A Randomized Phase II/III Study of the Combination of Cediranib and Olaparib Compared to Cediranib or Olaparib Alone, or Standard of Care Chemotherapy in Women With Recurrent Platinum-Resistant or -Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (COCOS)
Phase: PHASE2
Conditions: Fallopian Tube Clear Cell Adenocarcinoma, Fallopian Tube Endometrioid Adenocarcinoma, Fallopian Tube Serous Adenocarcinoma, Fallopian Tube Transitional Cell Carcinoma, Fallopian Tube Undifferentiated Carcinoma, Ovarian Clear Cell Adenocarcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian Seromucinous Carcinoma, Ovarian Serous Adenocarcinoma, Ovarian Transitional Cell Carcinoma, Ovarian Undifferentiated Carcinoma, Primary Peritoneal Serous Adenocarcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma
Sponsor: National Cancer Institute (NCI)

 
i 
 
SUMMARY OF CHANGES 
 
For Protocol Amendment #15 to: NRG-GY005 
NCI Protocol #: NRG-GY005 
Local Protocol #: NRG-GY005 
NCI Version Date: 07/27/2023 
 
This amendment is being submitted in response to an RRA from Dr. S. Percy Ivy 
(ivyp@ctep.nci.nih.gov). 
 
# 
Section 
Comments 
1. 
Title Pages 
x NCI Version Date is now July 27, 2023.  
 
2. 
7.3.2 
Revised Olaparib CAEPR (Version 2.6, June 5, 2023) inserted into 
protocol 
 
Added New Risk:  
x 
Rare but Serious: Vascular disorders - Other (venous 
thromboembolism) 
 
3. 
ICD 
See informed consent for additional changes. 

 
- 1 - 
 
 
NRG-GY005 
 
(ClinicalTrials.gov NCT # 02502266) 
A Randomized Phase II/III study of the combination of Cediranib and Olaparib 
compared to Cediranib or Olaparib alone, or Standard of care chemotherapy in 
women with recurrent platinum-resistant or -refractory ovarian, fallopian tube, or 
primary peritoneal cancer (COCOS) 
 NCI Version Date: July 27, 2023 
 
 
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 
Study Chair 
Study Co-Chair 
Jung-Min Lee M.D. 
Angeles Alvarez Secord M.D., MHSc. 
Center for Cancer Research 
Duke University Medical Center  
National Cancer Institute 
Room 25172 Morris Bldg.  
10 Center Drive, Bldg 10, Rm 12N226 
DUMC Box 3079 
Bethesda, MD 20892 
Durham, NC 27710 
240-760-6128/ FAX: 240-541-4547 
919-684-3765/FAX: 919-684-8719 
leej6@mail.nih.gov  
Secor002@mc.duke.edu 
 
 
Translational Science Co-Chair 
Translational Scientist  
Michael Birrer, MD, PhD 
Heather A Lankes, PhD, MPH  
University of Alabama at Birmingham 
NRG Oncology 
1824 Sixth Avenue South 
Four Penn Ctr, 1600 JFK Blvd, Ste 1020 
WTI 202 
Philadelphia, PA 19103 
Birmingham, AL  35294 
LankesH@NRGOncology.org 
205-934-5077 
 
mbirrer@uab.org  
 
 
 
 
Participating Organizations  
 
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG 
CCTG / Canadian Cancer Trials Group 

- 2 - 
 
Correlative Scientists 
Statistician 
Elizabeth Swisher, MD 
Austin Miller, PhD 
University of Washington 
NRG SDMC-Buffalo Office 
 
Roswell Park Cancer Institute 
Andrew Nixon, PhD, MBA 
Elm and Carlton Streets 
Duke University 
Buffalo, NY 14263-0001 
 
716-845-5702/ FAX: 716-845-8393 
William Rodgers,PhD, MD (06-AUG-2021) 
millera@nrgoncology.org 
 New York Presbyterian 
 
 
 
Data Manager (06-AUG-2021) 
Research Nurse 
Sandra Dascomb 
Nicole Houston, RN 
NRG SDMC-Buffalo Office 
Center for Cancer Research 
Roswell Park Cancer Institute 
National Cancer Institute 
Elm and Carlton Streets 
10 Center Drive, Bldg 10, Rm 12N226 
Buffalo, NY 14263-0001  
240-760-6127/ FAX: 240-541-4547 
716-845-5702/FAX: 716-845-8393 
houstonnd@mail.nih.gov 
dascombs@nrgoncology.org  
 
 
Quality of Life Chair 
Protocol Administrator (22-SEP-2022) 
Lari Wenzel, PhD 
Kathryn Miller 
lwenzel@uci.edu 
NRG Oncology 
 
Four Penn Ctr, 1600 JFK Blvd, Ste 1020 
Comparative Effectiveness Research Chair 
Philadelphia, PA 19103 
Laura Havrilesky, MD 
215-854-0770/FAX: 215-854-0716 
havri001@mc.duke.edu 
 millerk@nrgoncology.org  
 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Cediranib 
CTEP 
747856 
 
DCTD, NCI 
Olaparib 
CTEP 
732208 
 
DCTD, NCI 
 
Participating Sites 
_ U.S. 
 Canada 
 Approved International Member Sites 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 15 
07/27/2023 
 
Amendment 14 
09/22/2022 
 
Amendment 13 
08/27/2021 
 
Amendment 12 
08/06/2021 
 
Amendment 11 
09/06/2019 
 
Amendment 10 
07/16/2019 
 

- 3 - 
 
Amendment 9 
05/24/2019 
 
Amendment 8 
01/15/2019 
 
Amendment 7 
10/12/2018 
 
Amendment 6 
08/14/2018 
 
Amendment 5 
07/13/2018 
 
Amendment 4 
10/02/2017 
 
Amendment 3 
03/28/2017 
04/24/2017 
Amendment 2 
01/03/2017 
01/17/2017 
Amendment 1 
09/29/2016 
12/05/2016 
Activation 
11/17/2015 
02/04/2016 
 
 
 
 
 
 
 
  
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. 

NCI Protocol #: NRG-GY005 
Version Date: July 27, 2023 
- 4 - 
 
NRG-GY005 
A Randomized Phase II/III study of the combination of Cediranib and Olaparib 
compared to Cediranib or Olaparib alone, or Standard of care chemotherapy in 
women with recurrent platinum-resistant or -refractory ovarian, fallopian tube, or 
primary peritoneal cancer (COCOS) 
NCI Version Date: July 27, 2023 
 
Lead Organization: NRG / NRG Oncology 
 
CONTACT INFORMATION  
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: 
CTSURegulatory@ctsu.coccg.o
rg (for submitting regulatory 
documents only) 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
at 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 located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS.   
For clinical questions (i.e. patient eligibility or treatment-related) Contact the Study PI of the Lead 
Protocol Organization 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
The CTSU Website is located at https://www.ctsu.org. 
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. 

NCI Protocol #: NRG-GY005 
Version Date: July 27, 2023 
- 5 - 
 
SCHEMA 
 
 
 
Phase II accrual was suspended on June 16, 2017.  At the interim analysis in July 2018, the Data 
Monitoring Committee voted to drop the single-agent olaparib arm.  The Phase III trial will be 
continued with 3 arms: standard chemotherapy, cediranib+olaparib, and cediranib alone.  Phase 
II patients treated on these three arms will be included in the Phase III trial.  References to the 
single-agent olaparib arm have been retained in the protocol for context. 
  
 

NCI Protocol #: NRG-GY005 
Version Date: July 27, 2023 
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TABLE OF CONTENTS 
SCHEMA 
- 5 - 
TABLE OF CONTENTS 
- 6 - 
1.0 
OBJECTIVES 
- 8 - 
1.1 
Primary Objective 
- 8 - 
1.2 
Secondary Objectives 
- 8 - 
1.3 
Objectives with Integrated Biomarkers 
- 8 - 
1.4 
Exploratory Objectives 
- 8 - 
1.5 
Primary Objective 
- 9 - 
1.6 
Secondary Objectives 
- 9 - 
1.7 
Objectives with Integrated Biomarkers 
- 9 - 
1.8 
Exploratory Objectives 
- 9 - 
2.0 
BACKGROUND 
- 10 - 
2.1 
Platinum-resistant/refractory ovarian cancer 
- 10 - 
2.2 
Activity of olaparib and cediranib as single agents and in combination with chemo - 10 - 
2.3 
Activity of the combination of olaparib and cediranib in recurrent ovarian cancer 
- 11 - 
2.4 
Translational Science Background 
- 15 - 
2.5 
Quality of Life 
- 21 - 
2.6 
Rationale for trial design 
- 24 - 
2.7 
Inclusion of Women and Minorities 
- 25 - 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
- 25 - 
3.1 
Eligibility Criteria 
- 25 - 
3.2 
Ineligibility Criteria 
- 27 - 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
- 31 - 
4.1 
PHASE II study (12/05/2016) 
- 31 - 
4.2 
PHASE III study (12/05/2016) 
- 35 - 
5. 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEURE 
- 39 - 
5.1 
Treatment plan 
- 39 - 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT 
- 43 - 
6.1 
Reference regimens (Arm I) 
- 43 - 
6.2 
Arms II (cediranib and olaparib), III (cediranib alone), and IV (olaparib alone) 
- 56 - 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS 
- 64 - 
7.1 
Protocol Agents (12/05/2016) 
- 64 - 
7.2 
Adverse Events and Serious Adverse Events 
- 65 - 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List 
- 65 - 
7.4 
Adverse Events for Commercial Study Agents 
- 72 - 
7.5 
Expedited Reporting of Adverse Events 
- 72 - 
8. 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES 
- 76 - 
8.1 
Investigator and Research Associate Registration with CTEP 
- 76 - 
9.0 
DRUG INFORMATION 
- 81 - 
9.1 
Topotecan (NSC #609699) 
- 81 - 
9.2 
Paclitaxel (NSC #673089) 
- 83 - 
9.3 
Pegylated Liposomal Doxorubicin (DOXIL®, NSC #712227 Lipodox™ 
- 83 - 
9.4 
Cediranib (AZD2171) 
- 85 - 
9.5 
Olaparib (AZD2281, NSC 747856, LynparzaTM) 
- 89 - 
9.6 
Blood Pressure Cuffs (12/05/2016) 
- 92 - 

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Version Date: July 27, 2023 
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10. 
PATHOLOGY 
- 93 - 
10.1 
Stained Pathology Slide Requirements for Central Review to Confirm Eligibility: 
- 93 - 
11. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
- 93 - 
11.1 
Reimbursement 
- 93 - 
11.2 
Translational Science 
- 93 - 
11.3 
Quality of Life/ Patient Reported Outcomes 
- 97 - 
12. 
DATA AND RECORDS 
- 99 - 
13. 
STATISTICAL CONSIDERATIONS 
- 104 - 
13.1 
Study Design 
- 104 - 
13.2 
Statistical design for each correlative study 
- 110 - 
13.3 
Projected Race and Ethnicity of Enrollees 
- 115 - 
14. 
EVALUATION CRITERIA 
- 116 - 
14.1 
Antitumor Effect – Solid Tumors 
- 116 - 
15. 
REFERENCES 
- 124 - 
APPENDIX I. COLLABORATIVE AGREEMENT 
- 130 - 
APPENDIX II. PERFORMANCE SCALE 
- 132 - 
APPENDIX III. PATIENT DRUG DIARY 
- 133 - 
APPENDIX IV:  PATIENT BLOOD PRESSURE DIARY 
- 138 - 
APPENDIX V: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD - 139 - 
APPENDIX VI: ORAL ANTIHYPERTENSIVE MEDICATIONS. 
- 144 - 
APPENDIX VII – TRANSLATIONAL SCIENCE SPECIMEN PROCEDURES 
- 146 - 
APPENDIX VIII – TS LABORATORY TESTING PROCEDURES 
- 154 - 
APPENDIX IX: PRO SUPPLEMENTAL QUESTIONS AND PLAN 
- 165 - 
APPENDIX X: PLAN FOR QOL COMPLIANCE 
- 171 - 
APPENDIX XI:  PROTOCOL MONITORING PLAN (12/05/2016) 
- 172 - 
APPENDIX XII:  NRG GENERAL GUIDELINES (12/05/2016) 
- 175 - 
APPENDIX XIII:  DIAGNOSTIC IMAGE COLLECTION SUMMARY (12/05/2016) 
- 176 - 
APPENDIX XIV – KGOG BIOSPECIMEN REQUIREMENTS 
- 178 - 
APPENDIX XV – KGOG GUIDELINES FOR PLATELET COUNT DECREASED 
- 185 - 
 

NCI Protocol #: NRG-GY005 
Version Date: July 27, 2023 
- 8 - 
 
1.0 
OBJECTIVES  
 
 
Phase II study: 
 
1.1 
Primary Objective  
 
 
1.1.1 To assess the efficacy and identify (in)active arm(s) of the combination of 
cediranib and olaparib, cediranib alone, olaparib alone, and physician's choice 
standard of care chemotherapy, as measured by progression free survival (PFS) in 
the setting of recurrent platinum-resistant or-refractory ovarian, primary 
peritoneal or fallopian tube cancer. 
 
1.2 
Secondary Objectives 
 
1.2.1 To assess the efficacy of the combination of cediranib and olaparib, cediranib 
alone, olaparib alone, and physician's choice standard of care chemotherapy, as 
measured by objective response rate (ORR: partial or complete response) by 
RECIST 1.1 criteria, in the setting of recurrent platinum-resistant or-refractory 
ovarian, primary peritoneal or fallopian tube cancer. 
 
1.2.2 To assess safety endpoints, as measured by frequency and severity of adverse 
events by Common Terminology Criteria for Adverse Events (CTCAE).  
 
1.3 
Objectives with Integrated Biomarkers  
 
1.3.1 To assess correlation of homologous recombination deficiency (HRD) status, as 
assessed via BROCA-HR assay with response, as measured by PFS and ORR.  
 
1.3.2  To evaluate the prognostic and predictive role of circulating endothelial cells 
(CEC) on comparative effectiveness of targeted therapies and reference 
chemotherapy. 
 
1.3.3 To evaluate quality of life data compliance, as measured by the 9-item Disease 
Related Symptoms (DRS-P) subscale of the NCCN-FACT Ovarian Symptom 
Index (NFOSI) for utilization and analysis in the Phase III study. Additional 
QOL/PRO items will be collected, as proposed in 1.8.2. 
 
1.4 
Exploratory Objectives 
 
 
1.4.1  To assess exploratory biomarkers of potential HRD, including genomic scarring, 
BRCA1 methylation, BRCA1 protein expression, and mutations in NHEJ, and 
other genes that might modify HRD. 
 
1.4.2  To evaluate the prognostic and predictive role of angiogenic biomarkers, as 
assessed by the Duke plasma angiome. 
 

NCI Protocol #: NRG-GY005 
Version Date: July 27, 2023 
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Phase III study: 
 
1.5 
Primary Objective  
 
 
1.5.1 To assess the efficacy of the combination of cediranib and olaparib, and cediranib 
monotherapy, as measured by overall survival (OS) and PFS, as compared to 
physician's choice standard of care chemotherapy in women with recurrent 
platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube 
cancer. 
 
1.6 
Secondary Objectives 
 
1.6.1 To assess the efficacy of the combination of cediranib and olaparib, and cediranib 
monotherapy, as measured by ORR as compared to physician’s choice standard of 
care chemotherapy in the setting of recurrent platinum-resistant or-refractory 
ovarian, primary peritoneal or fallopian tube cancer. 
 
1.6.2.   To assess safety endpoints, as measured by frequency and severity of adverse 
events by Common Terminology Criteria for Adverse Events (CTCAE). 
 
1.7 
Objectives with Integrated Biomarkers  
 
1.7.1 To assess correlation of HRD status, as assessed via BROCA-HR assay with 
response, as measured by OS, PFS and ORR.  
 
1.7.2    To evaluate the prognostic and predictive role of circulating endothelial cells 
(CEC) on comparative effectiveness of targeted therapies and reference 
chemotherapy. 
 
1.7.3 To assess the effect on disease-related symptoms (DRS) as measured by the 9-
item DRS-P subscale of the NCCN-FACT Ovarian Symptom Index-18 (NFOSI-
18), of single agent cediranib and cediranib/olaparib combination, compared to 
standard chemotherapy, in the setting of recurrent platinum-resistant or-refractory 
ovarian, primary peritoneal or fallopian tube cancer. 
 
1.8 
Exploratory Objectives 
 
1.8.1  To assess exploratory biomarkers of potential HRD, including genomic scarring, 
BRCA1 methylation, BRCA1 protein expression, and mutations in NHEJ, and 
other genes that might modify HRD. 
 
1.8.2    To evaluate the prognostic and predictive role of angiogenic biomarkers, as 
assessed by the Duke plasma angiome 
 
1.8.3 To assess the effect on secondary measures of quality of life, as assessed by the 
treatment side effects (TSE) and function/well-being (F/WB) subscales of the 
NFOSI-18, sensory neuropathy as measured by the FACT/GOG-Ntx-4, and health 

NCI Protocol #: NRG-GY005 
Version Date: July 27, 2023 
- 10 - 
 
utility as measured by the EQ-5D, of single agent cediranib and cediranib/olaparib 
combination, compared to standard chemotherapy, in the setting of recurrent 
platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube 
cancer. 
 
2.0 
BACKGROUND  
 
2.1 
Platinum-resistant/refractory ovarian cancer 
 
Most patients with epithelial ovarian cancer present with advanced disease at diagnosis 
(Cannistra et al., 2004; Parmar et al., 2003). The combination of a platinum drug with a taxane is 
the standard of care for the systemic first-line treatment after primary cytoreductive surgery (du 
Bois et al., 2003; McGuire et al., 1996). This combination results in response rate (RR)s of ~70% 
in patients with suboptimally-debulked disease, and of ~ 80% in optimally cytoreduced patients 
(Ozols et al., 2003; Ledermann et al., 2010). However, disease recurrence is common in this 
patient population and most patients with recurrent ovarian cancer eventually develop platinum 
resistant disease (defined as disease recurring within 6 months after the last receipt of platinum-
based chemotherapy) (Markman et al., 2000). RRs and duration of response to second-line 
chemotherapy for patients with recurrent platinum-resistant disease are significantly lower than 
those with platinum-sensitive disease. In women with platinum-resistant disease, RRs range from 
10%-25% and duration of response is typically less than 6 months to chemotherapeutic agents, 
such as pegylated liposomal doxorubicin (PLD), topotecan, taxanes, etoposide, and gemcitabine. 
In comparison, the RRs are usually >30% and/or duration of response >8 months in women with 
platinum-sensitive disease (Markman et al., 2000; Matsuo et al, 2010). Overall, relapse therapy is 
not curative and is administered with palliative intent only. Thus, there is an urgent need for the 
development of alternative therapies given the poor response of recurrent disease to traditional 
cytotoxic agents. Two potential therapeutic targets are DNA damage repair and angiogenesis 
pathways.  
 
2.2 
Activity of olaparib and cediranib as single agents and in combination with 
chemotherapies  
 
Olaparib (LynparzaTM) is a FDA-approved oral PARP-inhibitor for the treatment of advanced 
ovarian cancer with germline BRCA mutation (gBRCAm). Olaparib has demonstrated activity 
both in women with gBRCAm-related and BRCA-wild type (BRCAwt) ovarian cancer, with 
reported RRs of ~40% in gBRCAm carriers and 24% in non-gBRCAm carriers (Ledermann et 
al., 2014; Lee et al., 2014). A phase II study comparing olaparib capsules monotherapy to PLD 
therapy in women with gBRCAm-related ovarian cancer, recurrent <12 months after last receipt 
of platinum-therapy, found no advantage to olaparib therapy in this setting, due to newly 
identified increased susceptibility of mutation carriers to PLD (Kaye et al., 2012). Data also 
suggest that olaparib capsules monotherapy response is associated with platinum-sensitivity; 
lower RRs were noted in platinum-resistant disease (Fong et al., 2010; Gelmon et al., 2011). 
Additionally, a phase I study of olaparib in capsule formulation and carboplatin in gBRCAm-
associated recurrent ovarian cancer (NCT01445418) yielded a RR of 25% (5 of 20) with a 
median PFS of 13 months (6-40+ months), in platinum-resistant and platinum-refractory patients 

NCI Protocol #: NRG-GY005 
Version Date: July 27, 2023 
- 11 - 
 
(Lee et al., 2014). These findings support the hypothesis that tumors with DNA repair defects 
may be sensitive to PARP inhibitor-based therapy even after acquiring platinum resistance.    
 
Cediranib is a small-molecule kinase inhibitor of VEGFR-1, -2, -3, with demonstrated activity in 
both platinum-sensitive and platinum-resistant ovarian cancers (Matulonis et al., 2009). A phase 
II study of cediranib (30 mg daily) for recurrent ovarian or peritoneal or fallopian tube cancer 
demonstrated a clinical benefit rate (CBR, defined as CR, PR, SD > 16 weeks, or CA-125 non-
progression > 16 weeks), of 30% (further detailed in Section 3.3). Overall, eight patients (17%) 
had a PR, and six patients (13%) had SD (Matulonis et al., 2009). The ICON6 study 
demonstrated that the combination of cediranib together with platinum-based chemotherapy and 
followed by cediranib maintenance, could extend PFS and OS, in women with platinum-sensitive 
ovarian cancer (Ledermann et al., 2013; Fig 1).  
A   
  B   
  
Figure 1. Kaplan-Meier survival curve: cediranib plus platinum-based chemotherapy followed 
by maintenance cediranib provides a statistically significant benefit in PFS (A) and OS (B), 
compared to chemotherapy alone in recurrent ovarian cancer.  
 
2.3 
Activity of the combination of olaparib and cediranib in recurrent ovarian cancer 
 
Kim and colleagues in unpublished studies found that the combination of cediranib and olaparib 
inhibited invasion of ovarian cancer cells (Fig 2A). Invasion was significantly decreased in 
pretreated ovarian cancer cell lines, CAOV3 and OVCAR8, exposed to concentrations attainable 
in patients, 50 nM cediranib or 10 uM olaparib, or a combination of both drugs (p<0.0001 for all 
treatments). Additional data showed that the combination of cediranib and olaparib inhibited in 
vitro endothelial vascular tube formation on Matrigel at concentrations well below those 
clinically attainable in patients (Fig 2B). Tube length was significantly reduced when endothelial 
cells were exposed to 5 nM cediranib or 100 nM olaparib (p<0.003 and p<0.001, respectively). 
The combination of olaparib and cediranib resulted in greater inhibition of tube formation than 
monotherapy (p<0.0001). These preclinical findings provide further rationale for clinical 
investigation of this new combination strategy for recurrent ovarian cancer.   
0.00
0.25
0.50
0.75
1.00
164
148
65
21
7
 
118
90
24
8
3
 
.
0
3
6
9
12
15
18
21
24
Months
Chemo. 
Maint. 
Chemotherapy 
Maintenance 
Restricted mean survival time increases by 
3.1 months with maintenance treatment 
Chemo. 
Maint. 
PFS events, n (%) 
112 (94.9) 
139 (84.8) 
Median, months 
8.7 
11.1 
Log-rank test 
p=0.00001 
HR (95% CI) 
0.57 (0.45 – 0.74) 
Test for non-proportionality p=0.024 
Restricted means, mo 
9.4 
12.5 
Progression-free survival – arms A vs. C 
0.00
0.25
0.50
0.75
1.00
164
159
139
89
48
22
22
 
118
106
89
46
27
11
11
 
.
0
6
12
18
24
30
Months
Chemo. 
Maint. 
OS events, n (%) 
63 (53.3) 
75 (45.7) 
Median, months 
20.3 
26.3 
Log-rank test 
p=0.042 
HR (95% CI) 
0.70 (0.51 – 0.99) 
Test for non-proportionality p=0.0042 
Restricted means, mo 
17.6 
20.3 
Restricted mean survival time increases 
by 2.7 months with maintenance 
treatment (over two years) 
Overall survival 
Chemo. 
Maint. 
Chemotherapy 
Maintenance 

NCI Protocol #: NRG-GY005 
Version Date: July 27, 2023 
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A. 
  B 
 
Figure 2. Cediranib and olaparib, with clinically relevant selected doses, combine effectively to 
(A) reduce invasion and (B) reduce microvascular cell tube organization as compared to either 
agent alone.  
 
There was unexpected response signal in platinum-resistant ovarian cancer from the phase I 
study of the combination of cediranib and olaparib in capsule formulation (Liu et al., 2013). 
There were a total of 6 platinum-resistant patients treated across all of the dose levels. The ORR 
was 50%, with a CBR of 67%. The median PFS was 7.5 months, with a range of 3.3 to 20.4 
months. In the 6 patients, there were 3 gBRCAm carriers (confirmed PR [1], unconfirmed PR [1] 
and SD x 8months [1]) and 3 non-gBRCAm carriers/unknowns (confirmed PRs [2] and 1 SD (<6 
months, by CA125 only [1]).  
 
A multi-institutional phase II trial comparing the activity of the cediranib/olaparib capsules 
combination to olaparib capsules alone in recurrent platinum-sensitive ovarian cancer completed 
planned accrual of 90 patients in May 2013 and findings from this study were reported in 2014 
(NCT01116648, Liu et al. 2014). Eligibility criteria for this trial included platinum-sensitive 
disease recurrence, with platinum-sensitivity defined as recurrence occurring greater than or 
equal to 6 months after the last platinum-containing regimen. Patients were allowed to receive an 
unlimited number of platinum-based lines of therapy, and up to one non-platinum-based regimen 
in the recurrent setting. No anti-angiogenics in the recurrent setting were allowed; no prior 
PARP-inhibitors were allowed.   
The combination of cediranib and olaparib capsules significantly extended both PFS and ORR 
compared to olaparib capsules alone, with a median PFS of 9.0 months for olaparib alone and 
17.7 months for cediranib/olaparib (HR 0.42, 95% CI 0.23-0.76, p = 0.005; Fig 3). 
 
 
 
        Cediranib 
        Olaparib 
  -      -          50  1            -     -          50    1 
  -      -           -     -          10  0.05      10  0.05 
Cediranib
Olaparib
Figure 3. Kaplan-Meier PFS curves 
in patients treated on olaparib and 
cediranib/olaparib in Phase 2 trial  

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There were 2 complete responses (CR) and 20 partial responses (PR) in patients on olaparib 
capsules alone (48% ORR) and 5 CRs and 30 PRs in patients on cediranib/olaparib capsules 
(80% ORR, p = 0.002).  47 of the 90 patients enrolled to the phase II cediranib/olaparib vs. 
olaparib trial were known gBRCAm carriers (25 olaparib; 23 cediranib/olaparib). A post-hoc 
subset analysis of PFS by BRCA mutation status (carrier vs. non-carrier/unknown) is shown in 
Fig 4.  In gBRCAm carriers, the median PFS was 16.7 months on the olaparib alone arm and 
20.2 months on the cediranib/olaparib arm (HR 0.541, 95% CI 0.230-1.26, p = 0.16). In 
gBRCAm non-carrier/unknown patients, there was a marked increase in PFS from 5.8 months 
with olaparib alone to 16.6 months with combination therapy in patients with BRCAwt or 
unknown BRCA status (HR 0.323, 95% CI 0.139-0.746, p = 0.008). The majority of patients on 
both arms had one or two previous lines of treatment (76% of patients on olaparib alone vs. 82% 
of patients on cediranib/olaparib arm, however, it is possible that the difference in the ORR and 
PFS in gBRCAm patients and BRCA non-carrier/unknown patients may be in part due to the 
degree of prior therapy.
Figure 4. Kaplan-Meier PFS curves in gBRCAm carrier and BRCA non-carrier/unknown 
patients.
Overall, the combination of cediranib and olaparib demonstrated significantly extended PFS over 
olaparib alone in women with recurrent, platinum-sensitive ovarian cancer, as measured both by 
PFS and ORR. The clinical benefit was greater in women with BRCAwt or unknown BRCA 
status. The platinum-resistant and refractory population is enriched in BRCAwt, non-HRD 
cancers. Toxicities were consistent with expected class-related toxicities of these drugs. 
Differentially occurring grade 3 or 4 toxicities attributed to study treatment included fatigue 
(27% cediranib/olaparib vs. 11% olaparib), diarrhea (23% vs. 0%), and hypertension (41% vs. 
0%). Two grade 4 events in the cediranib+olaparib arm: 1 grade 4 hypertension in a patient who 
was not fully compliant with blood pressure monitoring and 1 grade 4 myelodysplastic syndrome 
(MDS). The patient with MDS had had two prior lines of therapy, and had been on combination 
cediranib/olaparib for ~1 year when she was diagnosed with MDS. Otherwise, AEs were 
manageable with a combination of symptom management and dose holds and/or reductions, and 
removal from the study for reasons other than a PFS event was balanced between the arms (2 
withdrawal of consent, 1 MD decision, 5 clinical progressions on cediranib/olaparib vs. 3 
withdrawal of consent, 1 MD decision, 6 clinical progressions on olaparib alone). 
gBRCAm carrier
BRCAnon-carrier/unknown 

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Tables 1 and 2 summarize the clinical data of cediranib/olaparib combination compared to 
olaparib or cediranib alone in recurrent ovarian cancers. Olaparib capsules monotherapy 
response is associated with platinum-sensitivity (Fong et al., 2010); RR of 22% with a clinical 
benefit rate (CBR, defined as CR, PR and SD> 16 weeks) of 52%, and RR of 46% (CBR 69%) 
were noted in platinum-resistant/refractory, and -sensitive recurrent gBRCAm-associated ovarian 
cancers, respectively. Gelmon et al. also reported the ORR of 50% (10 of 20) in platinum-
sensitive ovarian cancer in the gBRCAm negative cohort, and 60% (3 of 5) in the gBRCAm 
positive cohort (Gelmon et al., 2011). Lower RRs were noted in platinum-resistant ovarian 
cancer patients; RR of 33% (4 of 12) in the mutation-positive cohort, and in only 4% (1 of 26) of 
those in the mutation-negative cohort, respectively (Gelmon et al., 2011). Additionally, Lee and 
colleagues reported a phase I study of olaparib in capsule formulation and carboplatin in 
gBRCAm-associated recurrent ovarian cancer; which yielded a RR of 71% (10 of 14) with a 
median PFS of 16 months (4-45+ months), and 25% (5 of 20) with a median PFS of 13 months 
(6-40+ months), in platinum-sensitive gBRCAm- and platinum-resistant/refractory gBRCAm-
associated recurrent ovarian cancer patients, respectively (Lee et al., 2014). These findings 
support the olaparib monotherapy may have activity in tumors with DNA repair defects even 
after acquiring platinum resistance.    
 
Table 1. Comparison of cediranib/olaparib to results of single-agent olaparib in recurrent 
ovarian cancer trials  
 
All patients on the phase II study of cediranib had between 0 and 2 lines of prior therapy in the 
recurrent setting (Matulonis et al., 2009). Majority of women (27 of 30) with platinum-resistant 
disease, received either 0 or 1 line of prior therapy at recurrence. Overall, eight patients (17%; 
95% CI, 7.6% to 30.8%) had a PR, and six patients (13%; 95% CI, 4.8% to 25.7%) had SD. The 
median PFS was 5.2 months. Grade 3 toxicities (> 20% of patients) included hypertension 
(46%), fatigue (24%), and diarrhea (13%). Grade 4 toxicities included CNS hemorrhage, 
hypertriglyceridemia/hypercholesterolemia/elevated lipase, and dehydration/elevated creatinine 
Trial 
   N 
PFS 
ORR (RECIST) % 
Ced/Olap RP2 (platinum-sensitive) (Liu, Lancet Onc 2014) 
Olap capsules 400mg BID 
Ced 30mg QD/olap capsules 200mg BID 
 
46 
44 
 
9.0 
17.7 
 
56.1 
83.7 
Study 12 (Olap vs. PLD) RP2, PFI<12mo (Kaye, JCO 2012)  
Olap capsules 200mg BID 
Olap capsules 400mg BID 
PLD 50mg/m2  
 
32 
32 
33 
 
6.5 
8.8 
7.1 
 
25 
31 
18 
Olap capsules single-arm Ph2 (Gelmon, Lancet Onc 2011) 
All ovarian (N = 63; 17 gBRCAm /46 BRCAwt) 
Platinum-sensitive 
Platinum-resistant 
 
63 
25 
38 
 
7.3 
N/A 
N/A 
 
29 
52 
13 

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(n = 1 for each). A phase I trial was previously conducted to establish the recommended phase II 
dosing of the cediranib/olaparib capsules combination, which enrolled a total of 28 patients (20 
ovarian, 8 breast). RR of 44% to the cediranib/olaparib capsules combination was observed in 
this phase I population, which included both gBRCAm carrier and non-carrier patients (Liu et 
al., 2013).  
 
Table 2. Comparison of cediranib/olaparib to results of single-agent cediranib in recurrent 
ovarian cancer trials  
Trial 
  N 
PFS 
ORR (RECIST) % 
Ced/Olap RP2 (platinum-sensitive) (Liu, Lancet Onc 2014) 
Olap capsules 400mg BID 
Ced 30mg QD/olap capsules 200mg BID 
 
46 
44 
 
9.0 
17.7 
 
56.1 
83.7 
Ced single-arm Ph2 (Matulonis, JCO 2009) 
Overall 
Platinum-sensitive 
Platinum-resistant 
 
47  
16 
30 
 
5.2 
5.2 
5.2 
 
17 
12.5 (6 pts off early for tox) 
17 (5 pts off early for tox) 
Ced single-arm Ph2 (Hirte – abstract ASCO 2008) 
Overall 
Platinum-sensitive 
Platinum-resistant 
 
60 
26 
34 
 
4.1  
(no sig 
diff 
between 
groups) 
 
 
3 PRs (of 17 pts) 
1 PR (of 24 pts) 
 
2.4 
Translational Science Background 
 
2.4.1 BROCA-HR and Genomic Scarring 
 
BRCA1 and BRCA2 (BRCA1/2) are tumor suppressor genes, in which inherited loss-of-function 
mutations confer a high lifetime risk of breast and ovarian carcinoma. BRCA1/2 are key 
components of the BRCA-Fanconi anemia (FA) pathway, which is critical to homologous 
recombination (HR)-mediated DNA repair. Other genes in this pathway (BRIP1/FANCJ, 
PALB2/FANCN, RAD51C/FANCO, RAD51D) also contribute to hereditary breast and ovarian 
cancer (Walsh et al., 2011; Pennington et al., 2012; Meindl et al. 2010; Rafnar et al., 2011; 
Loveday et al. 2011). The Cancer Genome Atlas Network (TCGA) recently suggested that up to 
half of serous ovarian carcinomas have HR defects (HRD), but that estimate was based on a 
variety of molecular findings, many with uncertain impact on DNA repair function (TCGA 
Network 2011). PARP inhibitors demonstrate synthetic lethality in cells with HRD, including 
cells deficient in BRCA1/2 (Bryant et al., 2005; Farmer et al., 2005). Recurrent ovarian 
carcinomas in BRCA1/2 mutation carriers have an approximate 40% response rate to PARP 
inhibitors and also have an increased response to platinum based chemotherapy (Kaye et al., 

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2012). Importantly, approximately 25% of serous ovarian cancers that are wildtype for BRCA1/2 
also respond to PARP inhibition (Gelmon et al. 2011). 
 
Germline BRCA1/2 mutations (gBRCAm) are the prototype molecular alterations that confer 
HRD (Bryant et al., 2005; Farmer et al., 2005). BRCA1 and BRCA2 somatic mutation (sBRCAm) 
occur in approximately 6% of cases (TCGA Network 2011; Pennington et al., 2013) and also 
appear to confer sensitivity to PARPi (Lederman et al, 2014). PARP inhibitors also selectively 
kill cells in vitro that are deficient in other homologous recombination (HR) genes including 
RAD51D, NBN, ATM, and CHEK2 (Loveday et al., 2011; McCabe et al., 2006). Germline and 
somatic mutations in BRCA1/2 and other BRCA-FA genes in ovarian carcinomas are associated 
with improved response to primary platinum therapy and longer overall survival (Pennington et 
al., 2013). Germline and somatic BRCA-FA mutations are not limited to high-grade serous 
ovarian carcinomas, but can be found in all histological sub-types with the exception of 
mucinous carcinomas (Pennington et al., 2013).  
 
In order to respond to a PARP inhibitor, cancer cells need to be deficient in HR but also 
proficient in the alternative error prone non-homologous end joining (NHEJ) DNA repair 
pathway (Patel et al., 2011; Adamo et al., 2010). Thus, loss of HR is not, by itself, sufficient for 
PARP inhibitor sensitivity, and an accurate predictor of PARP inhibitor responsiveness could 
require assessment of many components of both the HR and NHEJ pathways. A more efficient 
assay, which would not require a prior knowledge of the critical elements in these DNA repair 
pathways, would instead measure DNA repair capacity. Recent evidence suggests that BRCA1/2 
deficient cancers exhibit global DNA alterations termed “genomic scarring” that are consistent 
with their reliance on the NHEJ pathway (Nik-Zainal et al., 2012; Wang et al., 2012; Birkbak et 
al., 2012). This genomic scar could serve as a downstream functional output to measure DNA 
repair capacity, indicative of both HR deficiency and NHEJ proficiency. Therefore, mutations in 
NHEJ and other pathways that could affect HR as well as genomic scarring will also be 
evaluated as exploratory biomarkers.   
 
Relevance: The marked susceptibility of patients with gBRCAm-associated cancers has 
validated gBRCAm as a predictive biomarker for PARP inhibitor response (Fong et al., 2009). 
Other mechanisms of HRD may be a functional biomarker for response to DNA damaging 
agents and PARP inhibitors. Thus, it is important to identify which ovarian cancer patients have 
germline or somatic mutations in HRD genes and to examine their potential as predictive 
biomarkers. Additional exploratory biomarkers for HRD will include BRCA1 methylation, 
BRCA1 protein expression, and genomic scarring. We hypothesize that the BROCA test will 
identify subsets of ovarian cancer patients with HRD, and may yield biomarkers with potential to 
guide administration of this combination for the women we serve. 

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Preliminary Data: BROCA is a targeted capture and massively parallel sequencing assay that is 
capable of identifying all classes of mutations including gene rearrangements (Wickramanyake 
et al., 2012; Johnson et al., 2013). Using BROCA, Walsh et al demonstrated that nearly one-
fourth of women with ovarian carcinoma have germline loss of function mutations in at least 12 
genes (Walsh et al., 2011). Furthermore, most of these genes are in the BRCA-FA pathway. 
After BRCA1/2, the most common genes mutated in women with ovarian cancer are BRIP1 
(FANCJ), RAD51D, RAD51C (FANCO), and PALB2 (FANCN) (Walsh et al., 2011; 
Wickramanayake et al., 2012). Pennington et al applied BROCA to detect somatic mutations in 
tumor DNA from 363 women with ovarian carcinoma. Combining germline and somatic 
mutations increased the fraction of cases identified with HRD to 31%, including 23% with 
germline and 9% with somatic mutations in FA/HR genes (and 1% with both somatic and 
germline mutations) (Pennington et al., 2014). The presence of either a germline or somatic 
FA/HR mutation is highly predictive of an improved primary response to platinum chemotherapy 
(p<0.0005, Figure 5) and longer overall survival (p=0.001, Figure 6) (Pennington et al., 2014). 
Germline and somatic loss of function mutations were identified in all of the 13 FA/HR genes 
evaluated.
Dr. Swisher’s laboratory has designed a new version of 
BROCA (BROCA-HR) that includes many additional DNA repair genes (65 total genes) as well 
as 3000 single nucleotide polymorphisms (SNPs). Similar sequencing accuracy and sensitivity 
sequencing DNA is obtained from formalin fixed paraffin embedded (FFPE), fresh blood, and 
flash frozen specimens. BROCA-HR includes genes that are targets of both somatic and 
germline mutations. The BROCA-HR includes genes that regulate HR or NHEJ that, if mutated, 
could mediate resistance to PARP inhibition such as TP53BP1 (Bunting et al., 2010; Bouwman 
et al., 2010). The BROCA design is flexible and can be altered to include any genes of research 
interest. The current design for BROCA-HR includes the following genes:
BROCA-HR gene list (n=65)
a. BRCA-FA homologous recombination pathway: ATM, ATR, BABAM1, BAP1, BARD1, BLM, 
BRCA1, BRCA2 (FANCD1), BRCC3, BRE, BRIP1 (FANCJ), CDK12, CHEK1, CHEK2, ERCC1, 
ERCC4 (FANCQ), FAM175A (abraxas), FANCA, FANCB, FANCC, FANCD2,  FANCE, 
FANCF, FANCG (XRCCC9), FANCI, FANCL, FANCM, MRE11A, NBN, PALB2 (FANCO),
RAD51C (FANCO), RAD51D, RBBP8 (CtIP), SLX4 (FANCP), UIMC1 (RAP80), XRCC2, 
XRCC3, XRCC4;
b. DNA mismatch repair (Lynch syndrome) MLH1, MSH2 (and EPCAM), MSH6, PMS2;
c. Other DNA repair or surveillance genes: HELQ, NEIL1, PPM1D, POLD1, POLE, RIF1, 
TP53;
d. Other breast cancer genes or related pathways: GEN1, PTEN, PIK3CA, RINT1;
e. NHEJ pathway genes: DCLRE1C, LIG4, PARP1, PRKDC, TOPBP1, XRCC5, XRCC6;
Survival (months)
Percent survival
0
50
100
150
200
0
25
50
75
100
Germline HR mutation
Somatic HR mutation
No HR mutation
Figure 6
Figure 
5.

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f. Modifiers of homologous recombination:  CHD4, ID4, PAXIP1, TP53BP1, UPS28.
A common characteristic of genomic scarring is large (>15Mb) but sub-chromosomal deletions. 
Therefore, fine mapping of LOH is not necessary to identify the HRD genomic scar. A 3000 
SNP assay to define “genomic scarring” has been tested in existing TCGA data (Figure 7). 
Indeed, using only 3000 SNPs can define cases with high LOH which have better prognosis. 
Combining the BRCA mutation status and the LOH profile provides additional prognostic 
information. Therefore, we can assay 3000 SNPs in the same BROCA-HR assay at no additional 
cost which will provide an LOH profile to 
assess genomic scarring as an exploratory 
biomarker. 
2.4.2
BRCA1 Assays
BRCA1 promoter methylation: BRCA1
promoter methylation down regulates 
BRCA1 message and protein expression 
and occurs in 10-15% of ovarian 
carcinomas (Baldwin et al., 2000; Esteller et 
al., 2000). Unlike BRCA1 mutations, 
BRCA1 methylation does not correlate with 
platinum response to therapy or overall survival (Swisher et al., 2009). Therefore, the role of 
BRCA1 methylation in PARP inhibitor response is uncertain. In contrast, BRCA1 protein 
reduction occurs in 30-40% of ovarian carcinomas and is associated with better overall survival 
after platinum chemotherapy (Swisher et al., 2009; Thrall et al., 2006). The role of BRCA1 
promoter methylation and protein expression will be evaluated as exploratory biomarkers for 
response and correlation with treatment efficacy in this study. 
A variety of techniques for the study of DNA methylation have been developed. Dr. Levine’s 
laboratory utilizes a technique of pyrosequencing, which has the ability for the simultaneous 
analysis and quantification of the degree of methylation at several CpG positions in close 
proximity. The Pyrosequencing technology is based on the luminometric detection of 
pyrophosphate that is released on nucleotide incorporation and converted into a light signal by a 
cascade consisting of four enzymes. One of its major strengths is the quantitative nature of the 
results. The bioluminometric response is linear (R2 > 0.99) for the sequential addition of up to 
five identical nucleotides (C, G, and T) or three dATPs. In addition, it allows the interrogation of 
multiple consecutive CpG sites.
The assay utilized by Dr. Levine’s laboratory has been validated through the use of 15 samples 
previously tested through TCGA project. All of the results obtained by pyrosequencing analysis 
matched with TCGA reported results. Intra-assay reproducibility was confirmed by obtaining 
concordant results in six samples tested in triplicate in the same run. Inter-assay reproducibility 
was confirmed by obtaining concordant results in six samples assayed on multiple dates.  To 
determine the sensitivity of this assay, a dilution series experiment using 7 mixtures of 
methylated DNA (Millipore positive control) and unmethylated genomic DNA (100%, 50%, 
25%, 12.5%, 6.25%, 3.125%, and 1.56%) was performed. Overall, there was a high degree of 
correlation (r > 0.994). This data indicate that this Pyrosequencing assay always gives 
BRCAm or high genomic LOH (n=154)
Non-BRCA and low genomic LOH (n=155)
Log-rank: P=0.00009
HR=0.55, Median OS: 52.2 vs 37.3 months
Figure 7. Using TCGA data1, we evaluated the 
performance of 3000 SNPs defining high genomic 
LOH in combination with BRCAm status.

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concordant calls for the methylation status when a 10% threshold to declare methylation is used. 
The sensitivity of this assay is 6%. 
 
BRCA1 immunohistochemistry (IHC): BRCA1 protein function can be lost through a variety of 
mechanisms including germline mutation, somatic mutation, and epigenetic silencing. Combined 
these defects were found in ~30% of high-grade serous ovarian cancers by TCGA. BRCA1 IHC 
may be a useful candidate to modify response to PARP inhibitor treatment and link to a defect in 
homologous recombination. Dr. Levine’s lab has recently validated a BRCA1 antibody for IHC 
(Garg et al., 2013). The assay has a high negative predictive value of 92% indicating that it is not 
likely to show loss of expression in patients without BRCA1 alterations. The positive predictive 
value is lower at 83% indicating that some alterations may have retained protein expression, 
however, when the 13% of equivocal cases are excluded this increased to 94% with 
corresponding high levels of sensitivity and specificity. 
 
2.4.3 Duke Plasma Angiome 
 
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 our 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 our specific panel design 
(Table 3).  
Table 3.  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 

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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 
Alliance, the current ovarian cancer profiling can be compared to the profiles seen in other phase 
III studies, 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. 
 
2.4.4 Circulating Endothelial Cells (CEC) 
 
Vascular injury is known to be accompanied by an induction in CEC production (Lin et al., 
2013). Elevated numbers of CEC have been described in lymphoma, melanoma, and other solid 
tumors including ovarian cancer, reflecting the perturbation of vascular endothelium (Goon et 
al., 2006). A related circulating cell population is endothelial progenitor cells (CEP), which 
originate from the bone marrow rather than from vessel walls and relate to tumor angiogenesis 
(Rafii et al., 2002). Lee and colleagues recently reported prospectively planned exploratory 
biomarker endpoints in the phase II study of the combination of olaparib in capsule formulation 
and cediranib (Lee et al., Front Oncol. 2015). It is hypothesized that assessment of vascular 
endpoints within the olaparib/cediranib study would identify lead biomarker candidates. A subset 
of eligible patients voluntarily participated in the translational study at NCI. Blood samples were 
collected pre- and day 3 of therapy to measure CEC (nucleated CD133-CD146+ CD31+CD45-), 
CEP (viable nucleated CD133+, CD146-, CD31+ CD45 - or dim) in 12 patients. Patients 
receiving both agents had a median 3.5 fold increase in CEC compared to 0.7 for olaparib 
patients alone (p=0.032, Figure 8A). CEC fold increase pretreatment to day 3 correlated with 
survival (r=0.88, 95%CI 0.55-0.97, p<0.001; Figure 8B).  
 
A. 
 
 
 
 
     B. 
Figure 8. A. Patients receiving olaparib/cediranib had a larger fold median increase in CEC compared to olaparib 
alone (p=0.032). B. The fold increase in CEC on day 3 was associated with survival in all patients (r=0.88, 95%CI 
0.55-0.97, p<0.001). *Times at risk were censored on the date of their last contact for those women who were last 
reported alive and progression-free. 

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CEC/CEP have been examined in early clinical trials using anti-angiogenics (Ning et al., 2010; 
Park et al., 2013; Kummar et al., 2011). In the phase 2 study of docetaxel/prednisone v. 
docetaxel/prednisone with bevacizumab and thalidomide in metastatic prostate cancer, the 
numbers of post-treatment CEC inversely correlated with PSA response to the combinations of 
bevacizumab/thalidomide/docetaxel/prednisone (Ning et al., 2010); patients with ≥ 75% PSA 
decline had a increase in CEC levels compared with those who had < 75% PSA decline (p=0.02), 
indicating an inverse correlation between CEC levels and PSA response to anti-angiogenic 
therapy.  
 
These exploratory translational studies demonstrate that olaparib/cediranib caused vascular 
injury indicated by increase of CEC, supporting the hypothesis that cediranib and olaparib 
combination may yield greater inhibition in tumor vascularity and these changes may correlate 
with response rate and result in survival benefit. 
 
2.5 
Quality of Life   
 
Although there is a relatively small body of literature examining quality of life (QoL) with 
recurrent, platinum resistant ovarian cancer, QOL may be maintained for those receiving further 
chemotherapy, particularly if they are responding to treatment (Beesley et al., Gyn Onc 2014).  
Similarly, among a sample of recurrent, platinum resistant symptomatic patients, 40% derived a 
clinical benefit from chemotherapy, and 50% reported symptom improvement (Friedlander et al., 
IJGC 2014).   In the AURELIA trial, patients with platinum-resistant ovarian cancer were 
randomly assigned to chemotherapy alone, or with bevacizumab.  Patients who received 
bevacizumab with chemotherapy reported a significantly greater improvement in abdominal 
symptoms and QOL (Stockler et al., JCO 2013), supporting a role for bevacizumab with 
chemotherapy in the treatment of women with platinum-resistant ovarian cancer.  However, in a 
recent Cochrane report in which QOL data were deemed insufficient for meta-analyses, authors 
note that much more research is needed to determine the role of PARP inhibitors in platinum-
resistant disease (Wiggans et al., Cochrane Database Syst Rev May 2015).  Therefore, the effect 
on QoL of cediranib alone or olaparib alone, or in combination, compared to standard 
chemotherapy is a critically important and timely question in the setting of platinum resistant 
disease.   
 
In the absence of an OS benefit, it is difficult to place a value upon PFS. On the one hand, 
delaying cancer progression is likely to confer some benefit to a person’s quality of life, not only 
because of the psychological benefit of knowing one’s disease is stable, but also based upon the 
fact that delaying progression is also likely to delay the onset of life-limiting symptoms. On the 
other hand, treatment itself carries toxicities which themselves can be distressing and life-
limiting. In order to fully appreciate the benefits and risks associated with delaying PFS, these 
studies require careful assessment of targeted quality of life domains, in particular, disease 
symptoms, but also treatment side effects, acceptability of therapy and patient functioning.  
 
The patient reported outcome (PRO) plan for this trial was assembled to capture disease 
symptoms, treatment side effects, and general function and well-being. Disease related symptom 
benefit is the primary and only planned PRO analysis. Secondary (post-hoc) evaluation of 

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differences in side effects and function are also proposed, in order to estimate the extent to which 
symptoms and side effects affect function and well-being, and to plan for future study of the 
relative weight patients place upon each of these endpoints alongside clinical endpoints such as 
PFS. For this study, the following measures are proposed: 
• 
Disease-related symptoms: The NCCN/FACT-Ovarian Cancer Symptom Index-18 
(NFOSI-18; Jensen et al., 2011). Half (9 items) of the NFOSI-18 comprise the Disease-Related 
Symptom-Physical (DRS-P) scale, which is the primary planned PRO endpoint 
• 
Treatment side effects: Two measures of treatment side effects will be employed: The 5-
item Treatment Side Effects (TSE) scale from the NFOSI-18; and the 4-item FACT/GOG-Ntx-4 
measure of sensory neuropathy)  
• 
Patient function and well-being: Three brief measures of patient function and well-being 
will be employed: The 3-item function and well-being (F/WB) scale from the NFOSI-18, the 1-
item worry item from the NFOSI-18, the 5-item EQ-5D measure of patient preference (utility). 
 
Patient preferences for outcomes of treatment 
 
Outcomes of the treatment of cancer that are important to clinicians and researchers are not 
always the same as those that are important to patients.  Thus, it is important to evaluate patients’ 
preferences for the attributes of their treatments, including not only OS and PFS, but also the 
timing and convenience of treatment regimens, symptoms of cancer, side effects of treatments, 
and health utility out of pocket costs.  This will provide data elements that enable a more 
accurate and clinically relevant depiction of trial results for subsequent patients who have to face 
this challenging decision. (Note that the patient preference elicitation study will be done after the 
trial is completed, in a new cohort of women with advanced ovarian cancer, using clinical and 
PRO data from this trial to inform the preference elicitation exercises. As such, it will be 
necessary to collect sufficient information to inform this subsequent research in this trial). 
 
The regimens being evaluated in this trial differ significantly on many levels. Cytotoxic 
chemotherapy regimens are typically administered for a shorter time period than biologics, have 
a different toxicity profile, and do not include ongoing maintenance treatment once a CR is 
achieved. Out of pocket cost for cytotoxics may be lower due to a more limited treatment period, 
and the fact that longstanding therapies typically carry lower costs. The data collected in these 
trials, including PRO and cost estimates, will be extremely useful for subsequent research that 
can formally elicit patient preferences for one or another treatment based on their personal 
perspectives on each of the outcomes measured in this trial (PFS, OS, symptoms, side effects, 
function/well-being, utility). One standard preference elicitation method is conjoint analysis, in 
which participants evaluate a series of treatment choices with a set of attributes of varying levels.  
This ultimately allows the assignment of preference weights that could be considered for 
development of a composite endpoint or development of a patient focused decision tool. 
Although conjoint analysis is not part of this protocol per se, the data obtained will inform such 
important work in the future, much the same as is now being done by these same investigators in 
the area of intraperitoneal versus intravenous chemotherapy. (Note that this important work can 
be done with only a very modest time commitment from patients of 10 minutes per assessment 
over a 3-year period, and minimal cost to the trial).  
 

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With the exception of the DRS-P, the rationale and analysis plan for these PRO endpoints can be 
found in Appendix IX. A proposed PRO assessment comprises a total of 27 questions to measure 
symptoms, side effects, function, and well-being. This is a shorter assessment than has been used 
in prior GOG trials that have consistently seen >80% follow-up assessment adherence. Patient 
time to complete averages less than 10 minutes for the entire set of questions, and this has 
historically been a very motivated and engaged group of participants. To keep the assessment 
brief, questions were selected only if they served a specific and planned purpose as described 
below and in Appendix IX.  Within the Phase II trial, these same 27 items will be collected for 
their use rolling into the Phase III trial. Excluding these in Phase II would compromise the 
power to detect between-arm differences in Phase III.  
 
Study Hypotheses and Instrument Selection 
 
It is hypothesized that the treatment arm associated with PFS benefit will also demonstrate a 
PRO benefit relative to the others. This is based on the underlying hypothesis that the disease 
symptom benefit of delaying progression will be greater than any differences in toxicities that 
might exist between treatments. In order to test this hypothesis properly, it is critically important 
that all living patients be assessed, even after progression, for the full follow-up window 
specified in the protocols. If, as has been the case in many prior trials, PRO assessment stops at 
the time of progression, this will introduce a bias in the group comparison, one which typically 
disadvantages the more effective treatment (because it retains more patients, including some who 
may have progressed on the inferior treatment).  
 
In the PRO component of this trial, a primary emphasis will be placed on symptoms of disease 
(with the understanding that some symptoms such as fatigue and nausea are caused by both 
disease and treatment), and secondary (exploratory) emphasis on treatment side effects and 
burden/acceptability of treatment.  The tolerability of biological therapies small molecule 
inhibitors as compared to standard chemotherapy will also be of high interest in this population.  
Therefore, additional important questions that will be addressed by this trial include the 
assessment of disease related symptoms as an important secondary endpoint to evaluate the 
benefit of PFS as experienced by the patient, including the question of whether symptomatic 
progression accompanies radiographic progression.  Similarly, the patient experience of side 
effects (at least the more common or consequential ones) will be an important indicator of the 
acceptability of one treatment relative to another and will therefore also be assessed. 
 
A proposed PRO assessment comprises a total of 27 questions to measure symptoms, side 
effects, function, and well-being This is a shorter assessment than has been used in prior GOG 
trials that have consistently seen >80% follow-up assessment adherence. Patient time to 
complete averages is less than 10 minutes for the entire set of questions majority of patients, and 
this has historically been a very motivated and engaged group of participants. To keep the 
assessment brief, questions were selected only if they served a specific and planned purpose as 
described below. 
 
The Disease-Related Symptom-Physical (DRS-P) scale from the NCCN/FACT-Ovarian Cancer 
Symptom Index-18 (NFOSI-18), (Jensen et al., 2011), is a 9-item scale which comprises the first 
9 items of the NFOSI-18.  This scale was developed using a qualitative methodology with 50 

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advanced ovarian cancer patients and 10 expert clinicians.  Most of the items come from the 
FACT-O questionnaire (Basen-Engquist et al., 2001), but they have been supplemented, 
reorganized and validated to create a set of targeted outcome tools for disease related symptoms, 
treatment side effects, general functioning and well-being.  Of note, after establishing that these 
9 questions are the most important disease-related symptoms to women with ovarian cancer 
(Jensen et al., 2011), these questions have been further evaluated and demonstrated through 
cognitive debriefing interviews with 18 women with ovarian cancer to be understood as 
intended.  The targeted 9-item DRS-P subscale will serve as the main PRO endpoint.  
 
The hypothesis, as stated above, is that the treatment arm with the superior PFS benefit will also 
have a superior DRS-P benefit, lending confirmation as a patient-reported symptomatic benefit 
associated with delaying disease progression. 
 
2.6 
Rationale for trial design 
 
It is hypothesized that the combination of cediranib and olaparib will yield greater DNA damage 
and inhibition in tumor vascularity than single agent alone and/or standard chemotherapies, in 
women with recurrent platinum-resistant or-refractory ovarian, primary peritoneal, or fallopian 
tube cancers. These changes are believed to result in clinical benefit, as measured by prolonged 
PFS and/or OS.  
 
The phase I studies to assess the tolerability of cediranib and olaparib provided insufficient data 
for assessing the efficacy of these agents. Thus the GY005 design included a 4-arm, randomized 
phase II study for preliminary efficacy assessment. The component included interim and final 
analyses to drop treatment arms that failed to reach the defined thresholds for disease specific 
activity, as measured by PFS (Section 13.1.3).  
 
The RP2 study facilitated selection and testing of the experimental drugs, and allowed patients 
on the phase II component to contribute to the final phase III endpoint, saving clinical and 
financial resources. Based on the outcomes of the phase II study, the active monotherapy 
olaparib arm has been excluded.  The RP3 study has been simplified to compare the 
cediranib+olaparib combination and monotherapy cediranib with physician’s choice standard of 
care chemotherapy (single-agent PLD, weekly paclitaxel, or topotecan) (Section 13.1.3).  In 
addition, the RP3 primary endpoints (PFS and OS), monotherapy cedirinib and the combination 
of cediranib+olaparib will be compared against standard of care chemotherapy to assess their 
comparative disease-related symptoms, and tolerability, as assessed by patient report of common 
side effects. BRCA1/BRCA2-specific biomarkers and angiogenic biomarkers will be evaluated 
to correlate with treatment outcome and response. The goal of the correlative studies is to 
identify potential predictive biomarkers that could be utilized to direct targeted therapy. 
 
Patients with recurrent platinum-resistant or-refractory ovarian cancers, without gBRCAm are 
the enriched patient population with unmet medical needs. There is an urgent need for the 
development of targeted therapies for this patient population. The results of the phase II/III trials 
could potentially produce practice-changing results, given that limited data of targeted-therapy in 
recurrent platinum-resistant or-refractory ovarian cancer patients.  
 

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Hence, if positive, the results of this trial may provide a targeted agent alternative for women 
with recurrent platinum-resistant or-refractory disease with the potential for increased 
tolerability.  
 
2.7 
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 NRG Statistical and Data Management 
Center-Buffalo Office (via the contact list on the NRG web site).  
 
3.1 
Eligibility Criteria 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
 
3.1.1 Patients must have histologically or cytologically confirmed ovarian cancer, peritoneal 
cancer or fallopian tube cancer and must have a histological diagnosis of either serous or 
endometrioid cancer based on local histopathological findings. Both endometrioid and 
serous histology should be high-grade for eligibility of non-mutation carriers.  
Patients with clear cell, mixed epithelial, undifferentiated carcinoma, or transitional cell 
carcinoma histologies are also eligible, provided that the patient has a known deleterious 
germline BRCA1 or BRCA2 mutation identified through testing at a clinical laboratory. 
 
Note: Due to the long acceptance of BRCA testing through Myriad, Myriad testing will 
be accepted. If testing for BRCA is done by other organizations, documentation from a 
qualified medical professional (e.g., ovarian cancer specialty physician involved in the 
field, high risk genetics physician, genetics counselor) listing the mutation and 
confirming that the laboratory results showed a recognized germ line deleterious BRCA 1 
or BRCA 2 mutation or BRCA rearrangement is required. (12/05/2016) 
            A copy of Myriad or other BRCA mutational analysis (positive or VUS or negative) 
reports will be requested but not required for study enrollment.  
 
3.1.2 Patients should have recurrent platinum-resistant or- refractory disease - defined as 
disease that has progressed by imaging while receiving platinum or had recurrence within 
6 months of the last receipt of platinum-based chemotherapy. Rising CA125 only is not 
considered as platinum-resistant or refractory disease.  (12/05/2016) 
 
3.1.3 Phase II study: measurable disease by RECIST 1.1 criteria.  
If archival tumor sample is not available tumor sample from fresh biopsy is acceptable. 
(12/05/2016) 

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3.1.4 Phase III study: evaluable disease – defined as RECIST 1.1 measurable disease OR non-
measurable disease (defined as solid and/or cystic abnormalities on radiographic imaging 
that do not meet RECIST 1.1 definitions for target lesions OR ascites and/or pleural 
effusion that has been pathologically demonstrated to be disease-related in the setting of a 
CA125 > 2x ULN). 
 
3.1.5 Prior therapy: 
 
3.1.5.1 No more than 3 prior treatment regimens (including primary therapy; no more 
than 1 prior non-platinum based therapy in the platinum-resistant/-refractory setting). 
Hormonal therapies used as single agents (i.e. tamoxifen, aromatase inhibitors) will not 
count towards this line limit. (12/05/2016) 
 
3.1.5.2 Patients may not have had a prior anti-angiogenic agent in the recurrent setting. 
Prior use of bevacizumab in the upfront or upfront maintenance setting is allowed. 
 
3.1.5.3 Patients may not have previously received a PARP-inhibitor. 
 
3.1.6 Patient must have provided study specific informed consent prior to study entry. 
 
3.1.7 ECOG performance status 0 or 1 or 2 (see Appendix II).  
 
3.1.8 Patients must have adequate organ and marrow function as defined below (12/05/2016) 
 
x Absolute neutrophil count > 1,500/mcL 
x Platelets > 100,000/mcL 
x Hemoglobin > 10 g/dL 
x Total bilirubin < 1.5 times the upper limit of normal (ULN) institutional limits 
x AST (SGOT)/ALT (SGPT) < 3 × institutional ULN. If intrahepatic liver metastases are 
present, AST and ALT must be ˺ 5 times institutional ULN. 
x Creatinine < 1.5 X the institutional ULN  
x Urine protein: creatinine ratio (UPC) of ˺1 OR less than or equal to 2+ proteinuria on 
two consecutive dipsticks taken no less than 1 week apart. UPC is the preferred test. 
Patients with 2+ proteinuria on dipstick must also have a 24-hour urine collection 
demonstrating protein of ≤ 500mg over 24 hours. 
 
3.1.9 Toxicities of prior therapy (excepting alopecia) should be resolved to less than or equal to 
Grade 1 as per CTCAE 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). Patients 
with long-standing stable grade 2 neuropathy may be considered after discussion with the 
Study Chair. 
 
3.1.10  Adequately controlled blood pressure (SBP ≤140; DBP ≤ 90mmHg) on maximum of 
three antihypertensive medications. Patients must have a BP of ˺ 140/90 mmHg taken in 

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the clinic setting by a medical professional within 2 weeks prior to starting study. It is 
strongly recommended that patients who are on three antihypertensive medications be 
followed by a cardiologist or a primary care physician for management of BP while on 
protocol. Patients must be willing and able to check and record daily blood pressure 
readings. Blood pressure cuffs will be provided to patients randomized to cediranib alone 
and the combination of olaparib and cediranib arms. Please refer to section 9.6, and 
Appendix IV. (12/05/2016) 
 
3.1.11 Adequately controlled thyroid function, with no symptoms of thyroid dysfunction and 
TSH within normal limits. (12/05/2016)  
 
3.1.12 Able to swallow and retain oral medications and without GI illnesses that would preclude 
absorption of cediranib or olaparib. 
 
3.1.13 Age ≥ 18 years 
 
3.1.14 Cediranib has been shown to terminate fetal development in the rat, as expected for a 
process dependent on VEGF signaling.  For this reason, women of child-bearing potential 
must have a negative pregnancy test prior to study entry.  Women of child-bearing 
potential must agree to use two reliable forms of contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry, for the duration of study 
participation, and for 6 weeks after cediranib discontinuation.  Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she should inform her 
treating physician immediately. 
 
3.1.15 Olaparib adversely affects embryofetal survival and development in the rat. For this 
reason, women of child-bearing potential must have a negative pregnancy test prior to 
study entry.  Women of child-bearing potential must agree to use must agree to use two 
reliable forms of contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry, for the duration of study participation, and for 3 months after the last 
dose of olaparib. Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately. 
 
3.2 
Ineligibility Criteria 
Patients with one or more of the following conditions are NOT eligible for this study. 
 
3.2.1 Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) of starting treatment or those who have not recovered from 
adverse events due to agents administered more than 4 weeks earlier.  Patients may not 
have had hormonal therapy within 2 weeks prior to entering the study.  Patients receiving 
raloxifene for bone health as per FDA indication may remain on raloxifene absent other 
drug interactions. (12/05/2016) 
 
3.2.2 Any other investigational agents within the past 4 weeks.   
 

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3.2.3 Prior treatment affecting the VEGF/VEGFR pathway or the angiopoietin pathway in the 
recurrent setting, including but not limited to thalidomide, bevacizumab, sunitinib, 
sorafenib, pazopanib, cediranib, nintedanib, and trebananib.  Bevacizumab used in the 
upfront setting in conjunction with chemotherapy and/or as maintenance to treat newly 
diagnosed disease will be allowed. 
 
3.2.4 Prior use of PARP-inhibitors.  
 
 
3.2.5  CA-125 only disease without RECIST 1.1 measurable or otherwise evaluable disease. 
 
3.2.6 Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to starting cediranib. 
 
3.2.7 Current signs and/or symptoms of bowel obstruction or signs and/or symptoms of bowel 
obstruction within 3 months prior to starting study drugs  
 
3.2.8 History of intra-abdominal abscess within the past 3 months. 
 
3.2.9 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. (12/05/2016) 
 
3.2.10 Dependency on IV hydration or TPN. 
 
3.2.11 Any concomitant or prior invasive malignancies with the following curatively treated 
exceptions: 
 
3.2.11.1 Treated limited stage basal cell or squamous cell carcinoma of the skin. 
 
3.2.11.2 Carcinoma in situ of the breast or cervix. 
 
3.2.11.3 Primary endometrial cancer meeting the following conditions:  Stage not greater 
than IA, grade 1 or 2, no more than superficial myometrial invasion, without vascular or 
lymphatic invasion; no poorly differentiated subtypes, including papillary serous/serous, 
clear cell, or other FIGO grade 3 lesions. (12/05/2016) 
 
3.2.11.4 Prior cancer treated with a curative intent with no evidence of recurrent disease 5 
years following diagnosis and judged by the investigator to be at low risk of recurrence.  
 
3.2.12 Patients with untreated brain metastases, spinal cord compression, or evidence of 
symptomatic brain metastases or leptomeningeal disease as noted on CT or MRI scans 
should not be included on this study, since neurologic dysfunction may confound the 
evaluation of neurologic and other adverse events. Patients with treated brain metastases 
and resolution of any associated symptoms must demonstrate stable post-therapeutic 
imaging for at least 6 months following therapy prior to starting study drug. 

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3.2.13  Patients with any of the following: 
 
3.2.13.1    
History of myocardial infarction within six months 
 
3.2.13.2 
Unstable angina 
 
3.2.13.3 
Resting ECG with clinically significant abnormal findings. 
 
3.2.13.4 
New York Heart Association functional classification of III or IV 
. 
3.2.14 If cardiac function assessment is clinically indicated or performed:  LVEF less than 
normal per institutional guidelines, or <55%, if threshold for normal not otherwise 
specified by institutional guidelines.   
 
Patients with the following risk factors should have a baseline cardiac function 
assessment: 
 
3.2.14.1 
Prior treatment with anthracyclines 
 
3.2.14.2 
Prior treatment with trastuzumab 
 
3.2.14.3 
Prior central thoracic radiation therapy (RT), including RT to the heart 
 
3.2.14.4 
History of myocardial infarction within 6 to 12 months (Patients with    
history of myocardial infarction within 6 months are excluded from the 
study) 
 
3.2.14.5 
Prior history of impaired cardiac function 
 
3.2.15  History of stroke or transient ischemic attack within six months  
 
3.2.16 Clinical significant peripheral vascular disease or vascular disease (aortic aneurysm or 
aortic dissection) 
 
3.2.17 Evidence of coagulopathy or bleeding diathesis. Therapeutic anticoagulation for prior 
thromboembolic events is permitted. 
 
3.2.18  Evidence suggestive of myelodysplastic syndrome (MDS) or acute myelogenous 
leukemia (AML) on peripheral blood smear or bone marrow biopsy, if clinically 
indicated. 
 
No prior allogeneic bone marrow transplant or double umbilical cord blood 
transplantation (dUBCT). 
 

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3.2.19 Patients may not use any complementary or alternative medicines including natural 
herbal products or folk remedies as they may interfere with the effectiveness of the study 
treatments. 
 
3.2.20 Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (other 
than atrial fibrillation with controlled ventricular rate), or psychiatric illness/social 
situations that would limit compliance with study requirements. (12/05/2016) 
 
3.2.21 Known HIV-positive individuals are ineligible because of the potential for 
pharmacokinetic interactions with cediranib or olaparib. In addition, these individuals are 
at increased risk of lethal infections when treated with marrow-suppressive therapy. 
 
3.2.22 Participants receiving any medications or substances that are strong inhibitors or inducers 
of CYP3A4 are ineligible. Refer to a frequently updated drug information reference for a 
list of strong inducers and inhibitors. See Appendix V.  
 
Strong inhibitors and inducers of UGT/PgP should be used with caution. (12/05/2016) 
 
3.2.23 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
4.1 
PHASE II study (12/05/2016) 
 
PRE-TREATMENT ASSESSMENTS 
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 
 (calendar days) 
Prior to Cycle 1 Day 1 
Treatment 
(calendar days) 
 
Informed Consent 
≤ 28 days 
 
History and Physical 
≤ 28 days 
≤ 7 days 
Vital Signs (Blood Pressure, Heart Rate,   
Temperature and Pulse Oxygen Saturation) 
≤ 28 days 
Day of treatment 
Height 
≤ 28 days 
≤ 7 days 
Weight 
≤ 28 days 
≤ 7 days 
Performance Status (ECOG) 
≤ 28 days 
≤ 7 days 
Toxicity Assessment  
≤ 14 days 
≤ 7 days 
Patient Reported Outcome Assessment 
 
≤ 7 days 
Concurrent Medications 
≤ 14 days 
Day of treatment 
CBC with Differential 
≤ 14 days 
≤ 7 days 
Chemistries (including Sodium, Potassium, Chloride, 
bicarbonate, Calcium, Glucose, BUN/Creatinine, 
Total Bilirubin, Total Protein, ALT (SGPT), AST 
(SGOT), Alkaline Phosphatase, Albumin) 
≤ 14 days 
≤ 7 days 
Urine protein:creatinine ratio (preferred) or urinalysis 
≤ 14 days 
 
≤ 7 days 
TSH  
≤ 14 days 
≤ 7 days a 
CA125 
≤ 14 days 
≤ 7 days 
Pregnancy Test (for patients of child bearing 
potential) 
≤ 14 days 
≤ 3 daysb 
Chest imaging (X-ray or CT scan of the chest) 
≤ 28 days 
 
Radiographic Tumor Measurement (CT or MRI of 
the abdomen and pelvis)c 
≤ 28 days 
≤ 28 days 
Electrocardiogram 
≤ 14 days 
≤ 7 days 
MUGA or echocardiogramd 
≤ 28 days 
 
a For patients who receive cediranib only. 
b The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of hCG. 
c  Radiographic tumor measurements should be obtained via imaging of at least the chest, abdomen, and 
pelvis at baseline. If chest imaging at baseline reveals evidence of measurable disease, then subsequent 
radiographic tumor assessments must also include chest imaging. See RECIST 1.1 for allowable 
imaging modalities used to assess disease at baseline and subsequent assessments. Contrast CT is the 
preferred modality. 

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Tumor reassessment will be time-based at 9 +/- 1 week throughout the study for the first year 
and every 12 weeks (+/- 7 days) after the first year. 
d MUGA or echocardiogram should be performed at baseline for all patients at increased risk for 
compromised LVEF, including patients with 1) prior treatment with anthracyclines, 2) prior treatment 
with trastuzumab, 3) prior central thoracic RT, or 4) history of myocardial infarction within the 12 
months prior. LVEF assessment by MUGA or echocardiogram should be performed on an every 16 
week basis for patients with these risk factors on Arm II or Arm III of study treatment.  
 
 
ASSESSMENTS DURING TREATMENT 
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 11.2.1 for Specimen Requirements. 
 
 
Parameter 
Prior to day 1 of each 
cycle of therapy1 
 
Every other week for 
first 8 weeks of study 
therapy (Arms II, III 
and IV) 
After completion or 
stopping of 
therapy2 
Medical history and 
physical examination 
≤ 1 day of treatment 
 
 
See footnote 2 
Concomitant medications3,4 
≤ 1 day of treatment 
 
Day of 
treatment/assessment 
 
See footnote 2 
Adverse event assessment4 
≤ 1 day of treatment 
 
Day of 
treatment/assessment 
 
See footnote 2 
Vital signs (Blood  
Pressure, Heart Rate,   
Temperature and Pulse 
Oxygen Saturation) 
 
Day of 
treatment/assessment 
 
 
 
ECOG performance status 
≤ 1 day of treatment 
 
 
CBC with Differential 
≤ 3 days of treatment  
Day of 
treatment/assessment 
 
See footnote 2 
Serum chemistry5 
≤ 3 days of treatment 
 
See footnote 2 
TSH 6 
≤ 3 days of treatment  
 
6 months (+/- 1 
week) after stopping 
study treatment. 
Urine protein:creatinine 
ratio (preferred) or 
urinalysis 
≤ 3 days of treatment 
 
 
Electrocardiogram (ECG)7 
≤ 3 days of treatment 
 
 
MUGA or echocardiogram 
See footnote 8 
 
 
CA-125 measurement 
≤ 3 days of treatment 
 
 See footnote 2 
Tumor assessment 
See footnote 9 
 
 
Home BP assessment10 
Twice daily while on 
study treatment 
 
See footnote 10 

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Patient-reported outcome 
assessment11 
Every 12 weeks for 2 
years, unless the patient 
withdraws from study 
participation. 
 
 
PK and PD studies 
See footnote 12 
 
 
1 Timing of assessments prior to Cycle 1 Day 1 may be as per pre-treatment assessments schedule.  
  For Cycle 1 Day 1, laboratory evaluations, and ECG do not have to be repeated if they have been 
performed at screening within 7 days of Cycle 1 Day 1. 
2 For patients in Arm I at the time of completion of therapy, and for patients in all arms who discontinue 
study therapy for non-progression events. These (except TSH) should be continued every 9 weeks (+/- 1 
week) until time of progression or another therapy is initiated.  
3:  Because of a potential for interaction of cediranib and olaparib 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. 
4:  Participants on Arms II, III, and IV should be contacted at least once every 2 weeks by phone or 
assessed in person for the first 8 weeks of therapy to assess for adverse events and concomitant 
medications.  Pre-cycle and off-study AE assessments must be done at a scheduled clinic visit. 
5:  Serum chemistry includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
albumin, calcium, AST (SGOT), ALT (SGPT), alkaline phosphatase, total bilirubin. 
6:  For patients who receive cediranib. Should be performed pre-study and prior to the first two cycles of 
treatment for all participants.  Additional assessment of thyroid function should be performed as 
clinically indicated. 
7:  Should be performed pre-study and subsequent ECG should be done only if clinically indicated. 
8:  MUGA or echocardiogram should be performed at baseline for all patients at increased risk for 
compromised LVEF, including patients with 1) prior treatment with anthracyclines, 2) prior treatment 
with trastuzumab, 3) prior central thoracic RT, or 4) history of myocardial infarction within the 12 
months prior.  LVEF assessment by MUGA or echocardiogram should be performed on an every 16 
week basis for patients with these risk factors on Arm II or Arm III of study treatment.  Additionally, 
LVEF assessment by MUGA or echocardiogram should be performed every 12 weeks while on 
treatment for participants receiving Arm I, Regimen II (pegylated liposomal doxorubicin) but not for 
weekly taxol or topotecan. 
9:  Tumor reassessment will be time-based, and not cycle-based, with CT scan or MRI performed 
once every 9 weeks (+/- 7 days), for the first year and every 12 weeks (+/- 7 days) after the first 
year, and at any other time if clinically indicated based on symptoms or physical signs suggestive of 
progressive disease. Imaging assessments can be discontinued if disease progression is confirmed 
according to RECIST 1.1. However, if a patient discontinues study treatment for any reason other 
than progression, imaging studies should continue every 9 weeks (+/- 7 days) until progression. An 
Excel tool is available on the CTSU website to calculate dates of re-imaging. Utilize same imaging 
modality of abdomen and pelvis +/- chest (for patients with evidence of measurable disease on 
baseline chest imaging; then subsequent radiographic tumor assessments must also include chest 
imaging.  
10:  Because of the rapid changes in blood pressure that can occur and the potential for severe life-
threatening complications if hypertension is not appropriately managed, patients on Arms II and III 
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 
 

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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.   
11: Patient-reported outcomes should be performed every 12 weeks (+/- 1 week) for 2 years, unless the 
patient withdraws from study participation. Patients who stop study treatment for any reason other 
than death or withdrawal should be assessed on schedule. PRO assessments should continue post-
progression. 
12  PK studies will be done during the phase II study. See section 11.2.1.1 for more details for PK and 
other correlative study samples collection.  
 
 
 
 
ASSESSMENTS IN FOLLOW UP 
 
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. 
 
Assessments 
From end of treatment: 
Follow-up forms (Q forms) are collected for the 5- year follow-up period 
or until study termination 
Vital Status 
Every 3 months (+/- 1 week) x 2 years, then every 6 months (+/- 1 week) 
x 3 years or until death. 
Toxicity Assessment 
Report all adverse events that occur within 30 days of last protocol 
treatment on the Toxicity form for the last cycle of therapy administered. 
For reporting of delayed toxicity, see Section 7. 
Patient-reported outcome 
assessments 
PRO assessments will continue post-progression every 12 weeks (+/- 1 
week) until 2 years from the study enrollment, measured from 
approximately cycle 1, day 1, unless the patient withdraws from study 
participation.  
Radiography tumor 
measurement 
Every 9 weeks (+/- 7 days) x 1 year, then every 12 weeks (+/- 7 days) 
until progression if a patient discontinues study treatment for any reason 
other than progression, confirmed by RECIST 1.1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4.2 
PHASE III study (12/05/2016) 
 
PRE-TREATMENT ASSESSMENTS 
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 
 (calendar days) 
Prior to Cycle 1 Day 1 
Treatment 
(calendar days) 
 
Informed Consent 
≤ 28 days 
 
History and Physical 
≤ 28 days 
≤ 7 days 
Vital Signs(Blood Pressure, Heart Rate,   
Temperature and Pulse Oxygen Saturation) 
≤ 28 days 
Day of treatment 
Height 
≤ 28 days 
≤ 7 days 
Weight 
≤ 28 days 
≤ 7 days 
Performance Status (ECOG) 
≤ 28 days 
≤ 7 days 
Toxicity Assessment  
 
≤ 14 days 
≤ 7 days 
Patient Reported Outcomes Assessment 
 
≤ 7 days 
Concurrent Medications 
≤ 14 days 
Day of treatment 
CBC/Differential/Platelets 
≤ 14 days 
≤ 7 days 
Chemistries (including Sodium, Potassium, Chloride, 
bicarbonate, Calcium, Glucose, BUN/Creatinine, Total 
Bilirubin, Total Protein, ALT, AST, Alkaline 
Phosphatase, Albumin) 
≤ 14 days 
≤ 7 days 
Urine protein:creatinine ratio (preferred) or urinalysis 
≤ 14 days 
 
≤ 7 days 
TSH  
≤ 14 days 
≤ 7 days a 
CA125 
≤ 14 days 
≤ 7 days 
Pregnancy Test (for patients of child bearing potential) 
≤ 14 days 
≤ 3 daysb 
Chest imaging (X-ray or CT scan of the chest) 
≤ 28 days 
 
Radiographic Tumor Measurement (CT or MRI of the 
abdomen and pelvis)c 
≤ 28 days 
≤ 28 days 
Electrocardiogram 
≤ 14 days 
≤ 7 days 
MUGA or echocardiogramd 
≤ 28 days 
 
a For patients who receive cediranib only. 
bThe minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of hCG. 
c Radiographic tumor measurements should be obtained via imaging of at least the chest, abdomen, and 
pelvis at baseline. If chest imaging at baseline reveals evidence of measurable disease, then subsequent 
radiographic tumor assessments must also include chest imaging. See RECIST 1.1 for allowable imaging 
modalities used to assess disease at baseline and subsequent assessments. Contrast CT is the preferred 
modality. 
Tumor reassessment will be time-based at 9 +/- 1 week throughout the study for the first year and 
every 12 weeks (+/- 7 days) after the first year. 
d MUGA or echocardiogram should be performed at baseline for all patients at increased risk for 
compromised LVEF, including patients with 1) prior treatment with anthracyclines, 2) prior treatment 

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with trastuzumab, 3) prior central thoracic RT, or 4) history of myocardial infarction within the 12 months 
prior.  LVEF assessment by MUGA or echocardiogram should be performed on an every 16 week basis 
for patients with these risk factors on Arm II or III of study treatment.  
 
 
ASSESSMENTS DURING TREATMENT 
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 11.2.1 for Specimen Requirements. 
 
 
 
Parameter 
Prior to day 1 of each cycle 
of therapy1 
 
Every other week 
for first 8 weeks of 
study therapy 
(Arms II and III) 
After 
completion or 
stopping of 
therapy2 
Medical history and physical 
examination 
≤ 1 day of treatment 
 
 
See footnote 2 
Concomitant medications3,4 
≤ 1 day of treatment 
 
Day of 
treatment/assessment 
 
See footnote 2 
Adverse event assessment4 
≤ 1 day of treatment 
 
Day of 
treatment/assessment 
 
See footnote 2 
Vital signs (Blood 
Pressure, Heart Rate, 
Temperature and Pulse 
Oxygen Saturation) 
 
Day of treatment/assessment 
 
 
 
ECOG performance status 
≤ 1 day of treatment 
 
 
CBC with Differential13 
≤ 3 days of treatment  
Day of 
treatment/assessment 
 
See footnote 2 
Serum chemistry5 
≤ 3 days of treatment 
 
See footnote 2 
TSH 6 
≤ 3 days of treatment  
 
6 months (+/- 1 
week) after 
stopping study 
treatment. 
Urine protein:creatinine 
ratio (preferred) or 
urinalysis14 
≤ 3 days of treatment 
 
 
Electrocardiogram (ECG)7 
≤ 3 days of treatment 
 
 
MUGA or echocardiogram 
See footnote 8 
 
 
CA-125 measurement 
≤ 3 days of treatment 
 
See footnote 2 
Tumor assessment 
See footnote 9 
 
 

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Home BP assessment10 
Twice daily while on study 
treatment 
 
See footnote 10 
Patient-reported outcome 
assessment11 
Every 12 weeks for 2 years, 
unless the patient 
withdraws from study 
participation. 
 
 
PD studies 
See footnote 12 
 
 
 
1 Timing of assessments prior to Cycle 1 Day 1 may be as per pre-treatment assessments schedule.  
  For Cycle 1 Day 1, laboratory evaluations, and ECG do not have to be repeated if they have been 
performed at screening within 7 days of Cycle 1 Day 1. 
2 For patients in Arm I at the time of completion of therapy, and for patients in all arms who discontinue 
study therapy for non-progression events. These (except TSH) should be continued every 9 weeks (+/- 1 
week) until time of progression or another therapy is initiated.  
3:  Because of a potential for interaction of cediranib and olaparib 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. 
4:  Participants on Arms II and III should be contacted at least once every 2 weeks by phone or assessed 
in person for the first 8 weeks of therapy to assess for adverse events and concomitant medications.  
Pre-cycle and off-study AE assessments must be done at a scheduled clinic visit. 
5:  Serum chemistry includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
albumin, calcium, AST (SGOT), ALT (SGPT), alkaline phosphatase, total bilirubin. 
6:  Should be performed pre-study and prior to the first two cycles of treatment for all participants.  
Additional assessment of thyroid function should be performed as clinically indicated. 
7:  Should be performed pre-study and subsequent ECG should be done only if clinically indicated. 
8:  MUGA or echocardiogram should be performed at baseline for all patients at increased risk for 
compromised LVEF, including patients with 1) prior treatment with anthracyclines, 2) prior 
treatment with trastuzumab, 3) prior central thoracic RT, or 4) history of myocardial infarction 
within the 12 months prior.  LVEF assessment by MUGA or echocardiogram should be performed 
on an every 16 week basis for patients with these risk factors on Arm II or Arm III of study 
treatment.  Additionally, LVEF assessment by MUGA or echocardiogram should be performed every 
12 weeks while on treatment for participants receiving Arm I, Regimen II (pegylated liposomal 
doxorubicin) but not for weekly taxol or topotecan. 
9:  Tumor reassessment will be time-based, and not cycle-based, with CT scan or MRI performed 
once every 9 weeks (+/- 7 days), for the first year and every 12 weeks (+/- 7 days) after the first 
year, and at any other time if clinically indicated based on symptoms or physical signs suggestive of 
progressive disease. Imaging assessments can be discontinued if disease progression is confirmed 
according to RECIST 1.1. However, if a patient discontinues study treatment for any reason other 
than progression, imaging studies should continue every 9 weeks (+/- 7 days) until progression. An 
Excel tool is available on the CTSU website to calculate dates of re-imaging. Utilize same imaging 
modality of abdomen and pelvis +/- chest (for patients with evidence of measurable disease on 
baseline chest imaging; then subsequent radiographic tumor assessments must also include chest 
imaging. 
10:  Because of the rapid changes in blood pressure that can occur and the potential for severe life-
threatening complications if hypertension is not appropriately managed, patients on Arms II and III 
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 

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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.  
11: Patient-reported outcomes should be performed every 12 weeks (+/- 1 week) for 2 years, unless the 
patient withdraws from study participation. Patients who stop study treatment for any reason other than 
death or withdrawal should be assessed on schedule. PRO assessments should continue post-
progression. 
12 See section 11.2.1.1 for more details for PK and other correlative study samples collection.  
13 For patients receiving weekly paclitaxel or topotecan, CBC with differential will be obtained < 1 day 
prior to days 8, 15, 22 for paclitaxel, and days 8 and 15 for topotecan. 
14 For patients on the cediranib containing arms (arms 2 and 3) only 
 
ASSESSMENTS IN FOLLOW UP 
 
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. 
 
 
Assessments 
From end of treatment: 
Follow-up forms (Q forms) are collected for the 5 
year follow-up period or until study termination. 
Vital Status 
Every 3 months (+/- 1 week) x 2 years, then every 6 
months (+/- 1 week) x 3 years or until death. 
Toxicity Assessment 
Report all adverse events that occur within 30 days of 
last protocol treatment on the Toxicity form for the last 
cycle of therapy administered. For reporting of delayed 
toxicity, see Section 7. 
Patient-reported outcome assessments 
PRO assessments will continue post-progression every 
12 weeks (+/- 7 days) until 2 years from the study 
enrollment, measured from approximately cycle 1, day 
1, unless the patient withdraws from study participation.  
Radiography tumor measurement 
Every 9 weeks (+/- 7 days) x 1 year, then every 12 
weeks (+/- 7 days) until progression if a patient 
discontinues study treatment for any reason other than 
progression, confirmed by RECIST 1.1.  
Subsequent therapy assessment 
Patients will be followed every 3 months (+/- 1 week) x 
2 years, then every 6 months (+/- 1 week) x 3 years after 
progression on study treatment, to capture data including 
the date of initiation of the subsequent therapy, detailed 
information on the type of subsequent therapy received, 
and time to progression on the subsequent therapy. 
 
 
 
 

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5.
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEURE
5.1
Treatment plan
For the Phase II study, 4 treatments regimens were randomly assigned 1:1:1:1 to incoming 
patients.  In July 2018, the Data Monitoring Committee voted to exclude the olaparib alone 
regimen.  In the Phase III study, the 3 selected treatments will be randomly assigned 1:1:1 to 
incoming patients.  Phase II patients assigned to the selected treatment regimens will be included 
in the Phase III accrual, and will support the Phase III analyses.
The Phase II and Phase III studies are open-label, and the treatments are administered in an 
outpatient setting. Patients continue treatment until death, disease progression, unacceptable 
toxicity, or consent withdrawal. Patients may continue to be followed for up to five years after 
completion of their protocol therapy.
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.
Because of the differences in cycle lengths between the allowed regimens, tumor 
reassessment will be time-based, and not cycle-based, with CT scan or MRI performed 
once every 9 weeks (+/- 7 days) for the first year and every 12 weeks (+/- 7 days) after the 
first year, and at any other time if clinically indicated based on symptoms or physical signs 
suggestive of progressive disease. Imaging assessments can be discontinued if disease 
progression is confirmed according to RECIST 1.1. However, if a patient discontinues study 
treatment for any reason other than progression, imaging studies should continue on the protocol-
outlined schedule until progression. An Excel tool will be provided to sites to assist in 
determining imaging dates.
Treatment window (12/05/2016)
For 21 or 28 day cycles of Arm 1, a patient will be permitted to have a new cycle of 
chemotherapy delayed up to 7 days (without this being considered to be a protocol violation) for 
major life events (e.g., serious illness in a family member, major holiday, vacation which is 
unable to be scheduled).  
For patients treated with the experimental therapies (cediranib and/or olaparib, Arms 2-4), the 
“Day 1” visit of the cycle may take place within a “7-day window of the protocol-defined date” 
for major life events.  Sufficient drug to encompass this window should be dispensed to the 
patient at the preceding visit if needed.  Patients on the experimental drug arms (cediranib and/or 
olaparib, Arms 2-4) who have their visit delayed should have their next visit scheduled as per 
their original schedule (e.g., a patient whose Cycle 2 Day 1 visit was delayed by a week should 

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have their Cycle 3 Day 1 visit 3 weeks after the delayed Cycle 2 Day 1 visit occurs, not 4 weeks 
after the delayed visit). 
  
For patients on Arm 1, it will be acceptable for individual chemotherapy doses to be delivered 
within 24 hours before and after the protocol-defined date for Day 1 of weekly treatment or 21- 
or 28- day cycles.  If the treatment due date is a Friday, and the patient cannot be treated on that 
Friday, the treatment window includes the preceding Thursday (1 day earlier than due) through 
the following Monday (day 3 past due). 
  
For patients on the experimental drug therapies (cediranib and/or olaparib, Arms 2-4), it will be 
acceptable for the Day 1 visit of each cycle to take place within 72 hours before or after the 
protocol-defined date. 
 
No modification of the regimens is allowed. 
 
5.1.1 Phase II study Arms/regimens 
 
5.1.1.1 Arm 1 (Reference Regimen): Physician’s choice standard of care chemotherapy:  
 
Patients randomized to the non-platinum-based chemotherapy arm may be treated with one of 
the three regimens specified in this section per investigator discretion (the planned regimen must 
be specified prior to randomization). The number of cycles of therapy should be administered as 
clinically appropriate. After completion of chemotherapy, patients will be followed without 
further chemotherapy or maintenance therapy until disease progression. 
 
x Regimen 1: Paclitaxel 80 mg/m2 intravenously (IV) over approximately 60 minutes on 
days 1, 8, 15, and 22 every 28 days 
 
x Regimen 2: Pegylated liposomal doxorubicin 40 mg/m2 IV over approximately 60 
minutes on day 1, every 28 days 
 
x Regimen 3: Topotecan 4 mg/m2 IV over approximately 30 minutes on days 1, 8, and 15 
every 28 days or 1.25 mg/m2 IV over approximately 30 minutes on days 1 to 5 every 21 
days. 
 
x No modification of the assigned regimens, such as additional drugs (gemcitabine, or 
bevacizumab) is allowed. (12/05/2016) 
 
5.1.1.2 Arm 2: Cediranib and olaparib. (12/05/2016) 
 
Cediranib 30 mg orally once daily and olaparib 200 mg in tablet formulation orally twice daily 
continuous dosing. The starting doses of 30mg can be taken as two 15mg tablets. Cediranib 
should be taken on an empty stomach in the morning approximately one hour before taking the 
morning dose of olaparib. Olaparib should be taken twice a day approximately 12 hours apart. 
 

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One cycle will be considered 28 days. Cycles are continuously numbered regardless of any dose 
holds or interruptions. 
 
Patients will need to keep medication and blood pressure diaries while taking either oral 
medication or both and for a cediranib-containing regimen, respectively. A blood pressure cuff 
will be provided to patients randomized to Arms 2 and 3. 
 
5.1.1.3 Arm 3: Cediranib (12/05/2016) 
 
Cediranib 30 mg orally daily continuous dosing. Cediranib should be taken on an empty stomach 
in the morning. The starting doses of 30mg can be taken as two 15mg tablets. 
 
One cycle will be considered 28 days. Cycle days are continuously numbered regardless of any 
dose holds or interruptions. 
 
Patients will need to keep medication and blood pressure diaries while taking cediranib. 
 
5.1.1.4 Arm 4: Olaparib (12/05/2016) 
 
Olaparib 300 mg in tablet formulation orally twice daily continuous dosing. Olaparib tablets 
should be taken twice a day approximately 12 hours apart. 
 
One cycle will be considered 28 days. Cycle days are continuously numbered regardless of any 
dose holds or interruptions. 
 
5.1.2 Phase III study Arms/regimens  
 
Patients will be randomized to one of 3 treatment regimens: the standard chemotherapy arm, the 
combination of cediranib and olaparib arm and the cediranib alone arm.  
 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as specified 
in the treatment modality sections or until one of the following criteria applies: 
x Disease progression, 
x Intercurrent illness that prevents further administration of treatment, 
x Unacceptable adverse event(s), as described in Section 6 
x Patient decides to withdraw consent for participation in the study, or 
x General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
  
 
5.1.2.1 Arm 1 (Reference Regimen): Physician’s choice standard of care chemotherapy:  
 
Patients randomized to the non-platinum-based chemotherapy arm may be treated with one of 
the three regimens specified in this section per investigator discretion (the planned regimen will 
be specified prior to randomization). The number of cycles of therapy should be administered as 

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clinically appropriate. After completion of chemotherapy, patients will be followed without 
further chemotherapy or maintenance therapy until disease progression. 
 
x Regimen 1: Paclitaxel 80 mg/m2 intravenously (IV) over approximately 60 minutes on 
days 1, 8, 15, and 22 every 28 days 
 
x Regimen 2: Pegylated liposomal doxorubicin 40 mg/m2 IV over approximately 60 
minutes on day 1, every 28 days 
 
x Regimen 3: Topotecan 4 mg/m2 IV over approximately 30 minutes on days 1, 8, and 15 
every 28 days or 1.25 mg/m2 IV over approximately 30 minutes on days 1 to 5 every 21 
days. 
 
x No modification of the assigned regimens, such as additional drugs (gemcitabine or 
bevacizumab) is allowed. (12/05/2016) 
 
5.1.2.2 Arm 2: Cediranib and olaparib. (12/05/2016) 
 
Cediranib 30 mg orally once daily and olaparib 200 mg in tablet formulation orally twice daily 
continuous dosing. The starting doses of 30mg can be taken as two 15mg tablets. Cediranib 
should be taken on an empty stomach in the morning approximately one hour before taking the 
morning dose of olaparib. Olaparib should be taken twice a day approximately 12 hours apart. 
 
One cycle will be considered 28 days. Cycles are continuously numbered regardless of any dose 
holds or interruptions. 
 
Patients will need to keep medication and blood pressure diaries while taking either oral 
medication or both and for a cediranib-containing regimen, respectively. A blood pressure cuff 
will be provided to patients randomized to Arm 2. 
 
5.1.2.3 Arm 3: Cediranib (12/05/2016) 
 
Cediranib 30 mg orally daily continuous dosing. Cediranib should be taken on an empty stomach 
in the morning. The starting doses of 30mg can be taken as two 15mg tablets. 
 
Patients will need to keep medication and blood pressure diaries while taking cediranib. 
 
One cycle will be considered 28 days. Cycles are continuously numbered regardless of any dose 
holds or interruptions. 
 
 
 
 
 
 

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6. 
TREATMENT MODIFICATIONS/MANAGEMENT 
 
Dose delays and modifications will be made using the following recommendations.  
 
Toxicity assessments will be done using NCI Common Terminology Criteria for Adverse Events 
(CTCAE). CTCAE is identified and located on the CTEP website at 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
For adverse events (AEs) that are unrelated to the study drugs, study treatment may be held for 
up to 14 days at the discretion of the treating investigator.  Drug holds of greater than 14 days 
for unrelated AEs where the patient is experiencing ongoing clinical benefit may be considered 
after discussion with the Study Chair. 
 
All AEs experienced by participants will be collected from the time of the first dose of study 
treatment, through the study and until the final study visit. Participants continuing to experience 
toxicity at the off study visit may be contacted for additional assessments until the toxicity has 
resolved or is deemed irreversible. 
 
There will be no dose escalations or re-escalations on this study. 
 
6.1 
Reference regimens (Arm I) 
 
Table 6.1.A:  Guidelines for permanent dose reductions, Reference Regimens 
Drug         
 Initial dose level 
First reduction 
Second reduction 
Paclitaxel1 
80 mg/m2 
Decrease dose to 70 mg/m2 
Decrease dose to 60 mg/ m2 
Pegylated liposomal 
doxorubicin 
40 mg/m2 
Decrease dose to 30 mg/m2 
Decrease dose to 20 mg/ m2 
Topotecan weekly 
4 mg/m2 
Decrease dose to 3.5 mg/m2 
Decrease dose to 3 mg/m2 
Topotecan mg/m2 per 
day over 5 days 
1.25 mg/m2 
Decrease dose to 1 mg/m2 
Decrease dose to 0.75 
mg/m2 
1Up to 2 dose reductions (70 mg/m2 and 60 mg/m2) are acceptable for paclitaxel. Instead of a second dose 
reduction, 70 mg/m2 can be maintained if subsequently a one weekly dose is omitted within one cycle.  
For selected patients, after discussion with Study Chair, a third dose reduction in paclitaxel to 60 mg/m2 
days #1, #8, and #15 can be considered. 
 
6.1.1 Hematologic Issues 
 
6.1.1.1 Use of hematopoietic agents 
 
x Myeloid growth factors (filgrastim or pegfilgrastim) may be used per institutional 
standards.  It is recommended that NCCN and/or ASCO guidelines be consulted.  
Filgrastim should be administered subcutaneously starting 24 to 72 hours after the last 
dose of chemotherapy and continuing through hematopoietic recovery, but should not be 
administered within the 48 hours preceding the next dose of cytotoxic chemotherapy.  
Pegfilgrastim should be administered at 6mg subcutaneously 24 to 72 hours after the last 
dose of chemotherapy and should not be administered within 2 weeks preceding the next 
dose of cytotoxic chemotherapy.  Pegfilgrastim should not be used for patients receiving 
chemotherapy that is given less than every 2 weeks. 

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x Use erythropoietin (EPO) 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. Treating physicians should be aware of 
the recent changes in prescribing information for the erythropoiesis stimulating agents 
(including Aranesp, Epogen and Procrit) which note that there is a potential risk of 
shortening the time to tumor progression or disease-free survival, and that these agents 
are administered only to avoid red blood cell transfusions. They do not alleviate fatigue 
or increase energy. They should not be used in patients with uncontrolled hypertension. 
They can cause an increased incidence of thrombotic events in cancer patients on 
chemotherapy. The updated package inserts should be consulted.  
x Transfusions may be administered as clinically indicated for management of anemia. 
x Patients will NOT receive prophylactic thrombopoietic agents.  
x Patients may NOT receive amifostine.  
x Initial treatment modifications will consist of cycle delay and/or dose reduction as 
indicated below for each regimen.  
x All Arms require ANC of 1500/mm3 and platelets of 100,000/mm3 for treatment 
initiation, the start of each cycle (Day #1), and treatment resumption after holding 
treatment. 
 
6.1.1.2 Arm I, Regimen I: Weekly paclitaxel 
 
Dose reductions for next course will be performed according to following guidelines for nadir: 
 
Table 6.1.1.2.A:  Dose modifications for neutropenia, Paclitaxel 
 
Hematologic Event 
Dose Modification 
Initial 
Occurrence 
Febrile Neutropenia† 
Grade 4 neutropenia (< 500/mm3)
lasting >7 days 
ANC < 1000/mm3 on Day 1 
Treatment delays > 7 days for 
neutropenia 
Reduce paclitaxel dose to 70 
mg/m2 
Second 
Occurrence 
If any of the above toxicities 
occur after initial dose 
reduction 
Reduce paclitaxel dose to 60 
mg/m2†† 
Third 
occurrence 
If any of the above toxicities 
occur after two dose 
reductions 
Discontinue paclitaxel 
† Febrile neutropenia is defined within the CTCAE as a disorder characterized by an 
ANC <1000/mm3 and a single temperature of >101 degrees F or a sustained degree of 
≥ 100.4 degrees F for more than an hour. 
††Up to 2 dose reductions (70 mg/m2 and 60 mg/m2) are acceptable for paclitaxel. 
Instead of a second dose reduction, 70 mg/m2 can be maintained if subsequently a one 
weekly dose is omitted within one cycle.  For selected patients, after discussion with 
Study Chair, a third dose reduction in paclitaxel to 60 mg/m2 days #1, #8, and #15 can 
be considered. 
 
 
Table 6.1.1.2.B:  Dose modifications for thrombocytopenia, Paclitaxel 

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Hematologic Event 
Dose Modification 
Initial 
Occurrence 
Any occurrence of grade 4 
thrombocytopenia 
(platelets < 25,000/ mm3) 
Grade 3 thrombocytopenia 
with bleeding event 
(platelets 25,000 to  
<50,000/ mm3) 
Severe Bleeding 
Reduce paclitaxel dose to 70 mg/m2 
Any  
Occurrence 
Severe Bleeding associated 
with Febrile Neutropenia 
Discontinue paclitaxel 
Second 
Occurrence 
If any of the above toxicities 
occur after initial dose 
reduction 
Reduce paclitaxel dose to 60 mg/m2† 
Third 
occurrence 
If any of the above toxicities 
occur after two dose 
reductions 
Discontinue paclitaxel 
†Up to 2 dose reductions (70 mg/m2 and 60 mg/m2) are acceptable for paclitaxel. 
Instead of a second dose reduction, 70 mg/m2 can be maintained if subsequently a one 
weekly dose is omitted within one cycle.  For selected patients, after discussion with 
Study Chair, a third dose reduction in paclitaxel to 60 mg/m2 days #1, #8, and #15 can 
be considered. 
 
 
6.1.1.2.1 Hematologic toxicity 
 
The WBC count must be ≥ 3000/mm3, ANC ≥ 1500/mm3 and the platelet count ≥ 100,000/mm3 
prior to the beginning of the following course of treatment on day 1. 
 
The day 8, 15, and 22 paclitaxel dose will not be given unless the ANC is at least 500/mm3 and 
the platelet count is as least 50,000/mm3. If not given, these doses are omitted and not made up.  
 
For patients who do not achieve hematological recovery on scheduled day of the course, 
complete blood counts should be performed twice weekly until the above defined limits are 
achieved. If hematological recovery is achieved within 14 days after the scheduled day of the 
course, the full dose of paclitaxel adjusted for the previous nadir should be administered 
immediately. If hematological recovery is not achieved 14 days or more after the scheduled day 
of the course, the patient will discontinue treatment.  
 
No more than two dose-reductions because of postponed treatment are permitted. However, 
instead of a second paclitaxel dose reduction, 70 mg/m2 can be maintained if subsequently a one weekly 
dose is omitted within one cycle.  For selected patients, after discussion with Study Chair, a third dose 
reduction in paclitaxel to 60 mg/m2 days #1, #8, and #15 can be considered. 
 
6.1.1.2.2 Non-hematologic toxicity 
 
x Management of non-hematologic toxicities on the reference arm should be per 
institutional practice and guidelines except for mucositis, cutaneous, and hepatic toxicity 
as noted below.  Criteria for dose holds and modifications on the reference arms for non-

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hematologic toxicity should follow institutional practice and prescribing information.  
Permanent dose reductions should follow dose levels as outlined in Table 6.1.A.   
x Other Major Organ Toxicity (not evaluated as disease related): If the patient has any 
clinically significant non-hematological drug related toxicity CTCAE grade > 3, the 
patient should discontinue protocol therapy unless strong clinical benefit and discussion 
with the Study Chair. 
x Dose modifications for alopecia, nausea, constipation, or electrolyte abnormalities are not 
recommended.   
x If treatment is delayed for greater than 3 weeks due to a drug-related non-hematologic 
toxicity, the patient may be discontinued from protocol-directed therapy after 
consultation with the Study Chair. 
 
6.1.1.2.2.1 Mucositis and cutaneous toxicity  
 
The occurrence of mucositis and cutaneous toxicity grade > 2 leads to a dose reduction of 
one level. A second occurrence will lead to a second dose reduction of one level. A third 
occurrence will lead to discontinuation of patient from protocol-directed therapy 
 
6.1.1.2.2.2 Hypersensitivity premedication and infusion related reactions (12/05/2016) 
 
Premedication prior to paclitaxel should be administered in accordance with local standard of 
care in order to prevent severe hypersensitivity reactions associated with paclitaxel. An example 
of premedication is as follows:  
x Dexamethasone 20 mg IV 30 minutes prior to paclitaxel  
x An anti-histamine H1 (diphenhydramine 25-50 mg IV or orally, or an equivalent dose of 
an alternate H1blocker such as loratadine or fexofenadine) 30 minutes prior to paclitaxel  
x A standard dose of antihistamine H2 IV (such as cimetidine, ranitidine, or famotidine) 30 
minutes prior to paclitaxel  
x 5HT3 Antagonist Single dose IV 30 minutes prior to paclitaxel  
 
Since significant hypersensitivity reactions may occur, appropriate supportive equipment should 
be available. Signs or symptoms of a hypersensitivity reaction may include chest tightness, back 
pain, diffuse erythroderma, dyspnea, tachycardia, hypertension, hypotension, and sensation of 
extreme anxiety. Significant hypersensitivity reactions as characterized by dyspnea and 
hypotension requiring treatment, angioedema, and generalized urticaria have occurred in <1% of 
patients receiving paclitaxel after adequate premedication. These reactions are probably 
histamine-mediated.  
 
Of note, the occurrence of a hypersensitivity reaction is not considered a dose-limiting toxicity.  
Patients experiencing a hypersensitivity reaction may be retreated at full doses under institutional 
protocols to prevent hypersensitivity reactions. See additional treatment and management options 
below.  Sites may also follow institutional guidelines for prevention and/or avoidance of 
hypersensitivity reactions. 
 
 
 

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Table 6.1.1.2.2.2A. Hypersensitivity Reactions 
Infusion 
Reaction 
Definition 
Appropriate Treatment and 
Management 
Grade 1   
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated. 
Stop infusion immediately. May consider 
retreatment. Treat per institutional 
guidelines. Patients can also discontinue 
therapy at the discretion of the 
investigator. 
Grade 2 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDS, narcotics, IV 
fluids); prophylactic medications indicated 
for <=24 hrs. 
Stop infusion immediately. May consider 
retreatment or desensitization. Treat per 
institutional guidelines. Patients can also 
discontinue therapy at the discretion of 
the investigator. 
 
Consider diphenhydramine 50 mg IVP 
and hydrocortisone 100 mg IV piggy 
back. Consider reinitiation of paclitaxel 
infusion approximately 30 minutes after 
initially stopping its administration as 
long as there is complete resolution of 
signs and symptoms of the reaction 
(Markman et al., 2000).  
 
See information regarding desensitization 
below.  
Grade 3 
Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae.  
Stop infusion immediately. May consider 
desensitization. Treat per institutional 
guidelines. Patients can also discontinue 
therapy at the discretion of the 
investigator. 
 
For desensitization: Consider 
dexamethasone 20 mg po the night 
before and the morning of treatment.  
Consider adding anti-histamines such as 
diphenhydramine 25-50 mg IV, and H2 
blockers such as famotidine 20 mg IV, or 
ranitidine (50 mg IV, and lorazepam 0.5-
1 mg po or IV as needed for anxiety can 
be added as premedications. 
Consider paclitaxel 2 mg in NS IV 
starting 30 minutes after treatment with 
premedications. If reaction, then STOP; 
give diphenhydramine 50 mg IV push 
and hydrocortisone 100 mg IV piggy 
back. Start again 30 minutes after 
symptoms subside.  Then paclitaxel 10 
mg in NS IV starting 60 minutes after 
treatment time.  
Then paclitaxel 175 mg/m2 IV starting 90 
minutes after treatment time (Markman 
et al., 2000). Check with institutional 
pharmacy guidelines regarding dosing, 
dilution in NS, and administration.  
 

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A patient who develops dyspnea and 
hypotension with premedication should 
not be rechallenged. 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated. 
Do not rechallenge. Paclitaxel should be 
discontinued. 
 
6.1.1.2.2.3 Modifications for hepatic toxicity 
 
Grade 3 (or greater) elevations in SGOT (AST), SGPT (ALT), alkaline phosphatase or bilirubin 
requires reduction of one dose level and delay in subsequent therapy for a maximum of 2 weeks 
until recovered to grade 1. If no recovery after 2 weeks, patient should discontinue drug.  
 
A second occurrence will lead to a second dose reduction of one level. A third occurrence will 
lead to discontinuation of patient from protocol-directed therapy. 
 
6.1.1.3 Arm I, Regimen II: Pegylated liposomal doxorubicin (PLD) 
 
Dose reductions for next course will be performed according to following guidelines for nadir: 
 
Table 6.1.1.3.A:  Dose modifications for neutropenia, PLD 
 
Hematologic Event 
Dose Modification 
Occurrence 
500–< 1,500/ mm3 
Wait until ANC ≥ 1,500/ mm3; 
redose with no dose reduction 
Initial 
Occurrence 
Grade 4 neutropenia (< 500/mm3) 
Wait until ANC ≥ 1,500/ mm3; 
reduce PLD dose to 30 mg/m2 
Second 
Occurrence 
Grade 4 neutropenia (< 500/mm3) 
Wait until ANC ≥ 1,500/ mm3; 
reduce PLD dose to 20 mg/m2 
Third 
occurrence 
Grade 4 neutropenia (< 500/mm3) 
Discontinue PLD 
 
Table 6.1.1.3.B:  Dose modifications for thrombocytopenia, PLD 
 
Hematologic Event 
Dose Modification 
Occurrence 
25,000–< 75,000/ mm3 
Wait until platelets ≥ 100,000/ mm3; 
redose with no dose reduction 
Initial 
Occurrence 
Any occurrence of grade 4 
thrombocytopenia 
(platelets < 25,000/mcL) 
or Severe bleeding 
Wait until platelets ≥ 100,000/ mm3; 
reduce PLD dose to 30 mg/m2 
Second 
Occurrence 
If any of the above toxicities 
occur after initial dose 
reduction 
Wait until platelets ≥ 100,000/ mm3; 
reduce PLD dose to 20 mg/m2 
Third 
occurrence 
If any of the above toxicities 
occur after initial dose 
reduction 
Discontinue PLD 
 
 
 
 
 

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6.1.1.3.1 Hematologic toxicity 
 
The WBC count must be ≥ 3000/mm3, ANC ≥ 1500/mm3 and the platelet count ≥ 100,000/mm3 
prior to the beginning of the following course of treatment on day 1. 
 
For patients who do not achieve hematological recovery on scheduled day of the course, 
complete blood counts should be performed twice weekly until the above defined limits are 
achieved. If hematological recovery is achieved within 14 days after the scheduled day of the 
course, the full dose of PLD adjusted for the previous nadir should be administered immediately. 
If hematological recovery is not achieved 14 days or more after the scheduled day of the course, 
the patient will discontinue treatment.  
 
No more than two dose-reductions because of postponed treatment are permitted.  
 
6.1.1.3.2 Non-hematologic toxicity 
 
x Management of non-hematologic toxicities on the reference arm should be per 
institutional practice and guidelines except for mucositis, cutaneous, stomatitis and 
hepatic toxicity as noted below.  Criteria for dose holds and modifications on the 
reference arms for non-hematologic toxicity should follow institutional practice and 
prescribing information.  Permanent dose reductions should follow dose levels as 
outlined in Table 6.1.A.   
 
Other Major Organ Toxicity (not evaluated as disease related): If the patient has any 
clinically significant non-hematological drug related toxicity CTCAE grade > 3, the 
patient should discontinue protocol therapy unless strong clinical benefit and discussion 
with the Study Chair. 
 
x Dose modifications for alopecia, nausea, constipation, or electrolyte abnormalities are not 
recommended.   
 
x If treatment is delayed for greater than 3 weeks due to a drug-related non-hematologic 
toxicity, the patient may be discontinued from protocol-directed therapy after 
consultation with the Study Chair. 
 
6.1.1.3.2.1 Mucositis and cutaneous toxicity  
 
In case of grade ≥2 hand-foot syndrome (HFS) or stomatitis, the pegylated liposomal 
doxorubicin (PLD) dose will be delayed until resolved to grade ≤1 or discontinued if not 
resolved within 2 weeks. In addition, subsequent doses will be reduced if the HFS or stomatitis is 
grade ≥3. The following tables show the dose modifications for PLD and the course delays 
recommended as a function of the occurrence and severity of mucositis and cutaneous toxicity, 
respectively. 
 
 
 

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Table 6.1.1.3.2.1A: PLD Dose Modification Guidelines for Hand-Foot Syndrome (HFS) 
Toxicity Grade  
Dose Adjustment 
1: mild erythema, 
swelling, or 
desquamation not 
interfering with daily 
activities  
Redose unless patient has experienced previous Grade 3 or 4 
HFS.  
If so, delay up to 2 weeks and decrease reduce 1 dose level. Return 
to original dose interval.   
2: erythema, 
desquamation, or 
swelling interfering with, 
but not precluding 
normal physical 
activities; small blisters 
or ulcerations <2 cm in 
diameter  
Delay dosing up to 2 weeks or until resolved to Grade 0-1.  
If after 2 weeks there is no resolution, PLD should be 
discontinued.  
If resolved to Grade 0-1 within 2 weeks and there are no prior 
Grade 3-4 HFS, continue treatment at previous dose and return to 
original dose interval. If patient experienced previous Grade 3–4 
toxicity, continue treatment with reduce 1 dose level.and return to 
original dose interval. 
3: blistering, ulceration, 
or swelling interfering 
with walking or normal 
daily activities; cannot 
wear regular clothing  
Delay dosing up to 2 weeks or until resolved to Grade 0–1. 
Reduce 1 dose level.and return to original dose interval. If after 2 
weeks there is no resolution, PLD should be discontinued.  
 
4: diffuse or local 
process causing 
infectious complications, 
or a bed ridden state or 
hospitalization  
  
Delay dosing up to 2 weeks or until resolved to Grade 0–1. 
Reduce 1 dose level and return to original dose interval. If after 2 
weeks there is no resolution, PLD should be discontinued. 
 
 
 
Table 6.1.1.3.2.1B: PLD Dose Modification Guidelines for Stomatitis 
Toxicity Grade  
Dose Adjustment 
1: painless ulcers,  
erythema, or mild  
soreness  
Redose unless patient has experienced previous Grade 3 or 4 
toxicity. If so, delay up to 2 weeks and reduce 1 dose level. Return 
to original dose interval.   
2: painful erythema, 
edema, or ulcers, but can 
eat  
 
Delay dosing up to 2 weeks or until resolved to Grade 0-1.  
If after 2 weeks there is no resolution, PLD should be 
discontinued.  
If resolved to Grade 0-1 within 2 weeks and there are no prior 
Grade 3-4 stomatitis, continue treatment at previous dose and 
return to original dose interval. If patient experienced previous 
Grade 3–4 toxicity, continue treatment with a 1 dose level 
reduction and return to original dose interval. 
3: painful erythema, 
edema, or ulcers, and 
cannot eat  
Delay dosing up to 2 weeks or until resolved to Grade 0–1. 
Reduce 1 dose level and return to original dose interval. If after 2 
weeks there is no resolution, PLD should be discontinued.  
4: requires parenteral or 
enteral support  
 
Delay dosing up to 2 weeks or until resolved to Grade 0–1. 
Reduce 1 dose level and return to original dose interval. If after 2 
weeks there is no resolution, PLD should be discontinued. 
 
 

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6.1.1.3.2.2 Modifications for hepatic toxicity 
 
Limited clinical experience exists in treating patients with hepatic impairment with PLD. The 
pharmacokinetics of PLD has not been adequately evaluated in patients with hepatic impairment. 
Doxorubicin is eliminated in large part by the liver. Reduce PLD for serum bilirubin of 1.2 
mg/dL or higher. 
Based on experience with doxorubicin HCl, it is recommended that the PLD dosage be reduced 
if the bilirubin is elevated as follows: 
serum bilirubin 1.2 to 3 mg/dL: give 20mg/m2  
serum bilirubin > 3 mg/dL: discontinue treatment  
 
6.1.1.3.2.3 Hypersensitivity: Infusion related reactions 
 
Serious and sometimes life-threatening infusion-related reactions can occur with PLD including 
flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in 
the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, 
apnea, and hypotension. The majority of infusion-related events occurred during the first 
infusion. Seven percent of women with ovarian cancer treated on clinical trials with PLD 
experienced acute infusion-related reactions and all reactions occurred during cycle 1.  
 
Since significant hypersensitivity reactions may occur, appropriate supportive equipment should 
be available. Signs or symptoms of a hypersensitivity reaction may include chest tightness, back 
pain, diffuse erythroderma, dyspnea, tachycardia, hypertension, hypotension, and sensation of 
extreme anxiety. In case of a hypersensitivity reaction, the infusion will be stopped immediately 
and patient treated per institutional guidelines. If the reaction is completely disappeared, the 
infusion might be continued at a reduced infusion velocity. See additional treatment and 
management options below.  
 
Table 6.1.1.3.2.3A. Hypersensitivity Reactions 
Infusion 
Reaction 
Definition 
Appropriate Treatment and 
Management 
Grade 1   
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated. 
Stop infusion immediately. May consider 
retreatment. Treat per institutional 
guidelines. Patients can also discontinue 
therapy at the discretion of the 
investigator. 
Grade 2 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDS, narcotics, IV 
fluids); prophylactic medications indicated 
for <=24 hrs. 
Stop infusion immediately. May consider 
retreatment or desensitization. Treat per 
institutional guidelines. Patients can also 
discontinue therapy at the discretion of 
the investigator. 
 
Consider retreatment if resolution of 
symptoms. Resume PLD infusion at a 
reduced rate of 1 mg/min and increase 
rate as tolerated [see PLD package 
insert]. Discontinue PLD infusion for 

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serious or life-threatening infusion-
related reactions. 
 
Anti-histamines such as 
diphenhydramine 25-50 mg IV, and H2 
blockers such as famotidine 20 mg IV, or 
ranitidine (50 mg IV, and lorazepam 0.5-
1 mg po or IV as needed for anxiety can 
be added as premedications. 
Grade 3 
Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae.  
Stop infusion immediately. May consider 
desensitization. Treat per institutional 
guidelines. Patients can also discontinue 
therapy at the discretion of the 
investigator. 
 
For desensitization: Consider 
dexamethasone 20 mg po the night 
before and the morning of treatment. 
Consider adding anti-histamines such as 
diphenhydramine 25-50 mg IV, and H2 
blockers such as famotidine 20 mg IV, or 
ranitidine (50 mg IV, and lorazepam 0.5-
1 mg po or IV as needed for anxiety as 
premedications. PLD infusion at a 
reduced rate of 1 mg/min and increase 
rate as tolerated [see PLD package insert] 
or may follow formal desensitization 
protocol (Castells et al., 2008). 
 
Discontinue PLD infusion for serious or 
life-threatening infusion-related 
reactions. 
 
A patient who develops dyspnea and 
hypotension with premedication should 
not be rechallenged. 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated. 
Do not rechallenge. PLD should be 
discontinued. 
 
6.1.1.4 Arm I, Regimen III: Topotecan 
 
6.1.1.4.1 Weekly topotecan administration: definition of dose levels 
 
In the weekly schedule, the minimal infusion dose of topotecan is 3 mg/m2. Standard dose-
adjustments based on observed toxicities should be made, as follows:  
  
The WBC count must be ≥ 3000/mm3, ANC ≥ 1500/mm3 and the platelet count ≥ 100,000/mm3 
prior to the beginning of the following course of treatment on day 1. 
 
The day 8, and 15 topotecan dose will not be given unless the ANC is at least 1000/mm3 and the 
platelet count is as least 75,000/mm3. If day 8 dosing criteria are not met, hold the dose and treat 
on day 15 as planned if toxicity has resolved. If day 15 dosing criteria are not met, hold the dose. 
Start the next full cycle (i.e. Day 1 treatment) one week later if toxicity has resolved. If day 8 and 

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15 dosing criteria are not met, yet the patient’s counts recover within 2 weeks, start the next full 
cycle at 1 dose reduction level lower. 
 
For patients who do not achieve hematological recovery on scheduled day of the course, 
complete blood counts should be performed twice weekly until the above defined limits are 
achieved. If hematological recovery is achieved within 14 days after the scheduled day of the 
course, the full dose of topotecan adjusted for the previous nadir should be administered 
immediately. If hematological recovery is not achieved 14 days or more after the scheduled day 
of the course, the patient will discontinue treatment.  
 
 
Table 6.1.1.4.1.A:  Dose modifications for neutropenia, Weekly Topotecan 
 
Hematologic Event 
Dose Modification 
Initial 
Occurrence 
Febrile Neutropenia† 
Grade 4 neutropenia (< 500/mm3)
lasting >7 days 
 
Reduce weekly topotecan dose to 
3.5 mg/m2 
Second 
Occurrence 
If any of the above toxicities 
occur after initial dose 
reduction 
Reduce weekly topotecan dose to 
3 mg/m2 
Third 
occurrence 
If any of the above toxicities 
occur after two dose 
reductions 
Discontinue topotecan 
† Febrile neutropenia is defined within the CTCAE as a disorder characterized by an 
ANC <1000/ mm3 and a single temperature of >101 degrees F or a sustained degree of 
≥ 100.4 degrees F for more than an hour. 
*If day 8 and 15 dosing criteria are not met, yet the patient’s counts recover within 
2 weeks, start the next full cycle at 1 dose reduction level lower. 
 
Table 6.1.1.4.1.B:  Dose modifications for thrombocytopenia, Weekly Topotecan 
 
Hematologic Event 
Dose Modification 
Initial 
Occurrence 
Any occurrence of grade 4 
thrombocytopenia 
(platelets < 25,000/ mm3) 
or Severe bleeding 
Reduce weekly topotecan dose to 3.5 
mg/m2 
Second 
Occurrence 
If any of the above toxicities 
occur after initial dose 
reduction 
Reduce weekly topotecan dose to 3 
mg/m2 
Third 
occurrence 
If any of the above toxicities 
occur after initial dose 
reduction 
Discontinue topotecan 
*If day 8 and 15 dosing criteria are not met, yet the patient’s counts recover within 
2 weeks, start the next full cycle at 1 dose reduction level lower. 
 
 
6.1.1.4.2 Topotecan administration in the 5-day schedule: definition of dose levels  
 
In the daily schedule, the minimal infusion dose of topotecan is 0.75 mg/m2. Subsequent cycles 

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of therapy (i.e. Day 1 treatment) will not begin until the ANC is ˻ 1500/mm3 and the platelet 
count is ˻ 100,000/mm3. Standard dose-adjustments based on observed toxicities should be 
made, as follows:  
 
 
Table 6.1.1.4.2.A:  Dose modifications for neutropenia, 5-day Topotecan  
 
Hematologic Event 
Dose Modification 
Initial 
Occurrence 
Febrile Neutropenia† 
Grade 4 neutropenia (< 500/mm3)   
lasting >7 days 
Grade 3 neutropenia (500-900/ mm3) 
lasting beyond Day 21 of the treatmen
course or associated with fever or 
infection 
Reduce topotecan dose to 1 
mg/m2 
Second 
Occurrence 
If any of the above toxicities occur 
after initial dose reduction 
Reduce topotecan dose to 0.75 
mg/m2 
Third 
occurrence 
If any of the above toxicities occur 
after two dose reductions 
Discontinue topotecan 
† Febrile neutropenia is defined within the CTCAE as a disorder characterized by an 
ANC <1000/ mm3 and a single temperature of >101 degrees F or a sustained degree of 
≥ 100.4 degrees F for more than an hour. 
 
 
Table 6.1.1.4.1.B:  Dose modifications for thrombocytopenia, 5-day Topotecan  
 
Hematologic Event 
Dose Modification 
Initial 
Occurrence 
Any occurrence of grade 4 
thrombocytopenia 
(platelets < 25,000/ mm3) 
or Severe bleeding 
Reduce topotecan dose to 1 mg/m2 
Second 
Occurrence 
If any of the above toxicities 
occur after initial dose 
reduction 
Reduce topotecan dose to 0.75 
mg/m2 
Third 
occurrence 
If any of the above toxicities 
occur after initial dose 
reduction 
Discontinue topotecan 
 
If the criteria for topotecan administration are not met at the beginning of a new cycle, this cycle 
should be postponed, but not longer than 14 days, until the patient recovered. If the next 
treatment cycle is postponed by >7 days because of toxicity, a dose- reduction by one level 
applies. Patients who do not have hematologic recovery sufficient for treatment within 14 days 
should discontinue drug.  
 
6.1.1.4.3 Hematologic toxicity 
 
x Subsequent cycles of therapy (i.e. Day 1 treatment) will not begin until the ANC is ˻ 
1500/ mm3 and the platelet count is ˻ 100,000/ mm3. Therapy will be delayed for a 
maximum of two weeks until these values are achieved. Patients who fail to recover 
adequate counts within a 14 day delay should discontinue drug. Dose- adjustments 

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because of hematological toxicities are made based on the most severe toxicity of the 
preceding infusion.   
 
x For first occurrence of febrile neutropenia, and/or documented grade 4 neutropenia 
persisting > 7 days, reduce chemotherapy by one dose level on subsequent cycles. 
 
x For recurrent febrile neutropenia, and/or recurrent documented grade 4 neutropenia 
persisting ˻ 7 days (after initial dose reduction), add prophylactic growth factors as per 
ASCO and/or institutional guidelines (See 6.1.1.1). 
 
x Patients with grade 4 thrombocytopenia will have a 1 level dose reduction. 
 
x No more than two dose-reductions because of postponed treatment are permitted.  
 
6.1.1.4.4 Non-hematologic toxicity 
 
x Management of non-hematologic toxicities on the reference arm should be per 
institutional practice and guidelines except for hepatic toxicity as noted below.  Criteria 
for dose holds and modifications on the reference arms for non-hematologic toxicity 
should follow institutional practice and prescribing information.  Permanent dose 
reductions should follow dose levels as outlined in Table 6.1.A.   
 
x Other Major Organ Toxicity (not evaluated as disease related): If the patient has any 
clinically significant non-hematological drug related toxicity CTCAE grade > 3, the 
patient should discontinue drug unless strong clinical benefit and discussion with the 
Study Chair. 
 
x Dose modifications for alopecia, nausea, constipation, or electrolyte abnormalities are not 
recommended.   
 
x If treatment is delayed for greater than 3 weeks due to a drug-related non-hematologic 
toxicity, the patient should discontinue drug therapy. 
 
6.1.1.4.4.1 Modifications for renal toxicity 
 
Creatinine clearance (Clcr) 20 to 39 mL/min reduce dose of topotecan to 0.75 mg/m2 per dose.  
Insufficient data are available in patients with severe renal impairment (Clcr less than 20 mL/min) to 
provide a dosage recommendation for topotecan.  
 
If Clcr less than 20 mL/min delay in subsequent therapy for a maximum of 2 weeks until Clcr is 
acceptable for treatment (> 20 mL/min). If no recovery after 14 days, patient should discontinue 
the drug.  
 
6.1.1.4.4.2 Modifications for hepatic toxicity 
 
Plasma clearance of topotecan in patients with hepatic impairment (serum bilirubin levels between 

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1.7 and 15.0 mg/dL) no dose adjustment is necessary (The half-life is increased slightly; usual doses 
are generally tolerated).  
 
6.2 
Arms II (cediranib and olaparib), III (cediranib alone), and IV (olaparib alone)   
 
This study will not be blinded or placebo controlled as the treatment regimens used vary by route 
of administration, schedules, and anticipated drug related toxicities that make blinding less 
feasible and unnecessary. 
 
Arm II 
 
The dose levels and the general approach to dose modification of olaparib and cediranib 
combination therapy are shown below.  AEs should be treated with the appropriate maximum 
supportive care, and dose reductions should be clearly documented in the case report form. 
 
Dose Level 
Olaparib tablets 
1  
200 mg twice daily 
-1 
150 mg twice daily 
-2 
100 mg twice daily  
 
Dose level 
Cediranib tablets  
1 
30 mg daily 
-1 
30 mg Monday through Friday (weekend off) 
-2 
20 mg daily 
-3 
20 mg Monday through Friday (weekend off) 
 
For Arm II, at the discretion of the investigator, the study drugs may be held or dose modified 
independently if the observed toxicity is attributed to only one of the drugs, while the patient 
continues to receive the drug not associated with the observed toxicity.  The time a given drug is 
held should not exceed 14 days.  Patients experiencing ongoing clinical benefit who experience a 
related AE where continuation of one of the drugs is considered, in the judgment of the 
treating investigator AND the Study Chair, to be potentially life-threatening or with the 
potential for long-term harm to the patient, may be allowed to continue on the unrelated drug 
after discussion with the Study Chair. 
 
Arm III 
 
 
Dose level 
Cediranib tablets  
1 
30 mg daily 
-1 
30 mg Monday through Friday (weekend off) 
-2 
20 mg daily 
-3 
20 mg Monday through Friday (weekend off) 
 
 
 

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6.2.1 Hematologic toxicity 
 
6.2.1.1 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. Treating physicians should be aware of the recent 
changes in prescribing information for the erythropoiesis stimulating agents (including Aranesp, 
Epogen and Procrit) which note that there is a potential risk of shortening the time to tumor 
progression or disease-free survival, and that these agents are administered only to avoid red 
blood cell transfusions. They do not alleviate fatigue or increase energy. They should not be used 
in patients with uncontrolled hypertension. They can cause an increased incidence of thrombotic 
events in cancer patients on chemotherapy. The updated package inserts should be consulted. 
 
Use of granulocyte-colongy stimulating factors will not be allowed in Arms II, III and IV. 
 
6.2.1.2 Dose modifications  
 
Dose modifications for hematologic events on these arms should be managed per the following 
table.  
 
Table 6.2.1.2A:  Dose Modification and Management of Hematologic Adverse Events, 
Arms II-IV 
Hematologic Event 
Dose Modification 
Absolute neutrophil count ≥ 1500/mm3 
AND  
Platelets ≥ 100,000/mm3 
AND 
Hemoglobin ≥ 8 mg/dL  
Maintain dose level 
Absolute neutrophil count < 1500/mm3 
OR 
Platelets < 100,000/mm3 
OR 
Hemoglobin < 8 mg/dL 
Hold treatment for up to 14 days until 
absolute neutrophil count ≥ 1500/mm3, 
platelets ≥ 100,000/mm3, and 
hemoglobin ≥ 8 mg/dL. Treatment may 
be restarted at one dose level lower for 
the drug(s) causing the toxicity, as per 
the dose reduction levels in Section 6.2, 
at the treating investigator’s discretion.  
For patients whose treatment is held for 
ANC between 1000 and 1500/mm3, 
treatment may be resumed at the prior 
dose level, at the treating investigator’s 
discretion. 
 
Patients whose counts have not 
recovered to absolute neutrophil count ≥ 
1500/mm3, platelets ≥ 100,000/mm3, and 
hemoglobin ≥ 8 mg/dL after 14 days 

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should be removed from the study 
treatment. 
Grade 4 hematologic AE related to cediranib or 
olaparib that does not resolve to absolute 
neutrophil count ≥ 1500/mm3, platelets ≥ 
100,000/mm3, and hemoglobin ≥ 8 mg/dL 
despite maximum supportive care after 14 days. 
Discontinue study drug(s) 
 
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 4 weeks, patients should be referred to a hematologist for 
further assessment.  A bone marrow analysis should be considered per hematology assessment. 
 
For AEs that are unrelated to the study drugs, study drug may be held for up to 14 days at the 
discretion of the treating investigator.  Drug holds of greater than 14 days for unrelated AEs 
where the patient is experiencing ongoing clinical benefit may be considered after discussion 
with the Study Chair. 
 
Patients experiencing ongoing clinical benefit who experience a related AE where continuation 
of one of the drugs is considered, in the judgment of the treating investigator AND the Study 
Chair, to be potentially life-threatening or with the potential for long-term harm to the patient, 
may be allowed to continue on the unrelated drug after discussion with the Study Chair. 
 
 
6.2.2   Non-hematologic toxicity 
 
Table 6.2.2.A:  General Management of Non-Hematologic Toxicity, Arms II - IV 
Observation 
Action 
AE resolves promptly with supportive care  
Maintain dose level 
Any  t grade 3 non-hematologic (excluding grade 3 
fatigue or easily correctable asymptomatic grade 3 
laboratory abnormalities) 
Hold study drug(s)1 for up to 14 days 
until toxicity resolves to d grade 1. 
Treatment may be restarted at one dose 
level lower for the drug(s) causing the 
toxicity, as per the dose reduction 
levels in Section 6.2, at the treating 
investigator’s discretion2. The Study 
Chair should be informed regarding all 
dose modifications. 
Any grade 2 non-hematologic AE or grade 3 fatigue 
related to cediranib or olaparib that persists despite 
maximal support.  
Hold study drug(s)1 for up to 14 days 
until toxicity resolves to d grade 1.  
Treatment may be restarted at one dose 
level lower for the drug(s) causing the 
toxicity, as per the dose reduction 
levels in Section 6.2, at the treating 
investigator’s discretion2. The Study 
Chair should be informed regarding all 
dose modifications. Patients whose 

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The management of general adverse events not otherwise specified in the following sections 
should be as per Table 6.2.2.A. Management of specific toxicities, including hypertension, 
diarrhea, proteinuria, decrease in LVEF, fever and neutropenia, nausea and vomiting, thyroid 
toxicities, reversible posterior leukoencephalopathy syndrome (RPLS) and gastrointestinal 
perforation should be as further outlined in the below specific subsections and not per Table 
6.2.2.A. 
 
* Management of olaparib-induced nausea and vomiting 
 
Events of nausea and vomiting are known to be associated with olaparib treatment. In study 
D0810C00019 nausea was reported in 71% of the olaparib treated patients and 36% in the 
placebo treated patients and vomiting was reported in 34% of the olaparib treated patients and 
14% in the placebo treated patients. These events are generally mild to moderate (CTCAE grade 
1 or 2) severity, intermittent and manageable on continued treatment. The first onset generally 
occurs in the first month of treatment for nausea and within the first 6 months of treatment for 
vomiting. For nausea, the incidence generally plateaus at around 9 months, and for vomiting at 
around 6 to 7 months. 
 
No routine prophylactic anti-emetic treatment is required at the start of study treatment; however, 
patients should receive appropriate anti-emetic treatment at the first onset of nausea or vomiting 
and as required thereafter, in accordance with local treatment practice guidelines. Alternatively, 
olaparib tablets can be taken with a light meal/snack (ie 2 pieces of toast or a couple of biscuits). 
 
6.2.2.1 Hypertension (12/05/2016) 
 
Only doses of cediranib will be modified for hypertension; olaparib doses will not be reduced 
unless other toxicities are experienced.   
 
toxicity has not resolved after 14 days 
will be removed from the study 
treatment. 
1. Grade 3 or 4 non-hematologic AE related to 
cediranib and olaparib combination that does not 
resolve to grade 0-2 within 14 days despite 
maximum supportive care after treating patient at 
the lowest reduced dose level.3 
2. Grade 3 or 4 non-hematologic AE related to 
cediranib/olaparib lasting > 14 days despite 
maximum supportive care and treatment being held. 
Discontinue study drug(s) 
1At the discretion of the investigator, one drug may be held or dose modified or 
discontinued independently if the observed toxicity is attributed to only one of the drugs, 
while the patient continued to receive the second drug not associated with the observed 
toxicity.  The time a given drug is held should not exceed 14 days. 
2Patients who are at the lowest reduced dose level may have their drug resumed at that dose level 
after discussion with the Study Chair if evidence of clinical benefit. 
3For thromboembolic events, treatment may be resumed at the discretion of the investigator once 
patient is asymptomatic. 

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Table 6.2.2.1.A: Hypertension Monitoring and Management 
x 
See Appendix VI for suggested antihypertensive medications by class 
x 
Abbreviations: Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin II Receptor 
Blockers (ARB), selective beta blockers (BB), Dihydropyridine calcium channel blockers 
(DHP-CCP) 
x 
If patients require a delay of >2 weeks for management of hypertension, discontinuation of 
cediranib or protocol therapy may be considered after discussion with the Study Chair. 
x 
Patients may have up to 4 drugs for management of hypertension prior to any dose reduction 
in cediranib 
x 
Hypertension should be graded using the NCI CTCAE. Please note: patients may have 
baseline hypertension meeting CTCAE grading criteria on study entry.  Should patients require 
increase in dosing of BP medication or increased number of medications, they should then be 
noted to have hypertension related to study drug, with grading as per CTCAE criteria.  
Baseline grade of hypertension should also be recorded in the patient’s record. 
x 
Note:  Stopping or reducing the dose of cediranib is expected to cause a decrease in BP.  The 
treating physician should monitor the patient for hypotension (also during the weekend 
when the patients do not take cediranib for DL-1 and DL-3) and adjust the number and 
dose of antihypertensive medications accordingly. 
Event 
Definition 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Cediranib/ Dose 
Modification 
 
Grade 1 
 
 
Asymptomatic 
transient (<24 
hours) increase 
by >20 mmHg 
diastolic or to > 
140/90 mmHg if 
previously WNL 
Consider early initiation 
of BP medication for BP 
> 140/90 mmHg that is 
confirmed on a second 
reading.  Cediranib can 
cause rapid escalation in 
BP, and early initiation of 
BP management can 
reduce likelihood of 
HTN-related 
complications. 
Continue standard 
BP monitoring 
per treating MD 
and confirm 
resolution of BP 
to <140/90 
mmHg within 24 
hours. 
None 
 
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 
 
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. 
 
Increase 
frequency of 
monitoring until 
stabilized to BP 
<140/90 mmHg 
Do not hold 
cediranib unless 
otherwise clinically 
necessary 

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Study drug does not 
need to be held unless 
otherwise clinically 
necessary 
 
Consider renal consult 
 
Grade 3 
Requiring more 
than one drug or 
more intensive 
therapy than 
previously.     
Maximize 2 drug regimen 
x Suggestions: ACE-
inhibitor + BB 
 
Escalate doses of existing 
medication until BP is 
controlled or at a 
maximum dose. 
 
If BP is not controlled to 
< 140/90 mmHg with two 
drug regimen, then add a 
third agent. 
 
Study Drug will not be 
held during trial of 
multi- 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. 
Increase 
frequency of 
monitoring until 
stabilized to BP 
<140/90 mmHg 
Do not hold 
cediranib or other 
study drugs unless 
BP is not decreased 
to less than 
150/100 mmHg 48 
hours after multi-
drug therapy is 
instituted or if 
clinical symptoms 
worsen (e.g. 
headache). 
 
If BP is not 
controlled to less 
than 150/100 
mmHg with 
maximal therapy or 
if 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 
Grade 1 within 14 
days, cediranib 
may be resumed at 
prior dose. 
 
Grade 4 
If threatening 
consequences 
 
OR 
 
SBP ≥ 180mmHg 
 
OR 
 
DBP ≥ 
110mmHg 
Initiate treatment 
 
Hospitalize patient for 
ICU management, IV 
therapy as necessary 
 
14 days are allowed to 
maximize the full effect 
of anti-hypertensive 
agents. 
Intensive BP 
monitoring 
(hospitalization if 
necessary) 
Hold cediranib. 
 
If BP is reduced to 
Grade 1 within 14 
days, cediranib 
may be resumed at 
a reduced dose 
after discussion 
with the Study 
Chair and/or 
sponsor. 
WNL, within normal limits 

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6.2.2.2 Diarrhea 
 
Diarrhea is often observed with cediranib, and active and early management of diarrhea is 
recommended even with grade 1 diarrhea.  Management as follows: 
 
Table 6.2.2.2.A:  Management of Diarrhea 
Toxicity 
Management/Modifications 
Initial grade 1 or 2 diarrhea: 
Patients can take loperamide (per standard 
practice) and continue to take loperamide until 
patients are free from diarrhea for at least 12 
hours.  The dose of loperamide should not exceed 
16mg in a 24-hour period. Patients should also be 
counseled to start a BRAT (bananas, rice, 
applesauce, toast) diet. 
If diarrhea persists despite 24 hours of loperamide 
treatment, hold cediranib for a maximum of 7 
days, continue loperamide, and maintain 
hydration.  Cediranib may be restarted at the same 
dose once patients have been free from diarrhea 
for 12 hours. 
For either persistent grade 2 diarrhea or grade 3 or 
4 diarrhea:  
Follow 6.2.2.A  
 
6.2.2.3 Proteinuria 
 
Although patients with ≥1+ proteinuria at entry are ineligible, increases in proteinuria may occur 
during treatment and should be managed as follows:  
 
Table 6.2.2.3.A:  Management of Proteinuria 
Proteinuria Value if 
following by U/A 
Monitoring 
Dose modification 
Greater than 2+ on urine 
dipstick or U/A  
AND 
Creatinine ≤1.5x ULN 
Perform UPC.  
Continue study drugs at 
planned dose. 
Greater than 2+ on urine 
dipstick or U/A AND 
Creatinine >1.5x ULN 
Perform UPC. 
HOLD cediranib until 
results of UPC are known, 
and see below 
Based on results of the UPC†: 
UPC ≤ 1.0 
Continue monitoring prior to each cycle as 
per previous. 
Continue study drugs at 
planned dose. 

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UPC > 1.0 and ≤ 3.5 
AND Creatinine ≤1.5x 
ULN 
Perform UPC prior to each cycle. 
Continue study drugs at 
planned dose. 
UPC > 3.5 OR 
Creatinine >1.5x ULN 
Perform UPC prior to each cycle. 
Hold cediranib for up to 7 
days and repeat UPC and 
Creatinine assessment.  If 
UPC resolves to <3.5 and 
Creatinine to ≤1.5x ULN, 
resume cediranib with 
reduction in cediranib by one 
dose level.  Consider 
consultation with 
nephrologist. 
†If UPC is <1.0 and creatinine >1.5x ULN, AE management should be followed as per Table 6.2.2.3A 
 
6.2.2.4 Thyroid toxicities 
 
The use of cediranib has been associated with elevations of the thyroid stimulating hormone 
(TSH) and patients should be managed as per the following table.  
In all cases, study treatment should continue unless clinically contraindicated.  Referral to an 
endocrinologist should also be considered if thyroid abnormalities occur.  
 
Table 6.2.2.4.A:  Monitoring and Management of Thyroid Toxicities 
Result of TSH*, T4, and T3 
Action 
Increases of TSH with normal T4/T3:  
Monitor 
Increases in TSH with normal T4/T3 and adverse 
events suggestive of incipient hypothyroidism: 
Consider replacement thyroxine.   
Increase in TSH with reductions in T4 and T3: 
Consider replacement thyroxine. 
*Please consider requesting T3/T4 where TSH is elevated. 
 
6.2.2.5 Decrease in LVEF (12/05/2016) 
 
Patients who have any of the following should undergo an echocardiogram (ECHO) or multi-
gated acquisition (MUGA) scan at baseline and every four cycles (16 weeks) while on study: 
 
x Prior treatment with anthracyclines 
x Prior treatment with trastuzumab 
x Prior central thoracic radiation therapy (RT), including RT to the heart 

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x History of myocardial infarction within 6 to 12 months (Patients with history of 
myocardial infarction within 6 months are excluded from the study)  
 
The decision to continue or hold cediranib/olaparib is based on the LVEF as it relates to the 
institution’s lower limit of normal (LLN) and change in ejection fraction from screening (LVEF 
as measured at registration) according to the following table:    
 
Table 6.2.2.5.A:  Management and Monitoring of Decreased LVEF 
Relationship of 
LVEF to 
Institution’s LLN 
LVEF Decrease 
< 10% 
LVEF Decrease 
10-15% 
LVEF Decrease 
> 16% 
Normal 
Continue 
Continue 
Continue and 
repeat MUGA/ECHO 
within 1-2 cycles 
1-5% below LLN 
 
Continue and 
repeat MUGA/ECHO 
within 1-2 cycles 
Continue and 
repeat MUGA/ECHO 
within 1-2 cycles 
HOLD and 
repeat MUGA/ECHO 
within 1-2 cycles 
> 6% below LLN 
 
Continue and 
repeat MUGA/ECHO 
within 1-2 cycles 
HOLD and 
repeat MUGA/ECHO 
within 1-2 cycles 
HOLD and 
repeat MUGA/ECHO 
within 1-2 cycles 
 
6.2.2.6  Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 
 
Cediranib and/or olaparib should be held in patients with symptoms/signs suggestive of RPLS, 
pending work-up and management, including control of blood pressure. Cediranib and/or 
olaparib should be discontinued upon diagnosis of RPLS. Study drugs should not be resumed 
without consultation with the Study Chair. After consultation with the Study Chair and the NCI, 
consideration of restarting the study may be evaluated in light of any clinical benefit. 
 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS 
 
7.1 
Protocol Agents (12/05/2016) 
 
Investigational Agents 
The investigational agents administered in NRG-GY005 are: 
Cediranib: NSC# 732208 Sponsor:  DCTD, NCI 
Olaparib: NSC# 747856 Sponsor:  DCTD, NCI 
For patients on Arms 2, 3, or 4 receiving Cediranib and/or Olaparib, 
determination of whether an adverse event meets expedited reporting criteria, see 
the reporting table in Section 7.5.2.2 of the protocol. 
Commericial Agents 

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The commercial agents administered in NRG-GY005 are paclitaxel, topotecan, 
and PLD.  For patients on Arm 1 receiving only commercial agents, determination 
of whether an adverse event meets expedited reporting criteria, see the reporting 
table in Section 7.5.2.1. 
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                Adverse Effects (01/17/2017) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Cediranib (AZD2171, NSC 732208) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  
for further clarification. Frequency is provided based on 1608 patients. Below is the CAEPR for Cediranib 
(AZD2171). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 

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agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.15, November 7, 20181   
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Hemolytic uremic syndrome   
 
 
Thrombotic 
thrombocytopenic purpura 
  
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
ENDOCRINE DISORDERS 
  
 
Hyperthyroidism 
 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
  
 
Anal mucositis 
 
 Anal mucositis (Gr 2) 
 
Constipation 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dysphagia 
 
 Dysphagia (Gr 2) 
 
 
 Gastrointestinal fistula2 
  
 
 
 Gastrointestinal perforation3   
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
 
Pancreatitis 
  
 
Rectal mucositis 
 
 Rectal mucositis (Gr 2) 
 
Small intestinal mucositis 
 
 Small intestinal mucositis (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
 Infection4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase increased  
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Lymphocyte count decreased 
 
  
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
  

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 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
Thyroid stimulating hormone 
increased 
 
 Thyroid stimulating hormone 
increased (Gr 2) 
 
Weight loss 
 
 Weight loss (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Generalized muscle weakness  
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
Lethargy 
 
  
 
 
Leukoencephalopathy 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
 
Nephrotic syndrome 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Laryngeal mucositis 
 
 Laryngeal mucositis (Gr 2) 
 
Pharyngeal mucositis 
 
 Pharyngeal mucositis (Gr 2) 
 
Tracheal mucositis 
 
 Tracheal mucositis (Gr 2) 
Voice alteration 
 
 
 Voice alteration (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Palmar-plantar 
erythrodysesthesia syndrome 
 
 Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 2) 
VASCULAR DISORDERS 
  
 
 
Arterial thromboembolism 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event 
 
 Thromboembolic event (Gr 4) 
 
Vascular disorders - Other 
(hemorrhage)5 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS 
SOC. 
 

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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 

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NERVOUS SYSTEM DISORDERS - Ataxia; Central nervous system necrosis; Cognitive disturbance; 
Depressed level of consciousness; Dysarthria; Dysgeusia; Dysphasia; Encephalopathy; Hydrocephalus; 
Ischemia cerebrovascular; Memory impairment; Muscle weakness left-sided; Nervous system disorders - 
Other (coma); Nervous system disorders - Other (right hemiparesis); Olfactory nerve disorder; Peripheral 
motor neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; Spinal cord compression; 
Stroke; Syncope; Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Depression; Hallucinations; Insomnia; Suicide 
attempt 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Cystitis noninfective; 
Hematuria; Urinary retention; Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; Menorrhagia; Vaginal 
fistula 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Aspiration; Hypoxia; 
Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Pneumothorax; Pulmonary edema; Pulmonary 
fistula; Pulmonary hypertension; Sinus pain 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail loss; 
Pruritus; Purpura; Rash acneiform; Rash maculo-papular; Skin and subcutaneous tissue disorders - 
Other (petechiae); Skin and subcutaneous tissue disorders - Other (plantar warts); Skin ulceration; 
Urticaria 
VASCULAR DISORDERS - Capillary leak syndrome; Flushing; Hypotension; Vasculitis 
 
 
 
Note: Cediranib (AZD2171) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
1 
 
7.3.2  Adverse Effects (27-AUG-2021) (07.07.2023) 
  Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
Olaparib (AZD2281, NSC 747856) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 3449 patients. Below is the CAEPR for Olaparib 
(AZD2281). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
Version 2.6 June 5, 20231 

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 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 3449] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 4) 
 
 
Febrile neutropenia 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
  
Abdominal pain 
 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
INFECTIONS AND INFESTATIONS 
  
 
Upper respiratory infection 
 
  
 
Urinary tract infection 
 
  
INVESTIGATIONS 
  
 
Creatinine increased 
 
  
 
Neutrophil count decreased 
 
 Neutrophil count decreased 
(Gr 4) 
 
 
Platelet count decreased 
  
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
Muscle cramp 
 
  
 
Myalgia 
 
  
 
Pain in extremity 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)   
 
 
Leukemia secondary to 
oncology chemotherapy 
  
 
 
Myelodysplastic syndrome 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  

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 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 3449] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
 
Rash maculo-papular 
 
  
 
 
Skin and subcutaneous tissue 
disorders - Other (angioedema) 
  
 
 
Skin and subcutaneous tissue 
disorders - Other (erythema 
nodosum) 
  
VASCULAR DISORDERS 
  
 
 
Vascular disorders - Other 
(venous thromboembolism) 
  
 
NOTE: New Primary Malignancies other than MDS/AML 
New primary malignancies have been reported in <1% of patients. There were other contributing factors/potential 
alternative explanations for the development of the new primary malignancy in all cases, including documented 
BRCA mutation, treatment with radiotherapy and extensive previous chemotherapy including carboplatin, taxanes, 
anthracyclines and other alkylating and DNA damaging agents. Most are not attributed to olaparib. 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal 
Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
Adverse events reported on Olaparib (AZD2281) trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that Olaparib (AZD2281) caused the adverse event: 
 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (nodal rhythm); Chest pain - cardiac; Sinus 
bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Hypothyroidism 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Colonic obstruction; Dry mouth; Dysphagia; 
Enterocolitis; Esophageal stenosis; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other 
(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 

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NERVOUS SYSTEM DISORDERS - Amnesia; Ataxia; Cognitive disturbance; Concentration impairment; 
Encephalopathy; Intracranial hemorrhage; Peripheral sensory neuropathy; Reversible posterior leukoencephalopathy 
syndrome; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Hallucinations; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other (decreased 
glomerular filtration rate); Renal and urinary disorders - Other (hydronephrosis); Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Hypoxia; Oropharyngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders 
- Other (chronic obstructive pulmonary disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Pruritus 
VASCULAR DISORDERS - Arterial thromboembolism; Flushing; Hot flashes; Hypertension; Hypotension; 
Peripheral ischemia; Thromboembolic event 
 
 
 
Note: Olaparib (AZD2281) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
 
 
7.4 
Adverse Events for Commercial Study Agents  
Refer to the package insert for detailed pharmacologic and safety information. 
 
7.5 
Expedited Reporting of Adverse Events 
All serious adverse events that meet expedited reporting criteria defined in the 
reporting table below will be reported via the CTEP Adverse Event Reporting 
System, CTEP-AERS, accessed via the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to NRG and satisfies 
NRG requirements for expedited adverse event reporting. 
 
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 as the IND sponsor for this study by telephone at 301-
897-7497 and to NRG Regulatory Affairs by phone at 215-854-0770.  An 
electronic report must be submitted immediately upon re-establishment of the 
Internet connection. 
 
7.5.1 
Expedited Reporting Methods 
x Per CTEP NCI Guidelines for Adverse Events Reporting Requirement, a 
CTEP-AERS-24 Hour Notification must be submitted within 24 hours of 
learning of the adverse event. Each CTEP-AERS 24-hour notification must be 
followed by a complete report within 3 days. Supporting source 

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documentation is requested by CTEP as the IND sponsor for this study and 
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 NRG Regulatory Affairs by 
phone at 215-854-0716. 
x A serious adverse event that meets expedited reporting criteria outlined in the 
AE Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting 
obligations. Sites must bypass the “NOT recommended” assessment; the 
CTEP-AERS allows submission of all reports regardless of the results of the 
assessment.  
 
 
7.5.2 
 
Expedited Reporting Requirements for Adverse Events (12/05/2016) 
 
7.5.2.1 Phase 1, 2 and 3 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under a non-IND/IDE within 30 Days of the Last Administration of the 
Commercial Agent/Intervention 1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the commercial agent(s)/intervention  
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH 
E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to NRG via CTEP-AERS 
within 24 hours of learning of the AE, followed by a complete report within 3 calendar days of the initial 24-hour report. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
24-Hour 3 Calendar Days 
24-Hour 3 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 

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Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning 
of the AE, followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
 
1Serious adverse events that occur more than 30 days after the last administration of commercial agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
x 
All Grade 3, 4, and Grade 5 AEs 
x 
Grade 1 and 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
 
 
 
7.5.2.2 Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under a CTEP IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered 
serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS 
within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 

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NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of learning 
of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and 
have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
x 
All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
x 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
x 
Grade 3 adverse events 
 
 
7.5.3 
Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review 
Board (IRB) or Research Ethics Board (REB) responsible for oversight of the 
patient according to institutional policy. 
 
7.5.4  
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A secondary malignancy is not considered a metastasis of the 
initial neoplasm.  
 
CTEP requires all secondary malignancies that occur during or subsequent to 
treatment with an agent under an NCI IND/IDE be reported via CTEP-AERS. In 
addition, secondary malignancies following radiation therapy must be reported via 
CTEP-AERS. Three options are available to describe the event: 
x 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
x 
Myelodysplastic syndrome (MDS) 
x 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol.  
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy).  Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
 

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7.5.5   
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 
 
8.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations require IND sponsors to select qualified 
investigators.  NCI policy requires all persons participating in any NCI-sponsored clinical trial to 
register and renew their registration annually.  To register, all individuals must obtain a CTEP 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to Oncology Patient Enrollment 
Network (OPEN) or Rave or acting as a primary site contact) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 
in the table below. 
Documentation Required 
IVR 
NPIVR AP 
A 
FDA Form 1572 
D 
D 
 
 
Financial Disclosure Form 
D 
D 
D 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
D 
D 
D 
 
HSP/GCP training 
D 
D 
D 
 
Agent Shipment Form (if applicable) 
D 
 
 
 
CV (optional) 
D 
D 
D 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
x Added to a site roster 
x Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
x Act as the site-protocol PI on the IRB approval 
x Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 

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8.1.2 Site Registration Requirements (12/05/2016) 
 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain 
IRB approval for this protocol and submit IRB approval and supporting 
documentation to the CTSU Regulatory Office before they can be 
approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a 
determination of whether a site has fulfilled all regulatory criteria 
including but not limited to the following: 
x An active Federalwide Assurance (FWA) number 
x An active roster affiliation with the Lead Network or a participating 
organization 
x A valid IRB approval 
x Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
x Active registration status 
x The IRB number of the site IRB of record listed on their Form FDA 1572 
x An active status on a participating roster at the registering site 
 
Sites participating on the NCI CIRB initiative that are approved by the 
CIRB for this study are not required to submit IRB approval documentation to the 
CTSU Regulatory Office.  For sites using the CIRB, IRB approval information is 
received from the CIRB and applied to the RSS in an automated process.  
Signatory Institutions must submit a Study Specific Worksheet for Local Context 
(SSW) to the CIRB via IRBManager to indicate their intent to open the study 
locally.  The CIRB’s approval of the SSW is then communicated to the CTSU 
Regulatory Office.  In order for the SSW approval to be processed, the Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with 
the Signatory Institution are participating in the study. 
 
 
8.1.2.1 Downloading Site Registration Documents:   
 
Site registration forms may be downloaded from the NRG-GY005 
protocol page located on the CTSU members’ website.  Permission 
to view and download this protocol and its supporting documents 
is restricted and is based on person and site roster assignment 
housed in the CTSU RSS. 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 

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Click on the Protocols tab in the upper left of your screen 
Click on the NCTN NRG link to expand, then select trial protocol 
#### 
Click on the Site Registration Documents link 
 
8.1.2.2 Site Specific Requirements for NRG-GY005 Site Registration: 
 
• 
CTSU IRB Certification (for sites not participating via the NCI 
CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites 
not participating via the NCI CIRB)  
• 
IRB approved Informed Consent 
• 
Toxicity Management Training Site Initiation Visit (SIV)** 
**Toxicity Management Training (SIV) 
All institutions participating in this trial will be required to 
participate in a Toxicity Management Training SIV.  This training 
will focus on the toxicities and the toxicity management around 
cediranib. One investigator and one study coordinator/nurse from 
each site must attend an SIV to satisfy the regulatory requirement.  
This is an institution specific requirement to participate in this trial. 
Scheduled trainings and details for participation are on the NRG-
GY004 CTSU web site.  NRG Oncology will notify CTSU when 
an institution has satisfied this requirement. 
 
 
8.1.2.3 Submitting Regulatory Documents:  
 
Submit completed forms along with a copy of your IRB Approval 
and Model Informed Consent to the CTSU Regulatory Office, 
where they will be entered and tracked in the CTSU RSS.  
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory 
document submission only) 
 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific DTL.  The Clinical 
Investigator (CI) is required to review and electronically sign the DTL 
prior to the site receiving an Approved site registration status and 
enrolling patients to the study.  The DTL application is located on the 
CTSU members’ website at www.ctsu.org.  Any individual at the 

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enrolling site on a participating roster may initiate the site DTL.  
Instructions on completing the DTL are embedded in the DTL application. 
 
 
8.1.2.4 Checking Your Site’s Registration Status: 
 
Check the status of your site’s registration packets by querying the 
RSS site registration status page of the members’ section of the 
CTSU website.  (Note: Sites will not receive formal notification of 
regulatory approval from the CTSU Regulatory Office.) 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
Click on the Regulatory tab at the top of your screen 
Click on the Site Registration tab 
Enter your 5-character CTEP Institution Code and click on Go  
 
8.1.3 Investigator Pre-Registration Requirements (12/05/2016) 
- 
Documentation of the Principal Investigator’s and co-
investigators’ protocol-specific training through Firecrest 
 
OPEN will not allow an investigator to enroll a patient until the 
investigator specific training requirements have been satisfied. 
 
To Obtain Firecrest Access 
To request investigator and/or other staff access to Firecrest, please 
complete the excel document entitled “Firecrest Site and User Master 
Spreadsheet”, that is on the CTSU web site under the “LPO” tab.   
 
When completed, submit to NRG-GY-Regulatory@nrgoncology.org 
with the following subject line in the e-mail:   
 
[Study Number(s)] – Request for Firecrest Access [NCI CTEP 
Institution Code(s)] 
 
Failure to include the above subject line, may delay the request. 
 
The following fields in the spreadsheet must be completed: 
- 
Study* 
- 
Country* 
- 
Site Number (NCI CTEP Institution Code) 
- 
Institution Name 
- 
Title* 
- 
First Name 
- 
Last Name 
- 
Role* 
- 
Email address 

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*These fields have a drop down list of valid entries for selection 
 
Within 24 hours of receipt, the Regulatory Affairs Department will send a 
request for user accounts, for all the investigators/staff documented on the 
“Firecrest Site and User Master Spreadsheet”. A Firecrest account must be 
activated by ICON staff. 
 
Within 24-72 hours after the user account request has been sent to ICON, 
an email notification will be sent informing the investigator that he/she has 
been assigned to the study with a link to access the Firecrest portal, a 
username, and a link to retrieve a password.  A How-To User Manual will 
be available to download.  Investigators will automatically be assigned to 
the GCP and Protocol training once the investigator receives a user 
account. Investigators will receive weekly training reminders to complete 
the training. 
 
The Protocol training modules will be available in the “My Training” tab 
of the portal.  If the training has been previously completed, the status will 
be listed as completed and the training certification can be downloaded. 
 
8.1.3.2 Protocol Training 
 
Each investigator who enrolls a patient is required to complete a 
protocol-specific training course.  The protocol-specific training 
course is conducted in Firecrest and can be completed when the 
investigator receives his/her user account login.  The protocol-
specific training takes approximately 25 minutes to complete. 
 
Upon completion of the protocol-specific training course, please 
send the investigator’s training certificate to the NRG Regulatory 
Affairs Department by emailing  
nrg-gy-gcptraining@nrgoncology.org with the following 
information:  
 
- 
Study Number 
- 
Investigator’s Name 
- 
Investigator’s CTEP ID 
- 
Institution NCI CTEP Code 
- 
Institution Name 
- 
Training Certificate 
 
 
 
 
 

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8.2 
Patient Entry and Registration  
OPEN 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available to users on a 24/7 basis.  It is integrated with 
the CTSU Enterprise System for regulatory and roster data interchange.   
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
OPEN User Requirements 
 
OPEN users must meet the following requirements: 
x Have a valid CTEP-IAM account (i.e., CTEP username and password). 
x To enroll patients:  Be on a Participating Organization roster with the role of 
Registrar. Registrars must hold a minimum of an AP registration type. A DTL is 
required for the study.  The registrar(s) must also be assigned the OPEN Registrar 
task on the DTL.   
x Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN, site staff should verify the following: 
x All eligibility criteria have been met within the protocol stated timeframes.   
x If applicable, all patients have signed an appropriate consent form and Health 
Insurance Portability and Accountability Act (HIPAA) authorization form. 
 
Further instructional information is provided on the CTSU members' web site OPEN tab or 
within the OPEN URL. For any additional questions contact the CTSU Help Desk at 1-888-823- 
5923 or ctsucontact@westat.com. 
 
* The standard time to begin therapy following registration is 2 weeks, however, this may be not 
done on the specific dates and times due to the following reasons, including but not limited to, 
delayed clinic schedule, incremental weather, or national holidays. 
 
9.0 
DRUG INFORMATION  
 
9.1 
Topotecan (NSC #609699) 
 
9.1.1 Formulation:   
Topotecan is a cell cycle specific inhibitor of the nuclear enzyme topoisomerase I. It has a mean 
half-life of approximately three hours. Topotecan’s metabolism and clearance are complex but it 
is estimated that approximately 40% of the drug undergoes renal clearance.  
 
9.1.2 Supplier/How Supplied:   
Topotecan is commercially available and is supplied in a sterile form for intravenous use only.  
x Topotecan for Injection (lyophilized powder) is available generically as a sterile, 
lyophilized, buffered, light yellow to greenish powder available in single use vials 

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containing topotecan hydrochloride equivalent to 4 mg of topotecan as the free base, with 
mannitol 48 mg and tartaric acid 20 mg. Hydrochloric acid and sodium hydroxide may be 
used to adjust the product pH.  Available products do not contain an antimicrobial 
preservative; thus any unused product should be discarded within 24 hours of initial vial 
entry. 
x Topotecan Injection (solution) is available generically in individually-packaged single-
use vials containing a sterile, non-pyrogenic, clear, yellow to yellow-green solution of 
topotecan HCl equivalent to 4 mg of topotecan as the free-base at a concentration of 1 
mg/mL.   
 
 
9.1.3 Solution Preparation:   
Topotecan for Injection (lyophilized powder) reconstitution: 
x Reconstitute lyophilized topotecan HCl with 4 mL sterile Water for Injection, USP 
(SWFI), to produce a yellow to yellow-green solution with concentration equal to 1 
mg/mL and a pH within the range, 2.5 – 3.5. 
x Dilute an amount of drug appropriate for a patient’s dose in 50 – 250 mL of either 0.9% 
Sodium Chloride Injection (0.9%NS) or 5% Dextrose Injection (D5W), USP. 
 
 
Topotecan Injection (solution) reconstitution: 
x Each milliliter of solution contains topotecan hydrochloride equivalent to 1 mg of 
topotecan (free base), with 5 mg tartaric acid, NF, and SWFI. Hydrochloric acid and/or 
sodium hydroxide may be added to adjust product pH within the range 2.6 – 3.2. 
x Dilute an amount of Topotecan Injection (1 mg/mL) appropriate for a patient’s dose in a 
minimum volume of 50 mL of either 0.9% Sodium Chloride Injection (0.9%NS) or 5% 
Dextrose Injection (D5W), USP. 
 
9.1.4  Storage/Stability:   
Topotecan for Injection (lyophilized powder) storage and stability: 
• Store intact vials protected from light in the original cartons at controlled room temperature 
between 20° – 25°C (68° – 77°F). 
• After reconstitution with SWFI, vials should be used immediately.  
• After dilution with 0.9% NS or D5W, solutions prepared with Topotecan Injection are 
stable for at least 24 hours when stored at 20° – 25°C under ambient lighting conditions. 
Topotecan Injection (solution) storage and stability: 
x Store intact vials under refrigeration at 2° – 8°C (35.6° – 46.4°F) and protected from light 
in the original packaging carton. 
x After dilution with 0.9% NS or D5W, solutions prepared with Topotecan Injection are 
stable for 24 hours when stored at 20° – 25°C (68° – 77°F) under ambient lighting. 
 
9.1.5   Adverse effects:  
Hematologic:  thrombocytopenia, leukopenia, anemia, neutropenia 
Gastrointestinal:  nausea and vomiting, mucositis, diarrhea 
Skin: rash 
Other:  alopecia, fever, flu-like symptoms 
 
*Refer to Package Insert for additional information. 

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9.2 
Paclitaxel (NSC #673089) 
 
9.2.1  Formulation:  
Paclitaxel is supplied as a 6mg/mL non-aqueous solution in multi-dose vials containing 
30mg/5mL, 100mg/16.7mL, or 300mg/50mL of paclitaxel. In addition to 6mg of paclitaxel, each 
mL of sterile non-pyrogenic solution contains 527mg of purified Cremophor® EL 
(polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP. 
 
9.2.2   Storage/Stability  
Storage: Unopened vials of paclitaxel are stable to the date indicated on the package when stored 
between 20 to 25°C (68 to 77°F). Protect from light. 
 
Stability: Commercially available paclitaxel will be labeled with an expiration date. All 
solutions of paclitaxel exhibit a slight haziness directly proportional to the concentration of drug 
and the time elapsed after preparation, although when prepared as described below, solutions of 
paclitaxel (0.3-1.2 mg/ml) are physically and chemically stable for 27 hours. 
 
9.2.3 Preparation:  
Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% Sodium 
Chloride for Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium 
Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 
1.2mg/mL.  The solutions are physically and chemically stable for up to 27 hours at ambient 
temperature (approximately 25°C / 77°F) and room lighting conditions.   
 
NOTE: In order to minimize patient exposure to the plasticizer DEHP, which may be leached 
from PVC infusion bags or sets, diluted paclitaxel solutions should be stored in bottles (glass, 
polypropylene) or plastic (polypropylene, polyolefin) bags and administered through 
polyethylene-lined administration sets. 
 
Paclitaxel should be administered through an inline filter with a microporous membrane not 
greater than 0.22 microns. Use of filter devices such as IVEX-2® or IVEX-HP®, which 
incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of 
DEHP.   
 
All patients should be premedicated with corticosteroids, diphenhydramine, and H2 antagonists 
prior to paclitaxel administration in order to prevent severe hypersensitivity reactions. Patients 
who experience severe hypersensitivity reactions to paclitaxel may be re-challenged with the 
drug. See section 6.1.1.2.2.2.  
 
9.2.4 Adverse Effects: Consult the package insert for the most current and complete 
information.  
 
9.3 
Pegylated Liposomal Doxorubicin (DOXIL®, NSC #712227 Lipodox™; 
(NSC#673089)  
 

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Pegylated liposomal doxorubicin (PLD) is commercially available.  All commercially available 
sources are allowed including: 
x Generic PLD (http://www.caraco.com/outserts/Doxorubicin%20HClLip.pdf) 
x Lipodox ® (http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203263lbl.pdf) 
x Doxil ® (http://www.doxil.com/assets/DOXIL_PI_Booklet.pdf) 
 
Refer to the PLD package insert (Doxil, Lipodox™) for the most complete and current 
information on the following: 
 
9.3.1 Formulation:   
PLD (doxorubicin HCl liposome injection) is supplied as a sterile, translucent, red liposomal 
dispersion in 5 mL (Lipodox only), 10 mL, or 30 mL glass, single-use vials. Each vial contains 
doxorubicin HCl at a concentration of 2 mg/mL.  
 
9.3.2 Storage:  
Refrigerate unopened vials of PLD at 2°–8°C (36°–46°F). Avoid freezing. Prolonged freezing 
may adversely affect liposomal drug products; however, short-term freezing (less than 1 month) 
does not appear to have a deleterious effect on PLD. 
 
9.3.3 Preparation:  
PLD doses up to 90 mg must be diluted in 250 mL of 5% Dextrose Injection, USP prior to 
administration. Doses exceeding 90 mg should be diluted in 500 mL of 5% Dextrose Injection, 
USP prior to administration. Aseptic technique must be strictly observed since no preservative or 
bacteriostatic agent is present in PLD. Diluted PLD should be refrigerated at 2°C–8°C (36°F–
46°F) and administered within 24 hours. 
Do not mix with other drugs. 
Do not use with any diluent other than 5% Dextrose Injection.  
Do not use any bacteriostatic agent, such as benzyl alcohol.  
PLD is not a clear solution but a translucent, red liposomal dispersion.  
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. Do not use 
if a precipitate or foreign matter is present.  
 
Do not use in-line filter. 
 
9.3.4 Procedure for Proper Handling and Disposal:   
Caution should be exercised in the handling and preparation of PLD.  
 
The use of gloves is required.  
If PLD comes into contact with skin or mucosa, immediately wash thoroughly with soap 
and water.  
PLD should be considered an irritant and precautions should be taken to avoid 
extravasation. With intravenous administration of PLD, extravasation may occur with or 
without an accompanying stinging or burning sensation, even if blood returns well on 
aspiration of the infusion needle. If any signs or symptoms of extravasation have 
occurred, the infusion should be immediately terminated and restarted in another vein. 
PLD must not be given by the intramuscular or subcutaneous route.  

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PLD should be handled and disposed of in a manner consistent with other anticancer 
drugs.  
 
9.3.5 Adverse Effects:  Consult the PLD package insert for the most current and complete 
information. 
 
9.3.6 Supplier: Commercially available from Ortho Biotech Products, LP Raritan, NJ  
(DOXIL) and Caraco Pharmaceutical Laboratories Ltd, Detroit, MI (Lipodox).  
 
Consult the American Hospital Formulary Service Drug Information guide, Facts and 
Comparisons, or the package insert for additional information. 
 
9.4 
Cediranib (AZD2171) 
 
9.4.1  Description 
 
Chemical Name:  4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin 1- 
ylpropoxy) quinazoline maleate 
 
Other Names: Cediranib, AZD2171 maleate 
 
CAS Registry Number: 288383-20-0 (for the free base) 
 
Molecular Formula: C25H27FN4O3 · C4H4O4  
 
 
Molecular Weight: 566.59 as maleate salt (450.52 as free base) 
 
Approximate Solubility: The aqueous solubility of Cediranib 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).  
 
Mode of Action: Cediranib 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. 
 
9.4.2  How Supplied 
 
Astra-Zeneca supplies and CTEP, NCI, DCTD distributes Cediranib. The agent is available as beige 
film-coated tablets containing 15 mg, and 20 mg of Cediranib 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.  
 

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9.4.3  Storage and stability 
 
Storage: Store intact bottles at controlled room temperature [20°C-25°C, (68-77°F)].  
 
Stability: Stability studies are ongoing. Dispense AZD2171 (cediranib) 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 AZD2171 (cediranib) 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.  (12/05/2016) 
 
9.4.4 
Route of Administration 
 
Oral.  Cediranib tablets should be taken either one hour before or two hours after meals.  
 
9.4.5 
Potential Drug Interactions (12/05/2016) 
 
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.  
 

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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 
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. 
 
9.4.6 
Patient Care Implications  
Agents that inhibit VEGF signaling have the potential to affect wound healing; therefore, it is 
recommended that cediranib 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 cediranib 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. 
 
Cediranib has been shown to terminate fetal development in the rat, as expected for a process 
dependent on VEGF signaling.  For this reason, women of child-bearing potential must have a 
negative pregnancy test prior to study entry.  Women of child-bearing potential must agree to use 
two reliable forms of contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry, for the duration of study participation, and for 6 weeks after cediranib 
discontinuation.  Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately. 
 
9.4.7 
Availability 
 
NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned to the 
treatment arm prior to submitting the clinical drug request to PMB. 
Cediranib is an investigational agent and will be supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Cediranib is provided to the NCI under a Collaborative Agreement between AstraZeneca 
International and the DCTD, NCI (see Appendix I). 
 
9.4.8  Agent Ordering and Agent Accountability  
 

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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. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status.  For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time.  
Refer to the PMB’s website for specific policies and guidelines related to agent 
management.   
 
9.4.9  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. 
 
9.4.10 Investigator Brochure Availability (12/05/2016) 
 
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 and a “current” password. Questions about IB 
access may be directed to the PMB IB coordinator vial email. 
 
9.4.11  Destruction and Return 
 
Standard NCI return procedures will be followed. 
 
9.4.12   See Section 7.3.1 for the Cediranib CAEPR  
 
9.4.13 Useful Links and Contacts 
x CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
x NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
x PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
x PMB Online Agent Order Processing (OAOP) application:  

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https://ctepcore.nci.nih.gov/OAOP 
x CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
x CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
x IB Coordinator:  IBCoordinator@mail.nih.gov  
x PMB email:  PMBAfterHours@mail.nih.gov 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) 
 
 
9.5 
Olaparib (AZD2281, NSC 747856, LynparzaTM) 
 
9.5.1  Description  
 
Chemical Name: 4-[3-(Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluro- benzyl]-2-H-
phthalazin-1-one 
 
Other Names: AZD2281, KU-0059436; CO-CE 42; PARPi; Olaparib, LynparzaTM 
 
CAS Registry Number: 763113-22-0 
 
Molecular Formula: C24H23FN4O3 
Molecular Weight: 434.47 
 
Approximate Solubility: Olaparib is freely soluble in dimethylsulphoxide (DMSO) and 1- 
methyl-2-pyrrolidinone (NMP), sparingly soluble in ethanol and methanol, and only very slightly 
soluble in water (<0.25 mg/mL). 
 
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. 
 
9.5.2 
How Supplied 
 
AstraZeneca supplies and the CTEP, DCTD distributes olaparib as film-coated tablets in 100 mg 
and 150 mg strengths.  
 
• 100 mg tablets are 14.5 mm x 7.25 mm oval-shaped 
• 150 mg are 14.5 mm x 7.25 mm oval-shaped 
 
Tablets are packaged in induction-sealed high-density polyethylene (HDPE) bottles with child-
resistant closures. Each bottle contains 32 tablets with desiccant.  
 

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Tablet core components include active drug substance, copovidone, colloidal silicon dioxide, 
mannitol and sodium stearyl fumarate. Film coating contains hydroxypropyl methylcellulose 
(hypromellose), macrogol 400 (polyethylene glycol 400), titanium dioxide, iron oxide yellow 
and iron oxide black. 
 
9.5.3  Storage and stability 
 
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. 
 
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 
 
9.5.4   Route of Administration (12/05/2016) 
 
Oral. Olaparib tablets can be taken by mouth.  
 
9.5.5  Potential Drug Interactions (12/05/2016X) 
  
In vivo data indicate that CYP3A4/5 is important for olaparib metabolism and clearance in 
humans. For this reason, avoid concomitant administration of strong and moderate CYP 
3A4/5 inducers and inhibitors.  Consult the protocol document or study investigator prior 
to making any dose adjustments related to potential drug-drug interactions. 
 
In vitro data shows olaparib is a substrate for P-glycoprotein (P-gp), but not for organic 
anion-transporting polypeptides (OATP1B1 and OATP1B3), organic cation transporter 1 
(OCT1), multi-drug resistance protein 2 (MRP-2) efflux transporter or breast cancer 
resistance protein (BCRP). Administration of strong P-gp inhibitors and inducers should be 
avoided with concurrent olaparib.   
 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems and 
induces CYP 1A2, 2B6, and 3A4 and potentially induces CYP 2C9, 2C19 and P-gp. 
Therefore, avoid concomitant administration of sensitive substrates, particularly those with 
narrow therapeutic ranges.   
 
Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug and toxin 
extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP, but not an 
inhibitor of OATP1B3 or MRP-2. In vitro studies suggest that olaparib may increase 
exposure of substrates of these transport systems, although the clinical relevance is not clear. 
The manufacturer recommends that statins, in particular, should be administered with 
caution when given concomitantly with olaparib. 

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9.5.6 Patient Care Implications (12/05/2016) 
 
Pre-clinical data indicate that olaparib adversely affects embryofetal survival and 
development. Therefore, women of child-bearing potential and their partners should agree to 
use two (2) highly effective forms of contraception throughout study participation and for at 
least one (1) month after the last dose of olaparib.  Male study participants should avoid 
fathering a child or donating sperm during the study and for three (3) months after the last 
dose of olaparib. The study investigator should discuss the most appropriate forms of highly 
effective contraceptive methods for each patient.  
 
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. 
 
9.5.7 Availability  
 
NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned to the 
treatment arm prior to submitting the clinical drug request to PMB. 
 
Olaparib will be supplied to investigators by the Division of Cancer Treatment and Diagnosis 
(DCTD), NCI. 
 
Olaparib is provided to the NCI under a Clinical Trials Agreement (CTA) between AstraZeneca 
International (the Pharmaceutical Collaborator) and the DCTD, NCI (see Appendix I). 
 
9.5.8 Agent Ordering and Agent Accountability  
 
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution.  The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents.  The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead participating investigator at that institution. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active 
person registration status.  For questions about drug orders, transfers, returns, or accountability, 
call or email PMB any time.  Refer to the PMB’s website for specific policies and guidelines 
related to agent management.   
 
9.5.9 Agent Inventory Records  
 

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The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the 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. 
 
9.5.10 Invesitgator Brochure Availability (12/05/2016) 
 
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 and a “current” password. Questions about IB 
access may be directed to the PMB IB coordinator vial email. 
 
9.5.11  Destruction and Return 
 
Standard NCI return procedures will be followed. 
 
9.5.12 See Section 7.3.2 for the Olaparib CAEPR  
 
9.5.13 Useful Links and Contacts (12/05/2016) 
x CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
x NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
x PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
x PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
x CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/ 
x CTEP Associate Registration and IAM account help:  ctepreghelp@ctep.nci.nih.gov  
x PMB email:  PMBAfterHours@mail.nih.gov 
x PMB IB Coordinator: IBcoordinator@mail.nih.gov 
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 (12/05/2016) 
A patient who is randomized to a study group 2 or 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.  To 

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obtain the kits, please complete the “Blood Pressure Kit Order Request Form” and 
fax to Biologics at 919-256-0794.  The form is available on the CTSU website. 
Orders received before 2pm ET, Monday-Friday, will be processed and shipped 
the same day.  Orders received after 2pm ET, will be processed the following 
business day.  All orders will be shipped via FedEx Priority Overnight. 
 
10. 
PATHOLOGY  
 
10.1 
Stained Pathology Slide Requirements for Central Review to Confirm Eligibility:  
Not applicable 
 
11. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
11.1 
Reimbursement 
See the Funding Sheet found on the CTSU web site (www.ctsu.org). 
 
11.2 
Translational Science 
Note: Testing of banked specimens 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. 
 
11.2.1 Specimen Requirements (12/05/2016) 
Specimens listed below should not be submitted until after patient registration and Bank ID 
assignment. 
 
Sites in Korea: Please refer to Appendix XIV for biospecimen requirements and 
procedures. Some of the biospecimens included in the tables below are not applicable for 
sites in Korea.  
 
11.2.1.1 
Integrated Biomarker Specimen Requirements (12/05/2016) 
The patient must give permission to participate in this mandatory study component.   
Participating sites are required to submit the patient’s specimens as outlined below. 
ALL PATIENTS 
Required Specimen (Specimen Code) 
Collection Time Point 
Sites Ship Specimens To 
CEC Pre-treatment Whole Blood 
(WB02)1, 7 
8mL drawn into CPT (citrate) tube 
Prior to study treatment 
Preclinical Development 
Research Core (PDRC) the 
day the specimen is 
collected2 
CEC C1D3 Whole Blood (WB03)1, 7 
8mL drawn into CPT (citrate) tube 
Cycle 1, day 3 of study treatment, 
only if WB02 was submitted 
BROCA-HR Whole Blood (WB01)8 
7-10mL drawn into purple top (EDTA) 
tube(s) 
Prior to study treatment 
NRG BB-Columbus the day 
the specimen is collected3 
BROCA-HR FFPE Primary Tumor 
(FP02)4 
2 unstained slides (charged, 10μm)5 
Prior to all treatment 
 
Submit one - FP02 is preferred; 
Submit FM02 only if FP02 is not 
available 
NRG BB-Columbus within 2 
weeks of registration3 
BROCA-HR FFPE Metastatic Tumor 
(FM02)4 
2 unstained slides (charged, 10μm)5 

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Future Use Whole Blood (WB04) 
7-10mL drawn into purple top (EDTA) 
tube(s) and frozen6 
Prior to study treatment 
NRG BB-Columbus within 2 
weeks of registration3 
ALL PATIENTS RECEIVING OLAPARIB (ARMS 2 and 4) – PHASE II PORTION ONLY 
Olaparib PK C1D8 Pre-Treatment 
Plasma (PB01) 
prepared from 2mL of blood drawn into 
green top (lithium heparin) tube 
Cycle 1, day 8, within 30 minutes of 
administering study drug 
NRG BB-Columbus within 2 
weeks of registration3 
Olaparib PK C1D8 0.5-1 Hour Plasma 
(PB02) 
prepared from 2mL of blood drawn into 
green top (lithium heparin) tube 
Cycle 1, day 8, 0.5-1 hour (+/-5 
minutes) after administering study 
drug 
Olaparib PK C1D8 1-3 Hour Plasma 
(PB03) 
prepared from 2mL of blood drawn into 
green top (lithium heparin) tube 
Cycle 1, day 8, 1-3 hours (+/-10 
minutes) after administering study 
drug 
Olaparib PK C1D8 4-6 Hour Plasma 
(PB04) 
prepared from 2mL of blood drawn into 
green top (lithium heparin) tube 
Cycle 1, day 8, 4-6 hours (+/-30 
minutes) after administering study 
drug 
ALL PATIENTS RECEIVING CEDIRANIB (ARMS 2 and 3) – PHASE II PORTION ONLY 
Cediranib PK C1D8 Pre-Treatment 
Plasma (PB05) 
prepared from 2mL of blood drawn into 
purple top (K2EDTA) tube 
Cycle 1, day 8, within 30 minutes of 
administering study drug 
NRG BB-Columbus within 2 
weeks of registration3 
Cediranib PK C1D8 0.5-1 Hour Plasma 
(PB06) 
prepared from 2mL of blood drawn into 
purple top (K2EDTA) tube 
Cycle 1, day 8, 0.5-1 hour (+/-5 
minutes) after administering study 
drug 
Cediranib PK C1D8 1-3 Hour Plasma 
(PB07) 
prepared from 2mL of blood drawn into 
purple top (K2EDTA) tube 
Cycle 1, day 8, 1-3 hours (+/-10 
minutes) after administering study 
drug 
Cediranib PK C1D8 4-6 Hour Plasma 
(PB08) 
prepared from 2mL of blood drawn into 
purple top (K2EDTA) tube 
Cycle 1, day 8, 4-6 hours (+/-30 
minutes) after administering study 
drug 
1 CEC whole blood specimens must be shipped the day the specimen is collected. If Cycle 1 Day 3 falls on a Friday or weekend, 
the C1D3 (WB03) sample may be collected on Cycle 1 Day 4, Day 5, or Day 6. Additionally, patients starting study treatment 
on a Friday should have their baseline sample (WB02) collected the day prior to starting treatment, if possible. Please include a 
note stating if the sample was collected on a day other that the day indicated by the specimen collection time point. 
2 Preclinical Dveleopment Research Core, NCI, NIH, Bldg. 10, Rm 12N218, 10 Center Dr, Bethesda, MD 20892, Phone: 301-
496-1547, Emails: trepel@helix.nih.gov, leesun@mail.nih.gov, leemin@mail.nih.gov, akira.yuno@nih.gov; Note: Please 
notify the PDRC (via the four email addresses provided) when a patient is scheduled for a blood draw and when the specimen 
will be shipped. The FedEx tracking number should be included in the shipment. Additionally, CEC whole blood specimens 
must be shipped the day the specimen is collected. If the specimen absolutely cannot be shipped the same day, a note detailing 
why the specimen needed to be shipped the next day must be included. If the specimen cannot be shipped within 24 hours, it 
should be discarded. 
3 NRG BB-Columbus / Protocol NRG GY005, Nationwide Children’s Hospital, 700 Children’s Drive, WA1340, Columbus, OH 
43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: BPCBank@nationwidechildrens.org. 
4  A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the NRG BB-Columbus. 
5 If patient consents to the optional FFPE collection (FP01/FM01; section 11.2.1.2) and a block will be submitted on a 
permanent basis to fulfill both the mandatory (FP02/FM02; section 11.2.1.1) and optional (FP01/FM01; section 11.2.1.2) 
specimen requirements, then label the block FP01 (for primary) or FM01 (for metastatic). Complete and ship both the FP01 
and FP02 (for primary) or FM01 and FM02 (for metastatic) specimen transmittal forms (i.e., Form TR) with the block. 
6 Do not use glass blood collection tubes. 
7 Sites in Japan and Korea should not collect CEC whole blood biospecimens. 

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8 Sites in Korea should not collect BROCA-HR whole blood biopspecimens. 
 
 
11.2.1.2 
Exploratory Biomarker Specimen Requirements 
If the patient gives permission to participate in this optional study component, then participating 
sites are required to submit the patient’s specimens as outlined below. 
ALL PATIENTS 
Required Specimen (Specimen Code) 
Collection Time Point 
Sites Ship Specimens To 
FFPE Primary Tumor (FP01)* 
1st Choice: block1 
2nd Choice: 20 unstained slides (10 
charged, 5μm & 10 uncharged, 10μm) 
Prior to all treatment (Preferred 
FFPE) 
NRG BB-Columbus within 8 
weeks of registration2 
FFPE Metastatic Tumor (FM01)* 
1st Choice: block1 
2nd Choice: 20 unstained slides (10 
charged, 5μm & 10 uncharged, 10μm) 
Prior to all treatment (Optional if 
FP01, FRP01, or FRM01 is submitted) 
FFPE Recurrent Primary Tumor 
(FRP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5μm & 10 uncharged, 10μm) 
Prior to study treatment (Optional if 
FP01, FM01, or FRM01 is submitted) 
FFPE Recurrent Metastatic Tumor 
(FRM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5μm & 10 uncharged, 10μm) 
Prior to study treatment (Optional if 
FP01, FM01, or FRP01 is submitted) 
Research Pre-treatment Plasma (PB09) 
prepared from 7-10mL of blood drawn 
into purple top (EDTA) tube(s) 
Prior to study treatment 
NRG BB-Columbus within 5 
weeks of registration1 
Research C2D1 Plasma (PB10) 
prepared from 7-10mL of blood drawn 
into purple top (EDTA) tube(s) 
Cycle 2, day 1, prior to study 
treatment 
Research Final Plasma (PB11) 
prepared from 7-10mL of blood drawn 
into purple top (EDTA) tube(s) 
At disease progression or end of 
treatment 
NRG BB-Columbus within 
26 weeks of registration1 
* A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the NRG BB-Columbus. 
1 If patient consents to the optional FFPE collection (FP01/FM01; section 11.2.1.2) and a block will be submitted on a 
permanent basis to fulfill both the mandatory (FP02/FM02; section 11.2.1.1) and optional (FP01/FM01; section 11.2.1.2) 
specimen requirements, then label the block FP01 (for primary) or FM01 (for metastatic). Complete and ship both the FP01 
and FP02 (for primary) or FM01 and FM02 (for metastatic) specimen transmittal forms (i.e., Form TR) with the block. 
2 NRG BB-Columbus / Protocol NRG GY004, Nationwide Children’s Hospital, 700 Children’s Drive, WA1340, Columbus, OH 
43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: BPCBank@nationwidechildrens.org. 
 
11.2.2 Specimen Procedures 
A detailed description of specimen procedures can be found in Appendix VII. 
 
11.2.3 Laboratory Testing 
Assay details are included in Appendix VIII. 
 
11.2.3.1 
Circulating Endothelial Cells (Integrated Biomarker) (12/05/2016) 
Whole blood collected pre-treatment and on cycle 1, day 3, will be shipped by sites directly to 
the Preclinical Development Research Core (PDRC) on the day the specimen is collected for 
analysis of circulating endothelial cells (CECs) by flow cytometry. 

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Preclinical Development Research Core 
NCI, NIH 
Bldg. 10, Rm 12C208 
10 Center Dr, Bethesda, MD 20892 
Phone: 240-760-6330 
Emails: trepel@helix.nih.gov, leesun@mail.nih.gov, leemin@mail.nih.gov, akira.yuno@nih.gov 
 
11.2.3.2 
BROCA-HR (Integrated Biomarker) (12/05/2016) 
DNA extracted from whole blood and two unstained sections (charged, 10μm) of formalin-fixed, 
paraffin-embedded (FFPE) primary or metastatic tumor will be shipped every six weeks by the 
NRG BB-Columbus to Dr. Elizabeth Swisher for BROCA-HR testing. 
 
Special Note Regarding Genetic Testing: Given the potential clinical implications conferred 
by detecting a germline mutation in one of these proven cancer genes, the following 
disclosure procedure articulated by the American College of Medical Genetics and 
Genomics will be followed. 
 
1. For each subject with a clinically actionable result from BROCA sequencing, the testing 
laboratory will contact the NRG study PI at the enrolling institution to notify them that a 
research test result of potential clinical importance has been identified in one of their study 
participants. Please include the mutation in the genetic counselor’s report and place a copy of 
the report in the research record. 
2. The PI at the enrolling institution will be responsible for contacting the study participant to 
inform them that study-related research has uncovered genetic information that might affect 
their clinical care. Each participant can then: 
a. Elect not to receive the information, which will be retained by the enrolling physician in 
the event that the participant changes their mind at a later date.  
b. Elect to receive the information, in which case pre-test counseling should be provided 
prior to clinical testing of a freshly-drawn blood sample. After being counseled, the 
patient may (i) decide not to undergo clinical testing for the mutation identified under 
research, or (ii) decide to undergo clinical testing, in which case a new blood sample will 
be collected at the enrolling site and shipped directly to the CLIA-approved laboratory 
for mutation confirmation at no cost to the patient. The clinical genetic test result will be 
returned to the clinicians involved in counseling and managing this aspect of the patient's 
care and it will be their responsibility to disclose the results to the patient. 
 
11.2.3.3 
Future Olaparib Assay Development (Integrated Biomarker) (12/05/2016) 
Frozen whole blood will be batch shipped by the NRG BB-Columbus to Myriad for 
development of an olaparib companion diagnostic test. 
 
11.2.3.4 
Olaparib and Cediranib PK (Integrated Biomarker) 
Frozen plasma will be batch shipped by the NRG BB-Columbus every six months to Covance 
for olaparib and cediranib PK. 
 
11.2.3.5 
Plasma Angiome (Exploratory Biomarker) 

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Aliquots (1.5mL) of frozen plasma will be batch shipped by the NRG BB-Columbus upon trial 
completion to Duke University for analysis of the plasma angiome. 
 
11.2.3.6 
BRCA1 Promoter Methylation (Exploratory Biomarker) 
Five unstained sections (charged, 5μm) and one H&E stained section will be batch shipped by 
the NRG BB-Columbus upon trial completion to Dr. Douglas Levine for analysis of BRCA1 
promoter methylation. 
 
11.2.3.7 
BRCA1 Immunohistochemistry (Exploratory Biomarker) 
Three unstained sections (charged, 5μm) and one H&E stained section will be batch shipped by 
the NRG BB-Columbus upon trial completion to Dr. Douglas Levine (address above) for 
BRCA1 immunohistochemistry. 
 
11.2.4 Banking Specimens for Future Research 
Details regarding the banking and use of specimens for future research can be found in Appendix 
VII. 
 
11.3 
Quality of Life/ Patient Reported Outcomes  
The PRO endpoints proposed for this trial represent the best available approach to measuring 
disease related symptoms-physical (DRS-P) and treatment side effects (TSE) that are most 
important to women with advanced ovarian cancer. The 9-item NFOSI-18 DRS-P is the main 
PRO endpoint for the Phase II and III trials and has a specified analysis plan. All other endpoints 
(NFOSI-18 TSE, NFOSI-18 F/WB, NTX-4, EQ-5D) are exploratory PRO endpoints for the 
Phase III studies and will be analyzed post-hoc (see Appendix IX). 
 
The following PRO assessments will be performed every 12 weeks for 2 years, unless the patient 
withdraws from study participation. PRO assessments should continue post-progression. 
 
1. 
(primary QOL/PRO endpoint):  PRO: NFOSI-18 DRS-P 
2. 
(exploratory secondary):  PRO: NFOSI-18 TSE 
3. 
(exploratory secondary):  PRO: NFOSI-18 F/WB 
4. 
(exploratory secondary):  PRO: NTX-4 
5. 
(exploratory secondary):  EQ5D 
 
Disease-related Symptom-Physical (DRS-P)  
This 9-item scale, the first 9 items of the NFOSI-18, was developed using a qualitative 
methodology with 50 advanced ovarian cancer patients and 10 expert clinicians. Most of the 
items come from the FACT-O questionnaire (Basen-Engquist et al., 2001), but they have been 
supplemented, reorganized and validated to create a set of targeted outcome tools for disease 
related symptoms, treatment side effects, and general functioning and well-being. We propose 
the targeted 9-item DRS-P subscale as the main (secondary) PRO endpoint. Of note, after 
establishing that these 9 questions are the most important disease-related symptoms to women 
with ovarian cancer (Jensen et al., 2011), we further evaluated and demonstrated through 
cognitive debriefing interviews with 18 women with ovarian cancer, that these items are 
understood as intended.  
 

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Exploratory endpoints: TSE, Ntx-4, F/WB, EQ-5D. These endpoints will be included according 
to the schedule detailed below (Table 4). Platinum-based chemotherapies may cause neuropathy. 
The NTX-4 has been developed to assess neuropathy in cancer patients undergoing 
chemotherapy. Both of these scales are part of the FACIT arsenal of quality of life and symptom 
scales which are available in multiple languages. The EQ5D is a five-item instrument that offers 
a validated method of deriving utilities for use in CEA.  
 
a. Treatment side effects (TSE) and function/well-being (F/WB) from the NFOSI-18 will be 
secondary PRO endpoints. As the TSE scale is not intended to cover all, or even most, of the 
anticipated side effects across these two trials, we propose to use the single summary TSE item 
(“I am bothered by side effects of treatment”) as the unit of analysis comparing overall side 
effect bother of the treatment arms. There is precedent for this (Cella et al., 2013). The EQ5D 
will be included to estimate a single index value for health status.   
 
Table 11.1 Study calendar for PRO 
 
 
Pre-
Treatment 
During planned 
treatment*  
Following planned 
treatment* 
Post-Treatment*  
Quality of Life 
& Comparative 
Effectiveness 
Parameters 
Prior to 
Initial 
Study 
Treatment 
Week 12 
(or prior 
to cycle 
4) 
Week 24 
(or post 
cycle 6) 
Week 36 
Week 48 Every 3 months 
for 2 years for 
platinum- 
resistant 
PRO: DRS-9 
X 
X 
X 
X 
X 
X 
PRO:  TSE 
X 
X 
X 
X 
X 
X 
PRO:  F/WB 
X 
X 
X 
X 
X 
X 
PRO:  Ntx-4 
X 
X 
X 
X 
X 
X 
EQ5D 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
QOL Data compliance. 
 In GY005, similar to other trials with very advanced disease populations, the compliance 
challenge will occur because of the relatively short intervals of PFS and OS.  In the platinum-
resistant population, the median PFS is 12 weeks and the median OS is less than one year. Our 
QOL non-compliance is highest among those patients who have stopped study treatment for 
either progression or adverse events.  Importantly, these two reasons do not obviate the need for 
the research nurses and clinical research associates to continue to collect QOL data as scheduled.  
It is frequently the case, under these scenarios, that an institutions’ research team assumes that if 
the patient is off of the clinical trial, that she is also finished with her QOL assessments. These 
“institutional errors” can be remedied by diligent educational efforts and frequent reminders for 
follow-up, even if the patient is “off study.”  We are mindful of the fact that even with 
progressing disease, patients appreciate being asked about their health and well-being, and are 
compliant with completing the questionnaires. This is especially true for the ovarian cancer 
patient population. It is worth noting that in previous ovarian trials (e.g., 24 months follow-up) 
we achieved close to 80% compliance.  See Appendix X for the details of NRG’s strategies to 
optimize QOL long-term compliance with data reporting. 
 

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12. 
DATA AND RECORDS 
 
Data Management/Collection 
 
 
Data collection for this study will be done exclusively through Medidata Rave®. Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in Regulatory Support System (RSS). To access Rave via iMedidata, the site user 
must have an active CTEP-IAM account (check at https://ctepcore.nci.nih.gov/iam/) and the 
appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on either the LPO or 
participating organization roster at the enrolling site. 
 
Each person responsible for data entry must be on the NRG roster in order to receive access to 
Medidata Rave®.  
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata 
(iMedidata-Notification@mdsol.com) to activate their account. To accept the invitation, site 
users must log into the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-
IAM user name and password, and click on the “accept” link in the upper right-corner of the 
iMedidata page. Once an account is activated, eLearning modules will be available for Rave 
RDC instructions.  Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. Trainings will be listed in the 
upper right pane of the iMedidata screen. 
  
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU website under 
the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 
or by e-mail at ctsucontact@westat.com. 
 
NRG Data Management Forms 
 
 
The following forms must be completed and submitted to the NRG Statistical and Data 
Management Center—Buffalo Office (SDMC) in accordance with the schedule below.  NRG 
electronic case report forms must be submitted through the Medidata Rave Electronic Data Entry 
System (www.imedidata.com). All amendments to forms must also be submitted through 
Medidata Rave.   The pathology reports can be sent to the NRG SDMC via postal mail or 
uploaded in Medidata Rave. The upload option is an alternative method for submitting paper 
reports. 
 
 
 
 
 

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Form 
Comments 
Baseline Folder  
( Forms due within 2 weeks of registration) 
 
 
Baseline/History Forms: 
- 
Visit Information- Baseline Form 
- 
Registration Form 
- 
Pre-Treatment Summary Form 
- 
Pre-Study History Information 
- 
Pre-Study History Primary Surgery 
- 
Pre-Study History Chemotherapy 
- 
Pre-Study Radiation Therapy Information 
- 
Specimen Consent 
- 
ECHO/MUGA Form 
- 
ECG Information Form 
- 
Concomitant Medications Form 
- 
Vitals Form 
- 
Biomarker Information Form 
- 
Medical History Form 
- 
BRCA Status Form 
- 
Specimen Consent 
 
 
The appropriate forms will load in baseline folder 
based on answers reported on the corresponding 
Baseline Visit Information form. 
 
 
 

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Visit Folder 
(Forms due with in 2 weeks of completion of each cycle) 
 
Cycle Information and Treatment Forms: 
- 
Visit Information Form 
- 
Cycle Drug Information Form 
- 
Labs and Chemistries Form 
- 
Vitals Form 
- 
ECHO/MUGA Form 
- 
ECG Information Form 
- 
Concomitant Medications Form 
- 
Biomarker Information Form 
 
Toxicity (Adverse Event) forms:  
- 
Section 1 Form 
- 
Adverse Event Form 
- 
Adverse Event Grades 
 
The appropriate forms will load in folder based on 
answers reported on the corresponding Visit 
Information form. 
 
Solid Tumor Evaluation Folder 
 
Solid Tumor Evaluation Forms: 
 -     Tumor Assessment Visit Form 
 -     Target Lesions Form 
 -     Non-Target Lesions Form 
 -     No Target Lesions Form 
 -     New Target Lesions Form 
- 
Status and Response Form 
 
 
The appropriate forms will load in folder based on 
answers reported on the corresponding Tumor 
Assessment Visit Form. 
 
Pathology Folder 
- 
Pathology Report for Primary Disease 
- 
Pathology Report for Recurrent Disease 
 
 
Upload the reports online in Medidata Rave or 
submit via postal mail to the address below: 
 
NRG Oncology 
Statistics and Data Management Center 
Roswell Park Cancer Institute 
Elm and Carlton Streets 
Buffalo, NY 14263 
 
 
 

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Quality of Life Folder 
Patient Reported Outcome Forms (QOL 
Scantron): 
- 
Scantron: Prior to study therapy 
- 
Scantron: 12, 24, 36, 48, 60, 72, 84, 96, and 
108 weeks after starting study therapy 
- 
PRO/QOL Contact Information 
- 
Patient Reported Outcomes Schedule 
 
 
Please mail the original QOL Scantron forms to 
the address below: 
 
NRG Oncology 
Statistics and Data Management Center 
Roswell Park Cancer Institute 
Elm and Carlton Streets 
Buffalo, NY 14263 
 
Please note: QOL Scantron form must be ordered from 
the NRG Buffalo SDMC by submitting the Scantron 
Order Form posted on the CTSU website. 
Translational Research Folder 
TR Forms: 
- CEC Pre-treatment Whole Blood (WB02) 
- CEC C1D3 Whole Blood (WB03) 
- BROCA-HR Whole Blood (WB01) 
- BROCA-HR FFPE Primary Tumor (FP02) 
FP02 or FM02 must be submitted* 
- BROCA-HR FFPE Metastatic Tumor (FM02)  
FP02 or FM02 must be submitted* 
- Future Use Whole Blood (WB04) 
- FFPE Primary Tumor (FP01) 
- FFPE Metastatic Tumor (FM01) optional 
- FFPE Recurrent Primary Tumor (FRP01) 
optional 
- FFPE Recurrent Metastatic Tumor (FRM01) 
optional 
- Research Pre-treatment Plasma (PB09) 
- Research C2D1 Plasma (PB10) 
- Research Final Plasma (PB11) 
The appropriate forms will load in the 
Translational Research Folder based on the 
answers reported on the Specimen Consent form. 
 
An electronically completed copy of Form TR 
must accompany each specimen shipped. 
Handwritten forms will not be accepted. 
 
WB01-WB03 are due 1 week from registration. 
 
FP02 and FM02 are due 2 weeks from 
registration. *If patient consents to the optional 
FFPE collection (FP01/FM01; section 11.2.1.2) 
and a block will be submitted on a permanent 
basis to fulfill both the mandatory (FP02/FM02; 
section 11.2.1.1) and optional (FP01/FM01; 
section 11.2.1.2) specimen requirements, then 
label the block FP01 (for primary) or FM01 (for 
metastatic). Complete and ship both the FP01 and 
FP02 (for primary) or FM01 and FM02 (for 
metastatic) specimen transmittal forms (i.e., Form 
TR) with the block. 
 
WB04 is due 2 weeks from registration. 
 
FP01, FM01, FRP01, and FRM01 are due 8 
weeks from registration. 
 
PB09-PB11 are due 5 weeks from registration. 
Treatment Completion Folder 
( Forms due within 2 weeks of Treatment Completion) 

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- 
Treatment Completion Form 
Please submit the Treatment Completion Form 
after all protocol directed therapy has been 
discontinued. 
Follow-up Visit Folder 
(Forms due within 2 weeks of follow-up visits, disease progression or death) 
Visit Information Follow-Up Form 
 
Follow-up Form  
Concomitant Medications Form 
Labs and Chemistries Form 
Biomarker Information Form 
Non-Protocol Therapy Form. 
 
Follow-Up Adverse Event Reporting: 
 -     Part 1 Form 
 -     Terms Form 
 -     AE Grades Form 
The appropriate forms will load in folder based on 
answers reported on the corresponding Visit 
Information form. 
 
Source Documentation Upload Folder 
- 
Source Documentation Upload Form - SDV 
Baseline 
- 
Source Documentation Upload Form – Visit 1 
- 
Source Documentation Upload Form – Visit 2 
A source documentation review will be conducted 
for the first two patients enrolled from each site 
(as identified by a unique NCI identifier).  The 
review will require that source documentation be 
uploaded in Medidata Rave for eligibility, 
baseline, and the first two cycles of treatment.  
Please see Appendix XI:  Protocol Monitoring 
Plan for details. 
 
Summary of Data Submission 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times during the trial using Medidata Rave®. Additionally, certain adverse events must be 
reported in an expedited manner for more timely monitoring of patient safety and care. See 
Section 7 for information about expedited and routine reporting.   
 
For reporting of secondary cancers or other report forms available in Rave:  
Indicate form for reporting in Rave, timeframes, add if loading of the pathology report is 
required. 
 
Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are 
due January 31, April 30, July 31, and October 31. 
 
 

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13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design 
 
Phase II accrual was suspended on June 16, 2017.  At the interim analysis in July 2018, the Data 
Monitoring Committee voted to drop the single-agent olaparib arm.  The Phase III trial will be 
continued with 3 arms: standard chemotherapy, cediranib+olaparib, and cediranib alone.  Phase 
II patients randomized to these three arms will be included in the Phase III trial accrual targets, 
and will be included in the primary analysis according to their randomized treatment assignment.  
For clarity, references to the single-agent olaparib arm have been removed from the Phase III 
statistical methods sections. 
 
13.1.1 Endpoints.  
 
Phase II Study  (06-AUG-2021) 
Primary efficacy endpoint: Progression-Free Survival (PFS), defined as the time from study 
enrollment to the onset of progression as determined by RECIST v1.1 criteria, or death due to 
any cause, whichever occurs first. For individuals who are alive and progression-free the time at 
risk will be defined as the time from the study enrollment date to the date of the last disease 
assessment.  
 
Secondary endpoints:  
a. Secondary efficacy endpoint: Objective response rate (ORR, either partial or complete 
response) defined by RECIST v1.1 criteria, in the setting of recurrent platinum-resistant or 
refractory ovarian, primary peritoneal, or fallopian tube cancer. 
b. Safety endpoint: safety as measured by frequency and severity of adverse events by Common 
Terminology Criteria for Adverse Events (CTCAE).  
 
The median PFS reported in studies with the single agent standard chemotherapy in women with 
recurrent platinum-resistant or refractory ovarian cancer ranges between 3 months to 4 months.   
The primary analysis of PFS will be assessed using a proportional hazards model with patients 
analyzed according to the arm to which they were randomized, regardless of whether treatment is 
received. 
 
To allow for a better understanding of time to subsequent therapy and OS, patients on 
experimental study drug(s) or standard chemotherapy arm will be followed after progression, 
with data capture to include the date of initiation of the subsequent therapy, detailed information 
on the type of subsequent therapy received, and time to progression on the subsequent therapy. 
 
Phase III Study  (06-AUG-2021) 
Primary efficacy endpoint: The durations of PFS and overall survival (OS) are co-primary 
endpoints in the phase III component of this study.  
 
OS is defined as the time from study enrollment to death due to any cause. For those individuals, 
who have no death reported at the time of the analysis, the time at risk of death will be assessed 
from the date of study enrollment to the date that the patient was last known to be alive.  The 

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expected median time to death for this patient population receiving standard treatment is 15 
months. 
 
For the end of the Phase III primary analysis, Progression-Free Survival (PFS) is defined as the 
time from study enrollment to the onset of progression as determined by RECIST v1.1 criteria, 
or death due to any cause, whichever occurs first. PFS censoring rules for the primary analysis, 
and sensitivity analyses for the PFS endpoint, are provided in Section 15.1.6. 
 
Secondary endpoints:  
a. Secondary efficacy endpoint: ORR. 
b. Safety endpoints: frequency and severity of adverse effects as defined by CTCAE. 
 
Objective with Integrated Biomarkers 
a. To assess the effect on disease-related symptoms (DRS) as measured by the 9-item DRS-
P subscale of the NCCN-FACT Ovarian Symptom Index-18 (NFOSI-18), of single agent 
olaparib or cediranib and combination, compared to standard chemotherapy, in the setting 
of recurrent platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube 
cancer. 
 
13.1.2 Randomization Procedure. (06-AUG-2021) 
The treatment allocation procedure will allocate a nearly equal number of patients to each 
available study regimen.  Randomization will be stratified by the following factors:  
 
1) Receipt of prior bevacizumab (yes vs no),   
2) Prior platinum free interval (resistant vs. refractory disease)  
 
a) Resistant disease:  progression within 6-months of receiving the last course of platinum 
therapy. 
b) Refractory disease: progression while receiving platinum. 
 
To balance the treatments assigned to Japanese and Korean patients, the randomization will be 
stratified by Country of Treatment.  The country of Treatment will be determined by the NRG 
institution number and will have three levels:  (1) Japan, (2) Korea, and (3) Other.  The country 
of treatment stratification factor will not be included in the statistical analyses.  It serves 
administrative purposes only.   
 
The Country of Treatment stratification was incorporated in the Phase III randomization scheme.  
It was not used during Phase II. 
 
 
 
Japanese Cohort Accrual. (06-AUG-2021) 
 
Accrual to the Japanese cohort will remain open until about three months before the data cutoff 
or until 24 Japanese patients have enrolled, whichever occurs first.  These patients will follow 
the same study plan and procedures as patients recruited to the primary cohort. 

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To help clarify the analysis plans, the following cohorts are defined. 
 
Cohort Label 
Description 
Primary Cohort 
Includes the 510 patients enrolled during the global accrual period.  Four 
patients from Japan are included in this cohort.  The primary cohort will 
be considered mature when 137 deaths have been observed among 
patients randomized to the chemotherapy arm in this cohort (i.e. the data 
cutoff).  See Section 13.1.4. 
 
Japanese Cohort Includes all Japanese patients enrolled before the primary analysis data 
cutoff.  This cohort is expected to have up to 24 patients; four accrued to 
the primary cohort, and up to another 20 between the suspension of 
accrual to the primary cohort and the primary analysis data cutoff date.  
Analyses of the Japanese cohort may be performed when maturity in the 
Japanese cohort is similar to that of the primary cohort to allow for 
sufficient follow up within the Japanese cohort. 
 
 
All planned analyses described below relate to the primary cohort unless otherwise stated.  
 
 
 
 
13.1.3 Sample size with power justification. 
 
Phase II Study (06-AUG-2021) 
The target enrollment for the phase II component of the study is at least 52 patients randomized 
to each study regimen (approximately 208 patients). The randomization process will not be 
constrained to enroll only 52 patients in each regimen. In other words, the random allocation of 
study treatments to each patient will always have a stochastic component. Once the targeted 
number of patients has been enrolled, enrollment will be suspended to permit the PFS data to 
mature for the post-phase II analysis. The purpose of these analyses is to drop regimens that have 
insufficient evidence of activity to warrant further phase III evaluation at this time. 
 
The expected monthly accrual rate for this study is 10.6 patients and enrollment onto the phase II 
component of this study is expected to require approximately 1.6 years after a brief initial startup 
period. 
 
Comparison of experimental regimens to the standard chemotherapy regimen with regard to 
PFS:  
When at least 164 of the patients enrolled in the study have either progression or death reported, 
the relative PFS event rate for each of the single-agent experimental regimens will be compared 
to the standard chemotherapy regimen. A proportional hazards model will be used to estimate the 
relative hazards in which the stratification factors that were used for treatment randomization 
(see Section 13.1.2) will be included as model covariates (including these covariates in the PH 

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model as stratification factors may create some strata with too few events at this point in the 
study to be included in the estimate of some hazard ratios).  Those single agent experimental 
regimens that exhibit at least a 17% reduction in the estimated PFS event rate (compared to 
standard chemotherapy) at this time will be considered sufficiently active to warrant further 
evaluation in the phase III component of this study.  If an experimental regimen truly reduces the 
instantaneous PFS event rate by 37.5%, then there is a 90% chance that the regimen will advance 
to the phase III component of the study.  However, if the true PFS event rate for an experimental 
regimen is equivalent to standard chemotherapy, then there is an 80% chance that this regimen 
will be dropped following the phase III component of the study based on this criterion. 
 
If there is sufficient evidence for at least one of the single-agent experimental regimens to 
proceed to the phase III component of this study, then the experimental combination regimen 
will be compared to the experimental single-agent regimen with the lowest PFS event rate.  If the 
estimated PFS event rate among those randomized to the experimental combination regimen is 
lower than the single-agent regimen with the lowest PFS event rate, then the combination 
regimen will be considered to have sufficient activity to warrant further evaluation in the phase 
III component of the study.   
 
If neither of the single-agent experimental regimens demonstrates at least a 17% reduction in the 
PFS event rate, but the combination regimen does demonstrate at least a 17% reduction in the 
PFS event rate, then the combination regimen will be considered sufficiently active to warrant 
further evaluation in the phase III component of the study.   
 
 
Phase III Study (06-AUG-2021) 
The phase III component of this study includes the standard of care chemotherapy, single-agent 
cediranib, and the combination of cediranib/olaparib treatment arms.  The target sample size for 
the final analysis is 510 patients, with 170 patients randomized to the standard chemotherapy 
regimen (including those randomized during the phase II trial) and nearly an equal number of 
patients enrolled in each experimental regimen selected for phase III evaluation.  When accrual 
is complete, at least 562 patients will have enrolled in the study, including 52 Phase II patients 
from the Olaparib only arm who will not be included in the final analysis. The expected monthly 
accrual rate is 10.6 patients.  Enrollment onto the phase III component is expected to require 
about 2.7 additional years.   
 
Notation for Study Hypotheses 
Denote each of the study’s null hypotheses as Hx,y (H’ for alternative hypotheses) in which the 
first subscript indicates the endpoint and the second subscript indicates the treatment pair being 
compared.  Treatments will be denoted as: R for the reference regimen (chemotherapy), C for 
single-agent cediranib and C+O for the cediranib and olaparib combination.  For instance, H 
PFS,C:R will denote the null hypothesis that the PFS event rates on single-agent cediranib and the 
reference regimen are equivalent.   
 
Overview of Hypothesis Testing Strategy 
This study involves two families of hypotheses to evaluate treatment efficacy.  The null 
hypotheses in the first family of hypotheses are: H PFS,C:R, H PFS,C+O:R, H OS,C:R, H OS,C+O:R .  These 

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null hypotheses assert that the experimental arm PFS event and death rates are equal to these 
rates on the reference regimen (chemotherapy) in women with recurrent platinum-resistant or -
refractory ovarian, primary peritoneal or fallopian tube cancer.  The strategy for controlling type 
I error across this family of hypotheses involves Bonferroni correction and hierarchical testing 
procedures, which are intended to strongly limit type I error to 0.025 (1-tail) for the entire first 
family of hypotheses.   
 
Finally, if the experimental combination regimen is declared superior to chemotherapy and the 
single-agent cedirinib regimen is selected following the phase II component, a second family of 
hypotheses (H PFS,C+O:C, H OS,C+O:C) comparing the combination and single-agent cediranib will 
be evaluated for a 2-tail test.    
 
Hypothesis Testing Procedures 
 
Comparing the experimental regimens to the standard chemotherapy regimen with regard to 
PFS and OS (1st family of hypotheses):   
The first family of hypotheses involves comparing each of the experimental regimens selected 
from the phase II component of this study to the reference group with regard to PFS and OS. To 
limit the overall type I error for this family of hypotheses, the type I error allocated to each of the 
first three hypotheses (H PFS,C:R, H PFS,O:R, H PFS,C+O:R) will be 0.0083 (=0.025/3, 1-tail).  This type 
I error will not be redistributed among these hypotheses, even though the  
H PFS,O:R test will not be considered in the Phase III study. A hypothesis from the second set of 
hypotheses (H OS,C:R, H OS,O:R, H OS,C+O:R) will be tested, if and only if, the hypothesis concerning 
PFS with the same pair of treatment is rejected.  For instance, H OS,C:R will be tested only if  
H PFS,C:R is first rejected.  The type I error for each of these tests will also be 0.0083, when testing 
is appropriate.    
 
The study will be considered sufficiently mature for this family of tests when there are at least 
137 deaths reported among patients randomized to the standard chemotherapy regimen. If an 
experimental regimen truly reduces the death rate by 37.5%, then the expected number of deaths 
at that time in that treatment group is 110. This sample size provides nominal 90% power 
(provided the corresponding PFS hypothesis has already been rejected) for each of the pair-wise 
comparisons when the experimental regimen truly reduces the death rate 37.5% (OS hazard ratio 
(HR)=0.625) relative to the standard chemotherapy. This hazard ratio is comparable to increasing 
the median duration of survival by 9 months. The actual number of PFS events available at that 
time for each treatment-PFS comparison is random.  Assuming 95% of the patients involved in 
the phase III component of this study have progressed or died when survival has sufficiently 
matured for these hypotheses, then there is 96% power if the experimental regimen decreases the 
PFS event rate 37.5% (PFS HR=0.625).  This is comparable to increasing the median duration of 
PFS by 2-2.5 months.    
 
Comparing the experimental combination regimen to the single-agent cediranib with regard to 
PFS and OS (2nd family of hypotheses):  
If the experimental combination regimen demonstrates superiority to the standard chemotherapy 
regimen with regard to OS (H OS,C+O:R is rejected), then the experimental combination will be 
compared to single-agent cediranib. The type I error for this test will be 0.025 (2-tail).  The study 

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will be considered sufficiently mature when there are at least 227 total deaths reported among 
those patients who were randomized to either the experimental combination regimen or single-
agent cediranib. The power estimate of this test is complicated, since it not only depends on the 
true death rates of the two regimens being directly compared, but also the single-agent olaparib 
arm that is only implicitly involved in this comparison.  
 
Likewise, if H PFS,C+O:R is rejected, the H PFS,C+O:C test will be conducted. The type I error for this 
test will be 0.025 (2-tail).  
 
13.1.4 Analysis plan including plans for formal interim analysis. 
Phase II study: (06-AUG-2021) 
A single proportional hazards model (Cox 1972), which includes all four treatment groups with 
indicator covariates for the stratification factors used in the randomization procedure (see Section 
13.1.2).  This model will be used to estimate the hazard ratios for each of the experimental 
regimens relative to the chemotherapy group. This model will group patients by their randomized 
study regimen. All enrolled patients will be included in this analysis, regardless of their 
eligibility or compliance with their assigned study regimen.  
 
Consideration will be given to stopping enrollment onto any particular experimental regimen if 
there are no clinical responses (complete or partial response) among the first 20 patients who are 
randomized to the regimen (during the phase II component) and at least initiate their assigned 
study treatment. 
Phase III study: 
A stratified logrank test will be performed for each hypothesis, when hypothesis testing is 
appropriate. The logrank tests will involve only those treatments that were selected at the end of 
the phase II trial and all of the patients who were randomized to these treatment groups 
regardless of whether they were enrolled during the phase II or phase III component of the study. 
Patients will be grouped by their randomly assigned treatment and will be included in the 
analysis regardless of their compliance with their assigned study treatment. The logrank 
procedures will be stratified by the factors used to balance the treatments during randomization 
(see Section 13.1.2).   
 
 
Interim Analysis Plans: (06-AUG-2021) 
The interim analysis will include an assessment of both futility and superiority. A planned 
interim analysis will be performed when at least half of the number of deaths (137/2≈69) 
required for the final analysis of the 1st family of hypotheses has occurred among those patients 
in the reference group. Due to the complexity of this study design, the interim analyses will 
follow proposed recommendations for simplifying interim monitoring guidelines (Freidlin et al 
1999).  If any of the null hypotheses H PFS,C:R or H PFS,C+O:R is rejected at p < 0.0002 (1-tail) at the 
time of the interim analysis then the corresponding hypothesis involving the same treatments, H 
OS,C:R or H OS,C+O:R will be assessed.  If each of the hypotheses concerning PFS and OS can be 
rejected at p<0.0002 for any specified experimental regimen, then consideration will be given to 

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stop allocating the reference regimen to enrolling patients.  While amending the randomization 
procedure this way would require making some information from the interim analysis public, the 
Data Monitoring Committee will also consider separately whether to publically releasing 
detailed results of the interim analysis.   
 
On the other hand, if the conditional power under the alternative hypotheses (HR=0.625) for H 
PFS,C:R or H PFS,C+O:R is less than 0.40 at the time of the interim analysis then consideration will be 
given to stop enrolling patients onto the indicated experimental regimen and concluding that it is 
unlikely to be superior to the reference regimens.   
 
The interim analysis will also include estimates of the hazard ratios and the corresponding 
confidence intervals for each of the experimental regimens relative to the reference regimens.   
  
The results of interim analyses are reviewed by the NRG Data Monitoring Committee (DMC).  
The dates for the DMC’s meetings are administratively scheduled without knowing the study 
results.  Approximately eight weeks before its regularly scheduled meetings, the database is 
locked to prepare a progress report.  If the prerequisite number of events has been attained, an 
interim analysis is also prepared and presented to the DMC at their upcoming meeting.  The 
actual decision to terminate accrual or to release study results includes consideration of 
toxicities, treatment compliance, as well as results from external studies.   
 
Japanese Cohort Analysis Plan: (06-AUG-2021) 
At the data cutoff, the OS/PFS endpoints among the Japanese Cohort (defined above) will not be 
mature.  Analyses of the Japanese cohort may be performed when maturity in the Japanese 
cohort is similar to that of the primary analysis in the Primary Cohort to allow for sufficient 
follow up within the Japanese cohort.  This is expected about 24 months after the last Japanese 
patient enrolls.  After the data are cleaned, an updated dataset will be provided to support other 
analyses among the Japanese cohort.  Where data permit, summaries and analysis of primary and 
secondary efficacy endpoints will be performed for the Japanese cohort. 
 
 
13.2 
Statistical design for each correlative study  
 
13.2.1 Patient reported outcome (PRO) 
 
The analyses of PROs described here are not intended to be used for regulatory drug approval.  
These analyses are for research purposes. The primary objective of this component of the study 
is to assess patient-reported scores of disease-related symptoms (DRS) among the study 
treatments.  The primary measure for symptoms is the NFOSI-DRS-P, which is a 9-item PRO.  
The DRS-P score for the ith patient-assessment is calculated as  
 
where δij is equal to 1 when the jth item has a valid response, otherwise it is equal to 0, sij is the 
response score of the jth item and M is the number of items in the subscale.  The response score 
¦
¦
 
 
 
1
1
)
*
(
*
j
ij
j
ij
ij
i
s
M
S
G
G

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for each item ranges from 0 to 4, where higher values indicate preferred states.  The DRS-P score 
for a particular patient-assessment time is considered valid if the patient provides valid responses 
to at least 5 of the score’s items, otherwise it is considered incomplete and, for the purposes of 
analyses, it is treated as if it is missing.   
 
A mixed-effects model will be used to estimate and compare the mean DRS-P scores for the 
treatment groups.  Model covariates will include the patients’ randomly assigned study 
treatment, age at enrollment onto the study, initial performance status, pre-treatment DRS-P 
score, and assessment time.  The primary analyses will include only those treatments selected at 
the end of the phase II study and all of the patients assigned to one of these treatments during 
either the phase II or phase III component of the study regardless of their compliance with the 
study treatment or eligibility status, provided at least one baseline (pre-treatment) and one 
follow-up assessment is available. For the primary analysis, patients will be grouped by their 
randomly assigned study treatment.  
 
First, a mixed model will be used to conduct an omnibus test (across time) that compares the 
DRS-P scores from each experimental treatment group to the reference group.  If an omnibus 
hypothesis is rejected then comparisons (between the particular experimental group and the 
reference group) at individual assessment-times will also be conducted.  In order to control type I 
error, for treatment comparisons with regard to the DRS-P, the overall type I error for comparing 
each of the 3 experimenal regimens to the chemotherapy regimen will be limited to 0.0166 
(0.05/3, 2-sided).  The type I error will not be reallocated in the event that fewer than 3 
experimental arms are selected following the phase II component of the study.   
 
Exploratory analyses will include an assessment of the model residuals in order to evaluate the 
adequacy of modeling assumptions. 
 
Statistical Power for NFOSI-DRS-P 
A previously conducted study involving 51 patients indicates that the expected mean and 
standard deviation of the DRS-P are approximately 51.6 and 10.7, respectively.  The primary 
analysis of DRS-P will focus on the assessments scheduled during the first year following 
enrollment onto the study.  For the purposes of estimating power, it is assumed that there will be 
a 10% attrition of patients at the first reassessment time and 15% at each subsequent assessment 
time, due to death or non-compliance.  Also, it is assumed that the correlation between two 
consecutive assessments on the same individual will be 0.60, and between two assessments 
separated by 1 and 2 assessments will be 0.40 and 0.20, respectively.  The correlation between 
scores more than 2 assessments apart is assumed to be 0.10.  A simulation of 1000 trials 
indicates that the power to detect a constant 3.5 unit difference between treatment groups is 
approximately 85%.  Alternatively, if the difference in DRS-P scores between treatment groups 
increases from 0 to 6.5 units over the first year, then this study has 82% power.  If the null 
hypothesis concerning the equality of the mean DRS-P scores between an experimental regimen 
and chemotherapy is rejected, then a treatment-by-time interaction term will be added to the 
model in order to estimate temporal trends in the differences between these treatment groups. 
 
Other PRO Scales 

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Each of the other general PRO scales will be analyzed with mixed models using procedures 
similar to those described above for the DRS-P.  However, the scores from some PRO scales that 
are designed to assess very specific symptoms, like the NTX-4, usually involve a large number 
of individuals who report no such symptom, but a subset of patients will report significant 
symptoms (ie data exhibit clumping of scores at zero).  In this case, a mixed-effect mixed-
distribution (MEMD) (Berk et al, 2003) model will be used to estimate symptom scores.  This 
model includes two components.  One component involves a logistic model to estimate the 
probability of a nonzero score, and the second component models the mean of the nonzero 
scores. This model also incorporates random effects to account for repeated measures provided 
by each individual and permits specification of a correlation structure between the random 
effects for the two components of the model. This model also permits the inclusion of individuals 
with some missing follow-up observations.   
 
Missing PRO information 
Patient death, noncompliance, missed clinic appointments, and patient illiteracy, can cause 
observations to be missed.  One or more of the PRO assessments may be missing for an 
individual on any occasion.  Missing information is troublesome particularly in studies involving 
repeated patient assessments.  The frequency that assessments are missed will be monitored 
every 6 months throughout the study.  Data Coordinators will be working with the Study Team 
and the NRG’s Patient Centered Outcomes Research Committee to identify reasons that data are 
missing and recommending remedial actions when possible. 
    
The PRO instruments used in this study have been translated to several different languages.  
Women who are unable to read or have difficulty reading, will not be required to participate in 
the PRO component of this study, however, a woman may elect to have the items read to her and 
be assisted in completing the instruments.  
 
13.2.2 Translational Research Studies 
 
13.2.2.1 
BROCA-HR 
The hypothesis for this objective is that cancer cells need to be not only deficient in HR but also 
proficient in the alternative (error-prone) NHEJ DNA repair pathway to be sensitive to a PARPi.  
The BROCA-HR assay identifies mutations in genes that are involved in HR or NHEJ as well as 
the presence of several clinically relevant SNPs (See Section 2.4.1).  While the assay consists of 
several laboratory measurements, the ultimate result classifies each individual as either positive 
(at least one of the pre-specified mutations or SNPs) or negative (no such mutations or SNPs).  A 
single proportional hazards model (Cox, 1972) will be used to estimate the treatment hazard 
ratios (and variances) for each of the experimental treatments selected for phase III evaluation 
relative to the reference treatment (chemotherapy) group.  All of the patients with BROCA-HR 
scores who were assigned to one of these treatments during either the phase II or phase III 
component of this study will be included in the analysis.  The model will include adjustments for 
prior platinum-free interval, prior bevacizumab treatment, age at study enrollment, randomly 
assigned study treatment and BROCA-HR status. The estimated hazard ratio(s) for BROCA-HR 
and the corresponding confidence intervals will be depicted with a forest plot, and assessed for 
qualitative interaction(s) (Gail and Simon, 1985).  

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It is anticipated that 25-30% of the enrolled patients will have BROCA-HR deficiencies; 
however, these patients are expected to have a favorable prognosis compared to those patients 
without these HR deficiencies.  Therefore, assuming that 20% of the deaths at the time of the 
final analysis have BROCA deficiencies, then the number of deaths among those patients with 
BROCA deficiencies in each pairwise treatment comparison is projected to 
(D1=0.20*(110+137)≈49.  In this case, the variances of the log treatment hazard ratios are 
expected to be approximately 0.081 (4/D1 ≈ 4/49).  Among those without BROCA-HR 
deficiencies the variances are expected to be about 0.020 (4/(0.80*(110+137)). 
 
The other measures of homologous repair deficiency or NHEJ such as BRCA1 methylation, or 
genomic scarring will be analyzed in a similar manner.  Since these are exploratory objectives 
the primary focus is on the estimated treatment hazard ratios and confidence intervals for patient 
subgroups determined by their maker status.  Forest plots will be used to display these results.  
Also, Kaplan-Meier (Kaplan and Meier, 1958) plots will be used to depict the estimated 
probability of survival for women in each treatment group by their marker status.   
 
13.2.2.2 
Circulating endothelial cells (CECs) 
 
An increase in the level of CECs is thought to be an early indicator for drug induced vascular 
damage.  This component of the study seeks to determine whether the CEC levels that are 
measured after 3 days of treatment are independent of the treatment.  Also, this study will assess 
whether the change in CEC levels between the pretreatment value and the value on the 3rd-day 
of treatment is prognostic.  Finally, it will assess whether the prognostic effect size of the change 
in CECs levels depends on the treatment (ie. a predictive biomarker).   
CEC level is a continuous measure.  Based on 10 patients treated with olaparib or olaparib and 
cediranib from a previous study, the mean and standard deviation of pretreatment CEC (%) was 
1.1*10-4 and 1.5*10-4, respectively.  Three days following the initiation of treatment the mean 
and standard deviations were 1.3*10-4 and 1.6*10-4, respectively.  The correlation between pre- 
and post-treatment values was -0.10.  The CEC measurements from the current study will be 
used to better characterize the distributions of this biomarker for each of the treatment groups 
selected for phase III evaluation assessed using descriptive statistics, histograms, rug-plots or 
box-plots.  Extreme outliers will be noted.  The first null hypothesis is that the distribution of the 
3rd-day CEC values is independent of the treatment group assignment.  An ANCOVA model 
(Kleinbaum et.al, 1988) will be used to assess whether the 3-day CEC levels are independent of 
treatment.  All of the patients who were randomly assigned to the reference regimen or one of the 
experimental regimens selected for phase III evaluation will be included in this analysis, 
regardless of whether they were enrolled during the phase II or the phase III component of this 
study, provided they have valid pre-treatment and 3rd-day CEC values.  The ANCOVA model 
will include the randomly assigned treatment, pretreatment CEC values, and age at study 
enrollment as covariates.  Assuming that valid pre-treatment and 3-day measurements are 
available from 85% of the individuals in each treatment group (0.85*170=144) there is 
approximately 85% power to detect an effect size (difference in means/standard deviation) of 
0.39. Sensitivity analyses will be performed to determine whether statistical significance is 
influenced by extreme outliers. 

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A proportional hazards model will be used to assess a linear association between the change in 
CEC values and the log relative hazard of death within each treatment group.  For the primary 
analysis the proportional hazards model will include randomized treatment group as a 
polychotomous covariate.  Sensitivity analyses will include known prognostic factors in the 
model.  At the time of the final analysis there is expected to be 110-137 deaths reported in each 
treatment group depending of each treatment’s effect on overall survival. Assuming at least one 
experimental treatment is selected following the phase II component of the trial and 85% of 
individuals provide paired measurements, then this sample size (~250*0.85=212 deaths) 
provides 83% statistical power if the true reduction (or increase) in the hazard of death is 18% 
(HR=0.82) for individuals whose change in CEC values are one standard deviation apart (ie, one 
standard deviation of the change in CEC values).  Patients who were enrolled onto the phase II 
study and randomized to treatments that were not selected for the phase III study may also be 
included in these analyses.  A plot of the martingale residuals (Therneau et al, 2000) or estimated 
relative hazards by change in CEC quintiles will be used to qualitatively assess the assumption of 
a linear relationship between the change in CEC values and the log relative hazard. 
 
13.2.2.3 
Plasma Angiome 
 
This component of the study seeks to determine whether the angiogenic biomarkers in the 
plasma angiome are prognostic and/or predictive for survival.  Pretreatment biologic specimens 
from individuals receiving chemotherapy or any of the experimental treatments will be 
quantified.  Descriptive statistics and histograms will be used to assess the center and the 
dispersion of the values for each analyte, as well as identify outliers.  Scattergrans and 
Spearman’s rank correlation will be used to assess the associations between pairs of analytes.  
 
A proportional hazards model (Cox, 1972) will be used to assess whether the pretreatment values 
of any of these analytes have a prognostic association with overall survival.  The model will 
include clinical covariates: age, performance status, and the randomly assigned study treatment.   
A training set which includes a random selection of about 60% of the individuals in this study 
will be used to identify a subset of potentially prognostic analytes.  Proportional hazards models 
will be used to assess the relationship between patients’ analyte values and log hazard.  At the 
time of the final analysis, there are expected to be 110 to 137 deaths in each treatment group 
selected for the phase III trial. Provided at least one experimental treatment group is selected 
following the phase II trial and 95% of the patients provide a pretreatment sample, this sample 
size (~250*0.95=237) provides 87% power if the true hazard of death is reduced (or increased) 
18% (HR=0.82) for individuals who are separated by one standard deviation of the analyte.   
The results from these univariate analyses on individual analytes will be used to construct a 
multivariate classifier for prognosis.  Once the classifier has been defined and documented, its 
validity will be independently evaluated among those individuals who were not included in the 
training set. 
 
Prior to validating the composite putative prognostic score the team that developed the scoring 
procedure will prepare a document that completely and unambiguously defines scoring 
procedure and the validation procedure.  Then, an independent statistician, who was not involved 
in the training phase, will be identified.  This individual will review and confirm that the 
documentation for the scoring algorithm and validation procedure are unambiguous and 

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complete.  The independent statistician will also be responsible for maintaining this 
documentation in a secure location.  The independent statistician will then either use computer 
code provided by the development team or develop the computer code from the documentation 
to score each individual in the validation data set and validate the putative prognostic score.  If 
the validation process determines that the score is not clinically useful, then the development 
team may repeat this entire process to develop alternative scoring procedures.  In this case, 
however, the independent statistician will be responsible for maintaining the documentation for 
each attempt to validate a new scoring procedure.  Also, the clinical data from those patients who 
are in the validation group will not be transferred to the team involved in the training process.  If 
the prognostic score is validated, then the independent statistician can release the validation 
documentation and the validation dataset for external verification.  Though, the biospecimen 
identifiers will not be released so as not to compromise the validity of other validation studies 
that may use these samples for other purposes. 
 
In a similar fashion, a proportional hazards model will be used to assess the potential predictive 
associations between analytes, treatment and survival.  The models will include the covariates: 
age, performance status, randomly assigned study treatment, an analyte -by-treatment interaction 
term.  In this case, focus will be on the analyte-by-treatment interaction terms.  Those biomarkers 
that appear to be predictive will be used to construct a classifier for predicting responsiveness to 
treatment.  Once this classifier has been defined and documented, its validity will be 
independently documented and evaluated using those individuals who were not included in the 
training set. The validation procedures will be similar to those described above. 
 
Kaplan-Meier plots and forest plots will be used to summarize the associations between analytes 
and overall survival and relative risk of death. 
 
13.3 
Projected Race and Ethnicity of Enrollees (22-SEP-2022) 
 
Anticipated Accrual by Race and Ethnicity 
Assuming Full Phase 2 Accrual and Phase 3 Accrual to Three Treatment Arms 
 
DOMESTIC 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
 Male  
Female 
 Male  
American Indian or Alaska Native 
4 
0 
0 
0 
4 
Asian 
3 
0 
0 
0 
3 
Native Hawaiian or other Pacific Islander 
1 
0 
0 
0 
1 
Black or African American 
17 
0 
0 
0 
17 
White 
439 
0 
13 
0 
452 
More than one race 
0 
0 
0 
0 
0 
Not Reported 
0 
0 
0 
0 
0 
TOTAL 
464 
0 
13 
0 
477 

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FOREIGN 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
 Male  
Female 
 Male  
American Indian or Alaska Native 
0 
0 
0 
0 
0 
Asian 
8 
0 
0 
0 
8 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
0 
0 
0 
0 
White 
64 
0 
0 
0 
64 
More than one race 
0 
0 
0 
0 
0 
Not Reported 
0 
0 
0 
0 
0 
TOTAL 
72 
0 
0 
0 
72 
 
 
14. 
EVALUATION CRITERIA 
 
14.1 
Antitumor Effect – Solid Tumors (06-AUG-2021) 
 
Because of the differences in cycle lengths between the allowed regimens, tumor reassessment 
will be time-based, and not cycle-based, with CT scan or MRI performed once every 9 weeks 
(+/- 7 days), and at any other time if clinically indicated based on symptoms or physical signs 
suggestive of progressive disease. Imaging assessments can be discontinued if disease 
progression is confirmed according to RECIST 1.1.  However, if a patient discontinues study 
treatment for any reason other than disease progression, imaging studies should continue every 9 
weeks (+/- 7 days) until progression. After 1 year of protocol therapy or follow-up (measured 
from approximately cycle 1, day 1), imaging studies will be conducted every 12 weeks. An Excel 
tool will be provided to sites to assist in determining imaging dates.  In addition to a baseline 
scan, confirmatory scans should also be obtained at least 4 weeks following initial 
documentation of objective response; the next planned scan may be used as the confirmatory 
scan. 
 
 
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. 
 
For this study, a rise in CA-125 alone is not sufficient to declare progression, and progression 
events should be determined by radiographic evidence of progression.   
 
14.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with cediranib and/or olaparib.   
 

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Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
14.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >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 might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
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 

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lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, 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.  
 
14.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and t10 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 

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resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, 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. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST measurements 
and can be used interchangeably with conventional CT in accurately measuring cancer 
lesions over time.  Note, however, that the PET portion of the CT introduces additional 
data which may bias an investigator if it is not routinely or serially performed.  
The decisions are made on the diagnostic CT scans only if PET/diagnostic CT (with 
oral/iv contrast) is to be used for tumor measurements. 
New lesions may not be determined on the basis of FDG PET/CT.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
(JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008).  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer (JNCI 92:1534-1535, 2000). 
 

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Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
14.1.4 Response Criteria 
 
14.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 

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baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
14.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or the Study Chair). 
 
14.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the date of 
randomization until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the date of 
randomization).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
No 
PR 

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PD/not 
evaluated 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
14.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
 
 

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14.1.6 Progression-Free Survival 
 
The onset of progression will be determined using RECIST criteria (Section 15.1.4).  For 
analyses of the primary endpoint, the PFS duration will be defined as the time between 
the date of enrollment (and randomization) onto the study to the date of disease 
progression or death.  The date of progression will be determined by the local clinical 
staff.  The following censoring will apply to the primary PFS analyses: 
 
1. Patients with no baseline tumor assessments will be censored on the date of 
randomization 
2. Patients with no adequate post baseline tumor assessments and no death reported 
within 2 scan intervals following randomization will be censored on the date of 
randomization.   
3. Patients who have not progressed and are alive will be censored on the date of the last 
tumor assessment without documented disease progression   
4. Patients who have disease progression or death immediately after 2 or more 
consecutive missing tumor assessments will be censored at the date of last tumor 
assessment prior to the missing tumor assessments 
The following PFS sensitivity analyses are planned. (06-AUG-2021) 
 
1. Attrition-time bias: In addition to the PFS censoring rules described above, patients 
who receive non-protocol anticancer therapy before disease progression will be 
censored at the time of their last disease assessment before starting non-protocol 
therapy. The primary log-rank test will be used. Additionally, a Kaplan-Meier plot of 
the time to censoring, where the censoring indicator of the primary PFS analysis is 
reversed will provide an assessment of the independent censoring assumption. 
2. Evaluation-time bias: An interval-censored log-rank test (as implemented in SAS® 
Proc ICLIFETEST) will be used. 
 
 

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15. 
REFERENCES 
 
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. 
 
Adamo A, Collis SJ, Adelman CA, et al. Preventing nonhomologous end joining suppresses 
DNA repair defects of Fanconi anemia. Mol Cell 2010;39:25-35. 
 
Baldwin RL, Nemeth E, Tran H, et al. BRCA1 promoter region hypermethylation in ovarian 
carcinoma: a population-based study. Cancer Res 2000;60:5329-33. 
 
Basen-Engquist K, Bodurka-Bevers D, Fitzgerald MA et al. Reliability and validity of the 
functional assessment of cancer therapy-ovarian. J Clin Oncol. 2001; 19(6):1809-17. 
 
Beesley VL, Green AC, Wyld DK et al.  Quality of life and treatment response among women 
with platinum-resistant versus platinum-sensitive ovarian cancer treated for progression:  a 
prospective analysis. Gyn Onc 2014; 132(1):  130-06. 
 
Berk KN and Lachenbruch PA.  Repeated measures with zeros.  Stat Methods in Med Res 2003, 
11(4): 303-316.  
  
Birkbak NJ, Wang ZC, Kim JY, et al. Telomeric allelic imbalance indicates defective DNA 
repair and sensitivity to DNA-damaging agents. Cancer Discov 2012;2:366-75. 
 
Bouwman P, Aly A, Escandell JM, et al. 53BP1 loss rescues BRCA1 deficiency and is 
associated with triple-negative and BRCA-mutated breast cancers. Nature structural & molecular 
biology 2010;17:688-95. 
 
Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with 
inhibitors of poly(ADP-ribose) polymerase. Nature 2005;434:913-7. 
 
Bunting SF, Callen E, Wong N, et al. 53BP1 inhibits homologous recombination in Brca1-
deficient cells by blocking resection of DNA breaks. Cell 2010;141:243-54. 
 
Cannistra SA. Cancer of the ovary. The New England journal of medicine 2004;351:2519-29.  
 
Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: 
Outcomes and safety of rapid desensitization in 413 cases. Journal of Allergy and Clinical 
Immunology 2008; 122(3): 574-580 
 
Cella D, Neubauer N, Thomas J et al. The FACIT-AI, a new tool for assessing symptoms 
associated with malignant ascites. Gynecol Oncol. 2013; 128(2):187-90.  
 
Cox, DR.  Regression Models and life tables (with discussion), J of the Royal Statistical Society 
B 1972, 26: 103-110. 

NCI Protocol #: NRG-GY005 
Version Date: July 27, 2023 
- 125 - 
 
 
Du Bois A, Luck HJ, Meier W, et al. A randomized clinical trial of cisplatin/paclitaxel versus 
carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 2003;95:1320-
9. 
 
Duric VM, Stockler MR, Heritier S et al. Patients' preferences for adjuvant chemotherapy in 
early breast cancer: what makes AC and CMF worthwhile now? Ann Oncol. 2005; 16 (11):1786-
94. Epub 2005 Aug 26. 
 
Esteller M, Silva JM, Dominguez G, et al. Promoter hypermethylation and BRCA1 inactivation 
in sporadic breast and ovarian tumors. J Natl Cancer Inst 2000;92:564-9. 
 
Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as 
a therapeutic strategy. Nature 2005;434:917-21. 
 
Freidlin, B, Korn, EL and George, SL, Data monitoring committees and interim monitoring 
guidelines, Controlled Clinical Trials 1999; 20:395-407. 
 
Friedlander ML, Stockler M, O’Connell R et al. Symptom burden and outcomes of patients with 
platinum resistant/refractory recurrent ovarian cancer:  a reality check:  results of stage 1 of the 
gynecologic cancer intergroup symptom benefit study.  Int J Gynecol Cancer.  et al, IJGC 2014; 
24(5):857-64. 
 
Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from 
BRCA mutation carriers. N Engl J Med 2009;361:123-34. 
 
Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable 
responses in BRCA carrier ovarian cancer correlating with platinum-free interval. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 2010;28:2512-
9. 
 
Gail M and Simon R.  Testing for qualitative interactions between treatment effects and patient 
subsets.  Biometrics 1983, 41(2): 361-372.   
 
Garg K, Levine DA, Olvera N et al. BRCA1 immunohistochemistry in a molecularly 
characterized cohort of ovarian high-grade serous carcinomas. Am J Surg Pathol. 
2013;37(1):138-46.  
 
Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade 
serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, 
multicentre, open-label, non-randomised study. The lancet oncology 2011;12:852-61. 
 
Goon PKY, Lip GYH, Boos CJ et al., Circulating Endothelial Cells, Endothelial Progenitor 
Cells, and Endothelial Microparticles in Cancer. Neoplasia. 2006; 8(2): 79–88. 
 

NCI Protocol #: NRG-GY005 
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- 126 - 
 
Jensen SE, Rosenbloom SK, Beaumont JL et al. A new index of priority symptoms in advanced 
ovarian cancer. Gynecol Oncol. 2011; 120(2):214-9. 
  
Johnson N, Johnson SF, Yao W, et al. Stabilization of mutant BRCA1 protein confers PARP 
inhibitor and platinum resistance. Proceedings of the National Academy of Sciences of the 
United States of America 2013;110:17041-6. 
 
Kaplan EL and Meier P. Nonparametric estimation from incomplete observations.  J of the 
American Statistical Assoc 1958, 53: 457-481. 
 
Kaye SB, Lubinski J, Matulonis U, et al. Phase II, open-label, randomized, multicenter study 
comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and 
pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent 
ovarian cancer. J Clin Oncol 2012;30:372-9. 
 
Kleinbaum DG, Kupper LL and Muller KE (1988).  Applied Regression Analysis and other 
Multivariate Methods, 2nd edition, Duxberry Press, Belmont, CA. 
 
Kummar S, Gutierrez ME, Chen A, et al. Phase I trial of vandetanib and bevacizumab evaluating 
the VEGF and EGF signal transduction pathways in adults with solid tumours and lymphomas. 
Eur J Cancer 2011;47:997-1005. 
 
Lan GKKK, Demets, DL, Group Sequential Procedures: Calendar vs Information Time, Stats in 
Med 1989; 8:1191-8. 
 
Ledermann J, Harter P, Gourley C, et al. 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. 2014;15(8):852-61. 
 
Ledermann JA PJ, Raja FA, et al. Randomised double-blind phase III trial of cediranib (AZD 
2171) in relaposed platinum sensitive ovarian cancer:  Results of the ICON6 trial. Presented at 
the 38th Congress of the European Society for Medical Oncology (ESMO) 2013, Abst LBA10. 
 
Ledermann JA, Kristeleit RS. Optimal treatment for relapsing ovarian cancer. Ann Oncol 
2010;21 Suppl 7:vii218-22. 
 
Lee JM, Hays JL, Annunziata CM, et al. Phase I/Ib Study of Olaparib and Carboplatin in 
BRCA1 or BRCA2 Mutation-Associated Breast or Ovarian Cancer With Biomarker Analyses. 
Journal of the National Cancer Institute 2014;106. 
 
Lee JM, Ledermann JA, Kohn EC. PARP Inhibitors for BRCA1/2 mutation-associated and 
BRCA-like malignancies. Ann Oncol 2014;25:32-40. 
 
Lee JM, Trepel JB, Choyke P, et al. CECs and IL-8 have prognostic and predictive utility in 
patients with recurrent platinum-sensitive ovarian cancer: biomarker correlates from the 

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- 127 - 
 
randomised phase 2 trial of olaparib and cediranib verses olaparib in recurrent platinum-sensitive 
ovarian cancer. Front Oncol 2015, in press.  
 
Lin Y, Weisdorf DJ, Solovey A et al,. Origins of circulating endothelial cells and endothelial 
outgrowth from blood. J Clin Invest. 2000;105(1):71–77. 
 
Liu JF, Barry WT, Birrer M, et al. Combination cediranib and olaparib versus olaparib alone for 
women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet 
Oncol. 2014 Oct;15(11):1207-14. 
 
Liu JF, Tolaney SM, Birrer M, et al. A Phase 1 trial of the poly(ADP-ribose) polymerase 
inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in 
recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer 2013;49:2972-8. 
 
Loveday C, Turnbull C, Ramsay E, et al. Germline mutations in RAD51D confer susceptibility 
to ovarian cancer. Nat Genet 2011;advance online publication. 
 
Markman M, Bookman MA. Second-line treatment of ovarian cancer. Oncologist 2000;5:26-35. 
 
Markman M, Kennedy A, Webster K et al., Paclitaxel-Associated Hypersensitivity Reactions: 
Experience of the Gynecologic Oncology Program of the Cleveland Clinic Cancer Center. J Clin 
Oncol 2000;18:102-105 
 
Matsuo K, Lin YG, Roman LD, Sood AK. Overcoming platinum resistance in ovarian 
carcinoma. Expert Opin Investig Drugs 2010;19:1339-54. 
 
Matulonis UA, Berlin S, Ivy P, et al. Cediranib, an oral inhibitor of vascular endothelial growth 
factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and 
peritoneal cancer. J Clin Oncol 2009;27:5601-6. 
 
McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous 
recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 
2006;66:8109-15. 
 
McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with 
paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. The New England 
journal of medicine 1996;334:1-6. 
 
Meindl A, Hellebrand H, Wiek C, et al. Germline mutations in breast and ovarian cancer 
pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 2010;42:410-4. 
 
Network TCGA. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609-15. 
 
Nik-Zainal S, Alexandrov LB, Wedge DC, et al. Mutational processes molding the genomes of 
21 breast cancers. Cell 2012;149:979-93. 
 

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- 128 - 
 
Ning YM, Gulley JL, Arlen PM, et al. Phase II trial of bevacizumab, thalidomide, docetaxel, and 
prednisone in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 
2010;28:2070-6. 
 
Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with 
cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a 
Gynecologic Oncology Group study. J Clin Oncol 2003;21:3194-200. 
 
Park SR, Speranza G, Piekarz R, et al. A multi-histology trial of fostamatinib in patients with 
advanced colorectal, non-small cell lung, head and neck, thyroid, and renal cell carcinomas, and 
pheochromocytomas. Cancer Chemother Pharmacol 2013;71:981-90. 
 
Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy 
versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the 
ICON4/AGO-OVAR-2.2 trial. Lancet 2003;361:2099-106. 
 
Patel AG, Sarkaria JN, Kaufmann SH. Nonhomologous end joining drives poly(ADP-ribose) 
polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc Natl 
Acad Sci U S A 2011;108:3406-11. 
 
Pennington KP, et al. (2012) BRCA1, TP53, and CHEK2 germline mutations in uterine serous 
carcinoma. Cancer. 
 
Pennington KP, Walsh T, Harrell MI et al. Germline and somatic mutations in homologous 
recombination genes predict platinum response and survival in ovarian, fallopian tube, and 
peritoneal carcinomas. Clin Cancer Res. 2014;20(3):764-75.  
 
Pennington KP, Walsh T, Harrell MI, et al. Germline and Somatic Mutations in Homologous 
Recombination Genes Predict Platinum Response and Survival in Ovarian, Fallopian Tube, and 
Peritoneal Carcinomas. Clinical cancer research : an official journal of the American Association 
for Cancer Research 2013. 
 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in 
the controlled clinical trial. Biometrics 1975;31:103-15. 
 
Rafii S, Lyden D, Benezra R et al. Vascular and haematopoietic stem cells: novel targets for anti-
angiogenesis therapy? Nature Reviews Cancer 2002; 2:826-835. 
 
Rafnar T, Gudbjartsson DF, Sulem P, et al. Mutations in BRIP1 confer high risk of ovarian 
cancer. Nat Genet 2011. 
 
Ramsey S, Willke R, Briggs A et al. Good research practices for cost-effectiveness analysis 
alongside clinical trials: the ISPOR RCT-CEA Task Force report. Value Health. 2005; 8(5):521-
33. Review. 
 

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Stockler MR, Hilpert F, Friedland M et al, Patient-Reported Outcome Results From the Open-
Label Phase III AURELIA Trial Evaluating Bevacizumab- Containing Therapy for Platinum-
Resistant Ovarian Cancer. J Clin Onc 2013; 32(13):1309-16 
 
Swisher EM, Gonzalez RM, Taniguchi T, et al. Methylation and protein expression of DNA 
repair genes: association with chemotherapy exposure and survival in sporadic ovarian and 
peritoneal carcinomas. Molecular cancer 2009;8:48. 
 
Thrall M, Gallion HH, Kryscio R, et al. BRCA1 expression in a large series of sporadic ovarian 
carcinomas: a Gynecologic Oncology Group study. Int J Gynecol Cancer 2006;16 Suppl 1:166-
71. 
 
Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, 
and peritoneal carcinoma identified by massively parallel sequencing. Proceedings of the 
National Academy of Sciences of the United States of America 2011;108:18032-7. 
 
Walsh T, Lee MK, Casadei S, et al. Detection of inherited mutations for breast and ovarian 
cancer using genomic capture and massively parallel sequencing. Proceedings of the National 
Academy of Sciences of the United States of America 2010;107:12629-33. 
 
Wang ZC, Birkbak NJ, Culhane AC, et al. Profiles of genomic instability in high-grade serous 
ovarian cancer predict treatment outcome. Clin Cancer Res 2012;18:5806-15. 
 
Wickramanyake A, Bernier G, Pennil C, et al. Loss of function germline mutations in RAD51D 
in women with ovarian carcinoma. Gynecologic oncology 2012. 
 
Wiggans AJ1, Cass GK, Bryant A et al. Poly(ADP-ribose) polymerase (PARP) inhibitors for the 
treatment of ovarian cancer. Cochrane Database Syst Rev. 2015 May 20;5: CD007929. [Epub 
ahead of print] 
 
 
 
 

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

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

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APPENDIX III. PATIENT DRUG DIARY 
 
CEDIRANIB ONLY (12/05/2016) 
Today’s Date ______________________________ 
Cycle # ______ 
Patient Name ______________________________ 
Patient Study ID _________________ 
1. Complete one form for each cycle (28 days).  
3. Record the date, the number of pills you took, and when you took them.  
4. Bring your pill bottles (including empty bottles) and this form to every appointment. 
5. Do not chew, dissolve, or crush medications. DO NOT make up vomited doses. 
6. If you miss a dose, you have up to 2 hours to make this dose up. Otherwise, write “missed” where 
you would normally write the time of your dose. 
7. The first row in the table below is an EXAMPLE ROW for how to complete this diary. 
 
 
 
 
 
 
 
 
 
 
CEDIRANIB 
Take __(number) ____mg and __(number) ____ mg tablets once daily. Take on an empty stomach. 
Day 
Date 
15mg 
20mg 
AM 
1 
1/1/15 
2 
0 
7:00 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 

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Patient’s Signature: ___________________________________                    Date: _____________ 
Physician/Nurse’s Signature ________________________    Date______________ 
 
 

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OLAPARIB ONLY (12/05/2016) 
Today’s Date ______________________________ Cycle # ______ 
Patient Name ______________________________ Patient Study ID _________________ 
1. Complete one form for each cycle (28 days). 
2. Record the date, the number of tablets you took, and when you took them. 
3. Bring your pill bottles (including empty bottles) and this form to every appointment. 
4. Do not chew, dissolve, or crush medications. DO NOT make up vomited doses. 
5. If you miss a dose, you have up to 2 hours to make this dose up. Otherwise, write “missed” where you 
would normally write the time of your dose. 
6. The first row in the table below is an EXAMPLE ROW for how to complete this diary. 
OLAPARIB 
Take _____ (number) ___ mg and __(number) __mg tablets twice a day 12 hours apart. 
Day 
Date 
100mg 
150mg 
AM 
PM 
1 
1/1/15 
2 
0 
8:00 
8:00 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
Patient’s Signature: ___________________________________                    Date: _____________ 
Physician/Nurse’s Signature _________________________  Date______________ 

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 CEDIRANIB AND OLAPARIB (12/05/2016) 
 
Today’s Date ______________________________ Cycle # ______ 
Patient Name ______________________________ Patient Study ID _________________ 
7. Complete one form for each cycle (28 days). 
8. Record the date, the number of tablets you took, and when you took them. 
9. Bring your pill bottles (including empty bottles) and this form to every appointment. 
10. 
Do not chew, dissolve, or crush medications. DO NOT make up vomited doses. 
11. 
If you miss a dose, you have up to 2 hours to make this dose up. Otherwise, write “missed” where 
you would normally write the time of your dose. 
12. 
The first row in the table below is an EXAMPLE ROW for how to complete this diary. 
CEDIRANIB 
Take ____ (number) _____ mg tablets once a day. 
Take on an empty stomach 1 hour before taking 
the morning dose of olaparib. 
OLAPARIB 
Take _____ (number) ______ mg and _____ (number) _____ mg 
tablets twice a day 12 hours apart. 
Day 
Date 
15mg 
20mg 
AM 
Day 
Date 
100mg 
150mg 
AM 
PM 
1 
1/1/15 
2 
0 
7:00 
1 
1/1/15 
2 
0 
8:00 
8:00 
1 
 
 
 
 
1 
 
 
 
 
 
2 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
28 
 
 
 
 
 

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Patient’s Signature: ___________________________________                    Date: _____________ 
Physician/Nurse’s Signature _________________________  Date______________ 
 
 
 

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

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APPENDIX V: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
(12/05/2016) 
 
CEDIRANIB 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, AZD2171 (cediranib).  This clinical trial is sponsored by the National 
Cancer Institute (NCI).  This form is addressed to the patient, but includes important information 
for others who care for this patient.  
 
These are the things that you as a prescriber need to know: 
  
AZD2171 (cediranib) interacts with certain specific enzymes in the liver and certain transport 
proteins that help move drugs in and out of cells. 
 
x The enzymes in question are CYP 3A4, 2D6, flavin-containing monooxygenase (FMO) 
and UGT1A4. AZD2171 (cediranib) is metabolized by FMO1, FMO3 and UGT1A4 and 
may be affected by other drugs that strongly inhibit or induce these enzymes.  AZD2171 
(cediranib) weakly inhibits CYP 2D6 and 3A4 and may increase levels of affected 
substrates.   
x Cediranib (AZD2171) may induce gastrointestinal CYP3A and UGT enzymes, therefore 
potentially reducing the effectiveness of hormonal contraceptives. 
x The transport proteins in question are P-glycoprotein (P-gp) and breast cancer resistance 
protein (BCRP). AZD2171 (cediranib) requires P-gp to move in and out of cells. 
Cediranib (AZD2171) inhibits BCRP, P-gp, OATP1B1, OATP1B3, OCT2, MATE1, and 
MATE2-K and this may affect the clearance of other drugs that are dependent on these 
transport proteins. 
x AZD2171 (cediranib) 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. 
x Patients receiving AZD2171 (cediranib) are at increased risk of bleeding and hemorrhage. 
Increase monitoring in patients who also receive anticoagulation therapy.  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
June 2016 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Cediranib (AZD2171) interacts with many drugs which can cause side effects. Because of this, it 
is very important to tell your study doctors about all of your medicines before you enroll on this 
clinical trial.  It is also very important to tell them if you stop taking any regular medicines, or if 
you start taking a new medicine while you take part in this study.  When you talk about your 

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medications with your doctors, include medicine you buy without a prescription (over-the-
counter remedy), or any herbal supplements such as St. John’s Wort. It is helpful to bring your 
medication bottles or an updated medication list with you. 
 
Many health care prescribers can write prescriptions.  You must also tell your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
These are the things that you and they need to know: 
 
AZD2171 (cediranib) must be used very carefully with other medicines that need certain liver 
enzymes and transport proteins to be effective or to be cleared from your system.  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.” AZD2171 (cediranib) inhibits enzymes “CYP 2D6 and 
3A4, transport proteins BCRP, P-gp, OATP1B1, OATP1B3, OCT2, MATE1, and MATE2-K 
and is highly protein-bound.” These characteristics may change how other medicine works in 
your body. 
 
x Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctor or 
pharmacist to determine if there could be any side effects.  
x Cediranib (AZD2171) can increase the risk of bleeding and interferes with wound healing. 
Let your doctor know if you recently had or are planning to have any surgery.  
x Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is  
__________________________________________                and he or she can be contacted at  
 
_____________________________________. 
 
 
  
 
June 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD 
You are enrolled on a clinical trial using the experimental drug 
AZD2171 (cediranib).  This clinical trial is sponsored by the NCI.  
AZD2171 (cediranib) interacts with drugs that are processed by your 
liver, or use certain transport proteins in your body.  Because of this, it 
is very important to: 
¾ Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
¾ Tell all of your health care providers (doctors, physician assistant, 
nurse practitioners, pharmacists) that you are taking part in a clinical 
trial. 
¾ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
¾ AZD2171 (cediranib) interacts with CYP3A4, 2D6, FMO1, FMO3,  
 
 
 
UGT1A4 and transport proteins, P-gp and BCRP and must be used 
very carefully with other medicines that interact with these 
enzymes and proteins.  
¾ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines that are considered ““strong inducers/inhibitors of 
FMO1, FMO3, UGT1A4 and P-gp.” Cediranib (AZD2171) inhibits 
“CYP 2D6 and 3A4 and transport proteins BCRP, P-gp, 
OATP1B1, OATP1B3, OCT2, MATE1, and MATE2-K and is 
highly protein-bound.” It may change how other medicine works in 
your body. 
¾ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
¾ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

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PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
OLAPARIB 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, olaparib (AZD2281).  This clinical trial is sponsored by the National 
Cancer Institute (NCI).  This form is addressed to the patient, but includes important information 
for others who care for this patient.  
 
These are the things that you as a prescriber need to know: 
  
Olaparib interacts with certain specific enzymes in the liver and certain transport proteins that 
help move drugs in and out of cells. 
 
x The enzymes in question are CYP 3A4/5, 1A2, 2B6, 2C9, 2C19 and UGT1A1. Olaparib is 
cleared by CYP3A4/5 and is affected by strong and moderate inhibitors and inducers of 
CYP3A4/5. Olaparib inhibits CYP3A4 and UGT1A1enzymes and may increase levels of 
other drugs that are cleared by these enzymes. Olaparib induces CYP 1A2, 2B6 and 3A4 
enzymes and has the possibility of inducing CYP 2C9, 2C19 enzymes that may result in 
decreased levels of other drugs that are cleared by these enzymes.   
x The transport proteins in question are P-glycoprotein (P-gp), organic anion-transporting 
polypeptides (OATP1B1 and OAT3), organic cation transporters (OCT1 and OCT2), 
multi-drug and toxin extrusion proteins (MATE1 and MATE2K) and breast cancer 
resistance protein (BCRP). Olaparib requires P-gp to move in and out of cells and 
concomitant administration of strong P-gp inhibitors and inducers should be avoided. 
Olaparib inhibits P-gp, BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K 
transporters and has the possibility of inducing P-gp and that may affect the transport of 
other drugs that depend on these proteins to move in and out of cells. Use caution when 
taking substrates of these transporters, such as statins. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
November 2015 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Olaparib may interact with many drugs which can cause side effects. Because of this, it is very 
important to tell your study doctors about all of your medicines before you enroll on this clinical 
trial.  It is also very important to tell them if you stop taking any regular medicines, or if you start 
taking a new medicine while you take part in this study.  When you talk about your medications 
with your doctors, include medicine you buy without a prescription (over-the-counter remedy), 
or any herbal supplements such as St. John’s Wort. It is helpful to bring your medication bottles 
or an updated medication list with you. 
 
Many health care prescribers can write prescriptions.  You must also tell your health care 

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providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
These are the things that you and they need to know: 
 
Olaparib must be used very carefully with other medicines that need certain liver enzymes and 
transport proteins to be effective or to be cleared from your system.  Before you enroll onto the 
clinical trial, your study doctor will work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong inducers/inhibitors of CYP3A4/5 
and P-gp.” Olaparib inhibits enzymes “CYP3A4, UGT1A1, P-gp, OATP1B1, OCT1, OCT2, 
OAT3, MATE1, MATE2K and BCRP.” Olaparib possibly induces “CYP 1A2, 2B6, 3A4, 2C9, 
2C19 and P-gp.” These characteristics may change how other medicine works in your body. 
 
x Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctor or 
pharmacist to determine if there could be any side effects.  
x Avoid ingesting grapefruit, grapefruit juice and Seville oranges while taking olaparib. 
x You may need to be monitored more frequently if you are taking any drugs that have 
narrow therapeutic ranges. 
x Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is  
__________________________________________                and he or she can be contacted at  
 
_____________________________________. 
 
 
  
 
November 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following tables list CYP3A4 inducers and inhibitors.  Investigators should consult a 
frequently updated drug information reference for a list of strong inducers and prohibitors. 
 
CYP3A4 Inducers (prohibited) 
STUDY DRUG INFORMATION WALLET CARD 
You are enrolled on a clinical trial using the experimental drug 
olaparib (AZD2281).  This clinical trial is sponsored by the NCI.  
Olaparib interacts with drugs that are processed by your liver, or use 
certain transport proteins in your body.  Because of this, it is very 
important to: 
¾ Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
¾ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, pharmacists) that you are taking part in a clinical 
trial. 
¾ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
¾ Olaparib interacts with liver enzymes, CYP3A4/5, 1A2, 2B6, 2C9, 
2C19, UGT1A1, and transport proteins, P-gp, OATP1B1, OCT1, 
OCT2, OAT3, MATE1, MATE2K and BCRP.    
 
¾ Olaparib must be used very carefully with other medicines that 
interact with these enzymes and proteins.  
¾ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines that are considered ““strong or moderate 
inducers/inhibitors of CYP3A4/5 and P-gp.” Olaparib inhibits 
“CYP 3A4, UGT1A1 and transport proteins P-gp, OATP1B1, 
OCT1, OCT2, OAT3, MATE1, MATE2K and BCRP and induces 
CYP 1A2, 2B6, 3A4, 2C9, 2C19 and transport protein P-gp.” It 
may change how other medicine works in your body. 
¾ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
¾ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

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Armodafenil1 
Barbiturates2 
Bosentan1 
Carbamazepine  
Dexamethasone1  
Efavirenz   
Fosphenytoin1 
Glucocorticoids2 (see note) 
Modafinil2  
Nafcillin1  
Nevirapine  
Oxcarbazepine 
Pentobarbital1 
Phenobarbital 
Phenytoin 
Pioglitazone2 
Primidone1 
Rifabutin 
Rifampin 
Rifapentine1 
St. John’s 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 a superscript are cited in both the Lacy and Flockhart references. 
 
CYP3A4 Inhibitors 
Strong Inhibitors 
(prohibited) 
Moderate Inhibitors 
(use with caution, avoid if 
possible) 
  Weak Inhibitors 
(use with caution, avoid if 
possible) 
Amprenavir1 
Atazanavir1 
Clarithromycin 
Conivaptan1 
Delavirdine1 
Fosamprenavir1 
Fospropofol1 
Imatinib1 
Indinavir 
Isoniazid1 
Itraconazole 
Ketoconazole 
Miconazole1 
Nefazodone 
Nelfinavir 
Nicardipine1 
Posaconazole1 
Propofol1 
Quinidine1 
Ritonavir 
Saquinavir2 
Telithromycin 
Amiodarone1 
Aprepitant 
Cimetidine1 
Clotrimazole1 
Cyclosporine1 
Desipramine1 
Doxycycline1 
Efavirenz1 
Erythromycin 
Fluconazole 
Fosaprepitant1 
Grapefruit juice 
Haloperidol1 
Lidocaine1 
Metronidazole1 
Norfloxacin1 
Sertraline1 
Tetracycline1 
Verapamil 
Voriconazole1 
Chloramphenicol2 
Ciprofloxacin2 
Diethyldithiocarbamate2 
Fluvoxamine2 
Gestodene2 
Mibefradil2 
Mifepristone 
Norfluoxetine2 
Star fruit2 
Troleandomycin2 
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 a superscript are cited in both the Lacy and Flockhart references. 

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

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E Blockers 
(BB) 
atenolol 
25 mg daily 
50 mg daily 
100 mg 
daily 
No 
acebutolol 
100 mg 
twice daily 
200-300 mg 
twice daily 
400 mg 
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg daily 
5-10 mg 
daily 
20 mg daily 
CYP 3A4 
substrate 
D and E 
Blocker 
labetalol 
100 mg twice 
daily 
200 mg 
twice daily 
400 mg 
twice daily 
Yes, but not 
CYP450 
Diuretics 
Hydralazine 
10 mg four 
times daily 
25 mg four 
times daily 
50 mg four 
times daily 
no 
Hydrochlorot
hiazide 
12.5 mg AM 
daily 
25 mg AM 
daily 
50 mg AM 
daily 
no 
Furosemide  
20 mg daily 
20 mg twice 
daily 
40 mg twice 
daily 
no 
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  
 
 
 
 
 
 

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APPENDIX VII – TRANSLATIONAL SCIENCE SPECIMEN PROCEDURES 
 
Sites in Korea: Please refer to Appendix XIV for biospecimen requirements and 
procedures. Information in this appendix is not applicable to sites in Korea.  
 
 
I. Obtaining a Bank ID for Translational Science Specimens (12/05/2016) 
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. CEC Whole Blood 
Shipped to the Preclinical Development Research Core 
Note: Sites in Japan and Korea should not collect CEC whole blood specimens. 
 
A. Requesting CEC Whole Blood Specimen Kits (12/05/2016) 
CPT (citrate) tubes will be provided by the NRG Oncology Biospecimen Bank-Columbus for the 
collection of CEC whole blood specimens. Specimen kits are not provided for the shipment 
of CEC whole blood specimens to the Preclinical Development Research Core (PDRC). 
Sites must provide their own shipping kits and cover shipping costs. 
 
B. Labeling CEC Whole Blood 
A waterproof permanent marker or printed label should be used to label each translational 
science whole blood specimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG - GY # # #) 
specimen code (WB02 for pre-treatment, WB03* for C1D3) 
collection date (mm/dd/yyyy) 
 
*WB03 should be collected only if WB02 was submitted. 
 
C. CEC Whole Blood 
1.  Label the CPT (citrate) collection tube as described below. Note: CPT (citrate) tube should 
be at room temperature (i.e., 18-25°C). 
2. Draw 8mL of blood into the labeled CPT (citrate) tube. 
3.  Immediately after collection, gently invert the tube 6 times to mix the blood and citrate. 

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4. CEC whole blood should be stored upright at room temperature until the specimen can be 
shipped. Ship to the PDRC the day the specimen is collected. If the CEC whole blood 
absolutely cannot be shipped the day it is collected, the tube should be kept at room 
temperature until the specimen can be shipped the next day. Note: The laboratory testing to 
be done is time sensitive. CEC whole blood specimens must be shipped the day the 
specimen is collected. If the specimen absolutely cannot be shipped the same day, a note 
detailing why the specimen needed to be shipped the next day must be included. If the 
specimen cannot be shipped within 24 hours, it should be discarded. 
 
D. Shipping CEC Whole Blood Specimens (12/05/2016) 
CEC whole blood specimens should not be shipped until after patient registration and Bank ID 
assignment. 
 
An electronically completed copy of Form TR must be included for each CEC whole blood 
specimen.  
 
CEC whole blood specimens should be shipped using your own container at your own expense 
directly to: 
 
Preclinical Development Research Core 
NCI, NIH 
Bldg 10, Rm 12N218 
10 Center Dr 
Bethesda, MD 20892 
Phone: 301-496-1547 
Emails: trepel@helix.nih.gov, leesun@mail.nih.gov, leemin@mail.nih.gov, akira.yuno@nih.gov 
 
Note: Please notify the PDRC (via the four email addresses provided) when a patient is 
scheduled for a blood draw and when the specimen will be shipped. The FedEx tracking 
number should be included in the shipment. 
 
CEC whole blood specimens can be shipped to the PDRC Monday through Thursday for 
Tuesday through Friday delivery. Do not ship whole blood the day before a government 
holiday. Use your own shipping container to ship specimens via FedEx priority overnight.  
 
III. Translational Science Specimens 
 
 Shipped to the NRG Oncology Biospecimen Bank-Columbus (NRG BB-Columbus) 
A. Requesting Translational Science Specimen Kits (12/05/2016) 
Specimen kits are not provided for the collection and shipment of BROCA-HR whole blood 
and FFPE specimens shipped to the NRG BB-Columbus. 
 
Kits will be provided for the collection and shipment of frozen specimens. Two research plasma 
kits will be provided per patient. Research Plasma kit contents are the same for all patients, 
regardless of the arm to which the patient is randomized. The Research Plasma kit can be 
ordered when a potential patient is identified. The Final Research Plasma should not be ordered 

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until the time of disease progression or end of treatment. One of the Research Plasma kits should 
be used to ship the Future Use Whole Blood (WB04), in addition to the Research Plasma. 
 
Note: CPT (citrate) tubes will be provided by the NRG BB-Columbus for the collection of CEC 
whole blood specimens. These tubes are included in the Research Plasma kit and are not ordered 
separately. Specimen kits are not provided for the shipment of CEC whole blood specimens to 
the PDRC. Sites must provide their own shipping kits and cover shipping costs. The NRG BB-
Columbus will not provide additional CPT (citrate) tubes if the site fails to use them by the 
expiration date. 
 
Sites can order kits online via the Kit Management link (https://kits.bpc-apps.nchri.org/). (27-
AUG-2021). Each site may order two kit types per protocol per day (daily max = 6 kits).  
 
 
Please contact the NRG BB-Columbus if you need assistance (Email: 
BPCBank@nationwidechildrens.org; Phone: 866-464-2262). 
 
Be sure to plan ahead and allow time for kits to be shipped by ground transportation. Kits should 
arrive within 3-5 business days. 
 
Note: Unused materials and kits should be returned to the NRG BB-Columbus. A pre-paid 
shipping label for the return of unused supplies and kits may be obtained via the Kit 
Management system. Select “Empty Kit” for package contents when returning unused kits. 
 
B. Labeling Translational Science Specimens 
A waterproof permanent marker or printed label should be used to label each translational 
science specimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG - GY # # #) 
specimen code (see protocol section 11.2.1) 
collection date (mm/dd/yyyy) 
surgical pathology accession number (tissue specimens only) 
block number (tissue specimens only) 
 
Note for tissue specimens: 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. 
 
C. BROCA-HR Whole Blood 
Note: Sites in Korea should not collect CEC whole blood specimens. 
 
1.  Label the lavender/purple top (EDTA) collection tube(s) as described below. Multiple tubes 
may be used to collect the required amount. 
2. Draw 7-10mL of blood into the labeled lavender/purple top tube(s). A minimum of 3mL is 
needed for processing. 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the blood and EDTA. 

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4. Ship whole blood to the NRG BB-Columbus the day the biospecimen is collected. If the 
whole blood absolutely cannot be shipped the day it is collected, the tube(s) should be 
refrigerated (4°C) and shipped within 24 hours. 
 
D. Formalin-Fixed, Paraffin-Embedded (FFPE) Tissue 
1. BROCA-HR FFPE: Patients must agree to submit this mandatory specimen. 
BROCA-HR FFPE tissue should be the most representative of the specimen type (primary, 
metastatic). BROCA-HR primary (FP02) or metastatic (FM02) tumor should be collected prior 
to all treatment. 
 
Two consecutive unstained slides (charged, 10μm) must be provided.* 
 
*If patient consents to the optional FFPE collection (FP01/FM01; section 11.2.1.2) and a block 
will be submitted on a permanent basis to fulfill both the mandatory (FP02/FM02; section 
11.2.1.1) and optional (FP01/FM01; section 11.2.1.2) specimen requirements, then label the 
block FP01 (for primary) or FM01 (for metastatic). Complete and ship both the FP01 and FP02 
(for primary) or FM01 and FM02 (for metastatic) specimen transmittal forms (i.e., Form TR) 
with the block. 
 
2. OPTIONAL FFPE 
FFPE tissue should be the most representative of the specimen type (primary, metastatic, 
recurrent). Primary and metastatic tumor should be collected prior to all treatment. Recurrent 
tumor should be collected prior to the study treatment. Recurrent tumor collected from the site of 
primary disease should be labeled recurrent primary. Recurrent tumor collected from a site 
other than the site of primary disease (e.g., lymph node) should be labeled recurrent metastatic. 
Only one block may be submitted per tissue type. 
 
Every attempt should be made to provide a FFPE block; however, if a block cannot be provided 
on a permanent basis, then 22 unstained slides* (2 charged, 10μm; 10 charged, 5μm; and 10 
uncharged, 10 μm) should be submitted. All tissue sections should be cut sequentially from the 
same block. 
 
*Note: BROCA-HR FFPE tissue is a mandatory specimen requirement. If submitting slides, the 
two (charged, 10μm) unstained sections required for BROCA-HR testing should be cut first, 
followed by the 20 unstained sections (10 charged, 5μm and 10 uncharged, 10μm) for the 
optional translational science. 
 
The type of specimen (block, slides) should be specified on Form TR. If submitting slides, the 
slide type, thickness, and count should also be specified. 
 
All FFPE tissue should be submitted with the corresponding pathology report. 
 
E. Future Use Whole Blood 
1.  Label the purple top (EDTA) blood collection tube(s) as described below. Multiple tubes 
may be used to collect the required amount. Do not use glass blood collection tubes. 

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2. Draw 7-10mL of blood into the purple top (EDTA) 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. 
 
F. Research Plasma  
Note: The laboratory testing to be done is time sensitive. Plasma must be processed within 
one hour of collection. 
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.  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. Quickly, 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. 
 
G. Shipping Translational Science Specimens (12/05/2016) 
Translational science specimens should not be shipped until after patient registration and Bank 
ID assignment. 
 
An electronically completed copy of Form TR must be included for each translational science 
specimen.  
 
All translational science specimens should be shipped to: 
 
NRG BB-Columbus / Protocol NRG-GY005 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: 614-722-2865 
FAX: 614-722-2897 
Email: BPCBank@nationwidechildrens.org 
 
1. FFPE Tissue 

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FFPE tissue, an electronically completed copy of Form TR, and a copy of the corresponding 
pathology report should 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. 
 
2. BROCA-HR Whole Blood 
Whole blood biospecimens should be shipped to the NRG BB-Columbus (address above). 
 
Whole blood biospecimens can be shipped to the NRG -Columbus Monday through Friday for 
Tuesday through Saturday delivery. Do not ship whole blood the day before a holiday. Use 
your own shipping container to ship biospecimens via FedEx priority overnight. 
 
When shipping whole blood biospecimens, your site must comply with IATA standards 
(www.iata.org). If you have questions regarding your shipment, contact the NRG BB-Columbus 
at BPCBank@nationwidechildrens.org or by phoning 866-464-2262.  
 
To ship whole blood biospecimens you will need (1) a sturdy shipping container (e.g., a 
cardboard or styrofoam box), (2) a leak proof biohazard envelope with absorbent material*, (3) a 
puncture and pressure resistant envelope (e.g. Tyvek envelope), (4) an Exempt Human Specimen 
sticker, and (5) a pre-paid FedEx air bill. 
 
*If you will be shipping whole blood biospecimens from more than one patient, please put each 
biospecimen in a separate plastic zip-lock bag before placing the biospecimens in the shipping 
bag. You may include up to four different blood biospecimens in one biohazard envelope. 
 
If you do not have these materials available at your site, you may order them from any supplier 
(e.g., Saf-T-Pak; Phone: 800-814-7484; Website: www.saftpak.com). 
 
Shipping Whole Blood Using Your Own Shipping Container 
1. Place the whole blood biospecimen in a biohazard envelope containing absorbent material. 
Expel as much air as possible before sealing the bag. 
2. Wrap the biohazard envelope in bubble wrap or another padded material. 
3. Place the padded tube(s) into a Tyvek envelope. Expel as much air as possible before sealing 
the envelope. 
4. Place the Tyvek envelope in a sturdy shipping container (e.g., cardboard FedEx box). 
5. Insert a copy of Form TR for each biospecimen.  
6. Attach an Exempt Human Specimen sticker to the outside of the shipping container. 
7. Print a pre-paid FedEx air bill using the Kit Management link (https://kits.bpc-
apps.nchri.org/). (27-AUG-2021). Attach the air bill. 
8. Make arrangements for FedEx pick-up through your site’s usual procedure or by calling 800-
238-5355. 
 
3. Frozen Specimens 
Frozen plasma and future use whole blood should be shipped using the specimen kit provided to 
the NRG BB-Columbus (address above). 

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Frozen specimens should be shipped Monday through Thursday for Tuesday through Friday 
delivery. Do not ship frozen specimens on Friday or the day before a holiday. Note: Saturday 
delivery is not available for frozen specimens.  
 
Frozen specimens 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 specimens can be shipped. 
 
Shipping Frozen Translational Science Specimens in a Single Chamber Kit   
1. Pre-fill the kit chamber about 1/3 full with dry ice. 
2. Place the frozen specimens 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 specimens into the kit and fill the chamber to 
the top with dry ice. 
5. Insert a copy of Form TR for each specimen.  
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/). (27-AUG-2021). Attach the air bill. 
8. Attach the dry ice label (UN1845) and the Exempt Human Specimen sticker. 
9. Arrange for FedEx pick-up through your site’s usual procedure or by calling 800-238-5355. 
 
IV. Submitting Form TR 
An electronically completed copy of Form TR must accompany each specimen 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 
specimens are not collected. 
 
Form TR should be printed from the Translational Research Form screen in Rave using the 
“PDF File” link at the top of the form. Clicking this link will generate a single page PDF. Do 
not use the “Printable Version” or “View PDF” links at the bottom of the form or any other 
method, as these formats will not be accepted.  
  
Retain a printout of the completed form for your records. 
  
Please contact User Support if you need assistance (Email: support@gogstats.org). 
 
V. Banking Translational Science Specimens for Future Research 
Specimens 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 specimens for future health 
research.  
 
Note: Testing of banked specimens will not occur until an amendment to this treatment protocol 

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(or separate correlative science protocol) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies. 
 
The patient’s specimen consent choices will be recorded on the signed informed consent 
document and electronically via Specimen Consent form. At the time of specimen 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 specimens at any time if 
the patient changes her mind. 
 
If the patient revokes permission to use her specimens, the NRG BB-Columbus will destroy or 
return any remaining specimens. The patient’s specimens will not be used for any further 
research; however, any specimens 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 specimens distributed prior to revoking consent. 
 
Note: If return of specimens is requested, shipping will be at the site’s expense. 
 
 

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APPENDIX VIII – TRANSLATIONAL SCIENCE LABORATORY TESTING 
PROCEDURES 
 
I. BROCA-HR 
A. Overview 
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 formnalin-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 with 55 genes (BROCA-HR; Table 1) 
that serve as a single assay to test for inherited risk of ovarian carcinoma and for germline and 
somatic mutations that influence response to therapy will be utilized. Library preparation has 
been fully automated to increase sample turnaround and lower cost. 
 
Table 1: BROCA-HR Genes 
ATM 
BRCC3 
ERCC1 
FANCG 
MLH1 
PAXIP1 
RAD51 
SMARCA4 
XRCC3 
ATR 
BRE 
ERCC4 
FANCI 
MRE11A 
PIK3CA 
RAD51 
TOPBP1 
XRCC4 
BABAM1 
BRIP1 
FAM175A 
FANCL 
MSH2 
PMS2 
RAD51C 
TP53 
XRCC5 
BAP1 
CDH4 
FANCA 
FANCM 
MSH6 
POLD1 
RAD51D 
TP53BP1 
XRCC6 
BARD1 
CDK12 
FANCB 
GEN1 
NBN 
POLE 
RBBP8 
UIMC1 
 
BLM 
CHEK1 
FANCC 
HELQ 
NEIL1 
PPM1D 
RIF1 
USP28 
 
BRCA1 
CHEK2 
FANCD2 
ID4 
PALB2 
PRKDC 
RINT1 
WRN 
 
BRCA2 
DCLRE1C 
FANCF 
LIG4 
PARP1 
PTEN 
SLX4 
XRCC2 
 
 
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 pipleline (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 their lab or others to complement the determination of HR deficiency. 
 
B. Laboratory Testing Procedures 

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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 senstivity 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 
demonstrated that the lowest 5% of mutant or variant allele could be reliably detected in a willd 
type background. 

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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. Circulating Endothelial Cells (CECs) 
A. Overview 
Whole blood (8mL) will be collected in CPT citrate tubes (Becton Dickinson and Company, 
Franklin Lakes, NJ) pre-treatment and on cycle 1, day 3 of treatment. The samples will be kept at 
ambient temperature and shipped overnight at ambient temperature the day the specimen is 
collected. The sample is stable up to 24 hours at room temperature. 
 
After processing for viable freezing, the samples are frozen at -80oC and then stored in liquid 
nitrogen until use, per Trepel laboratory SOP (details below). Each patient sample is assigned a 
unique 2D barcode identifier. Flow cytometric analysis is performed as a batch analysis due to 
the necessity of running each patient’s pre-therapy and post-therapy samples contemporaneously 
and to minimize variability due to different runs, reagents, and ambient conditions. 
 
Peripheral blood mononuclear cells (PBMCs) isolated and viably frozen from patients will be 
analyzed; a minimum of 1 x 105 cells is required for each analysis. CECs will be analyzed on a 
MACSQuant flow cytometer (Miltenyi Biotec, Bergisch Gladbach, Germany) and analyzed 
using FlowJo software (FlowJo LLC, Ashland, OR). CEC assay components include 
fluorochrome-conjugated antibodies (CD45 (Clone HI30, BioLegend, San Diego, CA), CD31 
(Clone WM59, BD Biosciences), CD105 (Clone 43A3, Biolegend), CD146 (Clone P1H12, EMD 
Millipore, Billerica, MA), CD133 (Clone A133, Miltenyi Biotec), mouse IgG1 isotype controls 
(Clone DD7, Millipore; Clone IS5-21F5, Miltenyi Biotec)), Hoechst 33342 (Life Technologies, 
Thermo Fisher Scientific, Carlsbad, CA), MACSQuant™ calibration beads (Miltenyi Biotec), 
FcR blocking reagent (Miltenyi Biotec), 7-AAD Viability Stain (BioLegend) and Quantum® R-
PE MESF beads (Bangs Laboratories, Fishers, IN). Viability is defined by the absence of 7-
aminoactinomycin D (7-AAD) staining, and analysis will be restricted to nucleated cells by 
gating on Hoechst 33342-positive cells. These findings will be correlated with clinical results.  

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With regard to positive and negative controls for within-run repeats and for between-run repeats, 
Trepel laboratory will run bead standards that represent different quantal levels of fluorescence 
to provide a measure of immunofluorescence in different channels that can be used from one run 
to another.  Trepel labaoratory also runs isotype control samples for different fluorophores that 
provide standardization from one run to another. This analytical assay has been employed in 
multiple clinical trials (Ning et al. 2010, Park et al. 2013 and Thomas et al. 2015). 
The time points (pretreatment and on day 3 of treatment) were selected as Lee and colleagues 
have demonstrated predictive value of CECs in response to olaparib/cediranib combination in the 
recently reported phase II study of olaparib and cediranib (Lee et al., 2015). 
 
Preanalytical and analytical variables: It is possible that there may be false positive or negative 
values of CECs due to cryopreservation/thawing process, inadequate identification of CECs from 
other hematopoietic cells, or the suboptimal number of cells.  
In clinical trial settings, PBMCs are collected from patients over time after which they are 
examined in a batched setting. It has been known that freezing and thawing affects the number of 
viable cells, measured by a multiparametric flow cytometry assay; an approximately 25% 
reduction in the number of viable cells from frozen samples compared to fresh PBMC samples 
(p<0.05). (Lee et al. manuscript submitted) Trepel Lab has run a pilot experiment to examine 
percentages of CEC and CEP per viable PBMCs on fresh and viably frozen samples and did not 
observe siginificant differences between fresh and viably frozen PBMC samples. Trepel Lab will 
run pre and post-therapy samples together, and thus they will be under the same conditions to 
minimize variables (e.g. alignment and power of three lasers, microfluidics, FBS lots, antibody 
lots, etc). Further, CD45 (leukocyte common antigen) will be used to identify hematopoietic 
cells.  CD31, CD133, and CD146 will be used to characterize endothelial subpopulations and 
EpCAM/CD326 will be used to separate WBC from circulating tumor cells (CTC).  It has been 
well known that the values of CEC were significantly higher in patients with metastatic cancer 
compared to healthy donor (p <0.001; Jacques et al. J Immunol Methods 2008). Jacques and 
colleagues reported the values of CECs in healthy individuals and metastatic cancer patients. 
There, the median CEC count was 6.5/mL (range, 0–15) in 20 healthy individuals and was 
15.0/mL (mean +/− SD, 25.6 +/− 31.9; range, 0–179) in 125 patients with metastatic cancer, 
which are consistent with numbers Trepel lab has observed. Lastly, measuring CEC in PBMCs 
using 500,000 cells per sample has been highly reproducible (Jacques et al. J Immunol Methods 
2008; Park et al. Cancer Chemother Pharmacol 2013). For this study, where the sample is 
dedicated to identifying and quantifying only CECs, the Trepel Lab will run at least 500,000 
events (cells) per sample.  Eight mL whole blood will be collected in CPT citrate tube and thus at 
least 500,000 cells to be examined. 
 
B. Laboratory Testing Procedures 
1. Remix the blood sample immediately prior to centrifugation by gently inverting the tube 4-6 
times. Centrifuge tube/blood sample at room temperature (18-25°C) in a swinging bucket 
centrifuge rotor for 25 minutes at 1500-800 RCF (Relative Centrifugal Force) with NO 
BRAKE. 
2. Cryotube preparation: For each CPT tube, prepare 1 cryotube for plasma and 2 cryotubes for 
PBMC collection. Label each tube. 
3. After centrifugation, PBMCs will be a cloudy layer just below the plasma layer. Collect 1mL 

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of plasma with a 1000μL pipette and transfer to a labeled cryotube. Collect PBMC layer 
(approximately between 1-3mL) with a 1000μL pipette and transfer to a 50mL conical 
centrifuge tube. (Collection of cells immediately following centrifugation will yield best 
results). 
4. Cell washing: Add sterile 1X PBS to bring volume to 50mL. Cap the tube. Mix cells by 
inverting 5 times. Take 10μL of resuspended cells for cell counting. Centrifuge the 50mL 
tube at 4°C in a swinging bucket rotor for 5 minutes at 300 RCF (Relative Centrifugal 
Force). 
5. After centrifugation aspirate supernatant and gently tap tube with finger to loosen the pellet. 
6. Resuspend cell pellet by adding 1.5mL cryomedium (10% DMSO in FBS) for each cryotube 
that you are going to freeze. 
7. Transfer 1.5mL of resuspended cells to each labeled cryotube. 
8. Put cryotubes into a freezing container containing isopropanol (250mL) at room temperature 
and then store the freezing container in a -80°C freezer. After 24-48 hours, transfer the 
cryotubes from the -80°C freezer to a liquid nitrogen freezer. CAUTION: Transfer your 
samples from the -80°C freezer to the liquid nitrogen tank as quickly as possible to prevent 
cell damage. 
 
Note: After processing for viable freezing, the samples are frozen at -80oC and then in liquid 
nitrogen and stored in liquid nitrogen until use. Each patient sample is assigned a unique 2D 
barcode identifier. Flow cytometric analysis is performed as a batch analysis due to the necessity 
of running each patient’s pre-therapy and post-therapy samples contemporaneously, and to 
minimize variability due to different runs, reagents, and ambient conditions.  
 
C. References 
1. Lee JM, et al (2015) Development of a multiparameter flow cytometric assay as a potential 
biomarker for homologous recombination deficiency in women with high-grade serous ovarian 
cancer (submitted) 
2. Jacques N, et al. (2008) Quantification of circulating mature endothelial cells using a whole 
blood four-color flow cytometric assay. J Immunol Methods  
3. Park SR, et al. (2013) A multi-histology trial of fostamatinib in patients with advanced 
colorectal, non-small cell lung, head and neck, thyroid, and renal cell carcinomas, and 
pheochromocytomas. Cancer Chemother Pharmacol 
4. Ning YM, Gulley JL, Arlen PM, et al. Phase II trial of bevacizumab, thalidomide, docetaxel, 
and prednisone in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 
2010;28:2070-6. 
5. Park SR, Speranza G, Piekarz R, et al. A multi-histology trial of fostamatinib in patients with 
advanced colorectal, non-small cell lung, head and neck, thyroid, and renal cell carcinomas, and 
pheochromocytomas. Cancer Chemother Pharmacol 2013;71:981-90. 
6. Thomas A, Rajan A, Berman A, et al. Sunitinib in patients with chemotherapy-refractory 
thymoma and thymic carcinoma: an open-label phase 2 trial. Lancet Oncol. 2015;16(2):177-86. 
7. Jacques N, Vimond N, Conforti R et al. Quantification of circulating mature endothelial cells 
using a whole blood four-color flow cytometric assay. J Immunol Methods 2008 ;337(2):132-43 
 
III. Olaparib and Cederanib PK 

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Samples for determination of cediranib and olaparib concentrations in plasma will be analyzed 
by Covance using an appropriate bioanalytical method. Full details of the analytical method used 
will be described in a separate Bioanalytical Report. 
 
Results will be only reported for samples shipped within a timeframe for which the stability of 
cediranib and olaparib in the samples has been validated and shown to be acceptable.  
 
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or six 
months after issuance of the draft Bioanalytical Report (whichever is earlier), unless requested 
for future analyses.   
 
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling. 
Additional analyses may be conducted on the anonymised, pooled pharmacokinetic samples to 
further evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the Clinical Study Report. Anonymised samples will be retained for no 
more than 5 years after the Clinical Study Report is finalised. 
 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis of 
the test samples. The results from the evaluation will not be reported in the CSR but separately in 
a Bioanalytical Report. 
 
IV. Plasma Angiome 
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. 
3) Allow standards to sit at room temperature while preparing standard serial dilutions. 
Serial Dilution of Standards: 

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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. 
 
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. 

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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. 
 
V. BRCA1 Promoter Methylation 
A. Overview 
For the BRCA1 promoter methylation assay, genomic DNA samples will be bisulfite treated for 
hydrolytic deamination of nonmethylated cytosines to uracils, whereas methylated cytosines are 
resistant to conversion. The degree of methylation is calculated as allele frequency: methylation 
% = [peak height methylated/(peak height methylated + peak height non-methylated)]*100 using 
the allele quantification functionality of the PyroMark Q24 software and can be exported to be 
further treated with statistical or graphical software. Thresholds are established based on an 
average methylation value across 11 CpG sites and test interpretation is reported as positive if 
the mean methylation is between 10% and 99% and negative if the mean methylation is less than 
10%. These cut-offs were chosen based on multiple experiments where non-methylated samples 
were routine measured at <10% and generally ~5% and methylated samples were routinely 
>40%. 
 
BRCA1 promoter methylation is found in ~10% of high-grade serous ovarian cancers by The 
Cancer Genome Atlas (TCGA) and others. BRCA1 promoter methylation is a likely candidate to 
modify response to PARP inhibitor treatment. This assay has received CLIA approval in New 
York State and can be performed as an integrated biomarker or an exploratory biomarker. The 
methods are summarized briefly below.  
 
Realizing the important participation of DNA methylation in the pathogenesis of cancer and other 
diseases, a variety of techniques for the study of DNA methylation have been developed in the last 
few years. Pyrosequencing has the ability for the simultaneous analysis and quantification of the 
degree of methylation at several CpG positions in close proximity. The Pyrosequencing technology 
is based on the luminometric detection of pyrophosphate that is released on nucleotide 
incorporation and converted into a light signal by a cascade consisting of four enzymes. One of its 
major strengths is the quantitative nature of the results. The bioluminometric response is linear 
(R2 > 0.99) for the sequential addition of up to five identical nucleotides (C, G, and T) or three 
dATPs. Pyrosequencing is ideally suited for DNA methylation analysis after bisulfite treatment of 
DNA because it combines the ability of direct quantitative sequencing, reproducibility, speed, and 
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The assay was validated through the use of 15 samples previously tested through TCGA project. 
All of our results obtained by pyrosequencing analysis matched with the previous results. Intra-
assay reproducibility was confirmed by obtaining concordant results in six samples tested in 
triplicate in the same run. Inter-assay reproducibility was confirmed by obtaining concordant 
results in six samples assayed on multiple dates. To determine the sensitivity of this assay, we 
performed a dilution series experiment using seven mixtures of methylated DNA (Millipore 
positive control) and unmethylated genomic DNA (100%, 50%, 25%, 12.5%, 6.25%, 3.125%, 
and 1.56%). Overall, there was a high degree of correlation (r > 0.994). This data indicate that 
this Pyrosequencing assay always gives concordant calls for the methylation status when a 10% 
threshold to declare methylation is used. The sensitivity of this assay is 6%. The analytical 
metrics demonstrate that the assay had very high inter- and intra-assay reproducibility.  The 
bioluminometric response of pyrosequencing is linear as demonstrated by the high R-squared. 
The assay has 100% sensitivity and specificity. 
 
B. Laboratory Testing Procedures 
One H&E and five unstained formalin-fixed, paraffin-embedded (FFPE) tumor tissue sections 
(5μm thickness) are required for the testing. Adequate tumor should be present in the material 
submitted for analysis. A section should be confirmed to contain >75% tumor by a surgical 
pathologist. If the submitted material for analysis contains less than 75% tumor, areas of 
predominant tumor will be macrodissected using a scalpel to trim away non-neoplastic areas. 
The quality and quantity of genomic DNA preparation is essential for successful bisulfite 
conversion. The criteria for 260/280 ratio for DNA quality is set between 1.60 and 2.50. The 
minimum amount of DNA used for bisulfite treatment is 200 ng. 
 
Genomic DNA samples will be bisulfite treated for hydrolytic deamination of nonmethylated 
cytosines to uracils, whereas methylated cytosines are resistant to conversion. The degree of 
methylation is calculated as allele frequency: methylation % = [peak height methylated / (peak 
height methylated + peak height non-methylated)]*100 using the allele quantification functionality 
of the PyroMark Q24 software and can be exported to be further treated with statistical or graphical 
software. Thresholds are established based on an average methylation value across 11 CpG sites 
and test interpretation is reported as positive if the mean methylation is between 10% and 99% and 
negative if the mean methylation is less than 10%.  
 
C. References 
1. Banerjee S, Kaye SB, Ashworth A: Making the best of PARP inhibitors in ovarian cancer. Nat 
Rev Clin Oncol 7:508-19, 2010  
2. Colella S, Shen L, Baggerly KA, et al: Sensitive and quantitative universal Pyrosequencing 
methylation analysis of CpG sites. Biotechniques 35:146-50, 2003  
3. Tost J, Dunker J, Gut IG: Analysis and quantification of multiple methylation variable 
positions in CpG islands by Pyrosequencing. Biotechniques 35:152-6, 2003  
4. Ronaghi M, Uhlen M, Nyren P: A sequencing method based on real-time pyrophosphate. 
Science 281:363, 365, 1998  
5. Dejeux E, Audard V, Cavard C, et al: Rapid identification of promoter hypermethylation in 
hepatocellular carcinoma by pyrosequencing of etiologically homogeneous sample pools. J 
Mol Diagn 9:510-20, 2007 

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6. Garg K, Levine DA, Olvera N, et al: BRCA1 immunohistochemistry in a molecularly 
characterized cohort of ovarian high-grade serous carcinomas. Am J Surg Pathol 37:138-46, 
2013 
 
VI. BRCA1 Immunohistochemistry 
A. Overview 
For BRCA1 immunohistochemistry (IHC), sections will be evaluated for BRCA1 expression 
with a commercially available monoclonal antibody. Whole sections will be evaluated and will 
be classified as BRCA1 loss, BRCA1 retained, or BRCA1 equivocal. 
 
B. Laboratory Testing Procedures 
For BRCA1 immunohistochemistry (IHC), one whole section will be evaluated with a 
commercially available monoclonal antibody against BRCA1 (Ab-1) clone MS110 (mAb) from 
Calbiochem (catalogue number OP92). Whole sections will be used for evaluation. Heat retrieval 
is performed by steaming with EDTA pH 8 for 30 minutes. This is followed by incubation with 
the primary antibody for 30 minutes at room temperature (dilution 1:100), followed by 
incubation with a labeled polymer from Envision TM+ System HRP (Dako) for 30 minutes at 
room temperature; 3,30-Diaminobenzidine is used as the counterstain. 
 
The staining pattern will be recorded as BRCA1 loss, BRCA1 retained, or BRCA1 equivocal as 
follows:  
1. BRCA1 loss: Complete absence of staining with presence of positive internal control, or 
staining in <5% of tumor cells.  
2. BRCA1 retained: Staining in >10% of tumor cell nuclei, or moderate-intensity staining in 5% 
to 10% of tumor nuclei with a moderately intense internal control. 
3. BRCA1 equivocal staining: Weak staining in 5% to 10% of tumor cell nuclei, in the presence 
of moderate to strong internal positive control. Complete absence of staining without positive 
internal control. 
 
Initially, a semiquantitative assessment for intensity and amount of staining will be performed. 
The stains will be re-evaluated with knowledge of the BRCA status, and a cutoff separating 
tumors into distinct groups based on genotype was developed. In other words, semiquantitative 
assessment will be used to develop categorical criteria for scoring cases as BRCA1 loss, BRCA1 
retained, or BRCA1 equivocal. Two independent and blinded pathologists will validate these 
criteria.  In our published work (Garg et al., 2013) we demonstrated that this assay has a PPV of 
94%, NPV of 92%, sensitivity of 86% and specificity of 97%. 
 
C. References 
1. Meisel JL, Hyman DM, Garg K, Zhou Q, Dao F, Bisogna M, Gao J, Schultz ND, Grisham 
RN, Phillips M, Iasonos A, Kauff ND, Levine DA, Soslow RA, Spriggs DR. The 
performance of BRCA1 immunohistochemistry for detecting germline, somatic, and 
epigenetic BRCA1 loss in high-grade serous ovarian cancer. Ann Oncol. 2014 
Dec;25(12):2372-8. doi: 10.1093/annonc/mdu461. Epub 2014 Oct 3. PubMed PMID: 
25281711; PubMed Central PMCID: PMC4271017.    
2. Reyes MC, Arnold AG, Kauff ND, Levine DA, Soslow RA. Invasion patterns of metastatic 
high-grade serous carcinoma of ovary or fallopian tube associated with BRCA deficiency. 

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Mod Pathol. 2014 Oct;27(10):1405-11. doi: 10.1038/modpathol.2013.237. Epub 2014 Feb 
28. PubMed PMID: 24577588. 
3. Garg K, Levine DA, Olvera N, Dao F, Bisogna M, Secord AA, Berchuck A, Cerami E, 
Schultz N, Soslow RA. BRCA1 immunohistochemistry in a molecularly characterized cohort 
of ovarian high-grade serous carcinomas. Am J Surg Pathol. 2013 Jan;37(1):138-46. doi: 
10.1097/PAS.0b013e31826cabbd. PubMed PMID: 23232854;  PubMed Central PMCID: 
PMC3531916. 
4. Soslow RA, Han G, Park KJ, Garg K, Olvera N, Spriggs DR, Kauff ND, Levine DA.  
Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma. 
Mod Pathol. 2012 Apr;25(4):625-36. doi: 10.1038/modpathol.2011.183. Epub 2011 Dec 23. 
PubMed PMID: 22193042. 
 
 

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Appendix IX: Patient Reported Outcome Supplemental Questions and Plan 
 
Background 
 
Outcomes of the treatment of cancer that are important to clinicians and researchers are not 
always the same as those that are important to patients. In addition, outcomes of treatment trials 
do not always point in consistent directions, favoring one treatment over another. In this trial, it 
is possible that benefits and risks may compete with each other, presenting future patients with 
treatment choices that would ideally be made with information about these competing benefits 
and risks. We propose to collect data in this trial that will enable us in future studies to evaluate 
patients’ preferences for the attributes of their treatments, including not only overall survival and 
progression-free survival, but also the timing and convenience of treatment regimens, symptoms 
of disease, and side effects of treatments. To accomplish this, we will collect data elements that 
enable a more accurate and clinically relevant depiction of trial results with regard to not only 
disease symptoms, but also treatment side effects, function/well-being, and health utility. This 
information will enable us to examine the association of these outcomes with each other, and 
with clinical outcomes such as response rate, progression free survival and overall survival. 
 
The regimens being evaluated in this trial differ significantly on many levels.  Cytotoxic 
chemotherapy regimens are typically administered for a shorter time period than biologics, have 
a different toxicity profile, and do not include ongoing maintenance treatment once a CR is 
achieved. Out of pocket cost for cytotoxics may be lower due to a more limited treatment period, 
and the fact that longstanding therapies typically carry lower costs. The data collected in this trial 
will be extremely useful for subsequent research that can formally elicit patient preferences for 
one or another treatment based on their personal perspectives on each of the outcomes (RR, PFS, 
OS, symptoms, side effects, function/well-being, utility). One standard preference elicitation 
method is conjoint analysis, in which participants evaluate a series of treatment choices with a 
set of attributes of varying levels.  This ultimately allows the assignment of preference weights 
that could be considered for development of a composite endpoint or development of a patient 
focused decision tool. Although conjoint analysis is not part of this protocol per se, the data 
obtained will inform such important work in the future, much the same as is now being done by 
these same investigators in the area of intraperitoneal versus intravenous chemotherapy. We 
emphasize that this important work can be done with only a very modest time commitment from 
patients of 10 minutes per assessment over a 3-year period, and minimal cost to the trial.  
 
Other PRO Measures Beyond Disease Related Symptoms  
The DRS-P scale is half of the NFOSI-18 (9 of 18 items). The other 9 items measure Treatment 
Side Effects (TSE; 5 items) and Function/Well-being (3 items, plus 1 item on worry). 
The TSE is a 5-item measure of side effects commonly reported by women receiving treatment 
for ovarian cancer, selected based on their importance relative to other side effects (Jensen et al, 
2011). They include nausea, vomiting, hair loss, skin problems, and a general side effect bother 
question. We propose to compare groups on the sum of all 5 questions. Because we cannot ask 
about all possible side effects out of respect for patient time, we also propose to compare groups 
on the single ‘global’ side effect bother question. The hypotheses for these comparisons are 
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be worst on the platinum-based chemotherapy arm, followed by the combination olaparib-
cediranib arm, and then the olaparib only arm. That is, each arm will be significantly 
different from the others, with olaparib alone being least impairing. Differences in these 
scores will inform the comparative descriptions of side effect experience for future patient 
preference studies. 
Similarly, the FACT/GOG-Ntx-4 is an efficient 4-item measure of sensory peripheral neuropathy 
that has been shown to be responsive to platinum and taxane-based chemotherapy. We 
hypothesize that the Ntx-4 sum scores will be worse on the platinum-based chemotherapy 
arm compared to the other two arms which are not expected to differ from one another. 
Differences in these scores will inform the comparative descriptions of side effect experience for 
future patient preference studies. 
The remaining 8 questions in the proposed PRO plan address general function and well-being 
(NFOSI-18 F/WB and EQ-5D) as well as a single question about worry. Consistently, and 
confirmed in Jensen et al (2011), patients prioritize this area as important and subject to 
disruption caused by both disease and treatment. We have selected these 8 questions for the 
following reasons: The 3-item Function/Well-being scale of the NFOSI-18 represents the three 
most important areas identified by advanced ovarian cancer patients (mobility independence, life 
enjoyment, and global quality of life). The one-item regarding worry about condition worsening, 
emerges consistently among patients with advanced cancer as a high priority, and finally, the 5-
item EQ-5D is the internationally most widely used measure of health utility. 
 
The EQ5D is a 5 item, preference-based measure of health that can be administered in 
approximately one minute.  The EQ5D utility score is an internationally used metric that also 
allows validated calculation of quality-adjusted life years for cost-effectiveness analysis. We will 
use the EQ-5D as the basis for generating a utility score. Our hypotheses are: 1) Patient 
preference scores (utilities) will be higher (better) during active treatment in the non-cytotoxic 
therapy arms compared to cytotoxic therapy arms; 2) patient preference scores (utilities) will be 
lower (worse) in biologic arms than in chemotherapy arm between 6 months and disease 
progression (the time period when the biologic arms continue treatment but chemotherapy arms 
are off therapy); and 3) Patient preference scores (utilities) will drop at disease progression. 
 
Statistical Considerations 
 
The focus of the analyses of the NFOSI-18, FACT/GOG-NTX-4 and the EQ-5D is primarily 
descriptive and involves estimating mean scores with confidence intervals.   
 
Scores from the NFOSI-18, EQ5D will be analyzed with mixed models using procedures similar 
to those described for the NFOSI-DRS.  
 
Cost-effectiveness: 
 
Cost-effectiveness (cost utility) will be evaluated using a health-related quality of life (HRQoL) 
metric (utility) derived from the 5-item EQ5D. OS may additionally inform cost-effectiveness in 
the Phase III study. 
Using the EQ-5D, we will: 
1.  Compare treatment arms to each other at all study time points. 

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2.  Compare pre-progression to post-progression. 
 
Missing PRO information 
Patient death, noncompliance, missed clinic appointments, and patient low literacy, can cause 
observations to be missed.  One or more of the PRO assessments may be missing for an 
individual on any occasion.  Missing information is troublesome particularly in studies involving 
repeated patient assessments.  The frequency that assessments are missed will be monitored 
every 6 months throughout the study.  Data Coordinators will be working with the Study Team 
and the NRG’s Patient Reported Outcome Committee to identify reasons that data are missing 
and recommending remedial actions when possible. 
    
The PRO instruments used in this study have been translated to several different languages.  
Women, who are unable to read or have difficulty reading, will not be required to participate in 
the PRO component of this study, however, a woman may elect to have the items read to her and 
be assisted in completing the instruments. Interviewers will have been trained to read questions 
without leading patients toward one response or another, reminding patients as needed that there 
are no right or wrong answers and that the patient is in the best position to provide the right 
answer choice. 

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Appendix X: Plan for QOL compliance 
 
NRG will utilize the following strategies to optimize QOL long-term compliance: 
 
TARGET:  CLINICAL RESEARCH ASSOCIATES & NURSING  
Task 1.  Presentation at each semi-annual group meeting on compliance updates and challenges, 
sharing QOL results, and reinforcing the message that QOL should continue to be assessed after 
the patient progresses or is off the study treatment.   
Assigned to:  Presenters will include the leadership of the data management and nursing 
committees. 
Task 2.  Send an initial email message, prior to study activation to all institutions’ CRA’s, 
nurses and site PI detailing the requirements, and procedures for QOL data collection, along with 
the importance of continuing timely assessments.   
Assigned to:  This message can be prepared by the QOL study chair together with the Data 
Management and Nursing committee leaders. 
Task 3.  Quarterly distribution list email message to the data management and nursing 
committees on compliance updates and challenges, reinforcing the message that QOL should 
continue to be assessed after the patient progresses or is off the study treatment.   
Assigned to:  Compliance reports will be prepared by the statistical office, and the email message 
will be sent by the PCOR leaders. 
Task 4.  Newsletters with study updates, including QOL compliance can be prepared semi-
annually for activated trials.  Sites that are doing especially well with compliance can be 
featured. 
Assigned to:  The QOL study Chair, the study statistician and the data management leaders 
should contribute to individual study updates.   
Task 5.  The IT staff is developing a forms-due calendar in Medidata/Rave to remind clinic 
staff of upcoming assessments for each patient.Assigned to:  IT Staff with oversight from the 
Statistical Office 
Task 6.  A patient form schedule is provided to the institution at the time of registration, 
indicating due dates for QOL assessments. 
Assigned to:  IT Staff with oversight from the Statistical Office 
Task 7.   A monthly forms tracking list is provided to the institutions, listing all forms due, 
including QOL, projecting 30 days in advance. 
Assigned to:  IT Staff with oversight from the Statistical Office 
Task 8.  A 14-day advance notice is sent to institutions notifying them of QOL assessments that 
will be due.  Past due notifications will be sent out 15, 30, 60 and 90 days to the data 
management CRAs with site PIs copied. 
Assigned to:  IT Staff with oversight from the Statistical Office 
Task 9.  Delinquency reports will be generated with expectation of 80% compliance, sent to site 
PIs and CRAs.  
Assigned to:  IT Staff with oversight from the Statistical Office 
 
TARGET:  PATIENT ADVOCATES 
Task 1.  Provide advice on strategies to improve awareness of the importance of timely and 
complete QOL data (e.g., brochure, letter, message in the informed consent). 
Assigned to:  Disease site patient advocates. 

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Appendix XI:  Protocol Monitoring Plan (12/05/2016) (06-AUG-2021) 
 
1) Enhanced Centralized Data Monitoring  
a) Eligibility: The source records which document the eligibility for the first two 
individuals enrolled from each site (as identified by a unique NCI identifier) will be 
reviewed for completeness and consistency with the eligibility criteria, the data reported 
during the enrollment process and the data reported on the case report forms (CRFs).  
Documents should be submitted within two weeks of subject enrollment.   
 
In the event that this monitoring identifies unacceptable enrollment procedures or 
significant deviations from eligibility criteria, then the site will need to submit a 
corrective action plan within two weeks of being notified of the findings from the 
centralized monitoring.  The source records for the eligilibity of treatment for the next 
individual enrolled to the study from the site should then again be submitted and 
reviewed.  In the event of significant repeated deviations from the protocol, accrual at the 
site may be suspended per discretion of the Study Chair.  Findings associated with 
centralized monitoring also should be reported to CTMB (frequency and mechanism for 
reporting to be discussed as part of the Monitoring Working Group that is being 
established). 
 
The pretreatment documents to be reviewed include: 
i) Pathology Report to document the site, histology and grade of the primary tumor. 
ii) Baseline imaging reports to confirm the presence of RECIST measurable disease. 
iii) Verification of platinum-free interval 
iv) Clinic source documents to verify initial performance status, prior surgery for ovarian 
cancer, anti-cancer therapies (including agent names, as well as, start and stop dates), 
and concomitant medications. 
v) Germline BRCA1/2 Mutation analysis report. 
vi) Electrocardiogram and ECHO or MUGA reports. 
vii) Pretreatment hematology and chemistry Reports (including TSH, pregnancy tests and 
urinalysis).  
viii) Signed and dated informed consent form 
 
b) Drug Accountability, Drug-Dose Compliance and Adverse Events: The source 
records and adverse events (AEs) during the first two cycles of treatment for the first two 
individuals enrolled from each site will be reviewed for compliance with the protocol, 
completeness and consistency with the data reported on the case report forms, and drug 
accountability records.  The documents listed below should be submitted at two 
timepoints:  (1) within two weeks of beginning the second cycle of treatment (for records 
and AEs during the first cycle of treatment), and (2) within two weeks of beginning the 
third cycle of treatment (for records and AEs during the second cycle of treatment).  
 

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In the event that this monitoring identifies unacceptable procedures or significant 
deviations from protocol procedures, then the site will need to submit a corrective action 
plan within two weeks.  The source records for the first two cycles of treatment for the 
next individual enrolled to the study from the site should then again be submitted and 
reviewed.  In the event of significant repeated deviations from the protocol, accrual at the 
site may be suspended per discretion of the overall Study Chair.   
 
The documents to be reviewed include: 
i) Study drug orders, treatment dose calculations, and administration records. 
ii) Reports from protocol-directed laboratory studies. 
iii) Reports from any additional tests performed to document an adverse event. 
iv) Patient drug diaries and pill counts. 
v) Pharmacy drug accountability records. 
vi) Summaries of hospital admissions and discharges.  
vii) Summaries of surgical procedures performed. 
 
2) Documentation of Disease Progression 
All imaging studies that are used by the treating physician to evaluate the disease status 
for every enrolled patient from just before initiating study treatment up until progression 
or death, whichever occurs first, will be prospectively collected and stored electronically.  
All collected images will be appropriately de-identified.  If it is deemed appropriate, 
these images will be available for trained independent radiologists to review in a 
standardized fashion.  Also, if progression is based on the interpretation of a pathologic 
finding, a copy of the pathology report will be collected and stored. 
 
3) On-Site Auditing 
An on-site audit will be conducted at any site where a patient was enrolled within two 
years of the anticipated date when the study is expected to mature for the final analysis.  
 
4) Protocol Master File 
A Protocol Master File will be maintained centrally throughout the study which will 
include regulatory documents.  
a) The study-specific documents: 
i) The active-version of the study document (including the informed consent document). 
ii) A list of study amendments. 
iii) The active-version of the protocol and informed consent document prior to each study 
amendment. 
b) The institutional-specific documents: 
i) Documentation of the Principal Investigator’s, co-investigators’ and clinical research 
associates’ GCP training. 
ii) Documentation of the Principal Investigator’s, co-investigators’ and the clinical 
research associates’ protocol-specific training. 
 

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5) Submission of Documentation 
Regulatory documents, including 1572 Forms, and Financial Disclosure Forms, as well as 
instructions for submitting these forms, are available from 
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at  
RCRHelpDesk@nih.gov. 
 
Regulatory documents should be submitted to the CTSU Regulatory Office, as per 
Section 8.1.2.4 in the main protocol. 
 
The Case Report Forms (CRFs) and any required source documentation that will be used 
for enhanced centralized data monitoring will be submitted through the Medidata/RAVE 
electronic data capture (EDC) system.  
 
While the images (e.g. CT scans, X-rays) for documenting progression will not be stored 
in Medidata/RAVE, special CRFs in EDC system will be used to facilitate the process of 
uploading files to the image storage system and collecting the image metadata.  

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APPENDIX XII:  NRG General Guidelines (12/05/2016) 
 
x For 21 or 28 day cycles, a patient will be permitted to have a new cycle of chemotherapy 
delayed up to 7 days (without this being considered to be a protocol violation) for major 
life events (e.g., serious illness in a family member, major holiday, vacation which is 
unable to be scheduled).   
 
For patients on Arms II or III of this protocol, the “Day 1” visit of the cycle may take 
place within a “7 day window of the protocol-defined date” for major life events.  
Sufficient drug to encompass this window should be dispensed to the patient at the 
preceding visit if needed.  Patients on Arms II and III of this protocol who have their visit 
delayed should have their next visit scheduled as per their original schedule (e.g., a 
patient whose Cycle 2 “Day 1” visit was delayed by a week should have their Cycle 3 
“Day 1” visit 3 weeks after the delayed Cycle 2 “Day 1” visit occurs, not 4 weeks after 
the delayed visit). 
 
x For patients on Arm I of the protocol, it will be acceptable for individual chemotherapy 
doses to be delivered within a “24 hour window before and after the protocol-defined 
date” for “Day 1” treatment of 21 or 28 day cycles.   If the treatment due date is a Friday, 
and the patient cannot be treated on that Friday, then the window for treatment would 
include the Thursday (1 day earlier than due) through Monday (day 3 past due). 
 
x For patients on Arms II and III of the protocol, it will be acceptable for the “Day 1” visit 
of each cycle to take place within a “72 hour window before and after the protocol-
defined date.” 
 
x For weekly regimens, it will be acceptable for individual chemotherapy doses to be 
delivered within a “24-hour window,” for example; “Day 8 chemotherapy” can be 
delivered on Day 7, Day 8, or Day 9 and “Day 15 chemotherapy” can be given on Day 
14, Day 15, or Day 16. 
 
x Chemotherapy doses can be “rounded” according to institutional standards without being 
considered a protocol violation (most institutions use a rule of approximately +/- 5% of 
the calculated dose) 
 
x Chemotherapy doses are required to be recalculated if the patient has a weight change of 
greater than or equal to 10%.  Patients are permitted to have chemotherapy doses 
recalculated for <10% weight changes. 
 

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APPENDIX XIII:  DIAGNOSTIC IMAGE COLLECTION SUMMARY (12/05/2016) 
 
Accrual: 450 subjects 
Activation Date: February 4, 2016 
Duration of Trial (mos): 60 mos. 
 
Approx. scan collection per subject: 
a. ~6 scans per year up to 12 months or until progression 
b. After 12 months: ~4 scans per year until progression 
 
1. CT scan or MRI performed once every 9 weeks (+/- 7 days), and at any other time if 
clinically indicated based on symptoms or physical signs suggestive of progressive 
disease.  Imaging assessments can be discontinued if disease progression. 
2. If a patient discontinues study treatment for any reason other than progression, imaging 
studies should continue every 9 weeks (+/- 7 days) until progression.   
3. After 1 years of protocol therapy or follow-up (measured from approximately cycle 1, 
day 1), imaging studies will be conducted every 12 weeks.   
 
TRIAD Digital Image Submission: 
TRIAD is the secure electronic image upload application utilized for IROC Services of this trial. 
TRIAD de-identifies and validates the images as they are transferred. 
 
1. TRIAD Access Requirements: 
 
TRIAD will be the sole means of image transfer to the IROC Philadelphia DI. TRIAD should be 
installed prior to study participant enrollment to ensure prompt secure, electronic submission of 
imaging. 
• Site staff who submits images through TRIAD will need to be registered with the 
Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP-IAM account. 
• To submit images, the site user must be on the site’s affiliating rosters and be assigned 
the 'TRIAD site user' role on the CTSU roster. Users should contact the site’s CTSU 
Administrator or Data 
Administrator to request assignment of the TRIAD site user role. 
 
2. TRIAD Installations: 
 
After a user receives a CTEP-IAM account with the proper user role, he/she will need to have the 
TRIAD application installed on his/her workstation to be able to submit images. TRIAD 
installation. Documentation can be found by following this link 
https://triadinstall.acr.org/triadclient/ 
Questions regarding image submissions should be directed to: 
IROCPHILA-DI@acr.org.  

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Questions about TRIAD should be directed to: 
http://triadhelp.acr.org/ClinicalTrials.aspx 
 
Tech Support is available from Monday to Friday between 8am - 5pm EST. 
Contact By Phone:  
703.390.9858 
Contact By Email: 
Triad-Support@acr.org 
 
 
 
 

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APPENDIX XIV – KGOG BIOSPECIMEN REQUIREMENTS 
 
I. Integrated Biomarker Biospecimen Requirements 
The patient must give permission to participate in this mandatory study component. 
Participating sites are required to submit the patient’s specimens as outlined below. 
Required Specimen (Specimen Code) 
Collection Time Point 
Sites Ship Specimens To 
BROCA-HR FFPE – Submit one of the following 
BROCA-HR FFPE Primary Tumor 
(FP02)2 
2 unstained slides (charged, 10μm)2 
Prior to all treatment 
 
Submit one tissue type (FP02 or 
FM02) with FP02 being the preferred 
tissue type. 
KGOG central lab within 8 
weeks of registration3 
BROCA-HR FFPE Metastatic Tumor 
(FM02)1 
2 unstained slides (charged, 10μm)2 
BLOOD 
Future Use Whole Blood (WB04) 
7-10mL drawn into purple top (EDTA) 
tube(s) and frozen4 
Prior to GY005 study treatment 
KGOG central lab within 5 
weeks of registration3 
1  An English translated copy of the corresponding pathology report must be shipped with all tissue specimens sent 
to the NRG BB-Columbus. Note: The entire report must be translated, typed, and include diagnosis, clinical 
history, gross description or block number, and microscopic findings. 
2 Please refer to additional details in section V, A, c: “Special Instructions for BROCA-HR and Optional FFPE 
Submission” 
3  Sites should ship to the KGOG central lab. The KGOG central lab will batch ship all biospecimens to the US. 
4  Do not use glass blood collection tubes. 
 
II. Exploratory Biomarker Specimen Requirements 
If the patient gives permission to participate in this optional study component, then participating 
sites are required to submit the patient’s specimens as outlined below. 
Required Specimen (Specimen Code) 
Collection Time Point 
Sites Ship Specimens To 
FFPE – Submit one of the following 
FFPE Primary Tumor (FP01)1 
1st Choice: block2 
2nd Choice: 20 unstained slides (10 
charged, 5μm & 10 uncharged, 10μm) 
Prior to all treatment 
 
Submit one tissue type (FP02 or 
FM02) with FP02 being the preferred 
tissue type. 
KGOG central lab within 8 
weeks of registration3 
FFPE Metastatic Tumor (FM01)1 
1st Choice: block2 
2nd Choice: 20 unstained slides (10 
charged, 5μm & 10 uncharged, 10μm) 
FFPE Recurrent Primary Tumor 
(FRP01) 1 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5μm & 10 uncharged, 10μm) 
Prior to study treatment, only if FFPE 
tumor collected prior to all treatment is 
not available (i.e., FP01 or FM01) 
 
Submit one tissue type (FRP01 or 
FRM01) with FRP01 being the 
preferred tissue type. 
FFPE Recurrent Metastatic Tumor 
(FRM01)1 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5μm & 10 uncharged, 10μm) 
BLOOD 
Research Pre-treatment Plasma (PB09) 
prepared from 7-10mL of blood drawn 
into purple top (EDTA) tube(s) 
Prior to GY005 study treatment 
KGOG central lab within 5 
weeks of registration4 

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Research C2D1 Plasma (PB10) 
prepared from 7-10mL of blood drawn 
into purple top (EDTA) tube(s) 
Cycle 2, day 1, prior to GY005 study 
treatment, only if PB09 was submitted 
Research Final Plasma (PB11) 
prepared from 7-10mL of blood drawn 
into purple top (EDTA) tube(s) 
At disease progression or end of 
GY005 treatment, only if PB09 was 
submitted 
KGOG central lab within 26 
weeks of registration4 
1  An English translated copy of the corresponding pathology report must be shipped with all tissue specimens sent 
to the NRG BB-Columbus. Note: The entire report must be translated, typed, and include diagnosis, clinical 
history, gross description or block number, surgical pathology ID number and microscopic findings. 
2 Please refer to additional details in section V, A, c: “Special Instructions for BROCA-HR and Optional FFPE 
Submission” 
3 Sites should ship to the KGOG central lab. The KGOG central lab will batch ship all biospecimens to the US. 
 
III. 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). 
 
IV. Requesting Translational Science Specimen Kits 
Translational science biospecimen kits are not provided by the NRG BB-Columbus for sites in 
Korea. 
 
V. FFPE 
A. Instructions for Sites in Korea 
a. BROCA-HR FFPE: Patients must agree to submit this mandatory specimen. 
Only one tumor type should be submitted. The tissue submitted should be the most 
representative of the biospecimen type (e.g., primary tumor, metastatic tumor). 
 
x BROCA-HR primary (FP02) or metastatic (FM02) tumor should be collected 
prior to all treatment. 
 
 
Every attempt should be made to provide a FFPE block; however, if a block cannot 
be provided on a permanent basis, then two consecutive unstained slides cut 
sequentially from one block must be provided. Each tissue section must be cut at 10 
microns and placed on positively charged slides. 
 
b. OPTIONAL FFPE 
Only one tumor type should be submitted. The tissue submitted should be the most 
representative of the biospecimen type (e.g., primary tumor, metastatic tumor, 
recurrent tumor). 
 

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x Primary or metastatic tumor should be collected prior to all treatment. 
 
x Recurrent tumor should be collected prior to the study treatment. Recurrent 
tumor collected from the site of primary disease should be labeled recurrent 
primary. Recurrent tumor collected from a site other than the site of primary 
disease (e.g., lymph node) should be labeled recurrent metastatic. 
 
Every attempt should be made to provide a FFPE block; however, if a block cannot 
be provided on a permanent basis, then 20 unstained slides cut sequentially from one 
block must be provided: 
 
x Ten of these slides must be cut at five microns and placed on positively charged 
slides. 
x Ten of these slides must be cut at ten microns and placed on uncharged slides. 
 
c. Special Instructions for BROCA-HR and Optional FFPE Submission 
x Patient does not consent to optional FFPE collection: Submit the two 
mandatory unstained sections for BROCA-HR (FP02 or FM02) only. Complete 
the corresponding specimen transmittal form (Form TR). 
x Patent consents to optional FFPE collection and slides will be submitted: 
Submit the two mandatory unstained sections for BROCA-HR (FP02 or FM02) 
and 20 unstained sections for the optional FFPE collection (FP01, FM01). 
Complete the corresponding specimen transmittal forms (Form TR) for both slide 
sets. 
x Patient consents to optional FFPE collection and slides will be submitted for 
BROCA-HR, but a block will be submitted for optional FFPE collection: 
Submit the two mandatory unstained sections for BROCA-HR (FP02 or FM02). 
Submit a block for the optional FFPE collection (FP01, FM01). Complete the 
corresponding specimen transmittal forms (Form TR) for both the slides and the 
block. 
x Patient consents to optional FFPE collection and a block will be submitted 
for both BROCA-HR and the optional FFPE collection: Submit block labeled 
as FP01 or FM01 and complete the corresponding specimen transmittal form 
(Form TR). The FP02 and FM02 specimen transmittal forms (Form TR) should 
be completed as not collected; specify “submitted for other study.” 
 
d. Labeling Translational Science Specimens 
A waterproof permanent marker or printed label should be used to label each 
translational science tissue specimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG-GY005) 
specimen code (see sections I and II, as well as “special instructions” below) 
collection date (mm/dd/yyyy) 
surgical pathology accession number (tissue specimens only) 
block number (tissue specimens only) 

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Note for tissue specimens: 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. 
 
e. Completing Form TR for FFPE 
The type of specimen (block, slides) should be specified on Form TR. If submitting 
slides, the slide type, thickness, and count should also be specified. 
 
f. Pathology Reports 
An English translated copy of the corresponding pathology report must be shipped 
with all tissue specimens sent to the NRG BB-Columbus. Note: The entire report 
must be translated, typed, and include diagnosis, clinical history, gross description or 
block number, surgical pathology ID number, and microscopic findings. 
 
g. Shipping FFPE 
Sites in Korea should ship FFPE to the KGOG Central Lab within eight weeks of 
patient registration. 
 
B. Instructions for the KGOG Central Lab 
FFPE blocks and unstained sections should be batched shipped to the NRG Oncology 
Biospecimen Bank-Columbus (Columbus, Ohio, USA) every 4-5 weeks. A completed copy 
of Form TR and the corresponding translated pathology report must be included for each 
patient and time point. The KGOG Central Lab should contact the NRG Oncology 
Biospecimen Bank-Columbus by email (bpcbank@nationwidechildrens.org) prior to 
shipping to confirm that the shipping date is appropriate. Specimen packaging must comply 
with  IATA standards (www.iata.org). 
 
C. Instructions for the NRG BB-Columbus 
The NRG BB-Columbus will batch ship FFPE to Dr. Elizabeth Swisher (University of 
Washington, Seattle, WA, USA) every six months for BROCA-HR testing. Specimens from 
Korea will be included in regularly scheduled shipments. 
 
VI. Future Use Whole Blood (WB04) 
A. Instructions for Sites in Korea 
a. Processing Future Use Whole Blood 
1.  Label the purple top (EDTA) blood 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 purple top (EDTA) 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 

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freezer is not available for storage, store and ship on dry ice within 24 hours of 
collection. 
 
b. Labeling Future Use Whole Blood 
A waterproof permanent marker or printed label should be used to label each translational 
science Future Use whole blood specimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG-GY005) 
specimen code (WB04) 
collection date (mm/dd/yyyy) 
 
c. Shipping Whole Blood 
Sites in Korea should ship whole blood to the KGOG Central Lab within five weeks of 
patient registration. 
 
B. Instructions for the KGOG Central Lab 
Frozen whole blood should be batched shipped to the NRG Oncology Biospecimen Bank-
Columbus (Columbus, Ohio, USA) every 4-5 weeks. A completed copy of Form TR must be 
included for each patient and time point. The KGOG Central Lab should contact the NRG 
Oncology Biospecimen Bank-Columbus by email (bpcbank@nationwidechildrens.org) prior 
to shipping to confirm that the shipping date is appropriate. Specimen packaging must 
comply with  IATA standards (www.iata.org). Frozen biospecimens should be shipped by an 
international courier (e.g., World Courier) that will replenish dry ice in transit. 
 
C. Instructions for the NRG BB-Columbus 
The NRG BB-Columbus will bank frozen whole blood until requested by the sponsor for 
suture olaparib assay development. 
 
VII. 
Research Plasma (PB09-PB11) 
A. Instructions for Sites in Korea 
Note: The laboratory testing to be done is time sensitive. Plasma must be processed 
within one hour of collection. Blood may remain at room temperature until processed. 
a. Processing Research Plasma 
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.  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. 

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7. Quickly, 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. 
 
*If the Pre-Treatment Research Plasma (PB09) biospecimen is not collected, the subsequent 
Research Plasma (PB10 and PB11) biospecimens should not be collected. 
 
b. Labeling Research Plasma 
A waterproof permanent marker or printed label should be used to label each translational 
science Research plasma specimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG-GY005) 
specimen code (see section I) 
collection date (mm/dd/yyyy) 
 
c. Shipping Plasma 
Sites in Korea should ship plasma to the KGOG Central Lab within five weeks of patient 
registration. 
 
B. Instructions for the KGOG Central Lab 
Frozen research plasma should be batched shipped to the NRG Oncology Biospecimen Bank-
Columbus (Columbus, Ohio, USA) every 4-5 weeks. A completed copy of Form TR must be 
included for each patient and time point. The KGOG Central Lab should contact the NRG 
Oncology Biospecimen Bank-Columbus by email (bpcbank@nationwidechildrens.org) prior 
to shipping to confirm that the shipping date is acceptable. Specimen packaging must comply 
with  IATA standards (www.iata.org). Frozen biospecimens should be shipped using an 
international courier (e.g., World Courier) that will replenish dry ice in transit. 
 
C. Instructions for the NRG BB-Columbus 
The NRG BB-Columbus will batch ship frozen research plasma to Dr. Andrew Nixon (Duke 
University, Chapel Hill, North Carolina, USA) for testing following all appropriate NCTN 
approval. 
 
VIII. Submitting Form TR 
A specimen transmittal form (i.e., Form TR) for each biospecimen will be available in the 
Translational Research Folder in Rave, once the Specimen Consent (located in the Baseline 
Folder) has been completed. 
 
An electronically (i.e., Rave) completed copy of Form TR must accompany each 
biospecimen shipped to the NRG BB-Columbus. Handwritten forms will not be accepted. 
 

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Note: A copy does not need to be sent to the NRG BB-Columbus if biospecimens are not 
submitted. 
 
Form TR must be printed from the Translational Research Form screen in Rave using the “PDF 
File” link at the top of the form. Clicking this link will generate a single page PDF. Do not use 
the “Printable Version” or “View PDF” links at the bottom of the form or any other method to 
print the form, as these formats will not be accepted.  
  
Retain a printout of the completed form for your records. 
  
Please contact User Support if you need assistance (Email: support@nrgoncology.org; Phone: 
+17168457767). 
 
IX. Banking Translational Science Specimens for Future Research 
Specimens 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 specimens for future health 
research. 
 
Note: Testing of banked specimens 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 specimen consent choices will be recorded on the signed informed consent 
document and electronically via Specimen Consent form. At the time of specimen 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 specimens at any time if 
the patient changes her mind. 
 
If the patient revokes permission to use her specimens, the NRG BB-Columbus will destroy or 
return any remaining specimens. The patient’s specimens will not be used for any further 
research; however, any specimens 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 specimens distributed prior to revoking consent. 
 
Note: If return of specimens is requested, shipping will be at the site’s expense. 
 
 

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APPENDIX XV – KGOG GUIDELINES FOR PLATELET COUNT DECREASED 
 
To be consistent with the national approval of Olaparib (AZD2281) by the Ministry of Food and 
Drug Safety (MFDS) of Korea, ‘platelet count decreased’ will be kept as ‘Less Likely (<=20%)’ 
in the adverse events with possible relationship to Olaparib (Section 7.3.2) for the sites in Korea. 
This exemption related to ‘platelet count decreased’ will continue to apply throughout the study, 
regardless of future amendments. 
 
Although the Olaparib CAEPR (Version update 2.3, June 18, 2018) and Amendment # 6 of NRG 
GY005 (August 14, 2018) indicate the events of ‘platelet count decreased’ as Insufficient 
Evidence, the MFDS of Korea noted that thrombocytopenia (or platelet count decreased) is  
"Less Likely" adverse event for the national approval of Olaparib and thus did not allow change 
to undefined (Insufficient Evidence) due to discrepancy. The MDFS cited submitted data and 
clinical data as well as foreign permits for this decision; ‘thrombocytopenia’ or ‘platelet count 
decreased’ of Olaparib capsules are common (≥ 1/100 to <1/10) according to European permit 
and has been reported to occur in > 25% of patients per US permit. It is aligned with the common 
adverse event (≥ 1/100 to <1/10) of the Korea national permits. Therefore, domestic permits will 
be submitted based on the core label (CDS) of AstraZeneca according to the domestic regulation 
and will be submitted after global approval.