1:1:1: fashion to receive either cediranib alone (reference arm) olaparib alone, or the 
combination of olaparib and cediranib,  The combination of olaparib and cediranib will 
allow us to test the hypothesis that the addition of an anti-angiogenic agent to olaparib 
will induce context specific synthetic lethality resulting in synergistic anti-tumor activity 
and increased efficacy in women with EC compared to cediranib alone. The current new 
arms are added to test additional hypotheses, and to expand on the data provided from the 
first three arms (cediranib, olaparib and the combination).    
 
The study is powered to allow comparison of each of the experimental arms with the 
cediranib arm for the primary endpoint of progression free survival.  Cediranib remains the 

NRG-GY012 
21              NCI Version Date: May 23, 2024 
 
comparison arm for the subsequent arms, interim analysis demonstrated that the olaparib 
alone arm did not meet the prespecified endpoint. There were no new safety signals seen in 
the initial 3 arms of GY012 The Data Monitoring Committee reviewed a planned futility 
analysis for the first 3 rams and concluded that the  interim analysis results met the criterion 
for lack of sufficient activity for the olaparib alone arm relative to the reference arm 
(cediranib), while the cediranib/olaparib combination arm was sufficiently active to 
continue evaluation. The recommendation was to discontinue consideration of the 
olaparib alone arm and to maintain the combination and reference arms until definitive 
evaluation of the trial at completion. No further safety concerns were raised. 
 
Under Amendment 3, a formal safety review for the three new treatment arms will be 
conducted, as these arms contain agents or combinations that have not been previously 
explored in this patient population.  The safety review will occur after 36 patients have 
been accrued across all four arms, with a hard stop on accrual put in place by the NRG 
SDMC.  It is expected that there will be approximately 8 patients per treatment arm, and 
at least six patients on each of the three new treatment arms will be treated with at least 1 
cycle of treatment.  Accrual will stay suspended until the formal safety review is 
completed. 
Tissue collection incorporated as part of this trial for correlative studies will allow a 
greater understanding of the biology of DNA repair in this disease and we hypothesize 
will provide data leading to the development of potential predictive biomarker(s) in 
subsequent trials.  
 
2.12 
Translational Science Background 
 
Given the hypothesis underpinning this trial is that genomic events in EC effecting 
maintenance of genomic stability will pre-dispose to sensitivity to drugs, and drug 
combination strategies that prevent DNA repair, translational studies are warranted.  
Integrated and exploratory correlative studies undertaken on tissue collected as part of 
this clinical trial will allow us to gain a greater understanding into molecular events 
underlying DNA repair in EC.  In addition, these studies will provide an opportunity to 
identify potential predictive biomarkers for response for further investigation and 
validation in subsequent clinical trials. 
 
Homologous Recombination Defect (HRD) Studies (Integrated Biomarker) 
 
PARPi’s as a class are selectively lethal to HRD cells.  This synthetic lethality may occur 
as a result of impaired base excision repair (BER) although other mechanisms have been 
proposed including: PARP trapping at the replication fork, alterations in non-homologous 
end joining (NHEJ) and DNA repair protein recruitment.  Although initially focused on 
germ line mutation in BRCA genes (which do occur in small numbers in serous EC) 
[Shu, 2016] correlative studies conducted as part of ovarian cancer clinical trials have 
demonstrated that a broader patient population with HRD defects may benefit from this 
approach.  This included the use of gene panels using next-generation sequencing assays 
to identify relevant somatic mutations and investigation of genomic scaring assays 
[Stover, 2016]. In pre-clinical EC models a higher HRD score resulted in greater tumor 

NRG-GY012 
22              NCI Version Date: May 23, 2024 
 
response to olaparib [Hansen, 2016]. Data from the TCGA suggest a high proportion of 
patients with EEC may have mutations in genes of HR pathways. Following on from the 
work in ovarian cancer, investigating HRD in EC and correlating this with response to 
olaparib alone and in combination is indicated in this trial. The exact sequencing to be 
done will be determined by funding and the most appropriate assay at the time the 
investigators seek approval for distribution/testing. Sequencing data will be correlated 
with response. Given the evidence in other tumor types for response to PARPi’s 
occurring in cancers with HRD defects, and the availability of HRD panels, we are 
investigating HRD as an integrated biomarker.  
 
 
Markers of Angiogenesis (Integrated Biomarker) 
 
Plasma Angiome 
In further work assessing potential biomarkers related to response to antiangiogenic 
therapy in endometrial cancer, NRG/GOG published data from study GOG-0229E that 
linked response to bevacizumab to high VEGFA expression in tumors and plasma in a 
similar cohort of patients [Aghajanian, 2011].  Hence, as for bevacizumab, we intend to 
further evaluate the predictability of tumor (exploratory) and plasma (integrated) 
angiogenic biomarkers to identify the patients most likely to respond to cediranib. 
 
To date, the effort to identify candidate predictive blood-based markers for anti-
angiogenic inhibitors has been challenging for many reasons. These include biological 
complexity, limitations of available reagents, limited sample collection in most trials, and 
a lack of randomization, which is needed to deal with the potential confounding of 
prognostic and predictive markers. Many of these barriers have now been overcome. 
Compared to tissue-based biomarkers, blood-based biomarkers have the significant 
advantages of low cost, universal applicability, and the ability to be followed over the 
course of a patient’s treatment. By focusing on soluble factors of known biological 
relevance, further scientific, diagnostic, and therapeutic efforts are greatly facilitated. 
The application of multiplex ELISA approaches in clinical samples is rapidly evolving, 
having only recently shown positive results. The design of the Duke multiplex panel 
array to interrogate diverse biologies related to angiogenesis is novel. Many of the 
analytes in the multiplex array were developed and optimized for performance in plasma 
and serum samples from cancer patients. The Duke plasma angiome approach utilizes the 
Searchlight™ platform from Aushon BioSystems Inc., and the panel has been developed 
in tandem with the team at Aushon for over 7 years to develop multiple new assays and 
optimize the performance of the specific panel design.  
 
 
 
 

NRG-GY012 
23              NCI Version Date: May 23, 2024 
 
 
Plasma-based marker identification 
Soluble Angiogenic Factors 
Matrix-Derived Factors 
Markers of Vascular 
Activation and Inflammation 
ANG-2 
PDGF-BB 
sEndoglin 
CRP 
bFGF 
PlGF 
Osteopontin 
ICAM-1 
HGF 
VEGF-A 
TGFb1 
IL-6 
IGFBP1 
VEGF-D 
TGFb2 
IL-8 
IGFBP2 
sVEGFR1 
TGFbRIII 
PAI-1 Active 
IGFBP3 
sVEGFR2 
TIMP1 
PAI-1 Total 
PDGF-AA 
sVEGFR3 
TSP2 
SDF-1 
 
 
 
VCAM-1 
 
This approach is technically robust and readily adaptable to clinical practice. Because this 
data will be derived from patients, even preliminary data may significantly improve our 
understanding of how angiogenesis and tumor growth factors are regulated in cancer 
patients. Promising findings can be followed up in future clinical studies and in 
preclinical models. Because the Duke angiome lab serves as the core lab for multiplex 
ELISA analyses within the NCTN Group, Alliance, the current endometrial cancer 
profiling can be compared to the profiles seen in other disease site studies (including 
NRG Oncology ovarian studies, GY004 and GY005), helping to optimize future profiling 
approaches and provide the disease specific context needed for clinically meaningful 
companion diagnostics. Given the results of this prior work and the work of others, we 
anticipate being able to identify and validate or refute candidate markers of benefit that 
are specific for anti-angiogenic agents. 
 
2.13 
Inclusion of Women and Minorities 
NRG and NRG participating institutions will not exclude potential subjects from 
participating in this or any study solely on the basis of ethnic origin or socioeconomic 
status.  Every attempt will be made to enter all eligible patients into this protocol and 
therefore address the study objectives in a patient population representative of the entire 
population treated by participating institutions. 
 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY 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-Pittsburgh Office: 412-624-2666.  
 
3.1 
Eligibility Criteria 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
 
Patients must have recurrent or persistent endometrial carcinoma, which is refractory to 
curative therapy or established treatments. Histologic confirmation of the original 

NRG-GY012 
24              NCI Version Date: May 23, 2024 
 
primary tumor is required.  
 
Patients with the following histologic epithelial cell types are eligible: Endometrioid 
adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, mixed epithelial 
carcinoma, adenocarcinoma not otherwise specified (N.O.S.). NOTE: Clear cell and 
carcinosarcoma histology is excluded. 
 
3.1.2  Patients must have measurable disease as defined by RECIST 1.1 or non-measurable 
(detectable) disease. 
 
3.1.2.1 Measurable disease is defined as at least one lesion that can be accurately measured in at 
least one dimension (longest diameter to be recorded). Each lesion must be  10 mm 
when measured by CT, MRI or caliper measurement by clinical exam; or  20 mm when 
measured by chest x-ray. Lymph nodes must be > 15 mm in short axis when measured by 
CT or MRI (See section 14). Patients with measurable disease must have at least one 
“target lesion” to be used to assess response on this protocol as defined by RECIST 
version 1.1 (Section 14). Tumors within a previously irradiated field will be designated as 
“non-target” lesions unless progression is documented, or a biopsy is obtained to confirm 
persistence at least 90 days following completion of radiation therapy. 
 
3.1.2.2 Non-measurable (detectable) disease in a patient is defined in this protocol as one who 
does not have measurable disease but has at least one of the following conditions: 
• Ascites and/or pleural effusion attributed to tumor. 
• Solid and/or cystic abnormalities on radiographic imaging that do not meet 
RECIST 1.1 (see Section 14) definitions for target lesions. 
 
3.1.3 Patients must have signed an approved informed consent and authorization permitting 
release of personal health information. 
 
3.1.4 Prior Therapy: 
 
3.1.4.1 Patients must have had one prior chemotherapeutic regimen for 
management of endometrial carcinoma. Initial treatment may include chemotherapy, 
chemotherapy and radiation therapy, and/or consolidation/maintenance therapy. 
Chemotherapy administered in conjunction with primary radiation as a radio-sensitizer 
WILL be counted as a systemic chemotherapy regimen. 
 
3.1.4.2 Patients are allowed to receive, but are not required to receive, one additional cytotoxic  
regimen for management of recurrent or persistent disease according to the following 
definition: Cytotoxic regimens include any agent that targets the genetic and/or mitotic 
apparatus of dividing cells, resulting in dose-limiting toxicity to the bone marrow and/or 
gastrointestinal mucosa. Note: Patients on this non-cytotoxic study are allowed to receive 
one additional cytotoxic chemotherapy regimen for management of recurrent or persistent 
disease, as defined above. However, due to the novel nature of biologic compounds, 
patients are encouraged to enroll on second-line non-cytotoxic studies prior to receiving 
additional cytotoxic therapy. 

NRG-GY012 
25              NCI Version Date: May 23, 2024 
 
 
3.1.4.3 Patients may have received non cytotoxic therapy including immunotherapy (1 prior line 
in either upfront or recurrent setting) but excluding cediranib, olaparib, AZD5363 
(capivasertib), durvalumab (MEDI4736), or the combination of lenvatinib and 
pembrolizumab for the management of recurrent or persistent disease.  Prior hormonal 
therapy is allowed. Hormonal therapy for grade 1 endometrial cancers with low volume 
or indolent disease is encouraged. (24-MAY-2021) 
 
3.1.4.4 Bevacizumab, or one course of single-agent immune-checkpoint therapy,  
excluding durvalumab (MEDI4736), is permitted prior to enrollment on this trial. (24-
MAY-2021) 
 
3.1.4.5 Body weight >30 kg (24-MAY-2021) 
 
3.1.5 Age ≥ 18. 
 
3.1.6 The trial is open to females only (including women with an intact uterus with uterine 
cancer). Fertile females of childbearing potential need to agree to use adequate 
contraceptive measures from 2 weeks prior to the study and until 1 month after study 
treatment discontinuation and have a negative serum or urine pregnancy test within 3 
days prior to the start of study treatment. 
 
 
3.1.7 Patients must have an ECOG Performance Status of 0, 1 or 2 (Karnofsky ≥ 60%) within 7 
days prior to registration. Patients should have no deterioration over the previous two 
weeks. (24-MAY-2021) 
 
3.1.8 Patients must have adequate organ and marrow function measured within 28 days prior to 
administration of study drug including: 
 
3.1.8.1 Hemoglobin (Hgb) > 10 g/dL with no blood transfusion in the past 28 days  
 
3.1.8.2 Platelet count > 100 x 109/L 
 
3.1.8.3 ANC > 1.5 x 109/L 
 
3.1.8.4 Patients must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft 
Gault equation or based on a 24-hour urine test: 
 
Estimated creatinine clearance = 
 
 
 
(140-age [years]) x weight (kg)(x F)a 
 
 
 
serum creatinine (mg/dL) x 72 
 
 
a where F=0.85 for females and F=1 for males (24-MAY-2021) 
 
3.1.8.5 Serum bilirubin < 1.5 X ULN.  
 
3.1.8.6 Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) < 3 x ULN (24- 
 
MAY-2021)(27-APR-2022) 

NRG-GY012 
26              NCI Version Date: May 23, 2024 
 
 
 
3.1.8.7 Urinalysis (dipstick) <= 1+ proteinuria OR Urine protein creatinine ratio (UPCR) <1. 
(27-APR-2022) 
 
3.1.9 Patients must be able to swallow and retain oral medications and without gastrointestinal 
illnesses that would preclude absorption of cediranib, olaparib, or AZD5363 
(capivasertib). (24-MAY-2021) 
  
3.1.10 Patients must have adequately controlled blood pressure (BP), with a BP no greater than 
140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility.  Patients must have a BP of 
≤ 140/90 mmHg taken in the clinic setting by a medical professional within 2 weeks prior 
to starting study.  Patients with hypertension may be managed with up to a maximum of 
three antihypertensive medications.  It is strongly recommended that patients who are on 
three antihypertensive medications be followed by a cardiologist or blood pressure 
specialist for management of blood pressure while on protocol. 
 
Note: Patients must be willing and able to check and record daily blood  
pressure readings. 
 
3.1.11  The patient or a legally authorized representative must provide study-specific informed   
consent prior to study entry. 
 
3.1.12  Adequately controlled thyroid function, with no symptoms of thyroid dysfunction. 
 
3.1.13  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 IPs.  Postmenopausal is defined as: 
 
− 
Age ≥60 years, or 
− 
Age <60 with any one or more of the conditions below: 
o Amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal 
treatments, 
o Luteinizing hormone and/or Follicle stimulating hormone and/or estradiol 
levels in the post-menopausal range, 
o Radiation-induced oophorectomy with last menses >1 year ago, 
o Chemotherapy-induced menopause with >1 year interval since last menses, 
 
o Surgical sterilization (bilateral oophorectomy or hysterectomy). 
 
3.1.14 Patients must have a life expectancy of greater than 16 weeks. 
 
3.1.15  Patients with a previous diagnosis of immune or inflammatory colitis or  
chronic diarrhea > 1 month without immune or inflammatory colitis are eligible with 
adequately controlled colitis (no diarrhea greater than grade 1 for at least 28 days) and in 
the absence of symptoms related to colonic dysfunction. Patients who required steroids 

NRG-GY012 
27              NCI Version Date: May 23, 2024 
 
for prior immune related colitis are not eligible. (24-MAY-2021) 
 
3.1.16  Females of child-bearing potential should use two forms of highly reliable methods of 
contraception from the time of screening until 4 weeks after discontinuing study 
treatment.   
 
 
Acceptable methods of contraception include: 
• Established use of oral, injected or implanted hormonal methods of 
contraception. 
• Placement of an intrauterine device or intrauterine system. 
• Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. 
• Male partner sterilization (with the appropriate post-vasectomy documentation of 
the absence of sperm in the ejaculate). 
• True abstinence (ie, not engaging in sexual activity for the total duration of study 
treatment and the treatment washout period is an acceptable practice; however, 
periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of birth control).  
• Bilateral tubal occlusion or salpingectomy 
 
 
Acceptable Non-hormonal birth control methods include: 
• Total/True abstinence: When the patient refrains from any form of sexual 
intercourse and this is in line with their usual and/or preferred lifestyle; this must 
continue for the total duration of the trial and for at least 1 month after the last 
dose of study drug <<for 3 months after last dose for male patients>>. [Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods, or 
declaration of abstinence solely for the duration of a trial) and withdrawal are not 
acceptable methods of contraception]  
• Vasectomised sexual partner PLUS male condom.  With participant assurance 
that partner received post-vasectomy confirmation of azoospermia. 
• Tubal occlusion PLUS male condom  
• IUD PLUS male condom.  Provided coils are copper-banded. 
 
Acceptable hormonal methods: 
• Normal and low dose combined oral pills PLUS male condom.  
• Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the only 
highly efficacious progesterone-based pill. 
• Hormonal shot or injection (eg., Depo-Provera) PLUS male condom. 
• Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom.  
• Norelgestromin/EE transdermal system PLUS male condom  
• Intrauterine system [IUS] device (e.g., levonorgestrel releasing IUS -Mirena®) 
PLUS male condom.  
• Intravaginal device (e.g., EE and etonogestrel) PLUS male condom.  
(24-MAY-2021) 
 

NRG-GY012 
28              NCI Version Date: May 23, 2024 
 
3.2 
Ineligibility Criteria  
Patients with any of the following conditions are NOT eligible for this study. (24-
MAY-2021) 
 
3.2.1 Prior enrollment into a clinical trial including cediranib or olaparib. Note: prior  
 
bevacizumab is not an exclusion criterion. 
 
3.2.1.1 Prior enrollment into a clinical trial including cediranib, olaparib,  
AZD5363 (capivasertib), durvalumab (MEDI4736), or the combination of lenvatinib and 
pembrolizumab.  Note:  Prior bevacizumab or single-agent immune checkpoint blockade, 
excluding durvalumab (MEDI4736), is not an exclusion criterion. (24-MAY-2021) 
 
3.2.2 Prior chemotherapy, endocrine therapy, radiotherapy, or investigational agents within 4 
weeks. 
 
3.2.3  More than one prior line of treatment with immune checkpoint blockade  
therapy. (24-MAY-2021) 
 
3.2.3 Current signs/symptoms of bowel obstruction and/or signs/symptoms of bowel 
 
obstruction within the preceding 3 months. 
 
3.2.4 History of gastrointestinal perforation. Patients with a history of abdominal fistula will be 
considered eligible if the fistula was surgically repaired or has healed, there has been no 
evidence of fistula for at least 6 months, and patient is deemed to be at low risk of 
recurrent fistula. 
 
3.2.5 Uncontrolled intercurrent illness including, but not limited to known ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, extensive interstitial bilateral lung disease on High Resolution Computed 
Tomography (HRCT) scan or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
3.2.6 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 (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, 
verapamil).  The required washout period prior to starting study treatments is 2 weeks for 
strong inhibitors, and at least 1 week for moderate inhibitors. See Appendix IV. (24-
MAY-2021) 
 
3.2.7  Concomitant use of potent inhibitors or inducers of CYP3A4 within 2 weeks before the 
start of study treatment (3 weeks for St John’s wort), or sensitive substrates of CYP3A4, 
CYP2C9 and/or CYP2D6 with a narrow therapeutic window within 1 week before the 
start of study treatment. Concomitant use of drugs known to prolong the QT interval 
within 5 half-lives of the first dose of study treatment. (24-MAY-2021) 
 

NRG-GY012 
29              NCI Version Date: May 23, 2024 
 
3.2.8 Pregnant women are excluded from this study because cediranib and olaparib are agents 
with the potential for teratogenic or abortifacient effects. Because there is an unknown 
but potential risk of adverse events in nursing infants secondary to treatment of the 
mother with cediranib and olaparib, breastfeeding should be discontinued if the mother is 
treated with cediranib or olaparib. These potential risks may also apply to other agents 
used in this study. For women of childbearing capacity, a negative pregnancy test is 
required. 
 
3.2.9 Known HIV-positive individuals are ineligible because of the potential for 
pharmacokinetic interactions between many anti-HIV drugs and cediranib, olaparib, 
and/or AZD5363 (capivasertib). In addition, these individuals are at increased risk of 
lethal infections when treated with marrow-suppressive therapy. (24-MAY-2021) 
 
3.2.10  Known active Hepatitis B or Hepatitis C infection on antiviral treatment 
 
3.2.11 Prior history of stroke or transient ischemic attack within the last 6 months. 
 
3.2.12  Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) per institutional 
guidelines, or <55%, if threshold for normal not otherwise specified by institutional 
guidelines, for patients with the following risk factors: 
 
− Prior treatment with anthracyclines 
− Prior treatment with trastuzumab 
− Prior central thoracic RT, including exposure of heart to therapeutic doses of 
ionizing RT 
− History of myocardial infarction within 6-12 months prior to start of IPs 
− Prior history of other significant impaired cardiac function 
 
3.2.13 Patients with any of the following: 
 
o History of myocardial infarction within 6 months prior to starting treatment 
o Unstable angina 
o Resting electrocardiogram (ECG) with clinically significant abnormal findings or 
with   QTc > 470 msec on 2 or more time points within a 24-hour period or family 
history of long QT syndrome  
o New York Heart Association functional classification of II, III or IV. 
 
3.2.14 Prior history of hypertensive crisis or hypertensive encephalopathy. 
 
3.2.15 Major surgical procedure within 4 weeks prior to starting treatment; patients must have 
recovered from any effects of any major surgery and surgical wound should have healed 
prior to starting treatment. (24-MAY-2021) 
 
3.2.16  History of intra-abdominal abscess within 3 months prior to starting treatment. 
 
3.2.17 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 

NRG-GY012 
30              NCI Version Date: May 23, 2024 
 
treatments.   
 
3.2.18 No prior allogeneic bone marrow transplant or double umbilical cord blood 
transplantation (dUBCT). 
 
3.2.19 Whole blood transfusions in the last 120 days prior to entry to the study (packed red 
 
blood cells and platelet transfusions are acceptable. 
 
3.2.20 Patients with myelodysplastic syndrome (MDS)/treatment-related acute myeloid 
leukemia (t-AML) or with features suggestive of MDS/AML.  
 
3.2.21 Central nervous system metastases: 
• Symptomatic uncontrolled brain metastases requiring corticosteroid treatment. 
• History of spinal cord compression unless after definitive treatment the patient has 
clinically stable disease (SD) for at least 28 days prior to starting IPs.  
 
In the absence of these features and in an asymptomatic patient a scan to confirm the 
absence of brain metastases is not required. 
 
3.2.22 Other malignancy within the last 5 years except for: 
 
• Curatively treated basal cell or squamous cell carcinoma of skin; in situ cancer of 
the cervix, ductal carcinoma in situ of the breast or stage 1, grade 1 endometrial 
carcinoma. 
• Curatively treated other solid tumors including lymphomas (without bone marrow 
involvement) with no evidence of disease for ≥5 years prior to start of IPs. 
 
3.2.24  Persisting ≥Grade 2 CTCAE toxicity (except alopecia and Grade 2 peripheral 
neuropathy) from previous anti-cancer treatment(s). 
 
3.2.24 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to cediranib, olaparib, AZD5363 (capivasertib), or durvalumab 
(MEDI4736). (24-MAY-2021) 
 
3.2.25 Pneumonitis or moderate-severe pre-existing pulmonary disease. (24-MAY-2021) 
 
3.2.26 Patients who have a diagnosis of immunodeficiency or are receiving systemic steroid 
therapy or any other form of immunosuppressive therapy within 7 days of enrollment.  
 
• Premedication with steroids for CT scan contrast is allowed.  
• Inhaled or topical corticosteroids are allowed.  
• The use of mineralocorticoids (e.g., fludrocortisone) for patients with  
   
orthostatic hypotension or adrenocortical insufficiency is allowed.  
• The use of physiologic doses of corticosteroids may be approved after  
   
consultation with the study chair. (24-MAY-2021) 
 

NRG-GY012 
31              NCI Version Date: May 23, 2024 
 
3.2.27 Patients with active autoimmune disease or history of autoimmune disease that might 
recur, which may affect vital organ function or require immune suppressive treatment 
including systemic corticosteroids. This includes, but is not limited to, patients with a 
history of immune related neurologic disease, multiple sclerosis, autoimmune 
(demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic 
autoimmune disease such as SLE, connective tissue diseases, scleroderma, inflammatory 
bowel disease (IBD), Crohn’s, ulcerative colitis, hepatitis; and patients with a history of 
toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome 
because of the risk of recurrence or exacerbation of disease. (24-MAY-2021) 
  
3.2.28  Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis 
managed with replacement hormones including physiologic corticosteroids are eligible. 
(24-MAY-2021) 
 
3.2.29 Patients with rheumatoid arthritis and other arthropathies, Sjögren’s syndrome and 
psoriasis controlled with topical medication and patients with positive serology, such as 
antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the 
presence of target organ involvement and potential need for systemic treatment but 
should otherwise be eligible. (24-MAY-2021) 
 
3.2.30. Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and TB testing in line with local 
practice). (24-MAY-2021) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NRG-GY012 
32              NCI Version Date: May 23, 2024 
 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
4.1 
Pre-treatment Assessments (24-MAY-2021)(27-APR-2022) 
The following observations and tests 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 should begin within 14 days of registration. 
 
Assessments 
Prior to Registration 
 
Prior to Cycle 1 Day 1 
Treatment 
Informed Consent 
A 
 
Medical History 
A 
 
Physical Examination 
A 
C 
Concomitant Medications 
B 
D 
Performance Status 
A 
C 
Toxicity Assessment 
B 
C 
Vital Signs  
(Blood Pressure, Heart Rate, 
Temperature, and Pulse Oxygen 
Saturation)  
A 
D 
Weight 
A 
C 
CBC/Differential/Platelets 
B 
B 
Chemistries: sodium, potassium, 
chloride, bicarbonate, BUN, 
creatinine, glucose, albumin, calcium, 
AST (SGOT), ALT (SGPT), alkaline 
phosphatase, total bilirubin, total 
proteinJ 
B 
B 
TSH 
B 
B 
Urinalysis I 
B 
B 
Urine protein: creatinine ratioI 
B 
B 
Electrocardiogram 
A 
A 
Pregnancy Test (if childbearing 
potential exists)  
A 
EF 
Radiographic Tumor MeasurementG 
A 
A 
Echo or MUGAH 
A 
 
Assessments prior to registration must meet eligibility criteria.  Patients do not need to re-meet eligibility criteria 
on Cycle 1 Day 1 in order to be treated. 
A: ≤ 28 days 
B: ≤ 14 days 
C: ≤ 7 days 
D: Day of treatment 
E: ≤ 3 days 
F: The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of hCG. Two pregnancy tests 
on blood or urine samples will be performed for pre-menopausal women of childbearing potential one within 28 
days prior to the start of study treatment and the other on Day 1 of the study prior to commencing treatment.  Tests 
will be performed by the hospital’s local laboratory.  If results are positive the patient is ineligible/must be 
discontinued from the study.  In the event of a suspected pregnancy during the study, the test should be repeated. 
G:  Radiographic tumor measurements should be obtained via imaging of at least the chest, abdomen, and pelvis at 
baseline. See RECIST 1.1 for allowable imaging modalities used to assess disease at baseline and subsequent 
assessments. Contrast CT is the preferred modality. 
H: Patients who have undergone prior treatment with anthracyclines, trastuzumab, prior central thoracic RT or have 

NRG-GY012 
33              NCI Version Date: May 23, 2024 
 
a history of myocardial infarction within 6-12 months or other significant impaired cardiac function only. 
I: Urinalysis (dipstick) <= 1+ proteinuria OR Urine protein creatinine ratio (UPCR) <1 
J: All glucose samples should be done under fasting conditions. Fasting is defined as no caloric intake for ≥4 hours 
before sampling. 
 
4.2 
Assessments During Treatment (24-MAY-2021)(27-APR-2022) 
The following observations and tests 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.  
Please refer to Section 10 for Specimen Requirements.  
 
Assessments 
Prior to Day 
1 of Each 
Cycle  
Cycle 1 & 2, 
Day 15 (+/-3 
days) 
After 
completion or 
stopping of 
therapyA 
Timed (Treatment 
Cycle Independent) 
History and Physical 
D 
 
G 
 
Vital Signs  
(Blood  
Pressure, Heart Rate,   
Temperature and Pulse 
Oxygen Saturation) 
E 
 
 
 
Performance Status 
D 
 
 
 
Toxicity Assessment 
D 
X 
G 
 
CBC/Differential/Platelets 
F 
 
G 
 
Concomitant MedicationsJ 
D 
X 
G 
 
Chemistries: sodium, 
potassium, chloride, 
bicarbonate, BUN, 
creatinine, glucose, 
albumin, calcium, AST 
(SGOT), ALT (SGPT), 
alkaline phosphatase, total 
bilirubin, total proteinK, N 
F 
 
G 
 
Pregnancy Test (if 
childbearing potential 
exists)  
F 
 
 
 
TSHB 
F 
 
 
 
Urinalysis or Urine protein 
creatinine ratio (UPCR)L 
F 
 
 
 
Electrocardiogram 
C 
 
 
 
Home blood pressure 
assessment 
Please see footnote H 
Radiographic tumor 
measurement 
 
 
 
I 
Bone Marrow or Blood 
Cytogenetics 
 
 
 
M 
Echo or MUGA 
C 
 
 
 
A:In the case that protocol-directed therapy is discontinued for reasons other than disease progression, follow 
radiographic tumor measurement schedule as defined under Assessments During Treatment (until disease 
progression documented by RECIST 1.1 or until patient initiates a subsequent cancer therapy). The study team 

NRG-GY012 
34              NCI Version Date: May 23, 2024 
 
should clarify with the patient if withdrawal of consent is for treatment or for treatment and follow up. 
B: For patients on cedirinib and/or durvalumab containing arms, obtain TSH prior to every other cycle (e.g., C3, C5, 
etc.).  Additional assessment of thyroid function should be performed as clinically indicated. 
C: If clinically indicated.  
D:  ≤ 1 day of treatment 
E:  Day of treatment/assessment 
F: ≤ 3 days of treatment 
G: 30 days post End of Treatment (+/- 7 days) 
H: 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 Arm 1 and 3 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. 
I: Every 8 weeks (+/- 7 days) from cycle 1, day 1 (regardless of delays and/or changes in treatment schedule) for the 
first year; then every 12 weeks (+/- 7 days) thereafter until disease progression is confirmed; also repeat at any other 
time if clinically indicated based on symptoms or physical signs suggestive of new or progressive disease. An Excel 
tool is available on the CTSU website to calculate dates of re-imaging. Utilize same imaging modality as for pre-
cycle 1 baseline assessment.  
J: Because of a potential for interaction of cediranib and olaparib and AZD5363 (capivasertib) 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 V for a list of these medications.  
K: In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer to Appendix IX 
‘Actions required in cases of combined increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for further 
instructions 
L: For patients on cedirinib containing arm, obtain urinalysis (dipstick) OR Urine protein creatinine ratio (UPCR) 
prior to every other cycle (e.g., prior to C3, C5, etc.) 
M: Bone marrow or blood cytogenetic analysis may be performed according to standard hematological practice for 
patients with prolonged hematological toxicities as defined in Section 6. Bone marrow analysis should include an 
aspirate for cellular morphology, cytogenetic analysis and flow cytometry, and a core biopsy for bone marrow 
cellularity.  If it is not possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then 
attempts should be made to carry out the tests on a blood sample.  If findings are consistent with MDS/AML, study 
drug should be discontinued, and a full description of findings should be submitted with an SAE report by the 
investigator to AstraZeneca Patient Safety for documentation on the Patient Safety database. Presence or absence of 
blood cytogenetic abnormalities and flow cytometry will be documented on the clinical database." 
N: For patients on Capivasertib containing arm, glucose samples should be done under fasting conditions. Fasting is 
defined as no caloric intake for ≥4 hours before sampling. 
X: Phone, telehealth, or in person. 
 
 
 
 
 
 
 
 
 
 
 

NRG-GY012 
35              NCI Version Date: May 23, 2024 
 
4.3 
Assessments After Treatment (27-APR-2022) 
The following observations and tests 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 patient withdraws from study participation. Please note:  Each 
entry refers to the corresponding footnote at the end of the table. 
 
Assessments 
Timed 
Vital Status 
A 
Toxicity Assessment 
B 
Radiographic tumor measurement 
C 
A: Every 3 months for 2 years and then every 6 months for 3 years. Follow-up Forms are collected for the 5-year 
follow-up period or until study termination.  
B: 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. 
C: In the case that protocol-directed therapy is discontinued for reasons other than disease progression, follow 
radiographic tumor measurement schedule as defined under Assessments During Treatment (until disease 
progression documented by RECIST 1.1 or until patient initiates a subsequent cancer therapy). The study team 
should clarify with the patient if withdrawal of consent is for treatment or for treatment and follow up. 
 
Definition of Disease  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION (24-MAY-2021) 
 
All eligible patients will be randomized to one of three arms in a 1:1:1 basis. 
 
5.1 
Chemotherapy/Hormonal Therapy/Other Agent-Based Therapy (Amendments 1-2) 
• ARM 1: Cediranib 30 mg orally once daily. One cycle will be considered 28 days. 
Two dose reductions allowable. See section 6 
• ARM 2: Olaparib 300mg in tablet formulation orally twice daily. One cycle will 
be considered 28 days. Two dose reductions allowable. See Section 6 
• ARM 3: Olaparib 200mg in tablet formulation orally twice daily. Cediranib 30 
mg orally once daily. One cycle will be considered 28 days.  Two dose reductions 
allowable for each drug dependent on toxicity(s) observed.  See section 6. 
 
Accrual under Amendments 1 and 2 completed in June 2019.  Patients accruing under 
Amendment 3 and following will be randomized 1:1:1:1 to the following treatment arms.  
 
Subsequent Chemotherapy/Hormonal Therapy/Other Agent-Based Therapy 
  
• ARM 1 (Reference arm): Cediranib 30 mg orally once daily. One cycle will be 
considered 28 days. Two dose reductions allowable. 

NRG-GY012 
36              NCI Version Date: May 23, 2024 
 
• ARM 2 (Existing study arm completed accrual): Olaparib 300 mg in tablet 
formulation orally twice daily. One cycle will be considered 28 days. Two dose 
reductions allowable. 
• ARM 3 (Existing study arm completed accrual): Olaparib 200 mg in tablet 
formulation orally twice daily. Cediranib 30 mg orally once daily. One cycle will 
be considered 28 days.  Two dose reductions allowable for each drug dependent 
on toxicity(s) observed. 
• ARM 4: Olaparib 300 mg in tablet formulation orally twice daily. AZD5363 
(capivasertib) 400 mg orally twice daily taken 4 days on and then 3 days off each 
week. One cycle will be considered 28 days. Two dose reductions allowable for 
each drug dependent on toxicity(s) observed. 
• ARM 5: Olaparib 300mg in tablet formation orally twice daily. Durvalumab 
(MEDI4736) is administered at a dose of 1500 mg as an IV infusion over 
approximately 60 minutes (± 5 minutes) every 4 weeks. 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 Once cycle will be considered 28 days. 
Two dose reductions allowable for olaparib dependent on toxicity(s) observed.  
• ARM 6: Cediranib 20mg orally once daily 5 days on 2 days off each week. 
durvalumab (MEDI4736) is administered at a dose of 1500 mg as an IV infusion 
over approximately 60 minutes (± 5 minutes) every 4 weeks. 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. One cycle will be 
considered 28 days.  One dose reduction will be allowable for cediranib 
dependent on toxicity(s) observed.  
 
First radiological assessment of response will be at 8 weeks, then every 8 weeks 
thereafter for the first year; then every 12 weeks thereafter until disease progression is 
confirmed.  Radiological assessment will also be repeated at any other time if clinically 
indicated based on symptoms or physical signs suggestive of new or progressive disease. 
Patients demonstrating clinical or radiological progression of disease or toxicity 
prohibiting ongoing participation in study will be taken off study. Patients showing 
evidence of objective response or stabilization of disease subsequent to treatment will 
continue on study unless they become ineligible for alternative reasons. Modified 
RECIST 1.1 criteria will be used to determine on going eligibility. 
 
Patients removed from study due to PD will be seen at 1 month and followed for overall 
survival. Patients removed due to clinical progression will be followed with attempts to 
confirm radiological progression. 
   
Toxicity evaluation and grading will be per Common Toxicity Criteria for Adverse 

NRG-GY012 
37              NCI Version Date: May 23, 2024 
 
Events (CTCAE v 5.0). Dose modifications will be allowed for adverse events likely 
related to the study drugs. The time a drug is held should not exceed 21 days’ treatment, 
patients in whom toxicity has not resolved, despite maximal support, to grade 1 or better 
will be removed from study. 
 
The dose of cediranib and the morning dose of olaparib (Arm 3) can be taken at the same 
time and can be taken with or without food, at least 2 hours after a meal and 1 hour 
before the next meal in a similar way each morning. Twice daily doses should be taken 
12 hours apart in a similar way each day. 
 
Where possible, all doses of AZD5363 (capivasertib) should be taken at approximately 
the same time each day, 12 hours apart in a fasted state (water to drink only) from at least 
2 hours prior to the dose to at least 1-hour post-dose.  If vomiting occurs, a replacement 
dose should not be taken, and the patient should take their allotted dose at the next 
scheduled time. Should a patient miss a scheduled dose, the patient will be allowed to 
take the dose up to a maximum of 2 hours after the scheduled dose time, with a fasting 
state being maintained. If greater than 2 hours after the scheduled dose time, the missed 
dose should not be taken, and the patient should take their allotted dose at the next 
scheduled time. If a patient needs to take the dose earlier for whatever reason, the patient 
can take the dose up to 2 hours earlier than the scheduled dose time. The patient should 
make every reasonable effort to take the AZD5363 (capivasertib) tablet(s) on time. 
AZD4363 (capivasertib) and olaparib can be taken at the same time. AZD5363 
(capivasertib) should be taken at least 2 hours after a meal and 1 hour before the next 
meal. 
 
For those patients participating, olaparib will be dispensed on Day 1 and every 28 day 
thereafter until the patient completes the study, withdraws from the study or closure of 
the study.   
 
Patients will be administered olaparib orally twice daily at 300 mgs bid continually. 150 
mg olaparib tablets should be taken at the same time each day, approximately 12 hours 
apart with one glass of water.  The olaparib tablets should be swallowed whole and not 
chewed, crushed, dissolved or divided. Olaparib tablets can be taken with or without 
food. 
 
If vomiting occurs shortly after the tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted.  Should any patient enrolled 
on the study miss a scheduled dose for whatever reason (e.g., as a result of forgetting to 
take the tablets or vomiting), the patient should take their next allotted dose at the next 
scheduled time. (27-APR-2022) 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines (24-MAY-2021) 
 
5.2.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
All supportive therapy for optimal medical care will be given during the study protocol 
and documented on each site’s source documents as concomitant medication. 

NRG-GY012 
38              NCI Version Date: May 23, 2024 
 
• Anticonvulsants 
• Antiemetics 
• Analgesics 
• Nutritional supplementation 
 
▪ Over the counter and complementary/alternative medications are strictly prohibited 
due to the risk of drug interaction.  
 
▪ Anticoagulant Therapy 
Non-vitamin K antagonist oral anticoagulants (NOACs), subcutaneous heparin and 
low molecular weight heparin may be given concomitantly with study treatments and 
INR monitoring is not required. If NOACs are used, it is preferable to avoid CYP3A 
substrates (e.g., apixaban and rivaroxaban) if possible. 
▪ Anti-emetics/Anti-diarrheals 
If a patient develops nausea, vomiting and or diarrhea, then these symptoms should 
be reported as AEs (see Section 6) and appropriate treatment of the event given. 
 
▪ Palliative radiotherapy  
Palliative radiotherapy may be used for the treatment of pain at the site of bony 
metastases that were present at baseline, provided the investigator does not feel that 
these are indicative of clinical disease progression during the study period.  Study 
treatment should be discontinued for a minimum of 3 days before a patient undergoes 
therapeutic palliative radiation treatment.  Study treatment should be restarted within 
4 weeks as long as any bone marrow toxicity has recovered.   
 
▪ Administration of other anti-cancer agents 
Patients must not receive any other concurrent anti-cancer therapy, including 
investigational agents, while on study treatment. Patients may continue the use of 
bisphosphonates or denosumab for bone disease and corticosteroids for the 
symptomatic control of brain metastases provided the dose is stable before and during 
the study and they were started at least 4 weeks prior to beginning study treatment.  
 
▪ Corticosteroids  
Patients must not be receiving chronic administration of corticosteroids for the 
treatment of autoimmune disease or other medical disorders. 
• Premedication with steroids for CT scan contrast is allowed.  
• Inhaled or topical corticosteroids are allowed.  
• The use of mineralocorticoids (e.g., fludrocortisone) for patients with 
orthostatic hypotension or adrenocortical insufficiency is allowed.  
• The use of physiologic doses of corticosteroids may be approved after 
consultation with the study chair 
 
5.2.2 Prohibited Therapies and Drugs to be Avoided or Used with Caution (24-MAY-2021) 
CYP3A4 inhibitors and inducers are prohibited during the study. The following tables list 
CYP3A4 inducers and inhibitors. Investigators should consult a frequently updated drug 

NRG-GY012 
39              NCI Version Date: May 23, 2024 
 
information reference for a list of strong inducers and inhibitors. 
 
CYP3A4 Inducers (prohibited) 
Armodafenil1 
Barbituates2 
Bosentan1 
Carbamazepine 
Dexamethasone1 
Enzalutamide 
Efavirenz 
Fosphenytoin1 
Glucocorticoids2 (see note) 
Mitotane 
Modafenil2 
Nafcillin1 
Nevirapine 
Oxcarbazepine 
Pentobarbital1 
Phenobarbital 
Phenytoin 
Pioglitazone2 
Primidone1 
Rifabutin 
Rifampin 
Rifampicin 
Rifapentine1 
St. Johns Wort2 
Troglitazone3 
Note: topical steroids are permitted. Systemic steroids may be acceptable after discussion with 
overall PI.  
1. Cited in Cytochrome P450) Enzymes: Substrates, inhibitors and inducers. In: Lacy CF, Armstrong LL, 
Goldman MP, Lance LL, eds. Drug Information Handbook 20th ed. Hudson, OH; LexiComp Inc. 2011-
2012:1810-1818 
2. Cited in Flockhart DA. Drug Interactions: Cytochrome P450 Drug interaction Table. Indiana University 
School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.asp. Accessed Nov 2011. 
3. Weak Inhibitor per Lacy et al. May be used with caution.  
Note: Drugs without superscript are included in both Lacy and Flockhart references.  
 
CYP3A4 Inhibitors (prohibited or used with caution)  
Strong inhibitors 
(prohibited) 
Moderate Inhibitors 
(use with caution, 
avoid if possible) 
Weak Inhibitors 
(use with caution, 
avoid if possible 
Amprenaivr1 
Atazanavir1 
Boceprevir 
Clarithromycin 
Conivaptan1 
Cobicistat 
Delavirdine1 
Elvitegravir 
Fosamprenavir1 
Fospropofol1 
Imatinib1 
Indinavir 
Isoniazid1 
Itraconozole 
Ketoconazole 
Lopinavir 
Miconazole1 
Nefazodone 
Nelfinavir 
Nicardipine1 
Posaconazole1 
Amiodarone1 
Aprepitant 
Cimetidine1 
Clotrimatazole1 
Cyclosporine1 
Desipramine1Diltiazem 
Doxycycline1 
Efavirenz1 
Erythromycin 
Fluconazole 
Fosaprepitant1 
Grapefruit juice 
Halperidol1 
Lidocaine1 
Metronidazole1 
Norfloxacin1 
Sertaline1 
Tetracycline1 
Verapamil 
 
 
Chloramphenicol2 
Ciprofloxacin2 
Diethyldithiocarbamate2 
Fluvoxamine2 
Gestodene2 
Mibefradil2 
Mifepristone 
Norfluoxetine2 
Star Fruit2 
Troleandomycin2 

NRG-GY012 
40              NCI Version Date: May 23, 2024 
 
Propofol1 
Quinidine1 
Ritonavir 
Saquinavir1 
Telithromycin 
Tipranivir 
Telaprevir 
Troleandomycin 
Voriconazole 
1. Cited in Cytochrome P450) Enzymes: Substrates, inhibitors and inducers. In: Lacy CF, Armstrong LL, 
Goldman MP, Lance LL, eds. Drug Information Handbook 20th ed. Hudson, OH; LexiComp Inc. 2011-
2012:1810-1818 
2. Cited in Flockhart DA. Drug Interactions: Cytochrome P450 Drug interaction Table. Indiana University 
School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.asp. Accessed Nov 2011. 
Note: Drugs without superscript are included in both Lacy and Flockhart references. 
  
5.2.3     
CYP3A4, CYP2D6 or CYP2C9 and MATE1 and/or OCT2 transporter 
substrates whose exposure may be increased by AZD5363 (capivasertib) and 
should either be avoided or used with caution. 
 
 
CYP3A4, CYP2D6 or CYP2C9 substrates (prohibited or used with caution) 
Medication 
 
Recommendation 
Rationale 
Alfentanil  
Atorvastatin 
Carbamazepine 
Cerivastatin 
Cyclosporin 
Diergotamine 
Ergotamine 
Fentanyl 
Lovastatin 
Simvastatin 
Sirolimus  
Tacrolimus 
Prohibited one week prior 
to AZD5363 (capivasertib) 
administration and for one 
week following 
discontinuation of 
AZD5363 (capivasertib) 
CYP3A4 substrates, 
whose exposure may be 
increased by AZD5363 
(capivasertib) 
Amitriptyline 
Atomoxetine  
Desipramine 
Doxepin 
Metoprolol 
Nefazodone 
Nebivolol 
Perphenazine 
Tolterodine 
Trimipramine 
Tropisetron 
Prohibited one week prior 
to AZD5363 (capivasertib) 
administration and for one 
week following 
discontinuation of 
AZD5363 (capivasertib). 
CYP2D6 substrates, 
whose exposure may be 
increased by AZD5363 
(capivasertib). 
Haloperidol 
Tramadol 
Prohibited one week prior 
to AZD5363 (capivasertib) 
Combined CYP3A4 and 
CYP2D6 substrates, 

NRG-GY012 
41              NCI Version Date: May 23, 2024 
 
administration and for one 
week following 
discontinuation of 
AZD5363 (capivasertib). 
whose exposure may be 
increased by AZD5363 
(capivasertib). 
Alprazolam  
Domperidone 
Erythromycin  
Felodipine  
Isradipine 
Midazolam  
Methylprednisolone 
Nifedipine  
Pimozide  
Quinidine 
Sertraline 
Tamoxifen 
Trazodone  
Triazolam 
May be used with caution. 
CYP3A4 substrates, 
whose exposure may be 
increased by AZD5363 
(capivasertib).   
Fluoxetine 
Paroxetine 
Venlafaxine 
May be used with cautiona. 
 
 
CYP2D6 substrates, 
whose exposure may be 
increased by AZD5363 
(capivasertib).   
Warfarin 
May be used with cautiona. 
CYP2C9 substrate, whose 
exposure may be 
increased by AZD5363 
(capivasertib).   
Dofetilide 
 
May be used with cautiona. 
MATE1 and OCT2 
substrate with a narrow 
therapeutic window 
whose exposure may be 
increased by AZD5363 
(capivasertib). 
Metformin 
May be used with cautiona. 
MATE1 and OCT2 
substrate whose exposure 
may be increased by 
AZD5363 (capivasertib). 
Procainamide 
May be used with cautiona. 
OCT2 substrate with a 
narrow therapeutic 
window whose exposure 
may be increased by 
AZD5363 (capivasertib). 

NRG-GY012 
42              NCI Version Date: May 23, 2024 
 
 
a.  Drugs are permitted but caution should be exercised and patients monitored closely for possible 
 
drug interactions.  Please refer to full prescribing information for all drugs prior to co-administration 
 
with AZD5363 (capivasertib).   
 
 
Grapefruit juice 
 
It is prohibited to consume grapefruit juice while on olaparib therapy. 
 
Medications that may NOT be administered 
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy 
(Hormone replacement therapy (HRT) is acceptable), radiotherapy, biological therapy or 
other novel agent) is to be permitted while the patient is receiving study medication. 
Live virus and live bacterial vaccines should not be administered whilst the patient is 
receiving study medication and during the 30 day follow up period. An increased risk of 
infection by the administration of live virus and bacterial vaccines has been observed 
with conventional chemotherapy drugs and the effects with olaparib are unknown. 
 
5.3 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
▪ 
Disease progression, 
▪ 
Intercurrent illness that prevents further administration of treatment, 
▪ 
Unacceptable adverse event(s), as described in Section 6 
▪ 
Patient decides to withdraw consent for participation in the study, or 
▪ 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT (24-MAY-2021) 
 
6.1 
Potential dose modifications for each arm and drug are shown in Table 6.1.  
 
Table 6.1: Dose Modifications for Each Arm 
Arm 
Initial Dose 
1 level reduction 
2 level reduction 
Arm 1 - Cediranib 
30 mg daily 
20 mg daily 
15 mg daily 
Arm 2 - Olaparib 
300 mg BID 
200 mg BID 
150 mg BID 
Arm 3 - Olaparib 
200 mg BID 
150 mg BID 
100 mg BID 
Arm 3 - Cediranib 
30 mg daily 
20 mg daily 
15 mg daily 
Arm 4 - Olaparib 
300 mg BID 
200 mg BID 
150 mg BID 
Arm 4 – AZD5363 
(capivasertib) 
400 mg BID 4 
days on 3 days off 
320 mg BID 4 days 
on 3 days off 
200 mg BID 4 days 
on 3 days off 
Arm 5 - Olaparib 
300 mg BID 
200 mg BID 
150 mg BID 
Arm 5 – Durvalumab 
(MEDI4736)  
1500 mg every 28 
days 
No dose modifications* 
Arm 6 - Cediranib 
20 mg 5 days on 
2 days off 
15 mg 5 days on 2 
days off 
 
Arm 6- Durvalumab 
1500 mg every 28 No dose modifications* 

NRG-GY012 
43              NCI Version Date: May 23, 2024 
 
(MEDI4736)  
days 
Durvalumab (MEDI4736) is administered at a dose of 1500 mg every 4 weeks. 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. 
 
6.2 
Holding Study Medications 
 
 
For 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.   
 
 
 
Dose modifications will be allowed for adverse events likely related to the study drugs, 
see Section 6. The time a drug is held should not exceed 14 days.  Patients in whom 
toxicity has not resolved, despite maximal support, to grade 1 or better will be removed 
from study. 
 
 
Both study treatments in the combination arms (Arms 5, 6, and 7) (olaparib/AZD5363 
(capivasertib) or olaparib/durvalumab (MEDI4736) or cediranib/durvalumab 
(MEDI4736) should be discontinued at the same time if the AE may be attributable 
to either agent.  Patients are allowed to remain on monotherapy within an arm  (ARM 
5,6,7) with cediranib, olaparib; AZD5363 (capivasertib) or durvalumab (MEDI4736) 
only if the AE is strongly attributable to one or the other agent.  
 
 
Patients experiencing ongoing clinical benefit who develop a toxicity requiring 
permanent discontinuation of an investigational product (IP) may be allowed to continue 
on the unrelated drug if in the opinion of the treating investigator the risk benefit 
remains favorable and only after discussion with the Principal Investigator. 
 
 
Once a patient discontinues any arm of the study (both agents if dual therapy), other 
treatment options are at the discretion of the investigator. 
 
6.3 
Dose Modifications for Hematologic Events, Neutropenia or Thrombocytopenia 
 
Dose modifications related on these arms should be managed per Table 6.3:  
 
Table 6.3: Dose Modifications for Hematologic Events (neutropenia or  
thrombocytopenia) 
 
Action 
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. 
CTCAE Grade 3-4 
 
Dose interruption until recovered to CTCAE 
Grade <1 for a maximum of 2 weeks. Upon 

NRG-GY012 
44              NCI Version Date: May 23, 2024 
 
ANC<1.0 G/L 
or 
Platelet count <50 G/L 
recovery, olaparib dose should be reduced by 
one dose level. If repeat CTCAE grade 3-4 
occurrence, further dose reduce one or both 
IPs. 
Abbreviations: ANC absolute neutrophil count; CTCAE common terminology criteria for 
adverse events; IP investigational product 
 
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 2 weeks, patients should be referred to a 
hematologist for further assessment.  A bone marrow analysis should be considered per 
hematology assessment. 
 
6.3.1 Use of Hematopoietic Agents 
 
Use erythropoietin-stimulating agents per standard of care National Comprehensive 
Cancer Network (NCCN) and/or institutional guidelines, iron supplements, and/or 
transfusions as clinically indicated for management of anemia.  Prescribing information 
for the erythropoiesis stimulating agents (including Aranesp, Epogen and Procrit) 
highlight that there is a potential risk of shortening the time to tumor progression or 
disease-free survival.  Primary prophylaxis with granulocyte colony-stimulating factor 
(G-CSF) is not recommended. They do not alleviate fatigue or increase energy.  They 
should not be used in patients with uncontrolled hypertension.  The package inserts 
should be consulted. 
 
If a patient develops febrile neutropenia, IPs should be stopped and appropriate 
management including G-CSF should be given according to local hospital guidelines.  
Please note that G-CSF should not be used within at least 24 hours of the last dose of 
olaparib unless absolutely necessary. 
 
6.3.2  Management of Anemia Related to Olaparib Arms 4 and 5  
 
Common treatable causes of anemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed.  In some cases, 
management of anemia may require blood transfusions.  Any subsequently required 
dose interruptions, related to development of anemia, or coexistent with newly 
developed neutropenia, and/or thrombocytopenia, will require olaparib dose reductions 
to 150 mg twice daily as a first step and to 100 mg twice daily as a second step. 
 
If Hgb drops to < 8 g/dL despite the dose reduction or more than one blood transfusion 
is required to recover Hgb levels with no alternative explanation for the anemia, 
olaparib should be permanently discontinued. 
 
 
Platelet transfusions, if indicated, should be done according to local hospital guidelines. 
 
 
 

NRG-GY012 
45              NCI Version Date: May 23, 2024 
 
Exclude immune related toxicities as a cause of anemia e.g., colitis in Arm 6 (See 
Section 6.7)    
 
Table 6.3.2: Management of Anemia Arm 1 (Cediranib) 
 
 
 
Action 
Cediranib dose 
Hgb <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 Hgb <10 but ≥8 
g/dL, dose interrupt until Hgb 
≥10 g/dL for maximum of 2 
weeks and upon recovery 
dose reduce dose level -1 as a 
first step and to dose level -2 
as a second step. 
 
No change 
Hgb < 8 g/dL 
Give appropriate supportive 
treatment and investigate 
causality. 
 
Interrupt olaparib until 
improved Hgb > 10 g/dL. 
 
Upon recovery dose reduce 
olaparib to 150 mg bd. 
No change 
Abbreviations: bd twice daily; Hgb hemoglobin 
 
 
6.3.3 Management of prolonged hematological toxicities while on study treatment 
 
If a patient develops prolonged hematological toxicity such as: 
 
• ≥2 week interruption/delay in olaparib due to CTCAE Grade 3 or worse anemia 
and/or development of blood transfusion dependence 
• ≥2 week interruption/delay in 1 or both IPs due to CTCAE Grade ≥3 neutropenia 
      (ANC <1 x 109/L) 
• ≥2 week interruption/delay in 1 or both IPs due to CTCAE Grade ≥3 
thrombocytopenia and/or development of platelet transfusion dependence 
(Platelets <50 x 109/L) 

NRG-GY012 
48              NCI Version Date: May 23, 2024 
 
140/90 mmHg if 
previously WNL 
second reading.  
Cediranib can cause 
rapid escalation in 
BP, and early 
initiation of BP 
management can 
reduce likelihood of 
HTN-related 
complications. 
to <140/90 
mmHg within 24 
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. 
Suggestions:  ACE-
inhibitor or Calcium 
Channel Blocker 
 
Escalate dose of 
medication in step-
wise fashion 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 renal 
consult 
Increase 
frequency of 
monitoring 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 
• Suggestions: 
ACE-inhibitor + 
Calcium Channel 
Blocker 
 
Escalate doses of 
existing medication 
until BP is 
controlled or at a 
maximum dose. 
 
If BP is not 
Increase 
frequency of 
monitoring until 
stabilized to BP 
<140/90 mmHg 
Do not hold 
cediranib 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 

NRG-GY012 
49              NCI Version Date: May 23, 2024 
 
controlled to 
< 140/90 mmHg 
with two drug 
regimen, then add a 
third agent. 
 
Study Drug will 
not be held during 
trial of two drug 
combinations.  
Additional anti-
hypertensive 
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. 
than 150/100 
mmHg with 
maximal therapy or 
if clinical 
symptoms worsen, 
then hold cediranib 
(up to 14 days) 
until maximum 
effect of the anti-
hypertensive agents 
is achieved. 
 
If BP is reduced to 
less than 140/90 
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 anti-
hypertensive agents. 
Intensive BP 
monitoring 
(hospitalization if 
necessary) 
Hold cediranib. 
 
If BP is reduced to 
less than 140/90 
within 14 days, 
cediranib may be 
resumed at a 
reduced dose after 
discussion with the 
Study PI and/or 
sponsor. 
 
6.5.1 Diarrhea (24-MAY-2021) 
Diarrhea may be observed with cediranib or AZD5363 (capivasertib) or durvalumab 
(MEDI4736). Note Diarrhea occurring in patients on study Arms 5 and 6, containing 
durvalumab (MEDI4736), see  Section 6.7. 
 
Patients should be instructed to promptly contact investigators if they develop diarrhea 
due to any cause 
 
 
 

NRG-GY012 
51              NCI Version Date: May 23, 2024 
 
Table 6.5.1.2:  Dose Modifications for AZD5363 (capivasertib)-related Diarrhea  
NCI CTCAE v5 Toxicity Grade 
Action 
Grade 1 
Maintain same AZD5363 (capivasertib) dose. Anti-
diarrheal treatment (e.g., loperamide) should be 
initiated at first report of diarrhea. Maximize the 
supportive care (e.g., dietary modifications, 
appropriate hydration therapy and electrolyte 
supplements as clinically indicated). 
Grade 2 
Interrupt AZD5363 (capivasertib) dose (up to 21 
days) until recovery to ≤ Grade 1 and resume 
dosing at same dose level. Anti-diarrheal treatment 
(eg loperamide) should be initiated at first report of 
diarrhea. Maximize the supportive care (e.g., 
dietary modifications, appropriate hydration therapy 
and electrolyte supplements as clinically indicated).  
Consider secondary prophylaxis with anti-motility 
agents such as loperamide 
Grade ≥3 
 
Interrupt AZD5363 (capivasertib) dose (up to 21 
days) and institute appropriate anti-diarrhoeal 
treatment 
• Improves to Grade ≤1 
within 21 days 
 
• Resume dosing at same dose or one reduced 
dose level as clinically appropriate 
maintaining treatment for toxicity as 
necessary and/or start secondary 
phophylaxis 
 
6.5.2 Fatigue 
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). See Section 6.6 for 
patients receiving durvalumab (MEDI4736) in Arms 5 and 6. Additionally, short 
interruption for dosing (initially 2-3 days-or longer-up to a maximum of 14 days) may 

NRG-GY012 
55              NCI Version Date: May 23, 2024 
 
6.5.12 Pulmonary Symptoms (General) 
 
For specific recommendations in patients receiving durvalumab (MEDI4736) 
combinations (ARMS 5 and 6), see Section 6.7. 
  
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities 
occur in the absence of a clear diagnosis, an interruption in 1 or both IPs dosing is 
recommended and further diagnostic workup) should be performed to exclude 
pneumonitis. 
 
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then study drug (s) can be restarted, if deemed appropriate by the 
investigator.  If significant pulmonary abnormalities are identified, these need to be 
discussed with the Study Chair. 
 
6.5.13  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 treatment with the 
study; 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. 
 
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. 
 
6.5.14  Renal Impairment (olaparib and cediranib)  
Patients with mild and moderate renal impairment discontinued cediranib more often 
due to adverse events, particularly when cediranib was co-administered with 
chemotherapy. Population PK analysis showed that no adjustment of cediranib dose is 
required in this population as cediranib is minimally renally cleared; however, cediranib 
clearance may be decreased in patients with low body weight.  In the ICON6 pivotal 
study, patients with mild or moderate impairment had lower median body weight 
compared with patients with normal renal function.  Caution should be exercised in 
patients with mild and moderate renal impairment and a cediranib dose adjustment 
should be considered in case of signs of toxicity. (24-MAY-2021) 
 
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), 

NRG-GY012 
56              NCI Version Date: May 23, 2024 
 
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 bd. 
 
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. 
 
Olaparib has not been studied in patients with severe renal impairment 
(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.  For 
information on use of cediranib in patients with renal impairment, please see to Section 
6.5.3. 
 
6.5.15 Wound Healing (24-MAY-2021) (Cedarinib Arms 1 and 6)  
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 
judgment of adequate wound healing.  In patients who experience wound healing 
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. 
6.5.16 Elderly (24-MAY-2021) (Cediranib Arms 1 and 6)  
There is a limited amount of safety data available for cediranib use in patients aged 75 
years and older.  Based on a population PK analysis, the clearance of cediranib 
decreased with age, however, no dose adjustment is needed given the small impact on 
exposure or variability. Caution should be taken when treating patients who are aged 75 
years or older with cediranib. In case of toxicity dose pause or dose reduction may be 
considered. 
 
6.5.17Weight decreased (24-MAY-2021) (Cediranib Arms 1 and 6)  
In the ICON6 study, weight decreased was very commonly reported in cediranib treated 
patients.  Weight loss (≥7%) in cediranib-treated patients was associated with higher 
incidence of decreased appetite, vomiting and stomatitis, although these events were also 
commonly reported in patients who did not lose weight. 
 
6.6 
AZD5363 (capivasertib) Specific Toxicities (Arm 4)   
 
Dose Modifications due to general AZD5363 (capivasertib)-related toxicities  
Treatment with AZD5363 (capivasertib) should be temporarily interrupted for any 

NRG-GY012 
57              NCI Version Date: May 23, 2024 
 
intolerable adverse event regardless of grade or for any adverse events ≥Grade 3 that 
occurs despite optimal supportive care, are not attributable to the disease under 
investigation, where the Investigator considers the AE of concern to be specifically 
associated with AZD5363 (capivasertib). Dose modification guidelines for AZD5363 
(capivasertib)-related toxicities are shown in Table 3 below. Appropriate and optimal 
treatment of the toxicity is assumed prior to considering dose modifications. The study 
physician may be consulted prior to discontinuation of study drug due to toxicities.  
Please see Section 6.6.1-6.6.3 for the management of AZD5363 (capivasertib) specific 
toxicities including hyperglycemia, maculo-papular rash and other skin reactions, and 
diarrhea. 
 
 
AZD5363 (capivasertib) administration adjustments based on toxicity grading: 
Grade 1  
If clinically significant or intolerable, hold dosing of AZD5363 (capivasertib).  
 
If resolves to baseline or clinically tolerable within 21 days of onset, resume 
dosing at same dose or one reduced dose level as clinically appropriate. 
 
If does not resolve within 21 days of onset, discontinue study drug and 
observed until resolution.  
Grade 2 
If clinically significant or intolerable, hold dosing.  
 
If resolves to baseline or clinically tolerable within 21 days of onset, resume 
dosing at same dose or one reduced dose level as clinically appropriate. 
 
If does not resolve within 21 days of onset, discontinue study drug and observe 
patient until resolution.  
> Grade 3 
Hold dosing of AZD5363 (capivasertib). 
 
If >3 for < 21 days and resolves to < grade 2 or baseline within 21 days of 
onset, resume dosing at same dose or one reduced dose level as clinically 
appropriate. 
 
If does not resolve within 21 days of onset, discontinue study drug and observe 
patient until resolution.  
 
6.6.1.  Hyperglycemia related to AZD5363 (capivasertib) (24-MAY-2021) 
Hyperglycemia may be seen with AZD5363 (capivasertib). These are general 
recommendations, therefore, due consideration should be given to baseline values and 
fasting condition (and time since food if applicable) when interpreting glucose results. In 
diabetic patients, it may be beneficial to rule out concomitant aetiologies that could be 
associated with hyperglycaemia (e.g. infections, dehydration, vascular events, 
glucocorticoids).   
Patients should be made aware of symptoms of hyperglycaemia (eg, polydipsia and 
polyuria). 
Dose modification guidelines for AZD5363 (capivasertib)-related hyperglycemia are 

NRG-GY012 
58              NCI Version Date: May 23, 2024 
 
shown in Table 6.2.16.1. In addition, for all grades, patients may receive education on 
lifestyle changes (eg, a diabetic diet) and consider beginning home glucose monitoring 
(eg, fasting self-blood glucose monitoring [SBGM] once-daily) at the discretion of the 
investigator.  If glucose home monitoring is instituted, the AZD5363 (capivasertib) 
treatment decision should be based on the morning fasting glucose value obtained prior to 
the dose of AZD5363 (capivasertib).   
It is recommended that approaches to the management of AZD5363 (capivasertib)-
induced hyperglycaemia include advice from an endocrinologist where appropriate (eg, 
diabetic patients). Metformin is currently the preferred oral antidiabetic recommended for 
the management of hyperglycaemia occurring in patients participating in studies of 
AZD5363 (capivasertib) (see below for further guidance). If a second agent is required, 
consideration should be given to the intermittent schedule of AZD5363 (capivasertib) and 
the pattern of glucose changes (eg. sulphonylureas should be avoided due to their risk of 
hypoglycaemia secondary to their mechanism of action).   
Table 6.6.1:   Dose Modifications for AZD5363 (capivasertib)-related 
Hyperglycemia*  
NCI CTCAE v5 Toxicity Grade 
Action 
Grade 1 
Maintain same AZD5363 (capivasertib) dose 
level.  
Grade 2  
 
Asymptomatic:  
• Maintain same AZD5363 (capivasertib) 
dose level. 
•  Treatment as per local guidelines, 
consider the use of oral antidiabetic (e.g., 
metformin) on AZD5363 (capivasertib) 
dosing days [see further guidance on 
choice of antidiabetic agents on text 
above and below the table] 
Symptomatic: Appropriate clinical management 
as per local guidelines.  
• Interrupt AZD5363 (capivasertib) until 
resolution of symptoms and fasting blood 
glucose is ≤ 160 mg/dL or ≤8.9 mmol/L 
(treatment can be interrupt up to 21 days) 
• Restart at same dose level maintaining 
appropriate antidiabetic treatment (eg 
addition of/higher dose of oral 
metformin) 
• Consider consult with endocrinologist  

NRG-GY012 
59              NCI Version Date: May 23, 2024 
 
Table 6.6.1:   Dose Modifications for AZD5363 (capivasertib)-related 
Hyperglycemia*  
NCI CTCAE v5 Toxicity Grade 
Action 
Grade 3 
 
 
Hold AZD5363 (capivasertib) up to 21 days, until 
resolution of symptoms. Consult with 
endocrinologist. 
• If fasting blood glucose decreases to ≤ 
160 mg/dL or ≤ 8.9 mmol/L within 21 
days and under appropriate anti-diabetic 
treatment, resume AZD5363 
(capivasertib)  at 1 lower dose level. 
If fasting blood glucose does not decrease 
to ≤ 160 mg/dL or ≤ 8.9 mmol/L within 
21 days following appropriate 
antidiabetic treatment, permanently 
discontinue AZD5363 (capivasertib) 
Grade 4 
 
Appropriate clinical management of 
hyperglycemia per local guidelines. Consider 
consult with the diabetologist. 
Consider permanent cessation of AZD5363 
(capivasertib) 
*Patients may receive education on lifestyle changes (eg, a diabetic diet) and consider beginning home glucose 
monitoring (eg, fasting self-blood glucose monitoring [SBGM] once daily) at the discretion of the investigator.  If 
glucose home monitoring is instituted, the AZD5363 (capivasertib)/placebo treatment decision should be based on 
the morning fasting glucose value obtained prior to the dose of AZD5363 (capivasertib)/placebo. 
NCI CTCAE v5, National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0. 
SBGM, self-blood glucose monitoring 
 
6.6.1.1 Use of metformin 
Metformin is currently the preferred oral antidiabetic recommended for the management 
of hyperglycaemia occurring in patients participating in studies of AZD5363 
(capivasertib). Investigators should exercise caution in the dosing and management of 
patients receiving the metformin/AZD5363 (capivasertib) combination and must be 
vigilant for signs of renal impairment and metformin toxicity, such as lactic acidosis and 
hypoglycaemia, namely: lethargy, hypotension, poor urine output, drowsiness, irritation, 
tachypnoea, sweating, diarrhoea, and vomiting. 
 
Due to the potential interaction of metformin and AZD5363 (capivasertib) (cause by 
inhibition of renal transporters [eg. OCT2] involved in the excretion of metformin), when 
taking both AZD5363 (capivasertib) and metformin concurrently, patients should attend 

NRG-GY012 
60              NCI Version Date: May 23, 2024 
 
the clinic for monitoring of serum creatinine at least once per week for the first 3 weeks 
after initiation of metformin, then every 3 weeks thereafter. 
 
Metformin should only be given on the days when AZD5363 (capivasertib) is also 
administered (the half-life of AZD5363 (capivasertib) is approximately 7-15 hours) and 
should be withdrawn when treatment with AZD5363 (capivasertib) is withdrawn, unless 
otherwise clinically indicated. Consider withholding of metformin on the days patients 
are due to have imaging with contrast (in order to reduce the already low risk of lactic 
acidosis. 
 
6.6.2   Maculo-papular rash related to AZD5363 (capivasertib)  
Dose modifications for AZD5363 (capivasertib)-related maculo-papular rash, which is 
the most frequent skin toxicity observed in patients treated with AZD5363 (capivasertib), 
are provided in Table 6.2.17.2 below.  However, these management guidelines can be 
used for other skin toxicities at the discretion of the investigator and/or following 
consultation with the dermatologist.    
 
Table 6.6.2:  Dose Modifications for AZD5363 (capivasertib)-related Maculo-papular  
Rash  
NCI CTCAE v5 Toxicity Grade 
Action 
Grade 1 or 2 
Continue dosing at current dose and initiate 
dermatological treatment: 
• 
Topical steroid of moderate strength BD 
• 
Non-sedating oral antihistamines 
Grade ≥3 or clinically intolerable 
Withhold dosing for up to 28 days and initiate 
dermatological treatment (topical steroid of 
moderate strength and non-sedating oral 
antihistamines) with oral steroid for a short 
course (e.g. up to 2 weeks). Consultation with 
dermatologist is advised 

NRG-GY012 
61              NCI Version Date: May 23, 2024 
 
Table 6.6.2:  Dose Modifications for AZD5363 (capivasertib)-related Maculo-papular  
Rash  
NCI CTCAE v5 Toxicity Grade 
Action 
• 
Improves to Grade ≤ 1 and 
tolerable within 28 days from 
onset 
 
• 
Improves to Grade 2 and tolerable 
within 28 days from onset 
           
• 
Does not improve to Grade 2 and 
tolerable within 28 days from 
onset 
• 
Continue dermatological treatment* and 
restart dosing at same dose 
 
• 
Continue dermatological treatment* and 
restart dosing at reduced dose (1 dose level 
reduction) 
 
• 
Continue dermatological treatment* and 
discontinue AZD5363 (capivasertib) 
Recurrence of Grade ≥3, or Grade 4 
(e.g., severe bullous, blistering or 
exfoliating skin conditions), or any 
% BSA associated with extensive 
superinfection, with IV antibiotics 
indicated; life-threatening 
consequences) 
Discontinue AZD5363 (capivasertib) 
* In patients with persistent rash or previous occurrence of grade 3 consider secondary 
prophylaxis by continuing topical steroids and/or non-sedating oral antihistamines. 
 
6.6.3 Hypersensitivity reactions to AZD5363 (capivasertib) (24-MAY-2021) 
In the case of hypersensitivity reactions, AZD5363 (capivasertib) should be discontinued 
and symptomatic/supportive therapy should be initiated (including with antihistamines 
and/or steroids) as considered appropriate by the investigator/treating physician. Drug 
rechallenge is not recommended; any subsequent consideration on rechallenge with 
AZD5363 (capivasertib) at the same or a lower dose, with its potential for recurrence of 
such or more severe events should be carefully considered against the potential benefits 
to the individual patient from continuation of AZD5363 (capivasertib) therapy.  Further 
management should follow local guidelines on management of hypersensitivity reactions. 
 
 
6.7 
Management of toxicities related to durvalumab (MEDI4736) Arms 5 and 6   
 
Guidelines for the management and dosing modifications for immune-mediated reactions, 
infusion-related reactions, and non-immune-mediated reactions for durvalumab 
(MEDI4736) in combination with olaparib ARM5 and cediranib Arm 6 are provided in 

NRG-GY012 
81              NCI Version Date: May 23, 2024 
 
related to the study drug/study regimen by the reporting investigator. 
 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS 
 
7.1 
Protocol Agents 
 
Investigational Agents 
The investigational agents administered in NRG-GY012, cediranib and olaparib are being 
made available under an IND sponsored by CTEP.  For cediranib and olaparib, 
determination of whether an adverse event meets expedited reporting criteria, see the 
reporting table in section 7.4 of the protocol. 
7.2 
Adverse Events and Serious Adverse Events 
 
7.2.1 This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner. 
 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for CTEP Study 
Agents 
 
7.3.1 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' 

NRG-GY012 
84              NCI Version Date: May 23, 2024 
 
3Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the 
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 

NRG-GY012 
87              NCI Version Date: May 23, 2024 
 
 
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 
(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. 
 
 
 
 
 

NRG-GY012 
92              NCI Version Date: May 23, 2024 
 
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 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 - Disseminated intravascular coagulation; Febrile 
neutropenia; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Cardiac disorders - Other (coronary 
artery disease); Cardiac disorders - Other (valvular vegitation); Myocardial infarction; Palpitations; Pericardial 
effusion; Pericardial tamponade; Restrictive cardiomyopathy; Right ventricular dysfunction; Sinus bradycardia; 
Sinus tachycardia; Ventricular arrhythmia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired 
EYE DISORDERS - Eye disorders - Other (choroidal effusion with shut down of ciliary body) 
GASTROINTESTINAL DISORDERS - Ascites; Colonic obstruction; Colonic stenosis; Constipation; Dental 
caries; Dry mouth; Dysphagia; Esophagitis; Gastritis; Gastrointestinal disorders - Other (gastrointestinal 
hemorrhage); Ileal stenosis; Mucositis oral; Proctitis; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema trunk; 
General disorders and administration site conditions - Other (general physical health deterioration); General 
disorders and administration site conditions - Other (failure to thrive); Hypothermia; Neck edema; Non-cardiac chest 
pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic hemorrhage 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (drug-induced liver injury); Immune 
system disorders - Other (Giany cell arteritis syndrome); Serum sickness 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning, and procedural 
complications - Other (radiation pneumonitis); Wound complication 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; CPK increased; Cardiac troponin 
I increased; Ejection fraction decreased; Electrocardiogram QT corrected interval prolonged; Electrocardiogram T 
wave abnormal; GGT increased; Lipase increased; Lymphocyte count decreased; Neutrophil count decreased; 
Serum amylase increased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypermagnesemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; 
Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Generalized muscle 
weakness; Musculoskeletal and connective tissue disorder - Other (polymyalgia rheumatica); Pain in extremity; 
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 (increase in tumor mass); Neoplasms benign, malignant 
and unspecified (incl cysts and polyps) - Other (lung cyst); Neoplasms benign, malignant and unspecified (incl cysts 
and polyps) - Other (tumor flare); Treatment related secondary malignancy; Tumor hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dizziness; Edema cerebral; Encephalopathy; 
Headache; Ischemia cerebrovascular; Nervous system disorders - Other (axonal neuropathy); Nervous system 
disorders - Other (hemiparesis); Nervous system disorders - Other (hypoesthesia); Nervous system disorders - Other 
(neuropathy peripheral); Paresthesia; Seizure; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Confusion; Insomnia 

NRG-GY012 
93              NCI Version Date: May 23, 2024 
 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Aspiration; Bronchopulmonary hemorrhage; Hypoxia; Laryngeal obstruction; Pleural effusion; Pneumothorax; 
Pulmonary edema; Pulmonary fistula; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other 
(asphyxia); Respiratory, thoracic and mediastinal disorders - Other (granulomatous changes in the lung); 
Respiratory, thoracic and mediastinal disorders - Other (fungal pneumonia; Phialemonium spp.) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin 
VASCULAR DISORDERS - Hypertension; Thromboembolic event 
 
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. 
 
7.4 
Expedited Reporting of Adverse Events (27-APR-2022) 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via https://ctepcore.nci.nih.gov/ctepaers/security/login.  
 
Submitting a report via CTEP-AERS serves as notification to the NRG 
Biostatistical/Data Management Center and satisfies NRG requirements for expedited 
adverse event reporting. 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that 
involve radiation therapy only. These events must be reported via the CTEP-AERS 
radiation therapy-only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to CTEP by telephone at 301-897-7497 and the Biostatistical/Data Management 
Center by phone, (number to be provided). An electronic report must be submitted 
immediately upon re-establishment of the Internet connection. 
 
7.4.1 Expedited Reporting Methods 
• CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification 
is electronically submitted within 24 hours of learning of the adverse event. Each 
CTEP-AERS24-hour notification must be followed by a complete report within 3 
days.  
• Supporting source documentation is requested by NRG as needed to complete 
adverse event review. When submitting supporting source documentation, include the 
protocol number, patient ID number, and CTEP-AERS ticket number on each page, 
and fax supporting documentation to CTEP at 301-230-0159 and the NRG 
Regulatory Affairs at 215-854-0716. 
• A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations. Sites 
must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment.  
 
7.4.2 Expedited Reporting Requirements for Adverse Events  

NRG-GY012 
95              NCI Version Date: May 23, 2024 
 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
 
7.4.4  Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS. In addition, 
secondary malignancies following radiation therapy must be reported via CTEP-AERS. 
Three options are available to describe the event: 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
7.4.5   Reporting to the Pharmaceutical Company:  As the IND Sponsor, CTEP/DCTD will 
assume the responsibility of forwarding CTEP-AERS reports to the pharmaceutical 
collaborator as needed. 
 
8. 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES  
(24-MAY-2021)(26-JUL-2023)(23-MAY-2024) 
 
Investigator and Research Associate Registration with CTEP 
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) credentials necessary to access secure NCI Clinical 
Oncology Research Enterprise (CORE) systems. 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. 
• 
Investigator (IVR) — MD, DO, or international equivalent; 

NRG-GY012 
97              NCI Version Date: May 23, 2024 
 
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 (27-APR-2022)(26-JUL-
2023)(23-MAY-2024) 
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 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 through 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 (CTSURegPref@ctsu.coccg.org) or by calling 1-
888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation; 
• IRB-signed CTSU IRB Certification Form; and/or 
• Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 

NRG-GY012 
98              NCI Version Date: May 23, 2024 
 
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 to be completed: 
• Have an active CTEP status; 
• Have an active status at the site(s) on the IRB/REB approval on at least one 
participating organization’s roster; 
• If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
• Include the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile;  
• List all sites on the IRB/REB approval as Practice Sites in the FDA 1572 in the RCR 
profile; and 
• Have the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number; 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
• An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution  
• Compliance with all applicable protocol-specific requirements (PSRs). 
Additional Requirements for sites in Canada: 
All institutions in Canada must conduct this trial in accordance with International 
Conference on Harmonization-Good Clinical Practice (ICH-GCP) Guidelines [per section 
6.2.5 of ICH E6(R2)]. This trial is being conducted under a Clinical Trial Application 
(CTA) with Health Canada. As a result essential documents must be retained for 25 years 
following the completion of the trial at the participating site (25 years post final analysis, 
last data collected, or closure notification to REB, whichever is later), or until notified by 
the sponsor, NRG Oncology, that documents no longer need to be retained [per C.05.012 
(4) of the FDR].  In addition, upon request by the auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct 
access [per section 4.9.7 of ICH]. Prior to clinical trial commencement, sites in Canada 
must also complete and submit via the Regulatory Submission portal on the CTSU 
website: 
• Clinical Trial Site Information Form,  
• Qualified Investigator Undertaking Form  
• Research Ethics Board Attestation Form 
• Protocol Signature Page  
• Investigator Brochure Signature Page  
• Delegation of Tasks (DTL) Log  
 

NRG-GY012 
99              NCI Version Date: May 23, 2024 
 
The following items are collected By NRG Oncology Regulatory on a yearly or biyearly 
basis:   
• IRB/REB Membership Roster  
• Laboratory Certificates and Normal Values  
• CVs for Qualified Investigator and Sub-Investigators noted on the DTL log 
Record Retention: The sponsor, NRG Oncology, shall maintain records identified in 
Health Canada guidelines Part C, Division 5, section C.05.012 for a period of 25 years. 
 
 
Downloading Site Registration Documents:   
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and their associated investigators and 
staff on a participating roster. To view/download site registration forms:  
▪ 
Log in to the CTSU members’ website (https://www.ctsu.org); 
▪ 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select NRG, and 
protocol number NRG-GY012. 
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.)  
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-
CTSU (2878), or CTSURegHelp@coccg.org to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.  

NRG-GY012 
100              NCI Version Date: May 23, 2024 
 
• Click on Regulatory at the top of the screen; 
• Click on Site Registration; and 
• Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
 
8.2 
Patient Enrollment (26-JUL-2023)(23-MAY-2024) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
 
8.2.1 Requirements for OPEN Access: 
• Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems; 
• To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 
Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
• If a Delegation of Tasks Log (DTL) is required for the study, the registrars must 
hold the OPEN Registrar task on the DTL for the site; and 
• Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the Institutional Review Board (IRB) number 
used on the site’s IRB approval on their Form Food and Drug Administration (FDA 1572) in 
Registration and Credential Repository (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: 

NRG-GY012 
101              NCI Version Date: May 23, 2024 
 
• Patient has met all eligibility criteria within the protocol stated timeframes; and  
• All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) authorization form (if applicable). 
(27-APR-2022) 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
9. 
DRUG INFORMATION  
 
9.1 
Cediranib (AZD2171, NSC 732208) (24-MAY-2021) 
 
9.1.1 Chemical Name: 4-[(4-Fluoro-2-methyl-1H-indol-5-yl) oxy]-6-methoxy-7-(3-pyrrolidin 
1- ylpropoxy) quinazoline maleate 
 
9.1.2 Other Names: AZD2171 maleate  
 
9.1.3 CAS Registry Number: 288383-20-0 (for the free base) 
 
9.1.4 Molecular Formula: C25H27FN4O3 · C4H4O4 
 
9.1.5 Molecular Weight: 566.59 as maleate salt (450.52 as free base) 
 
9.1.6  Approximate Solubility: The aqueous solubility of AZD2171 is 0.0006 mg/mL for the 
free base (distilled water, pH 8.1 at 25°C) and 1.9 mg/mL for the maleate salt (distilled 
water, pH 4.4 at 25°C). 
 
9.1.7 Mode of Action: AZD2171 is a highly potent inhibitor of vascular endothelial growth 
factor receptor (VEGFR) tyrosine kinase activity, which inhibits VEGF-dependent 
angiogenesis, neovascular survival and vascular permeability. 
 
9.1.8 How Supplied: Astra-Zeneca supplies and CTEP, NCI, DCTD distributes AZD2171. The 
agent is available as beige film-coated tablets containing 15 mg, and 20 mg of 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. 
 
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. 
 

NRG-GY012 
102              NCI Version Date: May 23, 2024 
 
9.1.9 Storage: Store intact bottles at controlled room temperature [20°C-25°C, (68-77°F)] and 
protect from light and moisture. 
 
9.1.10 Stability:  Stability studies are ongoing. Dispense 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. 
 
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. 
 
9.1.11 Route of Administration:  Oral.  AZD2171 tablets should be taken either one hour before 
or two hours after meals.  
 
9.1.12 Potential Drug Interactions:   
AZD2171 (cediranib) is primarily metabolized by flavin-containing monooxygenase 
enzymes (FMO1 and FMO3) and UGT1A4. It is not a substrate of CYP450 enzymes. In 
vitro studies suggest that AZD2171 (cediranib) is a substrate for P-glycoprotein (Pgp), 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 UGT1A4 or 
Pgp 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 UGT 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, Pgp, 
OATP1B1, OATP1B3, OCT2 and MATE1. Use caution in patients who are taking 
concomitant medications that are sensitive substrates of these transporters since there is a 
low potential for drug-drug interactions. 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.  
 
AZD2171 (cediranib) is approximately 95% bound to human plasma proteins, with 
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 

NRG-GY012 
103              NCI Version Date: May 23, 2024 
 
are also highly protein-bound. 
 
Oral anticoagulants are not absolutely contraindicated during treatment with AZD2171 
(cediranib); however, use AZD2171 (cediranib) with caution and increase monitoring in 
patients while on study. Patients who receive VEGF inhibitors are at increased risk of 
bleeding and hemorrhage. 
 
9.1.13 Patient Care Implications: Agents that inhibit VEGF signaling have the potential to affect 
wound healing; therefore, it is recommended that AZD2171 is stopped two weeks prior to 
elective surgery and restarted when the surgical wound has healed. Patients should be 
excluded from participating in clinical studies with AZD2171 if they have had recent (at 
least two weeks, or until any wound has completely healed) major thoracic or abdominal 
surgery prior to study start, or a 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). Refer to the protocol document for specific guidance.  
 
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 
 
9.2.3 Classification: PARP inhibitor 
 
9.2.4 CAS Registry Number: 763113-22-0 
 
9.2.5 Molecular Formula: C24H23FN4O3 
 
9.2.6 Molecular Weight: 434.46 
 
9.2.7 Approximate Solubility: 0.1 mg/mL pH independent solubility across physiologic range 
 
9.2.8 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. 
 
9.2.9 Description: Crystalline solid 
 
9.2.10 How Supplied: AstraZeneca supplies and the CTEP, DCTD distributes olaparib as film- 
 
coated tablets in 100 mg and 150 mg strengths.  

NRG-GY012 
104              NCI Version Date: May 23, 2024 
 
 
 
100 mg tablets are 14.5 mm x 7.25 mm oval-shaped 
 
150 mg are 14.5 mm x 7.25 mm oval-shaped 
 
Tablets are packaged in induction-sealed high-density polyethylene (HDPE) bottles with 
child-resistant closures. Each bottle contains 32 tablets with desiccant.  
 
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. 
 
9.2.11 Storage: Store in a secure location below 30° C (86° F). 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 Stability:  Shelf-life studies are ongoing. If a storage temperature excursion is identified, 
promptly return olaparib 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. 
 
9.2.13 Route of Administration: Tablets can be taken by mouth.   
 
9.2.14 Potential Drug Interactions: In vivo data indicate that CYP3A4/5 is important for olaparib 
metabolism and clearance in humans. For this reason, avoid concomitant administration 
of strong and moderate CYP 3A4/5 inducers and inhibitors.  Consult the protocol 
document or study investigator prior to making any dose adjustments related to potential 
drug-drug interactions. 
 
In vitro data shows olaparib is a substrate for P-glycoprotein (Pgp), 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 Pgp 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 and potentially induces CYP 2C9, 2C19 and Pgp. 
Therefore, avoid concomitant administration of sensitive substrates, particularly those 
with narrow therapeutic ranges.   
 
Olaparib is also an inhibitor of Pgp, 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 

NRG-GY012 
105              NCI Version Date: May 23, 2024 
 
clear. The manufacturer recommends that statins, in particular, should be administered 
with caution when given concomitantly with olaparib. 
 
9.2.15 Patient Care Implications: Pre-clinical data indicate that olaparib adversely affects 
embryo fetal survival and development. Therefore, study participants and their partners 
who are of child-bearing potential should agree to use two (2) highly effective forms of 
contraception throughout their study participation and for three (3) months after the last 
dose of olaparib.  See Appendix E of Olaparib IB for “Acceptable Birth Control 
Methods”.  
 
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. 
 
 
9.3 
AZD5363 (capivasertib), (NSC 782347) (24-MAY-2021) 
 
9.3.1 Chemical Name: 4-Amino-N-[(1s)-1-(4-Chlorophenyl)-3- 
 
Hydroxypropyl]-1-(7h-Pyrrolo[2,3 D]pyrimidin-4-Yl)piperidine-4-Carboxamide 
 
9.3.2 Classification: oral Akt inhibitor 
 
9.3.3 Molecular Formula: C21H25ClN6O2 M.W.: 428.92 
 
9.3.4 Approximate Solubility: In pH 1.2 simulated gastric fluid and pH 6.5 Fasted State 
Simulated Intestinal Fluid (v2) both at 37ºC the solubility is >20 mg/mL and 0.44 
mg/mL, respectively. 
 
9.3.5 Mode of Action: AZD5363 is a potent, oral inhibitor of kinase activity of serine/threonine 
specific protein kinase (Akt). AZD5363 inhibits activity of three Akt isoforms (Akt1, 
Akt2, Akt3), which are activated in different solid tumors. AKT is a hub of multiple 
signaling pathways promoting tumorigenesis, inhibiting apoptosis, promoting invasion 
and migration and is often associated with resistance to established cancer therapies. 
AZD5363 is expected to have efficacy when combined with cytotoxic cancer therapies or 
other targeted or anti-hormonal agents. 
 
9.3.6 How Supplied: AstraZeneca supplies and PMB, CTEP, DCTD distributes AZD5363 as  
beige film-coated tablets in 160 mg and 200 mg strengths. Tablets are packed in high-
density polyethylene (HDPE) bottles. Each bottle is secured with a heat induction seal, 
child-resistant closure and no desiccant.  
 
• 160 mg tablet (round, 10 mm) in 76-count bottles 
• 200 mg tablet (caplet shaped, 14.5 × 7.25 mm) in 76-count bottles 
 
 
Each tablet contains AZD5363, microcrystalline cellulose, dibasic 
calcium phosphate, croscarmellose sodium and magnesium stearate. The tablet film coat 
contains hypromellose, titanium dioxide, polyethylene glycol, polydextrose, copovidone 

NRG-GY012 
106              NCI Version Date: May 23, 2024 
 
plasdone, medium chain triglycerides, yellow iron oxide, red iron oxide and black iron 
oxide. 
 
9.3.7 Storage: Store below 30°C. 
If a storage temperature excursion is identified, promptly return AZD5363 to below 30°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. 
 
9.3.8 Stability:  Stability studies are ongoing. 
  
9.3.9 Route and Method of Administration: Oral. Take on an empty stomach at least 2 hours 
after a meal and 1 hour before the next meal. 
 
9.3.10 Potential Drug Interactions: AZD5363 is primarily metabolized by CYP3A4/5, with 
contributions from CYPs 2C9 and 2D6, and is substrate of the transporter P-gp.  
UGT2B7 is primarily responsible for the formation of the major human metabolite, the 
glucuronide conjugate. AZD5363 is a time-dependent and reversible inhibitor of 
CYP3A4/5 and a reversible inhibitor of CYPs 2C9, 2D6, and UGT1A1 in vitro. It also 
inhibited, to a lesser extent, CYPs 2B6, 2C19, and UGT2B7 and the transporters BCRP, 
OATP1B1, OATP1B3, OCT2, MATE1, and MATE2K1 in vitro. 
 
Avoid co-administration of strong CYP3A4/5 and P-gp inducers/inhibitors, moderate 
inhibitors may be used with caution.  Use caution with co-administered substrates of 
CYPs 2B6, 2C19, 2C9, 2D6, UGT1A1, and UGT2B7 or the transporters BCRP, 
OATP1B1, OATP1B3, OCT2, MATE1, and MATE2K1, depending on the sensitivity to 
inhibition and the therapeutic window of the substrate. 
 
9.4 
Durvalumab (MEDI4736) (NSC 778709) (24-MAY-2021) 
 
9.4.1    Other Names: IMFINZI™ 
 
9.4.2 Classification: Anti-PD-L1 Mab 
 
9.4.3 Molecular Weight: ~ 149 kDa 
 
9.4.4 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. 
 
9.4.5 Description: MEDI4736 is a human immunoglobulin G1 kappa (IgG1κ)  
 
monoclonal antibody. 
 
9.4.6 How Supplied: Durvalumab (MEDI4736) is supplied by AstraZeneca, and distributed by 

NRG-GY012 
107              NCI Version Date: May 23, 2024 
 
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 
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. 
 
9.4.7 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. 
 
9.4.8 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. 
 
9.4.9 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.   
 
9.4.10 Route of Administration: IV infusion 
 
9.4.11 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. 
 
9.4.12 Patient Care Implications: Refer to Section 6.0 for information on  
 
evaluation and management of potential immune-related adverse events.  
 

NRG-GY012 
108              NCI Version Date: May 23, 2024 
 
9.5 
Agent Ordering, Accountability, Inventory, Investigator Brochures and Links (24-
MAY-2021) 
9.5.1 Agent Ordering:  Agent Ordering: NCI-supplied agents may be requested by eligible 
participating Investigators (or their authorized designee) at each participating institution.  
The CTEP-assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents.  The eligible participating investigators at each participating 
institution must be registered with CTEP, DCTD through an annual submission of FDA 
Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment Form, and 
Financial Disclosure Form (FDF).  If there are several participating investigators at one 
institution, CTEP-supplied investigational agents for the study should be ordered under 
the name of one lead participating investigator at that institution. 
NO STARTER SUPPLIES MAY BE ORDERED. Orders should be placed with CTEP 
after enrollment and treatment assignment.  Provide the patient ID number in the 
comment box when submitting an order request.  If expedited shipment is required, sites 
should provide an express courier account through the Online Agent Order Processing 
(OAOP) application. 
9.5.2 Agent Inventory Records: 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 NCI Investigational Agent Oral 
(Drug) Accountability Record (DARF) available on the CTEP forms page.  Store and 
maintain separate NCI Investigational Agent Accountability Records for each agent, 
strength, formulation and ordering investigator on this protocol. 
 
9.5.3  Investigator Brochure Availability: The current versions of the IBs for PMB-supplied 
agents will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application.  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, a “current” password, and active person 
registration status. 
 
 
Questions about IB access may be directed to the PMB IB coordinator. 
 
9.5.4 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
 

NRG-GY012 
109              NCI Version Date: May 23, 2024 
 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 
 
9.6 
Blood Pressure Cuffs  
A patient who is randomized to the cediranib only or olaparib and cediranib treatment 
arm (Arms 1 and 3) will be given a blood pressure cuff. Blood pressure cuffs that are 
supplied for this study, are only to be used for this study.  
 
9.6.1  Supply and Distribution: Blood pressure cuffs will be supplied by VWR and distributed 
by Biologics. 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.  
 
9.6.2 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 1 and 3). To obtain the kits, please complete the “Blood Pressure Kit Order 
Request Form” found on the CTSU website and submit it via email to the VWR contacts 
listed at the bottom of the form. Please allow 3 business days to process and ship orders. 
All orders will be shipped via FedEx Priority Overnight. (27-APR-2022) 
 
10. 
PATHOLOGY/BIOSPECIMEN    
 
10.1 
Stained Pathology Slide Requirements for Central Review to Confirm Eligibility  
Not applicable 
 
10.2 
Biospecimen Selection for Integral Biomarker Testing 
Not applicable  
 
10.3 
Biospecimen Selection for Integrated Biomarker testing 
 
10.3.1 Integrated Biomarker to be Tested 
Homologous Recombination Deficiency (HRD) assayed in tumor collected prior to all 
treatment and prior to the study treatment will be used to determine if these mutations can 
predict response to olaparib alone or in combination with cediranib. 
 
Plasma angiome will be used to assess if markers of angiogenesis in serial plasma 
samples are associated with response to cediranib alone or in combination with olaparib. 
 
10.3.2 Integrated Biomarker Testing Requirements and Reporting 
Archival FFPE tumor collected prior to all treatment and prior to starting study treatment 
will be used for HRD testing. See Mandatory Biospecimen Submission Table (Section 
10.4.1) for details. 
 
Serial plasma (2mL from each of three time points) will be used for plasma angiome 
assays. See Mandatory Biospecimen Submission Table (Section 10.4.1) for details. 
 

NRG-GY012 
112              NCI Version Date: May 23, 2024 
 
Appendix I. 
 
11. 
SPECIAL STUDIES (NON-TISSUE) 
 
Not applicable 
 
12. 
DATA AND RECORDS 
 
12.1 
Data Submission/Data Reporting (24-MAY-2021)(27-APR-2022)(26-JUL-2023)(23-
MAY-2024) 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 
• Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT  
systems; and 
• Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave Read  
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
 
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus  
   (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) or   
   Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
Upon initial site registration approval for the study in Regulatory application all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation email 
from iMedidata. No action will be required; each study invitation will be automatically 
accepted and study access in Rave will be automatically granted. Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings 
are completed. Trainings will be in the form of electronic learnings (eLearnings) and can 
be accessed by clicking on the eLearning link in the Tasks pane located in the upper right 
corner of the iMedidata screen. If an eLearning is required for a study and has not yet 
been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; once the successful completion of the 
eLearning has been recorded, access to the study in Rave will be granted, and a Rave 
EDC link will replace the eLearning link under the study name. 
No action will be required by site staff (to activate their account) who have not 
previously activated their iMedidata/Rave account at the time of initial site registration 
approval for the study in the Regulatory application. Pending study invitations 
(previously sent but not accepted or declined by a site user will be automatically accepted 
and study access in Rave will be automatically granted for the site user. Account 

NRG-GY012 
113              NCI Version Date: May 23, 2024 
 
activation instructions are located on the CTSU website in the Data Management section 
under the Data Management Help Topics > Rave resource materials (Medidata Account 
Activation and Study Invitation). Additional information on iMedidata/Rave is available 
on the CTSU members’ website in the Data Management > Rave section at or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by email at 
ctsucontact@westat.com.  
 
12.2 
Data Quality Portal (27-APR-2022)(26-JUL-2023) 
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 that are rostered to a site and have access to 
the CTSU website. Staff who have Rave study access can access the Rave study 
data via direct links available in the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice 
a month. These notifications serve as alerts that queries and/or delinquent forms 
require site review, providing a summary count of queries and delinquent forms 
for each Rave study that a site is participating in. Additional site staff can 
subscribe and 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, and DQP Delinquent Forms, DQP 
Form Status, and DQP Reports modules. 
 
12.3 
Rave-CTEP-AERS Integration (26-JUL-2023) 
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.  
 
Pre-existing medical conditions (formerly referred to as baseline AEs) identified during 
baseline assessment are not considered AEs and therefore should not be reported on the 
Pre-treatment Adverse Event form. If these pre-existing conditions worsen in severity, 
the investigator must reassess the event to determine if an expedited report is required. 
Whether or not an expedited report is required, the worsened condition should be 
reported in Rave as a routine AE. 

NRG-GY012 
114              NCI Version Date: May 23, 2024 
 
 
Treatment-emergent AEs: All AEs that occur after start of treatment are collected 
in Medidata Rave using the Adverse Event form, which is available for entry at 
each treatment course or reporting period and is used to collect AEs that start 
during the period or persist from the previous reporting period. AEs that occur 30 
days after the last administration of the investigational study agent/intervention 
are collected using the Late Adverse Event form. 
Prior to sending AEs through the rules evaluation process, site staff should verify 
the following on the Adverse Event form in Rave: 
• The reporting period (course/cycle) is correct; and 
• AEs are recorded and complete (no missing fields) and the form is query-free.  
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for 
rules evaluation by completing the Expedited Reporting Evaluation form (i.e., 
checking the box Send All AEs for Evaluation and save the form). Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited 
reporting. A report is initiated in CTEP-AERS using information entered in 
Medidata Rave for AEs that meet reporting requirements. The CRA completes the 
report by accessing CTEP-AERS via a direct link on the Medidata Rave 
Expedited Reporting Evaluation form. Contact the CTSU Help Desk at 1-888-
823-5923 or by email at ctsucontact@westat.com if you have any issues 
submitting an expedited report in CTEP-AERS. 
In the rare occurrence that internet connectivity is lost, a 24-hour notification is to 
be made to CTEP by telephone at 301-897-7497. Once internet connectivity is 
restored, the 24-hour notification that was phoned in must be entered immediately 
into CTEP-AERS using the direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the 
CTSU members’ website: 
• Study specific documents: Protocols > Documents> Protocol Related  
Documents> Adverse Event Reporting; and   
• Additional resources: Resources > CTSU Operations Information> User  
Guides & Help Topics. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
• NCI Guidelines for Investigators: Adverse Event Reporting Requirements is  
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguid
elines.pdf. 
 

NRG-GY012 
115              NCI Version Date: May 23, 2024 
 
12.4 
Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, 
July 31, and October 31.  Instructions for submitting data using the CDUS can be found 
on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
 
12.5 
Collaborative Agreements Language 
 
Protocols that involve agent(s) covered by a collaborative agreement with a 
biotech/pharma company (ies) must incorporate the NCI/ DCTD Collaborative 
Agreement Language shown below. 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the 
Pharmaceutical Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI 
Division of Cancer Treatment and Diagnosis.  Therefore, the following 
obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to 
Collaborator” (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained within the terms of award, apply to the use of the Agent(s) in this study: 
 
1.   Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing Agents contain confidential information and should not be shared or distributed 
without the permission of the NCI.  If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
 
2.   For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as “Multi-Party Data”): 
 
a.   NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NCI, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b.   Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own Agent. 

NRG-GY012 
116              NCI Version Date: May 23, 2024 
 
 
c.   Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
 
3.   Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as described 
in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, 
all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R. Part 164. 
 
4.   When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
5.   Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
 
6.   Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication.  Collaborator(s) will have 30 
days from the date of receipt for review.  Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to CTEP 
for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably 
at least three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings. Press releases and other media presentations 
must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract 
and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov   
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 

NRG-GY012 
117              NCI Version Date: May 23, 2024 
 
 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
NRG-GY012 Governance (24-MAY-2021) 
The NRG-GY012 protocol is being amended to allow for the addition of three new 
treatment arms:  
• olaparib + AZD5363 (capivasertib) 
• olaparib + durvalumab (MEDI4736) 
• cediranib + durvalumab (MEDI4736) 
 
Completing the Current three arms  
This study includes regular safety reviews for a safety lead-in, DMC monitoring while 
patients are on protocol therapy, including planned interim and final analyses, and finally 
publication.  The protocol includes specific thresholds for interim futility and efficacy to 
help the DMC decide whether to release the interim analysis results.  For efficacy, the 
DMC (at their discretion) can release ALL of the efficacy information if at least one 
interim comparison p-value<0.001 (relative to the reference arm).  Releasing all of the 
data will allow the Disease Site design team access to all the information available for the 
follow-on study design, with the caveat that none of the data on these arms is mature.  At 
the final analysis, the statistical report makes the efficacy results public.  The Disease Site 
Committees and their design teams decide whether and how to use that information in 
follow-on protocols. The DMC role reduces to an annual safety review while the 
remaining patients finish the prescribed protocol therapy.  
 
The Reference Arm 
The current reference arm, cediranib, will be maintained pending additional data from 
NRG-GY012 or other studies that suggest a change to the reference arm would be 
appropriate. Concurrent randomization to cediranib will occur while the three new 
treatment arms accrue.  As per the original rationale and approval for NRG-GY012, the 
reference arm is required as response rates are low and comparisons of PFS with 
historical controls can be challenging. Cediranib was evaluated in a phase II trial (GOG-
0229) in a mixed EC patient population with a partial response rate of 12.5% and  6-
month event-free survival of 29%, meeting the protocol specified efficacy objective to 
warrant further investigation. Median progression free survival was 3.6 months and 
overall survival 12.5 months, comparable to other agents in this patient population. In 
addition, the consistent reference arm for the first three arms and the next three arms will 
allow for clear and precise evaluation of the response rates and PFS comparisons. 
 
Designing the Definitive, Confirmatory Trial 
At the conclusion of GY012, the data will be reviewed by the DMC. Treatment arms 
passing the pre-specified efficacy threshold will be considered for further development 
into a definitive phase II or III randomized trial.  If more than one arm passes the efficacy 
threshold, the DMC will consider overall survival, tolerability/toxicity and comparative 
efficacy and any other information available to determine which arm(s) to recommend for 
a definitive comparison. The rationale for picking the best winner depends on the 

NRG-GY012 
118              NCI Version Date: May 23, 2024 
 
treatment landscape and other factors present when the study completes analysis.  These 
decisions may be informed by ancillary studies, including unplanned experimental arm 
comparisons or sub-group analyses within GY012, knowing that such studies are subject 
to bias and inflated error rates.  
 
The study design will allow us to efficiently identify drug (s) of interest to take 
forward into definitive randomized clinical trials to establish new standard(s) of 
care for women diagnosed with EC. 
 
13.2 
Study Design 
This is a randomized, open-label, three-arm study of women with recurrent, metastatic, or 
persistent endometrial cancer.  Patients will be randomized in a 1:1:1 ratio to the three 
treatment arms:  
• cediranib (the reference arm) 
• olaparib 
• olaparib + cediranib. 
 
The randomization will be stratified by histology (serous vs. endometrioid). 
 
The overall; objective of this study is to compare the relative efficacy and safety of each 
of the experimental treatment regimens to the reference arm of cediranib in patients with 
recurrent, metastatic, or persistent endometrial cancer. 
 
(24-MAY-2021) 
Accrual under Amendments 1-2 completed in June 2019. 
Amendment 3 adds three new experimental arms with concurrent randomization to the 
cediranib-alone reference.  Patients will be randomized in a 1:1:1:1 ratio to the four 
treatment arms: 
• cediranib (the reference arm) 
• olaparib + AZD5363 (capivasertib) 
• olaparib + durvalumab (MEDI4736) 
• cediranib + durvalumab (MEDI4736)) 
 
The randomization will be stratified by: 
• Histology (serous vs. endometrioid) 
• Prior immunotherapy (yes vs. no) 
 
Dynamic allocation will be used for randomization in order to account for multiple 
stratification factors. 
 
Details about a planned interim analysis and a planned safety analysis can be found in 
sections 13.5 and 13.8.3 respectively. 
 
 
13.3 
Study Endpoints (24-MAY-2021) 
 

NRG-GY012 
119              NCI Version Date: May 23, 2024 
 
Efficacy Endpoints 
• Progression-free survival (PFS) is defined as the time from the date of study 
enrollment to the investigator-determined date of progression (see Section 14.0 
for RECIST v1.1 definition of progression), or death due to any cause, whichever 
occurs first. For individuals who are alive and progression free, the censored time 
at risk will be defined as the time from the study enrollment date to the date of the 
patient’s last radiographic disease assessment. 
• Overall survival (OS) is defined as the time from the date of study enrollment to 
the date of death regardless of the cause. For those individuals who have no death 
reported at the time of the analysis, the censored time at risk will be assessed from 
the date of study enrollment to the date that the patient was last contacted and 
known to be alive. 
• Objective tumor response as assessed by the site investigator using RECIST v1.1 
(see Section 14.  Patients with complete or partial tumor response will be 
considered to have a response. 
 
Safety endpoints 
• The frequency and severity of adverse effects are defined using Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
 
Translational Endpoints  
The translational endpoints below are approved and funded via BIQSFP for the first three 
treatment arms only: cediranib alone, olaparib alone, and the combination of olaparib and 
cedaranib. Biomarkers for added treatment arms require either amendment or correlative 
science proposal submission and secured funding. (24-MAY-2021) 
 
• To assess if mutations in DNA Homologous Repair Genes (assayed prior to all 
treatment and prior to the study treatment) are predictive of response to olaparib 
alone or in combination with cediranib. (Integrated Biomarker) BIQSFP 
funded for ARMS 1-3 only 
• To assess if markers of angiogenesis in serial plasma samples are associated with 
response to cediranib alone or in combination with olaparib. (Integrated 
Biomarker) BIQSFP funded for  1-3 only 
 
13.4 
Primary Objectives Study Design (24-MAY-2021) 
 
13.4.1 Primary Hypothesis and Endpoints 
The primary hypotheses compare PFS for the two experimental regimens versus the 
cediranib reference arm. Let lC denote the PFS hazard for cediranib, and lj j={2,3,4,5,6} 
indicate the experimental arms described in Section 5.1. 
 
The null hypotheses are: 
• H0,j:C: 
lj/lC ≥ 1, i.e., the hazard of progression or death (PFS-hazard) in this 
patient population treated with experimental arm (j) is not better than that 
for those treated with cediranib 
 

NRG-GY012 
120              NCI Version Date: May 23, 2024 
 
The corresponding alternative hypotheses are one-sided: 
• H1,j:C: 
lj/lC < 1, i.e., the PFS-hazard in the patient population treated with 
experimental arm (j) is less than that for those treated with cediranib 
 
13.4.2 How Primary Endpoints Will Be Analyzed 
The null hypotheses above for PFS will be tested using pairwise log-rank tests stratified 
by the factors specified in section 13.2 above.  Each comparison can be considered a 
separate phase II comparison, so no adjustments for multiplicity will be made; all 
comparisons will be tested using a one-sided α of 0.05. 
 
The final analysis is planned when 39 PFS events are observed in the reference arm, 
which is what expected under the alternative hypothesis and with 73 events for the 
pairwise comparisons (see section 13.4.3 below). 
For the primary analyses, patients will be grouped according to their randomly assigned 
treatment and patients will be included in the analysis, regardless of their compliance 
with their assigned treatment plan. The primary analyses will use the duration of PFS as it 
is determined by the clinical investigator responsible for treating the patient. 
 
(24-MAY-2021): 
For treatment assignments under Amendments 1 and 2, the null hypotheses comparing 
olaparib and olaparib+cediranib vs. cediranib for PFS will be tested using pairwise log-
rank tests stratified by histology only as specified in section 13.2 above.   
 
For treatment assignments under Amendments 3, the null hypotheses for PFS will be 
tested using pairwise log-rank tests, stratified by both histology and prior 
immunotherapy.   
The 40 patients accrued to the cediranib arm under Amendment 1-2 will be used in the 
comparisons to the olaparib only arm and the olaparib+cediranib arm.   
The 40 patients accrued to the cediranib arm under Amendment 3 will be used in the 
comparisons to the olaparib+AZD5363 (capivasertib) arm, olaparib+durvalumab 
(MEDI4736) arm, and cediranib+durvalumab (MEDI4736) arm.   
The final analysis for Amendment 2 treatment comparisons (olaparib vs. cediranib and 
olaparib+cediranib vs. cediranib) will occur when data maturity for those comparisons is 
reached.  These analyses are not contingent on the Amendment 3 maturity or treatment 
comparisons. 
13.4.3  Sample Size and Power Calculations:  
We project the median PFS on the cediranib arm to be approximately 3.6 months (based 
on GOG-0229-J). In order to have 90% power to detect a doubling of PFS to 7.2 months 
(i.e., hazard ratio of 0.5), using a one-sided test with α=0.05 per comparison, we require 
73 events for each of the two comparisons and will do the final analysis when 39 events 
are observed in the control arm (which is what is expected under the planned alternative 
hypothesis), and thus plan to enroll 40 patients per arm (for a total of 120 patients). 
Calculations were done based on two-sample logrank test in East version 6.4.) 

NRG-GY012 
121              NCI Version Date: May 23, 2024 
 
 
(24-MAY-2021) 
The Amendment 3 treatment comparisons assume the same statistical considerations 
outlined above, including a median PFS in the cediranib arm of approximately 3.6 
months, 90% power to detect doubling of PFS to 7.2 months (i.e., hazard ratio of 0.5), 
one-sided tests with α=0.05 per comparison, and 73 events for each comparison for the 
final analysis.  Thus, 40 patients per arm for a total of 160 patients are required.  This 
total includes 40 new patients accruing to the cediranib arm for concurrent randomization 
with the three new treatment arms.  There are already 40 patients accrued to the cediranib 
arm.  Thus, the cediranib arm will close with a total of 80 patients at the end of the study. 
 
In order to allow for slight variation in the size per treatment arm due to dynamic 
allocation, a total sample size of 168 new patients will be targeted.  Calculations were 
done based on two-sample log rank test in East version 6.4. 
13.5 
Study Monitoring of Primary Objectives 
An interim analysis for futility is planned at 50% information time, i.e., when 37 PFS 
events are observed in any two combined treatments for which a pairwise comparison is 
being done; all interim analyses will be done at that time, meaning some will not be done 
at exactly 50% information time. At our expected accrual and event rates, we expect this 
to occur after approximately 17 months of accrual (with approximately 90 patients 
accrued). If the Z-score from the log-rank test (described in section 13.3.2 above) is >0 
then that arm will be stopped for futility; this corresponds approximately to a hazard ratio 
being >1.0 (i.e., favoring cediranib) for the given experimental arm compared to 
cediranib (i.e., lj/lC  j={2,3}). Under the null hypothesis, there is a 50% chance of 
stopping an arm for futility, and under the alternative hypothesis, there is a 1.8% chance 
of stopping. 
The study will not be suspended during the futility analysis. 
(24-MAY-2021) 
The interim analysis for Amendment 1-2 was complete at the time of Amendment 3.   
 
For the Amendment 3 treatment comparisons, an interim analysis for futility is planned at 
50% information time, i.e., when 37 PFS events are observed in any two combined 
treatments for which a pairwise comparison is being done.  All interim analyses for the 
three new treatment comparisons will be done at that time, meaning some will not be 
done at exactly 50% information time.  At our expected accrual and event rates, we 
expect this to occur after approximately 11 months of accrual (with approximately 110 
patients accrued).  If the Z-score from the log rank test is >0, then the experimental arm 
will be stopped for futility; this corresponds approximately to a hazard ratio being >1.0 
for the given experimental arm compared to cediranib.  Under the null hypothesis, there 
is a 50% chance of stopping an arm for futility.  Under the alternative hypothesis, there is 
a 1.8% chance of stopping.   
 
If accrual is ongoing, accrual will not be stopped for the futility analysis. 
 

NRG-GY012 
122              NCI Version Date: May 23, 2024 
 
Interim analysis for the DMC:  
The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a 
year with respect to patient accrual and morbidity. The DMC also will review the study 
on an “as needed” basis.  If, at the interim analysis, at least one treatment/reference 
hazard ratio has a p-value <0.001, the DMC may consider early release of the interim 
results for possible development of a definitive trial, as described in Section 13.1.   
 
13.6 
Accrual/Study Duration Considerations 
We plan on accruing a total of 120 patients (40 per arm) initially, but futility analyses are 
planned, which could reduce that number.  We project accrual of 120 patients to take 
approximately 24 months (~5 patients per month) followed by an additional 10 months of 
follow up after the date the last patient is enrolled and begins treatment.  The total accrual 
time could be lengthened by the suspension for the safety review (described below in 
section 13.8.3). 
 
(24-MAY-2021)  
Under Amendment 3, we plan on accruing a total of ~168 patients to the three new 
treatment arms and the reference arm (~40-42 patients per arm).  Planned futility analyses 
could reduce that number.  We project accrual of 168 patients to take approximately 17 
months (~10 patients per month) followed by an additional 10 months of follow up after 
the date the last patient is enrolled and begins treatment.  The monthly accrual rate was 
increased to 10 patients/month due to faster than anticipated accrual to under Amendment 
1-2.  The total accrual time could be lengthened by the suspension for the safety review 
(described below in section 13.8.3). 
13.7 
Dose Level Guidelines 
Not applicable. 
13.8 
Secondary or Exploratory Endpoints (Including Correlative Science Aims)(24-
MAY-2021) 
 
13.8.1 Secondary Hypotheses and Endpoints:  
The pairwise comparisons with respect PFS in the primary hypotheses (H0,j:C) will also be 
tested for overall survival. 
The pairwise comparisons with respect PFS in the primary hypotheses (H0,j:C) will also be 
tested for objective tumor response. 
 
For integrated biomarker-based hypotheses, the endpoints of PFS, OS, and objective 
tumor response are defined above, and the translational science endpoints are listed 
above.  These are applicable to the first three treatment arms only: cediranib alone, 
olaparib alone, and the combination of olaparib and cedaranib. Biomarkers for added 
treatment arms require either amendment or correlative science proposal submission and 
secured funding. (24-MAY-2021)  
 
The integrated biomarker-based hypotheses are: 
• Mutations in DNA Homologous Repair Genes are predictive of response in 
the experimental arms, as compared to the reference   

NRG-GY012 
123              NCI Version Date: May 23, 2024 
 
• Markers of angiogenesis determined by serum ELISA for VEGFA or IHC for 
VEGFR1, VEGFR2 and microvessel density (CD31) are associated with 
response in the experimental arms as compared to the reference  
 
13.8.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
 
The Amendment 1-2 null hypotheses for OS will be tested using pairwise log-rank tests 
stratified by the factors specified in section 13.2 above. Each comparison can be 
considered a separate phase II comparison, so no adjustments for multiplicity will be 
made; both comparisons will be tested using a one-sided α of 0.05. 
The null hypotheses for objective tumor response will be tested using pairwise Cochran-
Mantel-Haenszel tests stratified by the factors specified in section 13.1 above. Each 
comparison can be considered a separate phase II comparison, so no adjustments for 
multiplicity will be made; both comparisons will be tested using a one-sided α of 0.05. 
Proportional hazards models will be used to examine the prognostic association of 
integrated markers with PFS and OS; and interactions between markers and treatment 
arm will be used to examine the markers’ predictive association with the clinical 
endpoints. 
 
(24-MAY-2021)  
The same statistical assumptions and methods described above apply to the three new 
treatment comparisons, with corresponding modification of the stratification factors. 
 
13.8.3 Interim Analysis for All Other Endpoints (24-MAY-2021): 
 
We will conduct a formal safety review for the two arms that contain agents or 
combinations that have not been previously explored in this patient population: olaparib 
and olaparib+cediranib. This will occur after twenty-four (eight per arm) patients have 
been accrued—with the expectation that at least six patients on each of the arms will be 
treated with at least 1 cycle of treatment (rather than stopping after just six have been 
accrued on each arm with the greater possibility that <6 may get treated with one cycle). 
 
The safety review will allow for close monitoring in this population that may represent an 
older age range than previously studied and who may have undergone prior exposure to 
pelvic radiation. Safety and tolerability will be reviewed by the study team (study chair 
and co-chairs, study statistician) and Developmental Therapeutics Chair before 
continuing accrual. Clinical judgment rather than arbitrary statistical rules will be used. 
No rigid stopping boundaries will be set, and no dose limiting toxicities will be defined. 
The number of adverse events will be tabulated by grade and treatment arm, and 
consideration will be given to the nature of the AEs and their potential relatedness to 
study therapy. 
 
Under Amendment 3, patients in a safety lead-in will be monitored frequently according 
to NRG Oncology SOPs.  We will conduct a formal safety review for the three new 
treatment arms, as these arms contain agents or combinations that have not been 
previously explored in this patient population.  The safety review will occur after 36 

NRG-GY012 
127              NCI Version Date: May 23, 2024 
 
Evaluable for RECIST response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 
 
14.2 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray or as >10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area may be considered 
measurable if there has been interval progression since the time of radiation. 
 
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.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  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 

NRG-GY012 
128              NCI Version Date: May 23, 2024 
 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
14.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
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).   
 
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 

NRG-GY012 
129              NCI Version Date: May 23, 2024 
 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
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. 
 
 
 
 
 

NRG-GY012 
130              NCI Version Date: May 23, 2024 
 
 
15. 
REFERENCES (24-MAY-2021) 
 
Aghajanian, C., Sill, M.W. Darcy, K.M., Greer, B., McMeekin, D.S., Rose, P.G., 
Rotmessch,J. Barnes, M.N., Hanjani, P., Leslie, K.K. (2011). Phase II trial of 
bevacizumab in recurrent or persistent endometrial cancer: A Gynecologic Oncology 
Group study.  J. Clin Oncol. 2011 Jun 1; 29(16):2259-2265.  doi: 
10.1200/JCO.2010.32.6397   
 
Atkins, M.B., et al., Axitinib in combination with pembrolizumab in patients with 
advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-
expansion phase 1b trial. Lancet Oncol, 2018. 19(3): p. 405-415. 
 
Audeh, M. W., Carmichael, J., Penson, R. T., Friedlander, M., Powell, B., Bell-McGuinn, 
K. M., . . . Tutt, A. (2010). Oral poly(ADP-ribose) polymerase inhibitor olaparib in 
patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-
concept trial. Lancet, 376(9737), 245-251. doi:10.1016/S0140-6736(10)60893-8 
 
Barsoum, I.B., et al., A mechanism of hypoxia-mediated escape from adaptive immunity 
in cancer cells. Cancer Res, 2014. 74(3): p. 665-74. 
 
Bender, D., Sill, M. W., Lankes, H. A., Reyes, H. D., Darus, C. J., Delmore, J. E., . . . 
Leslie, K. K. (2015). A phase II evaluation of cediranib in the treatment of recurrent or 
persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study. 
Gynecol Oncol, 138(3), 507-512. doi:10.1016/j.ygyno.2015.07.018 
 
Binder, P. S., Peipert, J. F., Kallogjeri, D., Brooks, R. A., Massad, L. S., Mutch, D. G., . . 
. McCourt, C. K. (2016). Adult Comorbidity Evaluation 27 score as a predictor of 
survival in endometrial cancer patients. Am J Obstet Gynecol, 215(6), 766 e761-766 
e769. doi:10.1016/j.ajog.2016.07.035 
 
Bindra, R. S., Gibson, S. L., Meng, A., Westermark, U., Jasin, M., Pierce, A. J., . . . 
Glazer, P. M. (2005). Hypoxia-induced down-regulation of BRCA1 expression by E2Fs. 
Cancer Res, 65(24), 11597-11604. doi:10.1158/0008-5472.CAN-05-2119 
 
Brana, I., & Mackay, H. J. (2014). WEe1 inhibition as an anticancer strategy: First 
advances. Drugs of the Future, 39(3), 207.  
 
Chen, Q., L. Sun, and Z.J. Chen, Regulation and function of the cGAS-STING pathway of 
cytosolic DNA sensing. Nat Immunol, 2016. 17(10): p. 1142-9 
 
Coleman, T. R., & Dunphy, W. G. (1994). Cdc2 regulatory factors. Curr Opin Cell Biol, 
6(6), 877-882.  
 
Capivasertib Active against AKT1-Mutated Cancers. Cancer Discov, 2019. 9(1): p. OF7. 
Dedes, K. J., Wetterskog, D., Mendes-Pereira, A. M., Natrajan, R., Lambros, M. B., 

NRG-GY012 
131              NCI Version Date: May 23, 2024 
 
Geyer, F. C., . . . Reis-Filho, J. S. (2010). PTEN deficiency in endometrioid endometrial 
adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med, 2(53), 53ra75. 
doi:10.1126/scitranslmed.3001538 
 
Djordjevic, B., Hennessy, B. T., Li, J., Barkoh, B. A., Luthra, R., Mills, G. B., & 
Broaddus, R. R. (2012). Clinical assessment of PTEN loss in endometrial carcinoma: 
immunohistochemistry outperforms gene sequencing. Mod Pathol, 25(5), 699-708. 
doi:10.1038/modpathol.2011.208 
 
Dvorak, H. F. (2002). Vascular permeability factor/vascular endothelial growth factor: a 
critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J 
Clin Oncol, 20(21), 4368-4380. doi:10.1200/JCO.2002.10.088 
 
Engel, J.B., et al., Perifosine inhibits growth of human experimental endometrial cancers 
by blockade of AKT phosphorylation. Eur J Obstet Gynecol Reprod Biol, 2008. 141(1): p. 
64-9. 
 
Ferrara, N. (2004). Vascular endothelial growth factor: basic science and clinical 
progress. Endocr Rev, 25(4), 581-611. doi:10.1210/er.2003-0027 
 
Fidler, I. J., & Ellis, L. M. (1994). The implications of angiogenesis for the biology and 
therapy of cancer metastasis. Cell, 79(2), 185-188.  
 
Friedlander, M., Gebski, V., Gibbs, E., Bloomfield, R., Hilpert, F., Wenzel, L. B., . . . 
Pujade-Lauraine, E. (2017). Health-related quality of life (HRQOL) and patient-centered 
outcomes with maintenance olaparib compared with placebo following chemotherapy in 
patients with germline (g) BRCA-mutated (m) platinum-sensitive relapsed serous ovarian 
cancer (PSR SOC): SOLO2 phase III trial. J Clin Oncol, 35, suppl; abstr 5507.  
 
Frolova, A. I., Babb, S. A., Zantow, E., Hagemann, A. R., Powell, M. A., Thaker, P. H., . 
. . Mutch, D. G. (2015). Impact of an immunohistochemistry-based universal screening 
protocol for Lynch syndrome in endometrial cancer on genetic counseling and testing. 
Gynecol Oncol, 137(1), 7-13. doi:10.1016/j.ygyno.2015.01.535 
 
Fukumura, D., et al., Enhancing cancer immunotherapy using antiangiogenics: 
opportunities and challenges. Nat Rev Clin Oncol, 2018. 15(5): p. 325-340. 
 
Gabrilovich, D., et al., Vascular endothelial growth factor inhibits the development of 
dendritic cells and dramatically affects the differentiation of multiple hematopoietic 
lineages in vivo. Blood, 1998. 92(11): p. 4150-66. 
 
Giannini, G., Ristori, E., Cerignoli, F., Rinaldi, C., Zani, M., Viel, A., . . . Gulino, A. 
(2002). Human MRE11 is inactivated in mismatch repair-deficient cancers. EMBO Rep, 
3(3), 248-254. doi:10.1093/embo-reports/kvf044 
 
 

NRG-GY012 
132              NCI Version Date: May 23, 2024 
 
Gibson, W. J., Hoivik, E. A., Halle, M. K., Taylor-Weiner, A., Cherniack, A. D., Berg, 
A., . . . Salvesen, H. B. (2016). The genomic landscape and evolution of endometrial 
carcinoma progression and abdominopelvic metastasis. Nat Genet, 48(8), 848-855. 
doi:10.1038/ng.3602 
 
Gilks, C. B., Oliva, E., & Soslow, R. A. (2013). Poor interobserver reproducibility in the 
diagnosis of high-grade endometrial carcinoma. Am J Surg Pathol, 37(6), 874-881. 
doi:10.1097/PAS.0b013e31827f576a 
 
Hamilton, E. P., Wang, J. S.-Z., Falchook, G., Jones, S. F., Cook, C., Mugundu, G., . . . 
Spigel, D. R. (2016). A phase Ib study of AZD1775 and olaparib combination in patients 
with refractory solid tumors. Journal of Clinical Oncology, 34(15_suppl), 5562-5562. 
doi:10.1200/JCO.2016.34.15_suppl.5562 
 
Hansen, J. M., Ring, K. L., Baggerly, K. A., Wu, S., Timms, K., Neff, C., . . . Sood, A. 
(2016). Clinical significance of homologous recombination deficiency (HRD) score 
testing in endometrial cancer patients. Journal of Clinical Oncology, 34(15_suppl), 5584-
5584. doi:10.1200/JCO.2016.34.15_suppl.5584 
 
Hodi, F.S., et al., Bevacizumab plus ipilimumab in patients with metastatic melanoma. 
Cancer Immunol Res, 2014. 2(7): p. 632-42. 
 
Hu H, Juvekar A, Lyssiotis CA, et al. Phosphoinisitide 3-kinase regulates glycolysis 
through mobilization of aldolase from the actin cytoskeleton. Cell 2016; 164: 433.446. 
 
Huang, Y., et al., Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis 
associated with elevated levels of VEGF. Blood, 2007. 110(2): p. 624-31. 
 
Huang, Y., et al., Vascular normalization as an emerging strategy to enhance cancer 
immunotherapy. Cancer Res, 2013. 73(10): p. 2943-8. 
 
Ivy SP, de Bono J, Kohn E. (2016) The “pushmu-Pullyu” of DNA repair: clinical 
synthetic lethality. Trends in Cancer 2 (11), 646-656 
 
Jain, R.K., Antiangiogenesis strategies revisited: from starving tumors to alleviating 
hypoxia. Cancer Cell, 2014. 26(5): p. 605-22. 
 
Juvekar A, Burga LN, Hu H, et al. Combining a PI3K inhibitor with a PARP inhibitor 
provides an effective therapy for BRCA1-related breast cancer. Cancer Discov 2012; 2: 
1048-1063.  
 
Kandoth, C., Schultz, N., Cherniack, A. D., Akbani, R., Liu, Y., Shen, H., Levine, D. A. 
(2013). Integrated genomic characterization of endometrial carcinoma. Nature, 
497(7447), 67-73. doi:nature12113 [pii] 
 
Kaufman, B., Shapira-Frommer, R., Schmutzler, R. K., Audeh, M. W., Friedlander, M., 

NRG-GY012 
133              NCI Version Date: May 23, 2024 
 
Balmana, J., . . . Domchek, S. M. (2015). Olaparib monotherapy in patients with 
advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol, 33(3), 244-250. 
doi:10.1200/JCO.2014.56.2728 
 
Korets, S.B., et al., Targeting the mTOR/4E-BP pathway in endometrial cancer. Clin 
Cancer Res, 2011. 17(24): p. 7518-28. 
 
Lamarche, B. J., Orazio, N. I., & Weitzman, M. D. (2010). The MRN complex in double-
strand break repair and telomere maintenance. FEBS Lett, 584(17), 3682-3695. 
doi:10.1016/j.febslet.2010.07.029 
 
Lancaster, J. M., Powell, C. B., Chen, L. M., Richardson, D. L., & Committee, S. G. O. 
C. P. (2015). Society of Gynecologic Oncology statement on risk assessment for 
inherited gynecologic cancer predispositions. Gynecol Oncol, 136(1), 3-7. 
doi:10.1016/j.ygyno.2014.09.009 
 
Lee, J.M., et al., Safety and Clinical Activity of the Programmed Death-Ligand 1 
Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor 
Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in 
Women's Cancers: A Dose-Escalation, Phase I Study. J Clin Oncol, 2017. 35(19): p. 
2193-2202. 
 
Ledermann, J., Harter, P., Gourley, C., Friedlander, M., Vergote, I., Rustin, G., . . . 
Matulonis, U. (2014). Olaparib maintenance therapy in patients with platinum-sensitive 
relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by 
BRCA status in a randomised phase 2 trial. Lancet Oncol, 15(8), 852-861. 
doi:10.1016/S1470-2045(14)70228-1 
 
Leijen, S., van Geel, R. M., Sonke, G. S., de Jong, D., Rosenberg, E. H., Marchetti, S., . . 
. Schellens, J. H. (2016). Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in 
Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line 
Therapy Within 3 Months. J Clin Oncol, 34(36), 4354-4361. 
doi:10.1200/JCO.2016.67.5942 
 
Lheureux, S., Wilson, M., & Mackay, H. J. (2014). Recent and current Phase II clinical 
trials in endometrial cancer: review of the state of art. Expert Opin Investig Drugs, 23(6), 
773-792. doi:10.1517/13543784.2014.907272 
 
Li, M.O., et al., Transforming growth factor-beta regulation of immune responses. Annu 
Rev Immunol, 2006. 24: p. 99-146 
 
Liu, J. F., Barry, W. T., Birrer, M., Lee, J. M., Buckanovich, R. J., Fleming, G. F., . . . 
Matulonis, U. A. (2014). Combination cediranib and olaparib versus olaparib alone for 
women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. 
Lancet Oncol, 15(11), 1207-1214. doi:10.1016/S1470-2045(14)70391-2 
 

NRG-GY012 
134              NCI Version Date: May 23, 2024 
 
Lu, K. H., & Ring, K. L. (2015). One size may not fit all: the debate of universal tumor 
testing for Lynch syndrome. Gynecol Oncol, 137(1), 2-3. 
doi:10.1016/j.ygyno.2015.03.011 
 
Lu, X., et al., Erratum: Effective combinatorial immunotherapy for castration-resistant 
prostate cancer. Nature, 2017. 545(7652): p. 116. 
 
Mackay, H. J., Gallinger, S., Tsao, M. S., McLachlin, C. M., Tu, D., Keiser, K., . . . Oza, 
A. M. (2010). Prognostic value of microsatellite instability (MSI) and PTEN expression 
in women with endometrial cancer: results from studies of the NCIC Clinical Trials 
Group (NCIC CTG). Eur J Cancer, 46(8), 1365-1373. doi:S0959-8049(10)00158-9 [pii] 
MacKay, H. J., Levine, D. A., Bae-Jump, V. L., Bell, D. W., McAlpine, J. N., Santin, A., 
. . . Kohn, E. C. (2017 (in press)). Moving Forward with Actionable Therapeutic Targets 
and Opportunities in Endometrial Cancer: NCI Clinical Trials Planning Meeting Report 
on Identifying Key Genes and Molecular Pathways for Targeted Endometrial Cancer 
Trials Oncotarget.  
 
Maenhout, S.K., K. Thielemans, and J.L. Aerts, Location, location, location: functional 
and phenotypic heterogeneity between tumor-infiltrating and non-infiltrating myeloid-
derived suppressor cells. Oncoimmunology, 2014. 3(10): p. e956579. 
 
Makker, V., Rasco, D., Vogelsang, N., Brose M…Taylor, M. (2019) Lenvatinitb plus 
pembrolizumab in patients with advanced endometrial cancer; and interim analysis of a 
multicentre, open-label, single-arm, phase 2 trial. The Lancet 20(5) 711-178.  
 
Mateo, J., Carreira, S., Sandhu, S., Miranda, S., Mossop, H., Perez-Lopez, R., . . . de 
Bono, J. S. (2015). DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N 
Engl J Med, 373(18), 1697-1708. doi:10.1056/NEJMoa1506859 
 
Marcus, L., et al., FDA Approval Summary: Pembrolizumab for the treatment of 
microsatellite instability-high solid tumors. Clin Cancer Res, 2019 
 
Matulonis UA, Wolf GM, Barry WT, et al. Phase I dose escalation study of the PI3K 
pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor 
olaparib for the treatment of high-grade serous ovarian and breast cancer. Ann Oncol 
2017 Mar 1; 28(3): 512-418. 
 
McDermott, D.F., et al., Clinical activity and molecular correlates of response to 
atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell 
carcinoma. Nat Med, 2018. 24(6): p. 749-757. 
 
McGowan, C. H., & Russell, P. (1993). Human Wee1 kinase inhibits cell division by 
phosphorylating p34cdc2 exclusively on Tyr15. EMBO J, 12(1), 75-85.  
 
Meng, X., Dizon, D. S., Yang, S., et al. Strategies for Molecularly Enhanced 
Chemotherapy to Achieve Synthetic Lethality in Endometrial Tumors with Mutant p53. 

NRG-GY012 
135              NCI Version Date: May 23, 2024 
 
Obstetrics and Gynecology International, 2013, 828165. 
http://doi.org/10.1155/2013/828165 
 
Meng, X., Laidler, L. L., Kosmacek, E. A., et al. Induction of Mitotic Cell Death by 
Overriding G2/M Checkpoint in Endometrial Cancer Cells with Non-functional p53. 
Gynecologic Oncology, 128(3), 461–469. http://doi.org/10.1016/j.ygyno.2012.11.004 
 
Mhawech-Fauceglia, P., Wang, D., Kim, G., Sharifian, M., Chen, X., Liu, Q., . . . 
Pejovic, T. (2014). Expression of DNA repair proteins in endometrial cancer predicts 
disease outcome. Gynecol Oncol, 132(3), 593-598. doi:10.1016/j.ygyno.2014.02.002 
 
Miller, D., Filiaci, V., Fleming, G., Mannel, R., Cohn, D., Matsumoto, T., . . . Zaino, R. 
(2012). Late-Breaking Abstract 1: Randomized phase III noninferiority trial of first line 
chemotherapy for metastatic or recurrent endometrial carcinoma: A Gynecologic 
Oncology Group study. Gynecologic Oncology, 125(3), 771. 
doi:http://dx.doi.org/10.1016/j.ygyno.2012.03.034 
 
Miyasaka, A., Oda, K., Ikeda, Y., Wada-Hiraike, O., Kashiyama, T., Enomoto, A., . . . 
Fujii, T. (2014). Anti-tumor activity of olaparib, a poly (ADP-ribose) polymerase (PARP) 
inhibitor, in cultured endometrial carcinoma cells. BMC Cancer, 14, 179. 
doi:10.1186/1471-2407-14-179 
 
Motz, G.T., et al., Tumor endothelium FasL establishes a selective immune barrier 
promoting tolerance in tumors. Nat Med, 2014. 20(6): p. 607-15. 
 
Nadkarni NJ, Geest KD, Neff T, Young BD, Bender DP, Ahmed A, et al: Microvessel 
density and p53 mutations in advanced-stage epithelial ovarian cancer. Cancer Lett 2013; 
331:99-104. 
 
O'Reilly, K.E., et al., mTOR inhibition induces upstream receptor tyrosine kinase 
signaling and activates Akt. Cancer Res, 2006. 66(3): p. 1500-8. 
 
Parker, L. L., & Piwnica-Worms, H. (1992). Inactivation of the p34cdc2-cyclin B 
complex by the human WEE1 tyrosine kinase. Science, 257(5078), 1955-1957.  
 
Rahib, L., Smith, B. D., Aizenberg, R., Rosenzweig, A. B., Fleshman, J. M., & Matrisian, 
L. M. (2014). Projecting cancer incidence and deaths to 2030: the unexpected burden of 
thyroid, liver, and pancreas cancers in the United States. Cancer Res, 74(11), 2913-2921. 
doi:10.1158/0008-5472.CAN-14-0155 
 
Raman, D., et al., Role of chemokines in tumor growth. Cancer Lett, 2007. 256(2): p. 137-
65. 
 
Shen, J., Peng, Y., Wei, L., Zhang, W., Yang, L., Lan, L., . . . Peng, G. (2015). ARID1A 
Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP 
Inhibitors. Cancer Discov, 5(7), 752-767. doi:10.1158/2159-8290.CD-14-0849 

NRG-GY012 
136              NCI Version Date: May 23, 2024 
 
 
Shen, J., et al., PARPi Triggers the STING-Dependent Immune Response and Enhances 
the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness. 
Cancer Res, 2019. 79(2): p. 311-319. 
 
Shu, C. A., Pike, M. C., Jotwani, A. R., Friebel, T. M., Soslow, R. A., Levine, D. A., . . . 
Kauff, N. D. (2016). Uterine Cancer After Risk-Reducing Salpingo-oophorectomy 
Without Hysterectomy in Women With BRCA Mutations. JAMA Oncol, 2(11), 1434-
1440. doi:10.1001/jamaoncol.2016.1820 
 
Siegel, R. L., Miller, K. D., & Jemal, A. (2016). Cancer statistics, 2016. CA Cancer J 
Clin, 66(1), 7-30. doi:10.3322/caac.21332 
 
Sorensen, C. S., & Syljuasen, R. G. (2012). Safeguarding genome integrity: the 
checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA 
replication. Nucleic Acids Res, 40(2), 477-486. doi:10.1093/nar/gkr697 
 
Squire, C. J., Dickson, J. M., Ivanovic, I., & Baker, E. N. (2005). Structure and inhibition 
of the human cell cycle checkpoint kinase, Wee1A kinase: an atypical tyrosine kinase 
with a key role in CDK1 regulation. Structure, 13(4), 541-550. 
doi:10.1016/j.str.2004.12.017 
 
Stelloo, E., Bosse, T., Nout, R. A., MacKay, H. J., Church, D. N., Nijman, H. W., 
Creutzberg, C. L. (2015). Refining prognosis and identifying targetable pathways for 
high-risk endometrial cancer; a TransPORTEC initiative. Mod Pathol, 28(6), 836-844. 
doi:10.1038/modpathol.2015.43 
 
Stover, E. H., Konstantinopoulos, P. A., Matulonis, U. A., & Swisher, E. M. (2016). 
Biomarkers of Response and Resistance to DNA Repair Targeted Therapies. Clin Cancer 
Res, 22(23), 5651-5660. doi:10.1158/1078-0432.CCR-16-0247 
 
Tartour, E., et al., Angiogenesis and immunity: a bidirectional link potentially relevant 
for the monitoring of antiangiogenic therapy and the development of novel therapeutic 
combination with immunotherapy. Cancer Metastasis Rev, 2011. 30(1): p. 83-95. 
 
Tentori, L., Lacal, P. M., Muzi, A., Dorio, A. S., Leonetti, C., Scarsella, M., . . . Graziani, 
G. (2007). Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion 
reduces angiogenesis. Eur J Cancer, 43(14), 2124-2133. doi:10.1016/j.ejca.2007.07.010 
 
Turner, N.C., et al., BEECH: A dose-finding run-in followed by a randomised phase 2 
study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with 
paclitaxel in patients with oestrogen receptor-positive advanced or metastatic breast 
cancer, and in a PIK3CA mutant sub-population. Ann Oncol, 2019. 
 
Voron, T., et al., VEGF-A modulates expression of inhibitory checkpoints on CD8+ T 
cells in tumors. J Exp Med, 2015. 212(2): p. 139-48. 

NRG-GY012 
137              NCI Version Date: May 23, 2024 
 
 
Wada, J., et al., The contribution of vascular endothelial growth factor to the induction of 
regulatory T-cells in malignant effusions. Anticancer Res, 2009. 29(3): p. 881-8. 
 
Wang, Y., Decker, S. J., & Sebolt-Leopold, J. (2004). Knockdown of Chk1, Wee1 and 
Myt1 by RNA interference abrogates G2 checkpoint and induces apoptosis. Cancer Biol 
Ther, 3(3), 305-313.  
 
Wang, Y., Li, J., Booher, R. N., Kraker, A., Lawrence, T., Leopold, W. R., & Sun, Y. 
(2001). Radiosensitization of p53 mutant cells by PD0166285, a novel G(2) checkpoint 
abrogator. Cancer Res, 61(22), 8211-8217.  
 
Watanabe, N., Broome, M., & Hunter, T. (1995). Regulation of the human WEE1Hu 
CDK tyrosine 15-kinase during the cell cycle. EMBO J, 14(9), 1878-1891.  
 
Werner, H. M., Berg, A., Wik, E., Birkeland, E., Krakstad, C., Kusonmano, K., . . . 
Salvesen, H. B. (2013). ARID1A loss is prevalent in endometrial hyperplasia with atypia 
and low-grade endometrioid carcinomas. Mod Pathol, 26(3), 428-434. 
doi:10.1038/modpathol.2012.174 
 
Westin, S., et al., 391P - Phase I Expansion of olaparib (PARP inhibitor) and AZD5363 
(AKT inhibitor) in recurrent ovarian, endometrial and triple negative breast cancer. 
Annals of Oncology 2017. 28(suppl_5): p. v122-v141. 
 
Wiegand, K. C., Lee, A. F., Al-Agha, O. M., Chow, C., Kalloger, S. E., Scott, D. W., . . . 
Huntsman, D. G. (2011). Loss of BAF250a (ARID1A) is frequent in high-grade 
endometrial carcinomas. J Pathol, 224(3), 328-333. doi:10.1002/path.2911 
 
Williams, G. J., Lees-Miller, S. P., & Tainer, J. A. (2010). Mre11-Rad50-Nbs1 
conformations and the control of sensing, signaling, and effector responses at DNA 
double-strand breaks. DNA Repair (Amst), 9(12), 1299-1306. 
doi:10.1016/j.dnarep.2010.10.001 
 
Wu, R., et al., Preclinical testing of PI3K/AKT/mTOR signaling inhibitors in a mouse 
model of ovarian endometrioid adenocarcinoma. Clin Cancer Res, 2011. 17(23): p. 7359-
72. 
 
Yasuda, S., et al., Simultaneous blockade of programmed death 1 and vascular 
endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in 
vivo. Clin Exp Immunol, 2013. 172(3): p. 500-6. 
 
Yemelyanova A, Vang R, Kshirsagar M, Lu D, Marks MA, Shih Ie M, Kurman RJ. 
Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 
mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing 
analysis. Mod Pathol. 2011;24(9):1248-53. PubMed PMID: 21552211. 
 

NRG-GY012 
138              NCI Version Date: May 23, 2024 
 
APPENDIX I: TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES  
 
I. Obtaining a Bank ID for Translational Science Specimens  
Only one Bank ID (# # # # - # # - G # # #) is assigned per patient. All translational science 
specimens and accompanying paperwork must be labeled with this coded patient number. 
 
A Bank ID is automatically assigned once the Specimen Consent is completed and indicates that 
a patient has agreed to participate in the translational science component. If a patient has 
previously been assigned a Bank ID, please ensure the Bank ID appearing in Rave is the same as 
the previously assigned Bank ID. 
 
Please contact User Support if you need assistance or have assigned more than one Bank ID to a 
patient (Email: support@nrgoncology.org; Phone: 716-845-7767).  
 
II. Requesting Translational Science Biospecimen Kits 
Two single chamber kits will be provided per patient for the collection and shipment of frozen 
plasma and frozen whole blood. 
 
Sites can order kits online via the Kit Management system(https://kits.bpc-apps.nchri.org/). Each 
site may order two kit types per protocol per day (daily max = 6 kits). (27-AUG-21) 
 
 
Please contact the NRG BB-Columbus if you need assistance (Email: 
BPCBank@nationwidechildrens.org; Phone: 866-464-2262). 
 
Be sure to plan ahead and allow time for kits to be shipped by ground transportation. Kits should 
arrive within 3-5 business days. 
 
Note: Unused supplied and kits should be returned to the NRG BB-Columbus. A pre-paid 
shipping label for the return of unused supplies and kits may be obtained via the Kit 
Management system. Select “Empty Kit” for package contents when returning unused kits. 
  
III. FFPE Shipped to the NRG BB-Columbus 
***A copy of the corresponding pathology report must be shipped with all tissue specimens 
sent to the NRG BB-Columbus. 
 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the 
specimen type (e.g., primary, metastatic, recurrent, persistent). 
 
• Archival primary (FP01) and metastatic (FM01) tumor must be collected prior to the 
patient receiving any treatment. 
 
• Archival recurrent and persistent tumor must be collected prior to the patient receiving any 
study treatment. Recurrent or persistent tumor collected from the site of primary disease must 
be labeled recurrent primary (FRP01) or persistent primary (FPP01), respectively. 
Recurrent or persistent tumor collected from a site other than the site of primary disease (e.g., 

NRG-GY012 
139              NCI Version Date: May 23, 2024 
 
lymph node) must be labeled recurrent metastatic (FRM01) or persistent metastatic 
(FPM01), respectively.  
 
Only one block may be submitted per tissue type. 
 
Mandatory FFPE Biospecimen Requirement 
Every attempt should be made to provide a FFPE block; however, if a block cannot be provided 
on a permanent basis, then 25 unstained slides (15 charged 5µm and 10 uncharged, 10µm) 
should be submitted. All tissue sections must be cut sequentially from one block.  
 
Completing Form TR for FFPE Biospecimens 
The type of biospecimen (block, slides) must be specified on Form TR. If submitting slides, the 
slide type, thickness, and count must also be specified. 
 
Labeling FFPE 
A waterproof permanent marker or printed label must be used to label each translational science 
FFPE biospecimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG – GY012) 
specimen code (see section 10.4) 
collection date (mm/dd/yyyy) 
surgical pathology accession number 
block number 
 
Note: If labeling slides, only label on the top, front portion of the slide. Do not place a label on 
the back of the slide or over the tissue. The label must fit on the slide and should not be wrapped 
around the slide or hang over the edge. 
 
IV. Whole Blood Shipped to the NRG BB-Columbus 
1.  Label the lavender/purple top (EDTA) collection tube(s) as described below. Multiple tubes 
may be used to collect the required amount. Do not use glass blood collection tubes. 
2. Draw 7-10mL of blood into the labeled lavender/purple top tube(s). A minimum of 3mL is 
needed for processing. 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the blood and EDTA. 
4. Immediately freeze the whole blood in an upright position in a -70oC to -80oC freezer or 
by direct exposure with dry ice until ready to ship. If a -70oC to -80oC freezer is not available 
for storage, store and ship on dry ice within 24 hours of collection. 
 
Labeling Whole Blood 
A waterproof permanent marker or printed label must be used to label each translational science 
whole blood biospecimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG – GY012) 
specimen code (see section 10.4) 

NRG-GY012 
140              NCI Version Date: May 23, 2024 
 
collection date (mm/dd/yyyy) 
 
V. Plasma Shipped to the NRG BB-Columbus 
Note: The laboratory testing to be done is time sensitive. Plasma must be processed within 
one hour of collection. Special processing instructions are described below. 
1.  Label cryovials and a 15mL conical tube as described above. Use 2mL cryovials as plasma 
will be shipped to the NRG Oncology Biospecimen Bank-Columbus. 
2.  Draw 7-10mL of blood into lavender/purple top (EDTA) tube(s).  
3.  Immediately after collection, gently invert the blood collection tube 5-10 times to mix the 
blood and EDTA. 
4.  Centrifuge the blood at 1000g for 15 minutes at 4ºC (preferred) or room temperature to 
separate the plasma (top, straw-colored layer) from the red blood cells (bottom, red layer).  
5.  Using one of the pipettes, transfer the plasma into a pre-labeled 15mL conical tube and 
gently mix. 
6. Centrifuge the plasma again at 1000g for 15 minutes at 4ºC (preferred) or room 
temperature. 
7. Using the second pipette, evenly dispense (aliquot) the plasma into the pre-labeled cryovials 
and cap the tubes securely. Place a minimum of 0.25mL into each cryovial. Avoid any 
residual cells that pellet at the bottom of the conical tube. 
8.  Immediately freeze the plasma in an upright position in a -70oC to -80oC freezer or by 
direct exposure with dry ice until ready to ship. If a -70oC to -80oC freezer is not available for 
storage, store and ship on dry ice within 24 hours of collection. 
 
Labeling Plasma 
A waterproof permanent marker or printed label must be used to label each translational science 
plasma biospecimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG – GY012) 
specimen code (see section 10.4) 
collection date (mm/dd/yyyy) 
 
VI. Submitting Form TR 
A specimen transmittal form (i.e., Form TR) for each biospecimen will be available in the 
Translational Research Folder in Rave, once the Specimen Consent (located in the Baseline 
Folder) has been completed. 
 
An electronically (i.e., Rave) completed copy of Form TR must accompany each biospecimen 
shipped to the NRG BB-Columbus (or alternate laboratory). Handwritten forms will not be 
accepted. 
 
Note: A copy does not need to be sent to the NRG BB-Columbus (or alternate laboratory) if 
biospecimens are not collected. 
 
Form TR must be printed from the Translational Research Form screen in Rave using the “PDF 
File” link at the top of the form. Clicking this link will generate a single page PDF. Do not use 

NRG-GY012 
141              NCI Version Date: May 23, 2024 
 
the “Printable Version” or “View PDF” links at the bottom of the form or any other method to 
print the form, as these formats will not be accepted.  
 
Note: Biospecimens will not be marked as received in Rave without receipt of a corresponding 
electronically completed Form TR. Incomplete forms or those containing incorrect 
information will not be processed and may result in a data query. 
  
Retain a printout of the completed form for your records. 
  
Please contact User Support if you need assistance (Email: support@nrgoncology.org; Phone: 
716-845-7767). 
 
VII. Shipping Translational Science Biospecimens 
Translational science biospecimens must not be shipped until after patient registration and Bank 
ID assignment. 
 
An electronically completed copy of Form TR must be included for each translational science 
biospecimen. Handwritten forms will not be accepted. 
 
Note: Biospecimens will not be marked as received in Rave without receipt of a corresponding 
electronically completed Form TR. Incomplete forms or those containing incorrect information 
will not be processed. 
 
All translational science biospecimens should be shipped to: 
 
NRG BB-Columbus / Protocol NRG GY012 
Nationwide Children’s Hospital 
700 Children’s Dr., WA1340 
Columbus, OH 43205 
Phone: 614-722-2865 
FAX: 614-722-2897 
Email: BPCBank@nationwidechildrens.org 
 
A. FFPE Tissue Shipped to the NRG BB-Columbus 
FFPE tissue and a copy of the corresponding pathology report must be shipped using your own 
container at your own expense to the NRG BB-Columbus (address above).  
 
Do not ship FFPE tissue for Saturday delivery. 
 
B. Frozen Biospecimens Shipped to the NRG BB-Columbus 
Frozen plasma and whole blood should be shipped together to the NRG BB-Columbus (address 
above) using the biospecimen kit provided.  
 
Frozen biospecimens should be shipped Monday through Thursday for Tuesday through 
Friday delivery. Do not ship frozen biospecimens on Friday or the day before a holiday. Note: 
Saturday delivery is not available for frozen biospecimens.  

NRG-GY012 
142              NCI Version Date: May 23, 2024 
 
 
Frozen biospecimens should be stored in an ultra-cold freezing/storage space (i.e., ultra-cold ≤-
70oC freezer, liquid nitrogen, or direct exposure with dry ice) until the biospecimens can be 
shipped. 
 
Shipping Frozen Translational Science Biospecimens in a Single Chamber Kit  
 
1. Pre-fill the kit chamber about 1/3 full with dry ice. 
2. Place the frozen biospecimens from each time point in a separate zip-lock bag. 
3. Place the zip-lock bags in the biohazard envelope containing absorbent material. Do not put 
more than 25 cryovials in a single chamber kit. Put the secondary envelope into a Tyvek 
envelope. Expel as much air as possible before sealing both envelopes. 
4. Place the Tyvek envelope containing the frozen biospecimens into the kit and fill the chamber 
to the top with dry ice. 
5. Insert a copy of Form TR for each biospecimen.  
6. Place the cover on top of the kit. Tape the outer box of the kit closed with filament or other 
durable sealing tape. Please do not tape the inner chamber.  
7. Print a pre-paid FedEx air bill using the Kit Management link (: https://kits.bpc-
apps.nchri.org/). Attach the air bill. (27-AUG-21) 
8. Attach the dry ice label (UN1845) and the Exempt Human Specimen sticker. 
9. Arrange for FedEx pick-up through your site’s usual procedure or by calling 800-238-5355. 
 
VIII. 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. 
 
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. 

NRG-GY012 
143              NCI Version Date: May 23, 2024 
 
APPENDIX II: TRANSLATIONAL SCIENCE LABORATORY TESTING 
PROCEDURES (24-MAY-2021) 
 
I. BROCA-HR 
a. Overview 
The Swisher laboratory has previously published methodology and validation 
experiments for targeted capture and massively parallel sequencing of cancer genes (1-5). 
In brief, DNA will be extracted from peripheral blood mononuclear cells (PBMCs) and 
formalin-fixed, paraffin-embedded (FFPE) tumor containing at least 30% tumor nuclei. A 
targeted capture and massively parallel sequencing approach called BROCA will be 
applied to samples. 
 
For the proposed study, a more recent version of BROCA-HR will be utilized, which  has 
been developed to target 72 key genes leading to HRD as well as key targets for mutation 
in endometrial cancers that serve as a single assay to test for inherited risk and for 
germline and somatic mutations that influence response to therapy. This test includes an 
anlaysis of MSI and of total genomic LOH.  Library preparation has been fully automated 
to increase sample turnaround and lower cost. 
Table 1: BROCA-HR Genes 
ABCB1 
BRAF 
CHD4 
ERCC6 
MAD2L2 NF1 
POLE 
RAD51D 
SMARCA4 
ARID15B BRCA1 
CHEK1 
EZH2 
MLH1 
NRAS 
PPM1D 
RB1 
SPRTN 
ARID1A 
BRCA2 
CHEK2 
FAM111A MRE11 
PALB2 
PPP2R1A RIF1 
TP53 
ATM 
BRIP1 
CTCF 
FANCM 
MSH2 
PARP1 
PTEN 
RPL22 
TP53BP1 
ATR 
CCND1 
CTNNB1 FAT3 
MSH6 
PIK3CA 
RAD50 
SHLD1 
TSC1 
BAP1 
CCNE1 
ERBB2 
FBXW7 
MYC 
PIK3R1 
RAD51 
SHLD2 
TSC1 
BARD1 
CDK12 
ERCC2 
GABRA6 
MYCN 
PMS2 
RAD51B 
SHLD3 
WRN 
BLM 
CDKN2A ERCC4 
KRAS 
NBN 
POLD1 
RAD51C 
SLCA5A40 XRCC6 
 
Paired-end libraries with 350bp inserts will be prepared from 1ug of constitutional or 
neoplastic DNA and hybridized to a custom pool of oligonucleotides targeting genomic 
regions as previously described (2) using the SureSelectXT enrichment system on a 
Bravo liquid-handling instrument (Agilent). Following capture, samples will be barcoded 
with 48 different indexed primers. The pooled samples are sequenced on a single lane of 
a HiSeq flowcell (Illumina) with 2x101bp paired end reads and a 7bp index read to allow 
for de-multiplexing and binning of individual samples.  
 
Single nucleotide variants and insertions and deletions will be detected as previously 
described with some updates in the bioinformatics pipeline (2). Deletions and 
duplications of exons will be detected by a combination of depth of coverage and split 
read analysis as previously described (3), supplemented with additional alignments 
generated by SLOPE (6). All germline loss of function mutations in cancer susceptibility 
genes will be confirmed with PCR amplification and Sanger sequencing. Cases will be 
identified as HR proficient or deficient based on sequencing data of known Fanconi 
anemia (FA)-BRCA genes and then correlate HR proficiency with response to platinum 
or PARPi on the trial. Later, in exploratory analyses, the Swisher laboratory will add in 
analyses of NHEJ and other modifying genes, genomic scarring, or other somatic tests by 

NRG-GY012 
144              NCI Version Date: May 23, 2024 
 
their lab or others to complement the determination of HR deficiency. 
 
B. Laboratory Testing Procedures 
Assay and specimen parameters: If sample is fluid (blood, ascites, pleural, cyst or other fluid, 
samples will be initially stabilized with acid citrate dextrose, and both fixed (with 10% neutral 
buffered formalin) and frozen types of tumor specimens will be used for BROCA-HR testing. 
Minimum 3 micrograms of DNA from blood, or 2 tumor sections by 1 cm diameter and 10 
microns thickness will be required. An adjacent tissue section will be stained and examined by 
H&E to assess cellularity and tumor content; reference images of the H&E section will be kept 
and % cells that are tumor cells are reported as tumor content. Macrodissection will be used to 
enrich the sample for tumor cells.  
Design of Mutation Assay and Data Analysis: Swisher laboratory has fully automated library 
preparation to increase sample turnaround and lower cost. Agilent 2200 TapeStation will be used 
to assess DNA concentration. DNA purity will be assessed using Agilent 2200 TapeStation and 
DNA integrity will be evaluated using Agilent Bioanalyzer. Swisher laboratory will prepare 
paired-end libraries with ~200 bp inserts from 300 ng of constitutional DNA and hybridize to a 
custom pool of oligonucleotides for the genomic regions listed above (3) using the SureSelectXT 
enrichment system on a Bravo liquid-handling instrument (Agilent). Following capture, samples 
will be barcoded with 48 different indexed primers. The pooled samples will be sequenced on a 
single lane of a HiSeq flowcell (Illumina) in rapid mode with 2x101 base pair paired end reads 
and a 7 base pair index read. Sequencing reads will be processed from real-time base calls with 
RTA 1.17.20 (Bustard) and converted to qseq.txt files in house on a Dell PowerEdge R900 
server. Following demultiplexing, the reads will be aligned to the human reference genome 
(hg19) using BWA36. Duplicate reads and those not mapping within 2 standard deviations of the 
250bp insert size will be removed. Variants will be identified using GATK37 after indel 
realignment and base quality recalibration. Variants from low quality (≤50) and depth of 
coverage regions (<5 reads) are filtered out. Single nucleotide variants and insertions and 
deletions will be detected as previously described (3). Deletions and duplications of exons will 
be detected by a combination of depth of coverage and split read analysis as previously described 
(1), supplemented with additional alignments generated by split read algorithms (6). Missense 
mutations and in-frame deletions will only be classified as deleterious if a specific functional 
assessment has been carried out (i.e., BRCA1 C61G, RAD51C Q143R (7, 8)). Swisher 
laboratory will continue to update bioinformatics pipeline and integrate new alignment 
algorithms as they become available.  
 
Data Reports and Assay Accuracy: Assay results will be reported as “Positive for mutation”. 
Swisher laboratory has established assay accuracy by comparison to a reference method (Sanger 
Sequencing, MLPA) and using reference materials (e.g., specimens with a variety of known 
mutations). For true positive; Swisher laboratory has verified mutations with Sanger Sequencing 
in 500 cases. For true negative; there were no false positives in >2000 samples tested to date and 
verified with Sanger sequencing. False positives have only been verified when they decrease the 
read count and/or quality limits in order to increase sensitivity in tumor samples, in this case 
Swisher laboratory always verify the mutation with Sanger sequencing and they usually do, the 
total number of samples: 2000. Swisher laboratory has shown >99% of concordance for within-
run repeats and >99% of concordance for between-run repeats. With regard to limit of detection 
((lowest amount of analyte that gives an informative result), Swisher laboratory has 

NRG-GY012 
145              NCI Version Date: May 23, 2024 
 
demonstrated that the lowest 5% of mutant or variant allele could be reliably detected in a wild 
type background. 
C. References 
1. Nord AS, et al(2011) Accurate and exact CNV identification from targeted high-throughput 
sequence data. BMC Genomics 12:184. 
2. Walsh T, et al. (2011) Mutations in 12 genes for inherited ovarian, fallopian tube, and 
peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci. 
3. Walsh T, et al. (2010) Detection of inherited mutations for breast and ovarian cancer using 
genomic capture and massively parallel sequencing. Proc Natl Acad Sci 107:12629-12633. 
4. Pritchard CC, et al. (2012) ColoSeq Provides Comprehensive Lynch and Polyposis 
Syndrome Mutational Analysis Using Massively Parallel Sequencing. J Mol Diagn 14:357-
366. 
5. Pennington KP, et al. (2012) BRCA1, TP53, and CHEK2 germline mutations in uterine 
serous carcinoma. Cancer. 
6. Abel HJ, et al. (2010) SLOPE: a quick and accurate method for locating non-SNP structural 
variation from targeted next-generation sequence data. Bioinformatics 26:2684-2688. 
7. Osorio A, et al. (2012) Predominance of pathogenic missense variants in the RAD51C gene 
occurring in breast and ovarian cancer families. Hum Mol Genet 21:2889-2898. 
8. Bouwman P, et al. (2013) A high-throughput functional complementation assay for 
classification of BRCA1 missense variants. Cancer Discov. 
 
II. Plasma Angiome (Integrated Biomarker) 
A. Overview 
Plasma samples will be analyzed by multiplex ELISA assays for plasma-based 
biomarkers utilizing the Aushon Cirascan Imaging System. The Aushon Cirascan 
Imaging System is used specifically for the imaging and analysis of chemiluminescent 
protein arrays in a 96-well plate. The protein arrays are created by spotting up to 16 
different capture antibodies per well in each well of the 96-well plate. The advantage of 
this system is that multiple target proteins of interest can be analyzed at the same time 
reducing the amount of sample required for analysis. In brief, a small volume of sample 
and/or standard is added to each well of the 96-well plate resulting in the capture of the 
target proteins by the arrayed antibodies. Biotinylated antibodies are then added that 
specifically bind the captured target proteins. Streptavidin conjugated to HRP 
(horseradish peroxidase) is then added followed by a chemiluminescent substrate. 
Imaging of the plate is performed using Aushon Cirascan Imaging System. Protein 
concentrations in the samples are quantified by comparing the intensity of the spots in the 
unknown wells to standard curves. 
B. Laboratory Testing Procedures 
Dilution of Patient Samples: 
1) Add dilution buffer to staging plate followed by patient sample. 
2) Dilution strategies vary depending on target analyte. 
 
Reconstitution of Standards: 
1) Add proper volume of Sample Diluent to each standard vial; let stand for 1-2 minutes 
followed by gentle inversion. 
2) Ensure lyophilized standard on sides of tube and cap are added to solution. 

NRG-GY012 
146              NCI Version Date: May 23, 2024 
 
3) Allow standards to sit at room temperature while preparing standard serial dilutions. 
 
Serial Dilution of Standards: 
1) Perform serial dilutions for 7 standards and one blank as per Aushon instructions. 
2) Pipette 150-200ul of each standard to the pre-designated area on the staging plate. 
 
Loading Samples onto Ciraplex Plates: 
1) Once staging plates have been prepared; remove Ciraplex plates from package and 
label accordingly. 
2) Add 50ul of each patient sample and standard, in duplicate, onto Ciraplex Plate using 
a Rainin multi-channel manual pipetman without changing tips between replicates. 
3) Cover plates using adhesive plate sealer and incubate 2 hour at room temperature 
while shaking at setting 6 (Barnstead 4625). 
 
Washing plates: 
1) Washing plates is performed using the BioTek ELx405 plate washer. (See BioTek 
Plate Washer Instructions below) 
2) Use the Vacuboy Multi-Channel to remove all wash buffer followed by 20 second 
spin in Labnet MPS1000 plate spinner. 
 
Biotinylated Antibody Reagent Addition: 
1) Add the entire bottle of biotinylated antibody to a 50ml reagent reservoir.   
2) Pipette 50ul of biotinylated antibody reagent to each well using a Rainin multi-
channel manual pipetman. Do not change tips during the addition of this reagent. 
3) Cover plates using adhesive plate sealer and incubate 30 minutes at room temperature 
while shaking at setting 6 (Barnstead 4625). 
4) After 30 minutes, wash plates as described above. 
 
Streptavidin-HRP Reagent Addition: 
1) Add the entire bottle of streptavidin-HRP to a fresh 50ml reagent reservoir.   
2) Pipette 50ul of streptavidin-HRP reagent to each well using a Rainin multi-channel 
manual pipetman. Do not change tips during the addition of this reagent 
3) Cover plates using adhesive plate sealer and incubate 30 minutes at room temperature 
while shaking at setting 6 (Barnstead 4625). 
4) After 30 minutes, wash plates as described above. 
 
Signal Detection: 
1) Once plates have been washed and all wash buffer and bubbles have been removed; 
mix 4.0ml Super Signal and 4.0ml Peroxidase solutions in a 15ml conical tube and mix 
by inverting five times. 
2) Pipette 50ul of detection solution using a reagent reservoir and multi-channel 
pipetman. 
3) Protect from light and incubate 2 minutes at room temperature while shaking at 
setting 2 (Barnstead 4625). 
4) Read immediately on the Aushon Cirascan Instrument. 
 

NRG-GY012 
147              NCI Version Date: May 23, 2024 
 
C. References 
1. Liu Y, Starr MD, Bulusu A, Pang H, Wong NS, Honeycutt W, Amara A, Hurwitz HI, 
Nixon AB. (2013) Correlation of angiogenic biomarker signatures with clinical 
outcomes in metastatic colorectal cancer patients receiving Capecitabine, Oxaliplatin, 
and bevacizumab. Cancer Med. 2(2):234-242. 
2. Nixon AB, Pang H, Starr MD, Friedman PN, Bertagnolli MM, Kindler HL, Goldberg 
RM, Venook AP, Hurwitz HI. (2013) Prognostic and predictive blood-based 
biomarkers in patients with advanced pancreatic cancer: Results from CALGB 80303 
(Alliance). Clin Cancer Res. 19(24):6957-66. 
3. A.B. Nixon, S. Halabi I. Shterev, M.D. Starr, J.C Brady, J. Dutcher, J. Hopkins, H.I. 
Hurwitz, E. Small, B. Rini, P.G. Febbo, D. George (2013) Identification of predictive 
biomarkers of overall survival (OS) in patients (pts) with advanced renal cell 
carcinoma (RCC) treated with interferon alpha (I) +/- bevacizumab (B): Results from 
CALGB 90206 (Alliance) J Clin Oncol. 2013; 31: Suppl; abstr 4520. 
4. A.J. Hatch, H. Pang, M.D. Starr, J.C. Brady, J. Jia, D. Niedzwiecki, A.P. Venook, 
S.M. Cushman, H.I. Hurwitz, A.B. Nixon. (2014) Prognostic and predictive blood-
based biomarkers of overall survival (OS) in patients (pts) with advanced colorectal 
cancer (CRC) treated with cetuximab (C): Results from CALGB 80203 (Alliance).  J 
Clin Oncol 32:5s, 2014 (suppl; abstr 11022). 
5. Liu Y, Starr MD, Brady JC, Dellinger A, Pang H, Adams B, Theuer CP, Lee NY, 
Hurwitz HI, Nixon AB. (2014) Modulation of circulating protein biomarkers 
following TRC105 (anti-endoglin antibody) treatment in patients with advanced 
cancer. Cancer Med. Jun; 3(3): 580-91. 
.   

 
 
148 
 
 
APPENDIX III: 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 
Intermediate 
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 

149 
 
 
Selective 
 Blockers 
(BB) 
metoprolol 
25 mg 
twice 
daily 
50 mg 
twice daily 
100 mg 
twice daily 
CYP 2D6 
substrate 
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 
 and  
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 
Hydrochlor
othiazide 
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 
Nitrates 
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 
 
 
 

150 
 
 
APPENDIX IV: PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARDS  
(24-MAY-2021) 
 
CEDIRANIB 
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: 

151 
 
 
The study drug cediranib, may interact with other drugs which can cause side effects.  For this 
reason, it is very important to tell your doctors about all your medicines, including:  (a) 
medicines you are taking before this clinical trial, (b) medicines you start or stop taking during 
this study, (c) medicines you buy without a prescription (over-the-counter remedy), (d) herbals 
or supplements (e.g. St. John’s Wort).  It is helpful to bring your medication bottles or an 
updated medication list with you.  
 
Before you enroll onto the clinical trial, your study doctor will work with your regular health 
care providers to review any medicines and herbal supplements that are considered “strong 
inducers/inhibitors of 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.  
 
• 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. 
• Cediranib (AZD2171) may potentially reduce the effectiveness of hormonal 
contraceptives. Please check with your study provider about using contraception while on 
study treatment. 
• Patients receiving Cediranib (AZD2171) are at increased risk of bleeding. If you are 
receiving anticoagulation therapy, you will be monitored more frequently.  
• Make sure your doctor knows to avoid certain prescription medications.  
• 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 
 
 
(Next page: Patient Drug Interaction Wallet Card) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

154 
 
 
 
AZD5363 (CAPIVASERTIB) (24-MAY-2021) 
 
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): 
AZD5363 (capivasertib) 
 
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: 
AZD5363 (capivasertib) interacts with certain specific enzymes in your liver and certain 
transport proteins that help move drugs in and out of cells.  
 
 
Explanation 
CYP 
isoenzymes 
The enzymes in question are CYP3A4/5, 2B6, 2C19, 2C9, 2D6, and UGT1A 
and UGT2B7. AZD5363 (capivasertib) is broken down by CYP3A4/5, 
UGT1A9 and UGT2B7 and may be affected by other drugs that inhibit or 
induce these enzymes. AZD5363 (capivasertib) also inhibits CYP3A4/5, 2B6, 
2C19, 2C9, 2D6, UGT1A1 and UGT2B7, and may affect other drugs that use 
these enzymes to be broken down.   
 
Protein 
transporters 
The proteins in question are P-gp, BCRP, OATP1B1, OATP1B3, OCT2, 
MATE1 and MATE2K. AZD5363 (capivasertib) is moved in and out of 
cells/organs by P-gp and may be affected by other drugs that inhibit or induce 
this protein.  AZD5363 (capivasertib) inhibits BCRP, OATP1B1, OATP1B3, 
OCT2, MATE1 and MATE2K and may affect other drugs that are moved in and 
out of cells/organs by these transport proteins. 
  
These are the things that you need to know: 
The study drug AZD5363 (capivasertib), may interact with other drugs which can cause side 
effects. For this reason, it is very important to tell your doctors about all your medicines, 
including: (a) medicines you are taking before this clinical trial, (b) medicines you start or stop 
taking during this study, (c) medicines you buy without a prescription (over-the-counter remedy), 
(d) herbals or supplements (e.g. St. John’s Wort). It is helpful to bring your medication bottles or 
an updated medication list with you.  
 
Before you enroll onto the clinical trial, your study doctor will work with your regular health 

 
 
163 
 
 
APPENDIX VII: ACTIONS REQUIRED IN CASES OF INCREASE IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY’S LAW 
 
Introduction 
 
This Appendix describes the process to be followed in order to identify and appropriately report cases of 
Hy’s Law.  It is not intended to be a comprehensive guide to the management of elevated liver 
biochemistries. Specific guidance on the managing liver abnormalities can be found in Section 6.7 of the 
protocol. 
During the course of the study the Investigator will remain vigilant for increases in liver biochemistry.  
The investigator is responsible for determining whether a patient meets potential Hy’s Law (PHL) criteria 
at any point during the study. 
The Investigator participates, in review and assessment of cases meeting PHL criteria to agree whether 
Hy’s Law (HL) criteria are met.  HL criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the 
Investigational Medicinal Product (IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting Adverse 
Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review and assessment 
in line with standard safety reporting processes. 
 
Definitions 
 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of Normal 
(ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study following the start of 
study medication irrespective of an increase in Alkaline Phosphatase (ALP).  
 
Hy’s Law (HL) 
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the IMP, can be 
found to explain the combination of increases, e.g., elevated ALP indicating cholestasis, viral hepatitis, 
another drug.   
 
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the same day) 
the elevation in TBL, but there is no specified timeframe within which the elevations in transaminases 
and TBL must occur. 
 
Identification of Potential Hy’s Law Cases 
 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory data for 
any patient who meets any of the following identification criteria in isolation or in combination: 
• 
ALT ≥ 3xULN 
• 
AST ≥ 3xULN 
• 
TBL ≥ 2xULN