A Phase 2 Study of Olaparib and Cediranib for the Treatment of Recurrent Ovarian Cancer
Phase: PHASE2
Conditions: Fallopian Tube Carcinoma, Fallopian Tube Endometrioid Adenocarcinoma, Fallopian Tube Serous Adenocarcinoma, Ovarian Carcinoma, Ovarian High Grade Endometrioid Adenocarcinoma, Ovarian High Grade Serous Adenocarcinoma, Primary Peritoneal Carcinoma, Primary Peritoneal Endometrioid Adenocarcinoma, Primary Peritoneal Serous Adenocarcinoma
Sponsor: National Cancer Institute (NCI)

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NCI Protocol #:  9825 
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Protocol Version Date:  May 24, 2019 
Protocol Title: A Phase 2 Study of olaparib and cediranib for the treatment of recurrent ovarian 
cancer 
 
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7.1.1.1 
Revision of the Protocol CAEPR: 
  
Protocol Section(s) for Insertion of Revised CAEPR (Version 2.4, April 24, 2019): 7.1.1.1  
Page Number(s): 70-72 
 
• 
Increase in Risk Attribution: 
• 
Changed to Less Likely from Also Reported on Olaparib Trials But With 
Insufficient Evidence for Attribution: Platelet count decreased; White 
blood cell decreased 
 
• 
Provided Further Clarification: 
• 
A new note has been added to the CAEPR; “NOTE: New Primary 
Malignancies other than MDS/AML New primary malignancies have 
been reported in <1% of patients. There were other contributing 
factors/potential alternative explanations for the development of the new 
primary malignancy in all cases, including documented BRCA mutation, 
treatment with radiotherapy and extensive previous chemotherapy 
including carboplatin, taxanes, anthracyclines and other alkylating and 
DNA damaging agents. Most are not attributed to olaparib.” 
4. 
ICF 
Protocol version date in header changed from 12/31/2018 to 5/24/2018.  
5. 
ICF 
 Revision of the ICD as Specified Below: 
 
• 
Increase in Risk Attribution: 
• 
Changed to Occasional from Also Reported on Olaparib Trials But With 
Insufficient Evidence for Attribution: Bruising, bleeding 
 
• 
Provided Further Clarification: 
• 
Infection (under Occasional) is now reported as Infection, especially 
when white blood cell count is low (under Occasional).  

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NCI Protocol #: 9825 
 
DF/HCC Protocol #: 16-700 
 
TITLE:  A Phase 2 Study of olaparib and cediranib for the treatment of recurrent ovarian cancer  
 
Corresponding Organization LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
 
 
 
 
 
 
 
 
 
 
Principal Investigator (PI): 
Joyce Liu, M.D.  
 
Dana-Farber Cancer Institute 
 
450 Brookline Ave.  
 
phone: 617 632-5269 
 
fax: 617 632-3479 
 
joyce_liu@dfci.harvard.edu 
 
 
 
 
Participating Organizations: 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
Co-Investigators: 
 
Investigator #1 
Name: Bill Killam 
Address: User-Centered Design, Inc. 
20458 Deerwatch Place 
Ashburn, VA 20147 
Telephone: 703-729-0998 
E-mail address: bkillam@user-centereddesign.com 
Investigator #2 
Name: Holly Massett, PhD 

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Senior Behavioral Science Analyst 
Address: Clinical Trials Operation and Informatics Branch 
Cancer Therapy Evaluation Program 
National Cancer Institute 
9609 Medical Center Drive, 5W562 
Bethesda, MD 20892 
Telephone: 240-276-6628 
Email address: massetth@mail.nih.gov 
Investigator #3 
Name: Ursula Matulonis, MD 
Address: Dana-Farber Cancer Institute 
450 Brookline Ave.  
Telephone: 617-632-2334 
E-mail address: Ursula Matulonis@dfci.harvard.edu 
 
Statistician: 
 
Research Project Manager:  
William Barry, PhD 
 
Jennifer Curtis, MS 
Dana-Farber Cancer Institute 
Dana-Farber Cancer Institute 
450 Brookline Ave. 
450 Brookline Ave. 
Boston MA 02215 
Boston MA 02215 
phone: 617-632-5134 
phone:  617-582-7183 
fax:  617 632-2444 
fax:  617-394-2662 
bbarry@jimmy.harvard.edu 
Jennifer_curtis@dfci.harvard.edu  
                                                                               
 
Responsible Research Nurse: 
  
Christin Whalen, RN 
 
Dana-Farber Cancer Institute  
 
450 Brookline Ave. 
 
Boston MA 02215 
 
phone: 617 582-7738 
 
fax:  617 582-7921 
 
 
christin_whalen@dfci.harvard.edu 
 
 
NCI-Supplied Agents: 
Cediranib (NSC 732208; 
 
 supplied by CTEP 
Olaparib  (NSC 747856;
 supplied by CTEP  
 
Study Sponsor: CTEP 
 
Version # / Version Date:  May 24, 2019 

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Protocol Version Date: May 24, 2019 
 
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TABLE OF CONTENTS 
SCHEMA ............................................................................................................................... 3 
1. OBJECTIVES ..................................................................................................................... 7 
1.1 Study Design................................................................................................................ 7 
1.2 Primary Objectives ....................................................................................................... 7 
1.3 Secondary Objectives ................................................................................................... 7 
1.4 Exploratory Objectives ................................................................................................. 8 
2. BACKGROUND ................................................................................................................ 8 
2.1 Study Disease(s):  Ovarian cancer ................................................................................. 8 
2.2 IND Agent(s) ............................................................................................................... 8 
2.3 Correlative Studies Background .................................................................................. 27 
2.4 eCediranib-Olaparib (eCO) Application ...................................................................... 31 
3. PARTICIPANT SELECTION ........................................................................................... 43 
3.1 Eligibility Criteria ...................................................................................................... 43 
3.2 Exclusion Criteria ...................................................................................................... 45 
3.3 Inclusion of Women and Minorities ............................................................................ 48 
4. REGISTRATION PROCEDURES .................................................................................... 48 
4.1 Investigator and Research Associate Registration with CTEP ...................................... 48 
4.2 Site Registration ......................................................................................................... 49 
4.3 Patient Registration .................................................................................................... 51 
4.4 General Guidelines ..................................................................................................... 53 
5. TREATMENT PLAN ....................................................................................................... 53 
5.1 Treatment Regimen .................................................................................................... 53 
5.2 Pre-treatment Criteria ................................................................................................. 54 
5.3 Agent Administration ................................................................................................. 55 
5.4 General Concomitant Medication and Supportive Care Guidelines............................... 56 
5.5 Criteria for Taking a Participant Off Protocol Therapy................................................. 58 
5.6 Duration of Follow Up ............................................................................................... 58 
5.7 Criteria for Taking a Participant Off Study .................................................................. 59 
6. DOSING DELAYS/DOSE MODIFICATIONS.................................................................. 59 
6.1 Olaparib and Cediranib Dose Modification Tables....................................................... 59 
6.2 General Management of Adverse Events ..................................................................... 59 
6.3 Hypertension.............................................................................................................. 62 
6.4 Diarrhea ..................................................................................................................... 65 
6.5 Proteinuria ................................................................................................................. 65 
6.6 Decrease in LVEF ...................................................................................................... 66 
6.7 Fever and Neutropenia................................................................................................ 67 
6.8 Nausea and Vomiting ................................................................................................. 67 
6.9 Thyroid Toxicities ...................................................................................................... 67 
6.10Reversible Posterior Leukoencephalopathy Syndrome (RPLS)..................................... 68 

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6.11Gastrointestinal Perforation ........................................................................................ 68 
6.12Rotator Cuff Injury..................................................................................................... 68 
6.13Myelodysplastic Syndrome......................................................................................... 69 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS................................. 69 
7.1 Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ........................ 69 
7.2 Adverse Event Characteristics .................................................................................... 76 
7.3 Expedited Adverse Event Reporting............................................................................ 77 
7.4 Routine Adverse Event Reporting ............................................................................... 78 
7.5 Secondary Malignancy ............................................................................................... 79 
7.6 Second Malignancy .................................................................................................... 79 
7.7 Expedited Reporting to Hospital Risk Management ..................................................... 79 
8. PHARMACEUTICAL INFORMATION ........................................................................... 79 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ............................................ 85 
9.1 Specimen Requirements ............................................................................................. 85 
9.2 Integrated Correlative Studies ..................................................................................... 85 
9.3 eCO Mobile Application Study Plan ........................................................................... 97 
10. STUDY CALENDAR ...................................................................................................... 99 
11. MEASUREMENT OF EFFECT ..................................................................................... 101 
11.1Antitumor Effect – Solid Tumors .............................................................................. 101 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS107 
12.1Study Oversight ....................................................................................................... 107 
12.2Data Reporting ......................................................................................................... 107 
12.3Data Safety Monitoring ............................................................................................ 109 
12.4Collaborative Agreements Language......................................................................... 110 
13. STATISTICAL CONSIDERATIONS ............................................................................ 111 
13.1Study Design/Endpoints ........................................................................................... 112 
13.2Sample Size, Accrual Rate and Study Duration ......................................................... 112 
13.3Stratification Factors ................................................................................................ 113 
13.4Interim Monitoring Plan ........................................................................................... 113 
13.5Analysis of Secondary Endpoints .............................................................................. 113 
13.6Analysis of Secondary Objectives ............................................................................. 115 
13.7Analysis of eCO Objectives ...................................................................................... 117 
13.8Reporting and Exclusions ......................................................................................... 118 
14. PUBLICATION PLAN .................................................................................................. 118 
REFERENCES.................................................................................................................... 119 
APPENDIX A: PERFORMANCE STATUS CRITERIA ...................................................... 126 

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APPENDIX B: Patient drug diary......................................................................................... 127 
APPENDIX C: Patient’s blood pressure diary....................................................................... 128 
APPENDIX D: PATIENT DRUG INFORMATION HANDOUT AND WALlET CARD...... 129 
APPENDIX E: New York Heart Association Classifications................................................. 134 
APPENDIX F: GENOMIC DATA SHARING PLAN .......................................................... 135 
APPENDIX G: Oral Antihypertensive Medications .............................................................. 137 
APPENDIX H: eCO Mobile ................................................................................................ 139 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. OBJECTIVES 
 
1.1 
Study Design 
 
The purpose of this study is to test the clinical activity and safety of the 
combination of olaparib and cediranib in both patients with platinum resistant 
as well as platinum sensitive ovarian cancer and to evaluate integrated 
biomarkers as predictors of response to this regimen.  
 
1.2 
Primary Objectives 
 
1. To evaluate the association of BROCA-HR with the clinical activity of 
cediranib/olaparib, as measured by progression-free survival (PFS), in 
women with recurrent platinum-sensitive ovarian cancer. 
2. To assess the clinical activity of cediranib/olaparib, as measured by 
objective response, in women with recurrent platinum-resistant ovarian 
cancer.  
 
1.3 
Secondary Objectives 
 
1. To assess overall survival (OS), objective response, and clinical benefit 
(SD or response ≥ 16 weeks) in women with platinum-sensitive ovarian 
cancer, and PFS, OS, and clinical benefit in women with platinum-
resistant ovarian cancer 
2. To assess the safety of cediranib/olaparib in women with recurrent 
platinum-sensitive and -resistant ovarian cancer 
3. To evaluate the association of circulating endothelial cells at baseline and 
day 3 with the clinical activity of cediranib/olaparib, as measured by PFS, 
in women with platinum-sensitive and –resistant ovarian cancer. 
4. To evaluate changes in BROCA-HR status between archival and pre-
treatment biopsy samples. 
5. To evaluate the associate of BROCA-HR with the clinical activity of 
cediranib/olaparib as measured by PFS, in women with platinum-resistant 
ovarian cancer. 
6. To characterize genomic alteration by whole exome sequencing in women 
with platinum-sensitive and -resistant ovarian cancer. 
7. To identify biomarker signatures that correlate with the clinical activity of 
cediranib/olaparib in women with recurrent platinum-sensitive and -
resistant ovarian cancer, including changes in gene expression or acquired 
mutations in on-treatment tumor biopsies that are associated with clinical 
activity, and changes in gene expression or acquired mutations in post-
progression biopsies that are associated with clinical resistance. 
8. To explore changes in biomarker signatures and candidate angiogenic 
markers from pre-treatment to post-progression in women with platinum-
sensitive and -resistant ovarian cancer. 

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9. To evaluate the population PK of the combination of cediranib and 
olaparib (tablets) in platinum-sensitive and -resistant ovarian cancer. 
 
1.4 
Exploratory Objectives 
 
1. To determine the feasibility of a mobile phone app (eCO) to collect 
patient-generated blood pressure and symptom data based upon study 
protocol recommendations. 
2. Assess patient and health care professional perceived usability and 
satisfaction of the eCO app (for patients) and of a connected web portal 
(for health care providers). 
3. Assess the number of generated alerts to the study team (via the web 
portal and email “high” alerts) based on pre-determined severity levels 
 
2. BACKGROUND 
 
2.1 
Study Disease(s):  Ovarian cancer 
 
Ovarian cancer remains the leading cause of death from gynecologic malignancy in the United  
States.  Ovarian cancer will be diagnosed in 21,980 women in the United States in 2014 (Siegel 
et al 2014); the majority of patients are diagnosed with advanced FIGO stage III or IV cancer and 
will eventually develop cancer recurrence following initial platinum- and taxane-based 
chemotherapy (Bookman et al, 2009 and McGuire et al 1996).  Recurrences are defined by the 
duration of time between receipt of last platinum and evidence of cancer recurrence which is 
called the platinum-free interval (PFI).   Platinum doublets are standard of care for treatment of 
patients with platinum sensitive recurrence (> 6 month PFI) (Pfisterer et al, 2006 and Pujade-
Lauraine et al 2010).   Strategies to improve progression free survival (PFS) for patients with 
platinum sensitive recurrence are to add agents to chemotherapy and/or used as maintenance 
following completion of chemotherapy (Ledermann et al 2012 and Aghajanian et al 2012) as 
well as to devise new targeted agent combinations (Liu et al 2014). Also importantly, the 
realization that ovarian cancer is composed of several different subtypes with different 
molecular profiles, improved understanding of the genomics of these subtypes and eligibility 
restriction to specific histologic subtypes are all being employed in rational clinical trial design 
for ovarian cancer in order to improve patient outcomes (Liu et al 2014).    
 
 
2.2 
IND Agent(s) 
 
2.2.1 Cediranib (AZD2171) 
 
Cediranib (AZD2171, Recentin™; 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-
7-(3-pyrrolidin-1-ylpropoxy) quinazoline maleate; AZD2171 maleate) is a member of an 
emerging class of novel orally (PO) -administered small molecule vascular endothelial 
growth factor (VEGF) receptor tyrosine kinase (TK) inhibitors with anti-angiogenic 
properties (Hennequin et al., 1999; Wedge et al., 2005). 
 

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Mechanism of Action 
VEGF is a key angiogenic factor, and has been implicated in tumor blood vessel 
formation and in disease progression in a range of solid tumor malignancies (Hicklin and 
Ellis, 2005).  Two high-affinity VEGF transmembrane receptors (VEGFRs) with 
associated TK activity have been identified on human vascular endothelium, VEGFR-1 
(also known as fms-like tyrosine kinase 1 or Flt-1) and VEGFR-2 (also known as kinase 
insert domain-containing receptor or KDR) (Ferrara et al., 2003).  VEGFR-1 and 
VEGFR-2 signaling help mediate tumor progression.   Cediranib has been developed as a 
potent inhibitor of VEGFR-1 and VEGFR-2 (Wedge et al., 2005).  Cediranib also has 
activity against VEGFR-3 and c-Kit (Jurgensmeier et al., 2005).  Cediranib is expected, 
with chronic oral dosing, to inhibit VEGF-driven angiogenesis and as a result prevent the 
progression and metastasis of solid tumors, and may have broad-spectrum clinical utility.   
 
Nonclinical Efficacy 
The effect of cediranib was studied in athymic nu/nu mice bearing established 
subcutaneous human tumor xenografts of diverse histologies [SW620 (colon), PC-3 
(prostate), Calu-6 (lung), SKOV-3 (ovarian), and MDA-MB-231 (breast)].  Animals were 
administered cediranib PO at doses from 0.75-6 mg/kg/day (2.25-18 mg/m2/day) in a 
constant volume of 0.1 mL/10 g body weight for 24-28 days.  Cediranib produced a 
statistically significant inhibition of tumor growth in all human tumor types examined 
when dosed at 1.5 mg/kg/day (4.5 mg/m2/day) or higher.   
 
The murine renal cell carcinoma (RENCA) model, which rapidly (generally within 10 
days) metastasizes to the lung and abdominal lymph nodes, has also been used for 
cediranib efficacy studies (Drevs et al., 2004).  In experiments incorporating a vehicle 
control, cediranib (at a dose of 6.3 mg/kg/day PO) reduced primary tumor growth, 
metastasis, and microvessel density more potently than any other previously-studied 
VEGF RTK inhibitor reported in the literature. 
 
Using a transgenic mouse model in which multiple mammary tumors spontaneously 
develop after two pregnancies, investigators studied the temporal effects of cediranib 
administration (Klinowska et al., 2004).  When dosed with cediranib (0.75- 6 mg/kg/day 
PO) at the time early lesions start to develop, the number of tumor foci was not affected, 
but their growth was inhibited.  When tumors were well-established before cediranib was 
given (at doses of 3 and 6 mg/kg/day), dose-dependent growth inhibition occurred as well 
as tumor regression. 
 
Further details of the nonclinical efficacy of cediranib can be found in the Cediranib 
Investigator’s Brochure (2011). 
 
Nonclinical Pharmacology and Toxicology 
Nonclinical pharmacology and toxicology company-sponsored studies have been 
conducted in rats, dogs, and cynomolgus monkeys (Cediranib Investigator’s Brochure, 
2011).  In rats and dogs, oral bioavailability is high, but absorption is relatively slow, 
with Cmax of the agent seen 4-6 hours after PO dosing.  Plasma concentrations and 
exposure are generally linear over the dose ranges studied in rats.  Cediranib is excreted 

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in the feces (>70% of the dose) of rats, dogs, and cynomolgus monkey after both PO and 
intravenous (IV) administration.  Fecal excretion was the predominant route of 
elimination (>70% of the dose) in both rat, dog and cynomolgus monkey after both PO 
and IV administration.  Elimination was rapid in rats and monkeys with over 75% of the 
dose being recovered in the first 48 hours; in dogs, excretion was slightly slower but 
again substantially complete by 7 days.  Over the dose ranges examined in the rat, plasma 
concentrations and exposure generally increased in proportion to dose; however, in 
monkeys, plasma cediranib concentration-time profiles obtained following a single PO 
dose indicated that systemic exposure increased in a greater than dose-proportional 
manner over the dose range 0.05-2.5 mg/kg. 
 
Protein binding of cediranib (90-95%) was relatively high across all species examined 
and was independent of concentration (range: 0.03-10 mcg/mL) and gender (Cediranib 
Investigator’s Brochure, 2011).  Cediranib was approximately 95% bound to human 
plasma proteins, with human serum albumin and α1-acid glycoprotein accounting for 
most of this binding.   
 
VEGF has three major biological activities in endothelial cells of rats and primates of the 
age groups used in the nonclinical studies (Cediranib Investigator’s Brochure, 2011).  It 
is an important angiogenic factor, a potent physiological mediator of vascular tone 
(specifically of vasodilation), and a potent modulator of capillary permeability inducing 
endothelial cell fenestrations.  VEGF receptor inhibition was therefore considered to be 
the cause of many of the pathophysiological changes encountered.  Vascular 
(myocarditis, choroid plexus) and renal (glomerulosclerosis and tubular degeneration) 
pathologies have been seen in rat, dog, and primate dosed with cediranib which are 
considered to be consistent with lesions induced by hypertension, although a direct effect 
by cediranib on these tissues cannot be excluded.  Pathological findings were also seen in 
the adrenal glands (degenerative cortical changes), pancreas (acinar epithelial cell 
necrosis), thyroid (follicular epithelial cell atrophy), liver (hepatocyte necrosis), and 
biliary system (cholangitis and bile duct proliferation and bile duct cholangitis) of the rat.  
In addition in the primate, changes were seen in the gallbladder (mucosal hypertrophy) 
and bile duct (hyperplasia/hypertrophy). 
 
Cediranib did not induce rat hepatic microsomal P450 activity but caused a 40-60% 
reduction in CYP1A activity at the 2.5 mg/kg dose level (Cediranib Investigator’s 
Brochure, 2011).  Inhibition studies in vitro using human hepatic microsomal protein 
gave IC50 values for cediranib against CYP2D6, CYP3A4 testosterone, and CYP3A4 
midazolam of 32.9, 16.2, and 21.4 mcg/mL, respectively.  For CYP1A2, CYP2A6, 
CYP2C8, CYP2C9, CYP2C19, and CYP2E1, the IC50 values were outside the 
concentration range of cediranib examined.  As the clinically relevant plasma 
concentration of cediranib has not yet been determined, any possible effect on compound 
clearance and drug interaction is currently unknown.  
 
Further details of the nonclinical pharmacology and toxicity of cediranib can be found in 
the Cediranib Investigator’s Brochure (2011). 
 

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Clinical Pharmacology and Pharmacodynamics 
Preliminary pharmacokinetics (PK) information indicates a time to maximum serum 
concentration  (Tmax) of 2 hours (range, 2-6 hours), a Cmax of 107.8 ± 29.8 ng/mL, and a 
t1/2 of 12.1 ± 2.2 hours (Sridhar et al., 2008). 
 
Preliminary information on blood biomarkers in glioblastoma patients indicates that 
plasma VEGF, placental growth factor (PLGF), and stromal cell-derived factor 1 
(SDF1) were increased after treatment, and plasma PIGF and VEGF decreased upon 
cediranib discontinuation.  Plasma basic fibroblast growth factor (bFGF) and SDF1 and 
viable circulating endothelial cells (CECs) increased when tumors escaped treatment with 
cediranib (Batchelor et al., 2010). 
 
Additional information on the relationship between clinical outcome and biomarkers has 
been reported for a DCTD-sponsored trial (Sorensen et al., 2009).  Changes in vascular 
permeability/flow as measured by magnetic resonance imaging (MRI) methods (Ktrans), 
microvessel volume, and circulating collagen IV levels were determined.  Of the 30 
patients in the trial, all three parameters were reliably measured in 28.  A greater 
reduction in Ktrans after one dose of cediranib was seen in patients with increased PFS 
(P=0.0015) and overall survival (OS) (P=0.0039).  A greater increase in the calculated 
blood volume (CBV) of tumor microvessels after one dose of cediranib was seen in 
glioblastoma patients with extended OS (P=0.0056).  A greater increase in collagen IV 
levels in plasma was detected in patients with extended PFS (P=0.0010).  Peripheral 
blood was evaluated serially for VEGF concentration and CECs in another trial 
(Ramalingam et al., 2008).  A stark increase in CECs was noted at progression in several 
patients 
 
Adverse Events and Recommended Dose 
The most frequently reported AEs for cediranib on company-sponsored trials were 
fatigue, diarrhea, nausea, vomiting, hoarseness, hand-foot syndrome, and hypertension 
(Cediranib Investigator’s Brochure, 2011).  Hypertension is an expected pharmacologic 
effect of agents that inhibit VEGF, and is one of the most common adverse events (AEs) 
reported in trials of cediranib.  Dose-related increases in thyroid stimulating hormone 
(TSH) and decreases in total thyroxine have been observed at doses of 30 mg and above, 
and are most marked at 60 mg.  The recommended dose for cediranib monotherapy is 30 
mg/day; the recommended dose in combination with chemotherapy agents is 20 mg/day, 
although exceptions to these doses may be appropriate in other studies, depending on age, 
patient population, tumor type, or agent(s) given in combination with cediranib. 
 
Clinical Experience 
AstraZeneca has sponsored a total of 15 phase 1 studies of cediranib (single-agent or in 
combination with gefitinib, either FOLFOX, irinotecan [±cetuximab], pemetrexed or 
docetaxel, etoposide/cisplatin, or lomustine), 8 phase 2 studies (single-agent, or in 
combination with fulvestran, FOLFOX, or paclitaxel/carboplatin), one phase 2/3 study 
(cediranib plus bevacizumab), and two phase 3 studies (cediranib plus FOLFOX or 
XELOX and cediranib plus lomustine).  Details of the studies, responses, and safety 
assessments are summarized in the Cediranib Investigator’s Brochure (2011). 

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Cediranib has been administered to patients in 38 DCTD, NCI-sponsored clinical trials. 
 
CRs and PRs have been reported in clinical trials of cediranib in solid tumors such as 
NSCLC (Gadgeel et al., 2011), renal cell carcinoma (RCC) (Sridhar et al., 2008), 
prostate (Dahut et al., 2013), mesothelioma (Garland et al., 2011), and gynecologic 
tumors (Hirte et al., 2008; Matulonis et al., 2009). 
 
The MTD for cediranib in combination with 75 mg/m2 temozolomide and radiation was 
established at 30 mg/day in patients with newly-diagnosed glioblastoma, with no dose-
limiting toxicities (DLTs) observed (Gerstner et al., 2012).  Cediranib was then 
administered at 45 mg/day in a post-radiation setting, and in addition to the expected AEs 
of hypertension, fatigue and palmar/plantar erythema, one patient discontinued due to 
grade 3 transaminase elevation and one patient required dose reduction to 15 mg/day due 
to proteinuria.  Median PFS was 288 days (95% CI 240–∞) and median OS was 786 days 
(95% CI 411–∞); these values were improvements over historical controls.  Best 
radiographic response in patients who completed chemoradiotherapy was CR in two 
patients, PR in 20 patients, and SD in 15 patients.  Patients with increased tumor 
perfusion during chemoradiotherapy survived nearly 1 year longer (mean OS 611 days) 
than patients with decreased perfusion (mean OS 269 days). 
 
Among 31 patients in a phase 2 trial of cediranib in recurrent glioblastoma, radiographic 
PRs (>50% volume reduction) were reported in 17 patients, and minor responses (25-
50% volume reduction) in an additional 6 patients (Batchelor et al., 2010).  Median PFS 
was 117 days, and median OS was 227 days.  Additionally, cediranib alleviated brain 
edema, a major cause of morbidity in glioblastoma patients (Batchelor et al., 2007).  
DLTs were observed in 9 of the 16 patients with hypertension; fatigue and diarrhea were 
seen most often. 
 
Two phase 2 trials of cediranib at two different dose levels (30 mg/day and 45 mg/day) in 
patients with unresectable locally advanced or metastatic hepatocellular carcinoma 
(HCC) yielded no objective responses (Zhu et al., 2012; Alberts et al., 2012).  Grade 3 
AEs were observed in 93% of patients receiving 45 mg/day (Alberts et al., 2012).  
Fatigue, hypertension, and anorexia accounted for the majority of the AEs. 
 
Response information for 45 of 46 patients on a trial of cediranib in malignant pleural 
mesothelioma reported PR by RECIST in 4/47 patients (9%), including 2 patients with 
bulky disease who had 56% and 91% tumor shrinkage; and 16/47 (34%) had SD (Garland 
et al., 2011).  Median PFS was estimated at 2.56 months, median OS at 9.5 months.  The 
most common nonhematologic AEs were hypertension (70%), fatigue (64%), and 
diarrhea (64%). 
 
Among 47 evaluable patients receiving cediranib in a trial in ovarian, primary peritoneal 
serous, or fallopian tube cancer, the clinical benefit rate was 30%; eight patients had a PR 
and six had SD; there were no CRs (Matulonis et al., 2009).  Median PFS was 5.2 
months, and median OS had not been reached after a median follow-up time of 10.7 

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months.  Grade 4 AEs included CNS hemorrhage, lipase, and hypertriglyceridemia/ 
hypercholesterolemia/elevated lipase, and dehydration/elevated creatinine.  Grade 3 AEs 
include hypertension, fatigue, and diarrhea.  Hypertension occurred in 87% of the 
patients by the end of the study; in 43%, it was grade ≥3 (Robinson et al., 2010).  Grade 2 
hypothyroidism occurred in 43% of patients.  
 
Preliminary information from 60 patients in a phase 2 trial of cediranib in persistent 
ovarian, peritoneal, or fallopian tube cancer has been reported (Hirte et al., 2008).  
Patients were divided into those whose disease was found to be platinum-resistant and 
those whose disease was platinum-sensitive in a prior therapy regimen.  Response and 
prolonged SD rate was 41% for platinum-sensitive and 29% for platinum-resistant 
patients, respectively.  In the platinum-sensitive group, there were two confirmed PRs 
and one unconfirmed PR, while one unconfirmed PR was observed in the platinum-
resistant arm.  Median time to progression (TTP) and median survival for all patients was 
4.1 months and 11.9 months, respectively, with no significant differences between the 
platinum-sensitive and -resistant groups.  The most frequent AEs were fatigue, diarrhea, 
hypertension, and anorexia, while hypertension and fatigue were the most frequent grade 
3 or higher AEs.  Sixteen patients required dose reduction to 30 mg and 20 mg. 
 
Information on 59 patients in a trial of cediranib in metastatic androgen-independent 
prostate cancer has been reported (Dahut et al., 2013).  A total of 59 patients were 
enrolled, of whom 67% had received two or more previous chemotherapy regimens. Six 
of 39 patients with measurable disease had confirmed PRs and one had an unconfirmed 
PR.  At 6 months, 43.9% of patients were progression-free; the median PFS and OS 
periods for all patients were 3.7 months and 10.1 months, respectively.  Decreases in 
lymph node metastases as well as in lung, liver, and bone lesions were observed.  Grade 3 
AEs included vomiting, prolonged QTc interval, muscle weakness, weight loss, 
dehydration, fatigue, hypoxia, renal failure, transaminitis, and anorexia. 
 
Thirty-two of 43 patients enrolled in a trial of cediranib in renal cell carcinoma (RCC) are 
evaluable for response (Sridhar et al., 2008).  PRs were observed in 12 patients, SD in 15, 
and PD in 5.  Median PFS was 8.7 months and the 6-month progression-free proportion 
was 63%.  Treatment-related grade 3 or higher AEs included hypertension, fatigue, joint 
pain, abdominal pain, and dyspnea. 
 
Cediranib was administered in a phase 2 trial in small cell lung cancer (SCLC), in which 
one unconfirmed PR and eight SD were noted (Ramalingam et al., 2008).  Salient AEs 
were fatigue (four grade 3, two grade 4), and grade 3 diarrhea, skin rash, proteinuria, 
transaminitis, muscle weakness, and hypertension.  However, the original 45 mg/day 
dose was not tolerable in the patient population, and the modest activity seen at 30 
mg/day did not support the use of cediranib as monotherapy for SCLC. 
 
A combination trial of cediranib plus docetaxel, doxorubicin, and cyclophosphamide in 
advanced breast cancer accrued only two patients, and was closed due to systolic 
dysfunction that occurred with concurrent cediranib and doxorubicin (Denduluri et al., 
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Another combination trial of cediranib plus pemetrexed in NSCLC divided patients into 
two arms—those who had not received bevacizumab in prior chemotherapy regimens 
(Cohort A), and those who had (Cohort B) (Gadgeel et al., 2011).  The confirmed 
response rate was 16% (10% Cohort A, 25% Cohort B), and the disease control rate 
(CR/PR/SD) was 71% (74% Cohort A, 67% Cohort B).  Grade 3/4 AEs included 
neutropenia, febrile neutropenia, fatigue, diarrhea, hypertension, anorexia, cardiac 
ischemia, bronchopleural fistula, and esophagitis.  Of the 17 patients who received 
cediranib for 4 cycles, 71% required dose reduction from 30 mg/day, and of the 18 
patients who received pemetrexed for 4 cycles, 22% required dose reduction.   
 
Additional information on clinical trials conducted with cediranib is summarized in 
Lindsay et al. (2009). 
 
Safety Profile 
As of August 2009, 582 patients on DCTD, NCI-sponsored clinical trials of cediranib had 
been evaluated for AEs.  The most common grade 3/4 AEs were hypertension, fatigue, 
anorexia, diarrhea, and metabolic (ALT/SGPT and AST/SGOT). 
 
Hypothyroidism was observed in 14/21 pediatric patients with CNS tumors administered 
cediranib, including one with a prolonged elevated TSH and thyroxine (T4) that went 
untreated.  Proteinuria has been seen in seven patients, including two grade 3 events in 
Cycle 1 and Cycle 2, respectively.   Hypertension has been observed in 18/21 patients 
who received more than a few days of therapy.  Of the 18 cases, 10 experienced grade 2 
hypertension as the highest reported grade and 8 reported grade 3 hypertension.  
Reversible posterior leukoencephalopathy syndrome (RPLS) shortly after initiation of 
Cycle 2 of therapy was seen in one patient who had been appropriately managed for 
grade 3 hypertension  
 
In a phase 2 trial of cediranib in 46 patients with epithelial ovarian, fallopian tube, or 
peritoneal cancer, 31 patients (67%) developed hypertension by Day 3 of treatment, and 
87% had developed hypertension by the end of the study (Robinson et al., 2010).  
Fourteen women developed proteinuria, seven within the first 2 weeks of treatment.  
Only 7 of the 20 women who developed grade 3 hypertension developed proteinuria. 
 
In a phase 2 study of cediranib in patients with solid tumors, patients (n=126) were 
assigned to cediranib dose groups of either 45 or 30 mg/day with or without 
antihypertensive prophylaxis (Langenberg et al., 2009).  Severe hypertension occurred in 
one patient receiving prophylaxis versus 18 in the nonprophylaxis groups.  
Antihypertensive prophylaxis did not result in fewer dose reductions or interruptions.  
Increases in blood pressure, including moderate and severe readings of hypertension, 
were seen in all groups and successfully managed. 
 
Hypertension and kidney toxicity (i.e., proteinuria) are commonly observed AEs seen in 
the class of angiogenesis inhibitor agents (Izzedine et al., 2007; Launay-Vacher and 
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have been described in studies of other angiogenesis inhibitors (Herbst, 2006; Kappers et 
al., 2009).  A number of mechanisms have been described that account for AEs such as 
impaired wound healing, gastrointestinal perforation, hemorrhage and thrombosis, 
cardiac impairment, endocrine dysfunction, and RPLS (Kamba et al., 2007). 
 
 
2.2.2 Olaparib (AZD2281) 
 
Olaparib (AZD2281, KU-0059436, CO-CE 42, 4-[(3-{[4-
(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]phthalazin-1(2H)-
one) is a potent and well-tolerated oral inhibitor of polyadenosine 5’-diphosphoribose 
[poly-(ADP-ribose)] polymerization (PARP)-1 and PARP2.  Olaparib is an active 
monotherapy in tumors with defective components of homologous recombination repair 
(HRR), which includes those with BRCA1/2 mutations.  A first-in-man phase 1 dose 
escalation trial of single agent olaparib in a patient cohort enriched for patients with 
BRCA germline mutations indicated substantial PARP inhibition in surrogate tissues and 
anti-tumor activity in 40% of ovarian cancer patients with germline BRCA mutations, 
using combined RECIST and GCIG CA-125 criteria (Fong et al., 2010). 
 
Mechanism of Action 
Preclinically, olaparib displays antitumor activity against a variety of tumor cell lines and 
this sensitivity of the cells is believed to depend upon components of a defective HRR 
capability (Olaparib Investigator’s Brochure, 2013).  As a major example of this selective 
activity, both BRCA1- and 2-deficient (-/-) tumors are sensitive to PARP inhibition.  Early 
studies indicated that PARP inhibition in BRCA1/2 homozygous null cells, but not the 
isogenic BRCA heterozygous cells, led to cell death.  BRCA1 and 2 are proteins 
necessary for proper function of HRR, the high fidelity repair system that addresses DNA 
double-strand breaks (DSBs).  The backup repair system to HRR is base-excision repair 
(BER), which requires PARP function and primarily addresses single-strand breaks 
(SSBs).  However, the system works both ways in that repair of SSBs in BER can lead to 
stalled replication forks that strain the system and cause double strand breaks, resulting in 
a situation that requires intact HRR and BRCA1 or BRCA2.  Thus, HRR dysfunction 
sensitizes cells to PARP inhibition leading to further chromosomal instability, cell cycle 
arrest and apoptosis (Farmer et al., 2005).  This sensitivity is suggested to result in a large 
therapeutic window for PARP inhibition in mutation carriers.  Pre-clinical studies support 
these findings showing that other BRCA mutant, but not wild-type, human cell lines are 
highly sensitive to olaparib (Menear et al., 2008). 
 
Nonclinical Pharmacology and Efficacy 
Olaparib has demonstrated cellular activity in the low nM range with a cellular dose for 
50% inhibition (IC50) of 2 nM in HeLa cells (Olaparib Investigator’s Brochure, 2013).  
The effective concentration for inhibiting cellular PARP activity in cancer cells by >90% 
is approximately 30 nM to 100 nM olaparib in several tumor cell lines including ovarian 
A2780, breast MCF-7, and colorectal SW620.  These concentrations lead to significant 
ablation of PARP activity (based on the inhibition of PAR formation), with maximal 
PARP-1 inhibition occurring at around 100 nM.  Consistent with this, maximal 

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potentiation of an appropriate DNA SSB-inducing chemotoxic agent (MMS) was also 
seen in vitro at 100 nM, which equates to 43.4 ng/mL. 
 
An analysis of the correlation of olaparib response with several standard-of-care (SOC) 
chemotherapies in a panel of breast cancer cell lines has demonstrated a strong 
correlation with both carboplatin (0.84, p=0.0006) and camptothecin (0.8, p=0.0018) 
(Olaparib Investigator’s Brochure, 2013).  This is consistent with what is known about 
the types of DNA damage they induce (intra-strand and inter-strand cross-links for 
platinum and trapped topoisomerases-DNA adducts for camptothecins, both of which 
result in DNA DSB formation in replicating cells) and the DDR pathways that deal with 
them (primarily HRR in cells undergoing DNA replication).  The same does not hold for 
a mechanistically unrelated chemotherapy, such as paclitaxel (-0.11) whose mechanism 
of action is unrelated to the induction of DNA damage.  
 
The analysis of olaparib and platinum response was extended to additional tumor 
indications where platinum treatment is SOC and included ovarian, non-small cell lung 
cancer (NSCLC) and head and neck squamous cell carcinoma cell lines (Olaparib 
Investigator’s Brochure, 2013).  Consistent with the breast cancer cell line data, the 
strong correlation between platinum response and olaparib response was observed.  These 
in vitro data have been extended further into in vivo patient-derived tumor explant (PTX) 
models of both breast and NSCLC and again the correlation is seen between platinum 
sensitivity and olaparib sensitivity. 
 
In vitro combination studies demonstrate that olaparib is able to potentiate the 
cytotoxicity of DNA-damaging agents, including the monomethylating agent 
temozolomide (melanoma, glioblastoma, colorectal), topoisomerase-1 inhibitors such as 
camptothecin, irinotecan, and topotecan (ovarian, pancreatic, colorectal), and platinum-
based agents such as cisplatin and carboplatin (breast) (Olaparib Investigator’s Brochure, 
2013).  Studies with BRCA1-deficient orthotopically-transplanted in vivo mouse 
mammary tumor models showed that, in addition to single agent activity of olaparib, 
sequential treatment of mice with olaparib following a single dose of platinum agent 
increased the time to progression on treatment and extended OS.  These data support the 
idea that olaparib can extend the antitumor effect of platinum agents when given as a 
maintenance treatment. 
 
Following single oral doses, absorption was rapid (maximum plasma concentration 
[Cmax] <2 hours in mice, rats and dogs) while bioavailability was <60% in male and 
female mice, <20% in male and female rats and ~79% in male dogs (Olaparib 
Investigator’s Brochure, 2013).  Low oral bioavailability in rat may have been due to 
poor absorption or rapid first pass metabolism.  Distribution of olaparib is in the 
gastrointestinal tract and in tissues associated with the metabolism and elimination of 
foreign compounds.  Further investigations are still ongoing.  Excretion is primarily via 
the feces and, to a lesser extent, the urine. 
 
Investigations in human in vitro systems indicated metabolism of olaparib was CYP 
mediated and that CYP3A4 and 3A5 were the dominant metabolic enzymes (Olaparib 

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Investigator’s Brochure, 2013).  Similar studies indicated flavin mono-oxygenase-3 was 
not able to metabolize olaparib.  In in vitro direct inhibition assays, olaparib (100 μM) 
had only limited effect against CYP3A (up to 46% inhibition) and less effect against 
other CYPs tested. In time dependent inhibition assays, olaparib had only very minor 
effects against CYP3A and no effect against other CYPs.  Clinically significant direct 
inhibition of intestinal CYP3A is possible but significant effects against hepatic CYP3A 
are less likely.  The CYP induction potential of olaparib was investigated in cultures of 
human hepatocytes.  At the highest olaparib concentration (30 mcM), minor induction of 
CYP2B6 activity was observed (<40% positive control) and smaller effects on CYPs 2C9 
and 2C19 activities were noted.  These changes were unlikely to be of clinical 
significance.  A small decrease in CYP3A activity was noted, which may suggest time-
dependent inhibition, however, this was not explored further. 
 
In studies using Madin-Darby Canine Kidney (MDCK) II cells transfected with 
multidrug resistance 1 (MDR1; Pgp), BCRP or MRP-2 drug efflux transporters, olaparib 
was shown to be a substrate of MDR1 but not BCRP or MRP-2 (Olaparib Investigator’s 
Brochure, 2013).  In the same systems, olaparib was an inhibitor of BCRP and MRP-2 
but had little or no inhibitory effect on MDR1. 
 
In isolated human hepatocytes, olaparib was a substrate for organic anion transport 
proteins.  In the same system, olaparib was shown to be an organic cation transporter 1 
(OCT1) inhibitor (IC50 11.9 μM) (Olaparib Investigator’s Brochure, 2013).  In HEK-293 
cells transfected with OATP1B1, olaparib functioned as an inhibitor and IC50 values of 
20.3 mcM and 27.1 mcM were derived (substrate dependent).  Using the criteria defined 
in the European Medicines Agency (EMA) guidelines on the investigations of drug 
interactions (EMA 2013), it is possible olaparib may precipitate an interaction via hepatic 
drug uptake transporters, particularly OCT1. 
 
SimCYP population PK simulations of the separate effect of co-administration of 
itraconazole and rifampicin (clinically relevant CYP3A inhibitor and inducer, 
respectively) on olaparib PK in humans, when administered at the recommended human 
dose, were performed (Olaparib Investigator’s Brochure, 2013).  The itraconazole (200 
mg twice daily [BID] x 7 days) simulation indicated olaparib (400 mg bd x 7 days) steady 
state Cmax and area under the concentration-time curve (AUC) would increase by 2.8 and 
3.5 fold, respectively. The rifampicin simulation (600 mg x 6 days) indicated olaparib 
(400 mg BID x 6 days) steady state Cmax and AUC in the presence of rifampicin would be 
reduced to 33% and 29%, respectively, of the values in the absence of rifampicin. 
 
Nonclinical Toxicology 
Olaparib has been tested in dogs and rats (Olaparib Investigator’s Brochure, 2013).  
There were no noted effects on the cardiovascular or respiratory parameters of an 
anesthesized dog or any behavioral, autonomic, or motor effects in the rat.  Toxicology 
studies indicate that the target organ of toxicity is the bone marrow.  Ex vivo work has 
confirmed that olaparib is also active against human marrow.  The cytotoxic effect 
becomes evident at a higher concentration than required to fully ablate PARP activity.  
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Clinical Efficacy 
The first clinical study in man of olaparib (KU-36-92) was a dose-escalation study in 
patients with advanced solid tumors (Olaparib Investigator’s Brochure, 2013).  
Preliminary data demonstrated that olaparib is generally well-tolerated at doses up to and 
including the MTD of 400 mg BID in patients with various solid tumors.  As of October 
2, 2013, approximately 2103 patients with ovarian, breast, pancreatic, melanoma, and 
other advanced solid tumors have received olaparib, either as monotherapy or in 
combination with other chemotherapy agents.  AEs considered to be associated with 
olaparib included anemia (mild to moderate), neutropenia (mild to moderate), and 
thrombocytopenia (generally mild to moderate, sometimes severe), nausea and vomiting 
(mild to moderate), and fatigue (mild to moderate). 
 
Olaparib has also been studied in an expansion phase in BRCA-deficient ovarian cancer 
at a dose of 200 mg BID.  Fifty patients were treated, including 48 with BRCA-deficient 
germline mutations and two patients of unknown status or significance.  Twenty (40%) 
patients achieved complete response (CR) or partial response (PR) by RECIST and/or 
GCIG-CA125 criteria.  An additional three patients experienced stable disease (SD) for 
more than four cycles (Fong et al., 2010).  A multicenter phase 2 study enrolled two 
sequential cohorts of women with known germline BRCA2 or BRCA2 mutations and 
recurrent advanced ovarian cancer to receive olaparib continuously at a dose of 400 mg 
BID (Cohort 1) or 100 mg BID (Cohort 2) (Audeh et al., 2010).  Responses were 
observed in 33% (11 of 33) patients enrolled in the 400mg BID cohort and 13% (3 of 24) 
patients enrolled in the 100 mg BID cohort.  A phase 2 study of olaparib in advanced 
serous ovarian cancer and triple-negative breast cancer included a cohort of 46 ovarian 
cancer patients who were known not to carry a germline BRCA mutation, in which an 
overall response rate (ORR) of 23.9% was observed (Gelmon et al., 2010). 
 
Additional studies of olaparib as monotherapy or in combination with a platinum reagent 
for treatment of metastatic BRCA-deficient ovarian cancer are ongoing.  Results from a 
phase 2 trial investigating olaparib as maintenance therapy following platinum-based 
therapy for platinum-sensitive serous ovarian cancer demonstrated a significant 
progression-free survival (PFS) benefit (8.4 vs. 4.8 months, P<0.001), with subgroup 
analyses demonstrating evidence of benefit regardless of BRCA status (Ledermann et al., 
2012).  Lee and Kohn and colleagues have examined olaparib with carboplatin in two 
schedules in BRCA1/2 mutation carriers with breast and/or ovarian cancer and women 
with high grade serous ovarian cancers (Lee et al., 2011).  They also see activity with 
over 80% of ovarian cancer patients attaining either SD or PR lasting up to 18+ months.  
Additional phase 1 and 2 trials in both BRCA-deficient and BRCA-competent ovarian 
cancer are currently ongoing. 
 
Olaparib was granted accelerated approved by the FDA in the United States as 
monotherapy in women with advanced ovarian cancer associated with germline BRCA 
mutation in the companion diagnostic test BRACAnalysis CDx and who have received at 
least 3 prior lines of therapy for ovarian cancer on December 19, 2014. 
 
 

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2.2.3 Pre-clinical rationale for combination cediranib and olaparib 
Several lines of preclinical evidence support the combination of a PARP inhibitor and 
anti-angiogenic therapy. 
 
While the role of DNA damage repair pathways in tumors treated with anti-angiogenic 
therapies is not well understood, the hypoxic state is known to result in genetic instability 
and mutagenesis.  It is known that hypoxia triggers a DNA damage response, resulting in 
p53 accumulation and eventual apoptosis; p53-deficient tumors suppressed the apoptotic 
effect, promoting tumor survival in spite of the hypoxic state (Graeber et al., 1996).  
However, despite the presence of DSB markers such as histone H2AX, there is little 
evidence of DNA damage during the hypoxic state, and H2AX staining is atypical 
(diffuse rather than punctate), though severe hypoxia may result in aberrant replication 
complexes, SSBs, and regions of single-stranded DNA (Hammond et al., 2002).  After 
re-oxygenation, DSBs are noted to accumulate, and tumor survival is dependent upon 
intact DNA repair complexes (Hammond et al., 2004).  Thus, post-hypoxic tumor cells 
which rely upon angiogenic signaling may also be vulnerable to PARP inhibition. 
 
Human breast (MCF-7) and lung adenocarcinoma (A549) cell lines grown under hypoxic 
conditions exhibit severely reduced levels of BRCA1 and RAD51 due to transcriptional 
downregulation (Bindra et al., 2004; Bindra et al., 2005).  Subsequent work determined 
that chemical PARP inhibitors displayed increased cytotoxicity against A549, RKO 
(colon), and H460 (lung) cell lines under hypoxic conditions, compared to normoxic 
conditions (Hegan et al., 2010).  Exposure to PARP inhibitors or PARP-1 RNAi 
downregulated BRCA1 and RAD51 expression in a dose-dependent manner, regardless 
of oxygenation, and the addition of hypoxic conditions to PARP inhibition enhanced the 
downregulatory effect. 
 
In addition, studies in primary human umbilical vein endothelial cells (HUVECs) and 
immortalized human endothelial cell lines demonstrate a connection between hypoxia-
driven angiogenesis and DNA repair, and show that inhibition of DNA repair pathways 
can inhibit endothelial cell proliferation.  In HUVECs treated under a hypoxic state, 
H2AX foci are found primarily in proliferating endothelial cell populations (positive 
staining for proliferative cell nuclear antigen) where they co-localize with replication 
protein A, suggesting a replication stress-related origin of hypoxia-induced H2AX foci 
(Economopoulou et al., 2009).  Small interfering RNA (siRNA) knockdown of the 
replication stress-induced ataxia teleangiectasia mutated kinase (ATM)- and Rad3-related 
kinase (ATR) pathway, but not the ATM pathway, inhibited H2AX formation, and 
siRNA knockdown of H2AX significantly decreased growth factor-induced proliferation 
and fetal calf serum-induced HUVEC proliferation under hypoxic conditions.  PARP 
inhibition (via the specific small-molecule inhibitor GPI 15427) inhibited angiogenesis in 
matrigel in vitro (Tentori et al., 2007).  At drug levels that did not affect endothelial cell 
proliferation (0.1-1 mcM), PARP inhibition reduced the formation of tube-like structures 
and inhibited platelet-derived growth factor (PlGF)- and VEGF-induced endothelial cell 
migration.  At 1 mcM, GPI 15427 did not inhibit hypoxia-inducible factor 1 (HIF-1 ) 
induction by the hypoxia mimetic agent CoCl2, indicating that PARP inhibition’s effects 

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on migration were not exerted through influencing HIF-1 function. 
 
Collectively, the evidence indicates that anti-angiogenic therapy may complement PARP 
inhibition, particularly in the context of DNA repair-deficient tumors.  These results also 
suggest that the combination of cediranib and olaparib may synergize not only with 
regard to direct antitumor activity but also with regard to their anti-angiogenic effect on 
tumor vasculature. 
 
Nonclinical Efficacy 
 
Limited nonclinical data exist regarding the specific combination of olaparib and 
cediranib.  Olaparib (100 nM) and cediranib (5 nM) have potentially synergistic activity 
in in vitro microvascular cell tube growth assays (Figure 1), inhibiting cell tube growth 
and branching in a greater than additive fashion (Jung Min Lee, unpublished data)   
Olaparib (10 nM) and cediranib (50 nM) individually reduced tumor cell invasion, and 
the combination of both agents nearly completely abolished invasion compared to the 
control (Figure 2). 
 
 
Figure 1.  Microvascular cell tube formation assay. 
 

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Figure 2.  Tumor invasiveness assay. 
 
2.2.4 Clinical Background 
 
2.2.4.1 
Phase 1 experience with cediranib and olaparib 
 
NCI protocol 8348 included a Phase 1 component that established the recommended 
Phase 2 dosing (RP2D) of cediranib in combination with olaparib in the capsule 
formulation.  This Phase 1 enrolled a total of 28 patients (20 ovarian, 8 breast). (Liu et 
al., 2013)   
 
At the highest dosing level of cediranib 30 mg daily (QD) and olaparib 400 mg BID, two 
DLTs were observed (grade 4 neutropenia and thrombocytopenia), and the recommended 
phase 2 dose (RP2D) was declared to be cediranib 30 mg QD and olaparib 200 mg BID 
(Liu et al., 2013).  Only one additional grade 4 adverse event (AE) (neutropenia) was 
observed.  Fatigue (93%), diarrhea (86%), nausea (57%), and hypertension (45%) were 
the most commonly observed AEs, consistent with previously reported toxicities of 
cediranib and olaparib.  Fatigue, which has been observed with both cediranib and 
olaparib in single-agent studies, may have been more prominent due to overlapping 
toxicity.  Diarrhea was generally controllable with loperamide, although several patients 
required dose reduction.  Hypertension, a well-documented toxicity of cediranib, was 
manageable with aggressive anti-hypertensive therapy; of note, only one patient required 
dose reduction for hypertension.  Although all three grade 4 AEs observed were 
hematologic, in general, the combination was well-tolerated with primarily grade 1/2 
hematologic toxicities. 
 
Twenty-five patients (18 ovarian, 7 breast) from the phase 1 portion were evaluable for 
response by Response Evaluation In Solid Tumors (RECIST) criteria, version 1.1 (Liu et 
al., 2013).  The two ovarian cancer patients not evaluable by RECIST 1.1 were followed 
by Gynecologic Cancer InterGroup (GCIG) CA125 criteria.  The non-evaluable breast 
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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 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 
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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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). 
 
2.2.4.3 
Rationale for trial design 
 
The combination of cediranib and olaparib may offer a novel treatment regimen for 
women with recurrent ovarian cancer utilizing combination biologic agents as an 
alternative to standard cytotoxic chemotherapy.  However, unanswered questions exist 
regarding the activity of this regimen in the platinum-resistant population, as well as 
whether particular biomarkers may predict for more robust response to this regimen. 
 
The trial is designed to allow assessment of activity and BROCA-HR as a predictor of 
activity in two separate cohorts of women with recurrent ovarian cancer, either in the 
platinum-sensitive or platinum-resistant setting.  Women will be stratified to one of the 
two cohorts depending on their platinum-resistance status at the time of enrollment. 
 
Due to the findings in the Phase 2 randomized study of cediranib/olaparib versus 
olaparib, where the observed response rate in 44 women with platinum-sensitive ovarian 
cancer who received cediranib/olaparib was 80% with a median PFS of 17.7 months 
(detailed in Section 2.2.4.2), no interim futility is designed for this cohort. 
 
Data regarding the activity of the cediranib/olaparib combination in platinum-resistant 
patients is less robust.  Six patients in the Phase 1 study had platinum-resistant disease, of 
whom 3 had a response.  In preliminary results from a bridging Phase 1 study of 
cediranib together with olaparib in the tablet formulation, 4 of 14 patients with RECIST 
measurable disease had a partial or complete response.  Therefore, in the platinum-
resistant cohort, a Simon two-stage design will be utilized. 
 
2.2.4.4 
Rationale for on-study biopsies 
 
Pre-clinical studies suggest that synergy between cediranib and olaparib is mediated 
through induction of a more HR-deficient state.  However, it currently remains unknown 
whether a particular biomarker might predict for a more robust response to the 
cediranib/olaparib combination.  In prior clinical experience with PARP-inhibitors, the 
response to PARP-inhibitors appears to be most robust in patients with germline BRCA1 
or BRCA2 mutations (Gelmon et al., 2011).  However, certain patients without a gBRCA 
mutation may also benefit from PARP-inhibitor (Gelmon et al., 2011).  In the Phase 2 
study, benefit with cediranib and olaparib was observed in both women with and without 
gBRCA mutation. 
 
A pre-treatment biopsy is included in this trial as the tumor may be evolve between the 
time of collection of an archival sample and the time of initiating on study treatment.  
Recent data reported by McNeish et al. demonstrated that changes in a signature of HR-

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deficiency can be seen between archival and pre-treatment biopsies, and that the 
signature of HR-deficiency in pre-treatment biopsies can predict activity of the PARP-
inhibitor rucaparib (McNeish et al., 2015).  In this study, ARIEL2, patients with 
gBRCAmt had a median PFS of 9.4 months on rucaparib.  In comparison, patients who 
were gBRCAwt but had a HR-deficient signature on their pre-treatment biopsy had a 
median PFS of 7.1 months, while those who were gBRCAwt but lacked a signature for 
HR-deficiency had a PFS of only 3.7 months.  BROCA-HR will be assessed as the 
primary biomarker for HR-deficiency in the pre-treatment biopsy, and BROCA-HR 
assessment will be correlated with activity of the cediranib/olaparib combination in 
patients, as assessed by PFS.  As exploratory analyses, we will also compare BROCA-
HR in the pre-treatment biopsy to the archival sample. 
 
An on-treatment biopsy is being performed to assess for interval change in biomarkers 
that will be critical for understanding the mechanism of cediranib/olaparib synergy as 
well as potential mechanisms of resistance.  It has been hypothesized that the mechanism 
of synergy between cediranib and olaparib is the induction of a more HR-deficient state 
in the setting of hypoxia from anti-angiogenics.  In the on-treatment biopsy, gene 
expression analysis will ask whether proteins involved in HR are being downregulated 
after initiation of cediranib and olaparib.  Additionally, how this downregulation 
correlates with overall activity of the cediranib/olaparib combination would be explored.  
BROCA-HR will also be utilized to understand whether early mutations within elements 
of HR occur in response to challenge to cediranib/olaparib, and how such occurrences 
correlate with clinical activity. 
 
An optional off-treatment biopsy is being requested of patients at the time of progression.  
Resistance to PARP-inhibitors has been clearly documented in women with ovarian 
cancer.  Various mechanisms of resistance to PARP-inhibitors have been reported, 
including the development of “reversion mutations”, where the original germline mutated 
BRCA1 or BRCA2 in a patient’s tumor back-mutates into a functional version of the gene, 
leading to restoration of HR deficiency (Edwards et al., 2008; Sakai et al., 2008), loss of 
53BP1 (Jaspers et al., 2013), stabilization of BRCA1 (Johnson et al., 2013), or 
expression of certain miRNAs that may regulate HR-related genes (Moskwa et al., 2011).  
Molecular characterization from these off-treatment biopsies would be compared to the 
pre- and on-treatment biopsies to understand changes in gene expression or development 
of novel mutations/back-mutations that would allow for insight into mechanisms of 
resistance. 
 
The findings from these biomarker studies would identify biomarkers for patients most 
likely to derive clinical benefit from cediranib/olaparib, as well as those patients who are 
unlikely to respond to the combination.  Given the potential toxicities of this regimen, 
identification of patients who are more likely or less likely to respond would allow for 
future stratification of patients based upon a molecular signature to receive or not receive 
the cediranib/olaparib combination for treatment of their ovarian cancer. 
. 

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mutation is highly predictive of an improved primary response to platinum 
chemotherapy (P<.0005, Figure 1) and longer overall survival (P=.001, Pennington et 
al., 2014, Figure 2). Germline and somatic loss of function mutations were identified in 
all of the 13 FA/HR genes evaluated. 
 
Dr. Swisher’s laboratory has designed a new 
version of BROCA (BROCA-HR) that 
includes many additional DNA repair genes 
(75 total genes) as well as 3000 single 
nucleotide polymorphisms (SNPs). Similar 
sequencing accuracy and sensitivity 
sequencing DNA is obtained from formalin 
fixed paraffin embedded (FFPE), fresh blood 
and flash frozen specimens. BROCA-HR 
includes genes that are targets of both somatic 
and germline mutations. The BROCA-HR 
includes genes that regulate homologous recombination or NHEJ that, if mutated, could 
mediate resistance to PARPi such as TP53BP1 (Johnson et al., 2013; Bunting et al., 
2010; Bouwman et al., 2010). The BROCA design is flexible and can be altered to 
include any genes of research interest. The current design for BROCA-HR includes the 
following genes: 
 
BROCA-HR gene list (n=65) 
a. BRCA-FA homologous recombination pathway: ATM, ATR, BABAM1, BAP1, 
BARD1, BLM, BRCA1, BRCA2 (FANCD1), BRIP1 (FANCJ), BRCC3, BRE,, 
CHEK1, CHEK2, ERCC1, ERCC4 (FANCQ), FAM175A (abraxas), FANCA, 
FANCB, FANCC, FANCD2,  FANCE, FANCF, FANCG (XRCCC9), FANCI, 
FANCL, FANCM, GEN1, MRE11A, NBN, PALB2 (FANCO), RAD50, RAD51C 
(FANCO), RAD51D, RBBP8 (CtIP), SLX4 (FANCP), UIMC1 (RAP80), XRCC2,  
b. DNA mismatch repair (Lynch syndrome) MLH1, MSH2 (and EPCAM), MSH6, 
PMS2 
c.     Other DNA repair or surveillance genes : CDK12, CDH4, HELQ, NEIL1, PPM1D, 
POLD1, POLE, RIF1,TP53, ID4, PAXIP1, POLQ, RINT1, TP53BP1, USP28, 
WRN, XRCC3 
d. NER genes: ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, DDB1, XPA, SPC,  
e.    NHEJ pathway genes: DCLRE1C, LIG4, PARP1, PRKDC, TOPBP1, XRCC4, 
XRCC5, XRCC6 
f.    PI3K pathway:  PTEN, PIK3CA 
 
2.3.3 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 
Survival (months)
Percent survival
0
50
100
150
200
0
25
50
75
100
Germline HR mutation
Somatic HR mutation
No HR mutation
Figure 2 

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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 
TGF1 
IL-6 
IGFBP1 
VEGF-D 
TGF2 
PAI-1 Active 
IGFBP2 
sVEGFR1 
TGFRIII 
PAI-1 Total 
IGFBP3 
sVEGFR2 
TIMP1 
SDF-1 
PDGF-AA sVEGFR3 
TSP2 
VCAM-1 
This approach is technically robust and readily adaptable to clinical practice.   Because 
this data will be derived from patients, even preliminary data may significantly improve 
our understanding of how angiogenesis and tumor growth factors are regulated in 
cancer patients. Promising findings can be followed up in future clinical studies and in 
preclinical models. Because the Duke angiome lab serves as the core lab for multiplex 
ELISA analyses within the Alliance, the current ovarian cancer profiling can be 
compared to the profiles seen in other phase III studies, helping to optimize future 
profiling approaches and provide the disease specific context needed for clinically 
meaningful companion diagnostics. Given the results of this prior work and the work of 
others, we anticipate being able to identify and validate or refute candidate markers of 
benefit that are specific for anti-angiogenic agents. 
 
2.3.4 Circulating endothelial cells/circulating endothelial progenitor cells (CEC/CEP) 
 
The presence of CECs has been recognized as a potential biomarker of vascular damage 
(Bertolini et al., 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 et a,, 2006). CECs have been examined in early clinical 
trials using anti-angiogenics (Ning et al,. 2010, Park et al., 2013, Kummar et al., 2011). 

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Median OS:  High LOH 51.9 
mos vs low LOH 37.4 
Figure 3. Using TCGA data1, we found that 
3000 SNPs could be sued to define high genomic 
LOH, which is associated with significantly 
longer survival. 
In the phase II study of bevacizumab, thalidomide, docetaxel, and prednisone in 
metastatic prostate cancer (Ning et al, 2010), the numbers of post-treatment CEC 
correlated with PSA response; patients with ≥ 75% PSA decline had an increase in 
CEC levels compared with those who had < 75% PSA decline (p=0.02).  
 
As part of the Phase 2 cediranib/olaparib vs. olaparib study, a self-selected subset of 
eligible patients who had been randomized to receive either olaparib or 
cediranib/olaparib underwent correlative studies.  Blood samples were collected at 
baseline and day 3 to measure circulating endothelial cells (CEC:  nucleated CD133-
CD146+CD31+CD45-), and circulating 
endothelial progenitor cells (CPC: 
viable nucleated CD133+, CD146-, 
CD31+ CD45 - or dim).  10 patients 
had paired correlative CEC/CPC 
studies.  The increase of CEC 
pretreatment to day 3 was correlated 
with PFS>6mo in 6 pts on O+C 
(p=0.011, 95%CI 0.47-0.99, R2=0.91).  
The increase of CEC pretreatment to 
day 3 correlated with PFS>6mo in 5 
patients on cediranib and olaparib 
(P=0.011, 95%CI 0.47-0.99, R2=0.91, 
Lee et al. manuscript in preparation). 
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. We hypothesize a risk classifier by Flow 
Cytometry, including CECs, may correlate with clinical response to olaparib and 
cediranib combination in recurrent ovarian cancer.  
 
2.3.5 Genomic scarring 
 

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foci using antibodies specific to RAD51.  In addition, expression of many genes 
involved in HR mediated DNA double-strand break repair, including RAD51, is 
restricted to the S/G2 phases of the cell cycle.  Presence of RAD51 sub-nuclear foci is a 
surrogate measure of HR proficiency of the tumor sample. 
 
The D’Andrea Lab and the Center for DNA Damage and Repair at Dana-Farber Cancer 
Institute in Boston MA have developed an immunohistochemistry based assay that can 
identify RAD51-foci on pathology samples (unpublished data). 
 
Multiple studies have established the synthetic-lethal relationship between HR 
deficiency and sensitivity to inhibitors of Poly-ADP-ribose polymerase (PARP).  
Therefore, presence of RAD51-foci is expected to correlate with PARP inhibitor 
resistance.  Conditions for the assay have been developed and validated in a panel of 14 
patient-derived xenograft (PDX) models of high-grade serous ovarian cancer, where 10 
samples were BRCA1/2 wild-type and 4 samples carried mutations in BRCA1.  In-vivo 
testing of Olaparib response of these models showed that 13 models were resistant to 
Olaparib, including the BRCA1 mutant models, while a BRCA1/2 wild-type model, 
DF83, was sensitive.  Genomic analysis of DF83 revealed that the promoter of another 
HR pathway gene, RAD51C, was hyper-methylated resulting in HR-deficiency and 
PARP inhibitor sensitivity.  In correlation with PARP inhibitor response, all models 
except DF83 had sub-nuclear RAD51-foci (Figure 6). 
 
 
2.4 
eCediranib-Olaparib (eCO) Application 
 
Figure 6.  Presence of 
RAD51 foci tracks with 
PARP inhibitor response in 
ovarian cancer models.  
Sensitivity to olaparib, a 
PARP inhibitor, and the 
presence of RAD51 foci was 
determined in a cohort of 14 
PDX models derived from 
ovarian cancers.  
Characteristics of eadch PDX 
model are shown in the table 
and images of RAD51 in the 
FFPE sections of ascites-
derived cells is shown.  Note 
that DF83 is the only model 
that was sensitive to olaparib, 
and this model lacks RAD51 
foci 

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2.4.1 Rationale for developing an application for toxicity reporting 
 
The combination of cediranib and olaparib has been studied in several clinical trials, as 
outlined earlier.  Primary toxicities associated with cediranib include hypertension and 
diarrhea, which can be serious if not aggressively identified and managed and may 
require discontinuation of the drug.   These toxicities can be managed with symptom 
management, dose reductions, study drug “holidays” and use of clinical guidelines for 
management (Raja, 2011; Liu, 2015).  For example, in patients participating in the 
ICON6 study, which studied the combination of cediranib with chemotherapy followed 
by cediranib maintenance, the discontinuation rate due to diarrhea in the arm where 
cediranib was administered concurrently with chemotherapy with subsequent cediranib 
maintenance was 10.8% (Data on file, AstraZeneca).  Thus, consistent reporting and 
clinical management are key to successfully managing toxicities on the cediranib-
olaparib combination. 
 
As part of the planned study, participants are required to monitor blood pressure at 
home 2 times/day (or 1 time/day if stable after 8 weeks) and contact the study team if 
hypertension develops.  Paper diaries for self-blood pressure monitoring are kept by the 
patient and reviewed with the study team at each study visit.  However, intervention for 
any hypertensive event relies upon the patient contacting the study team to report an 
elevated blood pressure.  Reliability of self-monitoring of blood pressure has been 
previously demonstrated to be present certain challenges via use of paper diaries which 
are subject to under-reporting, over-reporting and incorrect entries (Mengden, 1998). 
 
Similarly, for diarrhea management, patients are educated about the occurrence of 
diarrhea and diarrhea management, including the use of loperamide and instructions for 
use based on the change in the number of stools from baseline.  Self-management 
instructions including initiation of a BRAT (bananas, rice, applesauce, toast) diet are 
also provided verbally by the study team.  Patients are informed when to contact the 
study team should diarrhea symptoms not be controlled using these strategies.  At each 
study visit, the patient is interviewed and the number and severity of diarrhea events are 
documented.  Again, however, interventions for diarrhea management rely on the 
patient contacting the study team when these events occur.  
 
The development of an app that might allow for better data reporting of hypertension 
and diarrheal events could therefore significantly improve early and successful 
management of these toxicities. 
 
2.4.2 Background on mobile health technology 
 
Over the past several years, the field of digital health has been rapidly growing.  Mobile 
health technologies are being utilized in a number of diseases for supporting patients 
and health care professionals including medication titration, symptom management, 
education and remote monitoring (Weaver, 2007; Kearny, 2009).  
 
Use of mobile health in oncology has been increasing in the past few years. In an early 

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pilot of use of mobile phone technology for symptom management in patients with 
colon cancer (QUASAR 2) symptoms and temperature were entered using the keypad 
by answering questions based on CTCAE criteria which were displayed on a pre-loaded 
mobile phone. Amber and red alerts were automatically sent from the server to a 
dedicated pager with response time required within 30 minutes. Clinical algorithms for 
management were utilized to assure quality and standardization. Red alerts were also 
generated if patients didn’t enter data >24 hours.  Data entry compliance was 98% and 
all patients reported positive experiences with use of the mobile phone (Weaver, 2007). 
An advanced symptom management system (ASySM©) has been evaluated in several 
clinical trials evaluating the impact of a mobile-phone based system to assess incidence, 
severity and distress related to six chemotherapy symptoms (nausea, vomiting, fatigue, 
mucositis, hand-foot syndrome and diarrhea) in patients with lung, breast of colorectal 
cancer.  These studies have shown that this technology can support symptom 
management, provide a more accurate reflection of chemotherapy related toxicity, 
provide a better means of monitoring in practice and were well received by patients 
(Kearny, 2009; Maguire, 2008; McCann, 2009).  Evaluations of telemonitoring, 
telehealth including video conferencing, text messages and mobile phone technology in 
oncology have been completed or are currently underway (Kroenke, 2010; Mooney, 
2014; Agboola, 2014). 
 
2.4.3 Background on eCO application development 
 
Therapeutic software, or companion software, is a new area of digital health providing 
a link between mobile technology and therapies.  Voluntis, a digital health company 
headquartered in Paris, France with offices in Cambridge, MA, is a pioneer in the 
development of therapeutic companion software medical devices.  In collaboration with 
the National Cancer Institute and Dana Farber Cancer Institute and supported by Astra 
Zeneca, the developer of cediranib and olaparib, Voluntis has developed eCO (e 
Cediranib-Olaparib), a mobile and web software application for use by healthcare 
providers and their adult female patients with recurrent ovarian cancer who are being 
treated with the investigational drug combination of cediranib and olaparib.  Since 
treatment with cediranib is frequently associated with hypertension and diarrhea, eCO 
provides patients with a means of capturing these symptoms on a mobile device and 
will convey, symptom management guidance to the patient, as required. This guidance 
is the same as detailed in the NCI #9825 study protocol.  eCO provides secure capture, 
storage and transmission of blood pressure and diarrhea data as well as other symptom-
related data to aid in remote monitoring of these symptoms by health care 
professionals.  The system captures symptom data through manual entry by the patient 
using icons and also includes wireless connectivity capability to measure a patient’s 
blood pressure and capture the data through a Bluetooth enabled monitor.  eCO 
supports symptom monitoring by HCPs via a secure web portal that reports and 
analyzes patient data entered in the eCO app.  The use of the app can provide 
reproducible, reliable, and immediate feedback to the patient and their healthcare team, 
consistently reinforcing self-management recommendations including when to contact 
the study team.  Additionally, the app can assist with adherence to the study protocol 
for blood pressure monitoring providing a means for the study team to be notified if 

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blood pressure values are outside of acceptable range or if monitoring is not being done 
according to the protocol recommendations. Updated diarrhea and blood pressure data 
collection protocols are incorporated into the eCO app (see Appendix H). This 
additional data collection does not change any treatment recommendations detailed in 
the study protocol. 
 
The recommendations communicated by the app are the same as those detailed in the 
study protocol, therefore, study subjects using the app will receive the same symptom 
management guidance as those not using the app. Study subjects who will not be using 
the eCO app will follow usual study procedures which include a paper diary for blood 
pressure monitoring and reporting of symptoms using guidelines provided by the study 
team 
 
Usability of the eCO app will be assessed as part of the pilot evaluation with the 
support of User-Centered Design, Inc., a Human Factors Engineering consulting firm 
headquartered in Ashburn, VA. User-Centered Design staff include psychologists, 
interaction designers, and developers who focus on improving the user experience. 
 
2.4.4 Description of the eCO Mobile Application and Web Portal 
 
eCO is a software medical device which is considered to be non-significant risk and 
will be used within the 9825 study under an Investigational Device Exemption (IDE). 
eCO consists of a mobile application for patients and a web software application for the 
study team. The eCO app and web portal have been evaluated by User-Centered 
Design, Inc. This human factors engineering/usability evaluation included a heuristic 
review and in-lab assessment with users similar to those who will participate in the 
pilot study.   
 
When enrolled in the pilot study, the patient will be entered into eCO via the study team 
web portal (see Figure 9).  Once the enrollment is completed a registration email will 
be sent to the patient which includes a temporary login and password.  Once this 
information is entered, the patient creates a 4-digit access code which is needed each 
time eCO is opened (Figure 6). During the set-up process, the patient also provides an 
answer to a security question which needs to be answered correctly in case of a 
forgotten access code.  Patients are also recommended to passcode protect her phone 
using the “Passcode” feature for the iPhone.  No data is stored in the app or on the 
phone; all data is stored in a secure, HIPPA compliant cloud server. Each phone will 
have a label placed on the outside (cover) with the User Support number in case of a 
lost or misplaced phone. 
 
2.4.5 eCO Mobile Application (for patients) 
 
The eCO App will be used by patients to: 
- 
Record self-monitored blood pressure automatically through a blue-tooth enabled 
blood pressure monitor (A&D Connected Blood Pressure Device UA651-BLE). 
- 
Manually record a self-monitored blood pressure as needed. 

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- 
Receive recommendations to recheck blood pressure within a specified timeframe 
or contact the study team based on pre-determined severity levels. 
- 
Record diarrhea based on number of bowel movements per day compared with 
baseline (pre-entered). 
- 
Receive self-management recommendations for loperamide (Imodium®) dosing 
and BRAT diet which are the same as provided to study patients who are not using 
the eCO app. 
- 
Contact the study team for hypertension and diarrhea events, as needed, based on 
pre-determined severity levels.  The “Contact” screen will allow the patient with 
one “tap” to call directly from the mobile phone using phone numbers entered by 
study staff at each study site. 
 
 
        
 
 
 
Figure 6. eCO mobile app login and home screens. “Login” screen which requires entry of a 
personalized  4-digit access code (shown on the left). “Home” screen (shown on the right)  
which is used to enter a blood pressure or a diarrhea event. The patient also can view summary 
graphs of her blood pressure and reported diarrhea as well as access phone numbers to contact 
the study team, if needed. 
 
 

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Figure 7: eCO mobile app screens for blood pressure monitoring.  Blood pressure (BP) can 
be entered into eCO automatically using the blue-tooth connected A&D BP monitor (shown on 
the left) or by manual entry using the +/- buttons (shown in the middle). Patients will be asked to 
enter any BP related symptoms. Based on these entries recommendations, using pre-determined 
severity levels, will be sent to the patient. These recommendations include continue checking 
blood pressure as prescribed, recheck BP within a specified time frame or contact the study team 
(shown on the right).  
 
             
         
Figure 8. eCO mobile app screens for recording diarrhea.  Baseline usual number of bowel 
movements per day is entered by the study team at the first study visit.  When experiencing 
diarrhea, the patient is asked to enter the number of bowel movements per day which is 
compared against baseline and any symptoms that are entered.  Using the patient entries, the 
app will provide recommendations, based on pre-determined severity levels. These 
recommendations include use of loperamide and start BRAT diet or contact the study team. 
 

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See the Appendix for full-size screenshots of the eCO app. eCO will be available for 
use on the Apple iOS platform with iPhone models starting from the 4S through the 
current model. Patients who currently use an iPhone will be asked to install the eCO 
app on their phone. Patients who use an Android phone or do not currently use a 
smartphone will be provided with an iPhone 6 which has the eCO app preloaded and 
includes a data plan for calling and receiving calls from the study team (intended for 
study use only). 
 
eCO User Support will be utilized to track any app malfunctions that occurred during 
the pilot study. Adverse event reporting will be done according the 9825 clinical trial 
protocol using the study approved eCRFs. Adverse events (device-related injury) that 
could be related to the investigational device (eCO app) will be recorded using CTEP 
procedures and reported to Voluntis, Inc., the legal manufacturer of eCO. 
 
Data collected via the eCO app will not be used for grading of adverse events nor used 
for primary study analysis. 
 
2.4.6 eCO Healthcare Professional Web Portal 
 
Each study center will be added to the eCO system by a back office administrator with 
assigned rights to add new study centers.  Each study center will have an identified staff 
person who will be responsible for identifying the health professionals (HCP) who are 
involved in the study at the site.  Upon adding study team members to eCO, a 
registration email will be sent to the HCP which includes a temporary login and 
password.  During the first sign in, the study team member will reset the password and 
answer a secret question which will be required to reset a password.  Each study team 
member will have his/her own personal account.  
 
The eCO Healthcare Professional Web Portal will be used by the study team to: 
- 
Add patients to the web portal who are participating in the pilot study. Adding a 
patient to the eCO web portal will generate an email to the patient with a temporary 
login ID and password. 
- 
Set frequency of blood pressure reminders (twice daily or once daily) based on the 
study protocol. 
- 
Monitor patients who are participating in the pilot study at their site including 
patients on the “Patient Watchlist” who are considered in a “BP event” with close 
monitoring. 
- 
Specify the team (Oncologist and Research Nurse) who will be receiving email 
alerts for BP >180/110 mmHg and systolic BP ≤ 90 mmHg. 
- 
Monitor patients who have entered or are continuing in a “diarrhea event” with 
severity indicated by number of flag icons (1-4). 
- 
Review the individual patient profile which includes patient demographics, 
summary of BP values, reported diarrhea events, notifications and 
recommendations. 
- 
Enter “Action recommendations” using a drop down list of actions for hypertension 
and diarrhea based on an individual BP or diarrhea entry. 

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- 
Review notifications received on individual patients based on pre-defined criteria. 
Notifications history will be maintained in the specific patient file on the web 
portal. 
- 
Inactivate patients who are no longer participating in the pilot study. 
- 
Have access to sections of the 9825 study protocol pertaining to hypertension and 
diarrhea management which have been uploaded into the web portal. 
 
Interventions for hypertension management or study drug holds will be done per 
protocol by the study team and documented as required in the study eCRFs and/or 
medical record. 
 
 
 
 
Figure 9. Adding a new patient profile into the eCO web portal. This screen shows some of 
the key information entered by the study team to add a new patient. At the first study visit, the 
study team enters required information for the eCO app including baseline diastolic blood 
pressure, frequency of BP reminders and baseline number of stools per day. 
 

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40 
 
 
Figure 10. eCO HCP Web Portal. Example of the home screen for the web portal includes a 
list of active patients and a summary of key data which can be used by the study team to monitor 
their patients.  The “Patient Watchlist” in red includes those patients who are currently being 
more closely monitored for a “BP event”.  Those patients who are currently considered in a 
“Diarrhea event” are indicated by a flag (number of flags indicate severity).   
 

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41 
  
 
 
Figure 11: Patient profile from the eCO Web Portal. Example of a patient profile which 
includes current and historical data on that patient for BP monitoring and diarrhea event 
reporting, notifications and hospitalization status. 
 
2.4.7 Cybersecurity Risk Controls 
 
Cybersecurity is the protection of information systems from theft or damage to the 
hardware, the software, and to the information on them, as well as from disruption or 
misdirection of the services they provide. It includes controlling physical access to the 
hardware, as well as protecting against harm that may come via network access, data 
and code injection, and due to malpractice by operators, whether intentional, accidental, 
or due to them being tricked into deviating from secure procedures.  
 
eCO has undergone a risk assessment/analysis and risk controls measures for 
cybersecurity. This Risk Management process is based on ISO 14971 (Application of 
Risk Management to Medical Devices, a nine-part standard which first establishes a 

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42 
framework for risk analysis, evaluation, control, and management, including a specified 
a procedure for review and monitoring during production and post-production). The 
EBIOS approach is used to express the security needs and identify the security 
objectives. It is compliant with standards ISO 27000  (Information technology -- 
Security techniques -- Information security management systems -- Overview and 
vocabulary), ISO 15408 (Information technology – Security techniques – Evaluation 
criteria for IT security) and ISO 17799 (Information technology -- Security techniques -
- Code of practice for information security management).This process is based on the 
analysis of the context of the application and defining the scope of the information 
system on which the risk assessment is performed (intended use, software requirements, 
critical functions, data workflow, architecture if the information system) in order to 
obtain a detailed and prioritized list of events that may affect the application. The 
security needs are based on availability, integrity, confidentiality and auditability, as 
well as the potential impacts of a cybersecurity breach. For each potential threat, a list 
of vulnerabilities is established depending on the equipment, architecture and software 
(example: web portal authentication, attacked obtains a user password via a server-side 
brute force attack). Then, a risk analysis is performed to define the risk level, 
corresponding to the highest threat a security breach could lead to, as well as the 
likelihood (probability of harm that could occur to a user of the application). 
Mitigations are then identified for each risk in order to eliminate or reduce to an 
acceptable level the identified risks. 
 
2.4.8 Participating Study Sites and Enrollment 
 
The 9825 main study plans to enroll 70 patients in 12 centers who are part of the 
ETCTN network.  Subjects who are eligible for enrollment in the 9825 study will be 
offered the opportunity to participate in the pilot.  Subjects previously enrolled in the 
study prior to the eCO app start date can choose to use the eCO app to track blood 
pressure and diarrhea, although this data will not be used for the pilot study analysis. 
 
Subjects who are willing to participate in the pilot will complete the informed consent 
form during a routine visit with their study coordinator.   
 
The pilot study intends to enroll a minimum of 12 patients and up to 20 patients. 
Accrual is anticipated to be 1-2 patients/month. 
 
Subjects who currently use an iPhone will have the option of installing the eCO app on 
their personal phone and use it during the study or will be provided with an iPhone 6 
for use during the study. Subjects who currently use an Android phone or who do not 
have a smartphone will be provided with an iPhone 6 at the first study visit. The 
iPhones provided will have the eCO app preinstalled as well as a limited data plan and 
will be restricted to study use only. A label will be applied to the outside of each phone 
with the User Support number in case of technical issues or lost or misplaced phone.  
Phones provided by the study will also be labeled with an inventory number which has 
been assigned to the patient. 
 

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43 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Participants must have histologically or cytologically confirmed ovarian cancer, 
peritoneal cancer or fallopian tube cancer and must have a histological diagnosis of 
either high grade serous or high grade endometrioid cancer based on local 
histopathological findings.  Participants with a deleterious BRCA-mutation on a 
commercial CLIA assay with other high-grade histologies are also eligible. 
 
Due to the long acceptance of BRCA testing through Myriad, Myriad testing will be 
accepted as documentation of a deleterious mutation.  If testing for BRCA is done by 
other organizations, documentation from a qualified medical professional (e.g., 
ovarian cancer specialty physician involved in the field, high risk genetics physician, 
genetics counselor) listing the mutation and confirming that the laboratory results 
show a recognized germline deleterious BRCA1 or BRCA2 mutation or BRCA 
rearrangements is required to document the presence of a deleterious mutation.  
Please collect a copy of Myriad or other BRCA mutational analysis (positive or VUS 
or negative) reports. 
 
3.1.2 Participants must have measurable disease via RECIST 1.1, defined as at least one 
lesion that can be accurately measured in at least one dimension (longest diameter to 
be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with 
conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by 
clinical exam.  See Section 11 for the evaluation of measurable disease. 
 
3.1.3 Prior therapy 
3.1.3.1 
Patients may not have received prior PARP inhibitors 
 
3.1.3.2 
Patients may have received but may not have progressed on prior anti-
angiogenic therapy in the upfront setting 
 
3.1.3.3 
For platinum sensitive cohort 
1)  Cancer that has not progressed within 6 months of the last receipt of 
platinum-based chemotherapy. 
2)  No limit on the number of platinum-based lines 
3)  No more than one prior non-platinum based line of therapy in the 
recurrent setting 
 
3.1.3.4 
For platinum-resistant or -refractory cohort 
1)  Disease that has progressed within 6 months of the last receipt of 
platinum-based chemotherapy 
2)  No more than 1 prior line of therapy in the platinum-resistant/-
refractory setting. 
3)  No limit on number of prior lines received in the platinum-sensitive 

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setting prior to development of platinum-resistance (defined as disease 
progression within 6 months of platinum-based chemotherapy). 
 
Hormonal therapies used as single agents (i.e. tamoxifen, aromatase inhibitors) will 
not count towards line limit considerations. 
 
3.1.4 Age ≥18 years of age.   Because no dosing or adverse event data are currently 
available on the use of cediranib or olaparib in patients under the age of 18, children 
are excluded from this study.    
 
3.1.5 ECOG performance status ≤2 (see Appendix A) 
 
3.1.6 Participants must have normal organ and marrow function as defined below: 
 
− 
Leukocytes 
≥3,000/mcL 
− 
Absolute neutrophil count 
≥1,500/mcL 
− 
Hemoglobin   
 
≥10 g/dL 
− 
Platelets 
≥100,000/mcL 
− 
Total bilirubin 
≤1.5 x the institutional upper limit of normal (ULN) 
− 
AST(SGOT)/ALT(SGPT) 
≤3 × institutional upper limit of normal 
− 
Creatinine 
less than or equal to the institutional upper limit of  
 
normal 
OR 
− 
Creatinine clearance 
≥60 mL/min/1.73 m2 for participants with creatinine 
levels above institutional normal. 
− 
Proteinuria  
 
 
less than or equal to 1+ proteinuria on two consecutive 
dipsticks taken no less than week apart, or a urine 
protein:creatinine (UPC) ratio of ≤1. 
− 
Coagulation parameters 
≤ 1.25 × ULN institutional limits, except where a  
(INR, aPTT)  
 
Lupus anti-coagulant has been confirmed 
 
 
3.1.7 Presence of biopsiable disease and willingness to undergo pre-treatment and on-
treatment biopsy 
 
3.1.8 The effects of olaparib and cediranib on the developing human fetus are unknown.  
For this reason, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry, for the duration of study participation, and up to 3 months after 
end of treatment.  Should a woman become pregnant or suspect she is pregnant 
while she or her partner is participating in this study, she should inform her treating 
physician immediately.   
 
3.1.9 Adequately controlled thyroid function, with no symptoms of thyroid dysfunction and 
TSH less than or equal to the upper limit of normal. 
 

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3.1.10 Patients must be able to tolerate oral medications and not have gastrointestinal 
illnesses that would preclude absorption of cediranib or olaparib. 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.1.12 Willingness to release and confirmed availability of archival tissue sample for 
research purposes.  
 
3.1.13 Willingness and ability to check and record daily blood pressure readings. Blood 
pressure cuffs will be provided to patients. Please refer to sections 5.4, and Appendix 
C (blood pressure diary). 
 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Participants may not have had chemotherapy or RT within 3 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study and must have recovered to 
≤ grade 1 from adverse events due to agents administered more than 3 weeks earlier.  
Patients should not have received hormonal therapy for treatment of their cancer 
within 2 weeks of study entry.  
 
3.2.2 Participants should not have received any other investigational agents nor have 
participated in an investigational trial within the past 4 weeks.   
 
3.2.3 Participants may not have had prior use of PARP inhibitors.  Patients may not have 
received prior treatment affecting the VEGF pathway in the recurrent setting, 
including but not limited to thalidomide, bevacizumab, sunitinib, or sorafenib.   
 
3.2.4 Participants may not have any evidence of ongoing inadequately controlled 
hypertension (defined as a systolic BP of >140 mmHg or a diastolic BP of >90 
mmHg).  Patients with hypertension may not be on more than three antihypertensive 
medications for management of their blood pressure (medications that combine two 
anti-hypertensives into one are considered as two medications).  It is strongly 
recommended that patients who require three antihypertensive medications for 
baseline management of pre-existing hypertension be actively followed by a 
cardiologist or blood pressure specialist for management of BP while on protocol. 
 
3.2.5 Participants may not have had any prior history of hypertensive crisis or hypertensive 
encephalopathy. 
 

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3.2.6 Participants may not have had history of abdominal fistula or gastrointestinal 
perforation. Patients with a history of abdominal fistula will be considered eligible if 
the fistula has healed or was surgically repaired, there has been no evidence of 
fistula for at least 6 months, and patient is deemed to be at low risk of recurrent 
fistula. 
 
3.2.7 Participants may not have had a history of intra-abdominal abscess within the past 3 
months. 
 
3.2.8 Participants may not have current signs and/or symptoms of bowel obstruction or 
signs and/or symptoms of bowel obstruction within 3 months prior to starting study 
drugs 
 
3.2.9 Participants may not have a dependency on IV hydration or TPN. 
 
3.2.10 Participants with any concomitant or prior invasive malignancies are ineligible with 
the following exceptions: 
 
• Treated limited-stage basal cell or squamous cell carcinoma of the skin 
• Carcinoma in situ of the breast or cervix 
• 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, 
clear cell, or other FIGO grade 3 lesions. 
• Prior cancer treated with curative intent with no evidence of recurrent disease 3 years 
following diagnosis and judged by the investigator to be at low risk of recurrence. 
 
3.2.11 Participants with any of the following: 
• History of myocardial infarction within six months 
• Unstable angina 
• NYHA classification of III or IV 
 
3.2.12 If cardiac function assessment is clinically indicated or performed:  participants will 
be ineligible if left ventricular ejection fraction (LVEF) is less than normal per 
institutional guidelines, or <55%, if the threshold for normal is not otherwise 
specified by institutional guidelines. 
 
Patients with any of the following risk factors should have a baseline cardiac function 
assessment: 
• Prior treatment with anthracyclines 
• Prior treatment with trastuzumab 
• Prior central thoracic radiation therapy (RT), including RT to the heart 
• History of myocardial infarction within 6 to 12 months (Patients with history of 
myocardial infarctin within 6 months are excluded from the study 
• A NYHA classification of II controlled with treatment (see Appendix E)  

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• Prior history of impaired cardiac function 
 
3.2.13 Participants may not have had a history of a stroke or transient ischemic attack within 
six months 
 
3.2.14 Participants should not have clinically significant peripheral vascular disease or 
vascular disease (including aortic aneurysm or aortic dissection). 
 
3.2.15 Participants may not have a major surgical procedure, open biopsy, or significant 
traumatic injury within 28 days prior to starting cediranib. 
 
3.2.16 Participants should not have any uncontrolled intercurrent illness including, but not 
limited to ongoing or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
 
3.2.17 Patients with untreated brain metastases, spinal cord compression, or evidence of 
symptomatic brain metastases or leptomeningeal disease as noted on computed 
tomography (CT) or magnetic resonance imaging (MRI) scans are ineligible.  
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 must demonstrate stable post-therapeutic imaging and 
resolution of any associated symptoms and must be stably off steroids with no 
symptoms for at least 6 months following therapy prior to starting study drug. 
 
3.2.18 Participants may not have a history of allergic reactions attributed to compounds of 
similar chemical or biologic composition to cediranib or olaparib. 
 
3.2.19 Participants receiving any medications or substances that are strong inhibitors or 
inducers of CYP3A4 or moderate inhibitors of CYP3A4 are ineligible (see 
Appendix D).  The study team should check a frequently-updated medical reference 
for a list of drugs to avoid or minimize use of. As part of the enrollment/informed 
consent procedures, the patient will be counseled on the risk of interactions with 
other agents, and what to do if new medications need to be prescribed or if the 
patient is considering a new over-the-counter medicine or herbal product.  
Dihydropyridine calcium-channel blockers are permitted for management of 
hypertension. Appendix D (Patient Drug Information Handout and Wallet Card) 
should be provided to patients. 
 
3.2.20 Pregnant women are excluded from this study because olaparib and cediranib have 
the potential for teratogenic or abortifacient effects.  Because there is an unknown 
but potential risk for adverse events in nursing infants secondary to treatment of the 
mother with olaparib and cediranib, breastfeeding should be discontinued if the 
mother is treated with cediranib and olaparib. These potential risks may also apply to 
other agents used in this study. 
 

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3.2.21 HIV-positive patients on combination antiretroviral therapy are ineligible because of 
the potential for pharmacokinetic interactions with cediranib or olaparib.  In 
addition, these patients are at increased risk of lethal infections when treated with 
marrow-suppressive therapy.  Appropriate studies will be undertaken in patients 
receiving combination antiretroviral therapy when indicated. 
 
3.2.22 Participants should not have evidence of coagulopathy or bleeding diathesis.  
Therapeutic anticoagulation for prior thromboembolic events is permitted. 
3.2.23 Current use of a prohibited medication.  The following medications or non-drug 
therapies are prohibited: 
• Other anti-cancer therapy while on study treatment. 
• Prophylactic use of bisphosphonates in patients without bone disease, except for 
the treatment of osteoporosis. 
• Because the composition, PK, and metabolism of many herbal supplements are 
unknown, the concurrent use of all herbal supplements is prohibited during the 
study (including, but not limited to, cannabis, St. John’s wort, kava, ephedra [ma 
huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, 
or ginseng). 
• Raloxifene is allowed for patients taking it for bone health. 
 
3.2.24 Participants may not have any features suggestive of myelodysplastic syndrome 
(MDS) or acute myelogenous leukemia (AML) on peripheral blood smear or bone 
marrow biopsy, if clinically indicated. 
 
 
 
 
3.3 
Inclusion of Women and Minorities 
 
Because only women can develop ovarian cancer, only women are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN or RAVE or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 

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50 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
  
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 9825 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based 
on person and site roster data housed in the CTSU RSS.  To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol 
organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password 
• Click on the Protocols tab in the upper left of your screen  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-MA036, 
and protocol #9825 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 
Submitting Regulatory Documents 
 
Requirements For 9825 Site Registration: 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 

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51 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption Form, 
or combination is accepted) 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.   
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
4.2.3 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU 
website.   
 
• 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 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
4.3 
Patient Registration 
 

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4.3.1 
OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 
initiation to check slot availability.  Registration staff should ensure that a slot is 
available and secured for the patient before completing an enrollment. 
 
Once a slot reservation request has been made, the following source documentation 
should be faxed to the Lead Institution or designee for confirmation of eligibility. 
• Copy of required laboratory tests: 
o CBC with differential 
o Serum chemistries (sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, albumin, calcium, phosphorus, AST (SGOT), ALT 
(SGPT), alkaline phosphatase, total bilirubin) 
o TSH, free T4 
o Urinalysis (2 measures at least 1 week apart) or urine protein:creatinine 
ratio 
o CA125 
• Signed informed consent form 
• HIPAA authorization form (if separate from the informed consent document) 
• EKG 
• MUGA or ECHO (if indicated) 
• CT scan (chest, abdomen, pelvis) 
• Pathology report 
• Screening or most recent clinic visit note (including documentation of oncologic 
history, past medical history, concomitant medications) 
• BRCA test report, if BRCA testing has been performed  
• Documentation of availability of archival tissue 
• Documentation of the presence of biopsiable disease 
• Documentation of patient’s willingness and ability to check and record daily 
blood pressure readings. 
 
The Lead Institution or designee may then approve the slot reservation to allow 
completion of enrollment.  
 
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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4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. Registrars must 
hold a minimum of an AP registration type.  If a DTL is required for the study, 
the registrar(s) must also be assigned the OPEN Registrar task on the DTL. 
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.  
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 
OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex website:  http://theradex.com/CTMS/Downloads.aspx. This 
link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk: 609-619-7862 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 14 days.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
  
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
Treatment will be administered on an outpatient basis.  The cycle length is 28 days, and patients 
will undergo cancer assessment per RECIST 1.1 criteria after every 2 cycles of therapy.   

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54 
Expected toxicities and potential risks as well as dose modifications for cediranib and olaparib 
are described in Section 6 (Expected Toxicities and Dosing Delays/Dose Modifications). No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant's malignancy.  
 
Toxicity assessments will be done using NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 until March 31, 2018. 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.  
 
Regimen Description 
Agent 
Dosing 
Instructions 
Dose 
Route 
Schedule 
Cycle 
Length 
Olaparib  
Olaparib will be 
given BID at the 
same times each 
day.  
200 mg 
PO 
Twice daily 
and 
continuously 
28 days  
(4 weeks) 
 
 
 
Cediranib 
Orally each 
morning on an 
empty stomach, 
either 1 hour 
before or 2 hours 
after breakfast. 
30 mg 
PO 
Daily and 
continuously 
 
The participant will be required to maintain an accurate medication diary of each dose of 
medication.  The medication diary will be returned to clinic staff at the end of each cycle. 
 
5.2 
Pre-treatment Criteria 
 
5.2.1 Screening Visit 
 
Patients must meet criteria at screening as outlined in Section 3.1 
 
5.2.2 Hematologic Parameters for Treatment 
 
Patients must meet the following absolute neutrophil count (ANC) and hematologic parameters 
for treatment.  Additionally, dosing parameters for hematologic AEs in Section 6.2 should be 
observed. 
 
• Cycle 1, Day 1:  ANC ≥ 1500/mm3  

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55 
 
• Cycle 1 Day 15: 
o ANC ≥ 1000/mm3 
o Platelets > 100,000/mcL 
o Hemoglobin > 8 mg/dL 
 
• Cycles 2 and beyond, Day 1:   
o ANC ≥ 1000/mm3 
o Platelets > 100,000/mcL 
o Hemoglobin > 8 mg/dL 
 
5.2.3 All Cycles, Day 1 
 
Patients must meet the following parameters on day 1 of each cycle to proceed with treatment.  
Patients who do not meet these criteria may resume treatment later in the cycle once criteria are 
met.  Cycles and days are numbered continuously regardless of any dose holds or delays in 
resumption of treatment. 
 
• Adequate blood pressure control, as detailed in Section 6.3 
• Serum creatinine ≤ 1.5 x the institutional upper limit of normal 
• Liver function tests (AST and ALT) ≤ 3 x the institutional upper limit of normal 
• ECOG performance status of 0, 1 , or 2 
• No evidence of life-threatening medical problems 
• Urine protein:creatinine ratio OR urine dipstick protein as detailed in Section 6.5 
 
5.2.4 Pre-Cycle 1 Therapy:  Translational Component 
 
All patients are required to participate in the translational component of the trial.  The presence 
of biopsiable disease should be determined before patients sign the informed consent based upon 
assessment of prior imaging studies.  If a patient previously deemed to be biopsiable is 
subsequently found to not have safely biopsiable disease, the patient is not prejudiced from 
receiving treatment.  Biopsiability should be re-determined at the time of each mandatory biopsy; 
if the patient does not have disease that can be safely biopsied at that time, the planned biopsy 
should be waived.  Drug therapy will be initiated after acquisition of initial translational 
components and dispensed for the 28-day cycle.  Translational component sample acquisition 
will occur as detailed in Section 9. 
 
5.3 
Agent Administration 
 
5.3.1 Cediranib 
 
Cediranib at the appropriate dose level will be given orally continuously each morning on an 
empty stomach, either 1 hour before or 2 hours after breakfast. Subjects should not “make up” a 
missed dose or a dose that was vomited. Subjects should take cediranib with a glass of water.  

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Cediranib will be dispensed at the start of each cycle. Patients will be provided with a pill diary 
for each drug (Appendix B), instructed in its use, and asked to bring it with them to each 
appointment. 
Frequent blood pressure monitoring is important in patients receiving cediranib. Clinical trials of 
cediranib demonstrate that increases in blood pressure may occur following dosing with 
cediranib for a number of weeks and that these increases may occur relatively quickly when 
starting the drug. Patients will be asked to record twice-daily blood pressure readings (Appendix 
C). If two successive systolic readings are >140 mmHg OR two successive diastolic readings are 
>90 mmHg OR any combination of elevated systolic and diastolic blood pressure are observed, 
patients will be instructed to contact their physician as soon as possible. Patients should seek 
medical advice if their BP exceeds 180 mmHg (systolic) or 105 mmHg (diastolic) at any time 
and should also be encouraged to contact their physician if they are concerned about any 
symptoms that may be associated with high blood pressure (e.g., headache). Section 6 includes 
specific guidelines on the management and, if appropriate, dose modifications for treatment- 
emergent hypertension. 
5.3.2 Olaparib (tablet formulation) 
 
Olaparib at the appropriate dose level will be given orally continuously twice daily, with doses 
taken at the same times each day approximately 12 hours apart. The correct number of 100mg or 
150mg tablets comprising the appropriate dose should be taken at the same times each day with 
approximately 240 mL of water. The morning dose may be taken approximately 1 hour after the 
cediranib dose, following a light meal/snack.  The evening dose may be taken with a light 
meal/snack.  The olaparib tablets should be swallowed whole and not chewed, crushed, 
dissolved, or divided. 
Olaparib will be dispensed at the start of each cycle. Patients will be provided with a pill diary 
(Appendix B), instructed in its use, and asked to bring it with them to each appointment. 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted. Should any patient enrolled on the 
study miss a scheduled dose, the patient will be allowed to take the scheduled dose up to a 
maximum of 2 hours after that scheduled dose time. If greater than 2 hours after the scheduled 
dose time, the missed dose should not be taken, and the patient should take their allotted dose at 
the next scheduled time.  Subjects should avoid grapefruit juice while on study, due to P450 
interactions. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Cediranib demonstrated minimal inhibitory effects on the activity of CYP3A4 (testosterone and 
midazolam) in vitro, although the IC50 was far in excess of the clinically relevant concentrations.  
Based on in vitro and clinical exposure data, olaparib is considered unlikely to cause clinically 
significant drug interactions through inhibition or induction of cytochrome P450 enzyme 
activity.  However, in vitro data have also shown that the principal enzyme responsible for the 

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formation of the 3 main metabolites of olaparib is CYP3A4.  Given these data, potent inhibitors 
or inducers of CYP3A4 as outlined in Appendix D must not be used during this study for 
patients receiving olaparib.  Moderate inhibitors of CYP3A4 should be avoided.  If the inhibitor 
cannot be avoided, the olaparib tablet should be reduced by 50% during the duration that the 
patient remains on the moderate CYP3A4 inhibitor, as per below the table below.  
Dihydropyridine calcium-channel blockers are allowed for management of hypertension. 
Olaparib tablet dose 
Olaparib tablet dose on moderate CYP3A inhibitor 
200mg BID 
100mg BID 
150mg BID 
150mg daily (patient should take AM dose) 
100mg BID 
100mg daily (patient should take AM dose) 
 
 
Because of the potential for interaction of cediranib with other concomitantly administered drugs 
through the cytochrome P450 system, the case report form must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies.   
 
Patient should receive general concomitant and supportive care medications based on best 
medical practice.  Neupogen and other bone marrow-supportive agents, including erythropoiesis-
stimulating agents, are not allowed during treatment. 
 
Other anti-cancer therapy while on study treatment is not permitted.  
 
Prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for 
the treatment of osteoporosis. 
 
The use of any natural/herbal products or other “folk remedies” is not allowed on study.  All 
medications must be recorded in the case report form and be reviewed by the treating physician 
at each visit. 
 
Frequent blood pressure monitoring is important in patients receiving cediranib.  Experience to 
date suggests that increases in blood pressure may occur following dosing with cediranib for a 
number of weeks and that these increases may occur over a relatively short time frame.  It is 
imperative that the investigator institute appropriate measures to control BP.  This may 
necessitate changes to existing antihypertensive medication, addition of new medication(s), 
and/or interruption/withdrawal of cediranib. Patients will be provided blood pressure cuffs and 
must be able and willing to monitor their blood pressure on a twice daily basis.  
 
Supply and Distribution: Blood pressure cuffs will be supplied by VWR.  Each kit contains a 
blood pressure monitor (which includes standard size cuff), an adaptor and a large size cuff.  Kits 
will be shipped in the original manufacturer’s packaging. 
 
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 email it to the VWR staff listed on the form.  The 
form is available on the CTSU website.  
 

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Section 6 includes specific guidelines on the management and, if appropriate, dose modifications 
for treatment-emergent hypertension.   
 
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 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. 
 
Cediranib can impair healing.  For this reason, cediranib should be held two weeks prior to any 
surgical procedures and may be restarted when the surgical wound is healed.  Patients who have 
had major surgical procedure, open biopsy, or significant traumatic injury within 28 days of 
starting cediranib are not eligible for the study, as per Section 3.2.16. 
 
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue on  
until one of the following criteria applies: 
 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
• 
Participant decides to withdraw from the protocol therapy 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
5.6 
Duration of Follow Up 
 
Participants removed from protocol therapy for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event. All participants’ vital status may be 
followed after removal from the study treatment using publically available databases. 
 

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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. 
 
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 PI, 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 PI. 
 
6.3 
Hypertension  
 
Increases in BP and cases of hypertension have been associated with many drugs acting on the 
VEGF pathway.  The proposed mechanism for this increase is through inhibition of VEGF-
induced peripheral vasodilation.  Hypertension following cediranib treatment has been seen in 
animal studies as well as clinical trials.   
 
Only doses of cediranib will be modified for hypertension; olaparib doses will not be reduced 
unless other toxicities are experienced.  Patients receiving cediranib will be provided with blood 
pressure monitors for home use and will check and record their blood pressures at least twice 
daily while on study treatment. 
 
See the table below for guidelines on hypertension management and Appendix G for suggested 
antihypertensive medications by class.  
 
Note: 
• If patients require a delay of >2 weeks for management of hypertension, management 
should be discussed with the overall PI and may require discontinuation from protocol 
therapy 
• Patients may have up to 4 drugs for management of hypertension prior to any dose 
reduction in cediranib. 
• Hypertension should be graded using the NCI CTCAE v4.0 until March 31, 2018. 
CTCAE version 5.0 should be utilized beginning April 1, 2018. Patients with baseline 
hypertension who require the addition of new medications for hypertension management 
while on study drug may not have an increase in CTCAE grade, but a change in 
attribution should be noted. 
• 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. 
 
Table 6.3: Hypertension Monitoring and Management 
• See Appendix G 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 

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second agent. 
 
Study drug does 
not need to be held 
unless otherwise 
clinically necessary 
 
Consider renal 
consult 
 
Grade 3 
Requiring more 
than one drug or 
more intensive 
therapy than 
previously.     
Maximize 2 drug 
regimen 
• 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. 

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indicated 
 
Consider shoulder MRI if 
symptoms warrant. 
2 
Moderate; minimal, local, 
or noninvasive 
intervention indicated; 
limiting age appropriate 
instrumental ADL 
Obtain shoulder MRI if 
not previously obtained. 
 
If rotator cuff injury 
present on MRI, refer for 
physical therapy.   
 
Consider referral to 
orthopedics for 
evaluation as appropriate. 
If deemed study-drug 
related, hold cediranib and 
olaparib for up to 14 days 
until symptoms resolve to 
Grade 1 or less.  Cediranib 
and olaparib may then be 
resumed at a reduced dose 
level of each study drug.  
If patient is on the lowest 
dose level(s) of cediranib 
or olaparib, please contact 
the study PI to discuss 
dose modifications. 
3 
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated; 
disabling; limiting self 
care ADL 
Obtain shoulder MRI if 
not previously obtained. 
 
Refer to orthopedic 
surgeon for evaluation. 
If deemed study-drug 
related, hold cediranib and 
olaparib for up to 14 days 
until symptoms resolve to 
Grade 1 or less.  Cediranib 
and olaparib may then be 
resumed at a reduced dose 
level of each study drug 
after discussion with the 
overall PI. 
 
6.13 
Myelodysplastic Syndrome 
 
Myelodysplastic syndrome (MDS) has been described in patients receiving olaparib. To monitor 
for any potential development of MDS, 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. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 

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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. 
 
7.1.1.2 
CAEPR for Cediranib 
 
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 

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PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, Enterovesical 
fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, Pancreatic fistula, 
Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS SOC. 
 
3Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the 
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 

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pain; Bone pain; Chest wall pain; Muscle cramp; Muscle weakness lower limb; Muscle weakness upper limb; 
Myalgia; Myositis; Neck pain; Pain in extremity; Rotator cuff injury 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Central nervous system necrosis; Cognitive disturbance; Depressed 
level of consciousness; Dysarthria; Dysgeusia; Dysphasia; Encephalopathy; Hydrocephalus; Ischemia 
cerebrovascular; Memory impairment; Muscle weakness left-sided; Nervous system disorders - Other (coma); 
Nervous system disorders - Other (right hemiparesis); Olfactory nerve disorder; Peripheral motor neuropathy; 
Peripheral sensory neuropathy; Seizure; Somnolence; Spinal cord compression; Stroke; Syncope; Transient ischemic 
attacks; Tremor 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Depression; Hallucinations; Insomnia; Suicide attempt 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Cystitis noninfective; 
Hematuria; Urinary retention; Urinary tract obstruction 
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. 
 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  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.   
 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 

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- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in 
the “NCI Guidelines for Investigators: Adverse Event Reporting Requirements for 
DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from 
the CTEP Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events
.htm).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization, the local treating physician, and the 
Reporter and Submitter.  CTEP-AERS provides a copy feature for other e-mail 
recipients.  
 
The Coordinating Center of the Corresponding Organization is responsible for submitting 
to the CTSU documentation of AEs that they deem reportable for posting on the CTSU 
protocol web page and inclusion on the CTSU bi-monthly broadcast. 
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 
provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” 
in the system organ class (SOC) “General disorders and administration site conditions.”  
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
 
 

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CTEP-AERS must also be reported in routine study data submissions. 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE 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.  
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.  
 
7.7 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1. 
 
 
8.1.1 Olaparib (AZD2281) (NSC 747856) 
 
Chemical Name:  4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-
fluorophenyl)methyl]phthalazin-1(2H)-one 
 
Other Names: AZD2281; KU-0059436; CO-CE 42 
 
Classification: PARP inhibitor 
 

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CAS Registry Number: 763113-22-0 
 
Molecular Formula: 
 C24H23FN4O3 
 
 
 
M.W.: 434.46 
 
Approximate Solubility: 0.1 mg/mL pH independent solubility across physiologic range 
 
Mode of Action: Olaparib is an inhibitor of subclasses 1, 2, and 3 of polyadenosine 5’ 
diphosphoribose polymerase (PARP-1, PARP-2, and PARP-3). In tumors that are deficient 
in the homologous recombination DNA repair pathway (example, BRCA mutants), 
inhibition of PARP by olaparib causes accumulation of DNA double-strand breaks and 
genomic instability. Olaparib may also enhance the effects of DNA damage caused by 
ionizing radiation and chemotherapy.  
 
Description: crystalline solid 
 
How Supplied: AstraZeneca supplies and the CTEP, DCTD distributes olaparib as green, 
film-coated tablets in 100 mg and 150 mg strengths.  
 
• 100 mg tablets are 14.5 mm x 7.25 mm oval-shaped 
• 150 mg are 14.5 mm x 7.25 mm oval-shaped 
 
Tablets are packaged in induction-sealed high-density polyethylene (HDPE) bottles with 
child-resistant closures. Each bottle contains 32 tablets with desiccant.  
 
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. 
 
Storage: Store in a secure location below 30° C (86° F). Sites are not permitted to re-
package tablets. Once the bottle is opened, olaparib tablets must be used within 3 months 
of the opening date; unused tablets should be discarded. Instruct patients not to open a 
bottle until they are ready to use it. 
 
Stability:  Shelf-life studies are ongoing.  If a storage temperature excursion is identified, 
promptly return olaparib to < 30 °C and quarantine the supplies.  Provide a detailed 
report of the excursion (including documentation of temperature monitoring and duration 
of the excursion) to PMBAfterHours@mail.nih.gov for determination of suitability.   
 
Route of Administration:  Tablets can be taken by mouth with a light meal/snack. 
 
Potential Drug Interactions:  In vivo data indicate that CYP3A4/5 is important for olaparib 
metabolism and clearance in humans. For this reason, avoid concomitant administration of 
strong and moderate CYP 3A4/5 inducers and inhibitors.  Consult the protocol document 

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or study investigator prior to making any dose adjustments related to potential drug-drug 
interactions. 
 
In vitro data shows olaparib is a substrate for P-glycoprotein (P-gp), but not for organic 
anion-transporting polypeptides (OATP1B1 and OATP1B3), organic cation transporter 1 
(OCT1), multi-drug resistance protein 2 (MRP-2) efflux transporter or breast cancer 
resistance protein (BCRP). Administration of strong P-gp inhibitors and inducers should be 
avoided with concurrent olaparib.   
 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems and 
induces CYP 1A2, 2B6, and 3A4 and potentially induces CYP 2C9, 2C19 and P-gp. 
Therefore, avoid concomitant administration of sensitive substrates, particularly those with 
narrow therapeutic ranges.   
 
Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug and toxin 
extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP, but not an 
inhibitor of OATP1B3 or MRP-2. In vitro studies suggest that olaparib may increase 
exposure of substrates of these transport systems, although the clinical relevance is not clear. 
The manufacturer recommends that statins, in particular, should be administered with 
caution when given concomitantly with olaparib. 
 
 
Patient Care Implications: Pre-clinical data indicate that olaparib adversely affects 
embryofetal 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.  It is recommended that olaparib be held 2 weeks prior to and 2 weeks after any 
major surgical procedures.  Olaparib does not need to be held for simple procedures, such as 
tooth extraction, port placement, or biopsy. 
 
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. 
 
Availability 
 
Olaparib is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
Olaparib is provided to the NCI under a Cooperative Research and Development 
Agreement (CRADA) between AstraZeneca Pharmaceuticals LP (the Pharmaceutical 
Collaborator) and the DCTD, NCI (see Section 12.3). 
 
8.1.2 AZD2171 (NSC 732208) 
 
Chemical Name:  4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin 1- 
ylpropoxy) quinazoline maleate 

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Other Names: Cediranib, AZD2171 maleate, Recentin™ 
 
CAS Registry Number: 288383-20-0 (for the free base) 
 
Molecular Formula: C25H27FN4O3 · C4H4O4 
 
 
 
Molecular Weight: 566.59 as maleate salt (450.52 as free base) 
 
Approximate Solubility: The aqueous solubility of 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).  
 
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.  
 
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 
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.  
 
Storage: Store intact bottles at controlled room temperature [20°C-25°C, (68-77°F)].  
 
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 AZD2171 (cediranib) to 
controlled 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. 
 
Route of Administration:  Oral.   AZD2171 tablets should be taken either one hour before 
or two hours after meals.  
 
Potential Drug Interactions: Cediranib (AZD2171) clearance is primarily mediated by 
flavin-containing monooxygenase enzymes (FMO1 and FMO3) and UGT1A4. It is not a 
substrate of CYP450 enzymes. In vitro studies suggest that cediranib (AZD2171) 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 

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patients taking concomitant medications that are strong inhibitors (e.g. ketoconazole) or 
strong inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin and St. John’s 
Wort) of UGT1A4 or Pgp in particular. If chronic concomitant administration of strong 
inducers or inhibitors is unavoidable, consult the protocol document and/or the principal 
investigator before making any dose adjustments. 
 
 
In vitro studies using hepatic cultures show that cediranib (AZD2171) did not inhibit 
CYP 1A2, 2A6, 2C8, 2C9, 2C19 and 2E1 and showed no induction of CYP 1A2, 2B6 
and 3A4/5. It did weakly inhibit CYP 2D6 and 3A4/5, but this inhibition not expected to 
cause any clinically relevant drug interactions.  The possibility that cediranib (AZD2171) 
may induce gastrointestinal CYP3A and UGT enzymes cannot be excluded; therefore the 
efficacy of hormonal contraceptives may be reduced. Advise women study participants to 
use an additional non-hormonal contraceptive method. 
 
In vitro studies show that cediranib (AZD2171) is a weak inhibitor of BCRP, Pgp, 
OATP1B1, OATP1B3, OCT2 and MATE1. Use caution in patients who are taking 
concomitant medications that are sensitive substrates of these transporters since there is a 
low potential for drug-drug interactions. In vivo studies show that cediranib (AZD2171) 
could increase exposure of drugs like metformin by inhibiting renal tubular transporter 
MATE2-K, but this is thought to be infrequent and mild in severity. Cediranib is not an 
inhibitor of OAT1 or OAT3.  
 
Cediranib (AZD2171) 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 cediranib (AZD2171) with caution and increase monitoring in 
patients while on study. Patients who receive VEGF inhibitors are at increased risk of 
bleeding and hemorrhage. 
 
 
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). 
 
Availability 
 

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AZD2171 is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
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).  
 
8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1 
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 (https://ctepcore.nci.nih.gov/OAOP/).  Access 
to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account (https://ctepcore.nci.nih.gov/iam/index.jsp) and the maintenance of an 
“active” account status and a “current” password.  For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
8.1.3.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all 
agents received from DCTD using the NCI Drug Accountability Record Form 
(DARF).  (See the NCI Investigator’s Handbook for Procedures for Drug 
Accountability and Storage.) 
 
8.1.3.3 
Investigator Brochure Availability – The current versions of the IBs for PMB-
supplied agents will be accessible to site investigators and research staff through the 
PMB Online Agent Order Processing (OAOP) application.  Access to OAOP requires 
the establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status and a “current” password.  Questions about 
IB access may be directed to the PMB IB coordinator at IBCoordinator@mail.nih.gov  
 
 

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9.2.1        BROCA testing (Integrated) 
9.2.1.1 
Collection of Specimen(s) 
 
Please refer to the Specimen Requirements table in Section 9.1. 
 
Whole blood should be collected in a yellow top (ACD solution A) collection tube as described 
below: 
1. Draw 7mL of blood into the labeled yellow top (ACD solution A) tube (BD vacutainer, 
catalog number 364606). 
2. Immediately after collection, gently invert the tube 6 times to mix the blood and ACD 
solution A. 
3. BROCA-HR whole blood should be stored upright at room temperature until the 
specimen can be shipped.  Ship to the University of Washington the day the specimen is 
collected (See Section 9.2.1.3 for specific shipping instructions).  Ship for Monday 
through Friday delivery only.  Do not ship on Fridays or weekends/holidays.  Patients 
starting protocol treatment on a Friday should have their specimens collected Monday 
through Thursday prior to starting on study treatment. 
4. Waterproof permanent marker or a printed label should be used to label the specimen 
with the Protocol Number (NCI#9825), Subject Study #, and Baseline Whole Blood. 
 
2 consecutive 10 µm archival FFPE sections (from primary tumor and/or metastatic sites) should 
be provided on charged slides.  Slides should be shipped in an appropriate slide container and 
labeled with a waterproof permanent marker or a printed label with the Protocol Number (NCI 
#9825), Subject Study #, and Archival FFPE. 
 
FFPE specimens from pre- and on-treatment biopsies should be collected as specified in Section 
9.2.4.1 (Core #1).  Core #1 (FFPE, uncut) should be shipped to the Swisher lab.  The FFPE 
specimen should be labeled with the Protocol Number (NCI #9825), Subject Study #, Date of 
Collection, and Sample timepoint (Pre-treatment Bx or On-treatment Bx). 
 
9.2.1.2 
Handling of Specimens(s) 
 
DNA will be extracted from PBMCs and FFPE archived tumor tissue containing at least 30% 
tumor nuclei.  A targeted capture and massively parallel sequencing approach called BROCA1 
will be applied to samples.  For the proposed study, a more recent version of BROCA with 55 
genes (BROCA-HR) 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.  
Paired-end libraries with 350bp inserts will be prepared from 1ug of constitutional or neoplastic 
DNA and hybridize to a custom pool of oligonucleotides targeting genomic regions as previously 
described (27) 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 (27).  Deletions and duplications of 

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exons will be detected by a combination of depth of coverage and split read analysis as 
previously described (39), supplemented with additional alignments generated by SLOPE (40).  
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, we 
will add in analyses of NHEJ and other modifying genes, genomic scarring, or other somatic 
tests by our lab or others to complement the determination of HR deficiency. 
 
9.2.1.3 
Shipping of Specimen(s) 
 
Please refer to the Specimen Requirements table in Section 9.1 for specific shipping 
requirements.  
 
Whole blood must be stored and shipped at ambient temperature for overnight delivery Monday-
Thursday on the same day the sample was drawn.  Whole blood samples should be shipped only 
for Monday through Friday delivery (do not ship samples on a Friday or holidays/weekends).  
FFPE specimens may be batched shipped on a monthly or otherwise basis, as coordinated with 
the Swisher lab.  Samples should be shipped with an accompanying sample shipment form.   
Sample should be shipped to the following address: 
 
Swisher Lab 
 
ATTN:  Kathy Agnew 
 
University of Washington 
 
1959 NE Pacific Street 
 
HSB BB632 
 
Seattle, WA 98195 
 
9.2.1.4 
Site(s) Performing Correlative Study 
 
BROCA-HR will be performed by the laboratory of Dr. Elizabeth Swisher at the University of 
Washington (Seattle, WA). 
 
9.2.2 CEC/CEP (Integrated) 
 
The objectives of the CEC/CEP translational studies in the phase II biomarker study are to 
determine if there is an association between levels of CEC at baseline, or the change in CEC 
from baseline to day 3, and PFS in patients receiving cedarinib/olaparib trial, and to determine if 
there are significant changes from baseline to day 3 in the levels of CEC. 
 
9.2.2.1 
Collection of specimens 
 
Please refer to the Specimen Requirements table in Section 9.1 for details regarding specimen 
collection. 
 
CEC specimens should be collected in CPT (citrate) collection tubes as described below.  Note:  
the CPT (citrate) tube should be at room temperature (i.e., 18-25°C) at the time of sample 

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collection. 
1. Label the CPT (citrate) collection tube (BD vacutainer, catalog number 362761) 
with a waterproof permanent marker or printed label with Protocol Number (NCI 
#9825), Subject Study #, Date of collection, Sample timepoint (Baseline or 
C1D3). 
2. Draw 8mL of blood into the labeled CTP (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 Preclinical Development Research Core the 
day the specimen is collected.  If the CEC whole blood absolutely cannot be 
shipped the day it is collected, the tube should be kept at room temperature until 
the specimen can be shipped the next day.  Note: The laboratory testing to be 
done is time sensitive. CEC whole blood specimens must be shipped the day 
the specimen is collected. If the specimen absolutely cannot be shipped the 
same day, a note detailing why the specimen needed to be shipped the next 
day must be included. If the specimen cannot be shipped within 24 hours, it 
should be discarded.  Due to the time-sensitive shipping requirements, patients 
starting protocol treatment on a Friday should have their Baseline specimens 
collected on the Thursday prior to starting on study treatment.  Patients whose 
Cycle 1 Day 3 specimen collection dates fall on a Friday, Saturday or Sunday 
may have this specimen collected on Cycle 1 Day 4 (if Cycle 1 Day 3 is a 
Sunday), Cycle 1 Day 5 (if Cycle 1 Day 3 is a Saturday), or Cycle 1 Day 6 (if 
Cycle 1 Day 3 is a Friday) to allow for appropriate processing and shipping. 
 
9.2.2.2 
Handling of specimens 
 
After processing for viable freezing, the samples are frozen at -80oC and then in liquid nitrogen 
and stored in liquid nitrogen until use, per our SOP.  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.  Identification and analysis of 
CECs will be performed using a MACSQuant flow cytometer and FlowJo software.  Viability is 
defined by the absence of 7-aminoactinomycin D (7-AAD) staining, and analysis will be 
restricted to nucleated cells by gating on Hoechst 33342-positive cells.  These findings will be 
correlated with clinical results. 
 
9.2.2.3 
Shipping of specimens 
 
Please refer to the Specimen Requirements table in Section 9.1 for specific shipping 
requirements. 
 
CEC specimens should be shipped at ambient temperature for overnight delivery Monday-

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89 
Thursday on the same day the sample was drawn.  Whole blood samples should be shipped only 
for Tuesday through Friday delivery (do not ship samples on a Friday).  Samples should be 
shipped with an accompanying sample shipment form.   Samples should be shipped to the 
following address: 
 
Trepel Lab, PDRC, NCI, NIH 
 
Bldg 10, Rm 12N218 
 
10 Center Dr 
 
Bethesda, MD 20892 
 
Phone: 301-496-1547 
 
Emails: trepel@helix.nih.gov, lees@pop.nci.nih.gov, yusuke.tomita@nih.gov 
 
Note: Please notify the PDRC (via the three 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. Ship specimens via FedEx priority overnight. 
 
9.2.2.4 
Site performing correlative study 
 
CEC/CEP will be performed by the laboratory of Dr. Jane Trepel in the Preclinical Development 
Research Core (https://ccr.cancer.gov/jane-b-trepel) of the Developmental Therapeutics Branch, 
CCR, NCI (Bethesda, MD). 
      
9.2.3 Plasma Angiome (Exploratory)  
9.2.3.1 
Collection of Specimen(s) 
 
Please refer to the Specimen Requirements table in Section 9.1 for details regarding specimen 
collection. 
 
Samples should be processed on site to obtain plasma and then shipped on dry ice.  Biomarker 
assays are time sensitive, blood should be processed within 2 hours of collection and may remain 
at room temperature until processed.  Instructions for processing and labeling samples are below: 
 
1. Draw two 4ml purple top (K2EDTA) tubes (BD Vacutainer, catalog no. 367861)  
2. Invert tubes 10 times to mix blood 
3. Centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 
manufacturer’s instructions) 
4. Remove plasma from each tube and transfer equally into two separate clean 15ml 
polypropylene tubes 
5. Repeat centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 
manufacturer’s instructions) 
6. Aliquot approximately 1.0ml of plasma from each tube into each 2.0ml pink-capped 
cryovial (Wheaton CryoElite Cryogenic Vials, Pink Cap, Mfr No. W985865).  A total of 
4 pink capped cryovials is needed for EDTA plasma.  

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7. Label and freeze at -80°C* (see labeling instructions below) 
 
*Please note:  If your site does not have a -80°C freezer, samples should be shipped on dry ice 
on the day of collection.  If unable to ship samples on the day of collection, please place the 
samples on dry ice until they can be shipped.  Samples can be stored on dry ice for no more than 
48 hours prior to shipping.  Please replenish dry ice as needed to ensure samples stay frozen and 
there is enough to last throughout shipment. 
 
Plasma-containing tubes should be labeled with the following information (using a waterproof 
marker or label): 
• Protocol Number (NCI #9825) 
• Subject Study # 
• Sample Collection Date and Time 
• Sample Type (EDTA plasma) 
 
9.2.3.2 
Handling of Specimens(s) 
 
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. 
 
9.2.3.3 
Shipping of Specimen(s) 
 
Please refer to the Specimen Requirements table in Section 9.1 for specific shipping 
requirements.  Samples should be stored at -80°C and batch-shipped as coordinated with Dr. 
Nixon’s laboratory.  Please provide notification of the sample shipment by e-mail to 
jchris.brady@duke.edu. All biomarker samples must be shipped on dry ice by overnight delivery 
Monday through Thursday (no holidays) to the following address: 
 
Attention: Phase I Biomarker Laboratory 
 
ATTN:  Chris Brady / Andrew Nixon, PhD 
Duke University Medical Center 
395 MSRB 1 
203 Research Drive 
Durham, NC 27710 
(919) 681-2239 

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9.2.3.4 
Site(s) Performing Correlative Study   
 
Plasma angiome will be performed by the laboratory of Dr. Andrew Nixon at Duke University 
Medical Center (Durham, NC). 
 
9.2.4 Whole exome sequencing (WES; Integrated) and RNASeq (Exploratory) 
 
9.2.4.1 
Collection of Specimen(s) 
 
Please refer to the Specimen Requirements table in Section 9.1 for details regarding specimen 
collection. 
 
Archival FFPE consisting of ten unstained sections of 10 µm thickness on charged slides should 
be obtained and shipped as per Section 9.2.4.3.  Each slide should be labeled with Protocol 
Number (NCI #9825), Subject Study Number, and Date of collection. 
 
Biopsies should be obtained under radiologic or other guidance, as appropriate, per institutional 
procedures.  Biopsies should be frozen on site, ideally with 5-10 minutes of devascularization.  
Frozen biopsies should be stored at -80°C and shipped on dry ice.   
 
A minimum of 3 and up to 6 core biopsies are requested; however, less than the goal amount of 
tissue is acceptable, and should be based upon the clinical judgment of the clinician performing 
the procedure.  Based upon prior studies, it is feasible for up to 6 to 8 core biopsies to be 
obtained depending on the site being sampled, the size of the mass, and the safety of the 
procedure. 
 
Research cores should be allocated in the following order: 
1.  Core #1:  Placed in neutral buffered formalin and then embedded in FFPE (Formalin Fixed 
Paraffin Embedded) no more than 16 hours after exposure to neutral buffered formalin. 
2.  Cores #2 and more: Embed in frozen OCT medium, per instructions below. 
a.  Use one 25 mm x 20 mm x 5 mm cryomold (Tissue Tek No. 4557) per core. 
b.  Label each cryomold with (i) Protocol Number (NCI #9825), (ii) Subject Study #, (iii) 
Date of Collection, (iv) Sample timepoint (Pre-treatment, on-treatment, or post-
progression) 
c.  Fill bottom of each cryomold with OCT medium. 
d.  Place the OCT filled cryomold on dry ice for 10 minutes to harden. 
e.  Place the fresh tissue sample on top fo the hardened OCT in cryomold 
f.  Entirely cover the tissue with OCT and place on dry ice for another 10 minutes. 
g.  Once frozen, the blocks can be stored in -80 freezer until shipping. 
 
Core #1 for pre-treatment and on-treatment biopsy should be shipped to Swisher Lab, as detailed 
in Section 9.2.1.  Cores #2 and more for pre-treatment and on-treatment biopsy, and all cores for 
post-progression biopsy should be shipped to the Broad Institute’s CCPM, as detailed in Section 
9.2.4.3. 
 

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DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
92 
9.2.4.2 
Handling of specimen(s) 
 
Sample Management and QC 
 
Sample handling includes an industry-grade high throughput registration, processing, and 
tracking system for biological samples. The system includes multiple points of quality control 
(i.e., sample quantitation, tracking, and genetic fingerprinting), allowing receipt and processing 
of an average of 16,000 samples per month. On arrival, each sample is assigned a unique bar 
code and entered into a validated database for sample analysis coupled to a bar code tracking 
system that records sample information (e.g., source, histology, clinical data), nucleic acid 
quality control information (e.g., genotyping, PCR), location information (e.g., freezer, shelf, 
rack), and project information.  The database is linked directly to the LIMS systems for array and 
sequencing analysis.  
 
Each DNA sample (optimized fingerprinting and WES processes require 50 to 100ng input 
DNA) received will be quantified and fingerprinted. Broad will perform triplicate PicoGreen® 
DNA quantitation. By genotyping a panel of 127 highly polymorphic SNPs (including SNPs on 
chromosomes X and Y), a unique genetic ‘fingerprint’ is generated for each sample. These 
genotypes are stored in the sample-tracking database and compared to genotypes obtained from 
whole exome sequencing to ensure integrity of sample handling and tracking from sample 
receipt through library sequencing.  
 
Exome Sequencing – Express Workflow 
 
The Illumina exome specifically targets approximately 37.7Mb of mainly exonic territory made 
up of all targets from our Agilent exome design (Agilent SureSelect All Exon V2), all coding 
regions of Gencode V11 genes, and all coding regions of RefSeq gene and KnownGene tracks 
from the UCSC genome browser (http://genome.ucsc.edu)  
 
The Illumina exome uses Illumina’s in-solution DNA probe based hybrid selection method that 
uses similar principles as the Broad Institute-AgilentTechnologies developed in-solution RNA 
probe based hybrid selection method (for details please see PMID 19182786 and 21205303) to 
generate Illumina exome sequencing libraries.  
 
Pooled libraries are normalized to 2nM and denatured using 0.2 N NaOH prior to sequencing. 
Flowcell cluster amplification and sequencing are performed according to the manufacturer’s 
protocols using either the HiSeq 2000 or HiSeq 2500. Each run is a 76bp paired-end with a dual 
eight-base index barcode read. Data is analyzed using the Broad Picard Pipeline, which includes 
de-multiplexing and data aggregation. 
  
Transcriptome Sequencing 
 
Total RNA is quantified using the Quant-iT™ RiboGreen® RNA Assay Kit and normalized to 
5ng/ul. An aliquot of 200ng for each sample is transferred into library preparation, which is an 
automated variant of the Illumina Tru Seq™ RNA Sample Preparation protocol (Revision A, 
2010).  This method uses oligo dT beads to select mRNA from the total RNA sample followed 

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
93 
by heat fragmentation and cDNA synthesis from the RNA template.  The resultant cDNA then 
goes through library preparation (end repair, base ‘A’ addition, adapter ligation, and enrichment) 
using Broad designed indexed adapters substituted in for multiplexing.  
 
Pooled libraries are normalized to 2nM and denatured using 0.1 N NaOH prior to sequencing. 
Flowcell cluster amplification and sequencing are performed according to the manufacturer’s 
protocols using either the HiSeq 2000 or HiSeq 2500. Each run is a 101bp paired-end with an 
eight-base index barcode read. Data is analyzed using the Broad Picard Pipeline, which includes 
de-multiplexing and data aggregation.  
 
9.2.4.3 
Shipping of specimens 
 
Please refer to the Specimen Requirements table in Section 9.1 for specific shipping 
requirements. 
 
FFPE and frozen biopsy specimens should be batch shipped to the Broad CCPM.  The CCPM 
research operations team will coordinate the schedule for shipping with individual sites.  Contact 
information for the CCPM Research Operations Team is as follows: 
a. Karla Helvie:  karlae helvie@dfci.harvard.edu; office: 617-582-7924 
b. Nelly Oliver:  nelly_oliver@dfci.harvard.edu; office: 617-582-8706 
c. Lori Marini:  lori marini@dfci.harvard.edu; pager: 617-430-3262 
 
FFPE samples should be shipped in slide holders in a separate package/shipment from frozen 
specimens.  A Specimen Submission Form (SSF) should be included for each sample included in 
the shipment.  Additionally, please complete the DFCI Shipping Manifest; include a printed copy 
of the Shipping Manifest with the package and email a separate copy to 
CCPM ResearchOps@dfci.harvard.edu at the time of shipment.  The shipping site should 
receive email confirmation of delivery receipt from the CCPM research operations team. 
 
Frozen samples should be shipped on dry ice in a separate package/shipment from FFPE 
specimens.  A Specimen Submission Form (SSF) should be included for each sample included in 
the shipment.  Additionally, please complete the DFCI Shipping Manifest; include a printed copy 
of the Shipping Manifest with the package and email a separate copy to 
CCPM ResearchOps@dfci.harvard.edu at the time of shipment.  The shipping site should 
receive email confirmation of delivery receipt from the CCPM research operations team.  Frozen 
samples should be shipped via FedEx Overnight priority according to the schedule discussed 
with the CCPM research operations team.  In additionl to the Specimen Submission Form, the 
shipping container for frozen tissue should include (i) Priority Overnight Frozen Material 
labeling, (ii) Dry Ice UN number, (iii) Class 9 label).  Frozen samples should only be sent for 
Monday through Friday delivery.  Please do not ship on Fridays or on weekends/holidays. 
 
All samples should be shipped to the following address: 
 
Lori Marini, PA 
 
Dana-Farber Cancer Institute, Dana 820 
 
450 Brookline Avenue 
 
Boston, MA 02215 

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
94 
 
9.2.4.4 
Site(s) performing the correlative study 
 
WES and RNASeq will be performed by the Center for Cancer Precision Medicine at the Broad 
Institute (Cambridge, MA). 
 
9.2.5 Pharmacokinetics (Integrated) 
 
9.2.5.1 
Collection of specimens 
 
The steady-state plasma pharmacokinetics of cediranib and olaparib will be tested at the 
recommended phase II doses of the combination, cediranib 30 mg QD and olaparib 200 mg BID.  
Pharmacokinetic sampling will be performed during a single 24 h dosing interval after steady-
state pharmacokinetic conditions for the repeated oral dosing schedules have been achieved fpr 
the two drug combination.  Pharmacokinetic samples will be collected before and for 8 hr after 
dosing on days 15-16 after the patients have received 14 days of combined therapy, as per the 
timepoints outlined below.   
 
The sampling schedule has been devised to accommodate treatment on an outpatient basis.  
Patients will be instructed to take the doses of the two drugs as per outlined in the protocol at the 
same time every day during the pharmacokinetic study.  Cediranib will be taken first thing in the 
morning on an empty stomach.  One hour later, the patient may have a light meal, followed by the 
morning dose of olaparib.  Dosing should be scheduled for times that will allow the patient to arrive 
at the clinic to obtain pharmacokinetic samples before dosing and to remain for an additional 8 
hours after the morning dose of olaparib.  The second daily dose of olaparib should be taken 12.0 
± 0.25 h after the morning dose.  It is very important that the patient is aware that the morning 
doses of the two drugs on day 16 must not be taken before arriving at the clinic and the 24.0 h 
pharmacokinetic sample has been collected.  Of note, on days that PKs are being obtained, 
olaparib will be taken 2 hours (instead of 1 hour) after cediranib (following a light meal) due to 
the timing required for PKs.  This will allow for cediranib and olaparib samples to be taken at the 
same timepoint and reduces the number of blood draws patients would be subjected to by 
approximately half. 
 
Blood samples (6 mL) will be obtained during cycle 1 starting on day 15 with the following 
schedule, to accommodate the sequential dosing schedule of the two drugs: 
 
PK specimen 
Day 
Timing 
#1 
Cycle 1 Day 15 
Just prior to cediranib dose 
#2 
Cycle 1 Day 15 
0.5 hrs after cediranib dose 
#3 
Cycle 1 Day 15 
1.0 hrs after cediranib dose 
#4 
Cycle 1 Day 15 
2.0 hrs after cediranib dose, just prior to olaparib dose 
#5 
Cycle 1 Day 15 
2.5 hrs after cediranib dose (= 0.5 hrs after olaparib dose) 
#6 
Cycle 1 Day 15 
3.0 hrs after cediranib dose (= 1.0 hrs after olaparib dose) 
#7 
Cycle 1 Day 15 
4.0 hrs after cediranib dose (= 2.0 hrs after olaparib dose) 
#8 
Cycle 1 Day 15 
5.0 hrs after cediranib dose (= 3.0 hrs after olaparib dose) 

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
95 
#9 
Cycle 1 Day 15 
6.0 hrs after cediranib dose (= 4.0 hrs after olaparib dose) 
#10 
Cycle 1 Day 15 
8.0 hrs after cediranib dose (= 6.0 hrs after olaparib dose) 
#11 
Cycle 1 Day 16 
24.0 hrs after C1D15 cediranib dose, just prior to C1D16 
cediranib dose 
#12 
Cycle 1 Day 16 
24.0 hrs after C1D15 morning olaparib dose, just prior to 
C1D16 morning olaparib dose 
 
PK samples #1 through #5 should be drawn within +/- 5 minutes of the appropriate timepoint.  
PK samples #6 through #9 should be drawn within +/- 10 minutes of the appropriate timepoint.  
PK sample #10 should be drawn within +/- 15 minutes of the appropriate timepoint.  PK samples 
#11 and #12 should be drawn within +/- 30 minutes of the appropriate timepoints.  Samples will 
be collected in plastic green stoppered Vacutainer 6.0 mL plasma collection tubes with spray-
coated sodium heparin (BD Vacutainer, catalog number 367878), gently inverted 5-times to 
thoroughly mix the blood with the anticoagulant, and placed on wet ice until centrifuged (1,300 x 
g, 10 min, 4°C) within 15 min after collection.  Separate the plasma from the blood cells using a 
disposable pipette and transfer the plasma into a 4.5 mL self-standing polypropylene cryogenic 
storage vial with external threads (Fisher Scientific, catalog number 12-565-291). Plasma from 
each timepoint should be aliquoted into 2 cryovials (Aliquot A and B). Affix a pre-printed label, 
with the protocol number, patient accession number, and sample number onto the cryovial, 
oriented crosswise toward the upper part of the tube, without overlapping the vial cap.  
Completely cover the label with polyester protective label tape (Fisher Scientific, catalog number 
03-411-631) to prevent the label from detaching from the vial when stored frozen.  Store the 
plasma samples in a freezer at < -70°C until packaged for shipment to the analytical laboratory.   
 
If PK samples cannot be obtained on Cycle 1 Day 15 and Day 16, these samples may be obtained 
on a separate date after the patient has received 14 continuous days of study drug dosing at the 
same dose, in consultation with the overall PI. 
 
9.2.5.2 
Handling of specimens 
 
The concentration of cediranib and olaparib in the plasma samples will be determined by the 
DF/HCC Cancer Pharmacology Core laboratory located on the main campus of the 
Massachusetts General Hospital (Boston, MA).  An analytical method facilitating the concurrent 
determination of the two drugs based upon for both compounds based upon high performance 
liquid chromatography with tandem mass spectrometric detection has been developed.  The 
analytical methods will be validated and applied to the analysis of study samples as 
recommended by the FDA Guidance for Industry:  Bioanalytical Method Validation, May 2001 
(http://www.fda.gov/-downloads/Drugs/Guidances/ucm070107.pdf).   
 
Individual patient plasma concentration-time curves will be analyzed by noncompartmental 
methods using routines supplied in the WinNonlin Professional Version 5.0.1 software package 
(Pharsight Corp., Cary, NC).  Pharmacokinetic parameters and variables will be calculated 
according to standard equations. Mean values of pharmacokinetic parameters will be statistically 
compared using the paired two-tailed t-test of the log-transformed data.   
 

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
96 
9.2.5.3 
Shipping of specimens 
 
Send complete sets of primary samples (labelled Aliquot A) from one or more patients by next 
day delivery to the address listed below.  Place the sample tubes in a zip lock plastic bag.  
Package samples in a seamless styrofoam container.  Place the sample bag over at least 3-4 
inches of dry ice on the bottom of the container and completely cover with an additional 3-4 
inches or more of dry-ice.  Seal the styrofoam container within a tight-fitting cardboard shipping 
box.  Insert copies of the redacted Cycle 1drug diaries and Pharmacokinetic Data Form for each 
set of samples into a separate zip-lock plastic bag placed on top of the styrofoam container 
before the external shipping box is sealed.  Send the samples from Monday to Wednesday by 
overnight courier for delivery by 10 a.m. on the following day.  Samples should not be shipped 
on a Thursday or Friday.  Please provide notification of the sample shipment by e-mail to 
jsupko@partners.org, Jmayo1@partners.org and Amartella1@partners.org. The shipping address 
is:  
 
Dr. Jeffrey G. Supko 
 
Massachusetts General Hospital 
 
55 Fruit St., GRJ 1025 
 
Boston, MA 02114 
 
Tel: 617-724-1970 
 
Back-up samples (labelled Aliquot B) should be shipped at a later date when/ if requested by Dr. 
Supko’s lab.   
 
9.2.5.4 
Site performing correlative study 
 
Pharmacokinetic studies will be performed by the DF/HCC Cancer Pharmacology Core 
laboratory located on the main campus of the Massachusetts General Hospital (Boston, MA). 
 
9.2.6 RAD51 assay (Exploratory)  
9.2.6.1 
Collection of Specimen(s) 
 
RAD51 assay testing will be performed on available archival and biopsy tumor samples after 
samples have been distributed for BROCA-HR and WES/RNASeq testing.  Two slides will be 
provided to the D’Andrea Lab for RAD51 and geminin control IHC. 
 
9.2.6.2 
Handling of Specimens(s) 
 
Staining will be performed on two serial 4-5um sections of tumor tissue for RAD51 and 
Geminin.  Samples will be analyzed per the following criteria: 
 
1. There must be more than 3 (>3) sub-nuclear RAD51 foci to call a cell RAD51-foci positive 
2. There must be 4 or more 40X fields of tumor cells with at least one RAD51-foci positive cell 
to call HR proficient 
3. If the percentage of Geminin positive cells is greater than 3 (i.e. >3%) and there are no 
RAD51-foci positive cells, the sample is HR deficient 
4. If the percentage of Geminin positive cells is less than 3 (i.e. <3%) and there are no RAD51 

NCI Protocol #: 9825 
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Protocol Version Date: May 24, 2019 
 
97 
foci positive cells, the assay is not informative. 
 
9.2.6.3 
Shipping of Specimen(s) 
 
No additional samples will be shipped by sites.  Samples will be provided centrally by the study 
team to D’Andrea Lab from previously shipped archival and biopsy specimens. 
 
9.2.6.4 
Site(s) Performing Correlative Study   
 
RAD51 assay will be performed by the laboratory of Dr. Alan D’Andrea at Dana Farber Cancer 
Institute (Boston, MA). 
 
 
9.3 
eCO Mobile Application Study Plan 
 
9.3.1 Study Visit 1 (Cycle 1, Day 1) 
 
At this study visit, the following procedures will be completed: 
- 
Answer baseline questions regarding current use of technology (smartphone, tablet, 
computers, and eReaders). (See Appendix) 
- 
Install the eCO app on the subject’s personal iPhone or provide pre-loaded iPhone 6 
(limited to study use only). 
- 
Instruct subject on the use of the eCO app and the User’s Guide. 
- 
Instruct subject on the use of the A&D Bluetooth enabled Blood Pressure Monitor 
and verify pairing with the iPhone. 
- 
Verify that the patient’s app works properly and that data entered are recorded 
properly before patient leaves site (i.e., test out the app for each patient and confirm 
that they can use it as intended) 
- 
Obtain baseline diastolic blood pressure. The study team member will enter the value 
into the patient profile on the eCO HCP web portal. 
- 
Obtain baseline stools per day. The study team member will enter the number into the 
patient profile on the eCO HCP web portal. 
- 
Provide paper BP diary used in the 9825 study as back-up should technical issues 
with the eCO app occur. 
- 
Provide the eCO User Support number to contact as needed. 
 
9.3.2 One Week Follow-up Phone Call 
 
Upon enrollment, patients will be asked to participate in a 1-week follow-up call conducted 
by User Centered Design. Structured questions to obtain initial feedback on the eCO app 
will be asked and the responses will be documented (See Appendix). This call will last 
approximately 10 minutes.  Patients will have the option to decline participation in this call. 
 
9.3.3 Study Visit 2 (Cycle 2, Day 1) 
 
At this study visit the following procedures will be completed: 

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Protocol Version Date: May 24, 2019 
 
98 
- 
Complete perceived usability and satisfaction questionnaires regarding the eCO app. 
(See Appendix) 
- 
Subjects will be offered to continue use of the eCO app during their participation in 
the 9825 trial.  At the end of the study, the iPhone 6 provided as part of the trial will 
be returned. 
 
9.3.4 Health care provider (HCP)/Study Team Survey 
 
HCP/Study Team feedback will be obtained several times during the study: 
- 
1 week after the first patient has been initiated at the site to gain their experience with 
the eCO app and web portal, they will be offered the option of discussing their 
experience learning and using the app and web portal. This discussion will occur by 
phone.  
- 
4 months after the first patient enrolled a survey will be completed by study team 
members who have worked with a patient using the app. 
- 
Upon completion of the patient’s use of the eCO app during the 1 st Cycle of therapy 
for all patients enrolled at the sites, the study personnel who were involved in patient 
care (oncologists, NP/PAs, clinical research coordinators, clinical research assistants) 
will complete the survey regarding their perceived usability and satisfaction with the 
eCO app and web portal. (Note: the 4 months and end of study survey is the same). 
- 
Monitor eCO User Support calls/questions. 
 
Surveys completed as part of the pilot study will be administered electronically using a pre-
loaded iPad (limited to study use only). 

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
99 
10. STUDY CALENDAR 
Scans, x-rays must, and ECHOs be done <4 weeks prior to the start of therapy. All other baseline 
assessments, including labs, must be done ≤14 days from the start of treatment. In the event that 
the participant’s condition is deteriorating, laboratory evaluations should be repeated within 48 
hours prior to initiation of the next cycle of therapy. 
 
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted. 
 
Pre-
Studya 
Each 
Cycle 
Day 1a 
Cycles 
1&2 
Weeklyb 
Additional studies 
Cycle 1 
Additional 
studies 
Cycle 2 
Every 2 
Cycles 
Every 4 
Cycles 
Off 
Treatmento 
Day 
Wk 
Day 
1 
3 
15 
16 
4 
1 
15 
Informed Consenta 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medicationsc 
Xc 
Xc 
Xc 
 
 
 
 
 
 
 
 
 
Xc 
Adverse Event 
Assessment 
 
X 
Xb 
 
 
 
 
 
 
 
 
 
X 
Vital Signsd 
Xd 
Xd 
 
 
 
 
 
 
 
 
 
 
Xd 
BP Measurement 
at Home 
 
As directed (see Section 5.4) 
 
Physical Exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Performance 
Status (ECOG)e 
Xe 
Xe 
 
 
 
 
 
 
 
 
 
 
Xe 
CBC with 
Differential 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Serum Chemistryf 
Xf 
Xf 
 
 
 
Xf 
 
 
 
Xf 
 
 
Xf 
INR and PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TSH and Free T4g 
Xg 
Xg 
 
 
 
 
 
 
 
 
 
 
X 
Urine protein: 
creatinine ratio 
X 
Xh 
 
 
 
 
 
 
 
 
 
 
Xh 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MUGA or 
Echocardiogrami 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy Testj 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
CA-125  
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Tumor 
Measurementsk 
Xk 
 
 
 
 
 
 
 
 
 
Xk 
 
 
Tumor Biopsy 
Xl 
 
 
 
 
 
 
Xl 
 
 
 
 
Xl 
Translational 
bloodworkm 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
Pharmacokinetic 
studiesn 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
Optional eCO sub-
 
Optional eCO substudy assessments, as per Section 9.3 
 

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Protocol Version Date: May 24, 2019 
 
100 
study 
 
a:   Informed consent will be obtained prior to any study-related screening tests and within 4 weeks of 
starting study drug.  For Cycle 1 Day 1, physical examination, and laboratory evaluations do not have 
to be repeated if they have been performed at screening within 7 days of Cycle 1 Day 1. 
b:   Participants should be contacted at least once weekly over the phone or be assessed in person for the 
first two cycles on study to assess for adverse events and concomitant medications.  Pre-cycle and 
off-study AE assessments must be done at a scheduled clinic visit. 
c:   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.   
d:   Temperature, pulse, blood pressure 
e:   See Appendix A for ECOG performance status 
f:   Sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, albumin, calcium, phosphorus, 
AST (SGOT), ALT (SGPT), alkaline phosphatase, total bilirubin. 
g:   Pre-study, prior to the first 2 cycles, and at off-study visit for all participants.  Otherwise, should be 
checked prior to each cycle if clinically indicated. 
h:   Urinalysis may be used instead.  See Section 6.5 for Management of Proteinuria. 
i:   MUGA or echocardiogram should be done at baseline and every 4 cycles for those patients at 
increased risk for compromised LVEF.  Increased risk patients have had one or more of the 
following:  (1) prior treatment with anthracyclines, (2) prior treatment with trastuzumab, (3) NY 
Heart Association classification of II, (4) prior central thoracic RT, (5) history of myocardial 
infarction within the 12 months prior. 
j:   beta-HCG for women of childbearing potential. 
k:  Tumor measurements by CT scans or MRI (of the chest, abdomen, and pelvis) will be performed 
within the 4 weeks prior to starting cediranib/olaparib and will be performed after every 8 weeks (+/- 
1 week) of treatment. The frequency of restaging studies will decrease to once every 12 weeks (+/- 1 
week) after the 20th cycle of treatment. If a partial or complete response is noted, a confirmatory CT 
scan or MRI should be performed.  The next planned restaging CT scan or MRI may be used as the 
confirmatory scan.  
l:   Presence of biopsiable disease is required for eligibility.  Willingness to undergo pre-treatment and 
on-treatment biopsies is mandatory for the study.  Pre-treatment biopsy should be performed within 
14 days of starting study treatment.  On-treatment biopsy should be performed during the 4th week of 
cycle 1 of treatment.  If, at the time of biopsy, the previously biopsiable disease is no longer deemed 
to be biopsiable, the biopsy may be waived.  The PI should be informed about mandatory biopsies 
that cannot be performed.  Inability to be biopsied for safety reasons will not preclude patients from 
receiving study treatment.  Post-progression biopsy is optional, but encouraged. 
m: Bloodwork will be drawn for translational studies of CEC on Cycle 1 Day 1 (pre-treatment) and 
Cycle 1 Day 3 (pre-treatment), BROCA-HR on Cycle 1 Day 1 (pre-treatment), and of plasma 
angiome on Cycle 1 Day 1 (pre-treatment), Cycle 2 Day 1(pre-treatment), and at Off-treatment/time 
of progression.  Participation in these translational studies is required for study participation.  Details 
on the required specimens are found in Section 9.  Patients may choose to opt out of translational 
bloodwork at the time of progression. 
n: Details on required specimens and timepoints for pharmacokinetic studies is found in Section 9. 
o:  Off-treatment assessments should be performed within 30 days of stopping study treatment.  

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Protocol Version Date: May 24, 2019 
 
101 
 
11. MEASUREMENT OF EFFECT 
 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every 8 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained 8 weeks following 
initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the 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. 
 
11.1.1 Definitions 
 
Evaluable for Target Disease response.  Only those participants 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 target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Participants 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.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by 
chest x-ray or ≥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 are not considered 
measurable.  
 
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. 
 

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102 
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, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, 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.  
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  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 

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followed cannot be imaged but are assessable by clinical exam.  
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in 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 thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of 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.  Please note:  
decisions regarding RECIST must be made on the diagnostic CT scan only.  New lesions 
may not be determined on the basis of the FDG PET. 
 
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 participant 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 

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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. 
 
11.1.4 Response Criteria 
 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
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. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 

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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). 
 
11.1.4.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 
11.1.4.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 

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Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        The next planned imaging scan may be used as the confirmatory scan. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants 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 Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 
Duration of overall complete response: 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, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation. 
 
 
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.  
 
11.1.6 Progression-Free Survival 
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 

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Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported. 
 
11.1.7 Response Review 
 
For patients enrolled at DF/HCC sites, tumor metrics central imaging will serve as the 
reading for all radiographic imaging for this study.  
 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
Regular  and  ongoing  communication  with Participating  Institutions,  will  be  accomplished  
by  holding  regular teleconferences with all sites. The Lead Institution will keep in close touch 
with the Participating Institutions via email and phone. 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 

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trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at < https://ctepcore.nci.nih.gov/iam  >) and 
the appropriate Rave role (Rave CRA, Read-Only, CRA Lab Admin, SLA or Site Investigator) 
on either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA 
role or CRA Lab Admin role, the user must hold a minimum of an AP registration type.  To hold 
the Rave Site Investigator role, the individual must be registered as an NPIVR or IVR.  
Associates can hold read-only roles in Rave.  If the study has a DTL, individuals requiring write 
access to Rave must also be assigned the appropriate Rave tasks on the DTL.  
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method  
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted on an 18-36 month basis as part of routine cancer center site visits. 
More frequent audits may be conducted if warranted by accrual or due to concerns regarding 
data quality or timely submission.  For CTMS monitored studies, after users have activated their 
accounts, please contact the Theradex Help Desk at (609) 799-7580 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 

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Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm)  and 
CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended 
phase 2 dose (RP2D), and a description of any dose-limiting toxicities (DLTs).  CTMS will 
utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) 
compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-
semantics/metadata-and-models).  Customized eCRFs will be included when appropriate to meet 
unique study requirements.  The PI is encouraged to review the eCRFs, working closely with 
CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs 
prior to study activation.  CTMS will prepare the eCRFs with built-in edit checks to the extent 
possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
 
12.3 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 

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The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. The DSMC will provide the Overall PI an outcome of the review, which 
will be forwarded to all sites, and discussed on regular teleconferences if needed. 
 
12.4 
Collaborative Agreements Language 
 
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 study participant or 
participant’s family member, 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 

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

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including 6% in BRCA1 and BRCA2 (Pennington et al., 2014). We will pool cases with BRCA1 
and BRCA2 mutations, somatic or germline, into a single group, the BRCA-mutant cases. A 
second exploratory group will be the pooled group of other germline or somatic mutations that 
would be predicted to cause HRD including PALB2, BRIP1, RAD51C, RAD51D, BARD1, ATM, 
NBN, BLM, CHEK2, and FAM175A.  The minimal expected germline mutation rate for BRCA1 
and BRCA2 is 15%, but studies with PARP inhibitors over-enroll BRCA1 and BRCA2 mutation 
carriers unless that enrollment is capped or limited. Therefore, the germline BRCA mutation rate 
could range between 15% and 60%, with a likely estimate of 35%. The somatic BRCA mutation 
rate may be slightly higher in a population selected for platinum sensitivity, but should be in the 
range of 6-10%. Therefore, we estimate the total BRCA germline and somatic mutated rate will 
be 40-45%. We estimate the mutation rate of other HRD genes to be consistent with our previous 
studies at about 8%. Approximately 50% of cases will have no HR mutation.  
 
With a total of 70 patients enrolled, there will 0.50 and 0.76 probabilities of observing at least 
one alternation if the true frequency is as low as 1% and 2%, respectively, in the general 
population of ovarian cancers represented by this cohort. The prevalence of each genetic 
alteration will be reported overall, and within stratum defined by platinum-sensitive and 
platinum-resistant disease using binomial exact 95% confidence intervals.   
 
The primary analysis will associate BRCA mutations (germline or somatic) and other HR gene 
mutations, as a pooled group, against progression-free survival as a time-to-event endpoint, using 
Kaplan-Meier product-limit estimates and stratified logrank test using a two-sided alpha of 0.05.  
With 24 months of patient accession, 12 months of additional follow-up, and a median PFS of 
16.7 months for platinum-sensitive disease (as observed in NCT01116648) and 5 months for 
platinum-resistant disease (Mutch et al. 2007; Gordon et al, 2001), a total of 26 and 33 events are 
anticipated at analysis for platinum-sensitive and platinum-resistant disease, respectively. Under 
the assumption that 40% of patients will have genomic mutations, there will be 80% power to 
detect a HR of 3.1 in the platinum-sensitive cohort.   
 
As secondary analyses, the association of pooled genetic mutations will be evaluated in the 
platinum-resistant cohort, and with more events anticipated with poorer prognosis, there will be 
80% power to detect a HR of 2.7.  Finally, exploratory analyses will evaluate genetic mutations 
across the two cohorts using multivariable Cox regression modes, and the table below gives a 
power analysis for analyses in the combined cohort with varying prevalences of genetic 
alterations, using nominal two-sided alpha = 0.05. 
 
Table: Power analysis of effect-sizes (HR) under varying prevalence rates of mutation 
 
Prevalence 
80% power 
40% 
HR = 2.1 
30% 
HR = 2.2 
20% 
HR = 2.5 
15% 
HR = 2.8 
10% 
HR = 3.4 
 

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For the exploratory analyses to develop biomarker signatures with the BROCA-HR assay, there 
will be inadequate power to control for family-wise error and false-discovery rates, and to detect 
associations for individual genetic alterations with lower prevalence in the individual cohorts. 
   
13.5.2 Clinical activity of cediranib/olaparib in platinum-resistant ovarian cancer 
 
Clinical activity in the platinum-resistant cohort will be established using a target 30% objective 
response rate as worthy of further study, while a rate of 10% would not be of clinical interest. 
The following two-stage Simon Optimal design gives high power (>90%) with a Type I error no 
more than 0.05:  In the first stage, 18 patients will be enrolled. If there are at least 3 responses, 
accrual will continue to the second stage where an additional 17 patients will be enrolled. If there 
are 7 or more responses among the 35 patients, the regimen will be considered worthy of further 
study in platinum-resistant disease. Objective response rates will be reported using the 
maximum-likelihood estimator, with 95% confidence interval adjusted for the two-stage design 
(Atkinson and Brown, 1985) 
 
13.6 
Analysis of Secondary Objectives 
 
13.6.1 Secondary clinical endpoints 
 
Secondary clinical endpoints will be evaluated separately in the platinum-sensitive and platinum-
resistant cohorts. Time-to-event endpoints, including OS and PFS, will be summarized using the 
Kaplan-Meier product-limit estimator with 95% confidence bands derived using Greenwood’s 
formula.  Binary endpoints, including maximum grade AE during treatment, will be reported 
using 95% binomial confidence intervals.  
 
13.6.2 CEC/CEP 
 
The objectives of the CEC/CEP translational studies in the phase II biomarker study are to 
determine if there is an association between levels of CEC at baseline, or the change in CEC 
from baseline to day 3, and PFS in patients receiving cedarinib/olaparib trial, and to determine if 
there are significant changes from baseline to day 3 in the levels of CEC. 
 
Patients with platinum-sensitive disease may have a median PFS of approximately 12 months. 
Assuming there are 35 samples at baseline and at 3 days, and therefore also 35 changes from 
baseline, there would be approximately 17 patients below the median baseline CEC or change in 
CEC, and approximately 17 at or above the median baseline CEC or change in CEC.  Using a 
log-rank test, there would be 75% power in each case to detect a difference between two groups 
having median PFS of 5 and 20 months divided on the basis of their CEC level or changes, using 
a two-sided 0.05 significance level test.  
 
Similarly, patients with platinum resistant disease may have a median PFS of approximately 5 
months.  Again, assuming 35 samples at baseline and at 3 days, and therefore 35 changes from 
baseline, approximately 17 patients would be below the median baseline CEC or change in CEC, 

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and approximately 17 at or above the median baseline CEC or change in CEC.  Using a log-rank 
test, there would be 88% power in each case to detect a difference between two groups having 
median PFS of 2 and 8 months divided on the basis of their CEC level or changes, using a two-
sided 0.05 significance level test. Power would be reduced to 81% if we required a 0.025 test for 
each to very conservatively account for two comparisons being performed; however, this 
adjustment and reduction in power may not be considered necessary if a Hochberg correction is 
applied instead of the overly conservative Bonferroni adjustment. 
 
Finally, separately within platinum sensitive and platinum resistant patients, we will form the 
change in CEC from baseline to 3 days and test whether this change differs from zero using a 
paired t-test. With 35 patients in either category there is 81% power to detect a difference equal 
to approximately 0.5 SD (0.5 effect size) with a two-sided 0.05 significance level test. If we 
require sample sizes to support a strict Bonferroni correction of 0.025 as the p-value for each 
group separately, this would have 80% power to detect a 0.54 SD effect size. In practice, the 
adjustment comparing the two results may be performed using a less overly stringent Hochberg 
correction. If we were to combine all 70 patients, there would be 90% power to detect an effect 
size of 0.40 SD using a two-tailed 0.05 significance level paired t-test. In addition, if the paired 
differences in values are not normally distributed (p<0.05 by a Shapiro-Wilk test), then a 
Wilcoxon signed rank test will be used instead of a paired t-test.  
 
13.6.3 Whole exome sequencing  
 
With a total of 70 patients enrolled, there will 0.50 and 0.76 probability of observing at least one 
alternation if the true frequency is as low as 1% and 2%, respectively, in the general population 
of ovarian cancers represented by this cohort. The prevalence of each genetic alteration will be 
reported overall, and within platinum-sensitive and platinum-resistant cohorts using binomial 
exact 95% confidence intervals.  Exploratory analyses will associate alterations of a single-gene 
against progression-free survival as a time-to-event endpoint, using Kaplan-Meier product-limit 
estimates and logrank test using a nominal two-sided alpha of 0.05.  There will be inadequate 
power to control for family wise error and false-discovery rates and to detect associations for 
genetic alterations with low prevalence 
 
13.6.4 Biomarker signatures 
 
For biomarker signature development, we will first evaluate the assay failure rates and data 
completeness of candidate markers from each platform. Imputation procedures (eg. K-nearest 
neighbors) will be considered if individual features are thought to be missing-at-random in 20% 
of the study population or less; otherwise features will be filtered before signature development.    
Genomic profiles will be explored using unsupervised hierarchical clustering of all analytes and 
patients.  The association of each candidate marker to PFS will be evaluated by Cox proportional 
hazard models using a two-sided alpha = 0.05, while estimating the false discovery rate for any 
sets of identified markers by the Benjamini-Hochberg step-up procedure. Assuming that 85% of 
subjects will provide evaluable tissue/blood and a landmark-time in the survival function of each 
cohort will give complete information and approximate 70%/30% split (e.g. 12-month PFS in 
platinum-sensitive disease, as seen in Figure 3), nominal Type I error control will have 85% 

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power to detect a 1.25 s.d. change in candidate marker levels between responders and non-
responders. 
 
Next, we will attempt to build classifiers from the identified sets of biomarkers using 
multivariate Cox proportional hazard models with L1 (lasso) constraints on coefficients to 
prevent overfitting in the high-dimensional biomarker space. Operating characteristics will be 
characterized under leave-one-out cross-validation, using Harrell’s C-index as a summary 
measure of the performance of predictive models. Sample size constraints are considered using 
the method from Dobbin and Simon (2007), whereby a classier developed from 100 candidate 
markers that has a standardized fold-change of 1.25 will have a tolerance of 10% (i.e. the 
expected accuracy of the predictor derived from 30 samples would be within 10% of the best 
accuracy possible for the general population).   
 
 
13.7 
Analysis of eCO Objectives 
 
Since participants will be volunteers, the total number of participants cannot be predicted.  
Participants will be obtained from several sites participating in the trial. Given an anticipated 
medium to large effect size, the goal is to obtain 20 participants depending on enrollment. A 
small sample is likely to provide statistical significant for the research questions using the 
intended nonparametric analysis. 
 
Demographic data: Demographic data on the participants will be summarized using descriptive 
statistics. The demographics collected will be age, race, and experience with smart phones. 
 
Perceived Usability/Satisfaction 
Patients 
Significance testing of perceived usability and satisfaction data will be done using a one 
tailed Wilcoxon Signed Rank Test (α = 0.05). 
 
Health Care Professionals 
Significance testing of perceived usability and satisfaction data will be done using a one 
tailed Wilcoxon Signed Rank Test (α = 0.05). 
 
eCO App/Web Portal Metrics 
Web portal metrics will be summarized using descriptive statistics. The metrics will include: 
- 
Number of patients who accessed the app 
- 
Number of diarrhea events reported 
- 
% BP values entered compared to the % expected 
- 
Number of follow-up BP measures entered compared to the number recommended 
- 
Number and type of BP events reported 
- 
Average duration of BP event and diarrhea event in days 
- 
Number of other symptoms reported (headache, change in vision, shortness of breath, 
chest pain, uncontrolled diarrhea, cramping, blood in stool) 
- 
Number and type of email alerts generated to the study team 
 

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User Support Call Summary 
User support calls will be summarized including: 
- 
Number of calls  
- 
The reason for contacting eCO User Support (patients and study team) 
 
 
13.8 
Reporting and Exclusions 
 
 
13.8.1 Evaluation of Toxicity 
 
All participants who receive at least one dose of cediranib or olaparib will be evaluable 
for toxicity from the time of their first treatment. Toxicities will be graded via CTCAE 
version 4.0 until March 31, 2018. CTCAE version 5.0 will be utilized beginning April 1, 
2018.  
 
13.8.2 Evaluation of the Primary Efficacy Endpoint 
 
The study populations for analyses of clinical activity will be as follows for stratum of 
platinum-sensitive and platinum-resistant ovarian cancer that are defined at enrollment. 
Analysis of clinical activity by progression free survival in platinum-sensitive and 
platinum-resistant will include all participants who receive at least one dose of cediranib 
or olaparib, even if there are major protocol therapy deviations.  For platinum resistant 
disease, clinical activity assessed by objective response will include all evaluable patients 
who have received at least on cycle of therapy. Participants who exhibit objective disease 
progression or discontinue treatment for toxicity prior to the end of cycle 1 will also be 
considered evaluable, but patients who go off study before the end of cycle 1 for other 
reasons will not be evaluable for objective response.  
 
13.8.3 Evaluation of the Integrated Biomarkers 
 
Analyses of integrated biomarkers will be based on all eligible and treated participants 
that are evaluable for each assay. 
  
 
14. PUBLICATION PLAN 
 
The results should be made public within 12 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  

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as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent 
glioblastoma patients.  Cancer Res.  69:5296-5300. 
 
Sridhar, S.S., M.J. Mackenzie, S.J. Hotte, et al.  (2008).  Activity of cediranib (AZD2171) in 
patients (pts) with previously untreated metastatic renal cell cancer (RCC).  A phase II trial of 
the PMH Consortium.  Proc Am Soc Clin Oncol.  26:A5047. 
 
Tentori, L., P.M. Lacal, A. Muzi.  (2007).  Poly(ADP-ribose) polymerase (PARP) inhibition or 
PARP-1 gene deletion reduces angiogenesis.  Eur J Cancer.  43:2124-2133. 
 
Walsh T, Casadei S, Lee MK, et al.  (2011).  Mutations in 12 genes for inherited ovarian, 
fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl 
Acad Sci U S A 108:18032-7. 
 
Walsh T, Lee MK, Casadei S, et al.  (2010)  Detection of inherited mutations for breast and 
ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U 
S A 107:12629-33. 
 
Weaver A, Young Am, Rowntree J, et al. (2007).  Application of mobile phone technology for 
managing chemotherapy-associated side effect.  Ann Oncol.  18(11):1887-92. 
 
Wedge, S.R., J. Kendrew, L.F. Hennequin, et al.  (2005).  AZD2171:  A highly potent, orally 
bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the 
treatment of cancer.  Cancer Res.  65:4389-4400. 
 
Wickramanayake A, Bernier G, Pennil C, et al.  (2012).  Loss of function germline mutations in 
RAD51D in women with ovarian carcinoma.  Gynecol Oncol, 127(3):552-5. 
 
Zhu, A.X., M. Ancukiewicz, J.G. Supko, et al.  (2012).  Clinical, pharmacodynamic (PD), and 
pharmacokinetic (PK) evaluation of cediranib in advanced hepatocellular carcinoma (HCC): A 
phase II study (CTEP 7147).  J Clin Oncol.  30(Suppl):A4112. 

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

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APPENDIX D: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
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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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, cediranib (AZD2171).  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: 
  
Cediranib (AZD2171) 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. Cediranib (AZD2171) is metabolized by FMO1, FMO3 and UGT1A4 and 
may be affected by other drugs that strongly inhibit or induce these enzymes.  Cediranib 
(AZD2171) weakly inhibits CYP 2D6 and 3A4 and may increase levels of affected 
substrates.  
• Cediranib (AZD2171) may induce gastrointestinal CYP3A and UGT enzymes, therefore 
potentially reducing the effectiveness of hormonal contraceptives.  
• The transport proteins in question are P-glycoprotein (P-gp) and breast cancer resistance 
protein (BCRP). Cediranib (AZD2171) requires P-gp to move in and out of cells. 
Cediranib (AZD2171) inhibits 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.  
• Cediranib (AZD2171) is 95% protein bound (human serum albumin and alpha-1-acid 
glycoprotein) and may displace other highly protein-bound drugs. Use caution in patients 
taking concomitant medications with narrow therapeutic ranges. 
• Patients receiving Cediranib (AZD2171) 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. 
 
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 

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clinical trial.  
 
These are the things that you and they need to know: 
 
Cediranib (AZD2171) 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.  
Cediranib (AZD2171) 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. 
➢ Cediranib (AZD2171) 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 KNOWN CYP3A4 INDUCERS AND INHIBITORS.  
INVESTIGATORS SHOULD ALSO REFERENCE THE FOLLOWING WEBSITES FOR UPDATED 
INFORMATION REGARDING CYP3A4 INTERACTIONS: 
 
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 allowed if clinically indicated while on 
trial after discussion with the overall PI. 
1 Cited in Cytochrome P450 Enzymes:  Substrates, Inhibitors, and Inducers.  In:  Lacy CF, Armstrong LL, Goldman MP, Lan ce 
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 
(avoid if possible; reduce olaparib 
dose per 5.4 if use unavoidable) 
  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 F: GENOMIC DATA SHARING PLAN 
 
NCI GENOMIC DATA SHARING PLAN FOR THE EXPERIMENTAL 
THERAPEUTICS CLINICAL TRIALS NETWORK 
 
Data produced through this award will be shared in a manner consistent with the NIH Genomic 
Data Sharing Policy (NOT-OD-14-124). 
 
Grants: 
  Awarded through FOA RFA-CA-13-006. 
Project Title:   NCI Experimental Therapeutics Clinical Trials Network 
Principal Investigators:  Joyce Liu, Dana-Farber Cancer Institute 
NCI Project Scientists:  S.P. Ivy, Investigational Drug Branch/CTEP/DCTD 
J. Moscow, Investigational Drug Branch/CTEP/DCTD 
 
1.   Data to be Shared 
 
Genomic data: 
The genomic data to be shared will be human (and may include the human microbiome).   
 
It will be acquired from analysis of either tumor or normal tissues or body fluids. 
 
It will include sequencing data from either RNA or DNA, from either genome-wide sequencing 
or more targeted panels or arrays. It may also include DNA methylation data, chromatin 
immunoprecipitation (ChIP-seq) data or other data types that fall under the NIH Genomic Data 
Sharing Policy. 
 
It may include either somatic or germline sequences. 
 
Phenotypic data: 
The phenotypic data to be shared will include at a minimum the information needed to reproduce 
the primary analysis of the clinical trial.  Relevant metadata (e.g. protocols and methods) will be 
shared. 
 
2.   Data Repository 
 
Each study will be registered in dbGAP and the data will be submitted for controlled-access 
release to an NCI-approved data repository (e.g., dpGAP or, Cancer Genomics Hub, NCI 
Genome Data Commons.) 
 
3.   Data Submission and Release Timeline 
 
Data should generally be submitted once it has been cleaned (e.g., the analytical dataset is 
finalized).” "Data will be released six months after initiation of submission process or at the time 
of first publication (whichever comes first); the exception to data submission and release 
timelines is for data subject to a binding collaborative agreement and is bound by the terms of 

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the agreement.   
 
In no case will this precede the publication of the primary analysis of the clinical trial.  Once 
released, data will be available for secondary research access without restrictions on publication. 
 
4.   IRB Assurance of the Genomic Data Sharing Plan 
 
This data sharing plan will be approved by the Central Institutional Review Board (IRB) of the 
ETCTN, which will assure, prior to protocol activation, that 
 
A.  The protocol for collection of genomic and phenotypic data is consistent with 45 CFR Part 
46; 
 
B.  Data submission and subsequent data sharing for research purposes are consistent with the 
informed consent of study participants from whom the data were obtained; 
 
C. Consideration was given to risks to individuals participants and their families associated with 
data submitted to NIH-designated repositories and subsequent sharing; 
 
D.  To the extent relevant and possible, consideration was given to risks to groups or populations 
associated with submitting data to NIH-designated data repositories and subsequent sharing, and 
 
E.  The plan for de-identifying datasets is consistent with the standards outlined in the GDS 
policy. 
 
An institutional certification signed by the Signing Official of each ETCTN awardee institution 
has been submitted and approved by the Central IRB of the ETCTN. 
 
5. Appropriate Uses of the Data 
 
The NCI model consent form provides consent for the data to be used for future research and to 
be shared through controlled-access databases subject to the following limitations: 
 
A.  The requestor must agree to make results of studies using the data available to the larger 
scientific community. 
 

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

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Selective 
 Blockers 
(BB) 
metoprolol 
25 mg 
twice daily 
50 mg 
twice daily 
100 mg 
twice daily 
CYP 2D6 
substrate 
atenolol 
25 mg daily 50 mg daily 
100 mg 
daily 
No 
acebutolol 
100 mg 
twice daily 
200-300 mg 
twice daily 
400 mg 
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg 
daily 
5-10 mg 
daily 
20 mg daily 
CYP 3A4 
substrate 
 and  
Blocker 
labetalol 
100 mg 
twice daily 
200 mg 
twice daily 
400 mg 
twice daily 
Yes, but not 
CYP450 
Diuretics 
Hydralazine 10 mg four 
times daily 
25 mg four 
times daily 
50 mg four 
times daily 
no 
Hydrochlor
othiazide 
12.5 mg 
AM daily 
25 mg AM 
daily 
50 mg AM 
daily 
no 
Furosemide  20 mg daily 20 mg twice 
daily 
40 mg twice 
daily 
no 
Nitrates 
Isosorbide 
dinitrate ER 
40 mg daily 40 mg twice 
daily 
80 mg twice 
daily 
CYP 3A4 
substrate 
Isosorbide 
mononitrate 
ER 
30 mg AM 
daily 
60 mg AM 
daily 
90 mg AM 
daily 
CYP 3A4 
substrate 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine 
XL 
30 mg daily 60 mg daily 90 mg daily 
CYP 3A4 
substrate 
amlodipine 
2.5 mg 
daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 
felodipine 
2.5 mg 
daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate  
 
 
 
 
 
 
 
 
 

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APPENDIX H: eCO MOBILE 
 
 
Section 
Page 
eCo Mobile App Screenshots 
 
133 
eCo User’s Guide – Patients 
 
 
166 
eCo Study Team Web Portal Screenshots 
 
213 
eCo Blood Pressure – Diarrhea Monitoring Data Collection 
224 
Baseline Technology Use Survey 
232 
Follow-up Phone Interview Questions 
 
233 
Survey – Patients 
236 
Survey – Study Team  
238 
Survey – Back Office  
240 
 

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eCo Mobile App Screenshots 
 
Patients 
 
 
 
 
 
 
 
Set-Up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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First Login Screen 
 
 
 

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Create Access Code 
 
 

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Change Password 
 

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Ongoing Use 

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Enter Access Code 
 
 

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Home Screen 
 
 

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Enter Blood Pressure (using Bluetooth enabled BP monitor) 
 
 

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Enter Blood Pressure (Manual) 
 
 

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Add Blood Pressure Related Symptoms  
 
 

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Examples of BP Recommendations 
 
 

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Record a Diarrhea Event: 
 
Tap on “Diarrhea” icon 
 
 

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Recording diarrhea using number of bowel movements 
 
 

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Recording diarrhea using ileostomy output 
 
 

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Adding diarrhea related symptoms 
 

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Diarrhea recommendations based on patient entry 

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- 
 

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Diarrhea reminders (sent every 24 hours until “No” is entered) 
 
 
 

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If a new diarrhea event is entered before time allowed, this message is sent: 
 
 

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History: 
 
Blood pressure 
 

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 Diarrhea 
 

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My Contacts: 
 

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Settings: 

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Information: 
 
 

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eCo Mobile App User’s Guide 

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User’s Guide 
Version 2017-06-30 
 
How to Get Help: If you have difficulty installing, using, or understanding eCO, check with 
your health care provider to ensure that your account was set up correctly, and that use of 
the application is intended for you. Use of eCO is restricted to the person for whom it was 
prescribed. 
 
eCO User Support 
Toll free: 1-800-326-1448 (1-800-ECO-1HIT)  
Email: support@ecostudy.us 
 
CAUTION: Investigational device. Limited by Federal (or United States) law to 
investigational use. 
 

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Contents  
 
About eCO.....................................................................................................................176 
What is eCO?...............................................................................................................177 
General Warnings and Precautions ...............................................................................178 
Contraindications .........................................................................................................180 
First Steps with eCO ....................................................................................................181 
Mobile application ........................................................................................................183 
General technical Information ......................................................................................184 
Installing eCO..............................................................................................................186 
Connecting to eCO mobile for the first time ..................................................................187 
Using eCO ...................................................................................................................190 
History ........................................................................................................................191 
Contacts.......................................................................................................................192 
Entering a blood pressure check....................................................................................193 
Entering diarrhea data ..................................................................................................203 
Settings........................................................................................................................208 
About and Help............................................................................................................211 
Technical Support.........................................................................................................213 
Help ...............................................................................................................................214 
Frequently Asked Questions .........................................................................................215 
Glossary and Abbreviations ..........................................................................................218 
Conditions of Use and Consent .......................................... Error! Bookmark not defined. 
Legal information ........................................................................................................219 
 
 

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What is eCO? 
eCO is medical software used to support symptom monitoring for women with recurrent 
ovarian cancer who are being treated with the investigational drug combination of Cediranib-
Olaparib. 
eCO is also used for remote patient monitoring by health professionals. 
eCO is intended to provide secure capture, storage and transmission of blood pressure and 
diarrhea data, as well as other symptom-related data, to aid in remote monitoring of these 
symptoms by health care professionals. 
eCO captures symptom data through manual entry by the patient and includes wireless 
connectivity to allow data capture via compatible Bluetooth enabled blood pressure monitors. 
eCO supports symptom monitoring by health care providers through analysis and reporting of 
the symptom related data reported by the patient via the app. In addition, eCO provides 
directions to patients related to symptom management, which are the same as directions that 
physicians provide to patients as part of routine clinical practice. 
eCO can be used at home or in a medical environment and includes a mobile application that 
can be accessed via iPhone 4s, 5, 5c, 5s, 6, 6+, 6s, 6s+, 7, 7+ or 7 SE running with iOS 8 or 9, or 
10 (depending on availability of iOS version), and with 3G, 4G or Wifi connection. 
Remark: eCO can only be used with a prescription from an authorized health care provider. 
Caution:  
• eCO is not intended to replace the care provided by a licensed healthcare professional, 
including prescriptions, diagnosis, or treatment. 
• eCO is intended for prescription use and will not be indicated for over-the-counter use nor 
will it be available for download or use without activation by authorized clinical study staff. 
• eCO should not replace a face-to-face consultation. 
• eCO is not a tool for managing a medical emergency. In case of emergency, dial 911. 

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General Warnings and Precautions 
1) Precautions for Use 
eCO is to be: 
• 
Used by patients who are have been enrolled in a clinical study aimed at studying the 
combination drugs Cediranib-Olaparib; 
• 
Used by health care providers who are experienced in the management of hypertension 
and diarrhea symptoms; 
• 
Used by patients who have the ability to regularly connect their mobile device to the 
Internet (3G, 4G, or wifi); 
• 
Used by a single person with a personal access code which must not be shared; 
• 
Used in conjunction with a mobile configuration (specific hardware and mobile operating 
system version) included on the list of compatible devices provided in the product 
information; 
• 
Used by users who speak English; 
• 
Installed on an operating system that runs in accordance with the manufacturer’s 
instructions (e.g. no ‘jail broken’ or ‘rooted’ operating systems); 
• 
Used by patients who have been trained in the use of the application and a compatible 
Bluetooth enabled blood pressure monitor; 
• 
Used by patients who are deemed by their health care provider to possess: 
- 
An appropriate level of visual acuity and understanding to operate the product (able 
to read and understand English). 
- 
A sufficient intellectual capacity to use the product (e.g. able to understand 
recommendations for hypertension and diarrhea side effects management). 
- 
A sufficient level of understanding of the functionalities of the product. 
- 
A sufficient level of sensorial and motor capabilities (to handle the device giving 
access to the mobile application). 
 

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2) Compatible Equipment 
The eCO mobile application requires an iPhone 4s, 5, 5c, 5s, 6, 6+, 6s, 6s+, 7, 7+ or 7 SE 
running with iOS 8 or 9, or 10 (depending on availability of iOS version), and with 3G, 4G or 
Wifi connection. 
 

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Contraindications 
eCO is: 
• 
Not to be used outside of a clinical study aimed at studying a combination of Cediranib-
Olaparib. 
• 
Not to be used by patients who haven’t been trained on the application and trained with a 
compatible Bluetooth enabled blood pressure monitor. 

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First Steps with eCO 
1) Prescription and registration information 
During an appointment with your health care provider, s/he will: 
• Identify a need for monitoring and support. 
• Verify that you meet the acceptance criteria for using eCO. 
• Prescribe eCO and establish your treatment plan, including: 
− 
Your diastolic blood pressure at baseline; 
− 
Your number of bowel movements per day at baseline. 
− 
(If you have had an ileostomy, this will be noted in your prescription.) 
You will receive an email confirming the eCO registration. This email contains: 
• Your login information (your user name). 
• Your temporary password. This password, known to you alone, is strictly confidential. Do 
not share it with anyone. 
2) Training 
In order to use eCO, you must attend a training session. Once the training is complete, you will 
be able to connect to the mobile application. 
3) Daily use 
Each day you will use eCO to: 
• Enter your blood pressure measures (either through a compatible Bluetooth enabled blood 
pressure monitor, or manually) with symptoms, if any. 
• Enter diarrhea events as needed with symptoms, if any. 
• Obtain recommendations based on the clinical study protocol. 

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4) Follow-up with your health care provider 
Your health care provider also has an eCO web portal to monitor your blood pressure and 
diarrhea, should it occur. 
When you use eCO on a mobile device, your data are saved on your device. The application 
must synchronize and transmit your data to your provider for it to be available to him/her. 
This synchronization requires an Internet connection (3G, 4G, or WIFI). 

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MOBILE APPLICATION 

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General technical Information 
1) Compatible equipment 
eCO is currently compatible with iPhone 4s, 5, 5c, 5s, 6, 6+, 6s, 6s+, 7, 7+ or 7 SE running 
with iOS 8, 9 or 10. 
Caution: If you update your mobile device's operating system after eCO is installed, it is 
possible that eCO may stop working if the new operating system is incompatible with the 
version of the eCO mobile application installed on your device. You may need to update eCO 
from the App Store. 
2) Connecting to eCO  
When starting up eCO (or after a period of inactivity), the application will request your 
personal 4-digit access code. If you enter the wrong code 10 times, the application will be 
locked for 1 minute. 
In the event of a forgotten access code, you may select “Forgot your code?” on the application 
entry page, and you will be able to reset your access code after entering your login and 
password.  
 
3) Automatic locking 
For your security, eCO will lock after one minute of non-use. To re-open the application, you 
will need to re-enter your four-digit access code.  To change your access code, select the 
“Change access code” option under Settings. 
 

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4) Securing your device 
Closing the application is not enough to protect your data. It is recommended that you your 
mobile device is protected by password. 
5) Time settings on your device 
eCO recommends that you utilize the automatic time settings of your mobile device for 
accurate synchronization.  
Refer to your iPhone instructions for information about how to utilize the automatic time 
settings of your mobile device. 
6) Errors 
If an error occurs when opening eCO, an update may be needed. This can be done by going to 
the Appstore and updating eCO.  
After updating eCO, if errors persist, contact eCO User Support (see Technical Support section 
in this document). 

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Installing eCO 
To use eCO, download the application from the App Store and install it on your device.   
Remark:  An active Internet connection (3G, 4G, wifi) is required to download and install eCO. 
 
App Store (for iPhone) 
  To download and install the application for iOS: 
1. 
Go to the App Store on your device. 
2. 
Search “eCO” in the search box. 
3. 
Select the eCO application and tap “Install”. 
 
4. 
The download and installation take place automatically. 
Caution:  Although it is rare, it is possible for the version of your mobile device operating 
system to be incompatible with eCO. If this occurs, update to the most current operating 
system available. For more information on updating your operating system, please see your 
mobile device instructions and the manufacturer's recommendations. 

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Connecting to eCO mobile for the first time 
When your health care provider sets up your account, they will ask for your email address. eCO 
will send a confidential temporary password for your account to that email address. Do not give 
the eCO password to anyone.  
The temporary password will expire in seven (7) days, so you must download and install eCO 
during that time. If your password expires, contact eCO user support (see “Technical Support” 
section in this document). 
After downloading and installing eCO on your device, you must go through a multi-step setup 
process:  
1. Launch eCO and press “OK” for Notifications. 
 
 
 
2. Enter your username and password and then tap “Log in” 

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3. Enter your new password.  
Your new password must: 
- be at least 8 characters long,  
- contain at least one uppercase character (A - Z), at least one lowercase 
character (a - z) and at least one digit character (0 -9). 
It may contain non alphanumerical characters (for instance: *,-,+ «). 
It shall not be equal to or contain your username or full name. 
It must be different from the 5 previous passwords. 
 
4. Create an access code by entering a 4-digit code, and confirm it by entering it again. 
 
 
Remark: You must have an active and stable Internet connection (3G, 4G, WIFI) during the 
entire set-up process. 
 
 
 

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Using eCO 
The eCO mobile app Home has three sections: 
• Top section: The dark purple header provides access to app Information screen 
and 
Settings screen 
.  
• Middle section: The center provides summaries of the most recent recommendations for 
blood pressure and diarrhea, and buttons to enter new blood pressure or diarrhea measures. 
• Bottom section: The dark purple footer provides access to History, Home and Contact:  
− 
History: A summary of previous blood pressures and diarrhea recordings, as well as 
related recommendations. 
− 
Home: Main eCO page to enter new blood pressure or diarrhea recordings, and see 
summary of the recommendation for the previous entries. 
− 
Contact: List of Study Team contacts. 
 

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History 
The Summary page displays a graph of your historical data for both blood pressure and 
diarrhea recordings and the recommendation related to the last recording. 
Select the corresponding tab to see the history and last recommendation made by eCO for 
blood pressure (left) and diarrhea (right). 
 
 
 
 
 
 

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Contacts 
The Contacts page displays your list of contacts. tap on the 
icon to call a contact. 
 
Caution:  Your main Study Team contacts are displayed on this page (phone and/or pager). If 
you can’t reach them, call After Hours and Weekend contact or 911. 
 
 

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Entering a blood pressure check 
Pairing your Bluetooth-enabled blood pressure monitor 
In the eCO app, if the Bluetooth connection is turned off on your iPhone, the eCO app 
will display a message asking you to turn on Bluetooth in your Settings. Press on 
“Settings” button. 
 
Caution: Do not press “OK”. If you do press “OK”, you will have to manually access 
your iPhone settings to enable Bluetooth connection. 
⚫ In your iPhone Settings: turn on Bluetooth. 
 

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⚫ In the eCO app: tap the blood pressure icon to reach the Automatic Blood Pressure 
measure page. 
 
⚫ On the Bluetooth enabled BP monitor: press on the Start button for at least 4 
seconds, until “Pr” (Pairing) is displayed. 
 
⚫ In the eCO app: a popup message “Bluetooth Pairing Request” is displayed; Press on 
“Pair” button. 

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⚫ The BPM displays “End”. 
 
 
⚫ The pairing is now successfully completed, you can use the Bluetooth BP monitor to 
measure your blood pressure 
 
 
Blood pressure reminders 
eCO will send you a notification when a blood pressure check is needed.  For routine 
monitoring, a blood pressure check is needed two times each day (or one time each day based 
on the recommendation from your health care provider).  You may also be reminded to do more 
blood pressure checks depending on the blood pressure result. 
To set your preferred times for routine monitoring, see the Settings section for instructions. 
 

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Using your Bluetooth enabled blood pressure monitor 
Once your Bluetooth enabled blood pressure monitor is paired to your iPhone, you can 
record your blood pressure checks with it. 
⚫ Sit and put on the blood pressure cuff as instructed by your health care professional. 
⚫ Press on the “Blood pressure” icon on the eCO Home page. 
 
 
⚫ Press on the Start button of your blood pressure monitor. It should start measuring 
your blood pressure. 
⚫ After 30 to 60 seconds, eCO will indicate that a blood pressure measurement is 
being transferred from the blood pressure monitor. 
 
⚫ The blood pressure measurement will be displayed on eCO screen. Check to make 
sure the number displayed on the eCO screen is the same number displayed on the 
blood pressure monitor screen. 
⚫ Tap “Next” if the number is correct. 
⚫ If the number is incorrect, tap “Cancel” and do a new blood pressure check. 
 

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⚫ In eCO, a confirmation message is displayed, tap “Yes” if your entry is correct. 
⚫ If your entry is incorrect, tap “No” then tap “Cancel” and do a new blood pressure 
check. 
 
 

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Adding symptoms 
Based on the blood pressure entered (either using Bluetooth or manually), eCO may ask you if 
you have any symptoms such as headache, chest pain, change in vision or shortness of breath.  
     
 

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⚫ 
Press “None” if you don’t experience any of the symptoms listed. 
⚫ 
Press on the icon of the symptom(s) if you have any of those symptoms.  
⚫ 
Any symptom icon image you select will be replaced by a “Check” icon. See an 
example on the right screen above. 
⚫ 
If you press a symptom icon by mistake, press it again to turn it off. 
⚫ 
When your symptom entry is correct, press “Next”. 
Blood pressure recommendations 
After each blood pressure measure (and any potential symptoms), a recommendation will be 
displayed. See examples below. 
 
 
⚫ 
Tap “OK” to return to the home screen. 
If eCO recommends an additional blood pressure recheck, eCO will send you a reminder when 
this recheck is due.  
If the eCO recommendation is to “Contact your study team now”, tap “Contact” and the My 
Contacts screen will be displayed.  Use the icon to 
make the call from your iPhone. 

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Caution: 
• It is important for you to follow the recommendation provided by eCO. 
• eCO is not intended to replace the care provided by a licensed healthcare professional, 
including prescriptions, diagnosis, or treatment. 
• eCO should not replace a face-to-face consultation. 
• eCO is not a tool for managing a medical emergency. In case of emergency, dial 911. 
 

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Entering diarrhea data 
eCO allows you to enter diarrhea when it occurs and a recommendation will be provided, based 
on your baseline number of stools, and the number of bowel movements you enter. If you have 
an ileostomy, it will be based on the amount of output you enter. At your first visit, your health 
care provider indicated which way you will be entering diarrhea data. 
Entering diarrhea data using number of bowel movements 
Diarrhea is when you have an increase in the number of bowel movements from your usual 
number and/or if your bowel movements are loose or watery.   
⚫ Press on the diarrhea icon on the eCO Home page. 
 
⚫ Use the +/- buttons to enter the number of bowel movements in the last 24 hours, 
then press “Next” button.  

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Entering diarrhea using ileostomy output. 
If you have an ileostomy, diarrhea is when your ileostomy output is increased from your usual 
output.  
⚫ Press on the diarrhea icon on the eCO Home page. 
 
⚫ Use the 
 slider to enter your ileostomy output in the last 24 hours, then press 
“Next”.  

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Entering symptoms 
In some cases of diarrhea, eCO might ask you if you have any symptoms, such as severe 
cramping, blood in stools (bright red, maroon or black, tarry color), or if your diarrhea feels 
uncontrollable.  
⚫ Select the symptoms you are having, if any. Press the “None” icon if you don’t 
experience any of the symptoms listed. 
⚫ Any symptom icon image you select will be replaced by a “Check” icon. See an 
example on the right screen below. 
⚫ If you press a symptom icon by mistake, press it again to turn it off. 
⚫ When your symptom entry is correct, press “Next”. 
            
 
Remark: A new diarrhea event cannot be entered less than 18 hours after the last one. This is 
to allow time for the diarrhea self-management recommendations to work. 

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Diarrhea recommendations 
After each diarrhea and symptom screen, a recommendation will be displayed. These 
recommendations are based on the information provided to you by your health care 
professional. 
See a few examples below. 
 
 
Caution: 
• It is important for you to follow the recommendation provided by eCO. 
• eCO is not intended to replace the care provided by a licensed healthcare professional, 
including prescriptions, diagnosis, or treatment. 
• eCO should not replace a face-to-face consultation. 
• eCO is not a tool for managing a medical emergency.  
• In case of emergency, dial 911. 

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Settings 
To access the Settings page in eCO, press on the 
 icon at the top right corner of the 
Summary, Home, or Contact pages. 
 
 
You can change the following items: 
• Change access code: Change the access code by tapping here. eCO will ask you first for 
your current access code, then the new access code twice. 
Remark: After the application is put in background mode for more than one minute, 
you will be asked to enter your access code to unlock your application. 
 

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• Reminders: Change the blood pressure reminder times. The reminders will be 
displayed on your lock screen. Your notifications must be turned on to receive 
reminders. 
 
Caution: 
• Regular blood pressure monitoring is important and you must accept notifications upon 
first login, by tapping on “OK” button. 
• Settings will not permit fewer than 8 hours separating the notifications. 
When notifications are sent, they are displayed on the iPhone lock screen, or in the notification 
list. 

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About and Help 
The “About and Help” section provides important information about eCO including legal 
information, the license end date, support documents, and terms of use. This section allows 
access to an electronic version of the User Guide, which is regularly updated.  
To access the “About and Help” section, press on the 
 icon at the top left corner of the eCO 
screen. 
 
Documents 
eCO’s User’s Guide is available in electronic format and can be accessed from here. 
The “eCO Technical Support” line displays the user support email and toll free number to call if 
you are experiencing technical problems when using eCO (see Technical Support section in this 
document). 
Remark: eCO user support provides technical support. For a medical problem, contact your 

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health care provider or for a medical emergency call 911. 
Product information 
The “Product Information” section displays the following information: 
• Product name 
• Version  
• Manufacturer 
• Release date 
• Expiration date 
 

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TECHNICAL SUPPORT 
For any technical question or issue, please contact the eCO User Support.  
Toll free: 1-800-326-1448 (1-800-ECO-1HIT)  
Email:support@ecostudy.us   

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HELP 

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Frequently Asked Questions 
Compatibility 
Which devices are compatible with eCO? 
eCO is available on all iPhone devices from iPhone 4S to iPhone 7 SE Plus.  
What should I do if eCO is not compatible with my iOS version or mobile device? 
eCO is compatible with iOS 8, 9 and 10. Upgrade your iPhone’s operating system and try 
connecting to the application again. If the problem persists, contact User Support. 
I installed a new iOS version and eCO is not compatible anymore. What should I do? 
After a new iOS version is released, a delay can exist before the application is available for this 
version. Contact User Support for more information. 
Access to eCO 
What should I do if I do not receive my password? 
It is possible that the email confirming your registration has been identified as spam by your 
email software. Check your “Spam” folder, and if the email is not there, contact eCO User 
Support 1-800-326-1448 (1-800-ECO-1HIT) or by email: support@ecostudy.us. 
What should I do if I have forgotten my temporary password? 
If you have forgotten your temporary password, call your Study team in order to have your 
password generated again. You should receive this new password shortly after in your mailbox. 
 
  
   
 
 
 
 
  
If you have forgotten your access code, tap on ”Forgot your code?” in the Access code entry 
screen. Confirm that you want to reset your access code and authenticate again. 
Internet connection 
Do I need an active Internet connection to connect to eCO? 
An active Internet connection is required during your first connection. Once you are logged in, 
you can open your application and enter your access code without being connected to Internet. 
Do I need an active Internet connection to enter data? 
eCO requires an active Internet connection to retrieve your contact information and your 
parameters. If you enter a blood pressure measure or report a diarrhea event without any 
internet connection, the recommendation may not take into account the settings made by your 
Study team. 

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
216 
 
Blood pressure entry 
I forgot to enter my blood pressure when eCO asked me to do it. Should I enter it now? 
Yes. The reminders are here to help you remember to enter your blood pressure. If you forgot 
to enter it before, you can still enter it now. 
I cannot transfer the data from my blood pressure monitor to eCO. What can I do? 
First, check that the Bluetooth function is activated on your iPhone. Then, check that your 
iPhone and your monitor are paired and try again. If the error persists, enter your BP manually 
and contact eCO User Support. 
The symptoms I want to enter are not displayed in the list. How can I report them? 
eCO displays the list of symptoms generally associated with hypertension. If the symptoms you 
want to report are not displayed in the list, it probably means that these symptoms are not 
related to your blood pressure. Select “None” and continue your blood pressure entry. If the 
symptoms worsen, contact your study team.  
eCO asked me to call my Study Team. Who should I contact first? 
Depending on the situation, you may prefer to call your research nurse or your oncologist. If 
your Study Team is not available, you can call the “After-hours and Weekend” number 
displayed in the application. In case of medical emergency, dial 911. 
Diarrhea entry 
a. When should I report a diarrhea episode? 
You can report a diarrhea episode at any time. When you report a diarrhea episode, you will 
be asked to enter the number of bowel movements you have had over the past 24 hours. 
b. I have an ileostomy and eCO asks for my number of bowel movements. What should I 
do? 
If eCO asks you for the number of bowel movements you have had over the past 24 hours 
even if you have an ileostomy, it means that your profile was incorrectly set. Contact your 
study team to correct this. 
c. I don’t have an ileostomy and eCO asks about my ileostomy output. What should I 
do? 
If eCO asks you about your ileostomy output even when you don’t have an ileostomy, it 
means that your profile was incorrectly set. Contact your study team to correct this. 
d. I have had several diarrhea episodes over the past 24 hours. Why won’t eCO let me 
enter several episodes in less than 24 hours? 
In order to provide you with the most accurate recommendation, eCO needs to know the 
number of bowel movements you’ve had over the past 24 hours. Once a recommendation is 

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
217 
 
made, it may take some time for the changes to be effective. Therefore, once you report a 
diarrhea episode, you must wait at least 18 hours to report another episode. 
e. The symptoms I want to enter are not displayed in the list. How can I report them? 
eCO displays the list of symptoms generally associated with diarrhea. If the symptoms you 
want to report are not displayed in the list, it probably means that these symptoms are not 
related to your diarrhea episode. Select “None” and continue your diarrhea report.  
 
If the symptoms worsen, contact your study team. 
Settings 
a. How can I update my personal information? 
Your personal information cannot be edited. If you want your personal information to be 
updated, call your study team. 
b. Can I change my number of daily blood pressure reminders? 
No. If you consider that you receive too many or not enough reminders, contact your study 
team to change this setting. 
eCO in other countries 
Does eCO work in other countries? 
eCO works normally in all locations, but if you use the mobile app, you must continue to use 
the application on a regular basis with Internet access. Depending on your mobile plan, this 
could lead to a surcharge if you are outside of your normal usage area. You may use wifi for 
your Internet connection, if available. 
Other questions 
If your question has not been answered, please contact eCO User Support: 1-800-326-1448 (1-
800-ECO-1HIT) or by email: support@ecostudy.us 
. 
  

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
218 
 
Glossary and Abbreviations 
Abbreviations 
• BP: Blood pressure 
• eCO: e Cediranib / Olaparib 
• mmHg: millimeters of mercury 
 
Technical terms 
• iOS: An operating system found on several types of mobile devices made by Apple. 
• Synchronization: Transfer of data between eCO mobile and the server.  

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
219 
 
Legal information 
 
Voluntis S.A. 
58, avenue Wagram 
75017 Paris 
FRANCE 
www.voluntis.com  
 

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
220 
 
 
 
eCO Web Portal – Study Team 
Screenshots 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
221 
 

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
222 
 
 
 
 
 

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
223 
 
 
Patient Watchlist 
 
 
 

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
224 
 
Example Completed Patient Profile 
 

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Protocol Version Date: May 24, 2019 
 
225 
 
Example of Notifications 
 
 
 

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Protocol Version Date: May 24, 2019 
 
226 
 
Blood Pressure History 
 
 
 

NCI Protocol #: 9825 
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227 
 
Diarrhea History 
 
 
 

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228 
 
Add Recommended Action by Study Team 
 
 
 
 
 
 

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Protocol Version Date: May 24, 2019 
 
229 
 
View Protocol 
 
Blood pressure 
 
 
 

NCI Protocol #: 9825 
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Protocol Version Date: May 24, 2019 
 
230 
 
Diarrhea 
 
 
 
  
 

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
231 
 
 
 
 
eCO Blood Pressure – Diarrhea 
Monitoring 
Data Collection 

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
232 
 
Not in BP event: 
BP ✓ (BID)
0 – 90 
0 – 90 
141 - 150
91 - 95
151 - 160
0 – 90 
140
90
≤
160
100
>
∆ DBP > 20 
with 
Symptoms?
CALL
Yes
No
CALL
Symptoms?
Yes
No
CALL
Continue BID ✓
Re ✓ 1 
hr
CALL
CALL
0 – 90 
0 – 90 
140
90
≤
∆ DBP > 20 
with 
Symptoms?
Yes
No
CALL
Continue BID ✓
140
90
>
CALL
 
 

NCI Protocol #: 9825 
DF/HCC Protocol #: 16-700 
Protocol Version Date: May 24, 2019 
 
233 
 
 
In BP event: 
BP ✓ (BID)
0 – 90 
0 – 90 
141 - 150
91 - 95
140
90
≤
150
95
>
Continue BID ✓
CALL
Symptoms?
CALL
Yes
No
CALL
Re ✓ 12 
hr
140
90
≤
∆ DBP > 20 
with 
Symptoms?
Yes
No
CALL
140
90
>
CALL
∆ DBP > 20 
with 
Symptoms?
Yes
No
CALL
Continue BID ✓
CALL
141 - 150
91 - 95
:
BP ✓ (BID)
0 – 90 
0 – 90 
141 - 150
91 - 95
140
90
≤
150
95
>
CALL
Symptoms?
CALL
Close 
event
Yes
No
CALL
Re ✓ 1 
hr
0 – 90 
0 – 90 
140
90
≤
∆ DBP > 20 
with 
Symptoms?
Yes
No
CALL
140
90
>
CALL
∆ DBP > 20
Yes
No
Continue BID ✓
CALL
:
∆ DBP > 20 
with 
Symptoms?
Symptoms?
Yes
No
CALL
Re ✓ 1 
hr
0 – 90 
0 – 90 
140
90
≤
∆ DBP > 20 
with 
Symptoms?
Yes
No
CALL
140
90
>
CALL
Continue BID ✓
CALL
0 – 90 
0 – 90 
 
 

 
238 
 
 
Patient User Surveys and  
Phone Interview Guide 

 
 
 
239 
 
eCO Baseline Survey: Technology Use 
 
Participant ID: ____________________________ 
 
Site ID:_______________________ 
 
Date: _______________________________ 
 
 
1. Which of the following items do you use?  
 
 Desktop computer 
 Laptop Computer 
 Mobile Phone  
 Tablet 
 eBook Read (i.e., Kindle) 
 
 
2. Answer if you use a Mobile Phone or Tablet 
 
What type of smart phone and/or tablet device type do you use?  
 iPhone (Model: ___________) 
 Android (Model: ___________) 
 Other Phone (Model: ___________) 
 Tablet (Model: ___________) 
 
 
3. Answer if you use a Mobile Phone, Tablet or eBook reader. 
 
What type of activities do you use your phone or tablet for? Check all that apply. 
 Phone calls 
 Texting 
 Playing games 
 Browsing the internet 
 Purchasing from the internet 
 Downloading new applications 
 
 
 
 
 

 
 
 
240 
 
 
Facilitator’s Guide for 
eCO Mobile App Phone Interviews 
 
 
 
Submitted by: 
User-Centered Design, Inc. 
20548 Deerwatch Place 
Ashburn, VA 20147 
(703) 729-2370 
www.user-centereddesign.com

 
241 
 
[Note: The purpose of this document is to guide the moderator. The questions and tasks contained herein may not 
be asked as written. The facilitator often draws on participant comments and the natural flow of the testing 
process to determine the flow of the session. While the facilitator will try to follow the order of the guide, many 
times tasks will come up ahead of time or in different order. The facilitator may allow the order of the tasks to 
change in order to let the process flow naturally. ] 
Obtain consent 
I need to ask you to formally agree to consent to participate in this interview. We are asking you for 
approximately 10 minutes of your time. 
We won’t be asking anything personal and no information identifying you will be shared with others.   
Your participation is voluntary, and if you choose not to participate it will not affect your involvement in the 
clinical trial. You may ask questions at any time during the interview and you're free to stop the interview at 
any time without penalty and without any questions being asked of you.  Do you have any questions for me 
before we start? 
If you agree to participate, you are saying that you understand what I’ve told you and that any questions you 
have were satisfactorily answered. Do you agree to participate in the interview?  
Interview 
A. INTRODUCTION 
Thank you for agreeing to talk to me today.  
You’ve had the eCO application for about a week now and I wanted to follow up to see how it was going for you 
with the app since you left your doctor’s office. I will only be asking about the mobile app and I will not be asking 
about your treatment. 
There are only a few questions and as I said, the main purpose for the call today is to find out if the app is working 
alright for you this past week or if you are having any challenges with it. You can decline to answer any question 
and end this call when you want. I have one of my colleagues with us today taking notes for me Is it ok for my 
colleague to listen in to take notes for me? Are you ok with starting the questions?  
Do you have any questions for me before we start? 
 
B. Interview for Users (status predetermined by study team) 
• 
Tell me about your use of the application. How often have you been using it?  (Probe for type of activities) 
o [For each] How did the experience go for you?  
▪ 
Did you experience any problems or difficulties? [Discuss any issues raised; probe for 
monitoring blood pressure, diarrhea, etc.] 
o  [If not mentioned] Have you reported a diarrhea event through the application yet? 
• 
Have you ever received a recommendation from the application?  
o If so, was the recommendation clear? 
• 
What parts of the application, if any, did you initially find difficult to learn how to use? Have you figured 
them out now? 
• 
What parts of the application, if any, do you still find difficult or awkward to use now that you’ve figured 
out how to use the app? 

 
 
 
242 
 
• 
Do you have any questions about how to use the app that you would like to ask me? 
C. Interview for Non-Users 
• 
According to the information I have, you decided not to use the application. 
o Can you share with me the reasons why you decided not to use it? [Probe for technical and 
situational] 
o Is there anything that might have changed your mind about your decision not to use the 
application, even now? 
D. Closure 
• 
OK, those are the questions I have. Are there any questions you would like to ask me about the 
application or anything else you’d like to discuss about the application before I let you go? 
• 
Thanks again for your participation. 

 
 
 
243 
 
 
eCO User Survey: Patients 
 
 
 
            
 
Participant ID: 
  
Site ID: 
 
Date: 
       
 
 
Strongly 
Disagree 
 
 
 
Strongly 
Agree 
 
1. I liked using this app. 
1 
2 
3 
4 
5 
 
2. Using the app made me feel my care 
was being closely monitored. 
1 
2 
3 
4 
5 
 
3. Using the app made me feel more 
connected to the health care team. 
1 
2 
3 
4 
5 
 
4. The app made me feel involved in my 
own care. 
1 
2 
3 
4 
5 
 
5. It was hard for me to initially learn how 
to use the app. 
1 
2 
3 
4 
5 
 
6. I imagine most people would find it 
easy to learn how to use the app. 
1 
2 
3 
4 
5 
 
7. Even after learning how to use it, I 
found the app hard to use. 
1 
2 
3 
4 
5 
 
8. It was easy to find where to set the 
time(s) to receive reminders to take my 
blood pressure. 
1 
2 
3 
4 
5 
N/A 
9. The process of setting blood pressure 
reminders on the app was difficult. 
1 
2 
3 
4 
5 
N/A 
10. The process of reporting blood 
pressure side effects on the app was 
easy. 
1 
2 
3 
4 
5 
 
11. The process of recording blood 
pressure itself was difficult. 
1 
2 
3 
4 
5 
 
12. It was clear when I should report 
diarrhea. 
1 
2 
3 
4 
5 
 

 
 
 
244 
 
 
13. The process of reporting diarrhea side 
effects on the app was difficult. 
1 
2 
3 
4 
5 
N/A 
14. The process of reporting diarrhea on 
the app was easy. 
1 
2 
3 
4 
5 
N/A 
15. Recommendations from the app were 
not very clear. 
1 
2 
3 
4 
5 
 
16. It was easy to find the last 
recommendation made by the app. 
1 
2 
3 
4 
5 
 
17. It was hard to find the Study Team 
Contact information. 
1 
2 
3 
4 
5 
 
 
Comments 
Feel free to add any additional comments you have about the application. 

 
 
 
245 
 
eCO User Survey: Study Team 
 
 
            
 
 MD 
   NP/PA    RN/Research Coordinator  Other______ 
 
Site ID:   
 
 
Date: 
 
 
 
Strongly 
Disagree 
 
 
 
Strongly 
Agree 
1. I liked using this website. 
1 
2 
3 
4 
5 
2. It was hard for me to initially learn how 
to use the website. 
1 
2 
3 
4 
5 
3. I imagine that most people would find it 
easy to learn how to use the website.  
1 
2 
3 
4 
5 
4. Even after learning how to use it, I 
thought the website was hard to use. 
1 
2 
3 
4 
5 
5. The website made my work more 
efficient. 
1 
2 
3 
4 
5 
6. The amount of alerts generated were 
appropriate. 
1 
2 
3 
4 
5 
7. The content of the alerts were hard to 
understand. 
1 
2 
3 
4 
5 
8. The content of the alerts were helpful. 
1 
2 
3 
4 
5 
9. The tables on the “My Patients” page 
were hard to understand. 
1 
2 
3 
4 
5 
10. The tables on the “My Patients” page 
had all the information I needed. 
1 
2 
3 
4 
5 
11. I liked the separation of patients into a 
“watchlist” and a “non-watchlist”. 
1 
2 
3 
4 
5 
12. The patient information section had all 
the information I needed. 
1 
2 
3 
4 
5 
13. The patient information section was 
1 
2 
3 
4 
5 

 
 
 
246 
 
hard to use. 
 
Comments 
Feel free to add any additional comments you have about the application. 
 

 
 
 
247 
 
 
eCO User Survey: Back-office 
 
 
            
 
 MD 
   NP/PA    RN/Research Coord. 
 
Site ID:   
 
 
Date:       
 
 
Strongly 
Disagree 
 
 
 
Strongly 
Agree 
1. I liked using this website. 
1 
2 
3 
4 
5 
2. It was hard for me to initially learn how 
to use the website. 
1 
2 
3 
4 
5 
3. I imagine that most people would find it 
easy to learn how to use the website. 
1 
2 
3 
4 
5 
4. Even after learning how to use it, I 
thought the website was hard to use. 
1 
2 
3 
4 
5 
5. Adding a new study center was easy to 
do 
1 
2 
3 
4 
5 
6. Managing existing study centers was 
hard to do. 
1 
2 
3 
4 
5 
7. Adding a new study was easy to do. 
1 
2 
3 
4 
5 
8. Managing existing studies was hard to 
do. 
1 
2 
3 
4 
5 
9. Adding a study protocol to a study was 
easy to do. 
1 
2 
3 
4 
5 
10. Adding new users was hard to do. 
1 
2 
3 
4 
5 
11. Managing existing users was easy to 
do. 
1 
2 
3 
4 
5 
 
 
 

 
 
 
248 
 
 
 
Comments 
Feel free to add any additional comments you have about the application.