A Phase III Study Comparing Single-Agent Olaparib or the Combination of Cediranib and Olaparib to Standard Platinum-Based Chemotherapy in Women With Recurrent Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Phase: PHASE3
Conditions: Fallopian Tube Clear Cell Adenocarcinoma, Fallopian Tube Transitional Cell Carcinoma, Fallopian Tube Undifferentiated Carcinoma, Ovarian Clear Cell Adenocarcinoma, Ovarian Endometrioid Tumor, Ovarian Seromucinous Carcinoma, Ovarian Serous Tumor, Ovarian Transitional Cell Carcinoma, Ovarian Undifferentiated Carcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Ovarian Endometrioid Adenocarcinoma, Recurrent Primary Peritoneal Carcinoma
Sponsor: National Cancer Institute (NCI)

 
 
NRG-GY004 
(ClinicalTrials.gov NCT #02446600) 
 
A Phase III study comparing single-agent olaparib or the combination of cediranib and olaparib 
to standard platinum-based chemotherapy in women with recurrent platinum-sensitive ovarian, 
fallopian tube, or primary peritoneal cancer 
NCI Version Date: 08/15/2019 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI).  
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 
JOYCE LIU, M.D 
URSULA MATULONIS, M.D. 
YAWKEY 1421 
See website directory 
DANA-FARBER CANCER INSTITUTE 
 
450 BROOKLINE AVENUE 
Disease Site Co-Chair 
BOSTON, MA 02215 
Carol Aghajanian, MD 
617-632-8927/ FAX: 847-723-5269 
See website directory 
EMAIL:  joyce_liu@dfci.harvard.edu 
 
 
 
Quality of Life-Chair 
Translational Scientist  
David Cella PhD 
Heather A Lankes, PhD, MPH 
See website directory 
NRG BB-Columbus 
 
Biopathology Center 
Comparative Effectiveness Chair 
The Research Institute at 
Laura Havrilesky, PhD 
Nationwide Children’s Hospital 
See website directory 
Columbus, OH 43205 
 
614-852-9853/FAX: 614-722-2897 
 
LankesH@NRGOncology.org 
 
Correlative Scientists 
Statistician 
Participating Organizations  
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG 
CCTG / Canadian Cancer Trials Group 
Please see Appendix XV for Japan 

- 2 - 
 
Jung-Min Lee, MD 
Austin Miller, Ph.D. 
National Cancer Institute 
NRG SDMC-Buffalo Office 
 
Roswell Park Cancer Institute 
Elizabeth Swisher, MD 
Elm and Carlton Streets 
University of Washington 
Buffalo, NY 14263-0001 
 
716-845-5702/FAX: 716-845-8393 
Andrew Nixon, PhD, MBA 
millera@nrgoncology.org 
Duke University 
 
 
 
Douglas Levine, MD 
 
Memorial Sloan Kettering Cancer Canter 
 
 
 
Data Manager and/or Data Operations Center  
Research Nurse 
Sandra Dascomb, MS,CCRP 
Christin Whalen, B.S.N 
NRG SDMC-Buffalo Office 
Dana Farber Partners Cancer Care 
Roswell Park Cancer Institute 
Gynecologic Oncology 
Elm and Carlton Streets 
44 Binney Street  /LG1B15 
Buffalo, NY 14263-0001  
Boston, MA 02115 
716-845-5702/FAX: 716-845-8393 
617-582-7738/Fax 617-582-7921 
dascombs@NRGOncology.org 
Christin_whalen@dfci.harvard.edu 
 
 
Protocol Administrator 
 
Kia Neff 
 
NRG Oncology 
 
Four Penn Center, 1600 JFK Blvd, Suite 1020 
 
Philadelphia, PA 19103 
 
215-854-0770/FAX: 215-854-0716 
 
neffk@nrgoncology.org 
 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Cediranib 
CTEP 
732208 
124225 
DCTD, NCI 
Olaparib 
CTEP 
747856 
124225 
DCTD, NCI 
 
Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Closure 
 
 
Amendment 11 
August 15, 2019 
 
Amendment 10 
January 15, 2019 
 

- 3 - 
 
Amendment 9 
August 13, 2018 
 
Amendment 8 
July 23, 2018 
 
Amendment 7 
June 22, 2018 
 
Amendment 6 
January 16, 2018 
May 21, 2018 
Amendment 5 
October 2, 2017 
October 17, 2017 
Amendment 4 
May 30, 2017 
July 31, 2017 
Amendment 3 
March 28, 2017 
April 24, 2017 
Amendment 2 
January 3, 2017 
January 17, 2017 
Amendment 1 
August 12, 2016 
November 7, 2016 
Activation 
November 5, 2015 
February 4, 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-GY004 
Version Date: 08/15/2019 
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NRG-GY004 
A Phase III study comparing single-agent olaparib or the combination of cediranib and olaparib 
to standard platinum-based chemotherapy in women with recurrent platinum-sensitive ovarian, 
fallopian tube, or primary peritoneal cancer 
NCI Version Date: 08/15/2019 
 
Lead Organization: NRG / NRG Oncology 
 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal: 
 
Regulatory Submission Portal 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-2878 
to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) 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. 
 

NCI Protocol #: NRG-GY004 
Version Date: 08/15/2019 
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SCHEMA 
 
 
 
 
†Platinum-based chemotherapy options may include carboplatin and paclitaxel, carboplatin and 
gemcitabine, or carboplatin and pegylated liposomal doxorubicin (further detailed in Section 5.1). 
(11/07/2016)  

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TABLE OF CONTENTS 
SCHEMA 
- 5 - 
1.0 
OBJECTIVES 
- 8 - 
1.1 Primary Objective 
- 8 - 
1.2 Secondary Objectives 
- 8 - 
1.3 Objectives with Integral Biomarkers 
- 8 - 
1.4 Objectives with Integrated Biomarkers 
- 8 - 
1.5 Exploratory Objectives 
- 9 - 
2.0 
BACKGROUND 
- 9 - 
2.1 Platinum-sensitive ovarian cancer 
- 9 - 
2.2 Activity of olaparib and other PARP-inhibitors (PARPi’s) in ovarian cancer 
- 10 - 
2.3 Activity of cediranib in ovarian cancer 
- 10 - 
2.4 Combination of cediranib and olaparib 
- 11 - 
2.5 Phase 2 experience with cediranib and olaparib combination 
- 12 - 
2.6 Rationale for trial design 
- 14 - 
2.7 Quality of Life 
- 15 - 
2.8 Translational Science Background 
- 18 - 
2.9 Inclusion of Women and Minorities 
- 23 - 
3.0 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
- 23 - 
3.1 Eligibility Criteria 
- 23 - 
3.2 Ineligibility Criteria  
- 26 - 
4.0 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
- 30 - 
4.1 Pre-treatment assessments 
- 30 - 
4.2 Assessments during treatment 
- 31 - 
4.3 Assessments After treatment 
- 33 - 
5.0 
TREATMENT PLAN/Regimen description 
- 33 - 
5.1 Arms/Regimens  
- 34 - 
5.2 Duration of Study 
- 36 - 
5.3 Follow-up after study treatment discontinuation and/or progression 
- 37 - 
6.0 
TREATMENT MODIFICATIONS/MANAGEMENT 
- 37 - 
6.1 Reference regimens (Arm I) 
- 37 - 
6.2 Arms II (olaparib) and III (olaparib and cediranib) 
- 42 - 
7.0 
ADVERSE EVENTS REPORTING REQUIREMENTS 
- 50 - 
7.1  Protocol Agents 
- 50 - 
7.2 Adverse Events and Serious Adverse Events 
- 51 - 
7.3 Comprehensive Adverse Events and Potential Risks (CAEPR) List 
- 51 - 
7.4 Adverse Events for Commercial Study Agents 
- 58 - 
7.5 Expedited Reporting of Adverse Events 
- 58 - 
8.0 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES 
- 62 - 
8.1 Registration Procedures 
- 62 - 
8.2 Patient Entry and Registration 
- 67 - 
9.0 
 DRUG INFORMATION 
- 68 - 
9.1 Gemcitabine, Gemzar ® (NSC #613327) 
- 68 - 
9.2 Paclitaxel (NSC #673089) 
- 69 - 
9.3 Carboplatin (Paraplatin® - NSC #241240) 
- 70 - 
9.4 Pegylated Liposomal Doxorubicin (DOXIL®, NSC #712227 Lipodox™ 
- 70 - 
9.5 Cediranib (AZD2171, NSC 732208) 
- 72 - 

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9.6 Olaparib (AZD2281, NSC 747856) 
- 76 - 
9.7 Blood Pressure Cuffs  
- 80 - 
10.0 
PATHOLOGY 
- 80 - 
10.1 Stained Pathology Slide Requirements for Central Review to Confirm Eligibility: 
- 80 - 
11.0 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
- 80 - 
11.1 Reimbursement 
- 80 - 
11.2 Translational Science 
- 80 - 
11.3 Quality of Life / Patient-Reported Outcomes 
- 85 - 
12.0 
DATA AND RECORDS 
- 86 - 
13.0 
STATISTICAL CONSIDERATIONS 
- 90 - 
13.1 Study Design 
- 90 - 
13.2 Treatment allocation 
- 90 - 
13.3 Measures of Efficacy and Safety 
- 90 - 
13.4 Progression-Free and Overall Survival 
- 91 - 
13.5 Enrollment 
- 92 - 
13.6 Study Hypotheses 
- 92 - 
13.7 Type I Error Allocation 
- 93 - 
13.8 Statistical Power for HC:E2,pfs HC:E1,pfs HE1:E2,pfs 
- 93 - 
13.9 Analytic Procedures for Testing Hypotheses: HC:E2,pfs HC:E1,pfs HE1:E2,pfs 
- 95 - 
13.10 Interim Analyses 
- 96 - 
13.11 Overall Survival and Clinical Response 
- 98 - 
13.12 Patient-Reported Outcomes 
- 98 - 
13.13 Translational Studies 
- 100 - 
14.0 
PUBLICATION INFORMATION AND ADMINISTRATIVE AGREEMENTS 
- 104 - 
15.0 
EVALUATION CRITERIA 
- 104 - 
15.1 Definitions 
- 105 - 
15.2 Disease Parameters 
- 105 - 
15.3 Methods for Evaluation of Measurable Disease 
- 106 - 
15.4 Response Criteria 
- 109 - 
16.0 
REFERENCES 
- 112 - 
APPENDIX I 
- 117 - 
APPENDIX II – PATIENT DRUG INFORMATION HANDOUT & WALLET CARD 
- 118 - 
APPENDIX III – Oral Antihypertensive Medications 
- 123 - 
APPENDIX IV – CARBOPLATIN DOSE CALCULATION INSTRUCTIONS 
- 126 - 
APPENDIX V – TRANSLATIONAL SCIENCE SPECIMEN PROCEDURES 
- 128 - 
APPENDIX VI – TRANSLATIONAL SCIENCE LABORATORY TESTING 
- 137 - 
APPENDIX VII:  PATIENT DRUG DIARY: OLAPARIB ONLY 
- 148 - 
APPENDIX VIII: PATIENT DRUG DIARY CEDIRANIB AND OLAPARIB 
- 149 - 
APPENDIX IX:  PATIENT BLOOD PRESSURE DIARY 
- 150 - 
Appendix X: Patient Reported Outcome Supplemental Questions and Plan 
- 151 - 
Appendix XI:  NCI/DCTD Collaborative Agreements Language 
- 156 - 
Appendix XII:  Protocol Monitoring Plan 
- 159 - 
APPENDIX XIII:  NRG General Guidelines 
- 162 - 
APPENDIX XIV:  DIAGNOSTIC IMAGE COLLECTION SUMMARY 
- 163 - 
APPENDIX XV: Japan 
- 165 - 

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1.0 
OBJECTIVES  
 
1.1 
Primary Objective 
1.1.1 Assess the efficacy of either single agent olaparib or the combination of 
cediranib and olaparib, as measured by PFS, as compared to standard 
platinum-based chemotherapy in the setting of recurrent platinum-
sensitive ovarian, primary peritoneal or fallopian tube cancer. 
1.2 
Secondary Objectives 
1.2.1 Assess the efficacy of single agent olaparib or the combination of 
cediranib and olaparib, as measured by response rate, and overall survival 
as compared to standard platinum-based chemotherapy in the setting of 
recurrent platinum-sensitive ovarian, primary peritoneal or fallopian tube 
cancer. 
1.3 
Objectives with Integral Biomarkers 
1.3.1 Assess the efficacy of single agent olaparib or the combination of 
cediranib and olaparib, as measured by PFS, in women with or without 
deleterious germline BRCA mutations (gBRCAmt) in the setting of 
recurrent platinum-sensitive ovarian, primary peritoneal, or fallopian tube 
cancer. 
1.4 
Objectives with Integrated Biomarkers 
1.4.1 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 olaparib, compared 
to standard platinum-based chemotherapy, in the setting of recurrent 
platinum sensitive ovarian, primary peritoneal or fallopian tube cancer. 
1.4.2 Assess the efficacy of single agent olaparib or the combination of 
cediranib and olaparib, as measured by PFS, in women with or without 
homologous repair deficiencies as measured by BROCA in the setting of 
recurrent platinum-sensitive ovarian, primary peritoneal, or fallopian tube 
cancer. 
1.4.3 To assess changes in the number of circulating endothelial cells (CECs) 
following three days of treatment with olaparib, combination 
olaparib/cediranib, or standard platinum-based chemotherapy in women 
with recurrent platinum-sensitive ovarian, primary peritoneal, or fallopian 
tube cancer 
1.4.4 To assess whether change in the number of circulating endothelial cells 
(CECs) following three days of treatment with olaparib, combination 
olaparib/cediranib, or standard platinum-based chemotherapy in women 
with recurrent platinum-sensitive ovarian, primary peritoneal, or fallopian 
tube cancer is prognostic for PFS. 

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1.4.5 To develop a profile from a panel of angiogenic biomarkers in women 
with recurrent platinum-sensitive ovarian, primary peritoneal, or fallopian 
tube cancer which is associated with PFS, and then validate the predictive 
value of this biomarker profile. 
1.5 
Exploratory Objectives 
1.5.1 To assess the time from randomization to the first non-study, anti-cancer 
therapy, surgery or death (TFST) for single-agent olaparib or combination 
cediranib and olaparib relative to standard platinum-based chemotherapy 
in the setting of recurrent platinum-sensitive ovarian, primary peritoneal or 
fallopian tube cancer. 
1.5.2 To assess the time from randomization to the second non-study, anti-
cancer therapy, surgery or death (TSST) for single-agent olaparib or 
combination cediranib and olaparib relative to standard platinum-based 
chemotherapy in the setting of recurrent platinum-sensitive ovarian, 
primary peritoneal or fallopian tube cancer. 
1.5.3 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 utility as measured by the EQ-5D, of single 
agent olaparib or cediranib and olaparib, compared to standard platinum-
based chemotherapy, in the setting of recurrent platinum sensitive ovarian, 
primary peritoneal or fallopian tube cancer. 
2.0 
BACKGROUND 
 
2.1 
Platinum-sensitive ovarian cancer 
Ovarian cancer remains the leading cause of death from gynecologic malignancy 
in the United States.  For patients with platinum-sensitive recurrence (defined as 
disease recurring at least 6 months after the last receipt of platinum-based 
chemotherapy), additional platinum-based therapy has been the general standard-
of-care.  Regimens used in this setting include platinum-based doublets such as 
carboplatin and paclitaxel, carboplatin and gemcitabine, and carboplatin and 
pegylated liposomal doxorubicin (PLD) (Pfisterer, Ledermann, 2006).  
Randomized clinical trials have demonstrated that the combination of carboplatin 
and paclitaxel and carboplatin and gemcitabine are effective therapies in this 
setting (Parmar, 2003), (Pfisterer, Plante, 2006).  The combination of carboplatin 
and PLD has also been shown to be equivalent to that of carboplatin and 
paclitaxel in the setting of recurrent platinum-sensitive ovarian cancer (Pujade-
Lauraine, 2010).  Repeat platinum-based chemotherapies carry increased side 
effects, including risk of allergic reaction to platinum as well as worsening 
neuropathy or hematologic toxicities.  However, few alternatives to platinum-
based chemotherapy in the recurrent platinum-sensitive setting exist. 

NCI Protocol #: NRG-GY004 
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2.2 
Activity of olaparib and other PARP-inhibitors (PARPi’s) in ovarian cancer 
PARPi’s are an emerging class of drugs, and development of these agents in 
ovarian cancer is of significant interest (Liu, 2014).  Olaparib is an oral PARPi 
that has demonstrated activity both in women with BRCA-related and BRCA-
wild type ovarian cancer, with reported response rates of ~40% in BRCA 
mutation carriers and 24% of non-BRCA mutation carriers (Gelmon, 2011).  
Nonetheless, a Phase 2 study comparing olaparib monotherapy to PLD therapy in 
women with BRCA-related ovarian cancer recurring <12 months after last receipt 
of platinum-therapy found no advantage to olaparib therapy in this setting, with a 
median PFS observed with single-agent olaparib at 400mg BID in the capsule 
formulation of 8.8 months (Kaye, 2012). 
Additionally, significant activity was demonstrated of olaparib maintenance 
therapy following completion of platinum-based chemotherapy in women with 
platinum-sensitive high-grade serous ovarian cancer (Ledermann, 2012).  In this 
randomized Phase 2 study, women were randomized to receive either 
maintenance olaparib or placebo, and the median PFS was increased from 4.8 
months to 8.4 months in the cohort as a whole.  In a study subgroup including 
women with germline BRCA mutations (gBRCAmt) and those with somatic 
BRCA mutations, the median PFS increased from 4.3 months to 11.2 months 
(Ledermann, 2014). 
As a single agent in ovarian cancer, olaparib and other PARP-inhibitors have 
demonstrated activity in platinum-sensitive patients, including those without a 
germline or somatic BRCA mutation.  In a randomized phase 2 trial comparing 
single-agent olaparib to combination cediranib/olaparib, a median PFS of 9.0 
months with olaparib monotherapy was observed, which falls within the range of 
activity typically observed with platinum-based chemotherapy.  In a separate 
Phase 2 trial in women of the PARP-inhibitor rucaparib in women with platinum-
sensitive recurrent ovarian cancer, a median PFS was reported of 9.4 months in 
women with germline or somatic BRCA mutation and of 7.1 months in women 
without a BRCA mutation but whose tumors demonstrated a signature suggesting 
the presence of HR deficiency (McNeish, 2015).  Research has also demonstrated 
that the use of olaparib does not jeopardize response to future standard of care 
therapy, with women with heavily pre-treated (median 3 prior lines) ovarian 
cancer demonstrating an overall response rate of 36% to chemotherapy and 40% 
to platinum-based agents after having progressed on prior olaparib therapy (Ang, 
2013). 
2.3 
Activity of cediranib in ovarian cancer 
Cediranib is a small-molecule kinase inhibitor of VEGFR with demonstrated 
activity in both platinum-sensitive and platinum-resistant ovarian cancer 
(Matulonis, 2009).  The overall response rate to single-agent cediranib in a Phase 
2 trial was 17% in the overall population, with a response rate of 12.5% in 
platinum-sensitive patients and 20% in platinum-resistant patients; the median 
PFS was 5.2 months.  A second Phase 2 trial preliminarily reported 4 PRs in 60 

NCI Protocol #: NRG-GY004 
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patients, with a median time to progression of 4.1 months in women with 
recurrent ovarian cancer (Hirte, 2008). 
ICON6 recently demonstrated that the combination of cediranib together with 
platinum-based chemotherapy and followed by cediranib maintenance, could 
extend progression-free and, preliminarily, overall survival, in women with 
platinum-sensitive ovarian cancer compared to chemotherapy alone (Ledermann, 
2013). 
2.4 
Combination of cediranib and olaparib 
Preclinical studies have demonstrated that angiogenesis inhibitors combined with 
PARPi’s can have supra-additive effects.  In vivo anti-angiogenic activity has 
been observed with PARPi’s and in PARP-1 knockout mice (Tentori 2007).  
Additionally, downregulation of homologous recombination repair genes, such as 
BRCA1 and RAD51, has been observed in conditions of hypoxia, with 
enhancement of PARPi sensitivity in the hypoxic setting (Bindra, 2004; Bindra, 
2005).  Preclinical work has demonstrated that cediranib and olaparib have 
potential synergistic activity in vitro in decreasing tumor cell invasion and blood 
vessel growth (Figure 1). 
 
Pre-clinical synergy exists between olaparib 
and cediranib in inhibiting both ovarian 
cancer cell invasion and microvascular 
endothelial cell tube formation in vitro 
(unpublished data).  Promising preliminary 
activity against recurrent ovarian cancer was 
seen in our Phase 1 dose-finding trial of the 
combination of cediranib and olaparib, 
which yielded an objective response rate of 
44% (Bouwman, 2010). 
A Phase 1 trial was previously conducted to 
establish the recommended Phase 2 dosing 
(RP2D) of cediranib in combination with olaparib (capsule formulation), which 
Fig 1:  Cediranib and olaparib combine effectively to (A) reduce invasion and (B) reduce microvascular cell 
tube organization as compared to either agent alone.
Fig 2:  Best response in ovarian cancer patients 
of cediranib/olaparib in dose-escalation Phase 2 
study. 

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enrolled a total of 28 patients (20 ovarian, 8 breast) (Liu, 2013).  A response rate 
of 44% to the cediranib/olaparib combination was observed in this Phase 1 
population, which included both BRCA mutation carrier and non-carrier patients.  
A waterfall plot of the observed activity is shown in Figure 2.  The RP2D was 
found to be cediranib 30mg daily with olaparib capsule 200mg twice daily. 
2.5 
Phase 2 experience with cediranib and olaparib combination 
A multi-center open-label randomized Phase 2 trial comparing the activity of the 
cediranib and olaparib combination to olaparib alone in platinum-sensitive 
recurrent ovarian cancer randomized 90 
patients in a 1:1 ratio to either the 
combination or single-agent olaparib 
(capsule formulation) (Liu, 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 significantly extended both PFS and 
overall response rate (ORR) compared to olaparib alone in this patient population, 
with a median PFS of 9.0 months for olaparib alone and 17.7 months for 
cediranib/olaparib (HR 0.418, 95% CI 0.229-0.763, p = 0.005) (Figure 3).  There 
were 2 complete responses (CR) and 20 partial responses (PR) in patients on 
olaparib alone (48% ORR) and 5 CRs and 30 PRs in patients on 
cediranib/olaparib (80% ORR, p = 0.002). 
Forty-seven of the 90 patients enrolled to the Phase 2 cediranib/olaparib vs. 
olaparib trial were known BRCA mutation 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 Figure 4 (next page).  In BRCA 
mutation carriers, the median PFS was 16.5 months on the olaparib alone arm and 
19.4 months on the cediranib/olaparib arm (HR 0.55, 95% CI 0.24-1.27, p = 
0.16).  In BRCA non-carrier/unknown patients, the median PFS was 5.7 months 
on the olaparib alone arm, and 16.5 months in the cediranib/olaparib arm (HR 
0.32, 95% CI 0.14-0.74, p = 0.008). 
Differentially occurring grade 3 or 4 toxicities attributed to study treatment 
included fatigue (27% cediranib/olaparib vs 11% olaparib, p = 0.06), diarrhea 
(23% vs 0%, p = 0.0004), and hypertension (41% vs 0%, p < 0.0001).  There were 
Fig 3:  Kaplan-Meier PFS curves in patients treated 
on olaparib and cediranib/olaparib in Phase 2 trial. 

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two Grade 4 events, both 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 two prior lines 
of therapy and had been on study for approximately 1 year when she was 
diagnosed with MDS.  Four patients on the cediranib/olaparib arm withdrew from 
study treatment secondary to toxicity (1 each due to weight loss, MDS, recurrent 
avascular necrosis in the setting of prior history of avascular necrosis, and vaginal 
fistula formation).  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 investigator decision, 5 clinical progressions on 
cediranib/olaparib vs. 3 withdrawal of consent, 1 investigator decision, and 6 
clinical progressions on olaparib alone). 
Overall, the results of the Phase 2 trial comparing cediranib/olaparib to olaparib 
alone in platinum-sensitive recurrent ovarian cancer demonstrated that the 
combination results in increased activity, as measured both by PFS and ORR.  
Toxicities were consistent with expected class-related toxicities of these drugs.  A 
list of the results of the Phase 2 trial and that of single-agent olaparib or cediranib 
trials is shown in Table 1 on the next page. 
Fig 4:  Kaplan-Meier PFS curves in gBRCAm and BRCA non-carrier/unknown patients. 
BRCA mut carrier 
BRCA non-carrier/unknown 

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2.6 
Rationale for trial design 
Repeat platinum-based chemotherapies carry increased side effects, including risk 
of allergic reaction to platinum as well as worsening neuropathy or hematologic 
toxicities.  However, few alternatives to platinum-based chemotherapy in the 
recurrent platinum-sensitive setting exist.  The PFS point estimate of 17.7 months 
on the cediranib/olaparib arm of the Phase 2 trial compares favorably with the 
median PFS range of between 8.4 months to 13 months (Parmar, 2003), (Pfisterer, 
Plante, 2006), (Pujade-Lauraine, 2010), (Ledermann, 2013), (Aghajanian, 2012) 
reported in studies of platinum-based doublets in platinum-sensitive ovarian 
cancer, and the observed PFS of 9.0 months on the olaparib monotherapy arm 
also falls within the range observed with platinum-based chemotherapy.  These 
results suggest that these biologic therapies may present an alternative to standard 
platinum-based chemotherapy in these women with an incurable recurrent ovarian 
cancer, and we therefore propose to compare the efficacy of single-agent olaparib 
or the combination of cediranib/olaparib to that of standard platinum-based 
chemotherapy in this population.  
This trial proposes to assess the efficacy and tolerability of single-agent olaparib 
versus the combination of cediranib and olaparib versus platinum-based 
chemotherapy in women with platinum-sensitive ovarian cancer.  There is clinical 
equipoise for inclusion of a single-agent olaparib arm given the point estimates 
for median PFS for single-agent PARPi in Phase 2 trials have been within the 
range that have been reported for platinum-based chemotherapy.  Additionally, 
research has suggested patients who have progressed on olaparib therapy continue 
to demonstrate response to standard of care chemotherapy, suggesting that the 
sequence of drug exposure dose not jeopardize clinical outcomes. 

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The trial design is a randomized Phase 3 trial that will randomize women with 
recurrent platinum-sensitive ovarian cancer in a 1:1:1 fashion to receive either 
olaparib, cediranib and olaparib, or platinum-based chemotherapy.  The trial is 
powered to allow comparison of both experimental arms to the reference 
platinum-based chemotherapy arm for assessment of the primary endpoint, 
progression-free survival.  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.  Interim futility analyses are included such that accrual of either the 
olaparib monotherapy or cediranib/olaparib combination arm could be halted if 
deemed futile. 
2.7 
Quality of Life 
The effect on quality of life of olaparib alone or combination cediranib/olaparib, 
compared to standard platinum-based chemotherapy, will also be of high interest.  
In the absence of an overall survival (OS) benefit, it is challenging 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, careful assessment of targeted quality of life 
domains, in particular, disease symptoms, but also treatment side effects, 
acceptability of therapy, and patient functioning, is required.  
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 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 
progression-free survival. We propose the following highly efficient measures: 
• 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: We will employ two measures of treatment side 
effects: 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: We will employ three brief measures of 
patient function and well-being: 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). 

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The patient reported outcome (PRO) plan for this trial was assembled to capture 
both disease symptoms and treatment side effects, placing disease symptom 
benefit as the primary outcome, with secondary evaluation of differences in side 
effects. 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 alongside clinical endpoints such as 
progression-free survival, and in the context of treatment costs, we propose highly 
efficient measures of function/well-being (NFOSI-18 F/WB) and utility (EQ-5D). 
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.  We 
propose to evaluate patients’ preferences for the attributes of their treatments, 
including not only overall survival and progression-free survival, but also the 
symptoms of cancer, side effects of treatments, and health utility.  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 patient-reported outcome data from this trial to inform the preference 
elicitation exercises. As such, we propose 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. 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.  
With the exception of the DRS-P, the rationale and analysis plan for these PRO 
endpoints can be found in Appendix X. Our proposed PRO assessment comprises 

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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 X. 
Study Hypotheses and Instrument Selection 
The overarching hypothesis is that the treatment arm associated with a PFS 
benefit will also demonstrate a PRO benefit relative to the other(s). 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 
share similarity with patients who 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 emphasis on 
treatment side effects and burden/acceptability of treatment.  The tolerability of 
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. 
Our 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. 
The Disease-Related Symptom-Physical (DRS-P) scale from the NCCN/FACT-
Ovarian Cancer Symptom Index-18 (NFOSI-18), (Jensen, 2011), is a 9-item scale 
which comprises the first 9 items of the NFOSI-18.  This scale was developed 

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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, 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.  Of note, after 
establishing that these 9 questions are the most important disease-related 
symptoms to women with ovarian cancer (Jensen, 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.  Treatment side 
effects, as summarized by a five-item subscale also included within the NFOSI-
18, is a secondary 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. 
2.8 
Translational Science Background 
2.8.1 Homologous Recombination Defect (HRD) Studies 
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 
combination (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, 2011; 
Pennington, 2012; Loveday, 2011; Rafnar, 2011; Meindl, 2010). 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 (Cancer Genome Atlas Research Network, 2011). 
PARPi’s demonstrate synthetic lethality in cells with HRD, including cells 
deficient in BRCA1/2 (Bryant, 2005; Farmer, 2005). Recurrent ovarian 
carcinomas in BRCA1/2 mutation carriers have an approximate 40% 
response rate to PARPi and also have an increased response to platinum 
based chemotherapy (Audeh, 2010; Kaye, 2012). Importantly, 
approximately 25% of serous ovarian cancers that are wildtype for 
BRCA1/2 also respond to PARPi (Gelmon, 2011). 
Germline BRCA1/2 mutations (gBRCAm) are the prototype molecular 
alterations that confer HRD (Bryant, 2005; Farmer, 2005). BRCA1 and 
BRCA2 somatic mutation (sBRCAm) occur in approximately 6% of cases 
(Cancer Genome Atlas Research Network, 2011; Pennington, 2014), and 
also appear to confer sensitivity to PARP inhibitors (Ledermann, 2014). 
PARP inhibitors also selectively kill cells in vitro that are deficient in 
other homologous recombination genes including RAD51D, NBN, ATM, 

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and CHEK2 (Loveday, 2011; McCabe, 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 survival13. 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, 2014). 
BRCA1 promoter methylation down regulates BRCA1 message and 
protein expression and occurs in 10-15% of ovarian carcinomas (Baldwin, 
2000; Esteller, 2000). Unlike BRCA1 mutations, BRCA1 methylation does 
not correlate with platinum response to therapy or overall survival (Cancer 
Genome Atlas Research Network, 2011; Swisher, 2009).  Therefore, the 
role of BRCA1 methylation in PARPi 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, 2009; Thrall, 2006).  The role of BRCA1 promoter methylation 
and protein expression will evaluated as exploratory biomarkers for 
response and correlation with treatment efficacy in this study. 
In order to respond to a PARP inhibitor, cancer cells need to be deficient 
in homologous recombination but also proficient in the alternative error 
prone non-homologous end joining (NHEJ) DNA repair pathway (Patel, 
2011; Adamo, 2010)). Thus, loss of HR is not, by itself, sufficient for 
PARPi sensitivity, and an accurate predictor of PARPi responsiveness 
could require assessment of many components of both the HR and NHEJ 
pathways. A more efficient assay, which would not require a priori 
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. 
2.8.2 BROCA-HR 
The marked susceptibility of patients with gBRCAm-associated cancers 
has validated gBRCAm as a predictive biomarker for PARP inhibitor 
(PARPi) response (Fong, 2009). Other mechanisms of HRD may be a 
functional biomarker for response to DNA damaging agents and PARPi. 
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. 

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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, 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, 2011; Wickramanayake, 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, 2014). The 
presence of either a germline 
or somatic FA/HR mutation 
is highly predictive of an 
improved primary response to 
platinum chemotherapy 
(P<.0005, Figure 5) and 
longer overall survival 
(P=.001, Figure 6; 
Pennington, 2014). Germline 
and somatic loss of function 
mutations were identified in 
all of the 13 FA/HR genes 
evaluated. 
Given the observed association between response to PARPi and platinum-
sensitivity (Fong, 2010), we hypothesize that the BROCA-HR test will 
identify subsets of ovarian cancer patients with HRD with increased 
sensitivity to olaparib or cediranib/olaparib combination, and may yield 
biomarkers with potential to guide administration of these therapies. 
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Germline HR mutation
Somatic HR mutation
No HR mutation
Platinum sensitive
Refractory/resistant
Figure  5.  Presence of HR mutation is predictive of improved primary response to platinum. 
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 

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2.8.3 Circulating Endothelial Cells (CEC) (11/07/2016) 
The presence of circulating endothelial cells (CEC) has been recognized as 
a potential biomarker of vascular damage (Bertolini, 2006). Elevated 
numbers of CEC have been described in lymphoma, melanoma, and other 
solid tumors including ovarian cancer, reflecting the perturbation of 
vascular endothelium (Goon, 2006). A related circulating cell population 
is endothelial progenitor cells (CEP), which originate from the bone 
marrow, rather than from vessel walls and related to tumor angiogenesis 
(Rafii, 2002). We recently reported prospectively planned exploratory 
biomarker endpoints in the phase II study of the combination of olaparib 
and cediranib (Lee et al., ASCO 2014, manuscript in preparation). We 
hypothesized 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 circulating endothelial cells (CEC: nucleated CD133-CD146+ 
CD31+CD45-), circulating endothelial progenitor cells (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 6). CEC fold 
increase pretreatment to day 3 correlated with survival (r=0.88, 95%CI 
0.55-0.97, p<0.001; Figure 7). 
 
 
 
Vascular injury is known to be accompanied by an induction in CEC 
production (Lin, 2013). CEC/CEP have been examined in early clinical 
trials using anti-angiogenics (Ning, 2010; Park, 2013; Kummar, 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, 
Figure 7. A. Patients receiving olaparib/cediranib had a larger fold increase 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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2010); patients with ≥ 75% PSA decline had an increase in CEC levels 
compared with those who had < 75% PSA decline (p=0.02).  
Our exploratory translational studies demonstrate that olaparib/cediranib 
caused vascular injury indicated by increase of CEC. These findings 
support 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. 
2.8.4 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 (see 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 
TGFβ1 
IL-6 
IGFBP1 
VEGF-D 
TGFβ2 
PAI-1 Active 
IGFBP2 
sVEGFR1 
TGFβRIII 
PAI-1 Total 
IGFBP3 
sVEGFR2 
TIMP1 
SDF-1 
PDGF-AA sVEGFR3 
TSP2 
VCAM-1 
 

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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. 
2.9 
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. 
3.0 
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 (11/07/2016) (07/31/2017) 
 
A patient cannot be considered eligible for this study unless ALL of the 
following conditions are met. 
 
3.1.1 Patients must have platinum-sensitive recurrent high-grade serous or high-
grade endometrioid ovarian, primary peritoneal, or fallopian tube cancers.   
 
Patients with other (clear cell, mixed epithelial, undifferentiated 
carcinoma, or transitional cell carcinoma) high-grade 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 germline BRCA testing through 
Myriad, Myriad testing will be accepted. If testing for germline 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 germline 

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deleterious BRCA1 or BRCA2 mutation or BRCA rearrangement is 
required.  Please collect a copy of Myriad or other BRCA mutational 
analysis (positive or VUS or negative) reports.  
 
3.1.1.1 Platinum-sensitive disease defined as no clinical or radiographic 
evidence of disease recurrence for > 6 months (or 182 days) after 
last receipt of platinum-based therapy. 
 
3.1.1.2 Patients must have had a complete clinical response to their prior 
line of platinum therapy and cannot have had progression through 
prior platinum-based therapy.   
 
3.1.2 Patients must have signed an approved informed consent and authorization 
permitting release of personal health information. 
 
3.1.3 Patients must have evaluable disease – defined as one of the following: 
 
3.1.3.1 RECIST 1.1 measurable disease OR  
 
3.1.3.2 Evaluable 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)  
AND a CA125 that has doubled from the post-treatment nadir and 
is also greater than 2 times ULN.  
 
3.1.4 Prior therapy: 
 
3.1.4.1 Prior chemotherapy must have included a first-line platinum-based 
regimen with or without intravenous consolidation chemotherapy. 
 
3.1.4.2 Patients may have received an unlimited number of platinum-based 
therapies in the recurrent setting. 
 
3.1.4.3 Patients may have received up to 1 non-platinum-based line of 
therapy in the recurrent setting.  Prior hormonal therapy will not be 
considered to count as this non-platinum-based line. 
 
3.1.4.4 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. 
 
3.1.4.5 Patients may not have previously received a PARP-inhibitor. 
 
3.1.4.6 Prior hormonal-based therapy for ovarian, primary peritoneal, or 
fallopian tube cancer is acceptable. 

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3.1.5 Patients must have an ECOG Performance Status of 0, 1 or 2 (Karnofsky ≥ 
60% (See Appendix I)  
 
3.1.6  Patients must have adequate organ and marrow function, including: 
 
3.1.6.1 Absolute neutrophil count ≥ 1,500/mcL 
 
3.1.6.2 Platelets > 100,000/mcL 
 
3.1.6.3 Hemoglobin ≥ 10 g/dL 
 
3.1.6.4 Creatinine ≤ the institutional upper limit of normal (ULN) OR 
creatinine clearance ≥60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal. 
 
3.1.6.5 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 ≤ 500mg over 24 hours. 
 
3.1.6.6 Total bilirubin ≤ 1.5x the institutional ULN 
 
3.1.6.7 AST (SGOT) and ALT (SGPT) ≤ 3 times institutional ULN. 
 
3.1.7 Toxicities of prior therapy (excepting alopecia) should be resolved to less 
than or equal to Grade 1 as per NCI-CTCAE (located on the CTEP 
website at  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.ht
m.   
 
Patients with long-standing stable grade 2 neuropathy may be considered 
after discussion with the overall PI, but may not receive carboplatin and 
paclitaxel as the reference regimen, if randomized to that arm. 
 
3.1.8   Patients must be able to swallow and retain oral medications and without 
gastrointestinal illnesses that would preclude absorption of cediranib or 
olaparib. 
 
3.1.9 Patients must have adequately controlled blood pressure (BP), with a BP 
no greater than 140 mmHg (systolic) and 90 mmHg (diastolic) for 
eligibility.  Patients must have a BP of ≤ 140/90 mmHg taken in the clinic 
setting by a medical professional within 2 weeks prior to starting study.  
Patients with hypertension may be managed with up to a maximum of 
three antihypertensive medications.  It is strongly recommended that 

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patients who are on three antihypertensive medications be followed by a 
cardiologist or blood pressure specialist for management of blood pressure 
while on protocol. 
 
3.1.10 Patients must be willing and able to check and record daily blood pressure 
readings. Blood pressure cuffs will be provided to patients randomized to 
Arm III. Please refer to sections 9.7, and Appendix IX. 
 
 
3.1.11 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. 
 
3.1.12 Adequately controlled thyroid function, with no symptoms of thyroid 
dysfunction and TSH within normal limits. 
 
3.1.13 Age > 18. 
 
3.2 
Ineligibility Criteria (11/07/2016) 
 
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.  
 
3.2.2 Patients may not be receiving any other investigational agents nor have 
participated in an investigational trial within the past 4 weeks. 
 
3.2.3 Patients may not be receiving any medication that may markedly affect 
renal function (e.g., vancomycin, amphotericin, pentamidine). 
 
3.2.4 Patients may not have received prior treatment affecting the VEGF 
pathway (including, but not limited to thalidomide, sunitinib, pazopanib, 
sorafenib, and nintedanib).  Bevacizumab used in the upfront setting in 

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conjunction with chemotherapy and/or as maintenance to treat newly 
diagnosed disease will be allowed. 
 
3.2.5 Patients may not have previously received a PARP inhibitor. 
 
3.2.6 CA-125 only disease without RECIST 1.1 measurable or otherwise 
evaluable disease as per section 3.1.3. 
 
3.2.7 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.  Screening imaging to rule out brain metastases is 
not required for screening, but should be performed prior to study 
enrollment if clinically indicated.  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. 
 
3.2.8 History of allergic reactions attributed to compounds of similar chemical 
or biologic composition to cediranib or olaparib. 
 
3.2.9 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 II.  
 
Strong inhibitors and inducers of UGT/PgP should be used with caution. 
 
3.2.10 History of gastrointestinal perforation. Patients with a history of 
abdominal fistula will be considered eligible if the fistula was surgically 
repaired or has healed, there has been no evidence of fistula for at least 6 
months, and patient is deemed to be at low risk of recurrent fistula. 
 
3.2.11 History of intra-abdominal abscess within the past 3 months. 
 
3.2.12 Current signs and/or symptoms of bowel obstruction or signs and/or 
symptoms of bowel obstruction within 3 months prior to starting study 
drugs. 
 
3.2.13 Dependency on IV hydration or TPN. 
 
3.2.14 Any concomitant or prior invasive malignancies with the following 
curatively treated exceptions: 
 

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3.2.14.1 Treated limited stage basal cell or squamous cell carcinoma of 
the skin. 
 
3.2.14.2 Carcinoma in situ of the breast or cervix. 
 
3.2.14.3 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.  
 
3.2.14.4 Prior cancer treated with a curative intent with no evidence of 
recurrent disease 3 years following diagnosis and judged by the 
investigator to be at low risk of recurrence.   
 
3.2.15 Patients with any of the following: 
 
3.2.15.1 History of myocardial infarction within six months 
 
3.2.15.2 Unstable angina 
 
3.2.15.3   Resting ECG with clinically significant abnormal findings. 
 
3.2.15.4 NYHA classification of III or IV 
 
3.2.16 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: 
 
3.2.16.1 Prior treatment with anthracyclines 
 
3.2.16.2 Prior treatment with trastuzumab 
 
3.2.16.3 Prior central thoracic radiation therapy (RT), including RT to the 
heart 
 
3.2.16.4 History of myocardial infarction within 6 to 12 months (Patients 
with history of myocardial infarction within 6 months are 
excluded from the study) 
 
3.2.16.5 Prior history of impaired cardiac function 
 
3.2.17 History of stroke or transient ischemic attack within six months. 

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3.2.18 Any prior history of hypertensive crisis or hypertensive encephalopathy. 
 
3.2.19 Clinically significant peripheral vascular disease or vascular disease 
(including aortic aneurysm or aortic dissection). 
 
3.2.20 Major surgical procedure, open biopsy, or significant traumatic injury 
within 28 days prior to starting cediranib. 
 
3.2.21 Uncontrolled intercurrent illness including, but not limited to ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia (other than atrial fibrillation with controlled 
ventricular rate), or psychiatric illness/social situations that would limit 
compliance with study requirements.  
 
3.2.22 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. 
 
3.2.23 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. 
 
3.2.24 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.  
 
3.2.25 No features suggestive of myelodysplastic syndrome (MDS) or acute 
myelogenous leukemia (AML) on peripheral blood smear or bone marrow 
biopsy, if clinically indicated. 
 
3.2.26 No prior allogeneic bone marrow transplant or double umbilical cord 
blood transplantation (dUBCT). 
 
 

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4.0 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
4.1 
Pre-treatment assessments (11/07/2016) (07/31/2017) 
The following observations and tests are to be performed and recorded on the appropriate 
form(s).  Please note:  Each entry refers to the corresponding footnote at the end of the 
table.  Cycle 1 Day 1 should begin within 14 days of registration. 
 
Assessments 
Prior to Registration 
 
Prior to Cycle 1 Day 1 
Treatment 
Informed Consent 
A 
 
Medical History 
A 
 
Physical Examination 
A 
C 
Concomitant Medications 
B 
D 
Performance Status 
A 
C 
Toxicity Assessment 
B 
C 
Vital Signs  
(Blood Pressure, Heart Rate, 
Temperature, and Pulse Oxygen 
Saturation)  
A 
D 
Height and Weight 
A 
C 
CBC/Differential/Platelets 
B 
C 
Serum chemistry: sodium, potassium, 
chloride, bicarbonate, BUN, 
creatinine, glucose, albumin, calcium, 
AST (SGOT), ALT (SGPT), alkaline 
phosphatase, total bilirubin, total 
protein  
B 
C 
TSH 
B 
CJ 
CA-125 
B 
C 
Urine protein: creatinine ratio 
(preferred) or urinalysis 
B 
C 
Electrocardiogram 
B 
C 
MUGA or echocardiogramG 
AG 
 
Pregnancy Test (if childbearing 
potential exists)  
A 
EF 
Radiographic Tumor MeasurementH 
A 
 
Patient-reported outcome assessments 
 
C 
BRCA1/2 testing 
I 
 
A: ≤ 28 days 
B: ≤ 14 days 
C: ≤ 7 days 
D: Day of treatment 
E: ≤ 3 days 
F: The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of hCG. 
G: MUGA or echocardiogram should be performed at baseline for all patients at increased risk for 
compromised LVEF, including patients with prior treatment with anthracyclines, prior treatment with 
trastuzumab, prior central thoracic RT, or history of myocardial infarction within the 12 months prior.   

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H: Radiographic tumor measurements should be obtained via imaging of at least the chest, abdomen, and 
pelvis at baseline. See RECIST 1.1 for allowable imaging modalities used to assess disease at baseline 
and subsequent assessments. Contrast CT is the preferred modality. 
I: Comprehensive BRCA1/2 testing (at minimum, full sequencing of BRCA1 and BRCA2 in a CLIA-
certified setting) must be available prior to randomization. Patients with prior BRCA1/2 testing should 
provide a formal copy of BRCA1/2 testing results, consisting of both the official BRCA1/2 testing report 
and, if appropriate, per 3.1.1, documentation by an appropriate qualified medical professional. Patients 
without prior testing or with less than comprehensive BRCA1/2 testing (as defined above), or those for 
whom testing results are not available, should have blood collected at screening for BRCA testing by the 
Comprehensive BRACAnalysis (Myriad Genetics, Salt Lake City, UT, USA).  BRCA1/2 testing kits for 
patients enrolling on GY004 may be obtained by contacting Alison Sibley (asibley@myriad.com) and 
Stephanie Hamilton (shamilto@myriad.com). The test requisition form and blood collection tube should 
be labeled with NCI site code, two patient initials, and patient DOB in the format mmddyyyy. Do not 
include any spaces, dashes, etc. (e.g., NY123JD04051967). All information should be legibly written. If 
additional space is needed on the tube label, a separate label should be added. Any labeling discrepancies 
between the form and tube may cause delays in processing. All patients are required to be informed of the 
BRCA test results per their treating institution's practice.  Patients may not be randomized until this 
genetic testing is completed and the results are available.  All patients should be appropriately counseled 
regarding genetic risk and testing. 
J: For participants in Arm III only. 
 
4.2 
Assessments during treatment (11/07/2016) 
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.  
 
Assessments 
Prior to Day 
1 of Each 
CycleA  
Every other 
week for first 
8 weeks of 
study therapy 
(Arms II and 
III) 
After 
completion or 
stopping of 
therapyB 
Timed (Treatment 
Cycle Independent) 
History and Physical 
E 
 
I 
 
Vital Signs  
(Blood  
Pressure, Heart Rate,   
Temperature and Pulse 
Oxygen Saturation) 
F 
 
 
 
Performance Status 
E 
 
 
 
Toxicity Assessment 
E 
F 
I 
 
CBC/Differential/Platelets 
G 
F 
I 
O 
Concomitant MedicationsN 
E 
F 
I 
 
Serum chemistry: sodium, 
potassium, chloride, 
bicarbonate, BUN, 
creatinine, glucose, 
albumin, calcium, AST 
(SGOT), ALT (SGPT), 
alkaline phosphatase, total 
bilirubin, total protein 
G 
 
I 
 

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Assessments 
Prior to Day 
1 of Each 
CycleA  
Every other 
week for first 
8 weeks of 
study therapy 
(Arms II and 
III) 
After 
completion or 
stopping of 
therapyB 
Timed (Treatment 
Cycle Independent) 
TSHC 
G 
 
 
H 
CA-125 
G 
 
I 
 
Urinalysis or urine protein: 
creatinine ratio 
G 
 
 
 
ElectrocardiogramD 
G 
 
 
 
MUGA or echocardiogram 
 
 
 
J 
Home blood pressure 
assessment 
Please see footnote K 
Radiographic tumor 
measurement 
 
 
 
L 
Patient-reported outcome 
assessments 
 
 
 
M 
A: Timing of assessments prior to Cycle 1 Day 1 may be as per pre-treatment assessments schedule. 
B: 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 should be continued until time of progression or another 
therapy is initiated.  
C: Should be performed pre-study and prior to the first two cycles of treatment for participants on Arm 
III.  Additional assessment of thyroid function should be performed as clinically indicated. 
D: Should be performed pre-study and prior to each cycle if clinically indicated  
E:  ≤ 1 day of treatment 
F:  Day of treatment/assessment 
G: ≤ 3 days of treatment 
H: 6 months (+/- 2 weeks) after stopping study treatment for participants on Arm III. 
I: Every 9 weeks (+/- 7 days) 
J: MUGA or echocardiogram should be performed at baseline for all patients at increased risk for 
compromised LVEF, including patients with prior treatment with anthracyclines, prior treatment with 
trastuzumab, prior central thoracic RT, or history of myocardial infarction within the 12 months prior.  
LVEF assessment by MUGA or echocardiogram should be performed on an every 16 week (+/- 7 days) 
basis for patients with these risk factors on Arm III of study treatment.  Additionally, LVEF assessment 
by MUGA or echocardiogram should be performed every 12 weeks (+/- 7 days) while on treatment for 
participants receiving Arm I, Regimen III (carboplatin/pegylated liposomal doxorubicin). 
K: Because of the rapid changes in blood pressure that can occur and the potential for severe life-
threatening complications if hypertension is not appropriately managed, patients on Arm 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 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. 

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L: Every 9 weeks (+/- 7 days) from cycle 1, day 1 (regardless of delays and/or changes in treatment 
schedule) for the first year; then every 12 weeks (+/- 7 days) thereafter until disease progression is 
confirmed; also repeat at any other time if clinically indicated based on symptoms or physical signs 
suggestive of new or progressive disease. An Excel tool is available on the CTSU website to calculate 
dates of re-imaging. Utilize same imaging modality as for pre-cycle 1 baseline assessment. Images from 
radiographic studies should be uploaded for future independent radiologic review via TRIAD Digital 
Image Submission as detailed in Appendix XIV.   
M: Patient-reported outcomes should be performed every 12 weeks for 3 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. 
N: 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.  
O: For patients on Arm I, Regimen II (gemcitabine/carboplatin), CBC needs to be drawn for day 8 
treatments.   
 
4.3 
Assessments After treatment (11/07/2016) 
The following observations and tests are to be performed and recorded on the appropriate 
form(s).  Vital status and patient-reported outcome assessments should be continued per 
the schedules noted below unless the patient withdraws from study participation. Please 
note:  Each entry refers to the corresponding footnote at the end of the table. 
 
Assessments 
Timed 
Vital Status 
A 
Toxicity Assessment 
B 
Radiographic tumor measurement 
C 
Patient-reported outcome assessments 
D 
A: Every 3 months for 2 years and then every 6 months for 3 years. Follow-up Forms are collected for the 
5-year follow-up period or until study termination.  
B: Report all adverse events that occur within 30 days of last protocol treatment on the Toxicity form for 
the last cycle of therapy administered. For reporting of delayed toxicity, see Section 7. 
C: In the case that protocol directed therapy is discontinued for reasons other than disease progression, 
follow radiographic tumor measurement schedule as defined under Assessments During Treatment. 
D: Patient-reported outcomes should be performed every 12 weeks for 3 years, unless the patient 
withdraws from study participation.  PRO assessments should continue post-progression. 
 
 
5.0 
TREATMENT PLAN/Regimen description 
 
Patients will be randomized to one of three treatment regimens in a 1:1:1 ratio, stratified 
by the following characteristics: 
 
a. Germline BRCA1/2 mutation status (deleterious or suspected deleterious versus non-
deleterious) 
b. Prior angiogenic treatment for ovarian cancer (yes versus no) 
c. Prior platinum-free interval (6-12 months versus >12 months) 
 

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All participants must have a known germline BRCA1/2 mutation status prior to 
randomization.  Participants who do not have a known BRCA1/2 mutation status by a 
CLIA-certified assay that includes at a minimum full sequencing of both BRCA1 and 
BRCA2 will be tested for germline mutation prior to randomization. 
 
5.1 
Arms/Regimens (11/07/2016) 
 
Patients will be randomized to one of the following three arms in an open-label 
manner.  Treatments will take place in an outpatient setting. Due to the differing 
schedules and routes of administration, patients on the reference regimen arm will 
not be blinded.  Additionally the study will not be blinded with regards to whether 
patients are receiving single agent olaparib or combination cediranib/olaparib. See 
Appendix XIII for general treatment guidelines. 
 
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. After 1 years of protocol 
therapy or follow-up (measured from approximately cycle 1, day 1), imaging 
studies will be conducted every 12 weeks. Excel tool will be provided to sites to 
assist in determining imaging dates. 
 
No modification of the assigned regimens is allowed. 
 
 
5.1.1 Arm I (Reference Regimen):  Platinum-based chemotherapy (07/31/2017) 
 
Patients randomized to the platinum-based chemotherapy arm may be 
treated with one of the three regimens specified in this section per 
investigator discretion (the planned regimen should be specified prior to 
randomization).  Patients should receive treatment per standard practice 
and may continue on treatment until progression per investigator 
discretion if having continued response and/or clinical benefit.  The 
number of cycles of therapy should be administered as clinically 
appropriate, although it is suggested that patients should receive at least 4 
cycles of therapy.  After completion of chemotherapy, patients must be 
followed without further chemotherapy or maintenance therapy until 
disease progression, defined as objective findings on imaging studies, 
and not progression of disease by CA125 alone.  Maintenance therapy 
(e.g. with bevacizumab or a PARP inhibitor) is not allowed on this study.  

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Dosing for patients receiving one of the reference regimens should be 
recalculated for weight changes ≥10% of baseline. 
 
5.1.1.1 Regimen I:   
 
A cycle will be 21 days in length, with paclitaxel and carboplatin 
infused IV as below on day 1.  Paclitaxel infusion should occur 
prior to carboplatin infusion.  Pre medications with 
dexamethasone, diphenhydramine, and famotidine (or other H2 
blocker) should be administered prior to paclitaxel infusion per 
institutional or practice standards.  Anti-emetics may be 
administered per institutional and practice standards. 
 
• Paclitaxel (175mg/m2) IV infused over 3 hours on day 1 
• Carboplatin (AUC 5 or 6) IV infused over 30-60 minutes 
on day 1 
 
5.1.1.2 Regimen II: 
 
A cycle will be 21 days in length, with gemcitabine infused IV on 
days 1 and 8 and carboplatin on day 1, as detailed below.  
Gemcitabine infusion should occur prior to carboplatin infusion on 
day 1.  Anti-emetics may be administered per institutional and 
practice standards. 
 
• Gemcitabine (1000mg/m2) IV infused over 30 minutes on 
days 1 and 8 
• Carboplatin (AUC4) IV infused over 30-60 minutes on day 
1 
 
5.1.1.3 Regimen III: (11/07/2016) 
 
A cycle will be 28 days in length, with pegylated liposomal 
doxorubicin (PLD) and carboplatin infused IV on day 1, as 
detailed below.  PLD infusion should occur prior to carboplatin 
infusion.  Anti-emetics may be administered per institutional and 
practice standards. 
 
• Pegylated liposomal doxorubicin (30mg/m2) IV on day 1 
per institutional standard. 
• Carboplatin (AUC5) IV infused over 30-60 minutes on day 
1 
 
5.1.2 Arm II:  Olaparib monotherapy (11/07/2016) 
 

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Olaparib 300mg 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.  Patients will 
remain on treatment until disease progression.  Patients randomized to 
Arm II will be required to maintain a medication diary (found in Appendix 
VII). 
 
5.1.3 Arm III:  Olaparib and cediranib (11/07/2016) 
 
Olaparib 200mg in tablet formulation orally twice daily continuous 
dosing.  Olaparib tablets should be taken twice a day approximately 12 
hours apart.  
 
Cediranib 30mg in tablet formulation orally once daily.  Cediranib should 
be taken on an empty stomach in the morning approximately 1 hour before 
taking the morning dose of olaparib. 
 
One cycle will be considered 28 days.  Cycle days are continuously 
numbered regardless of any dose holds or interruptions.  Patients will 
remain on treatment until disease progression.  Patients randomized to 
Arm III will be required to maintain medication and blood pressure diaries 
(found in Appendix VIII and IX).  A blood pressure cuff will be provided 
to patients randomized to Arm III. 
 
5.2 
Duration of Study 
 
5.2.1 Patients on the reference arm (Arm I) of the study will receive platinum-
based chemotherapy as outlined.  The number of cycles will be per the 
investigator’s discretion.  After completion of chemotherapy, patients will 
continue on active surveillance until disease progression.  Patients on 
Arms II and III of the study will continue on study treatment until disease 
progression, or adverse events, require discontinuing protocol treatment.  
All patients will continue to be followed after disease progression or 
discontinuation of protocol treatment for PROs.  The patient may 
voluntarily withdraw from the study at any time. 
 
5.2.2 All patients will be followed for disease status and toxicity (with 
completion of all required case report forms) until death or voluntary 
withdrawal from study. In addition, following study therapy, patients will 
continue with imaging studies until the time of progression as well as 
continued PRO assessments. 
 

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5.2.3 Adequate Duration of Study to Evaluate Toxicity. All patients who initiate 
any study therapy will be evaluated for toxicity 
 
5.3 
Follow-up after study treatment discontinuation and/or progression 
 
The median PFS reported in studies with platinum-based doublets in women with 
recurrent platinum-sensitive ovarian cancer ranges between 8.4 months to 13 
months (2-4, 8, 10).  The primary analysis of PFS will be a stratified log-rank test 
and intention-to-treat (ITT) with patients analyzed according to the arm to which 
they were randomized, regardless of whether treatment is received. 
 
To allow for better understanding of time to subsequent therapy and PFS2, 
patients will be followed after progression on study treatment, 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. 
 
6.0 
TREATMENT MODIFICATIONS/MANAGEMENT 
 
For AEs that are unrelated to the study drugs, study treatment may be held for up to 14 days at 
the discretion of the treating investigator.  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 overall PI. 
 
6.1 
Reference regimens (Arm I) 
 
6.1.1 Hematologic toxicity 
 
6.1.1.1 Use of hematopoietic agents 
 
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. 
 
Use erythropoietin-stimulating agents per standard of care National 
Comprehensive Cancer Network (NCCN) and/or institutional 
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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.  
 
Patients should not receive thrombopoietic agents.  Transfusions 
may be administered as clinically indicated for management of 
anemia. 
 
6.1.1.2 Arm I, Regimen I: Carboplatin and paclitaxel 
 
Day 1 of any given cycle of Regimen I should not be administered 
unless the ANC is ≥ 1,500/mcL and the platelet count is ≥ 
100,000/mcL.  Treatment may be delayed for a maximum of 3 
weeks until these parameters are met.  If patient counts fail to 
recover adequately within three weeks, discontinue protocol-
directed therapy.  
 
Dose modifications may occur for neutropenic or 
thrombocytopenic events, as detailed in the following tables.  Dose 
modifications should be carried through to future cycles of therapy 
once performed. 
 
Table 6.1.1.2.A:  Dose modifications for neutropenia, Regimen I 
 
Hematologic Event 
Dose Modification 
Initial 
Occurrence 
Febrile neutropenia† 
Grade 4 neutropenia lasting ≥ 
7 days 
ANC < 1000/mcL on Day 1 
Treatment delay > 7 days for 
neutropenia 
Reduce carboplatin by 1 AUC 
Initiate G-CSF if not already 
receiving 
Second 
Occurrence 
If any of the above toxicities 
occur after initial dose 
reduction 
Reduce carboplatin by 1 AUC†† 
Reduce paclitaxel dose to 135mg/m2 
Third 
occurrence 
If any of the above toxicities 
occur after two dose 
reductions 
Discontinue patient from protocol-
directed therapy 
† Febrile neutropenia is defined within the CTCAE as a disorder characterized by an 
ANC <1000/mcL and a single temperature of >101 degrees F or a sustained degree of 
≥ 100.4 degrees F for more than an hour. 

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††Carboplatin may not be reduced below AUC4.  If neutropenic event occurs at a 
carboplatin AUC of 4, carboplatin dosing should be maintained at AUC4 and 
paclitaxel dose reduced to 135mg/m2. 
 
 
Table 6.1.1.2.B:  Dose modifications for thrombocytopenia, Regimen I 
 
Hematologic Event 
Dose Modification 
Initial 
Occurrence 
Any occurrence of grade 4 
thrombocytopenia 
(platelets < 25,000/mcL) 
Grade 3 thrombocytopenia 
with bleeding event 
(platelets 25,000 to  
<50,000/mcL) 
Platelets < 75,000/mcL on 
Day 1† 
Treatment delay > 7 days for 
thrombocytopenia 
Reduce carboplatin by 1 AUC 
 
Second 
Occurrence 
If any of the above toxicities 
occur after initial dose 
reduction 
Reduce carboplatin by 1 AUC†† 
Reduce paclitaxel dose to 135mg/m2 
Third 
occurrence 
If any of the above toxicities 
occur after two dose 
reductions 
Discontinue patient from protocol-
directed therapy 
† At the discretion of the investigator, a dose reduction may be performed for platelet 
counts < 100,000/mcL on Day 1. 
††Carboplatin may not be reduced below AUC4.  If a thrombocytopenic event occurs 
at a carboplatin AUC of 4, carboplatin dosing should be maintained at AUC4 and 
paclitaxel dose reduced to 135mg/m2. 
 
6.1.1.3 Arm I, Regimen II: Carboplatin and gemcitabine 
 
Day 1 of any given cycle of Regimen I should not be administered 
unless the ANC is ≥ 1,500/mcL and the platelet count is ≥ 
100,000/mcL.  Treatment may be delayed for a maximum of 3 
weeks until these parameters are met.  Patients who fail to recover 
adequate counts within a three-week delay should discontinue 
protocol-directed cytotoxic therapy.  Day 8 treatment should be 
administered per the guidelines in Table 6.1.1.3.A below, and dose 
modifications for hematologic events should be performed per 
Table 6.1.1.3.B. 
 
Table 6.1.1.3.A:  Dosing guidelines for hematologic toxicity, Regimen II 
Treatment Day 
ANC  
(per mcL) 
 
Platelet count 
(per mcL) 
% of full dose 
Day 1 
≥ 1500 
< 1500 
and 
or 
≥ 100,000 
< 100,000 
100% 
Delay treatment cycle 
Day 8 
≥ 1500 
1000-1499 
and 
or 
≥ 100,000 
75,000-99,999 
100% 
50% 

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< 1000 
or 
< 75,000 
Hold 
 
Table 6.1.1.3.B:  Dose modifications for hematologic toxicity, Regimen II 
 
Hematologic Event 
Dose Modification 
Initial 
Occurrence 
Febrile neutropenia† 
ANC < 500/mcL for > 5 days 
ANC < 100/mcL for > 3 days 
Grade 4 thrombocytopenia 
(platelets < 25,000/mcL) 
Grade 3 thrombocytopenia 
with bleeding event 
(platelets 25,000 to  
<50,000/mcL) 
Treatment delay > 7 days for 
neutropenia or 
thrombocytopenia 
Permanently reduce gemcitabine to 
800mg/m2 on Days 1 and 8 
Initiate G-CSF for neutropenic 
events if not already receiving 
Second 
Occurrence 
If any of the above toxicities 
occur after initial dose 
reduction 
Permanently reduce gemcitabine 
dose to 800mg/m2 on Day 1 only 
(Day 8 gemcitabine is permanently 
omitted) 
Third 
occurrence 
If any of the above toxicities 
occur after two dose 
reductions 
Discontinue patient from protocol-
directed therapy 
†Febrile neutropenia is defined within the CTCAE as a disorder characterized by an 
ANC <1000/mcL and a single temperature of >101 degrees F or a sustained degree of 
≥ 100.4 degrees F for more than an hour. 
 
6.1.1.4 Arm I, Regimen III: Carboplatin and pegylated liposomal 
doxorubicin (PLD) 
 
Day 1 of any given cycle of Regimen III should not be 
administered unless the ANC is ≥ 1,500/mcL and the platelet count 
is ≥ 100,000/mcL.  Treatment may be delayed for a maximum of 3 
weeks until these parameters are met.  Patients who fail to recover 
adequate counts within a three-week delay should discontinue 
protocol-directed cytotoxic therapy. 
 
Dose modifications may occur for neutropenic or 
thrombocytopenic events, as detailed in the following tables.  Dose 
modifications should be carried through to future cycles of therapy 
once performed. 
 
Table 6.1.1.4.A:  Dose modifications for neutropenia, Regimen III 
 
Hematologic Event 
Dose Modification 
Initial 
Occurrence 
Febrile neutropenia† 
Grade 4 neutropenia lasting ≥ 
7 days 
ANC < 1000/mcL on Day 1 
Reduce carboplatin by 1 AUC 
Initiate G-CSF if not already 
receiving 

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Treatment delay > 7 days for 
neutropenia 
Second 
Occurrence 
If any of the above toxicities 
occur after initial dose 
reduction 
Reduce PLD dose to 25mg/m2 
Third 
occurrence 
If any of the above toxicities 
occur after two dose 
reductions 
Discontinue patient from protocol-
directed therapy 
† Febrile neutropenia is defined within the CTCAE as a disorder characterized by an 
ANC <1000/mcL 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.B:  Dose modifications for thrombocytopenia, Regimen III 
 
Hematologic Event 
Dose Modification 
Initial 
Occurrence 
Grade 4 thrombocytopenia 
(platelets < 25,000/mcL) 
Grade 3 thrombocytopenia 
with bleeding event 
(platelets 25,000 to  
<50,000/mcL) 
Platelets < 100,000/mcL on 
Day 1† 
Treatment delay > 7 days for 
thrombocytopenia 
Reduce carboplatin by 1 AUC 
 
Second 
Occurrence 
If any of the above toxicities 
occur after initial dose 
reduction 
Reduce PLD dose to 25mg/m2 
Third 
occurrence 
If any of the above toxicities 
occur after two dose 
reductions 
Discontinue patient from protocol-
directed therapy 
† At the discretion of the investigator, a dose reduction may be performed for platelet 
counts < 100,000/mcL on Day 1. 
 
6.1.2 Non-hematologic toxicity 
 
Management of non-hematologic toxicities on the reference arm should be 
per institutional practice and guidelines.  Criteria for dose holds and 
modifications on the reference arms for non-hematologic toxicity should 
follow institutional practice and prescribing information.  Permanent dose 
reductions should follow dose levels as outlined in Table 6.1.2.A.  Dose 
modifications for alopecia, nausea, or constipation are not recommended.  
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. 
 
Table 6.1.2.A:  Guidelines for permanent dose reductions, Reference Regimens 
Drug 
First reduction 
Second reduction 
Carboplatin† 
Decrease AUC by 1 
Decrease AUC by 1 

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Paclitaxel 
Decrease dose to 135 mg/m2 Decrease dose to 110 mg/m2 
Gemcitabine 
Decrease dose to 800mg/m2 
on Days 1 and 8 
Discontinue Day 8 dosing 
Pegylated liposomal 
doxorubicin 
Decrease dose to 25mg/m2 
Decrease dose to 20mg/m2 
†Carboplatin dose should not be reduced below an AUC of 4.  Patients requiring a dose 
reduction below AUC4 should be removed from protocol-directed therapy. 
 
6.1.3 Hypersensitivity reactions (11/07/2016) 
 
Of note, the occurrence of a hypersensitivity reaction may not be a dose-
limiting toxicity.  Depending on the severity of their hypersensitivity 
reaction, patients experiencing a hypersensitivity reaction may be retreated 
at full doses under institutional protocols to prevent hypersensitivity 
reactions.  The below table provides recommendations regarding approach 
to continued treatment for patients experiencing hypersensitivity reactions.  
Sites may also follow institutional guidelines for prevention and/or 
avoidance of hypersensitivity reactions. 
 
Table 6.1.3.A:  Guidelines for hypersensitivity reactions 
Grade 
Definition 
Recommended treatment and 
management 
Grade 1 
Mild transient reaction; infusion 
interruption not indicated; 
intervention not indicated 
May consider retreatment per 
institutional guidelines.  May 
consider pre-medication with 
steroids, antihistamines 
(diphenhydramine), or H2 
blockers. 
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, per institutional 
guidelines.  Patients may be 
discontinued from protocol-
directed therapy at the discretion 
of the investigator. 
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 sequel 
Stop infusion immediately.  May 
consider rechallenge under 
desensitization protocol, per 
institutional guidelines.  Patients 
may be discontinued from 
protocol-directed therapy at the 
discretion of the investigator. 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated. 
Do not rechallenge.  Protocol-
directed therapy should be 
discontinued. 
 
 
6.2 
Arms II (olaparib) and III (olaparib and cediranib) (07/31/2017) 
 

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Arm II 
 
Dose Level 
Olaparib tablets 
1 
300 mg twice daily 
-1 
250 mg twice daily 
-2 
200 mg twice daily 
-3 
150 mg twice daily 
 
Arm III 
 
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 
20 mg daily 
-2 
15 mg daily 
 
For Arm III, 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 overall 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 overall study chair.  
 
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 overall PI. 
 
6.2.1 Hematologic toxicity 
 
6.2.1.1 Use of hematopoietic agents 
 
Use of hematopoietic agents will not be allowed in Arms II and III. 
 

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6.2.1.2 Dose modifications  
 
Dose modifications for hematologic events on these arms should 
be managed per the following table.   
 
Table 6.2.1.2.A:  Dose Modification and Management of Hematologic Adverse 
Events, Arms II and III 
Hematologic Event 
Dose Modification 
Absolute neutrophil count ≥ 1500/mcL 
AND  
Platelets ≥ 100,000/mcL 
AND 
Hemoglobin ≥ 8 mg/dL  
Maintain dose level 
Absolute neutrophil count < 1500/mcL 
OR 
Platelets < 100,000/mcL 
OR 
Hemoglobin < 8 mg/dL 
Hold treatment for up to 14 days until 
absolute neutrophil count ≥ 
1500/mcL, platelets ≥ 100,000/mcL, 
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.  For 
patients whose treatment is held for 
ANC between 1000 and 1500/mcL, 
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/mcL, platelets ≥ 
100,000/mcL, and hemoglobin ≥ 8 
mg/dL after 14 days should be 
removed from study. 
Grade 4 hematologic AE related to cediranib or 
olaparib that does not resolve to absolute 
neutrophil count ≥ 1500/mcL, platelets ≥ 
75,000/mcL, and hemoglobin ≥ 8 mg/dL despite 
maximum supportive care after 14 days. 
Remove patient from study. 
 
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. 
 
6.2.2 
Non-hematologic toxicity 
 
The management of general adverse events not otherwise specified in the 
following sections should be as per Table 6.2.2.A below.  Management of 
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LVEF, thyroid toxicities, and RPLS should be as further outlined in the below 
specific subsections and not per Table 6.2.2.A. 
 
 
6.2.2.1 Hypertension 
Table 6.2.2.1.A: Hypertension Monitoring and Management 
• See Appendix III for suggested antihypertensive medications by class 
• Abbreviations: Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin II Receptor 
Blockers (ARB), selective beta blockers (BB), Dihydropyridine calcium channel blockers 
(DHP-CCP) 
• 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. 
• Patients may have up to 4 drugs for management of hypertension prior to any dose reduction 
in cediranib 
Table 6.2.2.A:  General Management of Non-Hematologic Toxicity, Regimens II and III 
Observation 
Action 
AE resolves promptly with supportive care  
Maintain dose level 
Any  ≥ 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 ≤ 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. 2  
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 ≤ 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 6.2.2  Patients whose 
toxicity has not resolved after 14 days 
will be removed from study. 
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. 
Remove patient from protocol-specified 
treatment. 
1At 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 
continued to receive the 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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• 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. 
• Note:  Stopping or reduce the dose of cediranib is expected to cause a decrease in BP.  The 
treating physician should monitor the patient for hypotension 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 drug 
regimen, then add a 
second agent. 
 
Study drug does 
not need to be held 
unless otherwise 
clinically necessary 
 
Consider renal 
Increase 
frequency of 
monitoring until 
stabilized to BP 
<140/90 mmHg 
Do not hold 
cediranib unless 
otherwise clinically 
necessary 

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consult 
 
Grade 3 
Requiring more 
than one drug or 
more intensive 
therapy than 
previously.     
Maximize 2 drug 
regimen 
• 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 two drug 
combinations.  
Additional anti-
hypertensive 
drugs, up to a total 
of 4, may be 
maximized for 
blood pressure 
control 
 
Consider consult 
with a blood 
pressure 
management 
specialist if greater 
than 3 drugs are 
required for BP 
control. 
 
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 
less than 140/90 
within 14 days, 
cediranib may be 
resumed at prior 
dose. 
 
Grade 4 
If threatening 
consequences 
 
OR 
 
SBP ≥ 
180mmHg 
 
OR 
Initiate treatment 
 
Hospitalize patient 
for ICU 
management, IV 
therapy as necessary 
 
14 days are allowed 
to maximize the full 
Intensive BP 
monitoring 
(hospitalization if 
necessary) 
Hold cediranib. 
 
If BP is reduced to 
less than 140/90 
within 14 days, 
cediranib may be 
resumed at a 
reduced dose after 
discussion with the 

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DBP ≥ 
110mmHg 
effect of anti-
hypertensive agents. 
Study PI and/or 
sponsor. 
 
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 or UPC > 1.0 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, and see below. 

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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. 
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 6.2.2.2.3A 
 
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. 
 
6.2.2.5 Decrease in LVEF (11/07/2016) 
 

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Patients randomized to Arm III who have any of the following should 
undergo an echocardiogram or MUGA at baseline and every four cycles 
(16 weeks) while on study:                                             
 
a.  Prior treatment with anthracyclines 
b.  Prior treatment with trastuzumab 
c.  Prior central thoracic radiation therapy (RT), including RT to the heart 
d.  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 Posterior Reversible Encephalopathy Syndrome (PRES) 
 
Cediranib and olaparib should be held in patients with symptoms/signs 
suggestive of RPLS, pending work-up and management, including 
control of blood pressure.  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. 
 
7.0 
ADVERSE EVENTS REPORTING REQUIREMENTS 
 
7.1  Protocol Agents (11/07/2016) 
 
 
Investigational Agents 
The investigational agents administered in NRG-GY004, cediranib and olaparib are 
being made available under an IND sponsored by CTEP.  For patients on Arm II or 
III receiving cediranib and olaparib, determination of whether an adverse event meets 
expedited reporting criteria, see the reporting table in Section 7.5.2.1 of the protocol. 

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Commercial Agents 
The commercial agents in NRG-GY004 are carboplatin, paclitaxel, pegylated liposomal 
doxorubicin, and gemcitabine. For patients on Arm I receiving only commercial agents, 
determination of whether an adverse event meets the expedited reporting criteria, see the 
reporting table in Section 7.5.2.2 of the protocol. 
 
 
7.2 Adverse Events and Serious Adverse Events 
7.2.1 The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized until March 31, 2018 
for AE reporting. CTCAE version 5.0 will be utilized for AE reporting beginning April 1, 
2018. All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner. 
 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for Study Agents 
 
7.3.1   
 Comprehensive Adverse Events and Potential Risks list (CAEPR) 
 for 
Cediranib (AZD2171, NSC 732208) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  
for further clarification. Frequency is provided based on 1608 patients. Below is the CAEPR for Cediranib 
(AZD2171). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 

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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. 
   
 
7.3.2 Adverse Effects 
 
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 2073 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 2.4, April 24, 20191 

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 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 2073] 
 
 
 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) 
GASTROINTESTINAL DISORDERS 
 
Abdominal distension 
 
Abdominal pain 
 Abdominal pain (Gr 2) 
Constipation 
 Constipation (Gr 2) 
Diarrhea 
 Diarrhea (Gr 2) 
Dyspepsia 
 Dyspepsia (Gr 2) 
Nausea 
 Nausea (Gr 3) 
Vomiting 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Edema limbs 
 
Fatigue 
 Fatigue (Gr 3) 
Fever 
 
INFECTIONS AND INFESTATIONS 
 
Infection2 
 
INVESTIGATIONS 
 
Creatinine increased 
 
Lymphocyte count decreased 
 
Neutrophil count decreased 
 
Platelet count decreased 
 
White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
Back pain 
 
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 
 
 
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 

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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. 
 
2Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATION SOC. 
 
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 - Cardiac disorders - Other (nodal rhythm); Chest pain - cardiac; Sinus 
tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Hypothyroidism 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Colonic obstruction; Dry mouth; Dysphagia; 
Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (gastrointestinal 
hemorrhage); Gastrointestinal disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other 
(intestinal perforation); Ileus; Jejunal perforation; Mucositis oral; Pancreatitis; Periodontal disease; Rectal 
hemorrhage; Small intestinal obstruction; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Malaise; Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (systemic inflammatory response 
syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - 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; 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 cramp; Muscle weakness lower limb; Myalgia; Neck pain; Pain in 
extremity; Rotator cuff injury 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Ataxia; Cognitive disturbance; Concentration impairment; 
Encephalopathy; Intracranial hemorrhage; Peripheral sensory neuropathy; 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; 
Oropharyngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders 
- Other (chronic obstructive pulmonary disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Pruritus; Rash maculo-papular 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension; Hypotension; Thromboembolic event 
 
 
Note: Olaparib (AZD2281) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 

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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 the 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 
• Per CTEP NCI Guidelines for Adverse Events Reporting Requirements, a CTEP-
AERS 24-hour notification must be  submitted within 24 hours of learning of the 
adverse event. Each CTEP-AERS24-hour notification must be followed by a 
complete report within 3 days. Supporting source 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 the CTEP at 301-230-0159 and NRG 
Regulatory Affairs at 215-854-0716. 
• A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations. Sites 
must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment.  
 
 
7.5.2 Expedited Reporting Requirements for Adverse Events (11/07/2016) 
7.5.2.1 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 

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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 
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: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
 
 
7.5.2.2 
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 

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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 
 
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: 
• 
All Grade 3, 4, and Grade 5 AEs 
• 
Grade 1 and 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
 
7.5.3 
Reporting to the Site IRB/REB (11/07/2016) 
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 (11/07/2016) 
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.  
 

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CTEP requires all secondary malignancies that occur during or subsequent to 
treatment with an agent under an NCI IND/IDE be reported via CTEP-AERS. In 
addition, secondary malignancies following radiation therapy must be reported via 
CTEP-AERS. Three options are available to describe the event: 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should 
also be reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting via CDUS unless otherwise specified. 
 
7.5.4  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. 
 

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8.0 REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES 
 
8.1 
Registration Procedures 
 
 
Food and Drug Administration (FDA) regulations and National Cancer 
Institute (NCI) policy require all investigators participating in any NCI-
sponsored clinical trial to register and to renew their registration annually. 
 
Registration requires the submission of: 
 
• a completed Statement of Investigator Form (FDA Form 1572) with an 
original signature 
• a current Curriculum Vitae (CV) 
• a completed and signed Supplemental Investigator Data Form (IDF) 
• a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP 
website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  
For questions, please contact the CTEP Investigator Registration Help Desk 
by email at <pmbregpend@ctep.nci.nih.gov>. 
 
8.1.1 
CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) application is a web-based application intended 
for use by both Investigators (i.e., all physicians involved in the 
conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff 
involved in the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial 
registration and annual re-registration) with CTEP and to obtain a user 
account. 
 
Investigators will use the CTEP-IAM application to obtain a user 
account only. (See CTEP Investigator Registration Procedures above 
for information on registering with CTEP as an Investigator, which 
must be completed before a CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP 
and CTSU (Cancer Trials Support Unit) websites and applications, 
including the CTSU members’ website. 
 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For 

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questions, please contact the CTEP Associate Registration Help Desk 
by email at <ctepreghelp@ctep.nci.nih.gov>. 
 
8.1.2 
Site Registration Requirements (11/07/2016) (07/31/2017) 
 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
8.1.2.1 
IRB Approval:   
 
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.  Study centers can check the status of their 
registration packets by querying the Regulatory Support 
System (RSS) site registration status page of the CTSU 
members’ website by entering credentials at 
https://www.ctsu.org.  For sites under the CIRB initiative, IRB 
data will automatically load to RSS. 
 
8.1.2.2 
Downloading Site Registration Documents:   
 
Site registration forms may be downloaded from the NRG-
GY004 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 
Click on the Protocols tab in the upper left of your screen 
Click on the NCTN NRG link to expand, then select trial 
protocol NRG-GY004 
Click on the Site Registration Documents link 
 
8.1.2.3 Site Specific Requirements for NRG-GY004 Site Registration:  
 
 
 
All the requirements listed below must be completed and 
submitted to the CTSU before the site can be activated. 
 
• 
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  

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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. 
 
8.1.2.4 
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 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory 
document submission only) 
 
8.1.2.5 
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 (11/07/2016) 
- 
Documentation of the Principal Investigator’s and co-
investigators’ GCP Training through Firecrest or another 
valid GCP training course 
- 
Documentation of the Principal Investigator’s and co-
investigators’ protocol-specific training through Firecrest 
 

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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 
*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 GCP and 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. 

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8.1.3.1 
GCP Training  
 
Each investigator who enrolls a patient is required to complete 
a GCP training course.  GCP training is offered in Firecrest and 
can be completed when the investigator receives his/her user 
account login. The GCP training takes approximately 50 
minutes to complete 
 
If an investigator has already completed a GCP training course, 
this certification will also be accepted.  It is the responsibility 
of each investigator to do his/her due diligence by submitting a 
renewed GCP training certification if the GCP was not 
completed in Firecrest.   
 
All GCP certifications will be accepted and a copy of the 
training certificate is to be sent to nrg-gy-
gcptraining@nrgoncology.org with the following information: 
 
- 
Investigator’s Name 
- 
Investigator’s CTEP ID 
- 
Institution NCI CTEP Code 
- 
Institution Name 
- 
Training Certificate 
 
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 (11/07/2016) 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN).  OPEN is a web-based registration system available on a 
24/7 basis.  To access OPEN, the site user must have an active CTEP-IAM 
account (check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 
'Registrar' role on either the LPO or participating organization roster. 
 
All site staff will use OPEN to enroll patients to this study.  It is integrated 
with the CTSU Enterprise System for regulatory and roster data.  OPEN can 
be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org. 
 
All site staff will use OPEN to enroll patients to this study.  OPEN can be 
accessed on the NRG web menu page by clicking on the OPEN link.  
  
Prior to accessing OPEN, site staff should verify the following: 
  
• All eligibility criteria have been met within the protocol stated 
timeframes. Site staff should use the registration forms provided on the 
group web site as a tool to verify eligibility. 
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
• The enrolling investigator has completed the GCP and protocol training. 
  
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for 
your records.  
 
Access requirements for OPEN: 
  
• Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account. This is the same account (user id and password) 
used for the CTSU members' web site.  
• To perform registrations, the site user must have been assigned the 
'Registrar' role on the NRG or CTSU roster.  
• To perform registrations you must have an equivalent 'Registrar' role on 
the Lead Group roster.  Role assignments are handled through the 
Groups in which you are a member.  
  
Note:  The OPEN system will provide the site with a printable 
confirmation of registration and treatment information.   Please print 
this confirmation for your records.  
  

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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.  
 
9.0  DRUG INFORMATION 
 
9.1 
Gemcitabine, Gemzar ® (NSC #613327) 
 
9.1.1  Formulation: Gemcitabine HCl is a nucleoside analog that exhibits 
anti-tumor activity.  
 
9.1.2 Supplier/How Supplied: Gemcitabine HCl is commercially available 
as a white lyophilized powder in sterile single use vials containing 
200mg (10 ml) or 1000 mg (50 ml) of gemcitabine as the 
hydrochloride salt or as a sterile 38mg/mL sterile solution in sterile 
single-use vials. 
 
9.1.3 Stability/Storage:  Unopened vials of gemcitabine powder are stable 
until the expiration date indicated on the package when stored at 
controlled room temperature between 20 to 25°C (68 to 77° F). 
Unopened vials of gemcitabine injection solution are stable until the 
expiration date indicated on the package when stored at 2 to 8°C (36 to 
46° F). Vials should not be frozen. 
 
9.1.4 Preparation:  To reconstitute lyophilized gemcitabine, add 5 ml of 
0.9% Sodium Chloride Injection to the 200 mg vials or 25 ml to the 
1000 mg vial. Shake to dissolve. These dilutions each yield a 
gemcitabine concentration of 38 mg/ml which includes accounting for 
the displacement volume of the lyophilized powder. The total volume 
upon reconstitution will be 5.26 ml or 26.3 ml, respectively. Complete 
withdrawal of the contents will provide 200 mg or 1 g of gemcitabine, 
respectively.  
 
The appropriate amount of gemcitabine solution may be administered 
as prepared or further diluted with 0.9% Sodium Chloride Injection to 
concentrations as low as 0.1 mg/ml. The solution should be clear, 
colorless to slightly straw colored. Do not administer if discoloration 
or particulate matter is found. Once the drug has been reconstituted or 
diluted, it should be stored at controlled room temperature and used 
within 24 hours.  
 
9.1.5 Administration: The mixed solution will be continuously infused over 
30 minutes. 
 
 
9.1.6 Adverse effects: 

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*See FDA-approved gemcitabine package insert for a comprehensive 
list of adverse events associated with gemcitabine. 
 
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: 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. 
 
9.2.3 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. 
 
9.2.4 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. 

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Patients who experience severe hypersensitivity reactions to paclitaxel 
should not be re-challenged with the drug. 
 
9.2.5 Adverse Effects: Consult the package insert for the most current and 
complete information.  
 
9.3 
Carboplatin (Paraplatin® - NSC #241240) 
 
9.3.1  Formulation: Carboplatin is supplied as a sterile, pyrogen-free, 
10mg/mL aqueous solution in multi-dose vials containing 50mg/5mL, 
150mg/15mL, 450mg/45mL, or 600mg/60mL of carboplatin. 
 
9.3.2  Storage: Unopened vials of carboplatin are stable to the date indicated 
on the package when stored at 25°C (77°F). Excursions from 15 to 
30°C (59 to 86°F) are permitted. Protect from light. Carboplatin multi 
dose vials maintain microbial, chemical, and physical stability for up 
to 14 days at 25°C following multiple needle entries. 
 
9.3.3 Preparation: Carboplatin aqueous solution can be further diluted to 
concentrations as low as 0.5mg/mL with 5% Dextrose in Water or 
0.9% Sodium Chloride for Injection, USP. When prepared as directed, 
carboplatin aqueous solutions are stable for 8 hours at room 
temperature (25°C / 77°F). Since no antibacterial preservative is 
contained in the formulation, it is recommended that carboplatin 
solutions be discarded 8 hours after dilution. 
 
See Appendix IV for current dose instructions.  
Note; Carboplatin dose will be recalculated if patient has weight 
change of greater than or equal to 10% from baseline.  
 
NOTE: Aluminum reacts with carboplatin causing precipitate 
formation and loss of potency; therefore, needles or intravenous sets 
containing aluminum parts that may come in contact with the drug 
must NOT be used for the preparation or administration of carboplatin. 
 
9.3.4  Adverse Effects: Consult the package insert for the most current and 
complete information. 
 
9.3.5  Supplier: Commercially available both from Bristol-Myers Squibb 
Oncology as well as generic manufacturers. Consult the American 
Hospital Formulary Service Drug Information guide, Facts and 
Comparisons, or the package insert for additional information. 
 
9.4 
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: 
∗ Generic PLD 
(http://www.caraco.com/outserts/Doxorubicin%20HClLip.pdf) 
∗ Lipodox ® 
(http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203263lbl.pdf
) 
∗ 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: 
 
9.4.1 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.  
 
9.4.2 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. 
 
9.4.3 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 an in-line filter 
9.4.4 Procedure for Proper Handling and Disposal:  Caution should be 
exercised in the handling and preparation of PLD.  
The use of gloves is required.  

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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.  
PLD should be handled and disposed of in a manner consistent with 
other anticancer drugs.  
 
Adverse Effects:  Consult the PLD package insert for the most current 
and complete information. 
 
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. 
 
9.5 
Cediranib (AZD2171, NSC 732208) 
 
9.5.1 Chemical Name: 4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-
methoxy-7-(3-pyrrolidin 1- ylpropoxy) quinazoline maleate 
 
9.5.2 Other Names: AZD2171 maleate  
 
9.5.3 CAS Registry Number: 288383-20-0 (for the free base) 
 
9.5.4 Molecular Formula: C25H27FN4O3 · C4H4O4 
 
9.5.5 Molecular Weight: 566.59 as maleate salt (450.52 as free base) 
 
9.5.6 Approximate Solubility: The aqueous solubility of AZD2171 is 0.0006 
mg/mL for the free base (distilled water, pH 8.1 at 25°C) and 1.9 
mg/mL for the maleate salt (distilled water, pH 4.4 at 25°C). 
 
9.5.7 Mode of Action: AZD2171 is a highly potent inhibitor of vascular 
endothelial growth factor receptor (VEGFR) tyrosine kinase activity, 
which inhibits VEGF-dependent angiogenesis, neovascular survival 
and vascular permeability. 
 

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9.5.8 How Supplied: Astra-Zeneca supplies and CTEP, NCI, DCTD 
distributes AZD2171. The agent is available as beige film-coated 
tablets containing 15 mg, and 20 mg of AZD2171 free base.  The 15 
mg and 20 mg tablets are 7 mm and 8 mm in diameter, respectively.  
Each high-density polyethylene bottle contains 35 tablets. 
 
Tablet excipients include mannitol, dibasic calcium phosphate 
anhydrous, sodium starch glycolate, microcrystalline cellulose, and 
magnesium stearate with a film coat containing hypromellose 2910, 
polyethylene glycol 400, red iron oxide, yellow iron oxide, black iron 
oxide, and titanium dioxide. 
 
9.5.9 Storage: Store intact bottles at controlled room temperature [20°C-
25°C, (68-77°F)] and protect from light and moisture. 
 
9.5.10 Stability:  Stability studies are ongoing. Dispense AZD2171 tablets in 
their original containers. Alternatively, if exact quantity is dispensed in 
a pharmacy bottle, the supply should be assigned a 30-day expiration. 
If a storage temperature excursion is identified, promptly return 
cediranib (AZD2171) to room temperature and quarantine the 
supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability. 
 
9.5.11 Route of Administration:  Oral.  AZD2171 tablets should be taken 
either one hour before or two hours after meals.  
 
9.5.12 Potential Drug Interactions:  (11/07/2016) 
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 

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relevant drug interactions.  The possibility that cediranib (AZD2171) 
may induce gastrointestinal CYP3A and UGT enzymes cannot be 
excluded; therefore the efficacy of hormonal contraceptives may be 
reduced. Advise women study participants to use an additional non-
hormonal contraceptive method. 
 
In vitro studies show that cediranib (AZD2171) is a weak inhibitor of 
BCRP, Pgp, OATP1B1, OATP1B3, OCT2 and MATE1. Use caution 
in patients who are taking concomitant medications that are sensitive 
substrates of these transporters since there is a low potential for drug-
drug interactions. In vivo studies show that cediranib (AZD2171) 
could increase exposure of drugs like metformin by inhibiting renal 
tubular transporter MATE2-K, but this is thought to be infrequent and 
mild in severity. Cediranib is not an inhibitor of OAT1 or OAT3.  
 
AZD2171 (cediranib) is approximately 95% bound to human plasma 
proteins, with human serum albumin and α1-acid glycoprotein 
accounting for most of this binding. Use caution in patients taking 
concomitant medications with narrow therapeutic ranges that 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. 
 
9.5.13 Patient Care Implications: Agents that inhibit VEGF signaling have 
the potential to affect wound healing; therefore, it is recommended that 
AZD2171 is stopped two weeks prior to elective surgery and restarted 
when the surgical wound has healed. Patients should be excluded from 
participating in clinical studies with AZD2171 if they have had recent 
(at least two weeks, or until any wound has completely healed) major 
thoracic or abdominal surgery prior to study start, or a surgical incision 
that is not fully healed. 
 
 
Advise women study participants of reproductive potential to use 
effective contraception while receiving study treatment and for at least 
6 weeks after the last dose of cediranib (AZD2171). Refer to the 
protocol document for specific guidance. (11/07/2016) 
 
9.5.14 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.AZD2171 is an 
investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 

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AZD2171 is provided to the NCI under a Clinical Trials Agreement 
(CTA) between   AstraZeneca International (the Pharmaceutical 
Collaborator) and the DCTD, NCI (see Section 12.3). 
 
9.5.15 Agent Ordering and Agent Accountability (11/07/2016) 
 
NCI-supplied agents may be requested by the Principal Investigator 
(or their authorized designee) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that agent 
be shipped directly to the institution where the patient is to be treated.  
PMB does not permit the transfer of agents between institutions 
(unless prior approval from PMB is obtained).  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied 
investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA Form 1572 (Statement of Investigator), 
Curriculum Vitae, Supplemental Investigator Data Form (IDF), 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 
investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated 
shipping designees and ordering designees can 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 and a “current” password.  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. 
 
9.5.16 Agent Inventory Records: – The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of the 
receipt, dispensing and final disposition of all agents received from the 
PMB using the NCI Investigational Agent Oral (Drug) Accountability 
Record (DARF) available on the CTEP forms page.  Store and 
maintain separate NCI Investigational Agent Accountability Records 
for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
9.5.17 Useful Links and Contacts: 
 
 
• CTEP Forms, Templates, Documents:  
http://ctep.cancer.gov/forms/ 

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• NCI CTEP Investigator Registration:  
PMBRegPend@ctep.nci.nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: 
https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: 
https://eapps-ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help:  
ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
PMB phone and hours of service: (240) 276-6575 Monday through 
Friday between 8:30 am and 4:30 pm (ET) 
 
 
9.6 
Olaparib (AZD2281, NSC 747856) 
 
9.6.1 Chemical Name: 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-
yl]carbonyl}-4-fluorophenyl)methyl]phthalazin-1(2H)-one 
 
9.6.2 Other Names: AZD2281; KU-0059436; CO-CE 42 
 
9.6.3 Classification: PARP inhibitor 
 
9.6.4 CAS Registry Number: 763113-22-0 
 
9.6.5 Molecular Formula: C24H23FN4O3 
 
9.6.6 Molecular Weight: 434.46 
 
9.6.7 Approximate Solubility: 0.1 mg/mL pH independent solubility across 
physiologic range 
 
9.6.8 Mode of Action: Olaparib is an inhibitor of subclasses 1, 2, and 3 of 
polyadenosine 5’ diphosphoribose polymerase (PARP-1, PARP-2, and 
PARP-3). In tumors that are deficient in the homologous 
recombination DNA repair pathway (example, BRCA mutants), 
inhibition of PARP by olaparib causes accumulation of DNA double-
strand breaks and genomic instability. Olaparib may also enhance the 
effects of DNA damage caused by ionizing radiation and 
chemotherapy. 
 
9.6.9 Description: Crystalline solid 
 
9.6.10 How Supplied: AstraZeneca supplies and the CTEP, DCTD distributes 
olaparib as film-coated tablets in 100 mg and 150 mg strengths.  
 

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• 
100 mg tablets are 14.5 mm x 7.25 mm oval-shaped 
• 
150 mg are 14.5 mm x 7.25 mm oval-shaped 
 
Tablets are packaged in induction-sealed high-density polyethylene 
(HDPE) bottles with child-resistant closures. Each bottle contains 32 
tablets with desiccant.  
 
Tablet core components include active drug substance, copovidone, 
colloidal silicon dioxide, mannitol and sodium stearyl fumarate. Film 
coating contains hydroxypropyl methylcellulose (hypromellose), 
macrogol 400 (polyethylene glycol 400), titanium dioxide, iron oxide 
yellow and iron oxide black. 
 
9.6.11 Storage: Store in a secure location below 30° C (86° F). Sites are not 
permitted to re-package tablets. Once the bottle is opened, olaparib 
tablets must be used within 3 months of the opening date; unused 
tablets should be discarded. Instruct patients not to open a bottle until 
they are ready to use it. 
 
9.6.12 Stability:  Shelf-life studies are ongoing. If a storage temperature 
excursion is identified, promptly return olaparib to room temperature 
and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of 
the excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability 
 
9.6.13 Route of Administration:  Tablets can be taken by mouth.  
(11/07/2016) 
 
9.6.14 Potential Drug Interactions:  (11/07/2016) 
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 

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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 
 
9.6.15 Patient Care Implications: Pre-clinical data indicate that olaparib 
adversely affects embryo fetal survival and development. Therefore, 
study participants and their partners who are of child-bearing potential 
should agree to use two (2) highly effective forms of contraception 
throughout their study participation and for three (3) months after the 
last dose of olaparib. 
 
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 
 
9.6.16 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 (AZD2281) is 
an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Olaparib (AZD2281) is provided to the NCI under a Clinical Trials 
Agreement (CTA) between   AstraZeneca International (the 
Pharmaceutical Collaborator) and the DCTD, NCI (see Section 12.3). 
 
9.6.17 Agent Ordering and Agent Accountability (11/07/2016) 
 
NCI-supplied agents may be requested by the Principal Investigator 
(or their authorized designee) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that agent 
be shipped directly to the institution where the patient is to be treated.  
PMB does not permit the transfer of agents between institutions 
(unless prior approval from PMB is obtained).  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied 
investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA Form 1572 (Statement of Investigator), 
Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 

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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 
investigator at that institution. 
Active CTEP-registered investigators and investigator-designated 
shipping designees and ordering designees can 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 and a “current” password.  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.   
 
9.6.18 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. 
 
9.6.19 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  
http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  
PMBRegPend@ctep.nci.nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: 
https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: 
https://eapps-ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help:  
ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
PMB phone and hours of service: (240) 276-6575 Monday through 
Friday between 8:30 am and 4:30 pm (ET) 
 

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9.7 
Blood Pressure Cuffs (11/07/2016) 
A patient who is randomized to the olaparib and cediranib treatment arm (Arm III) 
will be given a blood pressure cuff.  Blood pressure cuffs that are supplied for this 
study, are only to be used for this study.   
 
9.7.1 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. 
 
9.7.2 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 
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. 
 
10.0 
PATHOLOGY 
 
10.1 
Stained Pathology Slide Requirements for Central Review to Confirm Eligibility:  
Not applicable. 
 
11.0 
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 (11/07/2016) 
Specimens listed below should not be submitted until after patient registration and 
Bank ID assignment. 
 
Sites in Japan should refer to Appendix XV for specimen collection and shipping details. 
 
11.2.1.1 Integrated Biomarker Specimen Requirements (11/07/2016) (07/31/2017) 
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 
Prior to study treatment 
Preclinical Development 
Research Core (PDRC) the 

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8mL drawn into CPT (citrate) tube 
day the specimen is 
collected2 
CEC C1D3 Whole Blood (WB03)1 
8mL drawn into CPT (citrate) tube 
Cycle 1, day 3 of study treatment, only 
if WB02 was submitted 
BROCA-HR Whole Blood (WB01) 
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 
BROCA-HR FFPE Primary 
Neoadjuvant Treatment Tumor 
(FPT02)4 
2 unstained slides (charged, 10µm)5 
After patient receives neoadjuvant 
treatment, only if FFPE tumor is not 
available from prior to the patient 
receiving neadjuvant treatment (i.e., 
FP02 or FM02). 
 
Submit one – FPT01 is preferred; 
Submit FMT02 only if FPT02 is not 
available 
BROCA-HR FFPE Metastatic 
Neoadjuvant Treatment Tumor 
(FMT02)4 
2 unstained slides (charged, 10µm)5 
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 
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 registration3 
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, 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 
treatment, only if PB09 was 
submitted 
NRG BB-Columbus within 
26 weeks of registration3 
ALL PATIENTS RECEIVING OLAPARIB (ARMS II and III) 
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 
prior to 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 (ARM III) 
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 
prior to administering study drug 
NRG BB-Columbus within 2 
weeks of registration3 

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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 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. 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 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. 
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 (specimen codes ending in “01”; section 11.2.1.2) and a block will be 
submitted on a permanent basis to fulfill both the mandatory (specimen codes ending in “02”; section 11.2.1.1) and 
optional (specimen codes ending in “01”; section 11.2.1.2) specimen requirements, then label the block with the 
specimen code ending in “01.” Complete and ship both the “01” and “02” specimen transmittal forms (i.e., Form TR) 
with the block. 
6 Do not use glass blood collection tubes. 
 
11.2.1.2 Exploratory Biomarker Specimen Requirements (11/07/2016) (07/31/2017) 
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, FRM01, FPT01, or 
FMT01  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, FRM01, FPT01, or 
FMT01 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,  FRP01,  FPT01, or 
FMT01 is submitted) 

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FFPE Primary Neoadjuvant Treatment 
Tumor (FPT01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
After patient receives neoadjuvant 
treatment, only if FFPE tumor is not 
available from prior to the patient 
receiving neadjuvant treatment (i.e., 
FP02 or FM01). (Optional if FP01, 
FM01, FRP01, FRM01, or FMT01 is 
submitted) 
FFPE Metastatic Neoadjuvant 
Treatment Metastatic Tumor (FMT01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm & 10 uncharged, 10µm) 
After patient received neoadjuvant 
treatment, only if FFPE tumor is not 
available from prior to the patient 
receiving neadjuvant treatment (i.e., 
FP02 or FM01). (Optional if FP01, 
FM01, FRP01,  FRM01, or FPT01 is 
submitted) 
* A copy of the corresponding pathology report must be shipped with all tissue specimens sent to NRG BB-Columbus. 
1 If patient consents to the optional FFPE collection (specimen codes ending in “01”; section 11.2.1.2) and a block will be 
submitted on a permanent basis to fulfill both the mandatory (specimen codes ending in “02”; section 11.2.1.1) and 
optional (specimen codes ending in “01”; section 11.2.1.2) specimen requirements, then label the block with the 
specimen code ending in “01.” Complete and ship both the “01” and “02” 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 (11/07/2016) 
A detailed description of specimen procedures can be found in Appendix V. 
 
A detailed description of specimen procedures for sites in Japan can be found in Appendix 
XV. 
 
11.2.3 Laboratory Testing 
Assay details are included in Appendix VI. 
 
11.2.3.1 
Circulating Endothelial Cells (Integrated Biomarker) (11/07/2016) 
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. 
 
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 
 
11.2.3.2 
BROCA-HR (Integrated Biomarker) (11/07/2016) 
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. 
 
Swisher Lab 

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ATTN: Kathy Agnew 
University of Washington 
1959 NE Pacific St 
HSB BB632 
Seattle, WA 98195 
Phone: 206-685-7927 
Emails: kagnew@uw.edu, ovcalab@uw.edu 
 
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)    
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 
Plasma Angiome (Integrated Biomarker) 
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. 
 
Andrew Nixon 
Phase I Biomarker Laboratory 
Duke University Medical Center 
395 MSRB Building 
Research Dr. 

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Durham, NC 27710 
Phone: 919-613-7883 
FAX: 919-668-3925 
Email: anixon@duke.edu 
 
11.2.3.5 
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. 
 
11.2.3.6 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. 
 
Dr. Douglas Levine 
ATTN: Narciso Olvera 
GYN Research Lab, Z-427G 
Memorial Sloan Kettering Cancer Center 
417 E 68th St 
New York, NY 10065 
Phone: 646-888-3208 
Email: gynreslab@mskcc.org 
 
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. 
 
11.3 
Quality of Life / Patient-Reported Outcomes (11/07/2016) 
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 trial and has a pre-specified analysis plan.  All other endpoints 
(TSE, F/WB, Ntx-4 and EQ-5D) are secondary and will be analyzed as exploratory 
objectives (see Appendix X). 
 
The following PRO assessments will be performed every 12 weeks for 3 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. (secondary):  PRO: NFOSI-18 TSE 
3. (secondary):  PRO: NFOSI-18 F/WB 
4. (secondary):  PRO: NTX-4 
5. (secondary):  EQ5D 
 

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Instructions for completing Quality of Life scantron form 
 
Whenever possible, the QOL survey should be administered at the clinic visit before the 
patient is seen by the physician, before evaluations are performed, and before test results are 
shared with her. In the event the questionnaires are not administered at the clinic visit, the 
QOL data can be collected by telephone or mail as back-up methods, with telephone data 
collection being the preferred back-up method  
 
Patients should be instructed to answer all the questions regardless of whether the symptoms 
or conditions asked about are related to the cancer or cancer treatment. Discourage family 
members from being present during questionnaire completion or from influencing the 
patient’s response.  
 
Review the questionnaire for completeness before the patient leaves. If the patient marked 
more than one answer per question, ask the patient which answer best reflects how she is 
feeling. If the patient skipped a question or questions, assure the she noted in the space 
provided that she has chosen not to answer those questions.  
 
12.0 
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://eapps-
ctep.nci.nih.give/iam/index.jsp) 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 

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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 (11/07/2016) (07/31/2017) 
 
The following forms must be completed for all patients registered and submitted to the NRG 
Statistical and Data Management Center (SDMC) according to the schedule below. NRG 
electronic case report forms must be submitted through the Medidata Rave Electronic Data 
Entry System. All amendments to forms submitted through Medidata Rave must also be 
submitted through Medidata Rave. The operative report, discharge summary, pathology 
reports, and patient questionnaires can be sent to the NRG Statistical and Data Management 
Center via postal mail or uploaded in Medidata Rave. The upload option is an alternative 
method to submitting paper reports. 
 
This study will be monitored by the Abbreviated Clinical Data System (CDUS) Version 3.0 CDUS data will be 
submitted quarterly by the January 31, April 30, July 31 and October 31 due dates to CTEP by electronic 
means. 
 
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 Form 
- 
On Study History Surgery Form 
- 
Pre-Study History Chemotherapy 
Information Form 
- 
Pre-Study Radiation Therapy Information 
Form 
- 
Specimen Consent 
- 
ECHO/MUGA Form 
- 
ECG Information Form 
- 
Concomitant Medications Form 
- 
Vitals Form 
- 
Bio-Marker Information Form 
- 
Medical History Form  
- 
BRCA Status Form  
 
 
 
 
 
The appropriate forms will load in basline folder 
based on answers reported on the corresponding 
Baseline Visit Information form. 
 
Visit Folder 
(forms due with in 2 weeks of completion of each cycle) 
 
 
Cycle Information and Treatment Forms: 
 
 
 
 

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- 
Visit Information Form 
- 
Lab Loader 
- 
Cycle Drug Information Form 
- 
Labs and Chemistries Form 
- 
Vitals Form 
- 
ECHO/MUGA Form 
- 
ECG Information Form  
- 
Concomitant Medications Form 
- 
Bio-Marker Information Form 
 
Toxicity form:  
- 
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  
(Forms due within 2 weeks of disease evaluation) 
Solid Tumor Evaluation Forms: 
 -     Target Lesions Form 
 -     No Target Lesions Form 
 -     Non-Target Lesions Form 
 -     New Target Lesions Form 
 -     Status and Response Form 
 
PRO 
Patient-reported outcomes should be performed 
every 12 weeks for 3 years, unless the patient 
withdraws from study participation. Patients who 
stop study treatment for any reason other than 
death or refusal should be assessed on schedule. 
PRO assessments should continue post-
progression. 
 
Scantrons can be ordered by going to the NRG-
GY004 protocol documents on the CTSU 
Website and downloading the SCANTRON 
ORDER FORM to your computer. Please 
complete the form electronically and email 
form to nrg-gy-
scantronorders@nrgoncology.org or fax to 716-
845-8854. For questions, please contact NRG at 
716-845-5702 
 
Completed Scantrons should be mailed via 
postal mail to the address below 
 
NRG Oncology SDMC 
Roswell Park Cancer Institute  
Elm & Carlton Streets  
Buffalo, NY 14263-0001  
Phone: 716-845-5702 
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* 
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. 
 

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- BROCA-HR FFPE Primary Neoadjuvant 
Treatment Tumor (FPT02) 
FPT02 or FMT02 should only be submitted if 
FP02 or FM02 are not available* 
- BROCA-HR FFPE Metastatic Neoadjuvant 
Treatment Tumor (FMT02) 
FPT02 or FMT02 should only be submitted if 
FP02 or FM02 are not available* 
- Future Use Whole Blood (WB04) 
- PK Olaparib C1D8 Pre-Treatment Plasma 
(PB01) 
- PK Olaparib  C1D8 0.5-1 Hour Plasma 
(PB02) 
- PK Olaparib  C1D8 1-3 Hour Plasma (PB03) 
- PK Olaparib C1D8 4-6 Hour Plasma (PB04) 
- PK Cediranib C1D8 Pre-Treatment Plasma 
(PB05) 
- PK Cediranib C1D8 0.5-1 Hour Plasma 
(PB06) 
- PK Cediranib C1D8 1-3 Hour Plasma (PB07) 
- PK Cediranib C1D8 4-6 Hour Plasma (PB08) 
- 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) 
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 (specimen codes ending in “01”; 
section 11.2.1.2) and a block will be submitted 
on a permanent basis to fulfill both the 
mandatory (specimen codes ending in “02”; 
section 11.2.1.1) and optional (specimen codes 
ending in “01”; section 11.2.1.2) specimen 
requirements, then label the block with the 
specimen code ending in “01.” Complete and 
ship both the “01” and “02” specimen 
transmittal forms (i.e., Form TR) with the 
block. Complete and ship both the “01” and 
“02” specimen transmittal forms (i.e., Form 
TR) with the block. Complete the “01” Form 
TR as “collected” and include all requested 
specimen information. Complete the “02” Form 
TR as “not collected” and specify “submitted 
for another study.” 
WB04 and PB01-PB08 are 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)  
-Treatment completion form 
 
Follow-up Visit Folder 
(Forms due within 2 weeks of follow-up visits, disease progression or death) 
Visit Information Follow-Up Form 
Lab Loader 
Follow- up form  
Non-Protocol Therapy Form 
Concomitant Medications Form 
Labs and Chemistries Form  
Bio-Marker Reporting Form  
 
Follow-Up Period Adverse event: 
 -     Part 1Form 
 -     Adverse Event Form 
 -     AE Grades Form 
 
 
 
 
 
The appropriate forms will load in folder based on 
answers reported on the corresponding Visit 
Information form. 
 
 
- 
The required source documents, per appendix XII of the protocol, will be uploaded via 
Medidata Rave in the appropriate Form Folders   

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13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design 
 
This study is a three-arm, randomized phase III clinical trial.  The treatment 
for each enrolled patients will be randomized, and consist of either: 
 
a. Carboplatin with paclitaxel or gemcitabine or PLD (reference regimens) 
b. Olaparib (E1) 
c. Olaparib + cediranib (E2). 
 
The overall objective of this study is to evaluate the relative efficacy and 
safety of these treatment regimens in patients with recurrent high-grade serous 
or endometrioid ovarian, fallopian tube or peritoneal cancer.  
 
13.2 
Treatment allocation 
 
Treatments will be sequentially allocated from lists consisting of randomly 
permuted study treatments within blocks. This allocation procedure tends to 
allocate each of the study regimens to an equal number of enrollees within the 
8 groups defined by combinations of the following factors:  
a. Germline BRCA1/2 mutation status (Yes vs No) 
b. Prior platinum-free interval (6-12 months vs >12 months). 
c. Prior angiogenic treatment for ovarian cancer (Yes vs No). 
 
Patients are enrolled onto the study via a web-based registration system.  The 
randomized treatment for each individual remains concealed until after the 
registration process has been completed. 
 
13.3 
Measures of Efficacy and Safety 
 
The principal observations for evaluating the therapeutic efficacy and safety 
of the study regimens are:  
a. 
Primary efficacy endpoint: Progression-free survival (PFS) by 
RECIST 1.1 as determined by the treating physician. 
b. Secondary efficacy endpoint: Overall survival (OS) and response. 
c. 
Safety endpoints: frequency and severity of adverse effects as defined 
by Common Terminology Criteria for Adverse Events (CTCAE). 
d. Patient reported outcomes as measured by the NFOSI-18, DRS-P. 
e. 
Time from randomization to the first non-study, anti-cancer treatment 
or death. 
f. 
Time from randomization to the second non-study, anti-cancer 
treatment or death. 
 

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13.4 
Progression-Free and Overall Survival 
 
The onset of progression will be determined using RECIST 1.1 criteria (see 
Section 15).  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 
In the sensitivity analyses (section 13.9), patients who switch to a non-
protocol anticancer treatment prior to disease progression or discontinuing 
study treatment will be censored on the date of the last tumor assessment 
preceding the start of the non-protocol therapy. 
 
Tumor assessments will be time-based at 9 +/- 1 weeks for the first year 
and 12 +/- weeks thereafter throughout the study.  For the purposes of the 
primary analyses, the duration of PFS will be determined by the treating 
physician. 
 
Independent Radiologic Review 
The radiographic images will be prospectively collected and stored centrally 
for a blinded, independent central review (BICR) using RECIST 1.1 (as is 
done for the local evaluation).  The details for storing and reviewing images 
will be available in separate documents.  Sensitivity analyses using the BICR 
are described below in Section 13.9.2. Results from the BICR will not be 
communicated to investigators, and the management of patients will be based 
solely upon the results of the RECIST assessment conducted locally, at the 
institution. 
 
 
 
 
   
Expected Median Duration of Progression-Free and Overall Survival 

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The expected median durations of progression-free and overall survival for 
ovarian cancer patients with high-grade serous or endometrioid recurrent 
platinum-sensitive disease treated with standard platinum-based treatment are 
12 months and 38 months, respectively.   
 
13.5 
Enrollment (07/31/2017) 
 
The target enrollment for this study was originally 450 eligible patients but 
due to faster than expected accrual and in order to allow greater participation 
from international sites (which are not fully involved yet), the target has been 
raised to 549 patients.  This will have the additional benefit of moving up the 
projected final analysis date by approximately 5 months.  However, this 
change leaves the statistical analysis plan completely untouched. 
 
GOG-0213 is a recently completed trial that targeted ovarian cancer patients 
with platinum sensitive disease.  The accrual rate that study was 238 patients 
per year.  Approximately 76% of those patients had a high grade serous or 
endometrioid cancer.  Therefore, for planning purposes, it was estimated that 
approximately 180 eligible patients per year (15 patients per month) would be 
available for the current study and therefore, the enrollment period would 
require at least 2.5 years.  However, after two months of ramp up, accrual 
averaged 15 patients for 4 months and then has averaged ~30 patients per 
month for the next 8 months. At this rate of accrual, we project the accrual of 
549 patients to take approximately 20-24 months. It is anticipated that 30% 
(135) of these women will have at least one deleterious germline BRCA1 or 
BRCA2 mutation.   
 
13.6 
Study Hypotheses 
 
13.6.1 
Null Hypotheses for Primary Endpoint (PFS): 
 
1. HC:E1,pfs † : Olaparib (single agent) does not extend the duration of 
PFS compared to chemotherapy in patients with recurrent high-
grade serous or endometrioid ovarian, fallopian tube or peritoneal 
cancer. 
 
2. HC:E2,pfs : Olaparib and cediranib does not extend the duration of 
PFS compared to chemotherapy in patients with recurrent high-
grade serous or endometrioid ovarian, fallopian tube or peritoneal 
cancer. 
 
3. HE1:E2,pfs : Olaparib and cediranib does not extend the duration of 
PFS compared to olaparib (single agent) in patients with recurrent 
high-grade serous or endometrioid ovarian, fallopian tube or 
peritoneal cancer. 
 

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† Each hypothesis has two subscripts.  The first is the treatment 
comparison. C=reference treatment group (chemotherapy). 
E1=Olaparib treatment group (experimental group1). 
E2=Olaparib+Cedirinib treatment group (experimental group 2).  
The second subscript is the outcome measure: PFS=Progression-
free survival.   
 
 
13.7 
Type I Error Allocation 
 
This study will use a hierarchical testing procedure for testing HC:E1,PFS, 
HC:E2,PFS and HE1:E2,PFS .  First, the PFS times for the group of individuals who 
were randomized to the Olaparib+Cedirinib combination will be compared to 
the group randomized to chemotherapy (HC:E2,pfs).  If this null hypothesis is 
not rejected, then HC:E1,pfs and HE1:E2,pfs will not be evaluated..  If the null 
hypothesis, HC:E2,pfs, is rejected, then the PFS for those individuals who were 
randomized to Olaparib-alone will be compared to the group randomized to 
chemotherapy (HC:E1,pfs).  Finally if both null hypotheses, HC:E2,pfs and HC:E1,pfs, 
are rejected, then the PFS for the groups randomized to each of the 
experimental regimens (HE1:E2,pfs) will be compared.  The type I error for each 
of these hypothesis tests will be 0.025 for a one-tail test. 
 
13.8 
Statistical Power for HC:E2,pfs HC:E1,pfs HE1:E2,pfs 
 
 
Starting in September 2017, some control arm patients began taking non-protocol 
maintenance therapy prior to documentation of disease progression, in the context 
of FDA approvals of new drugs in the maintenance setting.  These protocol 
violations tend to reduce the power of the study.  In response to this, the design is 
being amended to increase the number of PFS events required for the primary 
analysis to 265 (from 204) to compensate for the loss of power. The timing of the 
interim analysis is modified accordingly. 
 
(Lachin,1986) approximates the control group hazard rate, adjusted for 
noncompliance, as the average of the hazards in the control and experimental 
arms weighted by the noncompliance rate among the controls.  Specifically, the 
adjusted hazard in the controls is estimated as 
 
𝜆𝜆𝐶𝐶
′ = (1 −𝜔𝜔𝐶𝐶)𝜆𝜆𝐶𝐶+ 𝜔𝜔𝐶𝐶𝜆𝜆𝐸𝐸 
 
where 𝜔𝜔𝐶𝐶 is the proportion of control patients who are noncompliant, and (𝜆𝜆𝐶𝐶,𝜆𝜆𝐸𝐸) 
are the hazards in the control and experimental arms respectively, when patients 
are fully compliant with the treatment plan.  From this, the adjusted hazard ratio is 
approximated by 
 
𝐻𝐻𝑅𝑅′ = [(1 −𝜔𝜔𝐶𝐶)𝐻𝐻𝑅𝑅−1 + 𝜔𝜔𝐶𝐶]−1 

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This approximation assumes that the hazard for the experimental arm (𝜆𝜆𝐸𝐸) applies 
to control patients who initiate parp inhibitor maintenance therapy before 
documentation of disease progression.  Table 13.8 shows how the noncompliance 
rate in the control arm impacts the hazard ratio estimate for the experimental arms 
(reference: controls) and the loss of power, given 265 events are available at the 
final analysis.  The assumptions in the Lachin(1986) methods are conservative 
when applied to this study, tending to over-correct for the effect of 
noncompliance among the controls.  For a given noncompliance rate, the adjusted 
hazard ratio and power estimates can be considered worst-case scenarios. 
 
Table 13.8: The relationship between noncompliance, hazard 
ratio, and power 
 
Noncompliance 
in the Control 
Arm 
Adjusted 
HR 
Power for 
265 
events 
0 
0.6500 
0.935 
0.20 
0.6989 
0.812 
0.22 
0.7042 
0.794 
0.24 
0.7096 
0.773 
0.26 
0.7151 
0.750 
0.28 
0.7206 
0.727 
0.30 
0.7263 
0.702 
 
 
The study will be considered sufficiently mature for the final analyses of 
HC:E2,PFS and HC:E1,PFS when there are at least 265 PFS events among those 
individuals randomized to either the chemotherapy regimen or the 
combination regimen (E2).   
 
This sample size provide 80% power for detecting a true treatment PFS hazard 
ratio of 0.70 for the hypotheses HC:E2,PFS.  If the null hypothesis, HC:E2,PFS, is 
rejected and there are at least 265 PFS events at this time among those 
randomized to the chemotherapy regimen or the single-agent olaparib regimen 
then the null hypothesis, HC:E1,PFS ,will then be evaluated. The power for 
HC:E1,PFS will be at least at least 80%.  Assuming a constant failure rate, a 0.70 
hazard ratio is comparable to increasing the expected median time to first 
progression or death from 12 months to 17.1 months.  The study will be 
considered sufficiently mature to assess HE1:E2,PFS when there are at least 204 
PFS events among those individuals randomized to either the Olaparib or the 
Olaparib+Cediranib regimens.  This sample size provides 85% power for a 
0.65 hazard ratio.  The comparison between the experimental arms is not 
impacted by noncompliance in the control arm. 
 

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Twenty four months after enrolling the last patient (excluding Japan Phase I 
patients), follow-up for the primary endpoint may be suspended.  Simulations 
suggest that 230 PFS events can be expected at this time, and the analysis 
would have 80% power to detect a diluted hazard ratio of 0.691.  A control 
arm noncompliance rate of 22% implies a true treatment hazard ratio of 0.636. 
The decision to suspend will be informed by the number of patients at risk, the 
effect of control group consent withdrawal on the at-risk set, and the time to 
obtaining 265 PFS events.  (8/15/2019) 
 
13.9 
Analytic Procedures for Testing Hypotheses: HC:E2,PFS HC:E1,PFS HE1:E2,PFS 
 
13.9.1 Primary Analysis 
A log rank procedure will be used to evaluate each of the study 
hypotheses.  The log rank procedure will be stratified by germline 
BRCA1/2 mutation status (yes vs no), last platinum-free interval (6-
12 months, vs > 12 months) and prior antiangiogenic treatment (yes 
vs no).  The analysis of PFS will consider all deaths as events, 
regardless of the cause of death.   
 
For the primary analyses patients will be grouped according to their 
randomly assigned treatment. Patients will be included in the analysis 
regardless of their compliance with their assigned treatment plan.  
The primary analyses will use the duration of PFS as it is determined 
by the clinical investigator responsible for treating the patient. 
 
Inferences regarding the significance of hypothesis tests will be made 
based on the above log rank tests; however, similarly structured 
proportional hazards models will also be run for the presentation of 
hazard ratios (HRs) and corresponding confidence intervals (CIs). 
 
13.9.2 Sensitivity Analyses 
The following sensitivity analyses for PFS will be done to address the 
potential stated biases. 
 
Evaluation-time bias 
An interval-censored log-rank test (as implemented in SAS®  Proc 
ICLIFETEST)  will be used, which will otherwise be as described 
above in section 13.9.1. 
 
Attrition-time bias 
In addition to the censoring rules in Section 13.4, patients who 
receive non-protocol anticancer therapy prior to disease progression 
will be censored at the time of their last disease assessment prior to 
the start of non-protocol therapy. The primary log-rank test from 
section 13.9.1 will be used.  Additionally a Kaplan-Meier plot of the 
time to censoring where the censoring indicator of the primary PFS 

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analysis is reversed will provide an assessment of the independent 
censoring assumption. 
 
Assessment Bias 
As described above in section 13.4, a BICR will be done for all scans. 
A proportional hazards regression model (using the stratification 
factors and ITT approach specified for the log-rank tests in section 
13.4) will be done using the BICR-assessed PFS.  If there is an 
important discrepancy between the primary analysis using 
investigator assessments and this sensitivity analysis using BICR 
assessments, then the proportion of subjects with central but no site 
confirmation of progression will be summarized. The approach of 
imputing an event at the next visit in the investigator assessed 
analysis may help inform the most likely HR value, but only if an 
important discrepancy exists. 
 
As suggested by Amit, et al (2011), disagreements between the local 
and BICR assessments of RECIST progression will be summarized 
with the following by treatment arm: 
• the early discrepancy rate (EDR), which is the frequency of 
local progressions declared early compared to the BICR (≥2 
weeks earlier) and including progressions declared locally but 
not by BICR as a proportion of all local progressions, and  
• the late discrepancy rate (LDR) which is the frequency of 
local progressions declared later than BICR progressions (≥2 
weeks later) and including progressions declared by BICR but 
not locally as a proportion of all discrepancies (including early 
and late discrepancies). 
Differential concordance for each measure will be calculated as the 
EDR (or LDR) value for each experimental arm minus the value for 
the control arm.  Negative differential concordance for EDR or 
positive differential concordance for LDR would be indicative of bias 
in the local PFS assessment in favor of an experimental arm. 
 
13.10 Interim Analyses (07/31/2017) 
 
Interim and final reports will include an accounting of all patients registered 
onto the study, regardless of their eligibility status or compliance to their 
assigned treatment.   
 
An interim analysis will be performed when at least 265/2=133 PFS events 
(approximately 50% of the information time) have been observed among 
those women who were randomly assigned to either the reference regimen or 
the Olaparib+Cediranib regimen.  Assuming that the accrual is as projected 
then this interim analysis is expected to occur approximately 2.0 years after 
initiating accrual, depending on the actual accrual rate.  

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The interim analysis will include an assessment of futility.    An O’Brien and 
Fleming-like (OBF-like) boundary (β(t)=2-2Φ(Zβ/2/√t), Kim, 1987) for type II 
error will be calculated at the time of the interim analysis.  Calculation of 
these boundaries requires that the fraction of the total information at the 
interim analysis be specified.  The fraction of information will be determined 
as the observed number of PFS events among those who are included in the 
HC:E2,PFS hypothesis test divided by the targeted number of PFS required for 
the final analysis of this hypothesis.  If HC:E2,PFS is not deemed futile, then the 
futility of HC:E1,PFS will also be assessed at this time using the same type II 
error spending function, but the boundary for its futility will depend on the 
number of PFS events among the individuals involved in that comparison.  It 
is worth emphasizing that if the interim analysis of HC:E2,PFS indicates futility 
then the hierarchical testing procedure also makes HC:E1,PFS and HE1:E2,PFS 
futile. 
 
While the precise boundaries will be calculated at the time of the interim 
analysis, the OBF-like boundary evaluated at 50% information time is 
approximately comparable to requiring that the observed PFS hazard for the 
experimental regimens to be at least 8% lower than the observed PFS hazard 
of the chemotherapy group.  Otherwise, consideration will be given to 
stopping the enrollment onto that experimental regimen and concluding that it 
is unlikely that the experimental regimen prolongs PFS relative to 
chemotherapy.  If the DMC decides to stop enrollment onto both experimental 
regimens then the study will be closed to accrual. 
 
At the time of the final PFS analysis, an interim analysis for OS will be 
performed.  We anticipate that approximately 25% of the 265 required OS 
events will have occurred at the time of the final PFS analysis.  The same 
order of testing hypotheses that will be used for the final OS analysis will be 
used for the interim OS analysis. Statistical significance will be declared at the 
interim analysis for OS if the null hypothesis for PFS is rejected and the 
observed p-value for OS is p<0.0001. This allows the significance level at the 
final analysis for OS to be controlled at the 2.5% level (1-sided) (Haybittle J L 
1971). 
 
The NRG Data Monitoring Committee (DMC) meets at least semi-annually.  
The dates for these meetings are administratively scheduled without any 
specific knowledge of the study results.  Approximately eight weeks prior to 
these meetings, the database is locked in order 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 meeting.  The decision to 
terminate accrual to a particular treatment or the entire study or to release 
study results includes consideration of toxicities, treatment compliance, 
overall survival as well as results from external studies. 
 

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13.11 Overall Survival and Clinical Response 
 
 
The expected median overall survival in this study population is about 38 months.  A 
final analysis of overall survival will be conducted when there are at least 265 
deaths among those individuals randomized to either the chemotherapy 
regimen or the combination regimen (E2).  A log rank test stratified by germline 
BRCA1/2 mutation status (yes vs no), last platinum-free interval (6-12 
months, vs  > 12 months) and prior antiangiogenic treatment (yes vs no).will 
be used to compare the distributions of survival times between treatment groups.  The 
type I error for this test will be set to 0.025 (one-tail) and this null hypothesis 
(HC:E2,OS) will not be rejected unless the hypothesis regarding PFS (HC:E2,PFS ) was 
previously rejected.  If HC:E2,PFS  is rejected, then this sample size provides 80% 
power if the combination of olaparib and cediranib reduces the death rate 30% 
(HR=0.70) relative to standard platinum-based chemotherapy.  Assuming a 
constant hazard, a hazard ratio of 0.70 is comparable to increasing the median 
duration of survival approximately 20 months.  Similarly, the rejection of 
HC:E1,OS and HE1:E2,OS will require first rejecting HC:E1,PFS and HE1:E2,PFS , 
respectively. 
 
 
Assuming that 80% of the patients enrolled onto this study have at least one 
target lesion, the standard error of the difference between two treatment 
groups in the proportion responding is limited to 6.4%. 
 
13.12 Patient-Reported Outcomes 
 
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 among the study treatments.  The primary 
measure for disease-related symptoms is the NFOSI-DRS-P, which is a 9-item 
PRO (a subset of items from the NFOSI-18).  The NFOSI-DRS-P score for 
the ith patient-assessment is calculated as  
∑
∑
=
=
=
1
1
)
*
(
*
j
ij
j
ij
ij
i
s
M
S
δ
δ
 
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 for each item ranges from 0 to 4, 
where higher values indicate preferred states.  The NFOSI-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.   
 
1. HC:E1,DRS : Olaparib (single agent) does not alter NFOSI-DRS-P 
scores compared to chemotherapy in patients with recurrent high-
grade serous or endometrioid ovarian, fallopian tube or peritoneal 
cancer. 

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2. HC:E2,DRS : Olaparib and cediranib does not alter NFOSI-DRS-P 
scores compared to chemotherapy in patients with recurrent high-
grade serous or endometrioid ovarian, fallopian tube or peritoneal 
cancer. 
 
3. HE1:E2,DRS: Olaparib and cediranib does alter DRS-P scores 
compared to olaparib (single agent) in patients with recurrent high-
grade serous or endometrioid ovarian, fallopian tube or peritoneal 
cancer. 
 
A mixed-effects model will be used to estimate and compare the mean 
NFOSI-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 NFOSI-DRS-P score, 
and assessment time.  The primary analyses will include all patients enrolled 
onto the study regardless of their compliance with the study treatment or 
eligibility status, grouped by their randomly assigned study treatment. 
Individuals will need to provide at least one baseline (pre-treatment) and one 
follow-up PRO assessment to be included in the mixed model analyses.   
 
A mixed model will be used to conduct a test of HC:E1,DRS and HC:E2,DRS (across 
assessment times). The primary hypothesis test will focus on the DRS-P 
assessments performed within the first 2 years of each patient’s enrollment.  
In order to limit the overall type I error to 0.05 for the hypotheses HC:E1,DRS 
and HC:E2,DRS, the type I error for each of these hypothesis tests will be 0.025 
(two-tailed). If either of these null hypotheses are rejected then a treatment-
by-assessment time interaction term will be added to the model in order to 
estimate and compare treatment difference at each assessment time.  The 
comparisons (between the particular experimental group and the reference 
group) at the individual assessment-times will also be conducted with 
alpha=0.025 (2 tail) for each time point.  
 
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 NFOSI-DRS are approximately 51.6 and 
10.7, respectively.  The primary analysis of NFOSI-DRS will focus on the 
assessments scheduled during the first 2 years following enrollment onto the 
study. For the purposes of estimating power, it is assumed that there will be a 
5% attrition of patients at each 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, 

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respectively.  The correlation between scores more than 2 assessments apart is 
assumed to be 0.10.  A simulation of 1000 trials indicates that there is 80% 
power to detect a difference in mean scores between treatment groups that 
increases linearly from 0 to 5 units over the first 2 years. If the null hypothesis 
concerning the comparison of the mean NFOSI-DRS scores between E2 and 
C (or E1 and C) is rejected, then temporal trends in the differences between 
treatment groups will be modeled in an exploratory fashion. 
 
Treatment Related Symptoms and Other PRO Scales 
There are no specific hypotheses and therefore no type I error allocation 
scheme for the wide-variety of potential treatment-related symptoms (TRS).  
The analyses of the TRS items contained in the NFOSI-18, the FACT/GOG-
Ntx-4 scale and the EQ-5D primarily involves estimating mean scores, 
proportions or relative odds with confidence intervals for each treatment 
group.  Identifying clinically relevant differences between treatment groups in 
these treatment-related symptom scores will be useful to future patients 
making treatment decisions based on results from this trial. See Appendix X 
for further detail on these analyses. 
 
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 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.  
 
13.13 Translational Studies 
 
13.13.1 
BRCA1 or BRCA2 Mutations (07/31/2017) 
 
It is expected that approximately 30% of the patients enrolled onto the study 
will have either a BRCA1 or BRCA2 mutation; however, these patients are 
expected to have a more favorable prognosis compared to those without these 
mutations.  At the time of the final analysis approximately 384 (70%) of all 
patients enrolled onto the study will have experienced a PFS event.  A 
proportional hazards model will be used to estimate the relative hazard of a 

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PFS event among patients with BRCA1 or BRCA2 mutations relative to those 
with no such mutations.  If a BRCA1 or BRCA2 mutation decreases the risk 
of progression and death 30% (HR=0.70), this sample size provides 81% 
statistical power when the type I error is limited to 0.05 for a two-tail test. 
 
The relative treatment efficacy in the subgroups of patients with or without 
germline BRCA1/2 mutation will be assessed by estimating the treatment 
hazard ratios and their corresponding confidence intervals within the 
subgroups with and without BRCA1/2 mutations.  The treatment hazard ratios 
will be estimated from a multivariable proportional hazards model. At the 
time of the final analysis, there will be at least 265 PFS events for estimating 
the C vs E2 treatment hazard ratio and about the same number of PFS events 
for estimating the C vs E1 hazard ratio.  Assuming that at least 20% of the 
PFS events have BRCA1/2 mutations then there will be about 53 events 
among those patients with mutations for estimating each of the treatment 
hazard ratios (D1=0.20*265=53). Assuming that there are nearly an equal 
number of events in each treatment group, then the variances of the log 
treatment hazard ratios in the subgroup with BRCA1/2 mutations are 
approximately 0.0755 (4/D1=4/53).  Likewise, among those with no mutations 
the expected number of PFS events is 212 (0.80*265) and the variances of the 
log treatment hazard ratios are approximately 0.0189 (4/D2=4/212) . 
 
13.13.2 BROCA-HR 
 
Cancer cells may need to be not only deficient in HR but also proficient in the 
alternative (error-prone) non-homologous end joining (NHEJ) DNA repair 
pathway to be sensitive to a PARP inhibitor (PARPi).  The BROCA-HR assay 
identifies mutations in genes that are involved in homologous repair (HR) or 
non-homologous end joining (NHEJ) as well as the presence of several 
clinically relevant SNPs.  While the BROCA-HR 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 multivariable proportional 
hazards model (Cox, 1972) will be used to estimate the treatment hazard ratios 
(and standard deviations) for each of the experimental treatments relative to 
the reference treatment (chemotherapy) group.  All of the patients with 
BROCA-HR assessments will be included in the analysis.  The model will 
include indicator variable(s) for the randomly assigned treatment, and 
BROCA-HR status, as well as term(s) for the interaction(s) between these 
factors.  The estimated hazard ratio(s) and their corresponding confidence 
intervals will be depicted with a forest plot, and assessed for qualitative 
interaction(s) (Gail and Simon, 1985).  It is anticipated that 35% 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 deficiencies and so only about 25% (D1=0.25*265=66) of the PFS 
events at the time of the final analysis are expected to have BROCA-HR 

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deficiencies.  Therefore, the variances of the log treatment hazard ratios (C:E1 
and C:E2) will be approximately 0.0606 (4/D1 = 4/66).  Among those without 
BROCA-HR deficiencies the variances are expected to be about 0.0202 
(4/(0.75*265)). 
 
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.   
 
13.13.3 
CEC 
 
An increase in the level of circulating endothelial cells (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 the 
treatment (i.e. 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 
deviation 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 prior to treatment and 3 days after initiating treatment for each of 
the treatment groups using 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, 1988) will be used to assess whether the 3-day 
CEC levels are independent of treatment.   All of the patients will be included 
in this analysis, 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 valid measurements are available from 90% of the individuals in 
each treatment group (0.90*183=164), there is approximately 85% power to 
detect an effect size (difference in group means/standard deviation) of 0.30.   
If the global null hypothesis of no differences among treatment groups can be 
rejected with type I error set to 0.05, then pairwise comparisons between the 

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treatment groups will be performed.  Sensitivity analyses will be performed to 
determine whether statistical significance is influenced by extreme outliers. 
 
A proportional hazards model will be used to assess a linear association 
between the change in CEC values and the log relative hazard of first 
progression or death (PFS). 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 approximately 70% (0.70*549=384) of the 
patients enrolled onto the study will have experienced a PFS event.  This 
sample size provides 81% statistical power if the true reduction in the hazard 
of progression or death is 15% (HR=0.85) for individuals whose change in 
CEC values are one standard deviation higher (i.e., one standard deviation of 
the change in CEC values).  A plot of the martingale residuals (Therneau, 
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. 
 
13.13.4 
Plasma Angiome 
 
This component of the study will use a panel which has been developed 
through collaborative efforts from Duke University and Aushon BioSystems 
to measure 14 soluble angiogenic factors, 7 matrix derived factors, as well as, 
7 markers of vascular activation and inflammation in patients’ serum or blood.  
The goal is to assess these biomarkers individually for prognostic value and 
then develop a composite score that is based on these biomarkers which is 
prognostic.  For these purposes, the study participants with analyzable 
specimens will be randomly separated into two mutually exclusive groups.  
Approximately half of the individuals will be assigned to a training group and 
the remaining individuals will be assigned to a validation group.  The clinical 
data and the biomarker data from the individuals in the training group will be 
combined and used to assess the prognostic value of each biomarker 
individually and to construct a composite prognostic score.  The prognostic 
value of a single biomarker with regard to PFS will be assessed with a 
proportional hazards model.  Since the expected number of PFS events in the 
entire study at the time of the final analysis is 384, then the expected number 
of PFS events in the training set at this time is 384/2=192. This sample size 
would provide 80% power when the true hazard of first progression or death 
(PFS) decreases 20% (HR=0.80) for individuals whose biomarker values are 
separated by one standard deviation and type I error is limited to 0.05 for a 
two-tail test.  In this case, however, the probability of falsely declaring at least 
one biomarker as prognostic, when none of the biomarkers are associated with 
PFS, is 76%.  (This underscores the need for a validation group.)  Also, a 
putative prognostic score will be developed based on multivariate modeling 
and biologic knowledge about these biomarkers and their potential for 
interactions.   

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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 
appropriate.  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 documenting 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.      
 
 
14.0 
PUBLICATION INFORMATION AND ADMINISTRATIVE 
AGREEMENTS 
 
 
Under discussion with NRG leadership. 
 
15.0 
EVALUATION CRITERIA 
 
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 progression, imaging studies should continue every 9 weeks (+/- 7 
days) until progression.  After 2 years of protocol therapy or follow-up (measured 
from approximately cycle 1, day 1), imaging studies will be conducted every 12 
weeks.   
 
 
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. 

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15.1 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the 
time of their first treatment with reference or investigational therapy. 
 
Evaluable for RECIST response.  Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for response.  
These patients will have their response classified according to the definitions 
stated below.  (Note:  Patients who exhibit objective disease progression prior 
to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present 
at baseline that are evaluable but do not meet the definitions of measurable 
disease, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for non-target disease.  The 
response assessment is based on the presence, absence, or unequivocal 
progression of the lesions. 
 
15.2 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm by chest x-ray or as >10 mm with CT scan, MRI, or 
calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area may be 
considered measurable if there has been interval progression since the time of 
radiation. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including 
small lesions (longest diameter <10 mm or pathological lymph nodes with 
≥10 to <15 mm short axis), are considered non-measurable disease.  Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal 
masses (not followed by CT or MRI), are considered as non-measurable. 
 

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Note:  Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described 
above. However, if non-cystic lesions are present in the same patient, these 
are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions 
per organ and 5 lesions in total, representative of all involved organs, 
should be identified as target lesions and recorded and measured at 
baseline.  Target lesions should be selected on the 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.  
 
15.3 
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. 
 

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Clinical lesions  Clinical lesions will only be considered measurable when 
they are superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 
mm diameter as assessed using calipers (e.g., skin nodules).  In the case of 
skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, CT is 
preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm 
or less.  If CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement.  Furthermore, the 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.  New lesions should 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 

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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]. 
 
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. 

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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. 
 
15.4 
Response Criteria 
 
15.4.1 
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.  CA-125 must normalize for a 
patient to be considered in complete clinical response. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the baseline sum 
diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest on study).  
In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also considered 
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. 
 
15.4.2 
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. 
 

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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 Principal Investigator). 
 
15.4.3 
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 randomization).  The patient's best response assignment will 
depend on the measurement criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
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. 
**      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 

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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 
 
15.4.4 
Duration of Response 
 
Duration of overall response:  The duration of overall response is 
measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease 
is objectively documented. 
 
 
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.  
 
15.4.5 
Evaluation of Biomarkers 
 
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. 
 
15.4.6 
Progression-Free Survival 
 
PFS is defined as the duration of time from the date of randomization 
progression or death, whichever occurs first. 
 
15.4.7 Time to First Subsequent Therapy (TFST) and time to Second 
subsequent therapy (TSST) 
 
Time to first subsequent therapy is defined as the duration of time 
from randomization to initiation of a non-protocol, anti-cancer 
treatment (including cytotoxic, surgical, or radiotherapy) or death. 
Time to second subsequent therapy is defined as the duration of time 
from randomization to initiation of the second-line non-protocol, anti-

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cancer treatment (including cytotoxic, surgical, or radiotherapy) or 
death.     
 
 
16.0 
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APPENDIX I 
 
PERFORMANCE SCALE  
 
GRADE  
KARNOFSKY SCALE  
PERFORMANCE  
 
0   
90 & 100  
 
 
 
FULLY ACTIVE  
 
 
1   
70 & 80  
 
 
 
RESTRICTED IN PHYSICALLY  
STRENUOUS ACTIVITIES,  
BUT AMBULATORY.  
 
 
2   
50 & 60  
 
 
 
AMBULATORY; CAPABLE OF  
 
 
 
 
 
 
 
SELF CARE; UNABLE TO WORK;  
UP 50% OF WAKING HOURS.  
 
 
3  
 30 & 40  
 
 
 
LIMITED SELF CARE;  
CONFINED TO BED OR 
CHAIR 50% OF WAKING 
HOURS.  
 
 
4   
10 & 20  
 
 
 
COMPLETELY DISABLED;  
NO SELF-CARE  
 
 
 
 
 
 
 
 
 
 
 
 
 
5/30/76  

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APPENDIX II – PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD (11/07/2016) 
 
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. 
 
• 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.   
• 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. 

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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: 
 
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. 
 
• 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.  
• Avoid ingesting grapefruit, grapefruit juice and Seville oranges while taking olaparib. 
• You may need to be monitored more frequently if you are taking any drugs that have 
narrow therapeutic ranges. 
• 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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: 
 Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, pharmacists) that you are taking part in a clinical 
trial. 
 Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 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.    
 
 
 
 Olaparib must be used very carefully with other medicines that 
interact with these enzymes and proteins.  
 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. 
 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.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

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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. 
 
• 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.   
• Cediranib (AZD2171) may induce gastrointestinal CYP3A and UGT enzymes, 
therefore potentially reducing the effectiveness of hormonal contraceptives 
• 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. 
• 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. 
• 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 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. 
 

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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.” Cediranib (AZD2171) 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. 
 
• 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.  
• 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.  
• 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: 
 Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistant, 
nurse practitioners, pharmacists) that you are taking part in a clinical 
trial. 
 Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 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.  
 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.. 
 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.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

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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) 
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 III – Oral Antihypertensive Medications (11/07/2016) 
 
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 
Interme
diate 
dose 
Maxim
um 
dose 
Hepatic 
metabolis
m 
Angioten
sin 
Converti
ng 
Enzyme 
Inhibitor
s 
(ACEIs) 
 
captopri
l 
12.5 mg 
3x daily 
25 mg 3x 
daily 
50 mg 
3x daily 
CYP 2D6 
substrate 
enalapri
l 
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) 
lisinopr
il 
5 mg 
daily 
10-20 
mg daily 
40 mg 
daily 
No 
fosinopr
il 
10 mg 
daily 
20 mg 
daily 
40 mg 
daily 
Yes, but 
not 
CYP450 
Rarely 
used: 
perindo
pril 
 
4 mg 
daily 
 
none 
 
8 mg 
daily 
 
Yes, but 
not 
CYP450 
Rarely 
used: 
quinap
ril 
10 mg 
daily 
20 mg 
daily 
40 mg 
daily 
No 
Angioten
sin II 
Receptor 
Blockers 
(ARBs) 
losartan 
25 mg 
daily 
50 mg 
daily 
100 mg 
daily 
CYP 3A4 
and 2C9 
substrate 
candesa
rtan 
4 mg 
daily 
8-16 mg 
daily 
32 mg 
daily 
CYP 2C9 
substrate 

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irbesart
an 
75 mg 
daily 
150 mg 
daily 
300 mg 
daily 
CYP 2C9 
substrate 
telmisa
rtan 
40 mg 
daily 
none 
80 mg 
daily 
Yes, but 
not 
CYP450 
valsart
an 
80 mg 
daily 
none 
160 mg 
daily 
Yes, but 
not 
CYP450 
Selective 
β 
Blockers 
(BB) 
metopro
lol 
25 mg 
twice 
daily 
50 mg 
twice 
daily 
100 mg 
twice 
daily 
CYP 2D6 
substrate 
atenolol 
25 mg 
daily 
50 mg 
daily 
100 mg 
daily 
No 
acebutol
ol 
100 mg 
twice 
daily 
200-300 
mg twice 
daily 
400 mg 
twice 
daily 
Yes 
(CYP450 
unknown) 
bisoprol
ol 
2.5 mg 
daily 
5-10 mg 
daily 
20 mg 
daily 
CYP 3A4 
substrate 
α and β 
Blocker 
labetalo
l 
100 mg 
twice 
daily 
200 mg 
twice 
daily 
400 mg 
twice 
daily 
Yes, but 
not 
CYP450 
Diuretics 
Hydrala
zine 
10 mg 
four 
times 
daily 
25 mg 
four 
times 
daily 
50 mg 
four 
times 
daily 
no 
Hydroc
hlorothi
azide 
12.5 mg 
AM 
daily 
25 mg 
AM daily 
50 mg 
AM 
daily 
no 
Furose
mide  
20 mg 
daily 
20 mg 
twice 
daily 
40 mg 
twice 
daily 
no 
Nitrates 
Isosorbi
de 
dinitrate 
ER 
40 mg 
daily 
40 mg 
twice 
daily 
80 mg 
twice 
daily 
CYP 3A4 
substrate 

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Isosorbi
de 
mononit
rate ER 
30 mg 
AM 
daily 
60 mg 
AM daily 
90 mg 
AM 
daily 
CYP 3A4 
substrate 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP 
CCB) 
nifedipi
ne XL 
30 mg 
daily 
60 mg 
daily 
90 mg 
daily 
CYP 3A4 
substrate 
amlodip
ine 
2.5 mg 
daily 
5 mg 
daily 
10 mg 
daily 
CYP 3A4 
substrate 
felodipi
ne 
2.5 mg 
daily 
5 mg 
daily 
10 mg 
daily 
CYP 3A4 
substrate  

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APPENDIX IV – CARBOPLATIN DOSE CALCULATION INSTRUCTIONS 
 
1) The Cockcroft-Gault formula will be used in GOG trials. 
2) Conversion of IDMS creatinine levels to “non-IDMS” values will not be permitted.  
3) The carboplatin calculation tool is available on the GOG website (Web Menu, Tools). 
 
Dosing of Carboplatin: 
 
1) The carboplatin dose will be calculated to reach a target area under the curve (AUC) 
according to the Calvert formula using an estimated glomerular filtration rate (GFR) from 
the Cockcroft-Gault formula. 
 
2) The initial dose of carboplatin must be calculated using GFR. In the absence of renal 
toxicity greater than or equal to CTCAE Grade 2 (serum creatinine >1.5 x ULN) or 
toxicity requiring dose modification, the dose of carboplatin will not need to be 
recalculated for subsequent cycles, but will be subject to dose modification for toxicity as 
noted in the protocol. 
 
3) Carboplatin 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. 
 
4) At the time of dose modification, if the patient’s age had changed (the patient has had a 
birthday), the site can use the current age. 
 
5) In patients with an abnormally low serum creatinine (less than 0.7 mg/dl), the creatinine 
clearance should be estimated using a minimum value of 0.7 mg/dl.  For trials where 
patients enter and are treated within less than or equal to 12 weeks of surgery:  If a more 
appropriate (higher) baseline creatinine value is available from the pre-operative period 
(within 4 weeks of surgery date), that value may also be used for the initial estimation of 
GFR. 
 
CALVERT FORMULA: 
 
Carboplatin dose (mg) = target AUC x (GFR + 25) 
 
NOTE:  the GFR used in the Calvert formula should not exceed 125 ml/min. 
 
Maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min. 
 
The maximum allowed doses of carboplatin are: 
 
AUC 6 = 900 mg 
 
AUC 5 = 750 mg 
 

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AUC 4 = 600 mg 
 
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated 
creatinine clearance. The estimated creatinine clearance (ml/min) is calculated by the method 
of Cockcroft-Gault using the following formula: 
 
Creatinine Clearance (mL/min) =    [140-Age (years)] x Weight (kg) x 0.85  
                                                             
72 x serum creatinine (mg/dl)  
 
Notes: 
1) Weight in kilograms (kg): 
a.  Body Mass Index (BMI) should be calculated for each patient.  A BMI calculator is 
available at the following link:  http://www.nhlbisupport.com/bmi/  
b. Actual weight should be used for estimation of GFR for patients with BMI of less than 
25. 
c. Adjusted weight should be used for estimation of GFR for patients with BMI of 
greater than or equal to 25. 
d. Adjusted weight calculation: 
Ideal weight (kg) = (((Height (cm)/2.54) – 60) x 2.3) + 45.5 
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal weight 
 
2) The Cockcroft-Gault formula above is specifically for women (it includes the 0.85 factor). 
 
At the time of a dose modification for toxicity:  If the creatinine at the time of a dose 
modification is lower than the creatinine used to calculate the previous dose, use the previous 
(higher) creatinine; if the creatinine at the time of a dose modification is higher than the 
creatinine used to calculate the previous dose, use the current (higher) creatinine.  This will 
ensure that the patient is actually receiving a dose reduction. 
 
 
 

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APPENDIX V – TRANSLATIONAL SCIENCE SPECIMEN PROCEDURES 
(07/31/2017) 
 
I. Obtaining a Bank ID for Translational Science Specimens (11/07/2016) 
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 (11/07/2016) 
     Shipped to the Preclinical Development Research Core 
A. Requesting CEC Whole Blood Specimen Kits  
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), but the collection tubes are shipped to sites in the Research Plasma kits. Sites 
must provide their own shipping kits and cover shipping costs. Do not ship CEC whole 
blood specimens to the PDRC using any of the specimen kits provided by the NRG BB-
Columbus. 
 
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. 
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 

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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  
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 (11/07/2016) 
       Shipped to the NRG Oncology Biospecimen Bank-Columbus (NRG BB-Columbus) 
A. Requesting Translational Science Specimen Kits  
Specimen kits are no longer provided for the collection and shipment of BROCA-HR whole 
blood and FFPE specimens shipped to the NRG BB-Columbus. Please note the updated 
specimen collection procedures below. 
 
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 
kit should not be ordered until the time of disease progression or end of treatment. 
 

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The Arm II PK or Arm III PK kit should be ordered after randomization, as contents are 
dependent on the arm to which the patient is randomized. The Arm II and Arm III PK kits 
should be used to ship the Future Use Whole Blood (WB04), in addition to the PK plasma 
specimens. 
 
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. 
 
Sites can order kits online via the Kit Management link 
(https://ricapps.nationwidechildrens.org/KitManagement/). 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. 
 
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 
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 (specimen codes ending in “01”; section 
11.2.1.2) and a block will be submitted on a permanent basis to fulfill both the mandatory 
(specimen codes ending in “02”; section 11.2.1.1) and optional (specimen codes ending in 
“01”; section 11.2.1.2) specimen requirements, then label the block with the specimen code 
ending in “01.” Complete and ship both the “01” and “02” 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). Only one block may be submitted per tissue type. 
• Primary and metastatic tumor should be collected prior to all treatment. 
• Primary neoadjuvant treatment and metastatic neoadjuvant treatment tumor 
(collected after the patient received neoadjuvant treatment) should only be submitted if 
tumor collected prior to all treatment is not available.  
• 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 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. 
 
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. 

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If patient consents to the optional FFPE collection (specimen codes ending in “01”; section 
11.2.1.2) and a block will be submitted on a permanent basis to fulfill both the mandatory 
(specimen codes ending in “02”; section 11.2.1.1) and optional (specimen codes ending in 
“01”; section 11.2.1.2) specimen requirements, then label the block with the specimen code 
ending in “01.” Complete and ship both the “01” and “02” specimen transmittal forms (i.e., 
Form TR) with the block. Complete the “01” Form TR as “collected” and include all 
requested specimen information. Complete the “02” Form TR as “not collected” and specify 
“submitted for another study.” 
 
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. 
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. Olaparib PK Plasma 
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. 
1.  Label one cryovial as described below. Use a 2mL cryovial as plasma will be shipped to 
the NRG Oncology Biospecimen Bank-Columbus. 
2.  Draw 2mL of blood into 2mL green top (lithium heparin) tube. Be sure to fill the 
blood collection tube completely. 
3.  Immediately after collection, gently invert the blood collection tube 8-10 times to mix the 
blood and heparin. 
4.  Centrifuge the blood at 1500-2000g for 15 minutes to separate the plasma (top, straw-
colored layer) from the red blood cells (bottom, red layer).  
5.  Quickly, transfer the plasma into the pre-labeled cryovial and cap the tubes securely. 
Place all plasma into the one cryovial.  
6.  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. 
 
Completing Form TR for Olaparib PK Plasma 
Green top (litium heparin) tubes must be used for the collection of blood used to process 
olaparib PK plasma biopsecimens. When completing Form TR, select “Other” for tube type 
and specify “lithium heparin.” 
 
G. Cediranib PK Plasma 

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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. 
1.  Label one cryovial as described below. Use a 2mL cryovial as plasma will be shipped to 
the NRG Oncology Biospecimen Bank-Columbus. 
2.  Draw 2mL of blood into 2mL purple top (K2EDTA) tube. Be sure to fill the blood 
collection tube completely. 
3.  Immediately after collection, gently invert the blood collection tube 8-10 times to mix the 
blood and EDTA. 
4.  Centrifuge the blood at 1500-2000g for 15 minutes to separate the plasma (top, straw-
colored layer) from the red blood cells (bottom, red layer).  
5.  Quickly, transfer the plasma into the pre-labeled cryovial and cap the tubes securely. 
Place all plasma into the one cryovial.  
6.  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. 
 
H. 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. 
 
*If the Pre-Treatment Research Plasma (PB09) biospecimen is not collected, the subsequent 
Research Plasma (PB10 and PB11) biospecimens should not be collected. 
 
I. Shipping Translational Science Specimens 
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. 

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All translational science specimens should be shipped to: 
 
NRG BB-Columbus / Protocol NRG GY004 
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 
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. 

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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://ricapps.nationwidechildrens.org/KitManagement/). 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). 
  
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 system 
(https://ricapps.nationwidechildrens.org/KitManagement/). 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 

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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; Phone: 716-
845-7767). 
 
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 
(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 VI – TRANSLATIONAL SCIENCE LABORATORY TESTING 
PROCEDURES 
 
I. BROCA-HR 
A. Overview 
The Swisher laboratory has previously published methodology and validation experiments for 
targeted capture and massively parallel sequencing of cancer genes (1-5). In brief, DNA will be 
extracted from peripheral blood mononuclear cells (PBMCs) and formalin-fixed, paraffin-
embedded (FFPE) tumor containing at least 30% tumor nuclei. A targeted capture and massively 
parallel sequencing approach called BROCA will be applied to samples. 
 
For the proposed study, a more recent version of BROCA 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 sensitivity in tumor samples, in this case 
Swisher laboratory always verify the mutation with Sanger sequencing and they usually do, the 
total number of samples: 2000. Swisher laboratory has shown >99% of concordance for within-
run repeats and >99% of concordance for between-run repeats. With regard to limit of detection 
((lowest amount of analyte that gives an informative result), Swisher laboratory has 
demonstrated that the lowest 5% of mutant or variant allele could be reliably detected in a wild 
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 and 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 

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gating on Hoechst 33342-positive cells. These findings will be correlated with clinical results. 
 
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 (4-6). 
 
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., in press, Frontiers in 
Oncology, 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).  (1). 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 significant difference 
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; ref 2). 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 (2, 4). 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.  8 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 

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PBMC collection. Label each tube. 
3. After centrifugation, PBMCs will be a cloudy layer just below the plasma layer. Collect 1mL 
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. 

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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. 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: 
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. 

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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. 
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). 

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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. 
 
IV. Olaparib and Cederanib PK 
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 anonymized by pooling. 
Additional analyses may be conducted on the anonymized, 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. Anonymized samples will be retained for no 
more than 5 years after the Clinical Study Report is finalized. 
 
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. 
 
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.  

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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 
ease-of-use. In addition, it allows the interrogation of multiple consecutive CpG sites. 
 
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%. 
 

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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 
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 was performed. The 
stains were then 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 was used to develop categorical criteria for scoring cases as BRCA1 loss, BRCA1 
retained, or BRCA1 equivocal. Two independent and blinded pathologists then validated these 

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criteria.  In our published work (ref 3) we demonstrate 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. 
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 VII:  PATIENT DRUG DIARY: OLAPARIB ONLY (11/07/2016) 
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/Data Manager’s Signature _________________________  Date______________ 

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APPENDIX VIII: PATIENT DRUG DIARY CEDIRANIB AND OLAPARIB (11/07/2016) 
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. 
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 
 
 
 
 
 
Patient’s Signature: ___________________________________                    Date: _____________ 
Physician/Nurse/Data Manager’s Signature _________________________  Date______________ 

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APPENDIX IX:  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. 
• Each morning while you are resting (not while you are active: dressing, making breakfast, etc.) 
• 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/Data Manager’s Signature __________________________ Date _______________ 

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Appendix X: 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 broad hypotheses for these comparisons 
are that patient side effect severity, both for the sum score and the single item global score, 

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will 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), and 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 differences in mean scores, proportions or log odds for each 
treatment group 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.   
 
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 

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

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

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Appendix XII:  Protocol Monitoring Plan (11/07/2016) 
 
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 of the 
centralized monitoring.  The source records for the eligibility 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 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, T4, 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 time-
points:  (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).  
 
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 

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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 discharge for hospitalizations.  
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 each and every enrolled patient from just prior to initiating study treatment up until 
progression or death, whichever occurs first, will be prospectively collected and stored 
electronically.  All collected images will be appropriate de-identified.  If it is deemed 
appropriate, then these images will be available for trained independent radiologists to 
review in a standardized fashion.  Also, in the event that 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. 
 
5) Submission of Documentation 
Regulatory documents, including 1572 Forms, and Financial Disclosure Forms, as well as 
instructions for submitting these forms, are available from 

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http://ctep.cancer.gov/investigatorResources/investigator_registration.htm.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
pmbregpend@ctep.nci.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 XIII:  NRG General Guidelines (11/07/2016) 
 
• 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). 
 
• 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). 
 
• 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.” 
 
• For weekly regimens, it will be acceptable for individual chemotherapy doses to be 
delivered within a “24-hour window,” for example; “Day 8 chemotherapy” can be 
delivered on Day 7, Day 8, or Day 9 and “Day 15 chemotherapy” can be given on Day 
14, Day 15, or Day 16. 
 
• Chemotherapy doses can be “rounded” according to institutional standards without being 
considered a protocol violation (most institutions use a rule of approximately +/- 5% of 
the calculated dose) 
 
• Chemotherapy doses are required to be recalculated if the patient has a weight change of 
greater than or equal to 10%.  Patients are permitted to have chemotherapy doses 
recalculated for <10% weight changes. 
 

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APPENDIX XIV:  DIAGNOSTIC IMAGE COLLECTION SUMMARY (11/07/2016) 
 
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 XV: Japan (11/07/2016) (07/31/2017) 
 
Background and Purpose 
 
The primary endpoint of NRG-GY004 trial is to evaluate the efficacy and safety of a regimen that 
combines cediranib and olaparib in women with platinum sensitive recurrent ovarian cancer.  Although, 
phase I studies of single agent olaparib1 or cediranib2 in the Japanese population showed similar toxicity 
profiles and the same MTDs as the Caucasian population, the safety information of the combination of 
olaparib and cediranib in Japanese women is lacking.  Safety evaluation of cediranib in the Japanese 
patients was tested in combination with mFOLFOX63 or S-14. Recommended dose of cediranib was 20-
30 mg with mFOLFOX6 and 20 mg with S-1.  
 
Cediranib is a small molecule tyrosine kinase inhibitor.  In a clinical trial using pazopanib, a multiple 
kinase inhibitor for c-KIT, FGFR, PDGFR, and VEGFR, as maintenance therapy after first line 
chemotherapy for ovarian cancer, significant prolongation of PFS was observed.  However, adverse 
events and dose reductions occurred significantly more frequently in an East Asian population and an 
improvement in the prognosis was not observed5. 
 
This has raised a concern that a similar ethnic difference may occur in the GY004 trial.  Therefore, 
GY004 will include a small Japanese run-in cohort to assess the toxicity profile and the frequency of 
unexpected toxicities in the Japanese population when the olaparib and cediranib combination is 
administered. 
 
Methods 
 
Eligibility 
Eligibility and ineligibility of the enrollment in this cohort is exactly the same as main protocol, section 
3.1 and 3.2. 
 
Protocol Therapy  
The treatment will be the same as Arm III of the main protocol, which is the combination of olaparib and 
cediranib. 
 
Olaparib 200mg in tablet formulation orally twice daily continuous dosing 
Cediranib 30mg in tablet formulation orally once daily. 
 
One cycle will be considered 28 days.   
Patients will remain on treatment until disease progression.   
Patients will be required to maintain medication and blood pressure diaries (found in Appendix VIII and 
IX).   
A blood pressure cuff will be provided to patients randomized to Arm III. 
 
 
Evaluation of Toxicity 
 
Toxicities will be evaluated based on CTCAE during the 1st Cycle of the protocol therapy. 
 
For the purposes of this sub-study a dose-limiting toxicity (DLT) will be any of the following adverse 
events occurring any time between the initiation of the first cycle of treatment and initiation of the second 
cycle of treatment   
 

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 
Non-Hematologic Toxicity 
 
Unanticipated Serious Adverse Events (SAEs) 
 
Hypertension or diarrhea SAEs that occur in the setting of optimal maximal medical management, 
as detailed in Section 6.2.2.1 and 6.2.2.2 of the main protocol 
 
Hematologic Toxicity 
 
Grade 4 neutropenia of >4 days duration 
 
Grade 4 neutropenia of any duration with fever or documented infection 
 
All other hematologic toxicities of Grade 4 
 
Inability to take 75% or more of the planned dose in Cycle 1 due to treatment-related AEs 
 
Management and dose modifications associated with the above adverse events are outlined in Section 6 of 
the main protocol. 
 
 
Accrual During the Run-in Phase 
A maximum of 12 patients who initiate the first cycle of treatment will be enrolled in this run-in cohort.    
At the time when first 6 patients enrolled, further enrollment will be interrupted, and the toxicities will be 
evaluated.   
If 3 or more patients experience a DLT, then the regimen will be considered poorly tolerated by Japanese 
patients and accrual from Japan will be stopped.   
Otherwise, an additional 6 Japanese patients will be enrolled and treated.   
If more than 4 patients experience a DLT among these 12 patients, then the regimen will be considered 
poorly tolerated by Japanese patients and no patients from Japan will be enrolled onto the randomized 
phase 3 study.   
 
Statistical Considerations 
Using the criteria mentioned above, if the true probability of a DLT is 0.20, then there is a 77% chance of 
declaring the regimen tolerable.  However, if the true probability of a DLT is 0.40, then there is a 79% 
chance of declaring the regimen poorly tolerated and a 45% chance of coming to this conclusion after 
only the first stage of accrual. 
 
Laboratory evaluation 
Bicarbonate is not required for patients enrolled in Japan for the serum chemistry assessments as outlined 
in Tables 4.1 and 4.2. 
 
Germline BRCA mutation test 
Germline BRCA mutation test is not required for run-in cohort patients. 
 
Collection of Biospecimens 
Collection of Biospecimen is not required except for PK sampling.  
PK sampling should be done according to the section 11.2.1.1 Integrated Biomarker Specimen 
Requirements of main protocol. 
 
 
 
 
References 
 
 
1. 
Yamamoto N, Nokihara H, Yamada Y, et al. A Phase I, dose-finding and pharmacokinetic study of 
olaparib (AZD2281) in Japanese patients with advanced solid tumors. Cancer science 2012;103:504-9. 

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2. 
Yamamoto N, Tamura T, Yamamoto N, et al. Phase I, dose escalation and pharmacokinetic study 
of cediranib (RECENTIN), a highly potent and selective VEGFR signaling inhibitor, in Japanese patients 
with advanced solid tumors. Cancer Chemother Pharmacol 2009;64:1165-72. 
3. 
Satoh T, Yamada Y, Muro K, et al. Phase I study of cediranib in combination with cisplatin plus 
fluoropyrimidine (S-1 or capecitabine) in Japanese patients with previously untreated advanced gastric 
cancer. Cancer Chemother Pharmacol 2012;69:439-46. 
4. 
Satoh T, Yamaguchi K, Boku N, et al. Phase I results from a two-part Phase I/II study of cediranib 
in combination with mFOLFOX6 in Japanese patients with metastatic colorectal cancer. Invest New Drugs 
2012;30:1511-8. 
5. 
du Bois A, Floquet A, Kim JW, et al. Incorporation of pazopanib in maintenance therapy of ovarian 
cancer. J Clin Oncol 2014;32:3374-82.