Conditions: Recurrent Platinum Resistant Ovarian Cancer
Keywords: ovarian cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 62
Healthy volunteers: no

Brief summary:
This is an open label, single arm, multi-center study to assess the efficacy and safety of the combination of cediranib and olaparib tablets in platinum-resistant relapsed high grade serous, high grade endometroid or clear cell ovarian, fallopian tube or primary peritoneal carcinoma patients who have received at least 3 prior lines of chemotherapy and who do not carry deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA) mutations.

Detailed description:
The study will recruit approximately 60 patients aged ≥18 years, with histologically proven diagnosis of platinum-resistant relapsed high grade serous, high grade endometroid or clear cell ovarian, fallopian tube or primary peritoneal carcinoma who have received at least 3 prior lines of therapy, and who do not carry a deleterious or suspected deleterious germline BRCA mutation. All patients should have recurrent platinum resistant disease. The receipt of prior antiangiogenic treatment (e.g. bevacizumab) is optional. If used, it can be in the first line or recurrent setting. To be eligible to enter the study, all patients should have measurable disease (as assessed by the Investigator).

There is no maximum duration for taking the study treatments (cediranib+olaparib). Patients should continue on study treatments until objective radiological disease progression, as defined by RECIST version 1.1 guidelines, or they meet other discontinuation criteria. Following discontinuation of study treatment patients will be followed for disease progression (if they have not already progressed), survival and post-progression anti cancer therapies until the data cut-off for the primary analysis, approximately 8 months after enrollment of the last patient.

Arms:
arm 1: Open label

Interventions: intervention 1: cediranib and olaparib
Intervention descriptions: intervention 1: Cediranib tablets oral dose 30 mg once daily; Olaparib(Lynparza) tablet 200 mg twice daily

Dose reduction for both products is allowed

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
Drug Substance
cediranib (AZD2171) plus 
olaparib (AZD2281)
Study Code
D8488C00001
Edition Number
5.0
Date
15 Jan 2019
A single arm, open-label, Phase IIb study to assess the efficacy and safety of 
the combination of cediranib and olaparib tablets in women with recurrent 
platinum resistant epithelial ovarian cancer, including fallopian tube and/or 
primary peritoneal cancer who do not carry a deleterious or suspected 
deleterious germline BRCA mutation
This document contains confidential commercial information, disclosure of which is prohibited without 
providing advance notice to AstraZeneca and opportunity to object.
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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!
Patients with primary platinum resistant/refractory disease defined as 
progression during or within 6 months of completing first-line platinum-based 
chemotherapy are not eligible. 
New text
4. Recurrent platinum-resistant disease, defined as disease progression within 6 months 
(182 days) of the last receipt of platinum-based chemotherapy. 
!
Patients with platinum refractory disease defined as disease progression
during the last receipt of platinum-based therapy, are not eligible
!
Patients with primary platinum resistant/refractory disease defined as 
progression during or within 6 months (182 days) of completing first-line 
platinum-based chemotherapy are not eligible. 
Rationale for change:
To clarify the length of time for disease progression by adding duration in days
Section 3.1 Inclusion criterion #8
Old text
8. Prior receipt of antiangiogenic treatment including but not limited to bevacizumab in first 
line or recurrent setting
New text
8. Prior receipt of antiangiogenic treatment, including but not limited to bevacizumab, is 
optional. If used, it can be in the first line or recurrent setting.
Rationale for change:
Bevacizumab has recently been approved by FDA for patients with recurrent ovarian 
cancer. Despite being an available treatment option in US, feasibility data show that nearly 
half of the recurrent ovarian cancer patients particularly in earlier lines of treatment do not 
receive bevacizumab. Therefore, to enable recruitment, prior receipt of antiangiogenic 
treatment is now changed from mandatory to optional.
Section 3.1 Inclusion criterion #9
Old text
9. At least 3 prior lines of chemotherapy for advanced ovarian cancer are required
∀
Up to 2 prior non-platinum chemotherapy regimens are allowed but not required
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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∀
Hormonal therapy (such as tamoxifen, aromatase inhibitors), bevacizumab or other 
immunotherapy used as a single agent will not count as a line of chemotherapy
New text
9. At least 3 prior lines of therapy for advanced ovarian cancer as follows: 
∀
Platinum chemotherapy: at least two prior lines required
∀
Non-platinum chemotherapy: up to two prior lines are allowed but not 
required
∀
Hormonal therapy (such as tamoxifen, aromatase inhibitors), bevacizumab or other 
immunotherapy used as a single agent will not count as a line of therapy
Rationale for change:
To clarify what treatments will count towards prior lines of therapy.
Section 3.10.2 – Survival status for withdrawn consent and lost to follow up patients
At the time of OS analysis, the survival status of all patients in the full analysis set should 
be re-checked, this includes those patients who withdrew consent or are classified as “lost to 
follow up.”
!
Lost to follow up – site personnel should check hospital records, the patients’ 
current physician, and a publicly available death registry (if available) to 
obtain a current survival status in the 2 weeks following data cut-off. (The 
SURVIVE module will be updated.)
!
In the event that the patient has actively withdrawn consent to the processing 
of their personal data, the survival status of the patient can be obtained by site 
personnel from publicly available death registries or resources (if available) 
where it is possible to do so under applicable local laws to obtain a current 
survival status in the 2 weeks following data cut-off. (The SURVIVE module 
will be updated.)
Rationale:
This new section has been created to clarify that at the time of OS analysis, site personnel 
should attempt to obtain the survival status for all patients in the full analysis set who had 
previously withdrawn consent or were considered lost to follow-up using publicly available 
resources where available.
Table 5 Schedule of study assessments
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Edition Number 5.0
Date 15 Jan 2019
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topics can be reviewed as needed.  The steering committee’s remit is to provide an agreed 
strategic direction for the study.
1.5.2 Data Monitoring Committee
In this Phase IIb study, a Data Monitoring Committee was not considered necessary as it is 
an open label study and the safety profiles of olaparib and cediranib as monotherapies and 
in combination, have previously been established.  
Rationale for change:
This section has been added, per AstraZeneca new Protocol Template. This was previously 
covered in Section 6.8 Study governance and oversight – which has been removed. The 
Section has been expanded to include further details on the structure and functioning of the 
steering committee.  
Section 3.1 Inclusion criteria #4
Old Text
4.
Recurrent platinum-resistant disease, defined as radiological evidence of disease 
recurrence within 6 months of the last receipt of platinum-based chemotherapy.  
Patients with platinum-refractory disease are not eligible.
New text
4.
Recurrent platinum-resistant disease, defined as disease progression within 6 
months of the last receipt of platinum-based chemotherapy.  
!
Patients with platinum refractory disease defined as disease progression 
during the last receipt of platinum-based therapy, are not eligible
!
Patients with primary platinum resistant/refractory disease defined as 
progression during or within 6 months of completing first-line platinum-
based chemotherapy are not eligible. 
Rationale for the change:
To allow clinical judgement by the investigator as per standard clinical practice without 
changing the definition of platinum resistant disease, the stipulation for radiological 
evidence of disease progression is removed. Previous criteria required radiological evidence 
of platinum-resistant disease which was dependent on when the CT scan was taken rather 
than on investigator’s clinical judgement of when disease progression occurred within the 
6-months of the last receipt of platinum-based chemotherapy. The GCIG criteria for 
platinum resistant ovarian cancer does not stipulate the requirement for radiological 
evidence of disease progression with 6 months of completing platinum-based chemotherapy 
(Friedlander M et al 2011, Int J Gynecol Cancer 2011: 21: 771-775).  The amendment will 
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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allow enrollment of patients in the study, if judged by the investigator to carry platinum-
resistant disease, who otherwise may not have been eligible for the study. 
Section 3.1 Inclusion criterion # 8
Old text
5.
Prior receipt of antiangiogenic treatment eg, bevacizumab in first line or recurrent 
setting
New text
5.
Prior receipt of antiangiogenic treatment including but not limited to
bevacizumab in the first line or recurrent setting
Clarification:
Text revised to clarify that prior antiangiogenic treatment is not limited to bevacizumab 
only.
Section 3.1 Inclusion Criteria #9
Old Text
9.
At least three prior lines of chemotherapy for advanced ovarian cancer.  Only one 
prior non-platinum treatment is allowed.  Hormonal therapies used as single 
agents (ie, tamoxifen, aromatase inhibitors) will not count towards this line limit.  
New Text
9.
At least three prior lines of chemotherapy for advanced ovarian cancer are 
required.  
!
Up to two prior non-platinum chemotherapy regimens are allowed but 
not required.    
!
Hormonal therapy (such as tamoxifen, aromatase inhibitors), 
bevacizumab (or other angiogenesis inhibitor), or other 
immunotherapy used as a single agent will not count as a line of 
chemotherapy.  
Rationale for the change:
The allowance of only one prior non-platinum regimen aimed to select patients who start 
study treatment as soon as platinum resistant relapse is diagnosed. However, in the heavily 
pre-treated setting of at least 3 prior lines of chemotherapy, it becomes too restrictive. 
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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Therefore, given the high unmet medical need, and considering no significant adverse 
impact on the study outcome, the criteria has been relaxed to enable recruitment.  
Section 3.1 Inclusion criterion # 11
Old text
∀
Urine protein:creatinine ratio (UPC) ≤1 OR ≤2+ proteinuria on two 
consecutive dipsticks taken no less than 1 week apart.  Patients with 2+ 
proteinuria on dipstick must also have UPC <0.5 on 2 consecutive samples. 
New text:
∀
Urine protein:creatinine ratio (UPC) ≤1 OR proteinuria ≤2+ on two 
consecutive dipsticks taken no less than 1 week apart.  Patients with 2+ 
proteinuria on dipstick must also have UPC <0.5 on 2 consecutive samples. 
Rationale for the change
Text is revised in Table 5 (footnote ‘n’) to clarify that 2+ refers to proteinuria and not to 
UPC.
Section 3.8 Restrictions; Section 4:/Table 5 and footnote ‘k’; Section 5.2.5.1 Serum or 
urine pregnancy test; Section 6.6.1 Maternal exposure
Rational for change
Sections have been updated to reflect the new guidance from the Olaparib IB edition 14 
which requires regular pregnancy test during olaparib treatment for fertile women of 
childbearing potential.
Section 4 Table 5
Clarification
The row header ‘dipstick’ has been revised to ‘urinalysis’ for clarification.
Correction
Footnote ‘i’ has been corrected to state that blood pressure should be measured at the clinic 
every 4 weeks, after Wk 8.
Section 5.3.1.2 PRO-CTCAE
Old text
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Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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The following 6 PRO-CTCAE AEs will be collected in the study: nausea, vomiting, 
diarrhea, decreased appetite, fatigue, and dizziness.
New text
The following 6 PRO-CTCAE AEs will be collected in the study: nausea, vomiting, 
diarrhea, decreased appetite, fatigue, and dizziness. In addition to these items from the 
PRO-CTCAE item bank, the following additional item will be asked together with the 
PRO-CTCAE items: "In the last 7 days, how much did LOOSE OR WATERY 
STOOLS (DIARRHEA) INTERFERE with your usual or daily activities?"
Rationale for the change
Data collection has been amended to include an additional question to a pre-existing 
question on Diarrhea in the instrument PRO-CTCAE, and to the ERT logpad. The rationale 
for this is that the item ‘Diarrhea’ was earlier assessed only on one dimension ‘frequency’. 
The addition of the new question will allow the assessment on two dimensions (frequency 
and interference). Although interference is not a standard NCI PRO-CTCAE item for 
diarrhoea, NCI accepts that individual sponsors can add dimensions to those in the item 
bank. Diarrhoea is a very common AE for cediranib and assessing the impact of the adverse 
event on patient well-being is clinically relevant. Furthermore, diarrhoea is reported as a 
very common event for olaparib, therefore assessing the impact of the combination on 
frequency and interference is important.  
Section 6.4 Reporting of serious adverse events
Administrative change
The following text has been added to replace Section 6.9 which was removed to align the 
protocol with the new protocol template: 
The AstraZeneca representative will be available between visits if the investigator(s) or 
staff at the center needs information or advice about the study conduct. AstraZeneca 
medical personnel will be readily available to discuss study related medical questions or 
problems with the investigator(s). Contact details are provided separately in the Investigator 
Study File.
Section 6.7 Medication error
This Section has been added to align with the new AstraZeneca Protocol Template.
Section 6.8 Study governance and oversight (Protocol v.2)
The Section has moved to Section 1.5 Study governance and oversight to align the 
protocol with the new AstraZeneca Template.
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Study Code D8488C00001
Edition Number 5.0
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Section 6.8.2 Non-hematologic toxicity (Table 11, footnote c) 
The Section has been amended to clarify that the footnote ‘c’ applies to venous 
thromboembolic events.
Section 6.8.3.1 (Table 12) 
Table 12 has been amended to provide clarity. Grades have been removed to avoid 
discrepancy between the Grades earlier used in Table 12 for the description of events for 
hypertension monitoring and management, and those defined by CTCAE v 4.03.
Section 6.8.3.4 (Table 14) 
Table 14 has been simplified by removing text ‘on urine dipstick or urinalysis’ from the 
column ‘Proteinuria Value if following by urinalysis’.
Section 6.9 Medical emergencies and AstraZeneca contacts (Protocol v.2)
The Section has been placed with the additional text in Section 6.4 ad 9.2 to align with the 
new AstraZeneca Template. The Sponsor’s contact information for medical emergencies 
will be provided separately to the participating sites in the Investigator Study File, to avoid 
the need to future amendments due to AZ personnel change. 
Section 8.2 Sample size estimate; Section 9.3 Study Timetable and End of Study
The Sections have been amended to clarify the requirement of 20 evaluable patients (ie, 
with measurable disease [by Investigator assessment]), for interim futility analysis of ORR.
Section 8.5.2 Analysis of the secondary variable(s)
The Section has been revised to clarify for Progression free survival (PFS) and Time to
discontinuation of study treatment or death (TDT) summaries as described in the section 
will also be provided at 18 months. 
Section 9.2 Monitoring of the study
Administrative change
Old text
The AstraZeneca representative will be available between visits if the Investigator(s) or 
other staff at the centre needs information and advice about the study conduct. The 
AstraZeneca Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week (see Section 6.9). 
New text
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PROTOCOL SYNOPSIS
A single arm, open label, phase IIb study to assess the efficacy and safety of 
the combination of cediranib and olaparib tablets in women with recurrent 
platinum resistant epithelial ovarian cancer, including fallopian tube and/or 
primary peritoneal cancer who do not carry a deleterious or suspected 
deleterious germline BRCA mutation
Principal Investigator
Dr Jung-Min Lee MD.
Center for Cancer Research 
National Cancer Institute,
Phone 
Email: 
Study site(s) and number of patients planned
Approximately 60 patients will be enrolled from approximately 40 sites, in the United States. 
Study period
Phase of development
Estimated date of first patient enrolled
Q1 2017
IIb
Estimated date of last patient completed
By Q3 2019
IIb
Study design
This is an open label, Phase IIb, single arm, multi-center study to assess the efficacy and 
safety of the combination of cediranib and olaparib tablets in platinum-resistant relapsed high 
grade serous, high grade endometroid or clear cell ovarian, fallopian tube or primary 
peritoneal carcinoma patients who have received at least 3 prior lines of therapy for advanced 
ovarian cancer and who do not carry deleterious or suspected deleterious germline breast 
cancer susceptibility gene (BRCA) mutations as determined in an appropriately accredited 
laboratory. Prior antiangiogenic treatment such as bevacizumab, either in a first line or 
recurrent setting is optional. To be evaluable for the primary endpoint of objective response 
rate (ORR), all patients should have measurable disease, defined as at least one lesion that can 
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PPD
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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be accurately measured at baseline by computed tomography (CT) or, if CT is not feasible, 
magnetic resonance imaging (MRI) and is suitable for repeated assessments per Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 
Objectives
Primary Objective:
Outcome Measure:
To determine the efficacy of the combination 
of cediranib and olaparib in patients with 
recurrent platinum resistant epithelial ovarian, 
fallopian tube and/or primary peritoneal cancer 
who do not carry deleterious or suspected 
deleterious germline BRCA mutations, as 
assessed by ORR.
ORR by independent central review (ICR), using 
RECIST version 1.1.
Secondary Objective:
Outcome Measure:
To assess the efficacy of the combination of 
cediranib and olaparib in this patient 
population by ORR, duration of response 
(DoR), disease control rate (DCR), progression 
free survival (PFS), time to treatment 
discontinuation or death (TDT) and overall 
survival (OS).
ORR by Investigator assessment using RECIST 1.1; 
DoR, PFS and DCR by ICR and Investigator 
assessment using RECIST 1.1, TDT and OS.
To assess the efficacy of the combination of 
cediranib and olaparib in patients carrying a 
somatic deleterious or suspected deleterious 
variant in either of the BRCA genes (BRCA1 or 
BRCA2) or in homologous recombination 
repair (HRR)-associated genes identified with 
current and potential future tumor based BRCA
or HRR gene mutation assays as assessed by 
ORR, DoR, DCR, PFS and OS.
ORR, DoR, PFS and DCR by ICR and Investigator 
assessment using RECIST 1.1, and OS.
To evaluate disease related symptoms and 
health-related quality of life when compared 
with baseline data
European Organization for Research and Treatment 
of Cancer (EORTC) quality of life questionnaire 
(QLQ) C30 and OV-28
Safety Objective:
Outcome Measure:
To evaluate the safety and tolerability of the 
combination of cediranib and olaparib.
Adverse events (AEs), and treatment emergent 
changes in vital signs and laboratory parameters.
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Edition Number 5.0
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Exploratory Objectives:
Outcome Measure:
To assess exploratory biomarkers of potential 
homologous recombination deficiency (HRD).
To assess exploratory angiogenic biomarkers 
such as vascular endothelial growth factor 
(VEGF)-A, C, D; sVEGFR2, Tie2, Ang1, 2; 
leptin; interleukin 6 (IL6) and exploratory 
immunologic biomarkers.
To evaluate exploratory biomarkers of 
potential resistance/sensitivity to cediranib or 
olaparib.
Potential biomarker research.
To assess adverse events by patient 
self-reporting of specific Patient Reported 
Outcomes version of the Common 
Terminology Criteria for Adverse Events 
(PRO-CTCAE™) symptoms.
Patient-Reported Outcomes version of the Common 
Terminology Criteria for Adverse Events 
(PRO-CTCAE™)
Target patient population
Female patients aged ≥18 years, with histologically proven diagnosis of platinum-resistant 
relapsed high grade serous, high grade endometroid or clear cell ovarian, fallopian tube or 
primary peritoneal carcinoma who have received at least 3 prior lines of therapy for advanced 
ovarian cancer, and who do not carry a deleterious or suspected deleterious germline BRCA
mutation as defined by a local test conducted in an appropriately accredited laboratory (eg, 
Clinical Laboratory Improvement Amendments [CLIA]-certified) that includes 
comprehensive DNA sequencing and large rearrangement analysis of BRCA1 and BRCA2. 
These patients will be required to provide a blood sample prior to receiving investigational 
products (IPs) which may be used to perform a subsequent confirmatory BRCA mutation test 
using Myriad’s BRACAnalysis CDx® test.
Patients who do not know their gBRCA status, or whose gBRCA status has not been 
determined by an appropriately accredited laboratory will be required to provide a blood 
sample at screening to allow determination of gBRCA status with Myriad’s BRACAnalysis 
CDx® test.  Such patients must fulfill all of the other eligibility criteria, prior to BRCA
mutation testing being carried out.
All patients should have recurrent platinum-resistant disease, defined as disease recurrence 
within 6 months (182 days) of the last receipt of platinum-based chemotherapy.
Duration of treatment
There is no maximum duration for taking the study treatments (cediranib + olaparib).  Patients 
should continue on study treatments until:
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∀
Objective radiological disease progression, as defined by RECIST version 1.1 
guidelines, 
∀
Unacceptable toxicity,
∀
Patient withdrawal of consent, or patient meets any other discontinuation criteria.  
∀
Severe non-compliance with the protocol
Both study treatments (cediranib and olaparib) should be discontinued at the same time; 
patients are not allowed to remain in the study if they are taking either cediranib or olaparib as 
monotherapy. However, in rare circumstances, patients experiencing ongoing clinical benefit 
who develop one of the toxicities listed below related to one of the investigational products 
(IPs) that prevents them to continue to take this IP, may be allowed to continue on the 
unrelated drug if in the opinion of the treating investigator the risk benefit remains favorable 
and only after discussion with AstraZeneca Study Physician and the Principal Investigator. 
AEs requiring cediranib to be discontinued:
!
Gastrointestinal (GI) perforation
!
Arterial Thromboembolic Event
!
Reversible Posterior Encephalopathy Syndrome (PRES)
!
Severe hemorrhage 
!
Severe persistent hypertension despite maximal anti-hypertensive 
treatment  
AEs requiring olaparib to be discontinued:
!
Bone marrow findings consistent with myelodysplastic syndrome 
(MDS)/acute myeloid leukemia (AML)
!
Severe persistent anemia
!
Pneumonitis
Once a patient discontinues both cediranib and olaparib, other treatment options are at the 
discretion of the investigator. 
Following discontinuation of study treatment patients will be followed for disease progression 
by RECIST 1.1 (if they have not already progressed), survival and post-progression 
anti-cancer therapies until the data cut-off for the primary analysis, approximately 8 months 
after the last patient has received her first dose of IP. This primary analysis is the final 
analysis for the study.
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Investigational products, dosage and mode of administration
Cediranib
Cediranib is available as a beige film-coated tablet containing 20 mg or 15 mg of cediranib.  
Patients will be administered cediranib study treatment tablets orally at a dose of 30 mg once 
daily (od).  The planned dose of 30 mg od will be made up of 2 × 15 mg tablets od.  
One x 20 mg and 1 x 15 mg tablets will be used to manage dose reductions.
Dose reduction steps for cediranib:
Dose Level
Cediranib tablets
Initial dose
30 mg daily
Dose reduction 1
20 mg daily
Dose reduction 2
15 mg daily
Olaparib
Olaparib is available as a green film-coated tablet containing 150 mg or 100 mg of olaparib.  
Patients will be administered olaparib study treatment tablets orally at a dose of 200 mg twice 
daily (bd).  The planned dose of 200 mg bd will be made up of 2 × 100 mg tablets bd.  One 
x 150 mg and 1 x 100 mg tablets will be used to manage dose reductions.
Dose reduction steps for olaparib:
Dose Level
Olaparib tablets
Initial dose
200 mg twice daily
Dose reduction 1
150 mg twice daily
Dose reduction 2
100 mg twice daily
The dose of cediranib and the morning dose of olaparib can be taken at the same time and can 
be taken with or without food, in a similar way each morning.  The evening dose of olaparib 
should be taken 12 hours after the morning olaparib dose with or without food in a similar 
way each day.
Statistical methods
The primary outcome measure is ORR by Independent Central Review (ICR) using 
RECIST 1.1 criteria.  An interim futility analysis of ORR (confirmed and/or unconfirmed 
complete responses [CR] and partial responses [PR]) will take place after 20 evaluable 
patients (ie, with measurable disease [by Investigator assessment] at baseline and received at 
least 1 dose of study drugs) have been followed for at least 4 months.  Enrollment will 
continue whilst the futility analysis is being conducted.  The criterion for declaring futility is 
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based on predictive probability within a Bayesian design framework.  If less than 4 of the 
20 patients have responded, the study may be stopped for futility.  If 4 or more patients have 
responded the study will continue to the primary analysis. 
Assuming the study passes the futility assessment, the data cut-off for the primary analysis of 
ORR (confirmed CRs + PRs only) will take place 8 months after the last patient has received 
her first dose of IP, to allow opportunity for all patients to complete at least 4 RECIST follow-
up assessments and estimate duration of response (DoR).  The primary analysis for the clinical 
study report (CSR) will be based on the confirmed ORR by ICR using RECIST 1.1 criteria 
and supported by Investigator assessment of ORR and by other efficacy endpoints (DoR, 
disease control rate [DCR] and progression free survival [PFS], time to treatment 
discontinuation or death [TDT]), patient reported outcomes (PROs), and safety and tolerability 
data.  For the primary analysis of ORR by ICR the mean and median of the posterior 
distribution of ORR will be presented, along with the standard deviation and a 95% credible 
interval around the mean (based on the highest posterior density [Lee 1997]).  ORR by ICR 
will also be presented with 95% exact (Clopper Pearson) confidence intervals (95% CI).
The posterior probabilities of the ORR being larger than 15%, 20% and 24% will also be 
computed.  To further characterize the response rate, the posterior probability of showing low 
(<15%), moderate (≥15%- <20%), high (≥20%- <24%) or substantial (≥24%) efficacy will be 
presented.  
At the time of primary analysis, ORR and exact 95% CI (Clopper Pearson) will also be 
presented for the following:
!
ORR by investigator assessment
!
ORR for both confirmed and unconfirmed responses for ICR assessment
!
ORR in the subgroup of patients carrying a somatic deleterious or 
suspected deleterious mutation in either of the BRCA genes (BRCA1 or 
BRCA2) or in predefined homologous recombination repair (HRR)-
associated genes identified with current and potential future tumor based 
BRCA or HRR gene mutation assays (ICR and Investigator assessment). 
The primary analysis of ORR, and analyses of DoR and DCR by ICR will be produced based 
on the Evaluable for response (EFR) analysis set; ie, all patients who have received at least 
one dose of study treatments and have measurable disease at baseline according to the ICR of 
baseline imaging data.  All other efficacy variables (ORR, DoR, DCR based on investigator 
assessment; PFS, time to treatment discontinuation or death [TDT] and overall survival [OS]), 
patient reported outcome (PRO) variables and safety variables will be summarized using the 
Full Analysis set (FAS) comprising all patients who received at least one dose of either of the 
IPs. 
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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
PROTOCOL SYNOPSIS...................................................................................13
TABLE OF CONTENTS...................................................................................19
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.........................27
1.
INTRODUCTION .............................................................................................32
1.1
Background and rationale for conducting this study ...........................................32
1.1.1
Epithelial ovarian cancer....................................................................................32
1.1.2
Cediranib ...........................................................................................................32
1.1.2.1
Activity of cediranib as single agent in ovarian cancer patients .......................... 33
1.1.2.2
Activity of cediranib in combination with chemotherapy in ovarian cancer 
patients .............................................................................................................. 33
1.1.3
Olaparib.............................................................................................................34
1.1.4
Activity of the combination of cediranib and olaparib ........................................ 35
1.1.4.1
Nonclinical experience with the combination of cediranib and olaparib..............35
1.1.4.2
Rationale for treatment with cediranib after prior exposure to bevacizumab ....... 36
1.1.4.3
Clinical experience with the combination of cediranib and olaparib ...................37
1.2
Rationale for study design, doses and control groups..........................................40
1.3
Benefit/risk and ethical assessment ....................................................................41
1.4
Study Design...................................................................................................... 42
1.5
Study governance and oversight.........................................................................46
1.5.1
Steering Committee............................................................................................46
1.5.2
Data Monitoring Committee...............................................................................46
2.
STUDY OBJECTIVES......................................................................................47
2.1
Primary objective...............................................................................................47
2.2
Secondary objectives.......................................................................................... 47
2.3
Safety objectives................................................................................................ 47
2.4
Exploratory objectives ....................................................................................... 48
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL.....................48
3.1
Inclusion criteria ................................................................................................ 49
3.2
Exclusion criteria ............................................................................................... 51
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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3.3
Patient enrollment and randomization ................................................................54
3.4
Procedures for handling incorrectly enrolled patients .........................................54
3.4.1
Screen failures ...................................................................................................54
3.4.2
Incorrectly enrolled patients...............................................................................54
3.5
Methods for assigning treatment groups.............................................................54
3.6
Methods for ensuring blinding ...........................................................................54
3.7
Methods for unblinding......................................................................................54
3.8
Restrictions........................................................................................................55
3.9
Discontinuation of investigational product .........................................................55
3.9.1
Procedures for discontinuation of a patient from investigational product ............56
3.10
Criteria for withdrawal....................................................................................... 57
3.10.1
Withdrawal of the informed consent...................................................................58
3.10.2
Survival status for withdrawn consent and lost to follow up patients .................. 58
3.11
Discontinuation of the study............................................................................... 58
4.
STUDY PLAN AND TIMING OF PROCEDURES...........................................59
4.1
Screening/Enrollment period..............................................................................65
4.2
Treatment period................................................................................................ 65
4.3
Follow-up period................................................................................................ 65
4.3.1
Discontinuation of study treatments due to disease progression..........................66
4.3.2
Discontinuation of study treatments in the absence of disease progression..........66
4.4
Final Protocol Visit ............................................................................................ 66
4.5
End of Study...................................................................................................... 66
5.
STUDY ASSESSMENTS..................................................................................67
5.1
Efficacy assessments.......................................................................................... 67
5.1.1
Tumor assessments by CT or MRI scans............................................................ 67
5.1.2
Tumor evaluation...............................................................................................68
5.1.3
Central reading of scans .....................................................................................69
5.1.4
Survival assessment ...........................................................................................69
5.2
Safety assessments............................................................................................. 69
5.2.1
Laboratory safety assessments............................................................................69
5.2.1.1
Full hematology assessments for safety..............................................................70
5.2.1.2
Biochemistry assessments for safety................................................................... 70
5.2.1.3
Disease specific tumor marker samples (CA-125) ..............................................71
5.2.1.4
Urinalysis...........................................................................................................71
5.2.1.5
Bone marrow or blood cytogenetic samples ....................................................... 71
5.2.2
Physical examination .........................................................................................72
5.2.3
ECG...................................................................................................................72
5.2.3.1
Resting 12-lead ECG .........................................................................................72
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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5.2.4
Vital signs..........................................................................................................72
5.2.4.1
Pulse and blood pressure.................................................................................... 72
5.2.4.2
Body temperature...............................................................................................73
5.2.5
Other safety assessments.................................................................................... 73
5.2.5.1
Serum or urine pregnancy test............................................................................73
5.3
Other assessments.............................................................................................. 73
5.3.1
Clinical Outcome Assessments........................................................................... 73
5.3.1.1
EORTC QLQ C30 and EORTC QLQ OV28 ......................................................73
5.3.1.2
PRO-CTCAE.....................................................................................................74
5.3.1.3
Administration of PRO questionnaires ............................................................... 74
5.3.2
Exploratory Immunologic/Molecular Assessments.............................................76
5.4
Pharmacokinetics ............................................................................................... 77
5.4.1
Collection of samples.........................................................................................77
5.4.2
Determination of drug concentration..................................................................77
5.4.3
Storage and destruction of PK samples...............................................................77
5.5
Pharmacodynamics ............................................................................................77
5.6
Genetics............................................................................................................. 77
5.7
Biomarker analysis............................................................................................. 77
5.7.1
Collection of blood sample for Myriad germline BRCA testing ..........................77
5.7.2
Collection of biomarkers biological samples ......................................................78
5.7.3
Storage, re-use and destruction of biological samples.........................................79
5.7.4
Labelling and shipment of biological samples ....................................................79
5.7.5
Chain of custody of biological samples ..............................................................79
5.7.6
Withdrawal of Informed Consent for donated biological samples.......................79
5.8
Biological sampling procedures .........................................................................80
5.8.1
Volume of blood................................................................................................ 80
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 83
6.1
Definition of adverse events............................................................................... 83
6.1.1
Adverse Events of Special Interest ..................................................................... 83
6.2
Definitions of serious adverse event ...................................................................83
6.3
Recording of adverse events...............................................................................84
6.3.1
Time period for collection of adverse events ......................................................84
6.3.2
Follow-up of unresolved adverse events.............................................................84
6.3.3
Adverse events after the 30 day follow up period ............................................... 84
6.3.4
Variables............................................................................................................ 85
6.3.5
Causality collection............................................................................................87
6.3.6
Adverse events based on signs and symptoms ....................................................87
6.3.7
Adverse events based on examinations and tests ................................................87
6.3.8
Hy’s Law ...........................................................................................................88
6.3.9
Disease progression............................................................................................88
6.3.10
New cancers.......................................................................................................88
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
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6.3.11
Lack of efficacy .................................................................................................88
6.3.12
Deaths................................................................................................................88
6.4
Reporting of serious adverse events ................................................................... 89
6.5
Overdose............................................................................................................90
6.6
Pregnancy .......................................................................................................... 90
6.6.1
Maternal exposure..............................................................................................91
6.7
Medication Error................................................................................................91
6.8
Management of IP related toxicities ...................................................................93
6.8.1
Hematologic toxicity..........................................................................................94
6.8.1.1
Use of hematopoietic agents...............................................................................95
6.8.1.2
Dose modifications for hematologic toxicity ......................................................95
6.8.1.3
Management of prolonged hematological toxicities while on study 
treatment............................................................................................................ 96
6.8.2
Non-hematologic toxicity................................................................................... 97
6.8.3
Management of cediranib-related toxicity ..........................................................98
6.8.3.1
Hypertension......................................................................................................98
6.8.3.2
Diarrhea........................................................................................................... 102
6.8.3.3
Fatigue............................................................................................................. 103
6.8.3.4
Proteinuria ....................................................................................................... 103
6.8.3.5
Management of Thyroid Toxicities .................................................................. 104
6.8.3.6
Decrease in LVEF............................................................................................ 105
6.8.3.7
Reversible Posterior Encephalopathy Syndrome (PRES).................................. 106
6.8.3.8
Gastrointestinal perforation.............................................................................. 106
6.8.3.9
Fistula.............................................................................................................. 106
6.8.3.10
Arterial thromboembolism ............................................................................... 106
6.8.3.11
Venous thromboembolism ............................................................................... 107
6.8.3.12
Wound healing................................................................................................. 107
6.8.3.13
Elderly............................................................................................................. 107
6.8.3.14
Mild/moderate renally impaired patients .......................................................... 107
6.8.3.15
Weight decreased............................................................................................. 107
6.8.4
Management of olaparib associated toxicity..................................................... 108
6.8.4.1
Management of MDS/AML ............................................................................. 108
6.8.4.2
Management of olparib-related new or worsening pulmonary symptoms.......... 108
6.8.4.3
Management of nausea and vomiting ............................................................... 108
6.8.4.4
Management of renal impairment..................................................................... 108
6.8.5
Interruptions for intercurrent non-toxicity related events .................................. 109
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................. 109
7.1
Identity of investigational product(s)................................................................ 109
7.1.1
Cediranib ......................................................................................................... 110
7.1.2
Olaparib........................................................................................................... 110
7.2
Dose and treatment regimens ........................................................................... 110
7.2.1
Cediranib ......................................................................................................... 110
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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7.2.2
Olaparib........................................................................................................... 111
7.3
Labelling.......................................................................................................... 111
7.4
Storage............................................................................................................. 111
7.5
Compliance...................................................................................................... 111
7.6
Accountability.................................................................................................. 112
7.7
Concomitant and other treatments .................................................................... 112
7.8
Post Study Access to Study Treatment ............................................................. 115
8.
STATISTICAL ANALYSES BY ASTRAZENECA........................................ 115
8.1
Statistical considerations .................................................................................. 115
8.2
Sample size estimate ........................................................................................ 116
8.3
Definitions of analysis sets............................................................................... 117
8.3.1
Full analysis set (FAS)..................................................................................... 117
8.3.2
Efficacy analysis set (EFR population)............................................................. 117
8.3.3
Safety analysis set............................................................................................ 117
8.3.4
PK analysis set................................................................................................. 117
8.4
Outcome measures for analyses........................................................................ 118
8.4.1
Primary Endpoint............................................................................................. 118
8.4.2
Secondary endpoints ........................................................................................ 119
8.4.3
Other endpoints................................................................................................ 120
8.5
Methods for statistical analyses........................................................................ 121
8.5.1
Analysis of the primary variable ORR.............................................................. 121
8.5.2
Analysis of the secondary variable(s) ............................................................... 122
8.5.3
Subgroup analysis (if applicable) ..................................................................... 123
8.5.4
Interim analysis................................................................................................ 123
8.5.5
Sensitivity analysis........................................................................................... 123
8.5.6
Exploratory analyses........................................................................................ 124
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA....................... 124
9.1
Training of study site staff................................................................................ 124
9.2
Monitoring of the study.................................................................................... 124
9.2.1
Source data ...................................................................................................... 125
9.2.2
Study agreements............................................................................................. 125
9.2.3
Archiving of study documents.......................................................................... 125
9.3
Study timetable and end of study...................................................................... 125
9.4
Data management by AstraZeneca ................................................................... 127
10.
ETHICAL AND REGULATORY REQUIREMENTS..................................... 127
10.1
Ethical conduct of the study ............................................................................. 127
10.2
Patient data protection...................................................................................... 127
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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10.3
Ethics and regulatory review ............................................................................ 128
10.4
Informed consent ............................................................................................. 128
10.5
Changes to the protocol and informed consent form......................................... 129
10.6
Audits and inspections ..................................................................................... 129
11.
LIST OF REFERENCES ................................................................................. 130
LIST OF TABLES
Table 1
ICON6 Summary of Results..................................................................33
Table 2
Overall response and duration of response in patients with 
gBRCAm advanced ovarian cancer who received 3 or more prior 
lines of chemotherapy ...........................................................................34
Table 3
Comparison of cediranib/olaparib and single-agent olaparib in 
recurrent ovarian cancer trials ...............................................................39
Table 4
Comparison of cediranib/olaparib and single-agent cediranib in 
recurrent ovarian cancer trials ...............................................................40
Table 5
Schedule of study assessments ..............................................................60
Table 6
Estimated maximum volume of blood to be drawn from each 
patient...................................................................................................82
Table 7
Dose modification cediranib..................................................................93
Table 8
Dose modification of olaparib ...............................................................93
Table 9
Management of neutropenia or thrombocytopenia.................................94
Table 10
Management of anaemia .......................................................................96
Table 11
General Management of Non-Hematologic Toxicity .............................97
Table 12
Hypertension Monitoring and Management...........................................99
Table 13
Management of Diarrhea.....................................................................102
Table 14
Management of Proteinuria .................................................................104
Table 15
Monitoring and Management of Thyroid Toxicities.............................105
Table 16
Monitoring and Management of Decreased LVEF...............................106
Table 17
Identity of investigational product(s)...................................................109
Table 19
ECOG/Karnofsky Scale ......................................................................146
Table 20
Summary of methods of assessment ....................................................148
Table 21
Evaluation of target lesions ................................................................. 152
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Clinical Study Proto ol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
26(173)
Appendix I
List of CYP3A4 inhibitors and inducers .............................................. 162
Appendix J
Acceptable Birth Control Methods ......................................................164
Appendix K
PRO questionnaires (EORTC QLQ-C30, QLQ OV28, and PRO-
CTCAE)..............................................................................................165
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
27(173)
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term
Explanation
ACE
Angiotensin Converting Enzyme
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase (serum glutamic pyruvate transaminase [SGPT])
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase 
[SGOT])
AUC
Area under the plasma drug concentration-time curve
BCRP
Breast cancer resistance protein
bd 
Twice daily
BP
Blood pressure
BRAT
Bananas, rice, apples, toast
BRCA
Breast cancer susceptibility gene (in accordance with scientific convention, 
gene and mutation is italicized whereas protein is not italicized)
CA-125
Cancer antigen-125
CI
Confidence interval
CLIA
Clinical Laboratory Improvement Amendments
CR
Complete response
CrCL
Creatinine clearance
CRO
Contract research organization
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
Circulating tumor DNA
CYP
Cytochrome
DAE
Discontinuation of Investigational Product due to Adverse Event
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
28(173)
Abbreviation or 
special term
Explanation
DBP
Diastolic blood pressure
DCR
Disease control rate
DNA
Deoxyribonucleic acid 
DoR
Duration of response
DSB
Double-strand break
EC
Ethics Committee, synonymous with Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
(e)CRF
(electronic) Case report form
EFR
Evaluable for response
EOC
Epithelial ovarian cancer
EORTC
European Organization for Research and Treatment of Cancer
ePRO
Electronic patient reported outcome device
FACS
Fluorescence-activated cell sorter
FAS
Full analysis set
FFPE
Formalin fixed, paraffin embedded
FPV
Final Protocol Visit
FT4
Free Thyroxine
gBRCAm
Germline breast cancer susceptibility gene mutated
gBRCAwt
Germline breast cancer susceptibility gene wild type (ie, non-gBRCAm)
GCP
Good Clinical Practice
G-CSF
Granulocyte- colony stimulating factor
Geomean
Geometric mean
GGT
Gamma glutamyltransferase
GI
Gastrointestinal
GMP
Good Manufacturing Practice 
Hb
Hemoglobin
HIV
Human immunodeficiency virus
HR
Hazard ratio
HRCT
High resolution computed tomography
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
29(173)
Abbreviation or 
special term
Explanation
HRD
Homologous recombination repair deficiency
HRR
Homologous recombination repair
HRQoL
Health-related quality of life
IB
Investigator Brochure
ICH
International Conference on Harmonization
ICR
Independent Central Review
ICU
Intensive care unit
IL6
Interleukin 6
INR
International normalized ratio
IP
Investigational Product 
IV
Intravenous
LLN
Lower limit of normal
LSLV
Last Subject Last Visit
LVEF
Left ventricular ejection fraction
MCH
Mean cell hemoglobin
MCV
Mean cell volume 
MDS
Myelodysplastic syndrome
MRI
Magnetic resonance imaging
MUGA
Multigated acquisition
N/A 
Not available
N/n 
Number of subjects
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NE
Not evaluable
NIH
National Institutes of Health
NTL
Non-target lesion
od
Once daily
ORR
Objective Response Rate
OS
Overall survival
PARP
Polyadenosine 5’diphosphoribose (poly [ADP ribose]) polymerization 
PARPi
PARP inhibitor
PBMC
Peripheral blood mononuclear cells
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
30(173)
Abbreviation or 
special term
Explanation
PD
Progressive disease
PFI
Platinum free interval
PFS
Progression free survival
Pgp
P glycoprotein
PI
Principal Investigator 
PK
Pharmacokinetics
PLD
PEGylated liposomal doxorubicin
PR
Partial response
PRES
Posterior reversible encephalopathy syndrome
PRO
Patient reported outcome
PRO-CTCAE™
Patient-Reported Outcomes version of the Common Terminology Criteria 
for Adverse Events
PSR
Platinum sensitive relapsed
QLQ-C30
Quality of life questionnaire for cancer patients
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RP2D
Recommended Phase II dose
RR
Response rate
RT
Radiotherapy
SAE
Serious adverse event 
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SD
Stable disease
SE 
Standard error
TDT
Time to treatment discontinuation or death
TSH
Thyroid stimulating hormone
UGT
Uridine diphosphate glucuronosyltransferase
ULN
Upper limit of normal
UPC
Urine protein:creatinine ratio
VEGF
Vascular endothelial growth factor
VEGFR
VEGF receptor
VUS
Variant of unknown significance
WBC
White blood cell count
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
31(173)
Abbreviation or 
special term
Explanation
WBDC
Web Based Data Capture
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Clinical Study Proto ol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
32(173)
1.
INTRODUCTION
1.1
Background and rationale for conducting this study
1.1.1
Epithelial ovarian cancer
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and the fifth most 
common cause of cancer-related death in women with the estimated annual incidence of just 
over 200,000 individuals and approximately 125,000 deaths (American Cancer Society 2015; 
Siegel et al 2015).  
Most patients with EOC present with advanced disease at diagnosis (Cannistra 2004; Parmar 
et al 2003).  The combination of a platinum drug with a taxane is the standard of care first-line 
treatment after primary cytoreductive surgery (du Bois et al 2003, McGuire et al 1996).  
Response to the first-line treatment is achieved in more than 70% of patients whose tumors are 
optimally or sub-optimally cytoreduced (Ozols et al 2003; Kang et al 2006).  However, of 
those who respond, 55% to 75% will relapse within 2 years of completing treatment (Edwards 
et al 2015).  
A patient’s response to first-line platinum-based therapy is indicative of their response to 
second and subsequent lines of platinum-based treatment, with the length of the platinum-free 
interval (PFI) and the extent of relapse (site and number of tumors) being particularly 
prognostic of response.  However, most patients will develop resistance to platinum-based 
therapy over time, with decreasing length of PFI with increasing rounds of treatment.  
Platinum-resistant ovarian cancer [defined as disease recurring within 6 months (182 days) 
after the last receipt of platinum based chemotherapy, Stuart et al 2011] has a particularly poor 
prognosis, with a low response rate (RR) to subsequent chemotherapy (< 15%), median 
progression free survival (PFS) of 3 to 4 months and overall survival (OS) of approximately 
12 months (Davis et al 2014).  
Pegylated liposomal doxorubicin (PLD), paclitaxel, topotecan and gemcitabine, the most 
commonly used agents in the setting of ‘platinum resistance’ (Luvero et al 2014), show RRs 
ranging from 10% to 15% and duration of response (DoR) of typically <6 months (Markman 
et al 2000; Matsuo et al 2010).
Therefore, there is a need to develop alternative therapies for patients with platinum resistant 
ovarian cancer, given the poor response to traditional cytotoxic agents.  Two potential 
therapeutic targets are DNA damage repair and angiogenesis pathways.  
1.1.2
Cediranib
Cediranib is a potent, oral once daily small-molecule tyrosine kinase inhibitor of vascular 
endothelial growth factor (VEGF)- signalling and angiogenesis that targets all 3 VEGF 
receptors (VEGFR-1,-2,-3) and has additional activity against stem cell factor receptor (c-kit)-
dependent tumor growth.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
33(173)
1.1.2.1
Activity of cediranib as single agent in ovarian cancer patients
Two studies showed the activity of single agent cediranib in recurrent ovarian cancer patients, 
the National Cancer Institute (NCI)-sponsored studies NCI 7102 (Matulonis et al 2009) and 
NCI 7129 (Hirte et al 2015); both studies enrolled patients with platinum-sensitive and 
platinum-resistant disease.  Single agent cediranib has shown an objective response rate 
(ORR) of 17% and a median PFS of 5.2 months in patients with platinum resistant ovarian 
cancer, treated in 2nd or 3rd line setting (Matulonis et al 2009); another study in platinum 
resistant ovarian cancer patients treated in 2nd line setting, showed an ORR of 0% (0/35 
patients) and a median PFS of 3.7 months (Hirte et al 2015).  Results are presented in Table 4.
1.1.2.2
Activity of cediranib in combination with chemotherapy in ovarian cancer 
patients
The ICON6 study, led by the Medical Research Council, was a Phase III randomized, double-
blind, placebo-controlled study in patients with platinum-sensitive relapsed (PSR) ovarian 
cancer who had received one prior chemotherapy regimen.  The ICON6 study recruited 
456 women who were randomized 2:3:3 to three parallel treatment arms: in arm A (reference) 
platinum-based chemotherapy plus placebo; in arm B (concurrent), platinum-based 
chemotherapy plus cediranib 20 mg, followed by placebo during the maintenance phase; in 
arm C (concurrent plus maintenance) platinum-based chemotherapy plus cediranib 20 mg 
followed by single agent cediranib 20 mg during the maintenance phase.  Six cycles of 
chemotherapy were planned, but patients unable to complete 6 cycles and who were 
responding to treatment could begin maintenance treatment after at least four cycles were 
completed. Results are summarized in Table 1:
Table 1
ICON6 Summary of Results
Treatment arm
Arm A 
(chemotherapy plus 
placebo followed by 
placebo in 
maintenance)
N= 118
Arm B (concurrent 
cediranib and 
chemotherapy 
followed by placebo in 
maintenance)
N = 174
Arm C (concurrent 
cediranib and 
chemotherapy 
followed by 
maintenance 
cediranib)
N = 164
Number of progression 
events (%)
113 (96%)
156 (90%)
141 (86%)
Median PFS in months 
(95% CI)
8·7 (7·7, 9·4)
9·9 (9·4, 10·5).
11·0 (10·4, 11·7)
Abbreviations:  CI  confidence interval; N  number of subjects; PFS  progression free survival
The primary efficacy analysis compared PFS between arm C and arm A; the result showed a 
hazard ratio (HR) of 0·56, (95% confidence interval [CI]: 0·44–0·72, p<0.0001). The PFS 
difference between arm B and arm A was also statistically significant (likelihood ratio 
ptrend<0.0001) demonstrating an effect of maintenance cediranib over and above the effect of 
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
34(173)
adding it to chemotherapy (Ledermann et al 2016).  OS data at 52% maturity showed median 
OS of 26.3 months in arm C and 21 months in arm A (HR 0.77; 95% CI: 0.55-1.07, p=0.11). 
Diarrhea, neutropenia, hypertension, and voice changes were significantly more common, 
during chemotherapy with cediranib, and diarrhea, hypothyroidism and voice changes were 
more common during maintenance.
Further details including pre-clinical data and efficacy and safety information are provided in 
the cediranib (AZD2171) Investigator Brochure (IB).
1.1.3
Olaparib 
Olaparib (AZD2281, KU-0059436, Lynparza™) is a potent polyadenosine 5’ diphosphoribose 
[poly (ADP ribose)] polymerization (PARP) inhibitor (PARPi; PARP-1, -2 and -3) which is 
now approved by FDA as monotherapy in patients with deleterious or suspected deleterious 
germline breast cancer susceptibility gene (BRCA) mutated (as detected by an FDA-approved 
test) advanced ovarian cancer who have been treated with three or more prior lines of 
chemotherapy.   
FDA approval for olaparib was based on data from Study D8180C000042 (Study 42); a 
Phase II non-comparative study in gBRCAm advanced tumors, including ovarian cancer using 
olaparib capsule formulation, 400 mg bd (Table 2).  
Table 2
Overall response and duration of response in patients with gBRCAm 
advanced ovarian cancer who received 3 or more prior lines of 
chemotherapy
Olaparib capsule formulation 80 mg bd
N = 137
ORR (95% CI)
34 % (26, 42)
Complete response
2%
Partial response
32%
Median DoR in months (95% CI)
7.9 (5.6, 9.6)
Abbreviations: bd  twice daily; CI  confidence interval; DoR  duration of response; gBRCAm  germline breast 
cancer susceptibility gene mutation; N  number of subjects; ORR  objective response rate.
Study 42 data were supported by data from Study D8180C000019 (Study 19); a Phase II, 
randomized, double-blind, placebo controlled multicenter study using olaparib capsule 
formulation, 400 mg bd.  In Study 19, 265 patients with PSR ovarian cancer in response to 
platinum based chemotherapy were randomized to olaparib 400 mg bd or placebo in a 
maintenance setting.  The primary analysis demonstrated that maintenance treatment with 
olaparib led to a significant PFS improvement vs placebo [HR 0.35 [95% CI: 0.25, 0.49]; 
p<0.00001; Ledermann et al 2012).  Moreover, pre-planned subgroup analysis by 
BRCA-mutation status identified patients with BRCA-mutated ovarian cancer (n=136, 51.3%) 
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
35(173)
as the subgroup that derived the greatest clinical benefit from olaparib maintenance 
monotherapy vs placebo (HR 0.18 [95% CI 0.10, 0.31]; p<0.00001; median 11.2 months 
versus 4.3 months).  A confirmatory study for Study 19, the SOLO2 study is currently 
ongoing and data are expected to be reported by the end of 2016.  SOLO2 is a Phase III 
randomized, double-blind, placebo controlled multicenter study using olaparib tablet 
formulation, 300 mg bd.  Unlike Study 19, which recruited patients with PSR ovarian cancer, 
regardless of their BRCA mutation status, patients in SOLO2 were required to have a 
documented BRCA mutation. 
Further details including pre-clinical data and efficacy and safety information are provided in 
the olaparib (AZD2281) IB. 
1.1.4
Activity of the combination of cediranib and olaparib 
1.1.4.1
Nonclinical experience with the combination of cediranib and olaparib
To determine whether cediranib has potential to combine with olaparib, the combination 
treatment was tested in an ovarian patient derived tumor explant model.  Tumors were 
implanted sub-cutaneously, then selected and randomized once they were 0.2 cm3.  Tumor 
bearing animals were treated with either monotherapy cediranib at 3 mg/kg on a 5 day on 
2 day off schedule, olaparib at 100 mg/kg daily, or a combination of cediranib and olaparib.  
Treatment with both cediranib and olaparib as monotherapies reduced tumor growth, however 
the combination of the 2 agents resulted in increased anti-tumor activity with tumors not 
progressing through therapy for the duration of the study.
Figure 1
Combination of cediranib and olaparib in OV2022 patient derived 
explant.  
Tumors were grown to 0.2cm3 and treated with cediranib once daily (od), olaparib once daily (od) or the 
combination as indicated.  The geometric mean tumor volume is shown +/- Standard error mean 
Abbreviations: Geomean geometric mean; od  once daily; SE  standard error.
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
36(173)
Potential mechanism of action for the combination
Specific mechanisms driving the clinical benefit observed with the combination of cediranib 
and olaparib are currently not defined (Liu et al 2014).  However, combining cediranib and 
olaparib have potential to synergize by increasing the anti-angiogenic effect of cediranib, or 
preventing the tumor cell from adapting to the anti-angiogenic treatment.  Alternatively, 
cediranib may lower the expression of DNA damage response genes and induce a synthetic 
“DNA damage response (DDR) phenotype” thereby increasing sensitivity to PARPi. 
Cediranib treatment results in a change in vasculature permeability and a reduction in vessels 
(refer to the cediranib IB for more information).  This in turn may induce tumor hypoxia, 
nutrient and metabolic stress in the tumor cell compartment, specifically, the hypoxia 
mediated micro-environmental stress has potential to induce both acute DNA damage and 
suppression of DNA repair pathways with downregulation of homologous recombination 
genes such as BRCA1 and RAD51 and mismatch repair genes (Bindra et al 2005; Bindra et al 
2007; Bristow and Hill 2008).  This increases the rate of background DNA damage.  An 
increase in metabolic stress as caused by hypoxia would also restrict the potential to generate 
nucleotides and co-factors to drive DNA repair.  Subsequently the combination with olaparib 
would impair the ability of the tumor cell to tolerate this increase in background DNA 
damage.  
Other mechanisms may also contribute to the combination effect.  BRCA1 can influence the 
hypoxia response (Kang et al 2006) and hence may prevent cells adapting to the reduction in 
oxygen.  Furthermore, VEGFR3 inhibition can sensitize ovarian cancer cells to chemotherapy 
via downregulation of BRCA1 and BRCA2 (Lim et al 2014).  Other studies have 
demonstrated that PARP inhibition can result in some anti-angiogenic activity, with PARPi 
and PARP knockouts showing reduced vascularization in a matrigel plug assay in vivo 
(Tentori et al 2007).
1.1.4.2
Rationale for treatment with cediranib after prior exposure to bevacizumab
While bevacizumab targets VEGF-A driven activation of VEGFR-1 and -2, evidence is 
emerging that patients either naturally possess alternative VEGF-VEGFR angiogenesis 
pathways/features not targeted by bevacizumab and/or acquire reactive resistance to 
bevacizumab following inhibition of VEGF-A.  VEGF-C and/or VEGF-D mediated activation 
of VEGFR-2 has now emerged as a potential resistance mechanism following inhibition of 
VEGF-A by bevacizumab (Van der Bilt et al 2012).  Recent data show that VEGF-C and its 
receptor VEGFR-3 are elevated in serum and ascites fluid isolated from ovarian cancer 
patients.  VEGF-C is described as a prognostic marker in ovarian cancer, with patients 
presenting with high serum VEGF-C (Cheng et al 2013) or high tumor expression (Nishida et 
al 2004) associated with a worse prognosis.  Similar data are described for the related ligand 
VEGF-D, which also activates VEGFR-3 (Yokoyama et al 2003a; Yokoyama et al 2003b). 
The selectivity and pharmacokinetic (PK) profile of cediranib, which targets all 3 VEGFRs 
(VEGFR-1, -2, -3) activated by different ligands (VEGF-A, -B, -C, -D) has the potential to 
achieve consistent and comprehensive suppression of the VEGF axis for the treatment of 
ovarian cancer in patients with natural or acquired resistance to bevacizumab.
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
37(173)
1.1.4.3
Clinical experience with the combination of cediranib and olaparib
Phase I study cediranib plus olaparib capsules
A Phase I study was initially conducted to establish the recommended Phase II dosing (RP2D) 
of the cediranib plus olaparib capsule combination, which enrolled a total of 28 patients 
(20 ovarian, 8 breast).  Among the 18 evaluable ovarian patients, an overall ORR of 44% to 
the cediranib/olaparib combination was observed in this Phase I population, which included 
both gBRCAm patients and patients who did not carry a deleterious or suspected deleterious 
gBRCA mutation (Liu et al 2013).  Two dose limiting toxicities (1 Grade 4 neutropenia 
≥4 days; 1 Grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30 mg 
daily; olaparib 400 mg bd).  The RP2D established in this study was cediranib 30 mg od plus 
olaparib capsules 200 mg bd.
In total, 6 platinum-resistant ovarian cancer patients were treated across all dose levels 
investigated; the patients comprised of 3 patients who harbored gBRCAm mutations (1 patient 
with each of the following responses: confirmed partial response [PR], unconfirmed PR and 
stable disease [SD] x 8 months) and 3 patients who did not carry deleterious or suspected 
deleterious gBRCA mutations, or patients whose mutation status was of unknown significance; 
amongst these patients, 2 had confirmed PRs and 1 patient had SD [<6 months, by CA-125 
only]).  The ORR was 50%, with a clinical benefit rate of 67%.  The median PFS was 
7.5 months, with a range of 3.3 to 20.4 months. 
Phase I study cediranib plus olaparib tablets
A Phase I study was subsequently conducted to establish the RP2D of cediranib plus olaparib 
tablets combination; the study enrolled 24 patients with recurrent ovarian, fallopian tube or 
primary peritoneal cancer.  Ten (42%) out of the 24 patients were known to carry a gBRCA
mutation; 13 patients were non-carriers and 1 patient had unknown BRCA status 
(Liu et al 2013).  Among 22 evaluable patients, an overall response rate of 27% was observed.  
Two of the responders were BRCA mutation non-carriers and 4 had platinum resistant disease.  
The most common toxicities included hypertension, diarrhea and fatigue.  The RP2D 
established for the combination were cediranib 30 mg od plus olaparib tablet 200 mg bd or 
cediranib 20 mg od plus olaparib tablet 300 mg bd.  
Phase II study
A Phase II study comparing the activity of cediranib and olaparib (capsule formulation) 
combination with olaparib alone in recurrent platinum-sensitive ovarian cancer is ongoing 
(NCT01116648, Liu et al 2014).  In the full analysis set (FAS), there were 2 CRs and 20 PRs 
in patients who received olaparib monotherapy (48% ORR) and 5 CRs and 30 PRs in patients 
who received the combination of cediranib and olaparib (80% ORR, p = 0.002).  The 
combination of cediranib and olaparib significantly extended both PFS and ORR compared 
with olaparib alone, with a median PFS of 9.2 months for olaparib alone and 16.7 months for 
cediranib/olaparib (HR 0.402, 95% CI 0.217, 0.741, p = 0.0036).
A post-hoc subset analysis of PFS by BRCA mutation status (patients with gBRCAm vs. 
patients without gBRCAm, including patients with mutation status unknown or variants of 
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Clinical Study Proto ol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
38(173)
unknown significance [VUS]) showed that in patients who were confirmed to be gBRCAm, 
median PFS was 16.7 months on the olaparib monotherapy arm and 20.2 months on the 
cediranib/olaparib arm (HR 0.541, 95% CI 0.230, 1.26, p = 0.16).  In patients who were not 
gBRCAm or had a VUS, there was a marked increase in PFS from 5.8 months with olaparib 
monotherapy to 16.6 months with cediranib/olaparib therapy (HR 0.323, 95% CI 0.139, 0.746; 
p = 0.008) and an increase in ORR from 32% to 76% (p = 0.006).  The majority of patients in 
both arms had received 1 or 2 previous lines of treatment (76% of patients on olaparib 
monotherapy vs. 82% of patients on cediranib/olaparib arm); it is unclear if the observed 
difference in ORR and PFS based on gBRCAm status could in part be attributable to the 
degree of prior therapy.
Overall, the cediranib/olaparib combination demonstrated a significant clinical benefit over 
olaparib alone, as measured both by PFS and ORR.  The increased clinical benefit of the 
cediranib/olaparib combination over olaparib monotherapy was greater in women with tumors 
that were not gBRCAm or who had a VUS status compared with women who harbored 
gBRCA1/2 mutations.  Toxicities were consistent with expected class-related toxicities of 
these drugs, with most common grade 3 or 4 toxicities attributed to each of the IPs including 
fatigue (27% cediranib/olaparib vs. 11% olaparib), diarrhea (23% vs. 0%), and hypertension 
(41% vs. 0%).  There were 2 Common Terminology Criteria for Adverse Event (CTCAE) 
Grade 4 events, both in the cediranib/olaparib arm: 1 event of Grade 4 hypertension in a 
patient who was not fully compliant with blood pressure (BP) monitoring and 1 event of 
Grade 4 myelodysplastic syndrome (MDS).
Summaries of the clinical data in patients with recurrent ovarian cancer for cediranib/olaparib 
combination compared with single agent olaparib or cediranib are shown in Table 3 and 
Table 4, respectively.  
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
39(173)
Table 3
Comparison of cediranib/olaparib and single-agent olaparib in 
recurrent ovarian cancer trials
Patient 
characteristics
Treatment
Number 
of 
patients
PFS 
(months)
ORR (%) 
by RECIST
Reference
gBRCAm
(N=47); 
gBRCAwt 
(N=43)
all platinum-
sensitive
Olaparib single agent 
400 mg bd
46
9.0
56.1
Liu et al 
2014
Cediranib 30 mg od plus 
olaparib 200 mg bd
44
17.7
83.7
all gBRCAm; 
all partially 
platinum 
sensitive
Olaparib 200 mg bd 
32
6.5
25
Kaye et al 
2012
Olaparib 400 mg bd 
32
8.8
31
PLD 50 mg/m2
33
7.1
18
gBRCAm
(N=17); 
non-gBRCAm 
(N=46)
Olaparib 400 mg bd; 
platinum-sensitive patients
25
N/A
52
Gelmon et 
al 2011
Olaparib 400 mg bd; 
platinum-resistant patients 
38
N/A
13
Olaparib 400 mg bd; 
platinum resistant 
(non-gBRCAm only)
26
N/A
4
Abbreviations: bd  twice daily; gBRCAm  germline BRCA mutant; gBRCAwt  germline BRCA wild type; N/A  not 
available; N  number of subjects; od once daily; ORR  objective response rate; PFS  progression free survival; 
PLD  Pegylated liposomal doxorubicin; RECIST  Response Evaluation Criteria in Solid Tumors; VUS  variant of 
unknown significance.
Note: these studies used the capsule formulation of olaparib.
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
40(173)
Table 4
Comparison of cediranib/olaparib and single-agent cediranib in 
recurrent ovarian cancer trials
Patient 
characteristics
Treatment
Number 
of 
patients
PFS 
(months)
ORR (%) 
by RECIST
Reference
gBRCAm
(n=47); 
gBRCAwt 
(n=43)
all platinum-
sensitive
Olaparib single agent 
400 mg bd
46
9.0
56.1
Liu et al 
2014
Cediranib 30 mg od plus 
olaparib 200 mg bd
44
17.7
83.7
N/A
Cediranib 45 mg/30 mg od; 
overall population
47
5.2
17
Matulonis et 
al 2009
Cediranib 30 mg od; 
platinum-sensitive patients
16
5.2
12.5a
Cediranib 30 mg od 
platinum-resistant patients
30
5.2
17b
N/A
Cediranib 45 mg/30 mg od; 
overall population
74
4.1
N/A
Hirte et al 
2015
Cediranib 45 mg/30 mg od; 
platinum-sensitive patients
39
7.2
23
Cediranib 45 mg/30 mg od 
platinum-resistant patients
35
3.7
0
Abbreviations:  bd  twice daily; gBRCAm  germline BRCA mutant;  gBRCAwt  germline BRCA wild type; 
N/A  not available; N  number of subjects; od  once daily; ORR  objective response rate; PFS  progression free 
survival; PLD  Pegylated liposomal doxorubicin;  RECIST  Response Evaluation Criteria in Solid Tumors;  
VUS  variant of unknown significance.
a
6 patients discontinued prematurely for toxicity reasons
b
5 patients discontinued prematurely for toxicity reasons
Note; these studies used the capsule formulation of olaparib.
1.2
Rationale for study design, doses and control groups
Single agent olaparib has shown limited activity in patients with non-BRCAm platinum 
resistant ovarian cancer with ORR 4% (1/26) (Gelmon et al 2011).  Single agent cediranib has 
shown an ORR of 17% and a median PFS of 5.2 months in patients with platinum resistant 
ovarian cancer, treated in 2nd or 3rd line setting (Matulonis et al 2009); another study in 
platinum resistant ovarian cancer patients treated in 2nd line setting, showed an ORR of 0% 
(0/35 patients) and a median PFS of 3.7 months (Hirte et al 2015).  
A Phase I trial of the combination of cediranib and olaparib in patients with recurrent ovarian 
cancer showed that cediranib 30 mg od in combination with olaparib tablet 200 mg bd is a 
tolerable regimen with preliminary evidence of activity in platinum resistant disease with an 
ORR of 29% (4/14 patients) including both BRCA mutation carriers and non-carriers 
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Clinical Study Proto ol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
41(173)
(Liu et al 2013).  Given the limited activity of single agent olaparib or cediranib in 
platinum-resistant recurrent ovarian cancer patients who do not carry a deleterious or 
suspected deleterious gBRCA mutation, and the synergistic effect of the combination observed 
both non-clinically and clinically, it is considered appropriate to evaluate only the
combination of olaparib/cediranib using an open-label, single arm design in this patient 
population of high unmet need for whom there are currently no therapies available other than 
palliative therapies.   
The study thus has the limitation that the current design would not allow an assessment of the 
contribution components within this study.  However, in parallel, a Phase II/III study (NRG-
GY005) is investigating in a randomized setting the activity of single agent olaparib and 
cediranib versus the combination of cediranib plus olaparib and versus standard of care non-
platinum based chemotherapy in patients with platinum resistant ovarian cancer who have 
received no more than 2 prior chemotherapies and may or may not carry gBRCA mutation.
Both studies will use the previously established and recommended Phase II dose for the 
combination of cediranib (30 mg, oral, once daily) plus olaparib tablet 200 mg oral twice daily 
(Liu et al 2014).
1.3
Benefit/risk and ethical assessment
Ovarian cancer remains a leading cause of death from gynecological cancers in the United 
States (American Cancer Society 2015) and is the fifth most common cause of cancer 
mortality in women (Siegel et al 2015).  Recurrent platinum resistant high grade serous 
ovarian cancer accounts for most EOC deaths (Vaughan et al 2011).  Effective targeted agents 
are needed that can improve prognosis with an acceptable toxicity profile without adversely 
impacting quality of life.  
The outlook for patients who develop platinum resistant disease is poor, with a low RR to 
subsequent chemotherapy (<15%), median PFS of 3 to 4 months and OS of approximately 
12 months (Davis et al 2014). 
Bevacizumab has recently been approved by the FDA, based on the results of AURELIA trial, 
in combination with investigator’s choice of chemotherapy (paclitaxel, pegylated liposomal 
doxorubicin [PLD] or topotecan) for the treatment of patients with platinum-resistant recurrent 
epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 
2 prior chemotherapy regimens.  In the 287 patients with responses evaluable by Response 
Evaluation Criteria in Solid Tumors (RECIST), the ORR was 11.8% versus 27.3% for 
chemotherapy and bevacizumab plus chemotherapy, respectively (p =0.001; Pujade-Lauraine 
et al 2014).
Olaparib is approved by the FDA as monotherapy in patients with deleterious or suspected 
deleterious germline BRCA mutated advanced ovarian cancer who have been treated with 
≥3 prior lines of chemotherapy and are either platinum sensitive or platinum resistant. 
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Clinical Study Proto ol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
42(173)
However, patients with platinum resistant ovarian cancer who do not carry a deleterious or 
suspected deleterious gBRCA mutation and who have received ≥3 prior chemotherapy 
regimens, including prior anti-angiogenic therapy (eg, bevacizumab), do not have effective 
therapeutic options currently available and there remains a high unmet need for new effective 
targeted agents for this population.  Moreover, efficacy rapidly declines in patients with 
platinum resistant disease with subsequent lines of therapy and, as per National 
Comprehensive Cancer network (NCCN) guidelines (NCCN guidelines), palliation should be 
considered after failure of 2 lines of treatment.  Available data demonstrate that the 
combination of cediranib/olaparib has the potential to provide clinical benefit in this group of 
patients, with toxicities being consistent with expected class-related toxicities of these drugs 
(Section 1.1.4.3).  
Patients who have progressed on prior anti-angiogenic therapy (eg, bevacizumab) have been 
reported to have an increase in alternate VEGF ligands suggesting that a more comprehensive 
inhibition of VEGF signaling as offered by cediranib may be appropriate at that point (Lieu et 
al 2013).  Therefore, there remains an unmet medical need for effective treatment options with 
an alternative anti-angiogenic treatment for patients at their relapse on bevacizumab.  
On balance, therefore the benefit/risk for the combination of cediranib plus olaparib in heavily 
pre-treated patients with platinum-resistant recurrent ovarian cancer patients who do not carry 
a deleterious or suspected deleterious gBRCA mutation, for whom only palliative therapies are 
available, is considered favorable. 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonization 
(ICH) Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca 
policy on Bioethics and Human Biological Samples.
1.4
Study Design 
This is an open label, Phase IIb, single arm, multi-center study to assess the efficacy and 
safety of the combination of cediranib and olaparib in platinum resistant relapsed high grade 
serous, high grade endometroid or clear cell ovarian, fallopian tube or primary peritoneal 
carcinoma who have received at least 3 prior lines of therapy for advanced ovarian cancer and 
who have no evidence of deleterious or suspected deleterious gBRCA mutation(s) as defined 
by a local test conducted in an appropriately accredited laboratory (eg, Clinical Laboratory 
Improvement Amendments [CLIA]-certified) that includes comprehensive DNA sequencing 
and large rearrangement analysis of BRCA1 and BRCA2. Prior antiangiogenic treatment such 
as bevacizumab, either in a first line or a recurrent setting is optional. To be eligible to enter 
the study, all patients should have measurable disease (as assessed by the Investigator), 
defined as at least 1 lesion that can be accurately assessed at baseline by computed 
tomography (CT)/ magnetic resonance imaging (MRI) and is suitable for repeated assessment 
per RECIST 1.1. All patients will have RECIST 1.1 tumour assessments at screening (within 
28 days prior to the start of study treatment) and every 8 weeks (±1 week) after start of 
treatment until objective radiological disease progression or withdrawal of consent. Objective 
radiological response on treatment (complete response [CR] or PR) will need to be confirmed 
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
43(173)
during next RECIST 1.1 visit assessment to ensure that identified responses are not a result of 
measurement error in a single arm clinical trial. 
Patients will receive the combination of:
!
Cediranib tablets 30 mg oral once daily
!
Olaparib tablets 200 mg oral twice daily
Patients should continue to receive IPs until objective radiological disease progression, 
unacceptable toxicity or withdrawal of consent.  The study originally planned to recruit 
100 patients over approximately 12 months.  Due to slower than projected recruitment, the 
study now plans to recruit approximately 60 patients.  An interim futility analysis will be 
undertaken once the first 20 evaluable patients (ie, with measurable disease [by Investigator 
assessment] and have received at least 1 dose of IP) have been followed for at least 4 months.  
If fewer than 4 radiological tumor responses are observed at this point, the trial may be 
considered futile and enrollment stopped.  Enrollment will continue whilst the futility analysis 
is being conducted.
The primary analysis of the study will be based on measurement of ORR in the evaluable for 
response (EFR) analysis set (CR+PR; confirmed responses only) by Independent Central 
review (ICR) using RECIST 1.1.  The primary analysis will also report analyses of DoR and 
disease control rate (DCR) by ICR in the EFR analysis set.  Other variables analyzed at the 
primary analysis (ORR, DoR, DCR based on investigator assessment; PFS, overall survival 
[OS], time to treatment discontinuation or death [TDT], patient-reported outcome [PRO] 
variables and safety variables) will be summarized using the FAS.  The data cut-off for the 
primary analysis will take place 8 months after the last patient has received her first dose of IP 
and is the final analysis for the study. This primary data cut-off will be followed by clinical 
database lock.  
Patients continuing to receive clinical benefit without meeting any discontinuation criteria 
during the study, will complete a FPV which will occur at their last scheduled visit prior to the 
primary data cut-off.  Beyond the FPV, patients may continue to receive cediranib and/or 
olaparib if they are deriving clinical benefit in the opinion of the investigator, and not 
fulfilling any discontinuation criteria (see Section 4.5). 
All patients will be required to provide an archival formalin fixed, paraffin embedded (FFPE) 
tumor sample from the primary or preferably recurrent cancer.  If an archival tumor sample is 
not available, a tumor sample from a fresh biopsy is acceptable.  Please note that a lesion that 
has been biopsied during screening cannot be selected as a target lesion for RECIST 
assessment.  Tumor samples will be tested for somatic (ie, non-germline) deleterious or 
suspected deleterious mutation in either of the BRCA genes (BRCA1 or BRCA2) and the 
following homologous recombination repair (HRR)-associated genes: ATM, BRIP1, PALB2, 
RAD51C, BARD1, CDK12, CHEK1, CHEK2, FANCL, PPP2R2A, RAD51B, RAD51D, and
RAD54L.  
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Clinical Study Proto ol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
44(173)
The design of the study is shown in Figure 2:
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
45(173)
Figure 2
Study flow chart
Abbreviations:  BRCA breast cancer susceptibility gene; DCO data cut-off; ECOG Eastern Cooperative Oncology Group; N  number of subjects; RECIST  
Response Evaluation Criteria in Solid Tumors; SAE  serious adverse event.
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
46(173)
1.5
Study governance and oversight
The patient safety data from the study will be closely monitored on an ongoing basis by the 
Sponsor and a Study Steering Committee.  Issues identified will be addressed; for instance, 
this could involve amendments to the study protocol and letters to Investigators.
1.5.1
Steering Committee
The Steering Committee will consist of two investigators (including the Principal Investigator) 
and AZ representatives including clinician, statistician and clinical scientist. The remit is to 
review the outcomes of the planned analyses conducted during the conduct of the trial 
including the futility analysis and the primary analysis. In addition, safety topics can be 
reviewed as needed.  The steering committee’s remit is to provide an agreed strategic direction 
for the study.
1.5.2
Data Monitoring Committee
In this Phase IIb study, a Data Monitoring Committee was not considered necessary as it is an 
open label study and the safety profiles of olaparib and cediranib as monotherapies and in 
combination, have previously been established.  
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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To determine the efficacy of the combination 
of cediranib and olaparib in patients with 
recurrent platinum resistant epithelial ovarian, 
fallopian tube and/or primary peritoneal cancer 
who do not carry deleterious or suspected 
deleterious germline BRCA mutations, as 
assessed by objective response rate (ORR).
ORR by independent central review (ICR) using 
RECIST version 1.1
2.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To assess the efficacy of the combination of 
cediranib and olaparib in this patient 
population by ORR, duration of response 
(DoR), disease control rate (DCR), progression 
free survival (PFS), time to treatment 
discontinuation or death (TDT) and overall 
survival (OS).
ORR by Investigator assessment using RECIST 1.1; 
DoR, PFS and DCR by ICR and Investigator 
assessment using RECIST 1.1, TDT and OS.
To assess the efficacy of the combination of 
cediranib and olaparib in patients carrying a 
somatic deleterious or suspected deleterious 
variant in either of the BRCA genes (BRCA1 or 
BRCA2) or in HRR-associated genes identified 
with current and potential future tumor based 
BRCA or HRR gene mutation assays as 
assessed by ORR, DoR, DCR, PFS and OS
ORR, DoR, PFS and DCR by ICR and Investigator 
assessment using RECIST 1.1, and OS
To evaluate disease related symptoms and 
health-related quality of life when compared 
with baseline data
European Organization for Research and Treatment 
of Cancer (EORTC) quality of life questionnaire 
(QLQ) C30 and OV-28
2.3
Safety objectives
Safety Objective:
Outcome Measure:
To evaluate the safety and tolerability of the 
combination of cediranib and olaparib
Adverse events (AEs), and treatment emergent 
changes in vital signs and laboratory parameters.
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2.4
Exploratory objectives  
Exploratory Objectives:
Outcome Measure:
To assess exploratory biomarkers of potential 
homologous recombination repair deficiency 
(HRD).
To assess exploratory angiogenic biomarkers 
such as vascular endothelial growth factor 
(VEGF)-A, C, D; sVEGFR2, Tie2, Ang1, 2; 
leptin; interleukin 6 (IL6) and exploratory 
immunologic biomarkers.
To evaluate exploratory biomarkers of 
potential resistance/sensitivity to cediranib or 
olaparib.
Potential biomarker research
To assess adverse events by patient 
self-reporting of specific Patient Reported 
Outcomes version of the Common 
Terminology Criteria for Adverse Events 
(PRO-CTCAE™) symptoms.
Patient-Reported Outcomes version of the Common 
Terminology Criteria for Adverse Events (PRO-
CTCAE™)
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
Patients who have prior documented evidence that they do not carry deleterious or suspected 
deleterious gBRCA mutation(s), as defined by a local test conducted in an appropriately 
accredited laboratory (eg, CLIA-certified) that includes comprehensive DNA sequencing and 
large rearrangement analysis of BRCA1 and BRCA2, may be enrolled provided they fulfill all 
of the inclusion criteria and none of the exclusion criteria.  These patients will be required to 
provide a blood sample prior to receiving investigational products (IPs) which may be used to 
perform a subsequent confirmatory BRCA mutation test using Myriad’s BRACAnalysis CDx®
test. 
Patients who do not know their gBRCA status, or whose gBRCA status has not been 
determined by an appropriately accredited laboratory will be required to provide a blood 
sample at screening to allow determination of gBRCA status with Myriad’s BRACAnalysis 
CDx® test.  Such patients must fulfill all of the other eligibility criteria, prior to BRCA
mutation testing being carried out.
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Study Code D8488C00001
Edition Number 5.0
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3.1
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:
1.
Ability and willingness to provide written informed consent, and to comply with the 
requirements of the protocol.
2.
Females aged ≥18 years with previous histologically proven diagnosis of high grade 
serous, high grade endometroid or clear cell ovarian cancer, fallopian tube or 
primary peritoneal carcinoma.
3.
No evidence of deleterious or suspected deleterious germline mutation in BRCA1 or 
BRCA2 genes.  BRCA1 and/or BRCA2 variants that are classified as “Variants of 
uncertain clinical significance” or “Variant of unknown significance (VUS)” are 
eligible, as well as “Variant, favor polymorphism” or “benign polymorphism”. 
4.
Recurrent platinum-resistant disease, defined as disease progression within 6 
months (182 days) of the last receipt of platinum-based chemotherapy.  
!
Patients with platinum refractory disease defined as disease progression during the 
last receipt of platinum-based therapy are not eligible.
!
Patients with primary platinum resistant/refractory disease defined as progression 
during or within 6 months (182 days) of completing first-line platinum based 
chemotherapy are not eligible. 
5.
CT/MRI evidence of measurable disease as per RECIST 1.1 defined as at least one 
lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 
mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 
mm) and which is suitable for accurate repeated measurements
6.
Eastern Cooperative Oncology Group (ECOG) performance status 0-2; see 
Appendix E 
7.
Life expectancy ≥12 weeks
8.
Prior receipt of antiangiogenic treatment, including but not limited to bevacizumab, 
is optional. If used, it can be in the first line or recurrent setting.
9.
At least 3 prior lines of therapy for advanced ovarian cancer as follows:  
∀
Platinum chemotherapy: at least two prior lines required
∀
Non-platinum chemotherapy: up to two prior lines are allowed but not required.    
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Edition Number 5.0
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∀
Hormonal therapy (such as tamoxifen, aromatase inhibitors), bevacizumab (or 
other angiogenesis inhibitor), or other immunotherapy used as a single agent will 
not count as a line of chemotherapy.  
10.
Confirmation of the availability of a formalin fixed, paraffin embedded (FFPE) 
tumor sample (or approximately unstained 20 sections mounted on glass slides 
prepared from the block) from the primary or recurrent cancer must be provided.  
All attempts should be made to provide the sample prior to first dose or soon 
thereafter.  If archival tumor sample is not available, tumor sample from fresh 
biopsy is acceptable; however, any lesion biopsied during screening can no longer 
be selected as a target lesion.
11.
Patients must have adequate organ and marrow function measured within 28 days 
prior to administration of IPs as defined below:
∀
Hemoglobin (Hb) ≥10.0 g/dL with no blood transfusion in the past 28 days  
∀
Absolute neutrophil count (ANC) ≥1.5 x 109/L
∀
Platelet count ≥100 x 109/L
∀
Total bilirubin ≤1.5 x institutional upper limit of normal (ULN)
∀
Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase 
[SGOT]) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate 
Transaminase [SGPT]) ]) ≤3 x institutional upper limit of normal (ULN) 
∀
Creatinine clearance ≥50 mL/min
∀
Urine protein:creatinine ratio (UPC) ≤1 OR proteinuria ≤2+ on two consecutive 
dipsticks taken no less than 1 week apart.  Patients with 2+ proteinuria on 
dipstick must also have UPC <0.5 on 2 consecutive samples. 
12.
Adequately controlled blood pressure (systolic blood pressure [SBP] ≤140 mmHg; 
diastolic blood pressure [DBP] ≤ 90mmHg) on maximum of 3 antihypertensive 
medications.  Patients must have a blood pressure (BP) of ≤ 140/90 mmHg taken in 
the clinic setting by a medical professional within 2 weeks prior to starting study.  It 
is strongly recommended that patients who are on three antihypertensive 
medications be followed by a cardiologist or a primary care physician for 
management of BP while on study.  Patients must be willing and able to check and 
record daily blood pressure readings.
13.
Adequately controlled thyroid function, with no symptoms of thyroid dysfunction 
14.
Able to swallow and retain oral medications and without gastrointestinal (GI) 
illnesses that would preclude absorption of cediranib or olaparib.
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Edition Number 5.0
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15.
Postmenopausal or evidence of non-childbearing status for women of childbearing 
potential as confirmed by a negative urine or serum pregnancy test within 7 days 
prior to start of IPs.  Postmenopausal is defined as: 
∀
Age ≥60 years, or
∀
Age <60 with any one or more of the conditions below:
o
Amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal 
treatments,
o
Luteinizing hormone and/or Follicle stimulating hormone and/or estradiol 
levels in the post-menopausal range, 
o
Radiation-induced oophorectomy with last menses >1 year ago,
o
Chemotherapy-induced menopause with >1 year interval since last menses,
o
Surgical sterilization (bilateral oophorectomy or hysterectomy).
3.2
Exclusion criteria
Patients must not enter the study if any of the following exclusion criteria are fulfilled:
1.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site)
2.
Previous enrollment in the present study
3.
Exposure to any IP during the last 4 weeks prior to enrollment.
4.
Previous treatment with PARP inhibitor.  For this study, BSI-201 (iniparib) is not 
considered as PARPi.
5.
Recent cancer-directed therapies: Radiotherapy (RT) within 4 weeks, chemotherapy 
or other systemic anti-cancer therapy within 4 weeks, hormonal therapy within 
2 weeks, or prior anti-angiogenic treatment (eg, bevacizumab) within 6 weeks prior 
to starting treatment.
6.
Cancer antigen-125 (CA-125) only disease without RECIST 1.1 measurable 
disease.
7.
Major surgical procedure within 2 weeks prior to starting treatment; patients must 
have recovered from any effects of any major surgery and surgical wound should 
have healed prior to starting treatment.
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Edition Number 5.0
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8.
Clinically significant signs and/or symptoms of bowel obstruction within 3 months 
prior to starting treatment.
9.
History of intra-abdominal abscess within 3 months prior to starting treatment.
10.
History of GI perforation.  Patients with a history of abdominal fistula will be 
considered eligible if the fistula was surgically repaired, there has been no evidence 
of fistula for at least 6 months prior to starting treatment, and patient is deemed to 
be at low risk of recurrent fistula.
11.
Other malignancy within the last 5 years except for:
∀
Curatively treated basal cell or squamous cell carcinoma of skin; in situ cancer of 
the cervix, ductal carcinoma in situ of the breast or stage 1, grade 1 endometrial 
carcinoma.
∀
Curatively treated other solid tumors including lymphomas (without bone 
marrow involvement) with no evidence of disease for ≥5 years prior to start of 
IPs.
12.
Persisting ≥Grade 2 CTCAE toxicity (except alopecia and Grade 2 peripheral 
neuropathy) from previous anti-cancer treatment(s). 
13.
Central nervous system metastases: 
∀
Symptomatic uncontrolled brain metastases requiring corticosteroid treatment. 
History of spinal cord compression unless after definitive treatment the patient 
has clinically stable disease (SD) for at least 28 days prior to starting IPs. In the 
absence of these features and in an asymptomatic patient a scan to confirm the 
absence of brain metastases is not required.
14.
Patients with any of the following:
∀
History of myocardial infarction within 6 months prior to starting treatment
∀
Unstable angina
∀
Resting electrocardiogram (ECG) with clinically significant abnormal findings
∀
New York Heart Association functional classification of III or IV.
15.
Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) per 
institutional guidelines, or <55%, if threshold for normal not otherwise specified by 
institutional guidelines, for patients with the following risk factors:
∀
Prior treatment with anthracyclines 
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Edition Number 5.0
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∀
Prior treatment with trastuzumab
∀
Prior central thoracic RT, including exposure of heart to therapeutic doses of 
ionizing RT 
∀
History of myocardial infarction within 6-12 months prior to start of IPs 
∀
Prior history of other significant impaired cardiac function 
16.
History of stroke or transient ischemic attack within 6 months
17.
Uncontrolled intercurrent illness including, but not limited to known ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, extensive interstitial bilateral lung disease on High Resolution 
Computed Tomography (HRCT) scan or psychiatric illness/social situations that 
would limit compliance with study requirements. 
18.
Patients with myelodysplastic syndrome (MDS)/treatment-related acute myeloid 
leukemia (t-AML) or with features suggestive of MDS/AML 
19.
No prior allogeneic bone marrow transplant or double umbilical cord blood 
transplantation.  
20.
Known active human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C 
infection on antiviral treatment. 
21.
Concomitant use of known strong cytochrome (CYP) 3A inhibitors 
(eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with 
ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or 
moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, 
fluconazole, verapamil).  The required washout period prior to starting study 
treatments is 2 weeks for strong inhibitors, and at least 1 week for moderate 
inhibitors.
22.
Concomitant use of known strong CYP3A inducers (eg, phenobarbital, 
enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, 
nevirapine and St John’s Wort) or moderate CYP3A inducers (eg. bosentan, 
efavirenz, modafinil).  The required washout period prior to starting study 
treatments is 5 weeks for enzalutamide or phenobarbital and 4 weeks for other 
agents.
For procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
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Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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3.3
Patient enrollment and randomization
Investigator(s) should keep a record, the patient screening log, of patients who entered 
pre-study screening.
The Investigator(s) will:
1.
Obtain signed informed consent from the potential patient or their guardian/legal 
representative before any study specific procedures are performed.  
2.
Assign potential patient a unique enrollment number, beginning with ‘E#’ through 
the Interactive Response Technology system.  This number is the patient’s unique 
identifier and is used to identify the patient on the electronic case report forms 
(eCRFs). 
3.
Determine patient eligibility. See Section 3.
If a patient withdraws from participation in the study, then her enrollment code cannot be 
reused.
This is an open-label study; there is no randomization.
3.4
Procedures for handling incorrectly enrolled patients
3.4.1
Screen failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be entered into the study.  Patients who fail to meet the eligibility criteria 
should not, under any circumstances, enter the study or receive IPs.  There can be no 
exceptions to this rule.  
3.4.2
Incorrectly enrolled patients
Where a patient does not meet all the eligibility criteria but is enrolled in error, or incorrectly 
started on treatment, the Investigator should inform the AstraZeneca study physician 
immediately, and a discussion should occur between the AstraZeneca study physician and the 
Investigator regarding whether to continue or discontinue the patient from treatment. The 
AstraZeneca study physician must ensure all decisions are appropriately documented.
3.5
Methods for assigning treatment groups
Not applicable; this is a single arm study.
3.6
Methods for ensuring blinding
Not applicable; this is an open-label, unblinded, study. 
3.7
Methods for unblinding 
Not applicable; this is an open-label, unblinded, study.
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Edition Number 5.0
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3.8
Restrictions
Patients should not donate blood while participating in this study and for at least 3 months 
following the last dose of IPs.   
Absorption of oral contraceptives can be impaired in case of GI symptoms such as diarrhea 
>24 hours or vomiting.  In addition, the possibility that cediranib may induce GI CYP3A and 
uridine diphosphate glucuronosyltransferase (UGT) enzymes cannot be excluded and the 
efficacy of hormonal contraceptives may be reduced if co administered with cediranib.  
Therefore, women of child-bearing potential must agree to use two highly effective forms of 
contraception (see Appendix J) during study treatment and for at least 6 weeks after 
discontinuation of study treatment and to perform pregnancy tests as required (see Sections 
5.2.5.1, 6.6.1).  Should a woman become pregnant or suspect she is pregnant during the study 
conduct, she should inform her treating physician immediately.  Breast-feeding is 
contraindicated whilst receiving IPs.
Restrictions related to pregnancy are provided in Section 6.6.  Restrictions related to 
concomitant medications (including medications metabolized via CYP3A4/5 or 
P glycoprotein (PgP)/UGT; anticoagulant therapy; anti-emetics/anti-diarrheal therapies; 
palliative RT and administration of other anti-cancer agents) are described in Section 7.7 and 
Appendix I.  
Patients may not use any complementary or alternative medicines including natural herbal 
products or folk remedies as they may interfere with the effectiveness of the IPs.
It is prohibited to consume grapefruit juice while on olaparib therapy.
3.9
Discontinuation of investigational product
Patients may be discontinued from IPs in the following situations:
!
Patient decision; the patient is at any time free to discontinue treatment, 
without prejudice to further treatment.  A patient who discontinues 
treatment is normally expected to continue to participate in the study 
unless she specifically withdraws her consent to further participation in 
any study procedures and assessments (see Section 3.10.1).
!
Adverse Event (AE), including AEs that meet criteria for discontinuation as defined 
in Section 6.7; any AEs that, in the opinion of the Investigator or AstraZeneca, 
contraindicates further dosing.
!
Objective progression according to RECIST version 1.1 criteria.
!
Severe non-compliance with the protocol
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Both IPs (cediranib and olaparib) should be discontinued at the same time; patients are not 
allowed to remain in the study if they are taking either cediranib or olaparib as monotherapy. 
However, in rare circumstances, patients experiencing ongoing clinical benefit but who 
develop one of the toxicities listed below, related to one of the IPs, that prevents them to 
continue to take this IP, may be allowed to continue on the unrelated drug if in the opinion of 
the treating investigator the risk benefit remains favorable and only after discussion with the 
AstraZeneca Study Physician and the Principal Investigator.
AEs requiring cediranib to be discontinued:
!
GI perforation
!
Arterial Thromboembolic Event
!
Reversible Posterior Encephalopathy Syndrome (PRES)
!
Severe hemorrhage 
!
Severe persistent hypertension despite maximal anti-hypertensive 
treatment  
AEs requiring olaparib to be discontinued:
!
Bone marrow findings consistent with MDS/AML.
!
Severe persistent anemia
!
Pneumonitis
Refer to Section 6.7 for more information on the management of IP-related toxicities. 
3.9.1
Procedures for discontinuation of a patient from investigational product
At any time, patients are free to discontinue IPs (ie, both cediranib and olaparib treatments) or 
withdraw from the study (ie, both cediranib and olaparib treatments and assessments) without 
prejudice to further treatment.  If a patient is withdrawn from study, see Section 3.10.
A patient that decides to discontinue the IPs will always be asked about the reason(s) and the 
presence of any AEs.  If possible, they will be seen and assessed by an Investigator(s).  AEs 
will be followed up (see Section 6) and all study drugs should be returned by the patient.
By discontinuing from IPs, the patient is not withdrawing from the study.  Any patient 
discontinuing the IPs should attend the scheduled Treatment Discontinuation visit, and the 
Follow Up visit 30 days post-discontinuation for the assessments outlined in the study 
schedule.  After discontinuation of IPs, the Principal Investigator (PI)/Sub-Investigator will 
perform the best possible observation(s), test(s) and evaluation(s) as well as give appropriate 
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medication and all possible measures for the safety of the patient.  In addition, they will record 
on the eCRF the date and reasons of discontinuation, any clinical manifestations and 
treatments required at the time of discontinuation.  
Any patient who has not yet shown objective radiological disease progression at 
discontinuation from cediranib and olaparib treatments should continue to be followed as per 
RECIST as detailed in Section 4 (ie, patients should be followed for progression by tumor 
assessments every 8 weeks).  Following objective radiological progression, patients should 
also be followed for survival as detailed in Section 5.1.4.
After discontinuation of the IPs at any point in the study, all ongoing AEs or serious adverse 
events (SAEs) must be followed until resolution unless, in the Investigator’s opinion the 
condition is unlikely to resolve due to the patients underlying disease, or the patient is lost to 
follow up (see Section 6.3.2) or until the patient starts new anti-cancer treatment.  All new 
AEs and SAEs occurring during the 30 calendar days after the last dose of IPs must be 
reported (if SAEs, they must be reported to AstraZeneca within 24 hours as described in 
Section 6.4) and followed to resolution as above.  For guidance on reporting AEs after the 
30 day follow up period see Section 6.3.3.  
All patients must be followed for survival, up to the data cut-off for the primary analysis.  If a 
patient is withdrawn from study, see Section 3.10.
3.10
Criteria for withdrawal
Reasons for withdrawal from the study:
!
Voluntary withdrawal* by the patient who is at any time free to 
discontinue their participation in the study, without prejudice to further 
treatment.
!
Incorrectly enrolled patients ie, the patient does not meet the required 
inclusion/exclusion criteria for the study (please refer to Section 3.4).
!
Patient lost to follow-up.
!
Death.
*If a patient withdraws consent, they will be specifically asked if they are withdrawing 
consent to continue further treatment with study medication:
!
BUT are willing to remain in the study and have further follow up (eg, 
CT/MRI assessments, survival calls) 
!
OR are also withdrawing consent to follow up; thereby withdrawing 
consent to participate in the study
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!
AND if they are withdrawing consent for the use of any samples (tumor 
or blood) Data obtained prior to withdrawal of consent will be maintained 
in the clinical database and used in the study reporting (see Section 
5.7.6).
3.10.1
Withdrawal of the informed consent 
Patients are free to withdraw from the study at any time (IPs and assessments), without 
prejudice to further treatment.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs.  The Investigator will follow up AEs outside of the clinical study. 
If a patient withdraws from participation in the study, then her enrollment code cannot be 
reused.  Withdrawn patients will not be replaced. 
If the patient is lost to follow-up, the Investigator should make every reasonable effort to 
contact the patient or a responsible relative.  Patients will be considered lost to follow-up only 
if no contact has been established at any time up to data cut-off for the primary analysis, such 
that there is insufficient information to determine the patient’s status at that time.  Patients 
who refuse to continue participation in the study, including telephone contact, should be 
documented as “withdrawal of consent” rather than “lost to follow-up.”  Investigators should 
document attempts to re-establish contact with missing patients throughout the study period.  
If contact with a missing patient is re-established, the patient should not be considered lost to 
follow-up and any evaluations should resume according to the protocol.
3.10.2
Survival status for withdrawn consent and lost to follow up patients
At the time of primary analysis, the survival status of all patients in the full analysis set should 
be re-checked, this includes those patients who withdrew consent or are classified as “lost to 
follow up.”
!
Lost to Follow up – site personnel should check hospital records, the patients’ current 
physician, and a publicly available death registry (if available) to obtain a current survival 
status in the 2 weeks following data cut-off. (The SURVIVE module will be updated.)
!
In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient can be obtained by site personnel from 
publicly available death registries or resources (if available) where it is possible to do so 
under applicable local laws to obtain a current survival status in the 2 weeks following 
data cut-off. (The SURVIVE module will be updated.)
3.11
Discontinuation of the study
The study may be stopped if, in the judgement of AstraZeneca, trial patients are placed at 
undue risk because of clinically significant findings that are not considered to be consistent 
with continuation of the study, or if the futility boundary is met at the Interim Analysis.
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Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF.  All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.
4.
STUDY PLAN AND TIMING OF PROCEDURES 
Table 5 shows the Schedule of Study Assessments. 
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Table 5
Schedule of study assessments
Screening
Treatment Period
Study treatments 
discontinued
Follow-up period
FPVa
For details, 
see protocol 
section
Week
Day 1 to 
Week 4 
Week 4 to 
Week 8 
Week 8 onwards
N/A
N/A
N/A
Visit (window)
Day
-28 to -1
Study 
Day 1
Weekly 
(±3 days)
Every 2 
weeks 
(±3 days)
Every 4 
weeks 
(±3 days)
Every 8 
weeks 
(±1 week)
Day 30 
Follow-
up
(±3 days)
Follow-up 
for 
progressionb
Survival 
Follow-up
Informed consent
X
3.3
Determine Eligibilityc
X
3.1/3.2
Demographics, height
X
4.1/5.2.2
Medical historyd
X
4.1
Germline BRCA
statuse
X
5.7.1
Archival tumor tissue 
sample
X
5.7.2
Adverse Eventsf
X
X
6
Concomitant 
medicationg
X
X
7.7
Physical Examination 
X
Xh
X
X
X
X
4.1/5.2.2
Performance Status 
(ECOG)
X
X
4.1
Vital signsi, weightj
X
X
X
X
X
X
X
X
5.2.2/5.2.4
ECGk
X
X
5.2.3
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
61(173)
Table 5
Schedule of study assessments
Screening
Treatment Period
Study treatments 
discontinued
Follow-up period
FPVa
For details, 
see protocol 
section
Week
Day 1 to 
Week 4 
Week 4 to 
Week 8 
Week 8 onwards
N/A
N/A
N/A
Visit (window)
Day
-28 to -1
Study 
Day 1
Weekly 
(±3 days)
Every 2 
weeks 
(±3 days)
Every 4 
weeks 
(±3 days)
Every 8 
weeks 
(±1 week)
Day 30 
Follow-
up
(±3 days)
Follow-up 
for 
progressionb
Survival 
Follow-up
Pregnancy Testl
For women of 
childbearing Potential
Xl
X
X
X
X
X
5.2.5.1
LVEFm
X
6.8.3.6
Urinalysisn
X
X
X
X
X
5.2.1.4
Hematologyo,p
X
X
X
X
X
X
X
X
5.2.1.1
Biochemistryo q
X
X
X
X
X
X
X
X
5.2.1.2
CA-125
X
Every 8 weeks relative to first dose until disease progression
5.2.1.3
TSH, FT4
X
X
X
5.2.1.2
Tumor assessments by 
CT/MRI scanr
X
Every 8 weeks relative to first dose until disease progression
5.1.1
Biomarker plasma and 
blood PBMC sampless
X
Week 4
Week 8
Xr
5.7.2
Blood biomarker 
sample for ctDNA
X
X
5.7.2
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
62(173)
Table 5
Schedule of study assessments
Screening
Treatment Period
Study treatments 
discontinued
Follow-up period
FPVa
For details, 
see protocol 
section
Week
Day 1 to 
Week 4 
Week 4 to 
Week 8 
Week 8 onwards
N/A
N/A
N/A
Visit (window)
Day
-28 to -1
Study 
Day 1
Weekly 
(±3 days)
Every 2 
weeks 
(±3 days)
Every 4 
weeks 
(±3 days)
Every 8 
weeks 
(±1 week)
Day 30 
Follow-
up
(±3 days)
Follow-up 
for 
progressionb
Survival 
Follow-up
EORTC-QLQ-C30/ 
EORTC-QLQ-OV28 
(by electronic device)
X
Every 8 weeks relative to first dose until 
discontinuation of IPs
X
X
5.3.1.1
PRO-CTCAE (by 
electronic device)
X
Weekly for the first 12 weeks, then every 4 weeks (relative 
to first dose) until discontinuation of IPs
X
5.3.1.2
PK Sample (plasma)t
Week 4 only
Week 8 
only
5.4.1
Survival and 
subsequent anticancer 
therapiesu
Every 8 weeks from discontinuation or 
progression
5.1.4
Compliance with 
investigational 
productsv
X
X
X
X
X
7.5
a.
The FPV applies to patients continuing to receive clinical benefit without meeting any discontinuation criteria during the study and will occur at their last scheduled 
visit prior to data cut-off. Beyond FPV, patients may continue to receive cediranib and/or olaparib if they are deriving clinical benefit in the opinion of the investigator, 
and not fulfilling any discontinuation criteria.  Such patients are to be followed in accordance with the Medical Standard of Care and as deemed appropriate by the 
investigators. SAE reporting (on paper) will continue to ensure safety data collection and monitoring of the patients while receiving the investigational product. Patients 
will continue to be monitored for all SAEs and pregnancies while receiving IPs and for 30 days after the last dose of IPs.
b.
Progression follow-up only required for patients who discontinue IPs prior to disease progression
c.
Review inclusion and exclusion criteria and ensure eligibility prior to enrolment
d.
Obtain relevant medical history, including all treatments for ovarian cancer in the past and any unresolved toxicity.  
e.
All patients whose gBRCA status is unknown or not determined by a local test conducted in an appropriately accredited laboratory, a blood sample for prospective 
analysis of gBRCA mutation status is required during screening.  Patients who do not carry deleterious or suspected deleterious germline BRCA mutation as determined 
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
63(173)
by a local test conducted in an appropriately accredited laboratory, may be enrolled on the basis of a documented test result; however, a blood sample is required prior 
to first dose of study treatments, which may be used for confirmation of the result in a retrospective analysis.
f.
Patients should be closely monitored for adverse events which should be recorded, as they occur.  SAEs that occurred during screening period will also be recorded.  
Patient diary data (via handheld electronic device) for blood pressure and diarrhea will be reviewed by the Investigator at each patient visit and any AEs and/or SAEs 
recorded in the AE eCRF
g.
All concomitant treatments will be recorded while the subject is taking IPs, together with the indication for which they are used
h.
Repeat assessment not required on Day 1, if already performed during previous 7 days for screening purposes   
i.
Pulse rate, systolic and diastolic blood pressure, respiration rate, pulse oxygen saturation and temperature.  Blood pressure should also be measured at the clinic weekly 
during the first 4 weeks of treatment, and every 2 weeks from Week 4 to Week 8 and every 4 weeks thereafter.  Daily home blood pressure monitoring is required via 
patient self-monitoring.  Patients are required to check their blood pressure twice daily for at least the first 8 weeks after starting study treatment, or, if antihypertensive 
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.  Daily blood pressure monitoring is required for as long as the patient remains on cediranib 
treatment and for 30 days after cediranib discontinuation, or until the FPV.  Daily blood pressure monitoring by the patient will be recorded using a handheld electronic 
device See Section 5.2.4.1.
j.
Required at baseline, at every 8 weeks, until treatment discontinuation and at the 30-day safety follow-up visit, or until the FPV. 
k.
ECGs are required within 7 days prior to starting IPs, and when clinically indicated thereafter.  Any clinically significant changes on all other visits should be recorded 
as adverse events.
l.
Required for women of childbearing potential within 7 days prior to the start of IPs, every 4 weeks thereafter during study treatment.  Pregnancy test for women of 
childbearing potential is required at the FPV and every 4 weeks thereafter until treatment discontinuation.  
m.
Left Ventricular Ejection Fraction required for patients with prior treatment with anthracyclines, or prior treatment with trastuzumab or central thoracic radiation 
therapy (RT) including exposure of heart to therapeutic doses of ionizing RT, history of myocardial infarction within 6-12 months prior to enrolment or history of other 
significant impaired cardiac function. For these patients LVEF will be done at screening and thereafter as clinically indicated, and per recommendations following 
review of initial safety data by the sponsor (see Table 16).
n.
At screening, UPC ≤ 1, OR proteinuria ≤2+ on two consecutive dipsticks taken no less than 1 week apart, is required. Patients with 2+ proteinuria on dipstick must also 
have UPC < 0.5 on 2 consecutive samples.  Refer to Section 5.2.1.4 for information on management of patients with potential nephrotic syndrome.
o.
Repeat assessment not required on Day 1, if already performed during previous 7 days for screening purposes.
p.
Full Blood Count as per Section 5.2.1.1: hemoglobin, platelets, mean cell volume, white blood cell count, absolute neutrophil count and absolute Lymphocyte count
q.
Biochemistry (sodium, magnesium, calcium, potassium, albumin, total protein, creatinine, total bilirubin, ALT, AST, alkaline phosphatase).  Creatinine clearance 
(Cockcroft-Gault or another validated method); to be calculated at baseline and re-calculated as clinically indicated during study conduct.
r.
Baseline tumor assessment should include CT/MRI of the chest, abdomen and pelvis. Follow-up CT/ MRI tumor assessments will cover chest (in those patients with 
disease in the chest or upper abdomen lymphadenopathy at baseline), abdomen and pelvis.  Any other sites at which new disease is suspected should also be 
appropriately imaged. Baseline radiological imaging is required within 4 weeks prior to first dose of investigational products (IPs).  Follow up assessments should be 
done every 8 weeks after first dose of IP until objective radiological disease progression, withdrawal of consent or the primary analysis. 
s.
Blood samples for PBMC testing (8 mL) and plasma biomarker testing (6 mL) will be taken at baseline; at Week 4; at Week 8 and treatment discontinuation.  Details to 
be found in the lab manual. 
t.
Eight PK samples per patient (4 samples for cediranib and 4 samples for olaparib) will be collected at steady state: 2 samples on Week 4 and 2 samples on Week 8 visit 
for cediranib and olaparib each.  At the Week 4 visit, the first 2 samples should be taken 0.5 hours prior to the first dose of cediranib at the Week 4 visit; the second 
2 samples should be taken 1 to 3 hours after the first dose of olaparib at the Week 4 visit.  At the Week 8 visit, 2 samples should be taken 0.5 hours prior to the dose of 
cediranib administration; the second 2 samples should be taken 1 to 3 hours after the first dose of olaparib at the Week 8 visit.
u.
Assessments for survival should be made every 8 weeks (relative to first dose) following objective disease progression.  Survival information may be obtained via 
telephone contact with the patient, patient’s family or by contact with the patient’s current physician. Subsequent anticancer therapies should also be recorded.  Patients 
should be contacted or other data sources checked (see Section 3.10.2) in the 2 weeks following the data cut-off for the primary analysis to provide current complete 
survival data.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
64(173)
v.
Missed doses of study medications will be reported by patients using a handheld electronic device.  These data will be reviewed by the Investigator at each patient visit 
and data entered in eCRF.
Abbreviations:  AE  adverse event; ALT  alanine transferase; AST  aspartate transferase; BRCA  breast cancer resistance protein; CA-125  cancer antigen-125; CT  computed 
tomography;  ctDNA  circulating tumor DNA;  ECG  electrocardiogram; ECOG  Eastern Cooperative Oncology Group; eCRF  electronic case report form; EORTC  European 
Organization for Research and Treatment of Cancer; FPV  final protocol visit; FT4  free thyroxine; IP  investigational product; LVEF  left ventricular ejection fraction; 
MRI  magnetic resonance imaging; N/A  not available; PBMC  peripheral blood mononuclear cells; PK  pharmacokinetics; PRO-CTCAE  Patient-Reported Outcomes version 
of the Common Terminology Criteria for Adverse Events; QLQ  quality of life questionnaire; SAE  serious adverse event; TSH  thyroid stimulating hormone; UPC  urine 
protein:creatinine ratio.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
65(173)
4.1
Screening/Enrollment period
Prior to inclusion into the study, patients will undergo screening.  All patients must sign the 
Informed Consent Form and if applicable, any locally required privacy act document 
authorization must also be obtained prior to the start of any screening procedures.  All 
screening procedures must be performed within 28 days before dosing (Day -28 to Day -1).
Consenting patients are assessed (Table 5) to ensure that they meet eligibility criteria and to 
discontinue other therapies, if required (Section 3.1, Section 3.4). Patients who do not meet 
these criteria must not be entered into the study. 
All patients agree to provide a sample of their archival FFPE tumor sample (or approximately 
20 unstained sections mounted on glass slides prepared from the block) from the primary or 
recurrent cancer for entry into this study, and a blood sample which may be used for a 
subsequent confirmatory BRCA mutation test using the Myriad BRACAnalysis CDx® test.  If 
archival tumor sample is not available tumor sample from fresh biopsy is acceptable.
4.2
Treatment period
Descriptions of the procedures for this period are included in the Schedule of Assessments 
(Table 5) with exceptions of the following specific requirements for the treatment period: 
The Study conduct period starts at the time of administration of the first dose of IPs (cediranib 
plus olaparib).  There is no maximum duration for taking IPs in this study.
While on study treatment, patients will be required to attend study visits every week during 
the first 4 weeks, every 2 weeks during the next 4 weeks and every 4 weeks (± 3 days) 
thereafter.  RECIST assessments will be performed every 8 weeks (±1 week) after first doses 
of IPs until disease progression.  Patients will continue the study treatments until:
∀
objective radiological disease progression, as defined by RECIST 1.1 guidelines, 
∀
unacceptable toxicity or
∀
discontinuation of IPs for other reasons (patient withdrawal of consent, physician 
discretion; see Section 3.9, Section 3.10 and Section 3.11).
∀
Severe non-compliance with the protocol.
4.3
Follow-up period
If both study treatments are discontinued, patients should undergo the assessments required at 
the discontinuation visit (see Table 5), whether or not radiological disease progression has 
occurred.  A safety follow-up visit should be conducted 30 days after the discontinuation visit.  
Any serious and/or non-serious AEs ongoing at this time should be followed-up to resolution 
or until, in the Investigator’s opinion, the condition is unlikely to improve or resolve due to 
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
66(173)
the patient’s underlying disease.  Descriptions of the procedures for the follow-up visit are 
included in the Schedule of Assessment (Table 5).
Assessments in the post study treatments follow-up period (following discontinuation of IPs), 
depend on whether a patient discontinues study treatments in the presence or absence of
radiological disease progression.
4.3.1
Discontinuation of study treatments due to disease progression
If a patient discontinues IPs because of radiological disease progression, she will be followed 
up for survival every 8 weeks (relative to first dose).  Survival information may be obtained 
via telephone contact with the patient, patient’s family or by contact with the patient’s current 
physician. 
4.3.2
Discontinuation of study treatments in the absence of disease progression
If a patient discontinues IPs in the absence of radiological disease progression, RECIST 
assessments for disease progression should continue to be performed every 8 weeks (±1 week) 
until radiological disease progression or withdrawal of consent.  Once a patient has 
radiological disease progression, she will be followed up as described in Section 4.3.1 above.  
Once patients have been discontinued from the IPs, other treatment options will be at the 
discretion of the Investigator.  All subsequent anti-cancer treatments should be recorded 
according to Section 7.8.  If the patient is lost to follow-up, then this should be noted in the 
eCRF.
4.4
Final protocol visit
Patients who continue to receive clinical benefit without meeting any discontinuation criteria 
during the study, will complete a FPV which will occur at their last scheduled visit prior to 
data cut-off for the primary analysis.  Beyond the FPV, patients may continue to receive 
cediranib and/or olaparib if they are deriving clinical benefit in the opinion of the investigator, 
and not fulfilling any discontinuation criteria.  
Beyond the FPV, patients continuing to receive IPs are to be treated as described in 
Section 4.5. 
4.5
End of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’ (ie, 
last subject last visit [LSLV]) or when the Sponsor decides to discontinue the study.  
There will be a primary data cut-off defined at approximately 8 months (LSLV) after the last 
patient received her first dose of study treatment.  This primary data cut-off will be followed 
by clinical database lock when all data for all patients have been collected.  The primary data 
analysis will be performed and a Clinical Study Report (CSR) written based on this data set.  
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
67(173)
Patients who continue to receive clinical benefit without meeting any discontinuation criteria 
during the study, will complete a FPV which will occur at their last scheduled visit prior to 
primary data cut-off.  Beyond the FPV, patients may continue to receive cediranib and/or 
olaparib (to be provided by the Sponsor), if they are deriving clinical benefit in the opinion of 
the investigator, and not fulfilling any discontinuation criteria.  
Such patients are to be followed in accordance with the Medical Standard of Care and as 
deemed appropriate by the Investigators.  Serious adverse event reporting (on paper) will 
continue to ensure safety data collection and monitoring of the patients while receiving the 
investigational product.  It is recommended that investigators continue to observe ongoing 
patients at the frequency employed prior to the FPV.  Protocol dose modification and stopping 
criteria are to be followed while a patient is receiving cediranib and/or olaparib.  Restrictions 
regarding concomitant medications (Section 7.7) must be followed while the patient is 
receiving cediranib and/or olaparib.  A change in the dose/schedule of cediranib and/or 
olaparib should only occur for safety reasons, based on the Investigator’s judgement, and 
should generally follow the approach for dose reduction and discontinuation as described in 
this protocol.  Combining cediranib and/or olaparib with other anti-cancer therapy is not 
allowed. 
If in the opinion of the investigator, a patient is no longer receiving clinical benefit from the 
IPs beyond the FPV, then the IPs will be stopped.  The Investigator will inform AstraZeneca 
when a patient discontinues the IPs.  Patients must return unused medication during routine 
clinic visits; drug accountability information must continue to be collected in patient source 
documents until the patient discontinues treatment.  Patients will continue to be monitored for 
all SAEs and pregnancies while receiving IPs and for 30 days after the last dose of IPs.
5.
STUDY ASSESSMENTS  
The RAVE Web Based Data Capture (WBDC) system will be used for data collection.  The 
investigator will ensure that data are recorded on the eCRFs as specified in the study protocol 
and in accordance with the eCRF completion guidelines.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded in the 
eCRF and the provision of answers to data queries according to the Clinical Study Agreement 
(CSA).  The Investigator will sign the completed eCRFs.  A copy of the completed eCRFs 
will be archived at the study site.
5.1
Efficacy assessments
5.1.1
Tumor assessments by CT or MRI scans
Radiological assessment should use the same modality of imaging throughout the trial. 
Contrast-enhanced CT scan is preferred but MRI is acceptable where CT is contraindicated.  
Please refer to the Image Acquisition Guidelines and Site Operations Manual for a quick 
reference guide for image acquisition and data handling.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
68(173)
Baseline tumor assessment should include CT/MRI of the chest, abdomen and pelvis within 
28 days prior to the start of IPs. Follow-up CT/ MRI tumor assessments will cover chest (in 
those patients with disease in the chest or upper abdomen lymphadenopathy at baseline), 
abdomen and pelvis with any other regions imaged at baseline where disease was present.  
Any other sites at which new disease is suspected should also be appropriately imaged.  
Radiological examinations performed in the conduct of this study should be retained at site as 
source data.  Copies of all imaging assessments including unscheduled visit scans will be 
collected on an ongoing basis and sent to Contract Research Organization (CRO) for ICR (see 
Section 5.1.3).
All treatment decisions will be based on Investigator assessment of scans.  All patients will 
have RECIST 1.1 tumor assessments at screening (within 28 days prior to the date of first 
dose of IPs) and thereafter every 8 weeks (±1 week) relative to the date of first dose of IPs 
(Table 5) until objective radiological disease progression as defined by RECIST 1.1 and as 
determined by the Investigator, or unless they withdraw consent.  Objective radiological 
response on treatment (CR or PR) will need to be confirmed during next RECIST 1.1 visit 
assessment.  
If a patient discontinues IPs for any reason other than disease progression or withdrawal of 
consent, RECIST 1.1 assessments should continue as per protocol schedule until evidence of 
objective radiological progression or withdrawal of consent (see Section 4.3).
It is important to follow the assessment schedule as closely as possible.  If scans are 
performed outside of scheduled visit (±1 week window) and the patient has not progressed, 
every attempt should be made to perform the subsequent scans at their scheduled time points.
5.1.2
Tumor evaluation
RECIST 1.1 will be used to assess progression and patient response to treatment by 
determining ORR, DCR, DoR and PFS.  The RECIST 1.1 guidelines for measurable, non-
measurable, target and non-target lesions (NTLs) and the objective tumor response criteria 
(CR, PR, SD or PD) are presented in Appendix F.
Categorization of objective tumor response assessment will be based on the RECIST 1.1 
criteria of response: CR, PR, SD or PD.  Target lesion progression will be calculated in 
comparison with when the tumor burden was at a minimum (ie, smallest sum of diameters 
previously recorded on study).  In the absence of progression, tumor response (CR, PR, or SD) 
will be calculated in comparison with the baseline tumor measurements obtained before 
starting treatment.  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 1.1 criteria.  For this study, a rise in CA-125 alone is not sufficient to declare 
progression, and progression events should be determined by radiographic evidence of 
progression.
If the Investigator is in doubt as to whether progression has occurred, particularly with 
response to NTLs or the appearance of a new lesion, it is advisable to continue treatment until 
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
69(173)
the next scheduled assessment or sooner if clinically indicated and reassess the patient’s 
status.  If repeat scans confirm progression, then the date of the initial scan should be declared 
as the date of progression.
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more NTLs is usually 
not sufficient to qualify for unequivocal progression status.
5.1.3
Central reading of scans 
An independent review of all scans used in the assessment of tumors using RECIST 1.1 will 
be conducted.  Copies of all imaging assessments including unscheduled visit scans will be 
collected on an ongoing basis and sent to an AstraZeneca appointed CRO for central analysis.  
If a patient had tumor biopsy during screening, but after the baseline RECIST scan, 
information on which lesion was biopsied will be provided to ICR so that such lesion is not 
chosen as the target lesion.  Results of this independent review will not be communicated to 
Investigators, and the management of patients will be based solely upon the results of the 
RECIST assessment conducted by the Investigator.  The primary analysis of ORR will be 
based on ICR assessment.
5.1.4
Survival assessment
Assessments for survival should be made every 8 weeks (relative to first dose) following 
objective disease progression or discontinuation from treatment.  Survival information may be 
obtained via telephone contact with the patient, patient’s family or by contact with the 
patient’s current physician.  OS will be analyzed at the time of the primary analysis; patients 
should be contacted or other data sources checked (see Section 3.10.2) in the 2 weeks 
following the data cut-off for the primary analysis to provide current complete survival data.  
Subsequent anti-cancer therapies should also be recorded.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the times indicated in the Schedule of Assessments (see Section 4).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
The clinical chemistry, hematology and urinalysis will be performed at a local laboratory at or 
near to the Investigator site.  Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site.
The following laboratory variables will be measured:
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
70(173)
5.2.1.1
Full hematology assessments for safety
!
Hemoglobin (Hb) 
!
Platelets
!
Mean cell volume (MCV)
!
White blood cell count (WBC)
!
Absolute neutrophil count (ANC) 
!
Absolute lymphocyte count. 
5.2.1.2
Biochemistry assessments for safety 
!
Sodium
!
Potassium
!
Calcium 
!
Magnesium 
!
Creatinine
!
Total bilirubin
!
Alkaline phosphatase [ALP]
!
Aspartate transaminase [AST]
!
Alanine transaminase [ALT]
!
Total protein
!
Albumin
In addition, samples for the measurement of thyroid stimulating hormone (TSH) and free 
thyroxine (FT4) are to be collected at screening, every 8 weeks during the treatment period, 
and for patients continuing to receive clinical benefit without meeting any discontinuation 
criteria during the study, at the FPV.  The Investigator should make an assessment of the 
available results with regard to clinically relevant abnormalities.  The laboratory results should 
be signed and dated and retained at center as source data for laboratory variables.  For 
information on how AEs based on laboratory tests should be recorded and reported, see 
Section 6.3.
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Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
71(173)
NB. In case a patient shows an AST or ALT ≥3xULN and total bilirubin ≥ 2xULN please 
refer to Appendix D ‘Actions required in cases of combined increase of Aminotransferase and 
Total Bilirubin – Hy’s Law’, for further instructions.
5.2.1.3
Disease specific tumor marker samples (CA-125)
As part of the routine blood samples, all patients will have CA-125 assessment at screening, 
every 8 weeks during the treatment period, and at study treatment discontinuation.  
A rise in CA-125 alone is not sufficient to declare progression, and discontinue IPs; 
progression events should be determined by radiographic evidence of progression, see 
Section 5.1.2.
Further assessment of CA 125 post radiological progression will be at the discretion of the 
investigator according to local clinical practice.
For blood volume see Section 5.8.1.
5.2.1.4
Urinalysis 
Urinalysis by dipstick should be performed as stated in Schedule of Assessments in Table 5.  
Microscopic analysis should be performed by the hospital’s local laboratory if required.  If 
appropriate, a spot urine protein-creatinine ratio may be performed.
Patient with urine protein ≥3.5 g/24 hours (CTCAE Grade 3 according to CTCAE v4) or 
urinary protein/creatinine ratio of >3.5 should be considered as nephrotic-range proteinuria.  
Following identification of nephrotic range proteinuria, the following steps should be taken to 
explore if the patient has a nephrotic syndrome:
!
Confirm if the patient had a normal renal function at baseline (creatinine 
≤ULN)
!
Check if the patient has reported any of the following as a treatment-
emergent and concurrent AE: hypoalbuminemia (laboratory value 
albumin <3 g/dL, or an AE of hypoalbuminemia CTCAE Grade ≥ 2); 
edema (any); dyslipidemia (hypercholesterolemia, hypertriglyceridemia); 
hyperlipidemia; or a thrombotic event. 
A specific safety questionnaire will be sent to the reporting Investigator, requesting detailed 
information, about patients who reported a nephrotic syndrome.
5.2.1.5
Bone marrow or blood cytogenetic samples 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
hematological toxicities as defined in Section 6.8.1.
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic 
analysis and flow cytometry, and a core biopsy for bone marrow cellularity.  If it is not 
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possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then 
attempts should be made to carry out the tests on a blood sample.  Full reports must be 
provided by the investigator for documentation on the Patient Safety database.  These data are 
not required to be entered into eCRF. 
5.2.2
Physical examination
A complete physical examination as per standard clinical practice should be performed by the 
Investigator at baseline, every 4 weeks during the treatment period, at the 30-day safety 
follow-up visit and, for patients continuing to receive clinical benefit without meeting any 
discontinuation criteria during the study, at the FPV.  If there are any clinically significant 
abnormal findings not related to disease progression, they should be recorded as an AE on the 
eCRF.  Height will be assessed at screening only.  Weight will be assessed at baseline, at 
every 4 weeks during the treatment period, at the 30-day safety follow-up visit and, for 
patients continuing to receive clinical benefit without meeting any discontinuation criteria 
during the study, at the FPV.
5.2.3
ECG
5.2.3.1
Resting 12-lead ECG
ECGs are required within 7 days prior to starting IPs, and when clinically indicated thereafter.
Twelve-lead ECGs will be obtained after the patient has been rested in a supine position for at 
least 5 minutes in each case.  The Investigator or designated physician will review the paper 
copies of each of the timed 12-lead ECGs on each of the study days when they are collected.
ECGs will be recorded at 25 mm/sec.  All ECGs should be assessed by the investigator as to 
whether they are clinically significantly abnormal / not clinically significantly abnormal.  If 
there is a clinically significant abnormal finding at baseline, the Investigator should record this 
in the baseline eCRF.  If there is a treatment emergent significant abnormal finding, the 
Investigator will record it as an AE on the eCRF.  The original ECG traces must be stored in 
the patient medical record as source data.
5.2.4
Vital signs
Any clinically significant changes in vital signs should be recorded as an AE. For information 
on how AEs based on changes in vital signs should be recorded and reported, see Section 6.3.
5.2.4.1
Pulse and blood pressure
Since rapid changes in BP can occur with cediranib treatment with the potential for life-
threatening complications if hypertension is not appropriately managed, all patients should 
check their BP twice daily for at least the first 8 weeks after starting IPs, or, if 
antihypertensive 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, BP monitoring may be reduced to once daily.  Twice daily monitoring 
should be re-implemented after any cediranib dose interruption for at least two weeks or until 
the patient is re-established on a stable antihypertensive regimen, whichever takes longer.  
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Patients should continue to check their BP for as long as they remain on cediranib treatment 
and for 30 days after cediranib discontinuation.  Patients will record their BP data using 
handheld electronic devices, to be provided by the study Sponsor.
Patient BP will be measured during routine study visits: weekly during the first 4 weeks, every 
2 weeks during the next 4 weeks and every 4 weeks thereafter to ensure that BP guidelines are 
being correctly followed.  During routine study visits, BP and pulse rate will be measured 
preferably using a semi-automatic BP recording device with an appropriate cuff size after 
10 minutes rest.  For timings of assessments refer to the Schedule of Assessments (see 
Table 5).
The date of collection and measurement will be recorded on the appropriate eCRF.
5.2.4.2
Body temperature
Body temperature will be measured in degrees Celsius according to local practice at the times 
indicated in the Schedule of Assessments (see Table 5; vital signs).
The date of collection and measurement will be recorded on the appropriate eCRF.
5.2.5
Other safety assessments
5.2.5.1
Serum or urine pregnancy test
Pregnancy tests on blood or urine samples will be performed only for pre-menopausal women 
of childbearing potential, within 7 days prior to the start of IPs, every 4 weeks thereafter 
during study treatment.  Pregnancy test for women of childbearing potential is required at the 
FPV and every 4 weeks thereafter until treatment discontinuation.  Tests will be performed by 
the hospital’s local laboratory.  If results are positive the patient is ineligible and must not be 
recruited into the study.  A confirmed pregnancy during the study conduct must be recorded in 
eCRF and immediately reported; the patient will be discontinued from the IPs, but should 
continue in the study.
5.3
Other assessments
5.3.1
Clinical Outcome Assessments
PROs is an umbrella term referring to all outcomes and symptoms that are directly reported by 
the patient.  PROs have become a significant endpoint when evaluating effectiveness of 
treatments in clinical trials.  The following PROs will be administered: European Organization 
for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30, 
QLQ OV28, and Patient-Reported Outcomes version of the Common Terminology Criteria 
for Adverse Events (PRO-CTCAE; see Appendix K).
5.3.1.1
EORTC QLQ C30 and EORTC QLQ OV28
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group 1993.  It consists 
of 30 items and measures cancer patients’ functioning health-related quality of life (HRQoL) 
and symptoms (Aaronson et al 1993) for all cancer types.  Questions can be grouped into 5 
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multi-item functional scales (physical, role, emotional, cognitive and social); 3 multi-item 
symptom scales (fatigue, pain, nausea and vomiting); a 2-item global HRQoL scale; 5 single 
items assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of 
appetite, insomnia, constipation, diarrhea) and 1 item on the financial impact of the disease.
The QLQ-OV28 is a module which is specific for ovarian cancer.  It consists of 28 items 
assessing abdominal/GI symptoms (6 items), peripheral neuropathy (2 items), other 
chemotherapy side effects (5 items), hormonal symptoms (2 items), body image (2 items), 
attitudes to disease/treatment (3 items), sexuality (4 items), and four other single items.
5.3.1.2
PRO-CTCAE
The Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse 
Events (PRO-CTCAE) system has been developed by the NCI.  PRO-CTCAE is an item-bank 
of symptoms experienced by patients while undergoing treatment of their cancer.  It was 
developed in recognition that collecting symptom data directly from patients using PRO tools 
can improve the accuracy and efficiency of symptomatic AE data collection.  This was based 
on findings from multiple studies demonstrating that physicians and nurses underestimate 
symptom onset, frequency, and severity in comparison with patient ratings (Basch et al 2009; 
Basch et al 2014; Litwin et al 1999; Sprangers and Aaronson 1992).  To date, 81 symptoms of 
the CTCAE (version 4) have been identified to be amenable to patient reporting.  These 
symptoms have been converted to patient terms (eg, CTCAE term “myalgia” converted to 
“aching muscles”). For several symptoms, like fatigue and pain, additional questions are asked 
about symptom frequency, severity, and interference with usual activities.  For other 
symptoms like rash, additional questions focus on the presence on the body.  The items 
included in the PRO-CTCAE have undergone extensive qualitative review among experts and 
patients.  These items and the additional questions for some of the symptoms have been 
extensively evaluated by cancer patients, using cognitive testing methods, to be clear, 
comprehendible, and measure the symptom of interest.  Not all items are administered in any 
one clinical trial. The intention is to only ask patients to complete those items which are 
considered relevant for the trial, site of cancer, and cancer treatment (see Appendix K).  The 
following 6 PRO-CTCAE AEs will be collected in the study: nausea, vomiting, diarrhea, 
decreased appetite, fatigue, and dizziness. In addition to these items from the PRO-CTCAE 
item bank, the following additional item will be asked together with the PRO-CTCAE items: 
"In the last 7 days, how much did LOOSE OR WATERY STOOLS (DIARRHEA) 
INTERFERE with your usual or daily activities?" 
5.3.1.3
Administration of PRO questionnaires
Patients will complete the PRO assessments at home and at site using the same handheld 
electronic device (ePRO).
All assessments should be completed according to the following parameters:
!
Without assistance from site staff or anyone else according to the 
assessment schedule (see Table 5)
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!
Before any other study procedures are conducted at a given visit
!
Before being seen by a study nurse or physician
Each center must allocate the responsibility for the administration of the ePROs to a specific 
individual (eg, a research nurse or study coordinator) and, if possible, assign a backup person 
to cover if that individual is absent.  Subjects may complete some of the ePROs at study sites 
if the assessment time point coincides with a scheduled site visit; otherwise, subjects may 
complete the ePROs at home.  Similarly, during the post-progression period, subjects should 
complete ePROs at home or at the study site if a scheduled visit coincides with the time point.  
If subjects have had scans or other tests at an outside facility or missed a scheduled data 
collection site visit, ePROs should still be completed by the subject at home for that scheduled 
visit within the window period.
The Investigator will arrange for relevant training in the set-up of the electronic device and 
training patients in how to self-administer the questionnaires using the electronic device. 
Subjects should complete the questionnaires in accordance with the study schedule (see 
Table 5). 
The significance and relevance of the data should be explained carefully to participating 
subjects so that they are motivated to comply with data collection.  Reminders should be sent 
to subjects at home as needed to ensure compliance with the assessment schedules.
The following best practice guidelines should be followed when collecting PRO data via an 
electronic device:
!
PRO questionnaires must be completed prior to any other study 
procedures (following informed consent) and before discussion of disease 
progression to avoid bias in patient’s responses to the questions.
!
When each instrument is due to be completed, the following order for 
completion should be ensured: EORTC-QLQ-C30, EORTC-QLQ-OV28, 
PRO-CTCAE.
!
PRO questionnaires must be completed by the subject in private.
!
The research nurse or appointed site staff must explain to subject the 
value and relevance of study participation and inform them that these 
questions are being asked to find out, directly from them, how they feel.  
The research nurse or appointed site staff should also stress that the 
information is confidential.  Therefore, if the subjects have any medical 
problems, they should discuss them with the doctor or research nurse 
separately from the ePRO assessment.
!
The research nurse or appointed site staff must train the subject on how to 
use the ePRO device, using the materials and training provided by the 
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Edition Number 5.0
Date 15 Jan 2019
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ePRO vendor, and provide guidance on whom to call if there are 
problems with the device if the patient is completing the ePRO at home.
!
The research nurse or appointed site staff should remind subjects that 
there are no right or wrong answers.
!
The research nurse or appointed staff must avoid clarifying items in order 
to avoid bias.
!
The subject must not receive help from relatives, friends, or clinic staff to 
answer the PRO questionnaires.  If a subject uses visual aids (eg, 
spectacles or contact lenses) for reading and does not have them when he 
attends the clinic, the subject will be exempted from completing the 
PROs.  
!
Site staff must not read or complete the PRO questionnaires on behalf of 
the subject.  If the subject is unable to read the questionnaire (eg, is blind 
or illiterate), that subject is exempted from completing PRO 
questionnaires and may still participate in the study.  Subjects exempted 
in this regard should be flagged appropriately by the site staff.
!
The subject should be given sufficient time to complete the PRO 
questionnaires at her own speed.
The research nurse or appointed site staff must monitor compliance to ensure all data is 
captured. Compliance must be checked at each study visit to identify problems early.  If a 
subject’s compliance drops below 85%, they will be flagged in the routine compliance report 
generated by the ePRO system and a check-in call from the site to ask the subject if she has 
any difficulties is highly recommended.
5.3.2
Exploratory Immunologic/Molecular Assessments
Assessment of somatic deleterious or suspected deleterious variant in BRCA genes (BRCA1 or 
BRCA2) or in HRR-associated genes, and potential homologous recombination deficiency 
(HRD), including genomic scarring, BRCA1 methylation, and other genes that might modify 
HRD, using current and/or potential future tumor based assays including, but not limited to, 
BRCA or HRR gene mutations may be carried out.
Markers of different T-cell populations and phenotypes of myeloid-derived suppressor cells 
and immune suppressive monocytes in peripheral blood mononuclear cells (PBMCs), 
including, but not limited to, the combination of cell-surface markers CD3, CD4, CD8, CD11, 
CD14, CD19, CD25, CD33, CD45, CD56, Foxp3, HLA-DR, TIM-3, PD1 and CTLA-4, will 
be analyzed by fluorescence activated cell sorter (FACS) analysis and/or mRNA analysis.
Assessment of biomarkers such as VEGF-A, C, D; sVEGFR2, Tie2, Ang1, 2, leptin and 
interleukin 6 (IL6), will be carried out to define the angiogenic and inflammatory biomarker 
profile.
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Sequencing of circulating tumor DNA (ctDNA) may also be conducted, to identify tumor-
derived mutations.
5.4
Pharmacokinetics
5.4.1
Collection of samples
Blood samples for determination of cediranib and olaparib concentrations in plasma will be 
taken at the times presented in the schedule of assessments Table 5.  Samples will be 
collected, labelled stored and shipped as detailed in the Laboratory Manual.
5.4.2
Determination of drug concentration
Samples for determination of cediranib and olaparib concentrations in plasma will be analyzed 
by Covance on behalf of AstraZeneca, using appropriate bioanalytical methods.
5.4.3
Storage and destruction of PK samples
PK samples will be disposed of after the Bioanalytical Report finalization or 6 months after 
issuance of the draft Bioanalytical Report (whichever is earlier), unless requested for future 
analyses.
PK samples may be disposed of or destroyed and anonymized by pooling. Additional analyses 
may be conducted on the anonymized, pooled PK samples to further evaluate and validate the
analytical method. Any results from such analyses may be reported separately from the 
Clinical Study Report (CSR).
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR, but 
separately in a Bioanalytical Report.
5.5
Pharmacodynamics
Pharmacodynamic samples will not be taken during the study.
5.6
Genetics
Genetic samples will not be taken during the study.
5.7
Biomarker analysis 
Key biomarker data will be reported in the main CSR.
5.7.1
Collection of blood sample for Myriad germline BRCA testing
All patients must have no evidence of deleterious or suspected deleterious germline 
mutation(s) in their BRCA1 or BRCA2 genes to be enrolled in the study.  BRCA1 and/or 
BRCA2 variants that are classified as “Variants of uncertain clinical significance” or “VUS” 
are eligible, as well as “Variant, favor polymorphism” or “benign polymorphism”.  Germline 
BRCA status may be assessed as part of the screening procedure for the study (via Myriad 
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Edition Number 5.0
Date 15 Jan 2019
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BRACAnalysis CDx®); or, patients may be entered into the study on the basis of a local test 
conducted in an appropriately accredited laboratory (eg, CLIA-certified) that includes 
comprehensive DNA sequencing and large rearrangement analysis of BRCA1 and BRCA2.
For patients that can be enter the study on the basis of a pre-existing known gBRCA status by 
a local test conducted in an appropriately accredited laboratory, a blood sample must be taken 
once the patient has consented to the study which may be used for a subsequent confirmatory 
BRCA mutation test using Myriad’s BRACAnalysis CDx® test.
For patients who meet the trial eligibility criteria, but do not know their BRCA mutation status, 
or whose gBRCA status was determined using a local test conducted in a local laboratory 
which was not appropriately accredited laboratory, or where the BRCA test result is non-
mutant but did not include comprehensive sequencing and large rearrangement analysis of 
BRCA1 and BRCA2, a blood sample for the Myriad BRCA test can be taken once all local 
ethical procedures (eg, genetic counselling) for such testing have been completed.  When the 
result from the Myriad BRACAnalysis CDx® test indicates the patient has no evidence of a 
deleterious or suspected deleterious germline mutation in BRCA1 or BRCA2 genes, the patient 
can be entered into the study.
Residual blood (or its derivatives) may be used to develop and validate future BRCA 
companion diagnostic tests and for additional exploratory work, to elucidate the mechanism of 
response, understand the mode of action of study treatment, and improve the understanding of 
disease recurrence. 
5.7.2
Collection of biomarkers biological samples
Biological samples (archived tumor samples and blood samples) will be collected only from 
patients who are eligible to start study treatment and will be analyzed for exploratory 
biomarkers to assess correlations with disease activity, effects of study drug, clinical outcomes 
and toxicity:
!
Mandatory: Archival tumor sample or fresh tumor biopsy
∀
FFPE tumor sample from the primary or recurrent cancer must be available for 
central testing (or approximately 20 unstained sections mounted on glass slides 
prepared from the block).  If there is not written confirmation of the availability 
of an archival tumor sample prior to enrollment, or if the patient does not consent 
to donating a fresh tumor biopsy sample (if an archival sample is unavailable), 
the patient is not eligible for the study.  The tumor samples will be collected and 
will be analyzed for somatic deleterious or suspected deleterious variants in 
BRCA1 or BRCA2 genes, and the following HRR-associated genes: ATM, BRIP1, 
PALB2, RAD51C, BARD1, CDK12, CHEK1, CHEK2, FANCL, PPP2R2A, 
RAD51B, RAD51D, and RAD54L, to assess correlations with disease activity, 
effects of study drug, clinical outcomes and toxicity. 
!
Mandatory: Blood sample for biomarker analysis
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∀
Blood samples for PBMC testing (8 mL) and plasma biomarker testing (5 mL) 
will be collected from all patients at baseline; at Week 4; at Week 8 and at 
discontinuation of IPs, for exploratory biomarker work. 
∀
Blood sample (10 mL) at baseline and at discontinuation of IPs to evaluate 
ctDNA. 
5.7.3
Storage, re-use and destruction of biological samples
Samples will be stored for a maximum of 15 years from the date of LSLV (ie, approximately 
12 months after the last patient received her first dose of IP) after which they will be 
destroyed.  The results of this biomarker research will be reported either in the CSR itself or 
as an addendum, or separately in a scientific report or publication.  The results of this 
biomarker research may be pooled with biomarker data from other studies with the study drug 
to generate hypotheses to be tested in future research.
5.7.4
Labelling and shipment of biological samples
The Investigator ensures that samples are labelled and shipped in accordance with the 
Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix C ‘IATA 6.2 Guidance Document’.
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved.
5.7.5
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each center keeps full traceability of collected biological samples from the 
patients while in storage at the center until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers. 
Samples retained for further use are registered in the AstraZeneca Biobank system during the 
entire life cycle.
5.7.6
Withdrawal of Informed Consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analyzed,
AstraZeneca is not obliged to destroy the results of this research.
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If the patient withdraws consent for the collection of the mandatory biological samples that 
are an integral part of the study (ie, the archival tumor sample or the mandatory biomarker 
blood samples), further study participation can be continued, if the patient is already receiving 
treatment with IPs.  
The PI:
!
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca
!
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented
!
Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the 
action documented and the signed document returned to the study site
!
Ensures that the patient and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
5.8
Biological sampling procedures
5.8.1
Volume of blood
The volume of blood that will be drawn from each patient will vary, dependent upon the 
length of time that the patient remains in the trial.  However, the volume of blood to be drawn 
from each patient (including for PK samples) during screening and up to and including Week 
8 should not exceed 154 mL, according to National Institutes of Health (NIH) guidance (NIH 
guidance 2009).
The total volume of blood to be drawn from each patient in the study, assuming they complete 
screening, 48 weeks of treatment, a treatment discontinuation visit and the 30-day follow-up 
visit, should not exceed 335 mL.
The procedures for the collection, handling, and shipping of laboratory samples are specified 
in the Sample Handling and Logistics Manual supplied to sites.
Safety laboratory assessments will be performed locally by means of their established 
methods.  The number of samples/blood volumes is therefore subject to site-specific change. 
Extra blood samples may also be collected if, for example, additional samples are required for 
repeat safety assessments.
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The estimated total volume of blood that will be drawn from each patient in this study is as 
shown in Table 6.
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Table 6
Estimated maximum volume of blood to be drawn from each patient
Assessment
Sample 
volume 
(mL)
No. of 
samples -
Screening
No. of 
samples 
Day 1 to 
Week 8
Every 4 weeks 
(Week 8 to 
treatments 
discontinuation)
Treatments 
Discontinuation 
visit 
30 day 
follow-
up visit
Final Protocol 
Visit
Whole Blood sample:
!
Prospective Myriad 
BRACAnalysis CDx® test 
for patients with unknown 
BRCA status or potential 
retrospective analysis in 
patients with a local test 
result 
9
1
Blood sample for ctDNA
10
1
1
Blood samples (PBMC) for 
biomarker analysis
8
1
2
1
Blood samples (plasma) for 
biomarker analysis
6
1
2
1
Safety
Clinical chemistry 
(locally assessed)
5
1
5
1
1
1
1
Hematology (locally 
assessed)
5
1
5
1
1
1
1
Blood sample for CA-125 
(locally assessed)
2
1
1
1
1
1
Pharmacokinetic (Blood 
samples processed to plasma & 
frozen)
2 mL for 
cediranib + 
2 mL for 
olaparib
0
8
Total volume (mL)
55
112
12 
36
12
10
Abbreviations:  BRCA  breast cancer susceptibility gene; CA-125  cancer antigen-125; ctDNA  circulating tumor deoxyribonucleic acid; PBMC  Peripheral 
blood mononuclear cell; PK  Pharmacokinetics.
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6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section.
6.1
Definition of adverse events
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, ECG).  In clinical studies, an AE 
can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no IPs have been administered.
The term AE is used to include both serious and non-serious AEs.
6.1.1
Adverse Events of Special Interest
Adverse events of special interest (AESIs) are events of scientific and medical interest specific 
to the further understanding of the safety profiles of cediranib and olaparib; AESIs require 
close monitoring and rapid communication by the investigators to AstraZeneca.  An AESI 
may be serious or non-serious.  
!
AESIs for cediranib are the Important Identified Risks: PRES, arterial 
thromboembolic events, and the Important Potential Risks: symptomatic 
left ventricular dysfunction and cardiac failure; nephrotic syndrome; renal 
thrombotic microangiopathy and liver failure.
!
AESIs for olaparib are the Important Potential Risks of MDS/AML, new 
primary malignancy (other than MDS/AML) and pneumonitis.
6.2
Definitions of serious adverse event
An SAE is an AE occurring during any study phase that fulfils one or more of the following 
criteria:
!
Results in death (NOTE: death is an outcome, not an event)
!
Is immediately life-threatening (NOTE: the term “Life-Threatening” 
refers to an event in which the patient was at immediate risk of death at 
the time of the event; it does not refer to an event which could 
hypothetically have caused a death had it been more severe)
!
Requires in-patient hospitalization or prolongation of existing 
hospitalization 
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!
Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the patient or may 
require medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol.  The full requirements of the ICH Guideline for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 will be adhered to.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
SAEs will be collected from time of signature of informed consent throughout the treatment 
period up to and including the 30-day follow-up period.  AEs will be collected between the 
date of the first dose of IPs and the end of the 30-day follow-up period.  All ongoing and any 
new AEs/SAEs identified during the 30 calendar days follow up period, after the last dose of 
IPs must be followed to resolution, unless resolution is unlikely to occur.  
6.3.2
Follow-up of unresolved adverse events
Any SAE or non-serious adverse event that is ongoing at the time of the 30-day 
follow up, must be followed up to resolution unless the event is considered by the 
investigator to be unlikely to resolve, or the patient is lost to follow up. 
AstraZeneca retains the right to request additional information for any patient 
with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3
Adverse events after the 30 day follow up period
For olaparib pharmacovigilance purposes and characterization of events of special 
interest, any case of MDS/AML or new primary malignancy occurring after the 
30 day follow up period should be reported to AstraZeneca Patient Safety whether 
it is considered a non-serious AE (eg, non-melanoma skin cancer) or SAE, and 
regardless of investigator’s assessment of causality.  These AEs must be reported 
according to the timelines for reporting an SAE (see Section 6.4).  Investigators 
will be asked during the regular follow up for OS if the patient has developed 
MDS/AML or a new primary malignancy and prompted to report any such cases.  
A questionnaire will be sent to any investigator reporting MDS/AML, 
pneumonitis, or new primary malignancy as an aid to provide detailed information 
on the case.
At any time after a patient has completed the study, if an Investigator learns of 
any SAE or death, unrelated to SAEs of special interest, and he/she considers 
there is a reasonable possibility that the event is causally related to the IPs, the 
Investigator should notify AstraZeneca, Patient Safety.
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Patients who are gaining clinical benefit in the opinion of the Investigator are 
allowed to continue IPs post FPV and all SAEs must continue to be collected and 
reported to Patient Safety within the usual timeframe.
Otherwise, after end of study there is no obligation to actively report information 
on new AEs or SAEs occurring in former study patients.  This includes new 
AEs/SAEs in patients still being followed up for survival but who have completed 
the post treatment follow up period (30 days).
6.3.4
Variables 
The following variables will be collected for each AE;
!
AE verbatim
!
The date when the AE started and stopped
!
Changes in CTCAE grade will be reported for AEs of diarrhea, fatigue, 
hypertension and nausea.  For all other AEs, only the highest attained 
CTCAE grade will be reported.
!
Whether the AE is serious or not
!
Investigator causality assessment against each of the IP(s) (yes or no)
!
Action taken with regard to each of the IP(s)
!
Outcome (if resolved with sequelae then sequelae should be recorded).
In addition, the following variables will also be collected for SAEs:
!
Date AE met criteria for SAE
!
Date Investigator became aware of SAE
!
AE seriousness criteria (see Section 6.2)
!
If the patient was hospitalized:
∀
Date of hospitalization
∀
Date of discharge
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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The following variables will also be collected for deaths:
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to IPs and/or Study procedure(s).
Investigators are also required to complete targeted safety questionnaires should any of the 
following events be reported:  MDS/AML, new primary malignancy or pneumonitis. 
The grading scales found in the NCI CTCAE version 4.03 will be utilized for all events with 
an assigned CTCAE grading.  For those events without assigned CTCAE grades the 
recommendation is that the CTCAE criteria that convert mild, moderate and severe events into 
CTCAE grades should be used.
A copy of NCI CTCAE version 4.03 is available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
Adverse events not listed by CTCAE version 4.03 will be graded using the following criteria:
Intensity rating scale:
1
mild (awareness of sign or symptom, but easily tolerated)
2
moderate (discomfort sufficient to cause interference with normal activities)
3
severe (incapacitating, with inability to perform normal activities)
Alternative intensity rating scale for in-patients:
4
mild (awareness of sign or symptom, but easily tolerated)
5
moderate (disturbing but still tolerable)
6
severe (intolerable).
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Section 6.2.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
87(173)
6.3.5
Causality collection
The Investigator will assess causal relationship between each IP and each AE, and answer 
‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the 
event may have been caused by one or both components of the combination therapy?’
Causality assessment for all AEs must be clearly assigned for each IP.  Causal relationship 
will also be assessed for other (ie, other than one of study IPs) medication and study 
procedures.  Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
6.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or care provider reported in response to the 
open question from the study personnel: ‘Have you had any health problems since the 
previous visit/you were last asked?’, or revealed by observation will be collected and recorded 
in the eCRF.  When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms; for example, for vomiting, nausea, fever, please 
consider providing diagnosis if available, as 1 AE of ‘gastroenteritis’ if appropriate, instead of 
3 separate AEs.  However, if a diagnosis is known and there are other signs or symptoms that 
are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
6.3.7
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarized in the 
CSR.  Deterioration as compared with baseline in protocol-mandated laboratory values, vital 
signs and ECG abnormalities should only be reported as AEs or SAEs if one of the following 
is met:
!
Any criterion for an AE or SAE is fulfilled
!
Causes discontinuation of IPs
!
Causes IP interruption
!
Causes IP dose reduction
!
The abnormality is considered clinically significant by the Investigator
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low Hb value).  In the 
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
88(173)
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters (ie, those not described in Table 5) should be reported as AE(s).
Deterioration of a baseline laboratory value or condition, which is unequivocally due to 
disease progression, should not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
6.3.8
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to 
be reported as SAEs. Please refer to Appendix D for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
6.3.9
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IPs are being studied.  It may be an increase in the severity of the 
disease under study and/or increases in the signs and symptoms of the cancer.  The 
development of new, or progression of existing metastasis to the primary cancer under study 
should be considered as disease progression and not an AE.  Events, which are unequivocally 
due to disease progression, should not be reported as an AE during the study.
6.3.10
New cancers
The development of a new primary cancer (including skin cancer) should be regarded as an 
AE and will generally meet at least one of the SAE criteria (see Section 6.2).  New primary 
cancers are those that are not the primary reason for the administration of the IPs and have 
developed after the inclusion of the patient into the study.  They do not include metastases of 
the original cancer.  Symptoms of metastasis or the metastasis itself should not be reported as 
an AE/SAE, as they are considered to be disease progression.
6.3.11
Lack of efficacy
When there is deterioration in the cancer, for which the IPs are being used, there may be 
uncertainty as to whether this is lack of efficacy or an AE.  In such cases, unless the Sponsor 
or the reporting physician considers that the IPs contributed to the deterioration of the 
condition, or local regulations state to the contrary, the deterioration should be considered to 
be a lack of efficacy and not an AE.
6.3.12
Deaths
All deaths that occur during the study, or within the protocol-defined 30-day post-study 
follow-up period after the administration of the last dose of IPs, must be reported as follows:
!
Death clearly the result of disease progression should be documented in the DEATH 
eCRF but should not be reported as an SAE.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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!
Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to the study monitor as a SAE 
within 24 hours (see Section 6.4 for further details).  The report should contain a 
comment regarding the co-involvement of progression of disease, if appropriate, and 
should assign main and contributory causes of death.  This information can be 
captured in the ‘death eCRF’.
Deaths with an unknown cause should always be reported as a SAE.  A post mortem maybe 
helpful in the assessment of the cause of death, and if performed a copy of the post-mortem 
results should be forwarded to AstraZeneca within the usual timeframes.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IPs, or to the 
study procedure(s).  All SAEs will be recorded in the electronic case report form (eCRF).  
For patients who continue to receive clinical benefit and IP after data cut-off, investigators 
will continue to report all SAEs to AstraZeneca Patient Safety until 30 days after study 
treatment is discontinued (Section 6.3.1).  As the clinical study database will have closed, 
investigators should complete paper SAE forms and fax them directly to the AstraZeneca 
Patient Safety Data Entry site for entering onto the AstraZeneca Patient Safety database.  Drug 
accountability should continue to be performed until the patient stops study treatment 
completely.
If any SAE occurs in the course of the study, then Investigators, or other site personnel, 
inform the appropriate AstraZeneca representatives within one day ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will be available between visits if the investigator(s) or staff 
at the center needs information or advice about the study conduct. AstraZeneca medical 
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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personnel will be readily available to discuss study related medical questions or problems with 
the investigator(s). Contact details are provided separately in the Investigator Study File.  
The reference documents for definition of expectedness/listedness are the IBs for cediranib 
and olaparib.
6.5
Overdose
The use of IPs in doses in excess of that specified in the protocol is considered to be an 
overdose.  
Approximately 290 patients have received cediranib at dose levels of 45 mg or higher.  At 
these higher dose levels the cediranib safety profile was similar to that observed at lower dose 
levels of 20 mg.  In cases of suspected overdose, cediranib should be paused, BP monitored 
and if needed, supportive care instituted.  There is no specific treatment for cediranib 
overdose.  At the discretion of the Investigator, re-starting cediranib at the recommended dose 
can be considered.
There is currently no specific treatment in the event of an overdose with olaparib and possible 
symptoms of overdose are not established.  In the event of an overdose, physicians should 
follow general supportive measures and AEs associated with overdose should be treated 
symptomatically.  Any dose, or frequency of dosing, that exceeds the dose regimen specified 
in the study protocol should be reported as an overdose.  The maximum tolerated dose is 
300 mg bd for the tablet formulation.
!
An overdose with associated AEs is recorded as the AE 
diagnosis/symptoms on the relevant AE eCRF, including the Overdose 
section of the eCRF.
!
An overdose without associated symptoms is only reported on the 
Overdose section of the eCRF.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
91(173)
6.6.1
Maternal exposure
Women of childbearing potential must use any two highly effective forms of contraceptive 
methods in combination to avoid becoming pregnant while receiving IPs and for at least 6 
weeks following the last dose of study treatments (cediranib + olaparib).  The efficacy of 
hormonal contraceptives may be reduced if co-administered with cediranib (see Section 3.8); 
therefore, an additional non-hormonal contraceptive method should be used during treatment 
(see Appendix J) and pregnancy tests performed as required per SOA See Table 5).  Should a 
pregnancy still occur, the IPs should be discontinued immediately and the pregnancy reported 
to AstraZeneca. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the IPs 
under study may have interfered with the effectiveness of a contraceptive medication.  
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs.  Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) occurring from the date of the first dose of 
study medication until 6 weeks after the last dose of study medication should be followed up 
and documented even if the patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy.
6.7
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the Patient or 
has the potential to cause harm to the Patient. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or Patient.
Medication error includes situations where an error: 
!
occurred
!
was identified and intercepted before the patient received the drug
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
92(173)
!
did not occur, but circumstances were recognized that could have led to 
an error
Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error eg, medication prepared incorrectly, even if it was not 
actually given to the subject
!
Drug not administered as indicated, for example, wrong route or wrong 
site of administration
!
Drug not taken as indicated eg, tablet dissolved in water when it should 
be taken as a solid tablet 
!
Drug not stored as instructed eg, kept in the fridge when it should be at 
room temperature 
!
Wrong subject received the medication (excluding IVRS/IWRS errors)
!
Wrong drug administered to subject (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IVRS/IWRS - including those which 
lead to one of the above listed events that would otherwise have been a 
medication error 
!
Subject accidentally missed drug dose(s) eg, forgot to take medication
!
Accidental overdose (will be captured as an overdose)
!
Subject failed to return unused medication or empty packaging
!
Errors related to background and rescue medication, or standard of care 
medication in open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.  
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
94(173)
AEs requiring cediranib to be discontinued:
!
GI perforation
!
Arterial Thromboembolic Event
!
PRES
!
Severe hemorrhage 
!
Severe persistent hypertension despite maximal anti-hypertensive 
treatment  
AEs requiring olaparib to be discontinued:
!
Bone marrow findings consistent with MDS/ AML
!
Severe persistent anemia
!
Pneumonitis
Patients experiencing ongoing clinical benefit who experience a related AE where 
continuation of one of the drugs is considered, in the judgment of the treating Investigator 
AND the Principal Investigator, 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 AstraZeneca Study Physician and the Principal Investigator.
6.8.1
Hematologic toxicity
Management of neutropenia and thrombocytopenia 
Neutropenia and thrombocytopenia are recognized common adverse drug reactions reported 
for both olaparib and cediranib.  Treatment should be managed according to Table 9:
Table 9
Management of neutropenia or thrombocytopenia
Olaparib dose 
Cediranib dose
CTCAE Grade 1-2
ANC >1.0 G/L
or
Platelet count >50 G/L
Investigator judgement to continue 
treatment or allow dose 
interruption; dose interruptions 
should be for a maximum of 
3 weeks; appropriate supportive 
treatment and causality 
investigation
Investigator judgement to continue 
treatment or allow dose interruption; 
dose interruptions should be for a 
maximum of 3 weeks; appropriate 
supportive treatment and causality 
investigation
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
95(173)
Table 9
Management of neutropenia or thrombocytopenia
Olaparib dose 
Cediranib dose
CTCAE grade 3-4
ANC <1.0 G/L
or
Platelet count <50 G/L
Dose interruption until recovered 
to CTCAE Grade ≤1 for a 
maximum of 3 weeks.  Upon 
recovery, olaparib dose should be 
reduced by one dose level.  If 
repeat CTCAE Grade 3-4 
occurrence, further dose reduce 
one or both IPs
Dose interruption until recovered to 
CTCAE Grade ≤1 for a maximum 
of 3 weeks. Upon recovery, 
cediranib dose should be reduced by 
one dose level.  If repeat CTCAE 
Grade 3-4 occurrence, further dose 
reduce one or both IPs
Abbreviations:  ANC  absolute neutrophil count; CTCAE  common terminology criteria for adverse events; 
IP  investigational product
6.8.1.1
Use of hematopoietic agents
Use erythropoietin-stimulating agents per standard of care National Comprehensive Cancer 
Network (NCCN) and/or institutional guidelines, iron supplements, and/or transfusions as 
clinically indicated for management of anemia.  Prescribing information for the erythropoiesis 
stimulating agents (including Aranesp, Epogen and Procrit) highlight that there is a potential 
risk of shortening the time to tumor progression or disease-free survival.  Primary prophylaxis 
with granulocyte colony-stimulating factor (G-CSF) is not recommended (Mountzios et al 
2016).  They do not alleviate fatigue or increase energy.  They should not be used in patients 
with uncontrolled hypertension.  The package inserts should be consulted.
If a patient develops febrile neutropenia, IPs should be stopped and appropriate management 
including G-CSF should be given according to local hospital guidelines.  Please note that 
G-CSF should not be used within at least 24 hours of the last dose of olaparib unless 
absolutely necessary.
Platelet transfusions, if indicated, should be done according to local hospital guidelines.
6.8.1.2
Dose modifications for hematologic toxicity
Patients who have IPs held for hematologic toxicities should have blood counts and 
differentials checked at least weekly until recovery; these data should be recorded in eCRF as 
extra laboratory examinations.  If counts do not improve to CTCAE Grade 1 or better despite 
drug cessation for 3 weeks, patients should be referred to a hematologist for further 
assessment.  A bone marrow analysis should be considered per hematology assessment. 
For AEs that are unrelated to the study drug, study drug may be withheld for up to 3 weeks at 
the discretion of the treating Investigator.  
Management of anemia
Anemia is a common adverse drug reaction related to olaparib.  Cediranib is not reported to 
increase the risk of anemia.  Management of anemia is in accordance with Table 10:
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
96(173)
Table 10
Management of anaemia
Olaparib dose 
Cediranib dose
Hb <10 but ≥8 g/dL
Give appropriate supportive treatment and investigate 
causality. 
Investigator judgement to continue olaparib or interrupt 
dose for a maximum of 3 weeks. 
If repeat Hb <10 but ≥8 g/dL, dose interrupt until Hb 
≥10 g/dL for maximum of 3 weeks and upon recovery 
dose reduce to 150 mg bd as a first step and to 100 mg 
bd as a second step
No change
Hb < 8 g/dL
Give appropriate supportive treatment and investigate 
causality. 
Interrupt olaparib until improved to Hb ≥10 g/dL.
Upon recovery dose reduce olaparib to 150 mg bd
No change
Abbreviations:  bd  twice daily; Hb  hemoglobin
Common treatable causes of anemia (eg, iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed.  In some cases, 
management of anemia may require blood transfusions.  Any subsequently required dose 
interruptions, related to development of anemia, or coexistent with newly developed 
neutropenia, and/or thrombocytopenia, will require olaparib dose reductions to 150 mg twice 
daily as a first step and to 100 mg twice daily as a second step. 
If Hb drops to < 8 g/dL despite the dose reduction or more than one blood transfusion is 
required to recover Hb levels with no alternative explanation for the anemia, olaparib should 
be permanently discontinued.
6.8.1.3
Management of prolonged hematological toxicities while on study treatment
If a patient develops prolonged hematological toxicity such as:
!
≥ 2 week interruption/delay in olaparib due to CTCAE Grade 3 or worse anemia 
and/or development of blood transfusion dependence
!
≥ 2 week interruption/delay in 1 or both IPs due to CTCAE Grade ≥3 neutropenia 
(ANC <1 x 109/L)
!
≥ 2 week interruption/delay in 1 or both IPs due to CTCAE Grade ≥3 
thrombocytopenia and/or development of platelet transfusion dependence (Platelets 
<50 x 109/L)
Check weekly differential blood counts including reticulocytes and peripheral blood smear.  If 
any blood parameters remain clinically abnormal after 3 weeks of dose interruption, the 
patient should be referred to hematologist for further investigations.  Bone marrow analysis 
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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and/or blood cytogenetic analysis should be considered at this stage according to standard 
hematological practice.  Both IPs should be discontinued if blood counts do not recover to 
CTCAE Grade ≤1 within 3 weeks of dose interruption.
Development of a confirmed myelodysplastic syndrome (MDS) or other clonal blood disorder 
should be reported as an SAE and full reports must be provided by the investigator to 
AstraZeneca Patient Safety.  Olaparib treatment should be discontinued if patient’s diagnosis 
of MDS and/or acute myeloid leukemia (AML) is confirmed.
6.8.2
Non-hematologic toxicity
Cediranib should be discontinued should any of the following AEs occur:  GI perforation; 
arterial thromboembolic events; PRES (radiologically confirmed); severe or medically 
significant hemorrhage and severe persistent hypertension despite maximal anti-hypertensive 
treatment.
Dose modifications for other non-hematologic events on IPs should be managed according to 
Table 11.
Table 11
General Management of Non-Hematologic Toxicity
Observation
Action
AE resolves promptly with supportive care
Maintain dose level
Any ≥Grade 3 non-hematologic (excluding grade 
3 fatigue or easily correctable asymptomatic 
grade 3 laboratory abnormalities)
Hold IP(s)a for up to 3 weeks until toxicity 
resolves to ≤ Grade 1.
Treatment may be restarted at one dose level 
lower for the IP(s) causing the toxicity (see Table 
7 and Table 8), at the treating investigator’s 
discretionb. Reoccurrence of Grade 3 or 4 toxicity 
would require dose reduction of both IPs.
Any grade 2 non-hematologic AE or grade 3 
fatigue related to cediranib or olaparib that 
persists despite maximal support.
Hold IP(s)a for up to 3 weeks until toxicity 
resolves to Grade ≥1.  Treatment may be restarted 
at one dose level lower for the IP(s) causing the 
toxicity (see Table 7 and Table 8), at the treating 
investigator’s discretionb.  
Grade 3 or 4 non-hematologic AE related to 
cediranib and olaparib combination that does not 
resolve to Grade 0-2 within 3 weeks despite 
maximum supportive care after treating patient at 
the lowest reduced dose levelc
Discontinue IP(s)
a.
At the discretion of the investigator, one IP may be held or dose modified or discontinued independently 
if the observed toxicity is attributed to only one of the drugs, while the patient continued to receive the 
second drug not associated with the observed toxicity. The time a given drug is held should not exceed 
3 weeks.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
98(173)
b.
Patients who are at the lowest reduced dose level may have their drug resumed at that dose level after 
discussion with the AstraZeneca Study Physician and the Principal Investigator if evidence of clinical 
benefit.
c.
For venous thromboembolic events, treatment may be resumed at the discretion of the investigator once 
patient is asymptomatic (Section 6.7.3.11).
Abbreviations:  AE  adverse event; IP  investigational product(s)
6.8.3
Management of cediranib-related toxicity
6.8.3.1
Hypertension
Only doses of cediranib will be modified for hypertension; olaparib doses will not be reduced 
unless other toxicities are experienced. 
In clinical trials, increases in BP have been reported within a few hours of starting cediranib.  
Since rapid changes in blood pressure can occur with cediranib treatment, with the potential 
for life-threatening complications if hypertension is not appropriately managed, all patients 
should check their BP twice daily for at least the first 8 weeks after starting cediranib, or, if 
antihypertensive 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, BP monitoring may be reduced to once daily.  Twice daily monitoring 
should be re-implemented after any cediranib dose interruption for 2 weeks or until the patient 
is re-established on a stable antihypertensive regimen, whichever takes longer. 
Patient BP will also be measured during routine study visits: weekly during the first 4 weeks, 
every 2 weeks during the next 4 weeks and every 4 weeks thereafter, to ensure that BP 
guidelines are being correctly followed.  Increase in BP should be treated promptly with 
standard antihypertensive therapy, ensuring that the maximum recommended dose and 
number of antihypertensive medicinal products is reached before considering cediranib dose 
adjustment.  See Appendix G for suggested antihypertensive medications by class.  Patients 
may have up to 4 drugs for management of hypertension prior to any dose reduction in 
cediranib.
If patients require a delay of > 3 weeks for management of hypertension, discontinuation of 
cediranib or protocol therapy may be considered after discussion with the PI and the 
AstraZeneca study physician.  In case of persistent or severe hypertension, despite the optimal 
use of antihypertensive medicinal products and cediranib dose reduction, cediranib should be 
permanently discontinued.
Patients already taking antihypertensive therapy at baseline or those aged 75 years or older are 
at a higher risk of having elevated BP or may require more than one medicinal product or 
more intensive therapy.  Pre-existing cardiovascular risks should be assessed and managed, 
and pre-existing hypertension should be adequately controlled before starting treatment with 
cediranib.  Note: Stopping or reducing the dose of cediranib is expected to cause a decrease in 
BP.  The treating physician should monitor the patient for hypotension and adjust the number 
and dose of antihypertensive medications accordingly. 
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
99(173)
Hypertension should be graded using the NCI CTCAE version 4.03.  Please note: patients 
may have baseline hypertension meeting CTCAE grading criteria on study entry provided this 
is adequately controlled on maximum of 3 antihypertensive medications (see Section 3.1). 
Baseline grade of hypertension should also be recorded in Medical History eForm.
Should patients require increase in dosing of BP medication or increased number of 
medications, they should then be noted to have hypertension related to study drug, with 
grading as per CTCAE version 4.03 criteria.
Table 12 provides hypertension monitoring and management guidance.  
Table 12
Hypertension Monitoring and Management
Event 
Antihypertensive
Therapy
Blood Pressure
Monitoring
Cediranib Dose 
Modification
Asymptomatic 
transient (<24 
hours) increase by 
>20 mmHg 
diastolic or to 
>140/90 mmHg if 
previously within 
normal limits
Consider early initiation 
of BP medication for BP 
> 140/90 mmHg that is 
confirmed on a second 
reading.  Cediranib can 
cause rapid escalation in 
BP, and early initiation 
of BP management can 
reduce likelihood of 
hypertension-related 
complications
Continue 
standard BP 
monitoring 
according to 
local practice 
and confirm 
resolution of BP 
to <140/90 
mmHg within 
24 hours.
None
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
100(173)
Table 12
Hypertension Monitoring and Management
Event 
Antihypertensive
Therapy
Blood Pressure
Monitoring
Cediranib Dose 
Modification
Recurrent or 
persistent 
(>24 hours) or 
symptomatic 
increase by 
>20 mmHg 
(diastolic) or to 
> 140/90 mmHg if 
previously within 
normal limits. 
Monotherapy may 
be indicated
Initiate BP medication 
for first line treatment. 
Suggestions: ACE 
inhibitor or Calcium 
Channel Blocker
Escalate dose of 
medication in step wise 
fashion until BP is 
controlled or at a 
maximum dose
If BP is not controlled to 
<140/90 mmHg with one 
“maximized” drug 
regimen, then add a 
second agent.
Study drug does not 
need to be held unless 
otherwise clinically 
necessary
Consider renal consult
Increase 
frequency of 
monitoring until 
stabilized to BP 
<140/90 mmHg
Do not withhold 
cediranib unless 
otherwise clinically 
necessary
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
101(173)
Table 12
Hypertension Monitoring and Management
Event 
Antihypertensive
Therapy
Blood Pressure
Monitoring
Cediranib Dose 
Modification
Requiring more 
than one drug or 
more intensive 
therapy than 
previously.
Maximize 2 drug 
regimen
Suggestions:  ACE-
inhibitor + Calcium 
Channel Blocker
Escalate doses of 
existing medication until 
BP is controlled or at a 
maximum dose.
If BP is not 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 
antihypertensive drugs, 
up to a total of 4, may be 
maximized for BP 
control.
Consider consult with a 
BP 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 withhold 
cediranib unless BP is 
not decreased to less 
than 150/100 mmHg 
48 hours after multi-
drug therapy is 
instituted or if clinical 
symptoms worsen 
(eg, headache).
If BP is not controlled 
to less than 
150/100 mmHg with 
maximal therapy or if 
clinical symptoms 
worsen, then withhold 
cediranib (up to 
3 weeks) until 
maximum effect of 
the antihypertensive 
agents is achieved.
If BP is reduced to 
Grade 1 within 
3 weeks, cediranib 
may be resumed at 
prior dose.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
102(173)
Table 12
Hypertension Monitoring and Management
Event 
Antihypertensive
Therapy
Blood Pressure
Monitoring
Cediranib Dose 
Modification
If threatening 
consequences 
OR
SBP ≥180mmHg 
OR
DBP ≥110mmHg
Initiate treatment
Hospitalize patient for 
ICU management, IV 
therapy as necessary.
14 days are allowed to 
maximize the full effect 
of anti-hypertensive 
agents.
Intensive BP 
monitoring 
(hospitalization 
if necessary)
Withhold cediranib.
If BP is reduced to 
Grade 1 within 
3 weeks, cediranib 
may be resumed at a 
reduced dose after 
discussion with the 
AstraZeneca Study 
Physician and the 
Principal Investigator.
Abbreviations: ACE  Angiotensin Converting Enzyme; BP  blood pressure; DBP  diastolic blood pressure; 
ICU  intensive care unit; IV  intravenous; SBP  systolic blood pressure. 
6.8.3.2
Diarrhea
Diarrhea is often observed with cediranib.  Diarrhea usually starts early (within the first 
4 weeks of treatment), however, it can occur at any time during treatment.  Management of 
diarrhea should start at the first sign of diarrhea. Loperamide and advice on how to manage 
diarrhea should be readily available to patients from the start of cediranib treatment so that 
they can be applied at first episode of diarrhea.  Active and early management of diarrhea is 
recommended even with Grade 1 diarrhea.  Management is as shown in Table 13:
Table 13
Management of Diarrhea 
Toxicity
Management/Modifications
Initial grade 1 or 2 diarrhea
Patients should start loperamide (per standard practice) and 
continue to take loperamide until patients are free from diarrhea 
for at least 12 hours.  The dose of loperamide should not exceed 
16 mg in a 24-hour period.  Patients should also be counselled to 
start a BRAT diet.
If diarrhea persists despite 24 hours of loperamide treatment, 
withhold cediranib for a maximum of 7 days, continue 
loperamide, and maintain hydration.  Cediranib may be restarted 
at the same dose once patients have been free from diarrhea for 
12 hours.
Patients should be instructed to contact their study physician if 
mild or moderate (NCI CTCAE Grade 1 or 2) diarrhea persists for 
over 48 hours despite treatment with loperamide and cediranib 
dose interruption.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
103(173)
Table 13
Management of Diarrhea 
Toxicity
Management/Modifications
For either persistent grade 2 
diarrhea or grade 3 or 4 diarrhea
Patients with persistent or severe diarrhea (NCI CTCAE Grade 3 
or higher) may also require dose reduction or discontinuation of 
therapy with cediranib, follow guidance in Table 7
Abbreviations:  BRAT  bananas, rice, applesauce, toast; CTCAE  Common Terminology Criteria for Adverse 
Event; NCI  National Cancer Institute.
6.8.3.3
Fatigue
Fatigue is a common adverse drug reaction reported for both cediranib and olaparib.  Fatigue 
experienced by patients taking cediranib may be rapid in onset.  During clinic visits, patients 
fatigue levels should be discussed.  Patients should seek medical advice early if Grade 2 
fatigue develops (moderate fatigue causing difficulty performing some activities of daily 
living).
Care should be taken to ensure that the nutritional status of the patients is optimized and 
patients should be encouraged to drink plenty of fluids. Patients should be encouraged to 
manage fatigue by alternating periods of rest with light aerobic exercise, which may improve 
the symptoms in some cases.
Consideration should be given to other possible causes of fatigue (eg, thyroid function, 
depression/insomnia and other concomitant medicinal products).  Additionally, short 
interruption of cediranib dosing (initially 2-3 days-or longer-up to a maximum of 21 days) 
may help relieve fatigue.  When symptoms improve cediranib should be restarted with the 
same dose or, if necessary, a dose reduction can be considered. 
6.8.3.4
Proteinuria
Proteinuria is a common adverse reaction reported for cediranib and if this occurs during 
treatment, it should be managed according to Table 14.  For management of suspected cases 
of nephrotic syndrome, refer Section 5.2.1.4.
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
104(173)
Table 14
Management of Proteinuria 
Proteinuria Value if following 
by urinalysis
Monitoring
Dose modification
Greater than 2+ 
AND
Creatinine ≤1.5x ULN
Perform UPC
Continue study drugs at planned 
dose
Greater than 2+ 
AND
Creatinine >1.5x ULN
Perform UPC
Interrupt cediranib until results 
of UPC are known (see below)
Based on results of the UPCa
UPC ≤ 1.0
Continue monitoring according 
to Schedule of Assessments 
(Table 5)
Continue study drugs at planned 
dose
UPC > 1.0 and ≤3.5 
AND 
Creatinine ≤1.5x ULN
Perform UPC at each routine 
visit
Continue study drugs at planned 
dose
UPC > 3.5 
OR
Creatinine >1.5x ULN
Perform UPC at each routine
visit
Interrupt cediranib for up to 
21 days and repeat UPC and 
creatinine assessment.  If UPC 
resolves to <3.5 and creatinine 
to ≤1.5x ULN, resume cediranib 
with reduction in cediranib by 
one dose level. Consider 
consultation with nephrologist
a
If UPC is <1.0 and creatinine >1.5x ULN, AE management should be followed as described above
Abbreviations:  ULN  upper limit of normal; UPC  urine protein:creatinine ratio
6.8.3.5
Management of Thyroid Toxicities 
The use of cediranib has been associated with elevations of TSH and patients should be 
managed as per Table 15.  In all cases, IPs should continue unless clinically contraindicated.  
Referral to an endocrinologist should also be considered if thyroid abnormalities occur.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
105(173)
Table 15
Monitoring and Management of Thyroid Toxicities
Result of TSH and FT4
Action
Increases of TSH with normal FT4
Monitor
Increases in TSH with normal FT4 and adverse 
events suggestive of incipient hypothyroidism
Consider replacement thyroxine
Increase in TSH with reductions in FT4
Consider replacement thyroxine 
Abbreviations: FT4  free thyroxine; TSH  thyroid stimulating hormone
6.8.3.6
Decrease in LVEF
Patients who have any of the following should undergo an echocardiogram (ECHO) or 
multigated acquisition (MUGA) scan at baseline and as clinically indicated (see Table 5) 
while on study:
!
Prior treatment with anthracyclines
!
Prior treatment with trastuzumab
!
Prior central thoracic RT, including RT to the heart
!
History of myocardial infarction within 6 to 12 months or history of other 
significant impaired cardiac function (Patients with history of myocardial 
infarction within 6 months are excluded from the study)
The decision to continue or interrupt cediranib/olaparib is based on the LVEF as it relates to 
the institution’s LLN and change in ejection fraction from screening (LVEF as measured at 
enrollment) according to Table 16.
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
106(173)
Table 16
Monitoring and Management of Decreased LVEF
Relationship of LVEF 
to Institution’s LLN 
at baseline
LVEF Decrease <10%
LVEF Decrease
10-15%
LVEF Decrease >15%
Normal
Continue
Continue
Continue and repeat 
MUGA/ECHO
within 4-8 weeks
1-5% below LLN
Continue and repeat 
MUGA/ECHO within 
4-8 weeks
Continue and repeat 
MUGA/ECHO within 
4-8 weeks
Interrupt cediranib and 
repeat MUGA/ECHO 
within 3 weeks
> 6% below LLN
Continue and repeat 
MUGA/ECHO within 
4-8 weeks
Interrupt cediranib and 
repeat MUGA/ECHO 
within 3 weeks
Interrupt cediranib and 
repeat MUGA/ECHO 
within 3 weeks
Abbreviations:  ECHO  echocardiogram; LLN  lower limit of normal; LVEF  left ventricular ejection fraction; 
MUGA  multigated acquisition. 
LVEF decreases in percentage points. 
6.8.3.7
Posterior Reversible Encephalopathy Syndrome (PRES)
Posterior reversible encephalopathy syndrome (PRES) has been uncommonly reported in 
clinical studies with cediranib.  PRES is a neurological disorder which can present with 
headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances, 
and can be fatal. Mild to severe hypertension may be present.  In patients developing PRES, 
treatment of specific symptoms including control of BP is recommended. Confirmation of 
PRES requires brain imaging, preferably MRI.  Cediranib should be discontinued following 
confirmation of PRES.  The safety of reinitiating cediranib in patients previously experiencing 
PRES is not known.
6.8.3.8
Gastrointestinal perforation
GI perforation has been uncommonly reported in cediranib treated patients and may be fatal.  
Cediranib should be used with caution in patients at risk and permanently discontinued in 
patients who develop GI perforation.
6.8.3.9
Fistula
In patients treated with cediranib, fistula has been reported and reflected the location of the 
underling malignancy.  In the ovarian cancer population, vaginal fistula has been uncommonly 
reported in cediranib treated patients.  Cediranib should be used with caution in patients at risk 
of fistula and discontinuation of cediranib should be considered in patients who develop 
fistulae.
6.8.3.10
Arterial thromboembolism
Arterial thromboembolic events (including transient ischemic attack and ischemic stroke) 
have been reported in clinical studies with cediranib.  Cediranib should be used with caution 
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
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in patients who are at an increased risk of thrombotic events or who have a history of 
thrombotic events.  Cediranib should be permanently discontinued in patients who develop an 
arterial thromboembolic event. 
6.8.3.11
Venous thromboembolism
Venous thromboembolic events including pulmonary embolism and deep vein thrombosis 
have been commonly reported in patients treated with cediranib.  Anticoagulant treatment 
should be started in accordance with clinical practice.  Discontinuation of cediranib may be 
considered.  Cediranib should be used with caution in patients at risk of venous 
thromboembolism.
6.8.3.12
Wound healing
Treatment with cediranib should be stopped at least 2 weeks prior to scheduled surgery.  The 
decision to resume cediranib therapy after surgery should be based on clinical judgment of 
adequate wound healing.  In patients who experience wound healing complications during 
therapy, treatment with cediranib should be interrupted until the wound is fully healed.  No 
formal studies of the effect of cediranib on wound healing have been conducted; however, in 
the ICON6 pivotal study there was no evidence of an increase in wound healing complications 
in cediranib treated patients compared with placebo.
6.8.3.13
Elderly
There is a limited amount of safety data available for cediranib use in patients aged 75 years 
and older.  Based on a population PK analysis, the clearance of cediranib decreased with age, 
however, no dose adjustment is needed given the small impact on exposure or variability. 
Caution should be taken when treating patients who are aged 75 years or older with cediranib. 
In case of toxicity dose pause or dose reduction may be considered.
6.8.3.14
Mild/moderate renally impaired patients
Patients with mild and moderate renal impairment discontinued cediranib more often due to 
adverse events, particularly when cediranib was co-administered with chemotherapy.  
Population PK analysis showed that no adjustment of cediranib dose is required in this 
population as cediranib is minimally renally cleared; however, cediranib clearance may be 
decreased in patients with low body weight.  In the ICON6 pivotal study, patients with mild or 
moderate impairment had lower median body weight compared with patients with normal 
renal function.  Caution should be exercised in patients with mild and moderate renal 
impairment and a cediranib dose adjustment should be considered in case of signs of toxicity.  
For information on use of olaparib in renally-impaired patients, please see Section 6.8.4.4
6.8.3.15
Weight decreased  
In the ICON6 study, weight decreased was very commonly reported in cediranib treated 
patients.  Weight loss (≥7%) in cediranib-treated patients was associated with higher incidence 
of decreased appetite, vomiting and stomatitis, although these events were also commonly 
reported in patients who did not lose weight.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
108(173)
6.8.4
Management of olaparib associated toxicity
6.8.4.1
Management of MDS/AML
Patients who develop MDS/AML on treatment should be discontinued from olaparib 
treatment and managed appropriately.
6.8.4.2
Management of olparib-related new or worsening pulmonary symptoms 
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormalities occur 
in the absence of a clear diagnosis, an interruption in 1 or both IPs dosing is recommended 
and further diagnostic workup (including a HRCT scan) should be performed to exclude 
pneumonitis.
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then IP(s) can be restarted, if deemed appropriate by the investigator.  If 
significant pulmonary abnormalities are identified, these need to be discussed with the Study 
Physician.
6.8.4.3
Management of nausea and vomiting
Events of nausea and vomiting are known to be associated with olaparib treatment.  In study 
D0810C00019 nausea was reported in 71% of the olaparib treated patients and 36% in the 
placebo treated patients and vomiting was reported in 34% of the olaparib treated patients and 
14% in the placebo treated patients.  These events are generally mild to moderate (CTCAE 
Grade 1 or 2) severity, intermittent and manageable on continued treatment.  The first onset 
generally occurs in the first month of treatment for nausea and within the first 6 months of 
treatment for vomiting.  For nausea, the incidence generally plateaus at around 9 months, and 
for vomiting at around 6 to 7 months.
No routine prophylactic anti-emetic treatment is required at the start of treatment with the IPs, 
however, patients should receive appropriate anti-emetic treatment at the first onset of nausea 
or vomiting and as required thereafter, in accordance with local treatment practice guidelines.  
Taking olaparib tablets with food may help alleviate symptoms of nausea and vomiting.
As per international guidance on anti-emetic use in cancer patients (European Society for 
Medical Oncology [ESMO], NCCN), generally a single agent antiemetic should be considered 
eg, dopamine receptor antagonist, antihistamines or dexamethasone.
6.8.4.4
Management of renal impairment
If subsequent to study entry and while still on study treatments, a patient’s estimated 
creatinine clearance (CrCL) falls below the threshold for study inclusion (<50 mL/min), 
retesting should be performed promptly.  A dose reduction of olaparib is recommended for 
patients who develop moderate renal impairment (calculated CrCL by Cockcroft-Gault 
equation of ≥31 mL/min and ≤50 mL/min) for any reason during the course of the study: the 
dose of olaparib should be reduced to 150 mg bd.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
109(173)
Because the CrCL determination is only an estimate of renal function, in instances where the 
CrCL falls to between 31 mL/minutes and 50 mL/minutes, the Investigator should use his or 
her discretion in determining whether a dose change or discontinuation of therapy is 
warranted.
Olaparib has not been studied in patients with severe renal impairment 
(CrCL ≤30 mL/minutes) or end-stage renal disease; if patients develop severe impairment or 
end stage disease is it recommended that olaparib be discontinued.  For information on use of 
cediranib in renally-impaired patients, please see Section 6.8.3.14.
6.8.5
Interruptions for intercurrent non-toxicity related events
IP(s) dose interruption for conditions other than toxicity resolution should be kept as short as 
possible.  If a patient cannot restart IP(s) within 3 weeks for resolution of intercurrent 
conditions not related to disease progression or toxicity, the case should be discussed with 
AstraZeneca study physician.
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF. 
Both IPs should be stopped at least 2 weeks prior to planned surgery.  After surgery both IPs 
can be restarted when the wound has healed.  No stoppage of IPs is required for any needle 
biopsy procedure.
Both IPs should be discontinued for a minimum of 3 days before a patient undergoes radiation 
treatment.  Both IPs should be restarted within 3 weeks as long as any bone marrow toxicity 
has recovered.
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, patients 
should be advised to use caution while driving or using machinery if these symptoms occur. 
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Table 17
Identity of investigational product(s)
Investigational producta
Dosage form and strength
Manufacturer
Olaparib 
150 mg and 100 mg tablet
Abbvie on behalf of 
AstraZeneca
Cediranib
20 mg and 15 mg tablet
AstraZeneca 
a
Descriptive information for olaparib and cediranib can be found in the respective olaparib and cediranib 
Investigator’s Brochures
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
110(173)
7.1.1
Cediranib
Cediranib is available as a beige film-coated tablet containing 20 mg or 15 mg of cediranib.  
Patients will be administered cediranib study treatment tablets orally at a dose of 30 mg od.  
The planned dose of 30 mg od will be made up of 2 × 15 mg tablets od.  One x 20 mg and 
1 x 15 mg tablets will be used to manage dose reductions.
The dose of cediranib can be taken at the same time as the morning dose of olaparib and can 
be taken with or without food, in a similar way each morning.
7.1.2
Olaparib
Olaparib is available as a green film-coated tablet containing 150 mg or 100 mg of olaparib.  
Patients will be administered olaparib study treatment tablets orally at a dose of 200 mg bd.  
The planned dose of 200 mg bd will be made up of 2 × 100 mg tablets bd.  One x 150 mg and 
1 x 100 mg tablets will be used to manage dose reductions.
The olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or 
divided.  Olaparib tablets can be taken with or without food.
7.2
Dose and treatment regimens
Dose reductions for toxicity are permitted for either or both IPs (see Section 6.7).
7.2.1
Cediranib
For all centers, cediranib will be packed in high-density polyethylene bottles with 
child-resistant closures.  The cediranib study treatment will be dispensed to patients.  Multiple 
bottles of study treatment may be required for dispensing in order to make up the desired dose.
Patients will be administered cediranib study treatment tablets orally at a dose of 30 mg od.  
The planned dose of 30 mg od will be made up of 2 × 15 mg tablets od.  One x 20 mg and 
1 x 15 mg tablets will be used to manage dose reductions.
Doses of study treatment should be taken at the same time each morning. The dose of 
cediranib can be taken at the same time as the morning dose of olaparib and can be taken with 
or without food, in a similar way each morning.  For patients with difficulty swallowing 
tablets, cediranib tablets may be dispersed in non-carbonated drinking water.  
If a patient misses a dose, the patient should be advised to take the dose as soon as possible 
provided this happens within 6 hours of the scheduled time.  If it is more than 6 hours after the 
scheduled time, cediranib should not be taken for that day.  Cediranib should be taken as 
scheduled on the next day.  A patient should not take more than a single daily dose on a given 
day.  
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
111(173)
7.2.2
Olaparib
For all centers, olaparib will be packed in high-density polyethylene bottles with 
child-resistant closures.  The olaparib study treatment will be dispensed to patients.  Multiple 
bottles of study treatment may be required for dispensing in order to make up the desired dose.
Patients will be administered olaparib study treatment tablets orally at a dose of 200 mg bd.  
The planned dose of 200 mg bd will be made up of 2 × 100 mg tablets bd.  One x 150 mg and 
1 x 100 mg tablets will be used to manage dose reductions.
Doses of study treatment should be taken at the same time each day approximately 12 hours 
apart.  All doses should be taken with approximately 240 mL of water.  The olaparib treatment 
tablets should be swallowed whole and not chewed, crushed, dissolved or divided.  Olaparib 
tablets can be taken with or without food.
If vomiting occurs shortly after the study treatment tablets are swallowed, the dose should 
only be replaced if all of the intact tablets can be seen and counted.  Should any patient 
enrolled on the study miss a scheduled dose for whatever reason (eg,, as a result of forgetting 
to take the tablets or vomiting), 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 is not to be taken and the patient should take their 
allotted dose at the next scheduled time.
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language. 
Specific dosing instructions will not be included on the label; the site must complete the 
“Patient Dispensing Card” with the details of the dosing instructions at the time of dispensing.  
The patient emergency contact details will not be on the label, but can be found in the 
informed consent and the ‘Patient Dispensing Card’.  For emergency purposes, the patient 
must be in possession of the emergency contact details at all times.
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  The IP 
labels on the bottles specify the appropriate storage.
7.5
Compliance
The administration of all study drugs (including IPs) should be recorded in the appropriate 
sections of the eCRF.
Treatment compliance will be assured by reconciliation of site drug accountability logs. 
Patients should be given clear instructions on how and when to take their IPs.  Patients will 
self-administer olaparib and cediranib.  Study site staff will make tablet counts at regular 
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
112(173)
intervals during treatment.  Compliance will be assessed by the tablet count and the 
information will be recorded in the appropriate section of the eCRF.  After the tablet count has 
been performed, the remaining tablets will not be returned to the patient but will be retained 
by the investigative site until reconciliation is completed by the study monitor.  All patients 
must return their bottle(s) of olaparib and cediranib at the appropriate scheduled visit, when a 
new bottle will be dispensed.  Patients will be instructed to record dates of missed or held 
doses using a handheld electronic device (the same device used for collection of PRO data; 
see Section 5.3.1).  These data will be reviewed by the Investigator at each patient visit and 
data entered in eCRF by the site staff.  Patients must return all containers and any remaining 
tablets at the end of the study. 
7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
The study personnel will account for all study drugs dispensed to and returned from the 
patient.
Study site personnel, will account for all study drugs received at the site, unused study drugs 
and for appropriate destruction.  Certificates of delivery, destruction and return (as applicable 
for particular study drug) should be signed.
7.7
Concomitant and other treatments 
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the study treatment period (treatment discontinuation or 
FPV visit).  Any concomitant medication(s), including herbal preparations, taken during the 
study will be recorded in the eCRF.
Medications that should NOT be administered
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (Hormone 
replacement therapy (HRT) is acceptable), RT, biological therapy or other novel agent) is to 
be permitted while the patient is receiving one or both IPs.
Live virus and bacterial vaccines should not be administered whilst the patient is receiving 
one or both IPs and during the 30 day follow up period. An increased risk of infection by the 
administration of live virus and bacterial vaccines has been observed with conventional 
chemotherapy drugs and the effects with the combination of cediranib and olaparib are 
unknown.  
The use of any natural/herbal products or other “folk remedies” should be discouraged; but 
use of these products, as well as use of all vitamins, nutritional supplements and all other 
concomitant medications must be recorded.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
113(173)
Cediranib and inducers of PgP/UGT 
In vitro data indicate that cediranib is unlikely to cause interactions with CYP450 inducers, 
inhibitors, and substrates.  Cediranib oxidative metabolism appears to be mediated by 
flavin-containing monooxygenase enzymes FMO1 and FMO3 and glucuronidation by 
UGT1A4.  Co-administration of cediranib with strong inducers of PgP/UGT decrease 
cediranib plasma concentrations; therefore, use of potent inducers of UGT/PgP (eg, 
rifampicin, carbamazepine, phenobarbital, phenytoin and St. John Wort) should be avoided if 
possible.  Cediranib is a substrate of MDR1 (Pgp), and possible substrate of breast cancer 
resistant protein (BCRP).  Cediranib is not an inhibitor of OAT1 and OAT3, but it has a low 
potential to inhibit MDR1 (Pgp), BCRP, OATP1B1, OATP1B3, OCT2, MATE1.  The clinical 
impact of this finding is unknown.  Cediranib may act as an inhibitor of renal tubular 
MATE2-K, this could increase exposure of co-administered agents such metformin or to 
endogenous agents such as creatinine; however, the ICON6 study showed that increases of 
blood creatinine caused by 20 mg/day cediranib treatment were infrequent (4.4%) and only 
mild in severity, suggesting the clinical impact of renal tubular MATE2-K inhibition by 
cediranib is small.
Olaparib and CYP 3A4/5 enzymes
CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance of 
olaparib.  Clinical studies to evaluate the impact of known CYP3A inhibitors and inducers 
have shown that co-administration of a strong CYP3A inhibitor increased olaparib maximum 
plasma concentration (Cmax) 1.42-fold (90% CI: 1.33-1.52) and increased mean area under the 
plasma drug concentration-time curve (AUC) 2.70-fold (90% CI: 2.44-2.97); co-
administration of a strong CYP inducer decreased Cmax by 71% (treatment ratio: 0.29; 90% 
CI: 0.24-0.33) and mean AUC by 87% (treatment ratio: 0.13; 90% CI: 0.11-0.16). 
Consequently, to ensure patient safety, the following potent inhibitors of CYP3A4/5 must not 
be used during this study for any patient receiving olaparib (eg, itraconazole, telithromycin, 
clarithromycin, boosted protease inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, 
telaprevir) or moderate inhibitors (ciprofloxacin, erythromycin, diltiazem, fluconazole, 
verapamil) of this isozyme should not be taken with the IPs in this study.
Strong CYP 3A4/5 inducers (eg, phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, 
carbamazepine, nevirapine, enzalutamide and St John’s Wort) and moderate inducers CYP 
3A4 inducers (eg, bosentan, efavirenz, modafinil) should not be taken with the IPs in this 
study.
After enrollment if the use of any potent inducers or inhibitors of CYP3A4/5 are considered 
necessary for the patient’s safety and welfare, the investigator must contact the AstraZeneca 
Study Physician.  A decision to allow the patient to continue in the study will be made on a 
case-by-case basis.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
114(173)
Effect of olaparib on other drugs
!
CYP3A4 substrates: hormonal contraceptive, simvastatin, cisapride, cyclosporine, 
ergot alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine
!
CYP2B6 substrates: bupropion, efavirenz
!
OATP1B1 substrates: bosentan, glibenclamide, repaglinide, statins and valsartan
!
OCT1, MATE1 and MATE2K substrates: metformin
!
OCT2 substrates: serum creatinine
!
OAT3 substrates: furosemide, methotrexate
Based on limited in vitro data, olaparib may increase the exposure to substrates of CYP3A4, 
OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K.  Based on limited in vitro data, 
olaparib may reduce the exposure to substrates of 2B6.  Caution should be observed if 
substrates of these isoenzymes or transporter proteins are co-administered.
Anticoagulant Therapy
Patients who are taking warfarin may participate in this trial; however, it is recommended that 
prothrombin time (International Normalized Ratio [INR] and activated partial thromboplastin 
time) be monitored carefully at least once per week for the first month, then monthly if the 
INR is stable.  Subcutaneous heparin and low molecular weight heparin are permitted. 
Anti-emetics/Anti-diarrheal
From screening onwards, should a patient develop nausea, vomiting and / or diarrhea, then 
these symptoms should be reported as AEs (see Section 6.3) and appropriate treatment of the 
event given.
Palliative radiotherapy 
Palliative RT may be used for the treatment of pain at the site of bony metastases that were 
present at baseline, provided the investigator does not feel that these are indicative of clinical 
disease progression during the study period.  Both IPs should be discontinued for a minimum 
of 3 days before a patient undergoes therapeutic palliative radiation treatment.  Both IPs 
should be restarted within 4 weeks as long as any bone marrow toxicity has recovered.  
Administration of other anti-cancer agents
Patients must not receive any other concurrent anti-cancer therapy, including investigational 
agents, while on one or both IPs.  Patients may continue the use of bisphosphonates or 
denosumab for bone disease and corticosteroids for the symptomatic control of brain 
metastases provided the dose is stable before and during the study and they were started at 
least 4 weeks prior to the first doses of IPs. 
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
115(173)
Subsequent therapies for cancer 
Details of first and subsequent therapies for cancer and/or details of surgery for the treatment 
of the cancer, after discontinuation of treatment, will be collected until the end of the study.  
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF.
In addition, any unplanned diagnostic, therapeutic or surgical procedure performed during the 
study period must be recorded in the eCRF.
7.8
Post Study Access to Study Treatment
There are no plans to provide olaparib and/or cediranib to the patients after discontinuation of 
the IPs.  After discontinuation of IPs, the investigator will be at liberty to define further most 
appropriate anti-cancer treatment.  Information on subsequent PARP and VEGF inhibitors and 
other anti-cancer therapies should be recorded on the clinical database as part of survival 
follow-up.
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to first patient 
enrolled and any subsequent amendments will be documented, with final amendments 
completed prior to database lock.  Additional details relating to the ICR will be detailed in the 
ICR Charter.
An interim futility analysis will take place after 20 evaluable (by Investigator assessment) 
patients have received at least 1 dose of IP and have been followed for at least 4 months.  
Patients in the futility analysis will also have their baseline scans reviewed by ICR to evaluate 
the concordance rate on measurable disease at this stage.  Enrollment will continue during the 
futility analysis.  Assuming the study passes the futility assessment, the data cut-off for the 
primary analysis of ORR will take place 8 months after the last patient has received her first 
dose of IP, to allow opportunity for all patients to complete at least 4 RECIST follow-up 
assessments.  Patients will be followed for survival and analysis of OS will also take place at 
this time.  Patients should be contacted or other data sources checked (see Section 3.10.2) in 
the 2 weeks following the data cut-off for the primary analysis to provide current survival 
data.  At this time, the CSR will be written including the analysis of the confirmed ORR by 
ICR using RECIST 1.1 criteria, supported by Investigator assessment of ORR and by other 
efficacy endpoints (DoR, DCR, PFS, OS and TDT), PROs and safety/tolerability variables. 
Following the data cut-off for the primary analysis, no further statistical analysis of the data 
will be conducted.  
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Clinical Study Proto ol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
116(173)
8.2
Sample size estimate
The study originally planned to recruit 100 patients over approximately 12 months.  The 
primary analysis scheduled at 8 months after the last patient received her first dose of IP 
(approximately 20 months after study start), allows all patients to have at least 4 RECIST 
follow-up assessments.
An interim futility analysis of ORR (confirmed and/or unconfirmed CRs and PRs based on 
investigator assessment) will take place after 20 evaluable patients (ie, with measurable 
disease (by Investigator assessment) have received at least 1 dose of IP and have been 
followed for at least 4 months.  If less than 4 of the 20 have responded the study may be 
stopped for futility.  If 4 or more patients have responded the study will continue to the 
primary analysis.
The study design was formulated within a Bayesian framework (Fisch et al 2015) based on 
dual criteria to show improvement over the expected response rate under current standard 
treatments (20% RR targeted as an improvement over <15% RR based on chemotherapy, 
Davis et al 2014) and to have a RR of a relevant size (approximately 30%, similar to the RR 
seen for bevacizumab plus chemotherapy in the AURELIA trial, Pujade-Lauraine et al 2014) 
defined as follows: 
1.
to have high confidence (>90%) that the true ORR is at least 20% or probability 
(ORR≥ 20%) >0.9 and  
2.
an observed rate of 30/100 is seen at the primary analysis.
The futility rule above (stop if number of responses is <4), was chosen so that the trial may 
stop if there is a low chance (<10% predictive probability) of 30 or more responses being 
observed at the primary analysis.  Computation of posterior and predictive probabilities used a 
neutral prior ie, beta (1/3, 1/3) distribution (Kerman 2011), for the ORR.  The predictive 
probability of observing a given number of responses at the end of the trial given the observed 
responses at the interim analysis is computed using a beta binomial distribution.
With 30 responders out of 100 at the primary analysis we would be >99% confident that the 
ORR is greater or equal to 20% and 94.6% confident that the ORR is ≥23%.  It is noted that 
the interim analysis is based on unconfirmed, investigator assessed RECIST data, whereas the 
primary analysis will be based on ICR assessed data with responses confirmed at least 4 
weeks after the initial response.  Data from the OCEANS study indicated an approximate 
1.5% reduction in response by ICR compared with investigator response (Aghajanian et al 
2014).  If only 26 patients out of 100 were to meet the latter definition of response at the 
primary analysis there would still be >90% confidence that the true rate was greater than or 
equal to 20%.
Assuming median PFS of 6 months, 73% PFS events are expected at the primary analysis at 
8 months after the last patient receives her first dose of IP.  The original analysis for OS at 
12 months after last patient receives her first dose of IP would expect 59% deaths.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
117(173)
The study now plans to recruit approximately 60 patients and analysis of OS, originally 
planned at 12 months after the last patient received her first dose of IP, will now occur at 
8 months after the last patient received her first dose of IP. Based on the revised duration of 
recruitment and assuming a median PFS of 6 months as originally planned and a median of 
12 months for OS, 80% PFS events and 57% OS events are expected to occur at the time of 
the analysis.
Table 18 presents the 95% CIs for some possible response rates which give an indication of 
the precision of the response rate that might be seen.
Table 18
Response rates and associated 95% CIs for a sample of 60
Response (n)
Response (%)
95% CI
5
8.3%
(1.3%, 15.3%)
10
16.7%
(7.2%, 26.1%)
15
25.0%
(14.0%, 36.0%)
CI confidence interval
8.3
Definitions of analysis sets
8.3.1
Full analysis set (FAS)
All patients who received at least one dose of either IP will be included in the full analysis set.
8.3.2
Efficacy analysis set (EFR population)
The EFR analysis set will be all patients who have received at least one dose of either IP and 
have measurable disease at baseline according to the independent review of baseline imaging 
data.
The primary analysis of ORR, and analyses of DoR and DCR by ICR will be produced based 
on the EFR analysis set.  All other efficacy variables (ORR, DoR, DCR based on investigator 
assessment; PFS, OS, TDT) and PRO variables will be summarized using the FAS.
Demographic data will be summarized for the FAS and to support the primary analysis, also 
for the EFR set (if different).
8.3.3
Safety analysis set
This is the same set as the FAS; ie, all patients who received at least one dose of either IP.
8.3.4
PK analysis set
All patients in the FAS providing at least 1 reportable PK concentration.
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
118(173)
8.4
Outcome measures for analyses
Independent Central Review of RECIST based assessments
The ICR of all radiological imaging data will be carried out using RECIST version 1.1. All 
radiological scans for all patients (including those at unscheduled visits, or outside visit 
windows) will be provided to the ICR.  Prior RT reports for patients (at baseline) and 
information on any lesions that were biopsied to provide a tumor sample for study entry (see 
Section 5.7.2) will also be provided to allow the selection of appropriate target lesions.  The 
imaging scans will be reviewed by two independent radiologists using RECIST 1.1 criteria 
and will be adjudicated if required.  For each patient, the ICR will define the overall visit 
response data (CR, PR, SD, PD or not evaluable [NE]) and the relevant scan dates for each 
time point (ie, for visits where response or progression is/is not identified).  If a patient has 
had a tumor assessment which cannot be evaluated then the patient will be assigned a visit 
response of NE (unless there is evidence of progression in which case the response will be 
assigned as PD).  
Further details of the ICR will be documented in the Independent Review Charter.
Investigator RECIST based assessments
From the investigators review of the imagining scans, the RECIST tumor response data will 
be used to determine each patient’s visit response according to RECIST version 1.1.  At each 
visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, PR, SD 
or PD depending on the status of their disease compared with baseline and previous 
assessments.  If a patient has had a tumor assessment which cannot be evaluated then the 
patient will be assigned a visit response of NE (unless there is evidence of progression in 
which case the response will be assigned as PD). 
8.4.1
Primary Endpoint 
Objective Response Rate (ORR)
ORR is defined as the number (%) of patients with measurable disease at baseline, with at 
least one visit response of CR or PR that is confirmed at least 4 weeks later.  For the primary 
analysis ICR is required for both the initial response and confirmation.  Data obtained up until 
progression, or last evaluable assessment in the absence of progression, will be included in the 
assessment of ORR.  However, any CR or PR which occurred or was confirmed after a further 
anticancer therapy was received will not be included in numerator of the ORR calculation.  In 
the case where a patient has two non-consecutive visit responses of PR or CR, then, as long as 
the time between the 2 visits of PR or CR is greater than 4 weeks and there is no PD between 
the PR visits, the patient will be defined as a responder.  Note that CR followed by PR is 
classed as progression.  
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
119(173)
8.4.2
Secondary endpoints
Duration of response (DoR)
DoR will be defined as the time from the date of first documented response, (that is 
subsequently confirmed) until date of documented progression or death in the absence of 
disease progression.  The date of the response start will be defined as the latest of the dates 
contributing towards the first visit response of PR or CR.  If the response is not confirmed, it 
will not be included.  The end of response should coincide with the date of progression or 
death from any cause used for the PFS endpoint.  If a patient does not progress following a 
response, then their duration of response will use the PFS censoring time.
Disease control rate (DCR)
DCR is defined as the percentage of patients who have a best overall response of CR or PR or 
SD (at 6 months).
Progression free survival (PFS)
PFS is defined as the time from date of first dose until the date of objective disease 
progression or death (by any cause in the absence of progression) regardless of whether the 
patient withdraws from study therapy or receives another anti-cancer therapy prior to 
progression. Patients who have not progressed or died at the time of analysis will be censored 
at the time of the latest date of assessment from their last evaluable RECIST assessment. 
However, if the patient progresses or dies after three or more missed RECIST assessments 
visits, the patient will be censored at the time of the latest evaluable RECIST assessment. If 
the patient has no evaluable visits or does not have baseline data they will be censored at 0 
days unless they die within two visits of baseline. 
The PFS time will always be derived based on scan/assessment dates not visit dates.  RECIST 
assessments/scans contributing towards a particular visit may be performed on different dates. 
The following rules will be applied:
!
Date of progression will be determined based on the earliest of the dates 
of the component that triggered the progression
!
When censoring a patient for PFS the patient will be censored at the latest 
of the dates contributing to a particular overall visit assessment.
Overall visit assessments will be determined for each assessment (scheduled or unscheduled) 
and will contribute to the derivation of PFS.  Objective disease progression is defined as: at 
least a 20% increase in the sum of the diameters of the target lesions (compared with a 
previous minimum sum) and an absolute increase of >5 mm, an overall assessment of 
progression or a new lesion.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
120(173)
Overall survival (OS)
OS is defined as the time from the date of first dose until death due to any cause. Any patient 
not known to have died at the time of analysis will be censored based on the last recorded date 
on which the patient was known to be alive.
Note: Survival calls will be made in the 2 weeks following the date of the data cut-off for the 
primary analysis, and if patients are confirmed to be alive (or if the death date is post the 
relevant data cut-off date) these patients will be censored in the associated analyses at the date 
of the data cut off.
Time to discontinuation of IPs or death (TDT)
TDT is defined as the time from the date of first doses of IPs to the earlier of the date of 
discontinuation of both IPs, or death date.  Both IPs should be discontinued at the same time 
but in rare circumstances discontinuation of one of the IPs before the other may be allowed 
(see Section 3.9).  In such a case, TDT will reflect the time from the date of first dose to the 
earliest IP discontinuation date.
HRQoL Analyses:
The EORTC-QLQ-C30 and EORTC-QLQ-OV28 questionnaires will be used.  Descriptive 
statistics of absolute scores and change from baseline of all subscales will be presented and 
plots will be generated as appropriate to interpret changes over time.  
Proportions of patients who had improved, stayed the same or deteriorated for all subscales 
(symptom and functioning scales) will be presented.  A 10 point change in score will be used 
as cut-off point.  The quantity and impact of missing data will be evaluated.  If warranted, 
some investigation of HRQoL data by whether patients are still taking study drug will be 
performed. 
!
Symptom Improvement Rate at 8 weeks
∀
For dyspnea, pain and constipation from QLQ-C30 and abdominal/GI symptoms 
from QLQ-OV28, the symptom improvement rate at 8 weeks will be defined as 
the number (%) of patients showing a clinically meaningful improvement (a 
decrease from baseline score >10; Osoba et al 2005) in that symptom from 
baseline.  The denominator will consist of a subset of the FAS population who 
have a baseline symptom score >10.
8.4.3
Other endpoints
Patient reporting of CTCAE symptoms
The PRO-CTCAE questionnaire will be used to derive patient reporting of CTCAE 
symptoms: nausea, vomiting, diarrhea, decreased appetite, fatigue, and dizziness.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
121(173)
Safety variables
Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, vital signs 
including BP and ECGs.  Any AE occurring before the start of IP will not be included in the 
summary tables of AEs.
Any AE occurring within 30 days of discontinuation of IPs (ie, the last dose of cediranib + 
olaparib) or the last dose of the last IP to be discontinued, in the rare case where 
discontinuation dates are different will be included in the AE summaries.
Blood pressure data collected electronically (see Section 5.2.4.1) will not be reported in the 
CSR.  Patient profiles and BP data over time for patients may be evaluated in an exploratory 
analysis at a later time.
8.5
Methods for statistical analyses
Descriptive statistics will be used for all variables, as appropriate.  Continuous variables will 
be summarized by the number of observations, mean, standard deviation, median, minimum, 
and maximum.  Categorical variables will be summarized by frequency counts and 
percentages for each category.  Unless otherwise stated, percentages will be calculated out of 
the FAS.
Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of IP.
8.5.1
Analysis of the primary variable ORR
The primary analysis will be based on ICR assessments of tumor response.  Only patients with 
a confirmed CR or PR, by ICR, at least 4 weeks after the initial response will be counted as 
responders.
The number of responders (confirmed CR or PR) will be modelled using a binomial 
distribution with a neutral Beta (1/3,1/3) prior distribution on the rate.
The mean and median of the posterior distribution of ORR will be presented, along with the 
standard deviation and a 95% credible interval around the mean (based on the highest 
posterior density [Lee, 1997]).  The observed ORR by ICR will also be presented with 95% 
exact (Clopper Pearson) CIs.
The posterior probabilities of the ORR being larger than 15%, 20% and 24% will be also 
computed.  To further characterize the RR, the posterior probability of showing low (<15%),
moderate (≥15%- <20%), high (≥20%- <24%) or substantial (≥24%) efficacy will be 
presented.
Summaries of the number of patients with best response in each of the follow categories will 
be presented: CR, PR, SD, PD and NE.  For the interim analysis, the CR (PR) category will be 
split into confirmed CR (PR) and unconfirmed CR (PR).
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
122(173)
At the time of primary analysis, ORR and exact 95% CI (Clopper Pearson) will be also be 
presented for the following:
!
ORR by investigator assessment
!
ORR for both confirmed and unconfirmed responses based on ICR 
assessment
!
ORR based on ICR assessment in the subgroup of patients carrying a 
somatic deleterious or suspected deleterious variant in either of the BRCA
genes (BRCA1 or BRCA2) or in HRR-associated genes identified with 
current and potential future tumor based BRCA or HRR gene mutation 
assays (ICR and Investigator assessment)
The concordance between ORR (confirmed responses) as assessed by ICR and by Investigator 
will be presented.
8.5.2
Analysis of the secondary variable(s)
Disease Control Rate (DCR)
DCR is defined as confirmed CR, PR or SD for at least 6 months.  DCR based on ICR in the 
evaluable for response analysis set will be presented together with 95% exact (Clopper 
Pearson) CIs.  DCR will be presented based on the Investigator assessment as a sensitivity 
analysis.
Duration of response (DoR)
DoR in responding patients will be summarized and the number (%) of responding patients 
with a DoR >3, >6, >9 and >12 months will be presented.  A Kaplan Meier plot and median 
DoR with 95% CI (calculated from the Kaplan-Meier plot) will be presented.  DoR will be 
presented based on the ICR, and (as a sensitivity analysis) based on the Investigator 
assessment.
Progression free survival (PFS)
PFS will be displayed using a Kaplan Meier plot. The number of events, the type of event 
(RECIST 1.1 progression or death), median time to event (calculated from the Kaplan-Meier 
plot), and the proportion of patients without an event at 3, 6, 12 and 18 months will be 
summarized. 
Overall survival (OS) 
OS will be displayed using a Kaplan-Meier plot.  The number of events, median time to event 
(calculated from the Kaplan-Meier plot), and the proportion of patients without an event at 3, 
6, 12 and 18 months will be summarized. 
Subsequent anticancer treatment
Subsequent anticancer treatment will be summarized descriptively at the primary analysis.
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Time to discontinuation of study treatment or death (TDT)
TDT will be displayed using a Kaplan-Meier plot.  The number of events, median time to 
event (calculated from the Kaplan-Meier plot), and the proportion of patients without an event 
at 3, 6, 12 and 18 months will be summarized.
HRQoL Assessments
HrQoL data will be presented using summaries and descriptive statistics, and will be detailed 
in the SAP.
Safety Assessments
Safety and tolerability data will be presented using summaries and descriptive statistics, and 
will be detailed in the SAP.
8.5.3
Subgroup analysis (if applicable)
The analyses of ORR, DCR, DoR, PFS and OS will be repeated for patients in and not in the 
following two subgroups:
!
patients carrying a somatic deleterious or suspected deleterious variants 
in either of the BRCA genes (BRCA1 or BRCA2) identified with current 
and potential future tumor based BRCA mutation assays 
!
patients identified as having a deleterious or suspected deleterious 
variants in HRR-associated genes identified with current and potential 
future HRR gene mutation assays.
Other subgroups may be analyzed, as detailed in the SAP.
8.5.4
Interim analysis
An interim futility analysis will take place after 20 evaluable (by Investigator assessment) 
patients have received IPs and have been followed for at least 4 months.  The study may be 
stopped for futility if there are less than 4 responders (confirmed and/or unconfirmed 
responses) out of the first 20 patients in which case the predictive probability of observing 
30 responders or more at the end of trial is ≤4.6%.  Computation of posterior and predictive 
probabilities will use a neutral prior ie, beta (1/3, 1/3) distribution (Kerman 2011), for the 
ORR.  The predictive probability of observing a given number of responses at the end of the 
trial given the observed responses at the interim analysis is computed using a beta binomial 
distribution. 
8.5.5
Sensitivity analysis 
ORR, DCR, DoR and PFS will be re-analyzed using the investigator assessment of tumor 
response instead of ICR assessment, as sensitivity analyses.
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8.5.6
Exploratory analyses
The analyses of the exploratory endpoints will be further detailed in the SAP.
PRO-CTCAE
PRO-CTCAE data will be presented using summaries and descriptive statistics based on the 
FAS and further details will be provided in the SAP.
Biomarkers 
The following biomarkers will be analyzed using plots and descriptive summary statistics.
!
Biomarker of potential HRDs, including genomic scarring, BRCA1
methylation, and other genes that might modify HRD.
!
Biomarkers of gene expression signature for 
angioimmune/angio/immune/metabolic categorization
!
Angiogenic biomarkers such as VEGF-A, C, D; sVEGFR2, Tie2, Ang1, 
2; leptin; IL6 
CA-125
Analysis of CA-125 samples will be described in the SAP.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site staff
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the 
WBDC/and/or ePROs system(s) utilized.
The PI will ensure that appropriate training relevant to the study is given to all site staff, and 
that any new information relevant to the performance of this study is forwarded to the staff 
involved.
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:
!
Provide information and support to the Investigator(s)
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!
Confirm that facilities remain acceptable
!
Confirm that the investigational team is adhering to the protocol, that data 
are being accurately and timely recorded in the eCRFs, that biological 
samples are handled in accordance with the Laboratory Manual and that 
study drug accountability checks are being performed
!
Perform source data verification (a comparison of the data in the eCRFs 
with the patient’s medical records at the hospital or practice, and other 
records relevant to the study) including verification of informed consent 
of participating patients. This will require direct access to all original 
records for each patient (eg, clinic charts)
!
Ensure withdrawal of informed consent to the use of the patient’s 
biological samples is reported and biological samples are identified and 
disposed of/destroyed accordingly, and the action is documented, and 
reported to the patient.
The AstraZeneca representative will be available between visits if the Investigator(s) or other
staff at the center needs information and advice about the study conduct.  AstraZeneca 
medical personnel will be readily available to discuss study related medical questions or 
problems with the investigator(s). Contact details are provided separately in the Investigator 
Study File.
9.2.1
Source data
Refer to the CSA for location of source data.
9.2.2
Study agreements
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study.  In the event of any inconsistency 
between this Clinical Study Protocol (CSP) and the CSA, the terms of CSP shall prevail with 
respect to the conduct of the study and the treatment of patients and in all other respects, not 
relating to study conduct or treatment of patients, the terms of the CSA shall prevail.
Agreements between AstraZeneca and the PI should be in place before any study-related 
procedures can take place, or patients are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’ (ie, 
LSLV) or when the Sponsor decides to discontinue the study.  There will be a primary data 
cut-off defined at approximately 8 months (LSLV) after the last patient received her first dose 
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of study treatment.  Data cut-off will be followed by clinical database lock when all data for 
all patients have been collected.  
The study is expected to start in Quarter 3, 2016 and to end by Quarter 3, 2019.
The study may be terminated at individual centers if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study
with either cediranib or olaparib.
An interim futility analysis will take place after 20 evaluable patients (ie, with measurable 
disease [by investigator assessment] and received at least one dose of IP) have been recruited 
and followed for at least 4 months.  Assuming the study passes the futility assessment, the 
data cut-off for the primary analysis of ORR and OS for the full CSR will take place 8 months 
after the last patient received her first dose of IP, to allow opportunity for all patients to 
complete 4 RECIST follow-up assessments and to allow responding patients to have a DoR 
greater than 6 months.  At this time, the clinical study database will close to new data and all 
efficacy, HRQoL and safety/tolerability information will be summarized for preparation of the 
CSR.  Patients are permitted to continue to receive IPs beyond the FPV if, in the opinion of 
the Investigator, they are continuing to receive benefit from treatment with cediranib and/or 
olaparib and have not met any discontinuation criteria.  Such patients will complete a FPV, 
which will occur at their last scheduled visit prior to data cut-off.  For further information 
regarding the FPV please refer to Section 4.4. For patients who continue to receive treatment 
beyond the FPV, Investigators will assume a manual drug ordering process for IPs.
Patients who continue to receive treatment beyond the FPV are to be followed in accordance 
with the Medical Standard of Care and as deemed appropriate by the Investigators.  Serious 
adverse event reporting (on paper) will continue to ensure safety data collection and 
monitoring of the patients while receiving the investigational product.  It is recommended that 
Investigators continue to observe ongoing patients at the frequency employed prior to the 
FPV.  Protocol dose modification and stopping criteria are to be followed while a patient is 
receiving cediranib and/or olaparib.  Restrictions regarding concomitant medications 
(Section 7.7) must be followed while the patient is receiving cediranib and/or olaparib.  A 
change in the dose/schedule of cediranib and/or olaparib should only occur for safety reasons, 
based on the Investigator’s judgement, and should generally follow the approach for dose 
reduction and discontinuation as described in this protocol.  Combining cediranib and/or 
olaparib with other anti-cancer therapy is not allowed.  
If in the opinion of the Investigator, a patient is no longer receiving clinical benefit from the 
IPs beyond the FPV, then the IPs will be stopped.  The Investigator will inform AstraZeneca 
when a patient discontinues the IPs.  Patients must return unused medication during routine 
clinic visits; drug accountability information must continue to be collected in patient source 
documents until the patient discontinues treatment.  Patients will continue to be monitored for 
all SAEs and pregnancies while receiving IPs and for 30 days after the last dose of IPs.
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9.4
Data management by AstraZeneca 
Data management will be performed by AstraZeneca Data Management Centre staff 
according to the Data Management Plan.  
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 
will be classified according to the AstraZeneca Drug Dictionary.  All coding will be 
performed by the Medical Coding Team at the AstraZeneca Data Management Centre.
The data collected through third party sources will be obtained and reconciled against study 
data.
Data queries will be raised for inconsistent or missing data.  All entries to the study database 
will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH GCP, applicable regulatory requirements 
and the AstraZeneca policy on Bioethics and Human Biological Samples.
10.2
Patient data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law.
Precautions are taken to preserve confidentiality and prevent genetic data being linked to the 
identity of the patient. In exceptional circumstances, however, certain individuals might see 
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both the genetic data and the personal identifiers of a patient.  For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data.  Also, Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.
10.3
Ethics and regulatory review
An Ethics Committee (EC)/ Institutional Review Board (IRB) should approve the final study 
protocol, including the final version of the Informed Consent Form and any other written 
information and/or materials to be provided to the patients.  The Investigator will ensure the 
distribution of these documents to the applicable EC/IRB and to the study site staff.
The opinion of the EC/IRB should be given in writing.  The Investigator should submit the 
written approval to AstraZeneca before enrollment of any patient into the study. 
The EC/IRB should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the protocol should be re-approved by the EC/IRB annually.
Before enrollment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, EC/IRB and the PI(s) at each center with 
safety updates/reports according to local requirements.
Each PI is responsible for providing the EC/IRB with reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the IPs.  AstraZeneca will provide 
this information to the PI(s) so that he/she can meet these reporting requirements.
10.4
Informed consent
The PI(s) at each center will:
!
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study
!
Ensure each patient is notified that they are free to discontinue from the study at any 
time
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!
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided
!
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study
!
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File
!
Ensure a copy of the signed Informed Consent Form is given to the patient
!
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the informed consent form that is approved by an EC/IRB.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the PI and 
AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised CSP).
The amendment is to be approved by the relevant EC/IRB and if applicable, also the national 
regulatory authority approval, before implementation.  Local requirements are to be followed 
for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each PI(s). For distribution to EC/IRB see Section 10.3.
If a protocol amendment requires a change to a center’s Informed Consent Form, AstraZeneca 
and the center’s EC/IRB are to approve the revised Informed Consent Form before the revised 
form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each EC/IRB.
10.6
Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an EC may perform 
audits or inspections at the center, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, ICH GCP and any applicable 
regulatory requirements.  The Investigator will contact AstraZeneca immediately if contacted 
by a regulatory agency about an inspection at the center.
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Optimally Resected Stage III Ovarian Cancer: A Gynecologic Oncology Group Study.  J Clin 
Oncol 2003;21 (17):1-7.
Parmar et al 2003
Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB et al.  
Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based 
chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial.  
Lancet. 2003 21;361(9375):2099-106.
Pujade-Lauraine et al 2014
Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al.  
Bevacizumab Combined With Chemotherapy for Platinum-Resistant Recurrent Ovarian 
Cancer: The AURELIA Open-Label Randomized Phase III Trial.  J Clin Oncol. 2014; 32(13): 
1302-1308.
Siegel et al 2015
Siegel RL, Miller KD, Jemal A.  Cancer statistics, 2015.  CA Cancer J Clin. 2015;65(1):5-29.
Sprangers and Aaronson 1992
Sprangers MA, Aaronson NK. The role of health care providers and significant others in 
evaluating the quality of life of patients with chronic disease: A review. J Clin 
Epidemiol.1992;45:743-60.
Stuart et al 2011
Stuart, GC, Kitchener, H, Bacon, M, du Bois, A., Friedlander, M., Ledermann, J. et al.  2010 
Gynecologic Cancer Intergroup (GCIG) consensus statement on clinical trials in ovarian 
cancer: report from the Fourth Ovarian Cancer Consensus Conference. Int J Gynecol Cancer 
2011;21: 750–755.
Tentori et al 2007
Tentori L, Lacal PM, Muzi A, Dorio AS, Leonetti C, Scarsella M, et al,  Poly(ADP-ribose) 
polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis. Eur J Cancer. 
2007; 43(14):2124–33.
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Van der Bilt et al 2012
van der Bilt AR, van der Zee AG, de Vries EG, de Jong S, Timmer-Bosscha H, et al. Multiple 
VEGF family members are simultaneously expressed in ovarian cancer: a proposed model for 
bevacizumab resistance. Curr Pharm Des. 2012 18(25):3784-92.
Vaughan et al 2011
Vaughan S, Coward JI, Bast RC Jr, Berchuck A, Berek JS, Brenton JD, et al.  Rethinking 
ovarian cancer: recommendations for improving outcomes.  Nat Rev Cancer. 2011 Sep 
23;11(10):719-25.
Yokoyama et al 2003a
Yokoyama Y, Charnock-Jones DS, Licence D, Yanaihara A, Hastings JM, Holland CM et al. 
Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 
3, as a prognostic factor in endometrial carcinoma. Clin Cancer Res. 2003; 9(4):1361-9.
Yokoyama et al 2003b
Yokoyama Y, Charnock-Jones DS, Licence D, Yanaihara A, Hastings JM, Holland CM et al. 
Vascular endothelial growth factor-D is an independent prognostic factor in epithelial ovarian 
carcinoma.Br J Cancer. 2003; 88(2):237-44.
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Appendix A
Signatures
This Clinical Study Protocol has been subjected to an internal AstraZeneca peer review and is 
electronically signed in the AstraZeneca Document Management System by the following 
people:
Director Clinical Development
Statistical Science Director
Global Clinical Leader (Physician)
Project Physician
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Appendix B
Additional Safety Information 
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation
Development of drug dependency or drug abuse
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A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.
!
Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?
!
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? AstraZeneca would not normally 
recommend or support a re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship and includes any toxicities 
considered related, probably related, or possibly related to the drug.
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Appendix C
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substance
s.htm). For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations
!
Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm)
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable
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!
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used.
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Appendix D
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
INTRODUCTION
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
DEFINITIONS
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline 
Phosphatase (ALP).
Hy’s Law (HL)
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:
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!
ALT ≥ 3xULN
!
AST ≥ 3xULN
!
TBL ≥ 2xULN
The Investigator will remain vigilant for local laboratory reports where the identification 
criteria are met, where this is the case the Investigator will:
!
Notify the AstraZeneca representative
!
Request a repeat of the test (new blood draw) 
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from the local laboratory results the Investigator will 
without delay:
!
Determine whether the patient meets PHL criteria (see Section 0 of this Appendix 
for definition) by reviewing laboratory reports from all previous visits 
!
The Investigator will without delay review each new laboratory report and if the 
identification criteria are met will:
!
Notify the AstraZeneca representative
!
Determine whether the patient meets PHL criteria (see Section 0 of this Appendix for 
definition) by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory CRF
FOLLOW-UP
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the patient has not met PHL criteria.
!
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
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Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
!
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Section 0)
!
Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:
!
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 
!
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.  This includes deciding which the tests 
available in the Hy’s law lab kit should be used
!
Complete the three Liver CRF Modules as information becomes available 
!
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
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!
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
!
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard
processes. 
∀
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
∀
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:
!
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above
!
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met.  Update the SAE report according to the 
outcome of the review
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW CRITERIA 
ARE MET BEFORE AND AFTER STARTING STUDY TREATMENT 
This section is applicable to patients who meet PHL criteria on study treatment having 
previously met PHL criteria at a study visit prior to starting study treatment.
At the first on study treatment occurrence of PHL criteria being met the Investigator will:
!
Determine if there has been a significant change in the patients’ condition#
compared with the last visit where PHL criteria were met#
∀
If there is no significant change no action is required
∀
If there is a significant change notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described is 
Section 4.2 of this Appendix
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
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whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.
Actions required for repeat episodes of potential Hy’s Law
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
!
Was the alternative cause for the previous occurrence of PHL criteria being met 
found to be the disease under study eg, chronic or progressing malignant disease, 
severe infection or liver disease, or did the patient meet PHL criteria prior to 
starting study treatment and at their first on study treatment visit as described in 
Section 0?
If No: follow the process described in Section 4.2 of this Appendix
If Yes:
Determine if there has been a significant change in the patient’s condition# compared with 
when PHL criteria were previously met
!
If there is no significant change no action is required
!
If there is a significant change follow the process described in Section 4.2 of this 
Appendix
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
REFERENCES
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf
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Appendix E
Example of Performance Status (Eastern Cooperative 
Oncology Group [ECOG]/Karnofsky Scale)
EXAMPLE OF PERFORMANCE STATUS (ECOG/KARNOFSKY 
SCALE)
Table 19
ECOG/Karnofsky Scale
Description
ECOG 
Grade
Karnofsky Equivalent
Fully active, able to carry on all pre-disease 
performance without restriction
0
100
Normal, no complaints; no evidence 
of disease.
90
Able to carry on normal activity; 
minor signs or symptoms of disease
Restricted in physically strenuous activity, 
but ambulatory and able to carry out work 
of a light or sedentary nature ie, light 
housework, office work
1
80
Normal activity with effort; some 
signs or symptoms of disease
70
Cares for self but unable to carry on 
normal activity or to do work.
Ambulatory and capable of self-care, but 
unable to carry out any work activities.  Up 
and about more than 50% of waking hours.
2
60
Requires occasional assistance but is 
able to care for most of personal 
needs.
50
Requires considerable assistance and 
frequent medical care.
Capable of only limited self-care, confined 
to bed or chair more than 50% of waking 
hours.
3
40
Disabled; requires special care and 
assistance.
30
Severely disabled; hospitalisation is 
indicated although death not 
imminent.
Completely disabled.  Cannot carry on any 
self-care. Totally confined to bed or chair.
4
20
Very ill; hospitalisation and active 
supportive care necessary.
10
Moribund.
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Appendix F
Guidelines for Evaluation of Objective Tumour Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumours)
INTRODUCTION
This appendix details the implementation of Response Evaluation Criteria In Solid Tumours 
(RECIST) 1.1 guidelines (Eisenhauer et al 2009) for the D8488C00001 study with regards to 
the Investigator assessment of tumour burden including protocol-specific requirements for this 
study.
DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET AND NON-
TARGET LESIONS
Only patients with measurable disease at baseline should be included in the study.  
Measurable disease is defined by the presence of at least 1 measurable lesion that has not been 
previously irradiated. 
Measurable:
A lesion, not previously irradiated or biopsied per the protocol prior to 
enrollment/randomisation, that can be accurately measured at baseline as ≥10 mm in the 
longest diameter (except lymph nodes which must have short axis ≥15 mm) with computed 
tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate 
repeated measurements.
Non-measurable:
!
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis at baseline1).
!
Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by CT or 
MRI.
!
Lesion biopsied per the protocol prior to randomisation
!
Previously irradiated lesions2
                                               
1 Nodes with <10 mm short axis are considered non-pathological and should not be recorded or followed as 
non-target lesions (NTLs).
2 Localised post-radiation changes which affect lesion sizes may occur.  Therefore, lesions that have been 
previously irradiated will not be considered measurable and must be selected as NTL at baseline and followed up 
as part of the NTL assessment.
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!
Skin lesions assessed by clinical examination
!
Brain metastasis.
Special cases:
!
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.  Blastic lesions are considered non-measurable.
!
Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present 
in the same patient; these should be selected as target lesions (TLs).
Target lesions:
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline.
Non-target lesions:
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.
METHODS OF ASSESSMENT
The same method of assessment and the same technique should be used to characterize 
each identified and recorded lesion at baseline and during follow-up visits.
A summary of the methods to be used for RECIST assessment is provided in Table 20.
Table 20
Summary of methods of assessment
Target lesions 
Non-target lesions
New lesions
CT (preferred)
MRI
CT (preferred)
MRI
Clinical examination 
X-ray, Chest X-ray
CT (preferred)
MRI
Clinical examination 
X-ray, Chest X-ray
Ultrasound
Bone scan
FDG-PET
CT  Computed tomography; FDG-PET  18-Fluoro-deoxyglucose positron emission tomography; MRI  Magnetic 
resonance imaging.
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CT and MRI 
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TL selected for response assessment and to assess NTL and identification 
of any new lesions. 
In the D8488C00001 study it is recommended that CT examinations of the chest and abdomen 
(including liver and adrenal glands) will be used to assess tumour burden at baseline and 
follow-up visits.  CT examination with intravenous contrast media administration is the 
preferred method.  MRI should be used where CT is not feasible or it is medically 
contra-indicated.  For brain lesion assessment, MRI is the preferred method.
Clinical examination 
In the D8488C00001 study, clinical examination will not be used for assessment of TL.  
Clinically detected lesions can be selected as TLs if they are assessed by CT or MRI scans.  
Clinical examination can be used to assess NTL and to identify the presence of new lesions.
Chest X-ray
In the D8488C00001 study, chest X-ray assessment will not be used for assessment of TL as 
they will be assessed by CT examination or MRI examination.  Chest X-ray can, however, be 
used to assess NTL and to identify the presence of new lesions.
Plain X-ray 
In the D8488C00001 study plain X-ray may be used as a method of assessment for bone NTL 
and to identify the presence of new bone lesions. 
Ultrasound 
In the D8488C00001 study, ultrasound examination will not be used for assessment of TL and 
NTL as it is not a reproducible method, does not provide an accurate assessment of tumour 
size and it is subjective and operator dependent.  Ultrasound examination can, however, be 
used to identify the presence of new lesions.  If new clinical symptoms occur and an 
ultrasound is performed then new lesions should be confirmed by CT or MRI examination.
Endoscopy and laparoscopy 
In the D8488C00001 study, endoscopy and laparoscopy will not be used for tumour 
assessments as they are not validated in the context of tumour assessment.
Tumour markers 
In the D8488C00001 study tumour markers will not be used for tumour response 
assessments as per RECIST 1.1.
Cytology and histology 
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In the D8488C00001 study histology will not be used as part of the tumour response 
assessment as per RECIST 1.1. 
Cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment is required when the measurable tumour has met criteria 
for response or stable disease.  In such circumstances, the cytology is necessary to 
differentiate between response/stable disease (an effusion may be a side effect of 
the treatment) and progressive disease (if the neoplastic origin of the fluid is 
confirmed).  Where cytology findings are not available, any effusion that 
significantly worsens (from trace to large) or appearance of clinically significant 
effusion (requiring change in drug therapy) during the study treatment will be 
considered to be progression of NTL, or disease progression due to new lesions. 
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, 
MRI or X-ray at baseline should be recorded as NTL and followed by the same 
method as per the baseline assessment.  
In the D8488C00001 study isotopic bone scans may be used as a method of 
assessment to identify the presence of new bone lesions at follow-up visits.  New 
lesions will be recorded where a positive hot-spot that was not present on the 
baseline bone scan assessment is identified on a bone scan performed at any time 
during the study.  The Investigator should consider the positive hot-spot to be a 
significant new site of malignant disease and represent true disease progression in 
order to record the new lesion.  Confirmation by CT, MRI and X-ray is 
recommended where bone scan findings are equivocal.
FDG-PET scan
In the D8488C00001 study, 18-Fluoro-deoxyglucose positron emission tomography 
(FDG-PET) scans may be used as a method for identifying new lesions, according 
with the following algorithm:  New lesions will be recorded where there is positive 
18-Fluoro-deoxyglucose uptake3 not present on baseline FDG-PET scan or in a 
location corresponding to a new lesion on CT/MRI at the same follow-up visit.  If 
there is no baseline FDG-PET scan available, and no evidence of new lesions on 
CT/MRI scans then follow-up CT/MRI assessments should be continued, scheduled 
as per protocol or clinical indicated, in order to confirm new lesions.
TUMOUR RESPONSE EVALUATION 
Schedule of evaluation
                                               
3 A positive FDG-PET scan lesion should be reported only when an uptake greater than twice that of the 
surrounding tissue is observed.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
151(173)
Baseline assessments should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based 
on signs and symptoms of individual patients and should be performed within the 28 days 
prior to randomisation and ideally as close as possible before the start of study treatment (see 
the Schedule of Assessments [Table 5] in the main body of the protocol).  Follow-up 
assessments will be performed every 8 weeks (±1 week), relative to first dose of 
investigational product(s) until confirmed objective disease progression as defined by 
RECIST 1.1 (irrespective of the reason for stopping treatment and/or subsequent therapy).
Any other sites at which new disease is suspected should also be adequately imaged at 
follow-up.
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits.  This 
schedule is to be followed in order to minimise any unintentional bias caused by some patients 
being assessed at a different frequency than other patients.
Target lesions
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph 
nodes), representative of all lesions involved should be identified as TL at baseline.  Target 
lesions should be selected on the basis of their size (longest diameter for non-nodal lesions or 
short axis for nodal lesions), 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.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes).  All measurements should be recorded in 
millimetres.  At baseline the sum of the diameters for all TL will be calculated and reported as 
the baseline sum of diameters.  At follow-up visits the sum of diameters for all TL will be 
calculated and reported as the follow-up sum of diameters.
Special cases:
For TL measurable in 2 or 3 dimensions, always report the longest diameter.  For pathological 
lymph nodes measurable in 2 or 3 dimensions, always report the short axis. 
If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan.
If a lesion has completely disappeared, the longest diameter should be recorded as 0 mm.
If a TL splits into 2 or more parts, then record the sum of the diameters of those parts. 
If 2 or more TLs merge then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s).  
If a TL is believed to be present and is faintly seen but too small to measure, a default value of 
5 mm should be assigned.  If an accurate measure can be given, this should be recorded, even 
if it is below 5 mm.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
152(173)
If a TL cannot be measured accurately due to it being too large, provide an estimate of the size 
of the lesion. 
When a TL has had any intervention eg, radiotherapy, embolisation, surgery, during the study, 
the size of the TL should still be provided where possible.
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumour visit 
response for TL (see Table 21).
Table 21
Evaluation of target lesions
Complete Response (CR)
Disappearance of all TLs since baseline.  Any pathological lymph 
nodes selected as TLs must have a reduction in short axis to 
<10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking 
as reference the baseline sum of diameters
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD
Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs, 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.
Not Evaluable (NE)
Only relevant if any of the TLs were not assessed or not evaluable 
or had a lesion intervention at this visit.  Note: If the sum of 
diameters meets the progressive disease criteria, progressive 
disease overrides not evaluable as a TL response
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; SD  Stable disease; 
TL  Target lesion.
Non-target lesions
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as 
NTL at baseline.  Measurements are not required for these lesions, but their status 
should be followed at subsequent visits.  At each visit an overall assessment of the 
NTL response should be recorded by the Investigator.  This section provides the 
definitions of the criteria used to determine and record overall response for NTL at 
the investigational site at each visit (see Table 22).
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
153(173)
Table 22
Evaluation of non-target lesions
Complete response (CR)
Disappearance of all NTLs since baseline.  All lymph nodes must 
be non-pathological in size (<10 mm short axis).
Non CR/Non PD
Persistence of 1 or more NTL.
Progression of disease (PD)
Unequivocal progression of existing NTLs.  Unequivocal 
progression may be due to an important progression in 1 lesion 
only or in several lesions.  In all cases the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy.
Not evaluable (NE)
Only relevant when 1 or some of the NTLs were not assessed and, 
in the Investigator's opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit.
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; NTL  Non-target 
lesion.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of stable disease or 
partial response in TLs, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of 1 or more NTLs is usually not 
sufficient to qualify for unequivocal progression status.
New lesions
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression. 
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour.
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
Symptomatic deterioration
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
154(173)
Symptomatic deterioration is not a descriptor of an objective response: it may be a reason for 
stopping study therapy.
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumour 
assessments where possible until objective disease progression is observed.
Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 23.
Table 23
Overall visit response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
N/A
No
CR
CR
Non CR/Non PD 
No
PR
CR
NE
No 
PR
PR
Non PD or NE
No
PR
SD 
Non PD or NE
No
SD
NE
Non PD or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR  Complete Response, PR  Partial Response, SD  Stable Disease, PD  Progressive Disease, NE  not evaluable, 
N/A  not applicable (only if relevant if there were no NTL at baseline)
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
155(173)
CONFIRMATION OF PROGRESSION
While disease progression may require confirmation, it is not mandated in this study.  
Confirmation will be subject to the investigator’s discretion (eg. if investigator is not sure of 
progression at initial assessment).  The confirmatory scan should occur preferably at the next 
scheduled visit and no earlier than 4 weeks after the initial assessment of progression of 
disease (PD) in the absence of clinical deterioration.
If a patient discontinues treatment (and/or receives a subsequent cancer therapy) prior to 
progression then the patient should still continue to be followed until objective disease 
progression.
CONFIRMATION OF RESPONSE 
In Study D8488C00001, imaging for confirmation of response (CR or PR) should be 
performed at the next scheduled RECIST assessment, 8 weeks (certainly no less than 4 weeks) 
following the date the criteria for response were first met.
CENTRAL REVIEW
The Contract Research Organisation appointed by AstraZeneca to perform the independent 
central review for the primary analysis of this study will provide specification for radiological 
imaging protocols in standard acquisition guidelines documentation. 
REFERENCES
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).  Eur J Cancer
2009;45(2):228-47.
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
156(173)
Appendix G
Hypertension Medication
The following anti-hypertensive medications have been provided as a guide and those used in 
this study will depend upon local practice.
Note: Agents in bold characters are suggested as optimal choices to avoid or minimize 
potential drug-interactions with cediranib through cytochrome P450 (CYP450)
Table 24
Dihydropyridine calcium-channel blockers
Agent
Initial dose
Intermediate dose
Maximum dose
Hepatic 
metabolism?
Nifedipine XL
30 mg po qd
60 mg po qd
90 mg po qd
CYP 3A4 substrate
Amlodipine
2.5 mg po qd
5 mg po qd
10 mg po qd
CYP 3A4 substrate
Felodipine
2.5 mg po qd
10 mg po qd
CYP 3A4 substrate 
+ inhibitor
Abbreviations: po  oral; qd  once daily
Table 25
Selective beta-blockers
Agent
Initial dose
Intermediate dose
Maximum dose
Hepatic 
metabolism?
Metoprolol
25 mg po bd
50 mg po bd
100 mg po bd
CYP2D6 substrate
Atenolol
25 mg po qd
50 mg po qd
100 mg po qd
No
Acebutolol
100 mg po bd
200-300 mg po bd
400 mg po bid
Yes (CYP450 
questionable)
Bisoprolol
2.5 mg po qd
5-10 mg po bd
20 mg po qd
Yes (CYP450 
questionable)
Abbreviations:  bd  twice daily; po  oral; qd  once daily
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Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
157(173)
Table 26
Angiotensin Converting Enzyme Inhibitors (ACEIs)
Agent 
Initial dose
Intermediate dose
Maximum dose
Hepatic metabolism?
Captopril
12.5 po tid
25 mg po tid
50 mg po tid
CYP 2D6 substrate
Enalapril
5 mg po qd
10-20 mg po qd
40 mg po qd
CYP 3A4 substrate
Ramipril
2.5 mg po qd
5 mg po qd
10 mg po qd
Yes (CYP450 
questionable)
Lisinopril
5 mg po qd
10-20 mg po qd
40 mg po qd
No
Fosinopril
Rarely used:
10 mg po qd
20 mg po qd
40 mg po qd
Yes (CYP450 
questionable)
Perindopril
4 mg po qd
none
8 mg po qd
Yes but not per 
CYP450
Quinapril
10 mg po qd
20 mg po qd
40 mg po qd
No
Abbreviations:  po  oral; tid  three times daily; qd  once daily
Table 27
Angiotensin II Receptors Blockers (ARBs)
Agent
Initial dose
Intermediate dose
Maximum dose
Hepatic metabolism?
Losartan
25 mg po qd
50 mg po qd
100 mg po qd
CYP3A4 substrate
Candesartan
4 mg po qd
8-16 mg po qd
32 mg po qd
CYP2C9 substrate
Irbesartan
75 mg po qd
150 mg po qd
300 mg po qd
CYP2C9 substrate
Telmisartan
40 mg po qd
none
80 mg po qd
Yes but not per 
CYP450
Valsartan
80 mg po qd
none
160 mg po qd
Yes but not per 
CYP450
Abbreviations:  po  oral;  qd  once daily
Table 28
Alpha and beta-blocker
Agent
Initial dose
Intermediate dose
Maximum dose
Hepatic metabolism?
Labetolol
100 mg po 
bid
200 mg po bd
400 mg po bd
CYP 2D6 substrate and 
inhibitor
Abbreviations:  bd  twice daily; po  oral
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
161(173)
 
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
162(173)
Appendix I
List of CYP3A4 inhibitors and inducers
GUIDANCE REGARDING POTENTIAL INTERACTIONS WITH CONCOMITANT 
MEDICATIONS
Note. While this is not an exhaustive list, it covers the known potent inhibitors and inducers, 
which have most often previously been reported to be associated with clinically significant 
drug interactions.  Please contact the Medical Monitor or AstraZeneca physician if further 
clarification is required.  For a more detailed list of CYP3A4 inhibitors/inducers, please visit 
FDA website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/ucm093664.htm#4
INTERACTIONS WITH P450:
Olaparib is substrate of CYP3A4.  Therefore, CYP3A4 inhibitors and inducers will affect 
olaparib’s exposure.  Cediranib is not substrate of CYP3A4, but it is substrate of UGT and 
PgP.  Some CYP3A4 inhibitors and inducers also inhibit or induce UGT/Pgp. 
POTENT INHIBITORS OF CYP3A4:
The following inhibitors of CYP3A4 must not be used during this study:
Table 30
Potent inhibitors of CYP3A4 
Drug
Minimum washout period prior to starting IP
Ketoconazole; Itraconazole; Indinavir; 
Saquinavir; Telithromycin; Nelfinavir; 
Clarithromycin; Ritonavir; Cobicistat; Indinavir; 
Saquinavir;  Nelfinavir; Boceprevir; Telaprevir 
and Clarithromycin
2 Weeks
Moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, 
verapamil) should be avoided with at least 1 week washout period.  
INDUCERS OF CYP3A4:
In addition, to avoid potential reductions in exposure due to drug interactions, the following 
CYP3A4 inducers should be avoided:
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
163(173)
Table 31
Potent inducers of CYP3A/4
Drug
Minimum washout period prior to starting IP
Carbamazepine; Modafinil; Nevirapine; 
Phenytoin; Rifabutin; Rifampicin; Rifapentin; St 
John’s Wort (Hypericum perforatum); 
Bosentan; Efavirenz; Modafinil.
4 Weeks
Phenobarbitone; Enzalutamide
5 Weeks 
After recruitment, if the use of any potent inducers or inhibitors of CYP3A4 are considered 
necessary for the patient’s safety and welfare, the investigator must contact the AstraZeneca 
Study Physician.  A decision to allow the patient to continue in the study will be made on a 
case-by-case basis.
NATURAL / HERBAL PRODUCTS:
The use of any natural/herbal products or other “folk remedies” should be discouraged but use 
of these products, as well as use of all vitamins, nutritional supplements and all other 
concomitant medications must be recorded in the appropriate eCRF.
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
164(173)
Appendix J
Acceptable Birth Control Methods
OLAPARIB AND CEDIRANIB ARE REGARDED AS COMPOUNDS WITH FOETAL
RISK
!
Women of childbearing potential and their partners, who are sexually active, must 
agree to the use of TWO highly effective forms of contraception in combination [as 
listed below], throughout the period of taking study treatment and for at least 6 
weeks after last dose of study drug(s), or they must totally/truly abstain from any 
form of sexual intercourse (see below).
ACCEPTABLE NON-HORMONAL BIRTH CONTROL METHODS INCLUDE:
!
Total sexual abstinence.  Abstinence must continue for the total duration of study 
treatment and for at least 1 month after the last dose.  Periodic abstinence 
(eg, calendar ovulation, symptothermal post ovulation methods) and withdrawal are 
not acceptable methods of contraception.
!
Vasectomised sexual partner PLUS male condom.  With participant assurance that 
partner received post-vasectomy confirmation of azoospermia.
!
Tubal occlusion PLUS male condom 
!
IUD PLUS male condom, provided coils are copper-banded
ACCEPTABLE HORMONAL METHODS:
!
Normal and low dose combined oral pills PLUS male condom 
!
Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the only highly 
efficacious progesterone based pill.
!
Hormonal shot or injection (eg., Depo-Provera) PLUS male condom
!
Etonogestrel implants (eg, Implanon, Norplant) PLUS male condom 
!
Norelgestromin / EE transdermal system PLUS male condom 
!
Intrauterine system [IUS] device (eg, levonorgestrel releasing IUS -Mirena®) PLUS 
male condom 
!
Intravaginal device (eg, EE and etonogestrel) PLUS male condom.
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
165(173)
Appendix K
PRO questionnaires (EORTC QLQ-C30, QLQ OV28, and 
PRO-CTCAE)
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Clinical Study Protocol
Drug Substance cediranib (AZD2171) plus olaparib (AZD2281)
Study Code D8488C00001
Edition Number 5.0
Date 15 Jan 2019
167(173)
10.  Did you need to rest?
1
2
3
4
11.  Have you had trouble sleeping?
1
2
3
4
12.  Have you felt weak?
1
2
3
4
13.  Have you lacked appetite?
1
2
3
4
14.  Have you felt nauseated?
1
2
3
4
15.  Have you vomited?
1
2
3
4
16.  Have you been constipated?
1
2
3
4
Please go on to the
next page
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ENGLISH
170(173)
Were you upset by the loss of your hair?
1
2
3
4
40.  Did food and drink taste different from usual?
1
2
3
4
41.  Have you had tingling hands or feet?
1
2
3
4
42.  Have you had numbness in your fingers or toes?
1
2
3
4
43.  Have you felt weak in your arms or legs?
1
2
3
4
44.  Did you have aches or pains in your muscles or joints?
1
2
3
4
45.  Did you have problems with hearing?
1
2
3
4
46.  Did you urinate frequently?
1
2
3
4
47.  Have you had skin problems (e.g. itchy, dry)?
1
2
3
4
48.  Did you have hot flushes?
1
2
3
4
49.  Did you have night sweats?
1
2
3
4
Please go on to next
page
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SAP_001.pdf: 
Statistical Analysis Plan 
Study Code D8488C00001
Edition Number 2.0
Date 20th September 2019
Statistical Analysis Plan
Study Code
D8488C00001
Edition Number
2.0
Date
20th September 2019
A single arm, open label, phase IIb study to assess the efficacy and safety of 
the combination of cediranib (30 mg orally daily) and olaparib (200 mg 
orally twice daily) tablets in women with recurrent platinum resistant 
epithelial ovarian cancer, including fallopian tube and/or primary 
peritoneal cancer who do not carry a deleterious or suspected deleterious 
germline BRCA mutation
62 of 118


Statistical Analysis Plan 
Study Code D8488C00001
Edition Number 2.0 
Date 20th September 2019
2(56)
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
TABLE OF CONTENTS .....................................................................................2
LIST OF ABBREVIATIONS...............................................................................5
AMENDMENT HISTORY..................................................................................8
1.
STUDY DETAILS...............................................................................................9
1.1
Study objectives...................................................................................................9
1.1.1
Primary objective .................................................................................................9
1.1.2
Secondary objectives............................................................................................9
1.1.3
Safety objective..................................................................................................10
1.1.4
Exploratory objectives........................................................................................10
1.2
Study design.......................................................................................................10
1.3
Number of patients.............................................................................................12
2.
ANALYSIS SETS..............................................................................................13
2.1
Definition of analysis sets ..................................................................................13
2.1.1
Full analysis set..................................................................................................13
2.1.2
Efficacy analysis set (evaluable for response population [EFR]).........................13
2.1.3
Safety analysis set ..............................................................................................14
2.2
Violations and deviations ...................................................................................14
3.
PRIMARY AND SECONDARY VARIABLES.................................................16
3.1
Derivation of RECIST visit responses ................................................................16
3.1.1
Target lesions (TLs) ...........................................................................................17
3.1.2
Non-Target Lesions (NTLs) and new lesions......................................................21
3.1.3
Overall visit response.........................................................................................23
3.2
Efficacy Variables..............................................................................................24
3.2.1
Primary Endpoint ...............................................................................................24
3.2.2
Secondary endpoints ..........................................................................................27
3.3
Safety and tolerability variables..........................................................................30
3.3.1
Exposure and dose interruptions.........................................................................30
3.3.2
Dose Intensity ....................................................................................................31
3.3.3
AEs....................................................................................................................31
3.3.4
Clinical chemistry, haematology and urinalysis..................................................33
3.3.4.1
Disease specific tumor marker samples (CA-125) ..............................................34
63 of 118


Statistical Analysis Plan 
Study Code D8488C00001
Edition Number 2.0 
Date 20th September 2019
3(56)
3.3.5
Physical examination, height and weight ............................................................35
3.3.6
ECG...................................................................................................................35
3.3.6.1
Resting 12-lead ECG..........................................................................................35
3.3.7
Vital signs..........................................................................................................35
3.3.7.1
Pulse and blood pressure ....................................................................................35
3.3.7.2
Body temperature...............................................................................................36
3.3.7.3
Serum or urine pregnancy test ............................................................................36
3.4
Patient reported outcomes ..................................................................................36
3.4.1
EORTC QLQ C30..............................................................................................38
3.4.2
OV-28................................................................................................................38
3.4.3
PRO CTCAE .....................................................................................................38
3.5
PK variables.......................................................................................................39
4.
ANALYSIS METHODS....................................................................................39
4.1
General principles ..............................................................................................39
4.1.1
Baseline .............................................................................................................40
4.1.2
Multiplicity adjustments.....................................................................................40
4.1.3
Visit windows ....................................................................................................40
4.2
Analysis methods...............................................................................................42
4.2.1
Patient disposition and data sets analysed...........................................................42
4.2.2
Protocol deviations.............................................................................................42
4.2.3
Demographic and other baseline characteristics..................................................42
4.2.4
Medical history ..................................................................................................43
4.2.5
Concomitant medications (prior, during, post treatment with IP) ........................43
4.2.5.1
Previous anti-cancer treatment modalities...........................................................44
4.2.5.2
Concomitant anti-cancer medications and radiotherapy......................................45
4.2.5.3
Post treatment anti-cancer medications and radiotherapy....................................45
4.2.6
Treatment exposure............................................................................................45
4.2.7
Efficacy..............................................................................................................46
4.2.7.1
Analysis of the primary efficacy variable ORR...................................................46
4.2.7.2
Analysis of the secondary efficacy variable(s)....................................................46
4.2.7.3
Sensitivity analysis.............................................................................................47
4.2.7.4
Subgroup analysis ..............................................................................................48
4.2.7.5
Exploratory endpoints ........................................................................................49
4.2.8
PROs..................................................................................................................49
4.2.8.1
PRO-CTCAE .....................................................................................................49
4.2.8.2
EORTC QLQ- C30 and EORTC QLQ- OV28....................................................49
4.2.9
Safety and tolerability ........................................................................................50
4.2.10
PK......................................................................................................................53
5.
INTERIM ANALYSES .....................................................................................54
6.
CHANGES OF ANALYSIS FROM PROTOCOL .............................................54
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7.
REFERENCES ..................................................................................................54
8.
APPENDIX........................................................................................................56
8.1
Appendix A........................................................................................................56
LIST OF TABLES
Table 1  
Response Rates and associated 95% CIs for a sample size of 60............13
Table 2
Analysis sets used for each endpoint......................................................14
Table 3
TL visit responses .................................................................................17
Table 4
NTL Visit Responses.............................................................................22
Table 5
Overall visit responses...........................................................................23
Table 6
Confirmed ORR and BoR criteria..........................................................26
Table 7
Laboratory safety variables....................................................................34
Table 8
PRO Schedule .......................................................................................36
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LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine Transaminase
AML
Acute myeloid leukaemia
ANC
Absolute Neutrophil Count
AST
Aspartate Transaminase
ATC
Anatomic-Therapeutic-Chemical 
BDRM
Blinded Data Review Meeting
BoR
Best Objective Response
CI
Confidence Interval
CLIA
Clinical Laboratory Improvement Amendments
CR
Complete Response
CRF
Case Report Form
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events 
DBL
Database Lock
DCO
Data Cut-off 
DCR
Disease Control Rate
DoR
Duration of Response
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EFR
Evaluable For Response
EORTC-QLQ
European Organisation for Research and Treatment of Cancer – Quality of 
Life Questionnaire 
FAS
Full Analysis Set
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Abbreviation or 
special term
Explanation
FFPE
Formalin Fixed, Paraffin Embedded
GCIG
Gynaecologic Cancer InterGroup 
HLT
High Level Term
HRD
Homologous Recombination Deficiency
HRQoL
Health-Related Quality of Life
HRR
Homologous Recombination Repair
ICR
Independent Central Review
IP
Investigation Product
IVRS
Interactive Voice Response System
KM
Kaplan-Meier
LD
Longest Diameters
LFT
Liver Function Test 
LVEF
Left Ventricular Ejection Fraction
MCV
Mean Cell Volume
MDS
Myelodysplastic Syndrome
MedDRA
Medical Dictionary for Regulatory Activities 
MRI
Magnetic Resonance Imaging
NA
Not Applicable
NE
Not Evaluable
NTL
Non-Target Lesion
OAE
Other significant Adverse Events
ORR
Objective Response Rate
OS
Overall Survival
PD
Progressive Disease
PFS
Progression Free Survival
PK
Pharmacokinetic
PR
Partial Response
PRES
Posterior Reversible Encephalopathy Syndrome 
PRO-CTCAE
Patient Reported Outcomes – Common Terminology Criteria for Adverse 
Events
PT
Preferred Term
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Abbreviation or 
special term
Explanation
QoL
Quality Of Life
RDI
Relative Dose Intensity
REACT
Real-time Analytics for Clinical Trials
RECIST
Response Evaluation Criteria in Solid Tumours
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease
SOC
System Organ Class
TBL
Total Bilirubin
TDT
Time to Discontinuation or Death
TL
Target Lesion
ULN
Upper Limit of Normal
VEGF
Vascular Endothelial Growth Factor 
WBC
White Blood Cells 
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AMENDMENT HISTORY
Date
Brief description of change
19th September 
2019
Amended signature pages with latest details of study statistician and global 
product statistician.
Updated subject to patient in SAP for consistency.
Removed reference to PK analysis set population as no PK will be analysed for 
study CSR.
Updated sample size and OS analysis per latest Protocol Amendment version 5.
Added clarity to last date calculation for OS analysis in section 3.2.2.
Clarified that OAEs are different to AESIs in section 3.3.3.
Amended disposition section 4.2.1 for clarification of enrolment.
Added platinum sensitivity and HRR/BRCA information to section 4.2.3.
Added PRO-CTCAE analysis to section 4.2.8.
Removed post treatment AE analysis from section 4.2.9.
Added AEs leading to dose interruption/modification/reduction to section 4.2.9.
Changes from protocol section updated as new protocol amendment means that the 
changes mentioned are now present in version 5 which this SAP is based off.
Replaced references to randomisation with start of treatment
9th September 2016
New document
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1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objective
To determine the efficacy of the combination of cediranib and olaparib in patients with recurrent 
platinum resistant epithelial ovarian, fallopian tube and/or primary peritoneal cancer who do not 
carry deleterious or suspected deleterious germline BRCA mutations, as assessed by Objective 
Response Rate (ORR) by independent central review (ICR), using RECIST version 1.1.
1.1.2
Secondary objectives
To assess the efficacy of the combination of cediranib and olaparib in this patient population in 
terms of:
!
Objective Response Rate by Investigator assessment using RECIST 1.1 
!
Duration of Response (DoR) by ICR and investigator assessment using RECIST 1.1
!
Disease Control Rate (DCR) by ICR and investigator assessment using RECIST 1.1
!
Progression Free Survival (PFS) by ICR and investigator assessment using RECIST 1.1
!
Time to discontinuation or death (TDT)
!
Overall Survival (OS)
To assess the efficacy of the combination of cediranib and olaparib in subgroups of patients
o
carrying and not carrying a somatic deleterious or suspected deleterious variant in 
either of the BRCA genes (BRCA1 or BRCA2)
o
carrying or not carrying a deleterious or suspected deleterious variant in 
homologous recombination repair (HRR)-associated genes identified with current 
and potential future tumor based BRCA or HRR gene mutation assays
To evaluate disease related symptoms and health-related quality of life in patients treated with 
combination of cediranib and olaparib tablets when compared with baseline data in terms of:
!
European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire (QLQ) C30
!
EORTC QLQ OV-28
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1.1.3
Safety objective
To evaluate the safety and tolerability of the combination of cediranib and olaparib using 
Adverse Events (AEs), and treatment emergent changes in vital signs and laboratory parameters.
1.1.4
Exploratory objectives
To assess adverse events by patient self-reporting of specific Patient Reported Outcomes version 
of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) symptoms.
To assess exploratory biomarkers of potential homologous recombination deficiency (HRD), 
including genomic scarring, BRCA1 methylation, and other genes that might modify HRD.
To assess exploratory angiogenic biomarkers such as vascular endothelial growth factor 
(VEGF)-A, C, D; sVEGFR2, Tie2, Ang1, 2; leptin; interleukin 6 (IL6) and exploratory 
immunologic biomarkers.
To evaluate exploratory biomarkers of potential resistance/sensitivity to cediranib or olaparib.
To assess exploratory biomarkers of gene expression signature for 
angioimmune/angio/immune/metabolic categorization.
Data relating to exploratory biomarkers may be reported separately to the CSR.
1.2
Study design
This is an open label, Phase IIb, single arm, multi-center study to assess the efficacy and safety 
of the combination of cediranib and olaparib in platinum resistant relapsed high grade serous, 
high grade endometroid or clear cell ovarian, fallopian tube or primary peritoneal carcinoma who 
have received at least 3 prior lines of chemotherapy and who have no evidence of deleterious or 
suspected deleterious gBRCA mutation(s) as defined by a local test conducted in an appropriately 
accredited laboratory (e.g., Clinical Laboratory Improvement Amendments [CLIA]-certified) 
that includes comprehensive DNA sequencing and large rearrangement analysis of BRCA1 and 
BRCA2. All patients should have received prior antiangiogenic treatment e.g. bevacizumab, 
either in a first line or a recurrent setting. To be eligible to enter the study, all patients should 
have measurable disease (as assessed by the Investigator), defined as at least 1 lesion that can be 
accurately assessed at baseline by computed tomography (CT)/ magnetic resonance imaging 
(MRI) and is suitable for repeated assessment per RECIST 1.1. All patients will have RECIST 
1.1 tumor assessments at screening (within 28 days prior to the start of study treatment) and 
every 8 weeks (±1 week) after start of treatment until objective radiological disease progression 
or withdrawal of consent. Objective radiological response on treatment (complete response [CR] 
or PR) will need to be confirmed during next RECIST 1.1 visit assessment to ensure that 
identified responses are not result of measurement error.
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Patients will receive the combination of:
!
Cediranib tablets 30 mg oral once daily
!
Olaparib tablets 200 mg oral twice daily
Patients should continue to receive IPs until objective radiological disease progression, 
unacceptable toxicity or withdrawal of consent. 
The study originally planned to recruit 100 patients over approximately 12 months. Due to 
slower than projected recruitment, the study now plans to recruit approximately 60 patients. An 
interim futility analysis will be undertaken once the first 20 evaluable (by Investigator 
assessment) patients have received at least 1 dose of IP and have had opportunity to be followed 
for at least 4 months. If fewer than 4 radiological tumor responses are observed at this point, the 
trial may be considered futile and stop enrollment. Enrollment will continue whilst the futility 
analysis is being conducted.
The primary analysis of the study will be based on measurement of ORR in the evaluable for 
response (EFR) analysis set (CR+PR; confirmed responses only) by Independent Central review 
(ICR) using RECIST 1.1. The primary analysis will also report analyses of DoR and disease 
control rate (DCR) by ICR in the EFR analysis set. Other variables analyzed at the primary 
analysis (ORR, DoR, DCR based on investigator assessment; PFS [ICR and investigator 
assessment], time to discontinuation or death [TDT], OS, patient-reported outcome [PRO] 
variables and safety variables) will be summarized using the FAS. 
The data cut-off for the primary analysis will take place 8 months after the last patient has 
received their first dose of IP and is the final analysis for the study. This primary data cut-off will 
be followed by clinical database lock.
An analysis of OS will also occur using this data cut-off point.
Patients continuing to receive clinical benefit without meeting any discontinuation criteria
during the study, will complete a Final Protocol Visit (FPV) which will occur at their last 
scheduled visit prior to the primary data cut-off. Beyond the FPV, patients may continue to 
receive cediranib and/or olaparib if they are deriving clinical benefit in the opinion of the 
investigator, and not fulfilling any discontinuation criteria.
All patients will be required to provide an archival formalin fixed, paraffin embedded (FFPE) 
tumor sample from the primary or preferably recurrent cancer. If an archival tumor sample is not 
available, a tumor sample from a fresh biopsy is acceptable. Please note that a lesion that has 
been biopsied during screening cannot be selected as a target lesion for RECIST assessment. 
Tumor samples will be tested for tumor (i.e., somatic [non-germline] or non-germline) 
deleterious or suspected deleterious mutation in either of the BRCA genes (BRCA1 or BRCA2) 
and the following homologous recombination repair (HRR)-associated genes: ATM, BRIP1, 
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PALB2, RAD51C, BARD1, CDK12, CHEK1, CHEK2, FANCL, PPP2R2A, RAD51B, RAD51D, 
and RAD54L.
1.3
Number of patients
The study originally planned to recruit 100 patients over approximately 12 months. Due to 
slower than projected recruitment, the study now plans to recruit approximately 60 patients. The 
primary analysis scheduled at 8 months after the last patient received her first dose of IP 
(approximately 20 months after study start), allows all patients to have at least 4 RECIST follow-
up assessments. 
An interim futility analysis of ORR (confirmed and/or unconfirmed CRs and PRs based on 
investigator assessment) will take place after 20 patients have received at least 1 dose of IP and 
have had opportunity to be observed for at least 4 months. If less than 4 of the 20 have responded 
the study may be stopped for futility. If 4 or more patients have responded the study will 
continue to the final analysis. 
The study design was formulated within a Bayesian framework (Fisch et al 2015) based on dual 
criteria to show improvement over the expected response rate (RR) under current standard 
treatments (20% RR targeted as an improvement over <15% RR based on chemotherapy, Davis 
et al 2014) and to have a RR of a relevant size (approximately 30%, similar to the RR seen for 
bevacizumab plus chemotherapy in the AURELIA trial, Pujade-Lauraine et al 2014) defined as 
follows:
1. to have high confidence (>90%) that the true ORR is at least 20% or probability (ORR≥ 
20%) >0.9 and
2. an observed rate of 30/100 is seen at the final analysis.
The futility rule above (stop if number of responses is <4), was chosen so that the trial may stop 
if there is a low chance (<10% predictive probability) of 30 or more responses being observed at 
the final analysis. Computation of posterior and predictive probabilities used a neutral prior i.e. 
beta (1/3, 1/3) distribution (Kerman 2011), for the ORR. The predictive probability of observing 
a given number of responses at the end of the trial given the observed responses at the interim 
analysis is computed using a beta binomial distribution.
With 30 responders out of 100 at the final analysis we would be >99% confident that the ORR is 
greater or equal to 20% and 94.6% confident that the ORR is ≥23%. It is noted that the interim 
analysis is based on unconfirmed, investigator assessed RECIST data, whereas the final analysis 
will be based on ICR assessed data with responses confirmed at least 4 weeks after the initial 
response. Data from the OCEANS study indicated an approximate 1.5% reduction in response by 
ICR compared with investigator response (Aghajanian et al 2014). If only 26 patients out of 100 
were to meet the latter definition of response at the final analysis there would still be >90% 
confidence that the true rate was greater than or equal to 20%.
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Assuming median PFS of 6 months, 73% PFS events are expected at the primary analysis at 8 
months after the last patient receives her first dose of IP. 
The original analysis for OS at 12 months after last patient receives her first dose of IP would 
expect 59% deaths.
The study now plans to recruit approximately 60 patients and analysis of OS, originally
planned at 12 months after the last patient received her first dose of IP, will now occur at
8 months after the last patient received her first dose of IP. Based on the revised duration of
recruitment and assuming a median PFS of 6 months as originally planned and a median of
12 months for OS, 80% PFS events and 57% OS events are expected to occur at the time of
the analysis.
Table 1  
Response Rates and associated 95% CIs for a sample size of 60
Response (n)
Response (%)
95% CIs
5
8.3%
(1.3%,15.3%)
10
16.7%
(7.2%, 26.1%)
15
25.0%
(14.0%, 36.0%)
2.
ANALYSIS SETS
2.1
Definition of analysis sets
Table below details the analysis set for each type of endpoint.
2.1.1
Full analysis set
All patients who received at least one dose of either IP will be included in the full analysis set.
2.1.2
Efficacy analysis set (evaluable for response population [EFR])
The evaluable for response (EFR) analysis set will be all patients who have received at least one 
dose of treatment and have measurable disease at baseline according to the independent review 
of baseline imaging data.
The primary analysis of ORR, and analyses of DoR and DCR by ICR will be produced based on 
the EFR analysis set.  All other efficacy variables (ORR, DoR, DCR based on investigator 
assessment; PFS [ICR and investigator assessment], OS, TDT) and PRO variables will be 
summarized using the FAS.
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Demographic data will be summarized for the FAS and to support the primary analysis, also for 
the EFR set (if different).
2.1.3
Safety analysis set
This is the same set as the FAS; i.e. all patients who received at least one dose of either IP.
Table 2
Analysis sets used for each endpoint
Endpoint
Analysis set
Primary endpoint:
ORR by ICR (primary analysis)
Evaluable for response
-
ORR by ICR (sensitivity analysis)
Full analysis set
-
ORR by Investigator assessment (sensitivity analysis)
Full analysis set
Secondary endpoints:
DoR, DCR by ICR
Evaluable for response
PFS by ICR
Full analysis set
DoR, DCR, PFS by investigator assessment (sensitivity analyses)
Full analysis set
Time to discontinuation or death
Full analysis set
Overall survival
Full analysis set
Demography and disposition
Full analysis set
Evaluable for response (if different to FAS)
2.2
Violations and deviations
None of the deviations will lead to patients being excluded from the analysis sets described in 
Section 2. A per-protocol analysis excluding patients with significant protocol deviations is not 
planned; however, a ‘sensitivity analysis on the primary endpoint will be performed excluding 
patients with deviations that may affect the efficacy of the trial therapy if > 10% of patients:
!
did not have the intended disease or indication or
!
fulfil deviation 3 (as labelled in brackets below) .
The need for such a sensitivity analysis will be determined following review of the protocol 
deviations ahead of database lock.  
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Eligibility criteria deviations are deviations from the protocol inclusion and exclusion criteria. 
Post-entry deviations are deviations from the protocol that occurred after the patient was 
assigned to the study.
The following general categories will be considered important deviations and be listed and 
discussed in the CSR as appropriate for the study. If a sensitivity analysis is conducted then 
patients with these deviations will be excluded from the sensitivity analysis:
!
Patients who deviate from key entry criteria (inclusion criteria 2, 3, 4, 8, 9, and 
exclusion criteria 4 from the CSP section 3.1 and 3.2) (Deviation 1). 
!
Baseline RECIST scan > 28 days before date of first dose of study IP (Deviation 2).
!
No baseline RECIST 1.1 assessment on or before date of first dose of study IP 
(Deviation 3).
!
Received prohibited concomitant medications (including other anti-cancer agents) 
(Deviation 4). Please refer to the Clinical Study Protocol (CSP) section 7.7 for those 
medications that are detailed as being ‘excluded’ from permitted use during the study. 
This will be used as a guiding principle for the physician review of all medications 
prior to database lock.
The categorisation of these as important deviations is not automatic and will depend on duration 
and the perceived effect on efficacy.
In addition to the programmatic determination of the deviations above, monitoring notes or 
summaries will be reviewed to determine any important post entry deviations that are not 
identifiable via programming, and to check that those identified via programming are correctly 
classified. The final classification of deviations will be made at the blinded data review meeting 
(BDRM) prior to database lock or data cut-off. Decisions made at the BDRM will be 
documented and approved by AstraZeneca prior to analysis.
All important deviations related to the study inclusion or exclusion criteria and study conduct 
will be identified. 
Patients who were enrolled into the study but did not receive study treatment will be listed.
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3.
PRIMARY AND SECONDARY VARIABLES
The primary analysis of ORR (primary endpoint), DoR, PFS, and DCR (secondary endpoints) 
will be reported based on the Independent Central Review of radiological data. ORR will also be 
reported based on the Investigator assessment (secondary endpoint).
In addition, sensitivity analyses will be performed of DoR, PFS, and DCR using investigators 
assessments of RECIST. 
3.1
Derivation of RECIST visit responses
For all patients, the RECIST tumor response data will be used to determine each patient’s visit 
response according to RECIST version 1.1.  It will also be used to determine if and when a 
patient has progressed in accordance with RECIST and also their best objective response.  
Baseline radiological tumor assessments are to be performed no more than 28 days before the 
start of IPs and ideally as close as possible to the start of IPs.  Tumor assessments are then 
performed every 8 weeks following the first dose of IPs until disease progression. 
If an unscheduled assessment is performed, and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits. This schedule is 
to be followed in order to minimise any unintentional bias caused by some patients being 
assessed at a different frequency than other patients.
An ICR of all radiological imaging data will be carried out using RECIST version 1.1 and the 
overall visit response will be provided at each visit (i.e. the reviewers will provide the overall 
visit response according to RECIST 1.1 and no programmatic derivation of visit response is 
necessary). 
From the investigator’s review of the imaging scans, the RECIST tumor response data will be 
used to determine each patient’s visit response according to RECIST version 1.1. At each visit, 
patients will be programmatically assigned a RECIST 1.1 visit response of CR, PR, SD or PD 
depending on the status of their disease compared with baseline and previous assessments.  If a 
patient has had a tumor assessment which cannot be evaluated then the patient will be assigned a 
visit response of not evaluable (NE) (unless there is evidence of progression in which case the 
response will be assigned as PD).
Please refer to sections 3.1.1 and 3.1.2 for the definitions of CR, PR, SD and PD. 
RECIST outcomes (ie PFS, ORR etc.) will be calculated programmatically for both the ICR and 
site investigator data (see section 3.2). 
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3.1.1
Target lesions (TLs)
Measurable disease is defined as having at least one measurable lesion, not previously irradiated, 
which is ≥ 10 mm in the longest diameter (LD) (except lymph nodes which must have short axis 
≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is 
suitable for accurate repeated measurements. A patient can have a maximum of 5 measurable 
lesions recorded at baseline with a maximum of 2 lesions per organ (representative of all lesions 
involved suitable for accurate repeated measurement) and these are referred to as target lesions 
(TLs).  If more than one baseline scan is recorded then measurements from the one that is closest 
and prior to start of treatment will be used to define the baseline sum of TLs. 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.
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline.  
Measurements are not required for these lesions, but their status should be followed at 
subsequent visits.
Table 3
TL visit responses 
Visit Reponses
Description
Complete Response (CR)
Disappearance of all TLs.  Any pathological lymph nodes 
selected as TLs must have a reduction in short axis to 
<10mm.
Partial response (PR)
At least a 30% decrease in the sum of diameters of TLs, 
taking as reference the baseline sum of diameters as long 
as criteria for PD are not met.
Progressive disease (PD)
A ≥ 20% increase in the sum of diameters of TLs and an 
absolute increase of ≥5mm, taking as reference the 
smallest sum of diameters since treatment started 
including the baseline sum of diameters.
Stable disease (SD)
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD. Stable disease can 
only be declared at or after the first scheduled RECIST 
scan.
Not Evaluable (NE)
Only relevant in certain situations (i.e. if any of the target
lesions were not assessed or not evaluable or had a lesion
intervention at this visit; and scaling up could not be 
performed for lesions with interventions). Note: If the
sum of diameters meets the progressive disease criteria,
progressive disease overrides not evaluable as a target
lesion response
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Rounding of TL data
For calculation of PD and PR for TLs percentage changes from baseline and previous minimum 
should be rounded to 1 d.p. before assigning a TL response.  For example 19.95% should be 
rounded to 20.0% but 19.94% should be rounded to 19.9%  
Missing TL data 
For a visit to be evaluable then all TL measurements should be recorded.  However, a visit 
response of PD should still be assigned if any of the following occurred
!
A new lesion is recorded
!
A NTL visit response of PD is recorded
!
The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute 
increase of ≥5mm, from nadir even assuming the non-recorded TLs have disappeared
Note: the nadir can only be taken from assessments where all the TLs had a LD recorded. 
If there is at least one TL measurement missing and a visit response of PD cannot be assigned, 
the visit response is not evaluable (NE).
Lymph nodes
For lymph nodes, if the size reduces to < 10mm then these are considered non-pathological. 
However a size will still be given and this size should still be used to determine the TL visit 
response as normal.  In the special case where all lymph nodes are < 10mm and all other TLs are 
0mm then although the sum may be >0mm the calculation of TL response should be over-written 
as a CR. 
TL visit responses subsequent to CR
A CR can only be followed by CR, PD or NE.  If a CR has occurred then the following rules at 
the subsequent visits must be applied:
!
Step 1:  If all lesions meet the CR criteria (i.e. 0mm  or < 10mm for lymph nodes) then 
response will be set to CR irrespective of whether the criteria for PD of TL is also met i.e. 
if a lymph node LD increases by 20% but remains < 10mm. 
!
Step 2:  If some lesion measurements are missing but all other lesions meet the CR 
criteria (i.e. 0mm or < 10mm for lymph nodes) then response will be set to NE 
irrespective of whether, when referencing the sum of TL diameters, the criteria for PD are 
also met. 
!
Step 3:  If not all lesions meet the CR criteria and the sum of lesions meets the criteria for 
PD then response will be set to PD
!
Step 4:  If after steps 1 – 3 a response can still not be determined the response will be set 
to remain as CR
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TL too big to measure
If a TL becomes too big to measure this should be indicated in the database and a size (‘x’) 
above which it cannot be accurately measured should be recorded.  If using a value of x in the 
calculation of TL response would not give an overall visit response of PD, then this will be 
flagged and reviewed by the study team blinded to treatment assignment.  It is expected that a 
visit response of PD will remain in the vast majority of cases.  
TL too small to measure
If a TL becomes too small to measure a value of 5mm will be entered into the database and used 
in TL calculations, unless the radiologist has indicated and entered a smaller value that can be 
reliably measured.  If a TL response of PD results then this will be reviewed by the study team 
blinded to treatment assignment.
Irradiated lesions/lesion intervention
Previously irradiated lesions (i.e. lesion irradiated prior to entry into the study) should be 
recorded as NTLs and should not form part of the TL assessment.
Any TL (including lymph nodes), which has had intervention during the study (for example, 
irradiation / palliative surgery / embolisation), should be handled in the following way and once 
a lesion has had intervention then it should be treated as having intervention for the remainder of 
the study noting that an intervention will most likely shrink the size of tumors:
!
Step 1: the diameters of the TLs (including the lesions that have had intervention) will be 
summed and the calculation will be performed in the usual manner. If the visit response is 
PD this will remain as a valid response category. 
!
Step 2: If there was no evidence of progression after step 1, ignore the lesion diameter for 
those lesions with intervention and scale up as described below as long as there remain ∀
1/3 of the TLs with intervention.  If the scaling results in a visit response of PD then the 
patient would be assigned a TL response of PD.  
!
Step 3: If after both steps PD has not been assigned, then, if appropriate, a scaled sum of 
diameters will be calculated (as long as ∀1/3 of the TLs have interventions), and PR or 
SD then assigned as the visit response.  Patients with intervention are evaluable for CR as 
long as all non-intervened lesions are 0 (or <10mm for lymph nodes) and each lesion that 
has experienced intervention also has a value of 0 recorded. If scaling up is not 
appropriate due to too few lesions without intervention then the visit response will be set 
as NE.
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At subsequent visits the above steps will be repeated to determine the TL and overall visit 
response.  When calculating the previous minimum sum of TL diameters, lesions with 
intervention should not be used and the sum of diameters scaled up where appropriate (as per 
step 2 above).
If ≤ 1/3 of the TL measurements have interventions then the results will be scaled up based on 
the sizes at the nadir visit, to give an estimated sum of diameters and this will be used in 
calculations; this is equivalent to comparing the visit sum of diameters of the non-intervention 
lesions to the nadir sum of diameters excluding the lesions with interventions..
If > 1/3 of TL measurements have interventions then TL response will be NE, unless the sum of 
diameters of TL without intervention would result in PD (i.e. if using a value of 0 for non-
intervention lesions, the sum of diameters has still increased by 20% or more compared to nadir 
and the sum of TLs has increased by ≥5mm from nadir).  
Example of scaling
Lesion
Longest diameter at nadir visit
Longest diameter at follow-up visit
1
7.2
7.1
2
6.7
6.4
3
4.3
4.0
4
8.6
8.5
5
2.5
Intervention
Sum
29.3
26
Lesion 5 has had an intervention at the follow-up visit. 
The sum of lesions 1-4 at the follow-up is 26 cm.  The sum of the corresponding lesions at nadir 
visit is 26.8 cm.
Scale up as follows to give an estimated TL sum of 28.4cm:
CR will not be allowed as a TL response for visits where there are lesions with intervention. 
Only PR, SD or PD (or NE) could be assigned as the TL visit response in these cases. However, 
for visits with ∀1/3 lesion assessments with intervention, the scaled up sum of TLs diameters will 
be included when defining the nadir value for the assessment of progression.
cm
4.
28
3.
29
8.
26
26
#
∃
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Lesions that split in two
If a TL splits in two, then the LDs of the split lesions should be summed and reported as the LD 
for the lesion that split.
Lesions that merge
If two TLs merge, then the LD of the merged lesion should be recorded for one of the TL sizes 
and the other TL size should be recorded as 0cm.
Change in method of assessment of TLs
CT, MRI and clinical examination are the only methods of assessment that can be used within a 
trial, with CT and MRI being the preferred methods and clinical examination only used in special 
cases. If a change in method of assessment occurs between CT and MRI this will be considered 
acceptable and no adjustment within the programming is needed.  
If a change in method involves clinical examination (e.g. CT changes to clinical examination or 
vice versa), any affected lesions should be treated as missing.  
3.1.2
Non-Target Lesions (NTLs) and new lesions.
At each visit an overall assessment of the NTL response should be recorded by the investigator. 
This section provides the definitions of the criteria used to determine and record
overall response for NTL at the investigational site at each visit.
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NTL response will be derived based on the Investigator’s overall assessment of NTLs as follows:  
Table 4
NTL Visit Responses
Visit Responses
Description
Complete Response (CR)
Disappearance of all NTLs present at baseline with all 
lymph nodes non-pathological in size (<10 mm short 
axis).
Progressive Disease (PD)
Unequivocal progression of existing NTLs. Unequivocal 
progression may be due to an important progression in 
one lesion only or in several lesions. In all cases the 
progression MUST be clinically significant for the 
physician to consider changing (or stopping) therapy.
Non-CR/Non-PD
Persistence of one or more NTLs with no evidence of 
progression.
Not Evaluable (NE)
Only relevant when one or some of the NTLs were not 
assessed and, in the investigator's opinion, they are not 
able to provide an evaluable overall NTL assessment at 
this visit.
Note: For patients without TLs at baseline, this is relevant 
if any of the NTLs were not assessed at this visit and the 
progression criteria have not been met.
Not Applicable (NA)
Only relevant if there are no NTLs at baseline
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of SD or PR in
TLs, the overall tumor burden has increased sufficiently to merit a determination of disease 
progression. A modest ‘increase’ in the size of one or more NTLs is usually not sufficient to 
qualify for unequivocal progression status.
Details of any new lesions will also be recorded with the date of assessment. The presence of one 
or more new lesions is assessed as progression. 
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: i.e. not attributable to differences in scanning 
technique, change in imaging modality or findings thought to represent something other than 
tumor.
New lesions will be identified via a Yes/No tick box. The absence and presence of new lesions at 
each visit should be listed alongside the TL and NTL visit responses.
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A new lesion indicates progression so the overall visit response will be PD irrespective of the TL 
and NTL response.
If the question ‘Any new lesions since baseline’ has not been answered with Yes or No and the 
new lesion details are blank this is not evidence that no new lesions are present, but should not 
overtly affect the derivation.   
Symptomatic progression is not a descriptor for progression of NTLs: it is a reason for stopping 
study therapy and will not be included in any assessment of NTLs.
Patients with ‘symptomatic progression’ requiring discontinuation of treatment without
objective evidence of disease progression at that time should continue to undergo tumor
assessments where possible until objective disease progression is observed.
3.1.3
Overall visit response
Table 5 defines how the previously defined TL and NTL visit responses will be combined with 
new lesion information to give an overall visit response for investigator assessments.
Table 5
Overall visit responses
TARGET
NON-TARGET
NEW LESIONS
OVERALL VISIT 
RESPONSE
CR
CR or NA
No (or NE)
CR
CR
Non-CR/Non-PD or NE
No (or NE)
PR
PR
Non-PD or NE or NA
No (or NE)
PR
SD
Non-PD or NE or NA
No (or NE)
SD
PD
Any
Any
PD
Any
PD
Any
PD
Any
Any
Yes
PD
NE
Non-PD or NE or NA
No (or NE)
NE
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3.2
Efficacy Variables
The endpoints (ORR, DoR, DCR, PFS) will be derived from the overall visit response date and 
the scan dates. RECIST assessments/scans contributing towards a particular visit may be 
performed on different dates and the date of progression will be determined based on the earliest 
of the scan dates of the component that triggered the progression.
Independent Central Review of RECIST based assessments
The ICR of all radiological imaging data will be carried out using RECIST version 1.1. All 
radiological scans for all patients (including those at unscheduled visits, or outside visit 
windows) will be provided to the ICR.  Prior radiotherapy reports for patients (at baseline) and 
information on any lesions that were biopsied to provide a tumor sample for study entry will also 
be provided to allow the selection of appropriate target lesions.  The imaging scans will be 
reviewed by two independent radiologists using RECIST 1.1 criteria and will be adjudicated if 
required.  For each patient, the ICR will define the overall visit response data (CR, PR, SD, PD 
or NE) and the relevant scan dates for each time point (i.e. for visits where response or 
progression is/is not identified).  If a patient has had a tumor assessment which cannot be 
evaluated then the patient will be assigned a visit response of not evaluable (NE) (unless there is 
evidence of progression in which case the response will be assigned as PD).  
Results of this independent review will not be communicated to Investigators and the 
management of patients will be based solely upon the results of the RECIST 1.1 assessment 
conducted by the Investigator.
Further details of the ICR will be documented in the Independent Review Charter.
Investigator RECIST based assessments
From the investigators review of the imagining scans, the RECIST tumor response data will be 
used to determine each patient’s visit response according to RECIST version 1.1.  At each visit, 
patients will be programmatically assigned a RECIST 1.1 visit response of CR, PR, SD or PD 
depending on the status of their disease compared with baseline and previous assessments.  If a 
patient has had a tumor assessment which cannot be evaluated then the patient will be assigned a 
visit response of not evaluable (NE) (unless there is evidence of progression in which case the 
response will be assigned as PD). 
3.2.1
Primary Endpoint 
The primary efficacy endpoint variable is Objective Response Rate (ORR), defined as the 
percentage of patients with objective response according to RECIST 1.1 by ICR using the 
evaluable for response analysis set (all patients who have received at least 1 dose of IPs and have 
measurable disease at baseline according to ICR). 
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The secondary endpoint variable of ORR using the investigators assessment of RECIST and 
based on the full analysis set will also be analysed.
An additional sensitivity analysis of ORR will be performed using the ICR data summarized 
using the full analysis set.
ORR will only include patients whose response has been confirmed by a second scan at least 4 
weeks after the initial response. A confirmed response of CR/PR means that a response of 
CR/PR is recorded at 1 visit and confirmed by repeat imaging not less than 4 weeks after the visit 
when the response was first observed with no evidence of progression between the initial and 
CR/PR confirmation visit.  Data obtained up until progression, or last evaluable assessment in 
the absence of progression, will be included in the assessment of ORR.  Patients who receive a 
subsequent anti-cancer therapy (note that for this analysis radiotherapy is not considered a 
subsequent anti-cancer therapy) and then respond will not be included as responders in the ORR 
(i.e. both visits contributing to a response must be prior to subsequent therapy for the patient to 
be considered as a responder).
In the case where a patient has two non-consecutive visit responses of PR, then, as long as the 
time between the 2 visits of PR is greater than 4 weeks and there is no PD between the PR visits, 
the patient will be defined as a responder.  Similarly, if a patient has visit responses of CR, NE, 
CR, then, as long as the time between the 2 visits of CR is greater than 4 weeks, then a best 
response of CR will be assigned.
Table 6 below outlines scenarios for the first and subsequent visit responses and the rules that 
will be followed to determine whether such patients would be counted in the numerator of ORR 
for the primary analysis and their classification for Best Objective Response (BOR) for the 
primary analysis. BOR is included as supportive data for the ORR endpoint.
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Table 6
Confirmed ORR and BoR criteria
First time point
Second time point
Confirmed Responder for ORR
Best objective response
CR
CR
Yes
CR
CR
PR
Scenario not possible, CR can only 
be followed by CR PD, NE
SD, PD or PRa
CR
SD
Scenario not possible, CR can only 
be followed by CR PD, NE
SD provided minimum criteria for 
SD duration met, otherwise, PD
CR
PD
No
SD provided minimum criteria for 
SD duration met, otherwise, PD
CR
NE
No
SD provided minimum criteria for 
SD duration met, otherwise NE
PR
CR
Yes
PR
PR
PR
Yes
PR
PR
SD
No
SD
PR
PD
No
SD provided minimum criteria for 
SD duration met, otherwise, PD
PR
NE
No
SD provided minimum criteria for 
SD duration met, otherwise NE
CR/PR
Second timepoint not 
reached at time of 
analysis
No*
SD provided minimum criteria for 
SD duration met, otherwise NE
CR/PR
Patient withdrew 
consent before second 
timepoint reached
No*
SD provided minimum criteria for 
SD duration met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = inevaluable. 
(Eisenhauer et al 2009).
* Note for the interim analysis, ORR will include both confirmed and unconfirmed responses, so patients in these 
scenarios would be counted as responders.  
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met (scan at least 7 weeks post-baseline). However, 
sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and in fact the 
patient had PR, not CR at the first time point. Under these circumstances, the original CR should be changed to PR and 
the best response is PR.
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3.2.2
Secondary endpoints
Duration of response (DoR)
DoR will be defined as the time from the date of first documented response (which is 
subsequently confirmed) until date of documented progression or death in the absence of disease 
progression (ie, date of PFS event or censoring – date of first response + 1).  The end of response 
should coincide with the date of progression or death from any cause used for the PFS endpoint.  
The time of the initial response will be defined as the latest of the dates contributing towards the 
first visit that was CR or PR that was subsequently confirmed.
If a patient does not progress following a response, then their DoR will use the PFS censoring 
time.
Disease control rate
Disease control rate is defined as the percentage of patients who have a best overall response of 
CR or PR or SD (at 6 months).  For SD to be counted, patients should have demonstrated SD for 
a minimum interval of 23 weeks (24 weeks minus 1 week to allow for an early assessment within 
the assessment window, ie, 161 days) following the start of treatment.
Progression free survival (PFS)
PFS is defined as the time from date of first dose until the date of objective disease progression 
or death (by any cause in the absence of progression) regardless of whether the patient withdraws 
from study therapy or receives another anti-cancer therapy prior to progression (i.e. date of PFS 
event or censoring – date of first dose + 1). Patients who have not progressed or died at the time 
of analysis will be censored at the time of the latest date of assessment from their last evaluable 
RECIST assessment. However, if the patient progresses or dies after two or more missed 
RECIST assessments visits, the patient will be censored at the time of the latest evaluable 
RECIST assessment prior to the two missed visits. 
If the patient has no evaluable visits or does not have baseline data they will be censored at Day 
1 unless they die within 2 visits of baseline (16 weeks plus 1 week allowing for a late assessment 
within the visit window).
The PFS time will always be derived based on scan/assessment dates not visit dates. RECIST 
assessments/scans contributing towards a particular visit may be performed on different dates. 
The following rules will be applied:
!
For ICR assessments, the date of progression will be determined based on the earliest
of the scan dates of the component that triggered the progression for the adjudicated 
reviewer selecting PD or of the reviewer who read baseline first if there is no 
adjudication for ICR data.
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!
For Investigator assessments, the date of progression will be determined based on the 
earliest of the dates of the component that triggered the progression.
!
For both ICR and investigator assessments, when censoring a patient for PFS the 
patient will be censored at the latest of the dates contributing to a particular overall 
visit assessment. 
Note: for TLs only the latest scan date is recorded out of all scans performed at that assessment 
for the TLs and similarly for NTLs only the latest scan date is recorded out of all scans 
performed at that assessment for the NTLs.
Overall visit assessments will be determined for each assessment (scheduled or unscheduled) and 
will contribute to the derivation of PFS.  Objective disease progression is defined as: at least a 
20% increase in the sum of the diameters of the target lesions (compared with a previous 
minimum sum) and an absolute increase of >5 mm, an overall assessment of progression or a 
new lesion.
Overall survival (OS)
Overall survival is defined as the time from the date of first dose until death due to any cause 
regardless of whether the patient withdraws from treatment or receives another anti-cancer 
therapy (i.e. date of death or censoring – date of first dose + 1).  Any patient not known to have 
died at the time of analysis will be censored based on the last recorded date on which the patient 
was known to be alive.
Survival calls will be made in the 2 weeks following the date of the data cut-off for the primary 
analysis, and if patients are confirmed to be alive (or if the death date is post the relevant data 
cut-off date) these patients will be censored in the associated analyses at the date of the data cut 
off. Data will be recorded on the SURVIVE module of the eCRF and this dataset will be used as 
priority for analysis.
For the OS analysis for the primary analysis at the 8 month DCO the Date last known alive on 
survival status CRF (SURVIVE: SUR_DAT) will be used.
If this date is missing the last date for each individual patient is defined as the latest among the 
following dates recorded on the case report forms (CRFs):
• AE start and stop dates (AE: AESTDAT, AEENDAT)
• Admission and discharge dates of hospitalization (SERAE: AESHODAT, AESDIDAT)
• Study treatment date (EX & EX1: EXSTDAT)
• End of treatment date (EX & EX1: EXENDAT)
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• Laboratory collection dates (LB & LB1-6: LBDAT)
• Date of vital signs (VS & VS1: VSDAT)
• Disease scan dates on RECIST CRF (1,3RECIST1: R1ASMDAT)
• Start and stop dates of alternative anticancer treatment (CAPRX1: CXSDAT, CXEDAT)
• Start and stop dates of post-IP radiotherapy (CAPRXR1: CXRDSDAT, CXRDEDAT)
• End of study date (DS: DSSTDAT)
• Visit date (VISIT: VIS_DAT)
The status of ongoing, withdrawn (from the study) and “lost to follow-up” patients at the time of 
the final OS analysis should be obtained by the site personnel by checking the patient’s notes, 
hospital records, contacting the patient’s general practitioner and checking publicly-available 
death registries. In the event that the patient has actively withdrawn consent to the processing of 
their personal data, the vital status of the patient can be obtained by site personnel from publicly-
available resources where it is possible to do so under applicable local laws.
Best objective response (BoR)
Best objective response (BoR) is calculated based on the overall visit responses from each 
RECIST assessment, described in section 3.1.3. It is the best response a patient has had 
following start of treatment, but prior to starting any subsequent cancer therapy and up to and 
including RECIST progression or the last evaluable assessment in the absence of RECIST 
progression. Categorisation of BoR will be based on RECIST using the following response 
categories: CR, PR, SD, PD and NE.
CR or PR must be confirmed. For determination of a best response of SD, the earliest of the 
dates contributing towards a particular overall visit assessment will be used.  SD should be 
recorded at least 8 weeks minus 1 week, i.e. at least 49 days (to allow for an early assessment 
within the assessment window), after start of treatment.  For CR/PR, the initial overall visit 
assessment which showed a response will use the latest of the dates contributing towards a 
particular overall visit assessment.
BoR will be determined programmatically based on RECIST from the overall visit response 
using all ICR data up until the first progression event.  It will also be determined 
programmatically based on RECIST using all site investigator data up until the first progression 
event.  The denominators for each case will be consistent with those used in the ORR analysis. 
For patients who die with no evaluable RECIST assessments, if the death occurs ≤ 9 weeks (i.e. 
8 weeks + 1 week to allow for a late assessment within the assessment window) after start of 
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treatment, then BoR will be assigned to the progression (PD) category.  For patients who die 
with no evaluable RECIST assessments, if the death occurs > 9 weeks after start of treatment
then BoR will be assigned to the NE category.
Time to discontinuation of IPs or death (TDT)
Time to discontinuation of IPs or death is defined as the time from the date of first dose of IP to 
the earlier of the date of discontinuation of both IPs, or death date.   Both IPs should be 
discontinued at the same time but in rare circumstances discontinuation of one of the IPs before 
the other may be allowed. In such a case, TDT will reflect the time from the date of first dose to 
the earliest IP discontinuation date. 
Any patient not known to have died at the time of analysis and not known to have discontinued 
study treatment will be censored based on the last recorded date on which the patient was known 
to be alive.
3.3
Safety and tolerability variables
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of “< x” (i.e., below the lower limit of quantification) or > x (i.e., above the upper limit of 
quantification) will be imputed as “x” in the calculation of summary statistics but displayed as “< 
x” or “> x” in the listings. Additionally, adverse events that have missing causality (after data 
querying) will be assumed to be related to study drug.
Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, vital signs 
including blood pressure and ECGs.  Refer to section 4.1 for general considerations for safety 
assessments. The safety analysis set will be used for all summaries.
3.3.1
Exposure and dose interruptions
Exposure will be defined as follows:
Total (or intended) exposure of study treatment
!
Total (or intended) exposure = min(last dose date where dose > 0mg, date of death, date 
of DCO) – first dose date + 1   
Actual exposure of study treatment
!
Actual exposure = intended exposure – total duration of dose interruptions, where 
intended exposure will be calculated as above and a dose interruption is defined as any 
length of time where the patient has not taken any of the planned daily dose.
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The actual exposure calculation makes no adjustment for any dose reductions that may have 
occurred. An interruption is defined to be any time a patient has not received study treatment for 
at least 1 day.
Missed or forgotten doses
Missed and forgotten doses should be recorded on the EX module as a dose interruption with the 
reason recorded as “Subject forgot to take dose”.  These missed or forgotten doses will not be 
included as dose interruptions in the summary tables.  However, these missed and forgotten 
doses will be considered in the derivation of actual exposure.
Patients who permanently discontinue during a dose interruption
If a patient permanently discontinues study treatment during a dose interruption, then the date of 
last administration of study medication recorded on DOSDISC will be used in the programming
Safety Follow-up
!
Total Safety Follow-up = min((last dose date + 30 days), date of withdrawal of 
consent, date of death, date of DCO) – first dose date +1
3.3.2
Dose Intensity 
Relative dose intensity (RDI) is the percentage of the actual dose delivered relative to the 
intended dose through to treatment discontinuation.  Relative dose intensity (RDI) will be 
defined as follows:
RDI = 100% * d/D, where d is the actual cumulative dose delivered up to the actual 
last day of dosing and D is the intended cumulative dose up to the or the actual last 
day of dosing. D is the total dose that would be delivered, if there were no 
modification to dose or schedule. 
Intensity of cediranib and olaparib will summarised separately. The intended cumulative dose is 
defined as 200mg olaparib twice daily and 30mg cediranib once daily. 
3.3.3
AEs
AEs and SAEs will be collected throughout the study, from date of first dose of either IP until 30 
days after the last dose of study medication. The Medical Dictionary for Regulatory Activities 
(MedDRA)(using the latest MedDRA version available at database lock) will be used to code the 
AEs. AEs will be graded according to the National Cancer Institute Common Terminology 
Criteria for AEs (CTCAE Version 4.03).
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If partial dates of onset occur, a conservative approach will be followed and events will be 
assumed to be treatment emergent unless there is convincing evidence to the contrary.
The following variables will be collected for each AE;
!
AE verbatim
!
The date when the AE started and stopped
!
Changes in CTCAE grade will be reported for AEs of diarrhoea, fatigue, hypertension 
and nausea. For all other AEs, only the highest attained CTCAE grade will be reported.
!
Whether the AE is serious or not
!
Investigator causality assessment against each of the IP(s) (yes or no)
!
Action taken with regard to each of the IP(s)
!
Outcome (if resolved with sequelae then sequelae should be recorded).
In addition, the following variables will also be collected for SAEs:
!
Date AE met criteria for SAE
!
Date Investigator became aware of SAE
!
AE seriousness criteria
!
If the patient was hospitalized:
!
Date of hospitalization
!
Date of discharge
The following variables will also be collected for deaths:
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to IPs and/or Study procedure(s).
Groups of preferred terms will be used to identify adverse events of special interests (AESIs); 
these preferred terms will be listed before database lock and documented in the Study Master 
File. The AESIs for cediranib will include PRES, arterial thromboembolic events, symptomatic 
left ventricular dysfunction and cardiac failure, nephrotic syndrome, renal thrombotic 
microangiopathy, liver failure, diarrhea, fatigue, hypertension and nausea. The AESIs for 
olaparib will include MDS/AML, new primary malignancy (other than MDS/AML) and 
pneumonitis.
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For the purposes of this study all AESIs identified above will be reported for both IPs.
Any AE occurring before the start of IP or more than 30 days after discontinuation of IPs will be 
included in the data listings but will not be included in the summary tables of AEs.
Any AE occurring within 30 days of discontinuation of IPs (i.e., the last dose of 
cediranib+olaparib) or the last dose of the last IP to be discontinued, in the rare case where 
discontinuation dates are different will be included in the AE summaries.  Any events in this 
period that occur after a patient has received further therapy for cancer (following 
discontinuation of cediranib+olaparib ) will be flagged in the data listings.
3.3.4
Clinical chemistry, haematology and urinalysis
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis will 
be taken at the following times:
!
Hematology and Biochemistry data will be taken during screening, at day 1, weekly till 
week 4, every 2 weeks till week 8, and every 4 weeks from week 8 onwards. If the study 
treatment is discontinued then a blood sample will be taken at this time and during the 
day 30 follow-up visit
!
A urine dipstick will be conducted during screening, at day 1, and every 4 weeks from 
week 8 onwards. If the study treatment is discontinued then a blood sample will be taken 
at this time and during the day 30 follow-up visit
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection and results (values, units and reference ranges) will be 
recorded on the appropriate eCRF.
The clinical chemistry, hematology and urinalysis will be performed at a local laboratory at or 
near to the Investigator site.  Sample tubes and sample sizes may vary depending on laboratory 
method used and routine practice at the site.
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The following laboratory variables will be measured:
Table 7
Laboratory safety variables
Clinical chemistry
(Serum/Plasma)
Haematology
(Blood)
Urinalysis
(Urine)
Albumin
Hemoglobin
Protein
Alanine Transaminase (ALT)
Platelet counts
Aspartate Transaminase (AST)
Mean Cell Volume (MCV)
Alkaline Phosphatase (ALP)
White Blood Cell count (WBC)
Bilirubin, total
Absolute Neutrophil Count 
(ANC)
Calcium
Absolute Lymphocyte Count
Creatinine
Magnesium
Potassium
Sodium
All values will be classified as low (below range), normal (within range) and high (above range) 
based on project-specific reference ranges (Appendix A). Patient with urine protein ≥3.5 g/24 
hours (CTCAE Grade 3 according to CTCAE v4) or urinary protein/creatinine ratio of >3.5 
should be considered as nephrotic-range proteinuria.
Changes from baseline to each visit for all patients who have a baseline laboratory test and the 
corresponding post-baseline laboratory test will be calculated as the post-baseline test value 
minus the baseline test value, where baseline is the latest non-missing value collected prior to the 
first dose of study drug
3.3.4.1
Disease specific tumor marker samples (CA-125)
As part of the routine blood samples, all patients will have CA-125 assessment at screening, 
every 8 weeks on treatment, and at study discontinuation.  
A rise in CA-125 alone is not sufficient to declare progression, and discontinue IPs; progression 
events should be determined by radiographic evidence of progression.
Retrospectively based on the data, CA-125 progression will be defined based on the 
Gynaecological Cancer Intergroup (GCIG) criteria, which are well-established and followed in 
clinical practice (Rustin et al 2011).
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A patient is considered to have CA125 progression if any of the following are met:
1.
Patients with elevated CA125 pre-treatment and normalisation of CA125 must show 
evidence of CA125 ≥2 × upper limit of normal (ULN) on 2 occasions at least 1 week 
apart or
2.
Patients with elevated CA125 before treatment, which never normalises, must show 
evidence of CA125 ≥2 × the nadir value on 2 occasions at least 1 week apart or
3.
Patients with CA125 in the reference range before treatment must show evidence of 
CA125 ≥2 × ULN on 2 occasions at least 1 week apart.
3.3.5
Physical examination, height and weight
A complete physical examination as per standard clinical practice should be performed by the 
Investigator at baseline and every 4 weeks.  If there are any clinically significant abnormal 
finding not related to disease progression, they should be recorded as an AE on the eCRF.  
Height will be assessed at screening only.  Weight will be assessed at baseline, at every 4 weeks 
until treatment discontinuation and the 30 day safety follow-up visit.
Change from baseline weight will be calculated.
3.3.6
ECG
3.3.6.1
Resting 12-lead ECG
ECGs are required within 7 days prior to starting IPs, and when clinically indicated thereafter.
All ECGs should be assessed by the investigator as to whether they are clinically significantly 
abnormal / not clinically significantly abnormal.  If there is a clinically significant abnormal 
finding at baseline, the Investigator should record this in the baseline eCRF.  If there is a 
treatment emergent significant abnormal finding, the Investigator will record it as an AE on the 
eCRF.  
3.3.7
Vital signs
Any clinically significant changes in vital signs (pulse rate, systolic and diastolic blood pressure, 
respiration rate, pulse oxygen saturation, and temperature) should be recorded as an AE. 
3.3.7.1
Pulse and blood pressure
Patient blood pressure will be measured during routine study visits: weekly during the first 
4 weeks, every 2 weeks during the next 4 weeks and every 4 weeks thereafter to ensure that 
blood pressure guidelines are being correctly followed.  
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3.3.7.2
Body temperature
Body temperature will be measured in degrees Celsius weekly during the first 4 weeks, every 2 
weeks during the next 4 weeks and every 4 weeks thereafter.
3.3.7.3
Serum or urine pregnancy test
Pregnancy tests on blood or urine samples will be performed for pre-menopausal women of 
childbearing potential, within 7 days prior to the start of IPs. Tests will be performed by the 
hospital’s local laboratory. If results are positive the patient is ineligible and must not be 
recruited into the study. In the event of a suspected pregnancy during the study, the test should 
be repeated.   A confirmed pregnancy must be recorded in eCRF and immediately reported; the 
patient will be discontinued from the IPs, but should continue in the study.
3.4
Patient reported outcomes
Patient reported outcomes will be assessed by EORTC-QLQ-C30, and EORTC-QLQ-OV28, 
according to the schedule listed in Table 8. They will also be assessed using PRO-CTCAE.
The PROs will be collected (using an electronic diary) according to the following schedule and 
assessments will be mapped into scheduled visits using a windowing rule similar to other 
endpoints collected by visit:
Table 8
PRO Schedule
PRO Tool
Week 1-12
Week 12 -
Progression
Post-progression until end of study
EORTC QLQ-C30
Day1, then every 8 
weeks
Every 8 weeks
Day 30 follow-up
EORTC QLQ-OV28
Day 1, then every 8 
weeks
Every 8 weeks
Day 30 follow-up
PRO-CTCAE
Day 1, then weekly
Every 4 weeks
Day 30 follow-up
An outcome variable consisting of a score from 0 to 100 will be derived for each of the symptom 
scales/ items, the functional scales and the global health status scale in the QLQ-C30 and for 
each of the symptom scales/items in the QLQ OV28 according to the EORTC QLQ-C30 Scoring 
Manual and EORTC QLQ OV28 instructions.  Higher scores on the global health status and 
functional scales indicate better health status/function.  Higher scores on the symptom scales 
indicate greater symptom burden.
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The following endpoints will be used to assess the HRQoL:
!
Absolute scores and change from baseline of all subscales
!
Proportions of patients with a best observed change of improved, stayed the same or 
deteriorated for all subscales (symptom and functioning scales).  A minimum 
clinically meaningful change is defined as a 10 point change in score from baseline.
!
Best observed change of improvement will be defined as the number (%) of patients 
with two assessments at least 18 days apart (i.e. 21 days allowing a visit window of 3 
days) which showed a clinically meaningful improvement (a decrease from baseline 
score ≥10) in that symptom from baseline.
!
Symptom improvement rate at 8 weeks for dyspnea, pain and constipation from QLQ-
C30 and abdominal/GI symptoms from QLQ-OV28.
Summary measures of overall compliance and compliance over time will be derived for the 
EORTC-QLQ-C30 and OV28 respectively. These will be based upon:
!
Received questionnaire = a questionnaire that has been received and has a completion 
date and at least one individual item completed.
!
Expected questionnaire = a questionnaire that is expected to be completed at a scheduled 
assessment time e.g. a questionnaire from a patient who has not withdrawn from the 
study at the scheduled assessment time but excluding patients in countries with no 
available translation. For patients that have progressed, the latest of progression and 
safety follow-up will be used to assess whether the patient is still under HRQoL follow-
up at the specified assessment time. Date of study discontinuation will be mapped to the 
nearest visit date to define the number of expected forms.
!
Evaluable questionnaire = a questionnaire with a completion date and at least one 
subscale that is non-missing.
!
Overall PRO compliance rate is defined as: Total number of evaluable questionnaires 
across all time points, divided by total number of questionnaires expected to be received 
across all time points multiplied by 100.
!
Overall patient compliance rate is defined as: Total number of patients with an evaluable 
baseline and at least one evaluable follow-up questionnaire (as defined above), divided 
by the total number of patients expected to have completed at least a baseline 
questionnaire multiplied by 100.
Compliance over time will be calculated separately for each visit, including baseline, as the 
number of patients with an evaluable questionnaire at the time point (as defined above), divided 
by number of patients still expected to complete questionnaires. Similarly the evaluability rate 
over time will be calculated separately for each visit, including baseline, as the number of 
evaluable questionnaires (per definition above), divided by the number of received 
questionnaires.
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3.4.1
EORTC QLQ C30 
The EORTC QLQ-C30 questionnaire was developed to assess HRQoL and is a commonly used 
cancer-specific HRQoL tool.  The EORTC QLQ-C30 comprises 30 questions designed for all 
cancer types.  Questions can be grouped into the following scales:
!
5 multi-item functional scales (physical, role, emotional, cognitive and social) 
!
3 multi-item symptom scales (fatigue, pain, nausea vomiting) 
!
A 2-item global HRQoL scale 
!
5 single items assessing the following common cancer symptoms: dyspnea, loss of 
appetite, insomnia, constipation, and diarrhea 
!
1 item on the financial impact of the disease
3.4.2
OV-28
The EORTC QLQ-OV28 is a module which is specific for ovarian cancer.  It consists of 
28 items assessing the following:
!
6 items on abdominal/GI symptoms
!
2 items on peripheral neuropathy
!
5 items on other chemotherapy side effects
!
2 items on hormonal symptoms
!
2 items on body image
!
3 items on attitudes to disease/treatment
!
4 items on sexuality 
!
And four other single items
3.4.3
PRO CTCAE
The PRO-CTCAE questionnaire will be used to derive patient reporting of selected CTCAE 
symptoms.
PRO-CTCAE is an item library of symptoms of the CTCAE experienced by patients while 
undergoing treatment of their cancer that has been converted to patient terms (i.e., CTCAE term 
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“myalgia” converted to “aching muscles”). The following 6 PRO-CTCAE AEs will be collected 
in the study: nausea, vomiting, diarrhoea, decreased appetite, fatigue, and dizziness.
3.5
PK variables
Blood samples for determination of cediranib and olaparib concentrations in plasma will be 
taken at week 4 and week 8.  Samples will be collected, labelled stored and shipped as detailed in 
the Laboratory Manual.
Samples for determination of cediranib and olaparib concentrations in plasma will be analyzed 
by Covance on behalf of AstraZeneca, using appropriate bioanalytical methods.
4.
ANALYSIS METHODS
An interim futility analysis of ORR (confirmed and/or unconfirmed complete responses [CR] 
and partial responses [PR]) will take place after 20 evaluable patients (i.e., with measurable 
disease [by Investigator assessment] at baseline and at least 1 dose of study drugs) have received 
first dose of IPs and had opportunity to be observed for at least 4 months. Assessment of 
measurable disease and of ORR will be based on investigator assessment.  The criterion for 
declaring futility is based on predictive probability within a Bayesian design framework as 
described in Section 1.3.  If less than 4 of the 20 patients have responded, the study may be 
stopped for futility.  If 4 or more patients have responded the study will continue to the final 
analysis. 
Evaluation of baseline data to determine measurable disease will also be performed by ICR to 
assess concordance with the investigator determined measurable disease status.   The 
concordance evaluation will be done for information and is not required in order to make the 
decision to stop or continue the study.
Assuming the study passes the futility assessment, the data cut-off for the primary (and final)  
analysis of ORR (confirmed CRs + PRs only, based on ICR assessed using the EFR analysis set) 
will take place 8 months after the last patient has received their first dose of IPs, to allow 
opportunity for all patients to complete at least 4 RECIST follow-up assessments and estimate 
duration of response (DoR). The primary analysis for the clinical study report (CSR) will be the 
confirmed ORR by ICR using RECIST 1.1 criteria and supported by Investigator assessment of 
ORR and by other efficacy endpoints (DoR, DCR, PFS, OS and TDT), PROs and safety and 
tolerability data. 
4.1
General principles
Descriptive statistics will be used for all variables, as appropriate.  Continuous variables will be 
summarized by the number of observations, mean, standard deviation, median, minimum, and 
maximum.  Categorical variables will be summarized by frequency counts and percentages for 
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each category.  Unless otherwise stated, percentages will be calculated out of the full analysis 
set.  A row or column denoted ‘Missing’ will be included in count tabulations where necessary to 
account for missing values
For continuous data the mean and median will be rounded to 1 additional decimal place 
compared to the original data. The standard deviation will be rounded to 2 additional decimal 
places compared to the original data. Minimum and maximum will be displayed with the same 
accuracy as the original data. For categorical data, percentages will be rounded to 1 decimal 
place.
4.1.1
Baseline
Baseline will be the last assessment of the variable under consideration prior to the intake of the 
first dose of investigational product. 
4.1.2
Multiplicity adjustments
No adjustments for multiplicity will be made.
4.1.3
Visit windows
The following conventions will apply: 
!
Listings should display all values contributing to a time point for a patient.
!
For summaries at a patient level, all values should be included, regardless of whether they 
appear in a corresponding visit based summary, when deriving a patient level statistic 
such as a maximum.
!
The time windows should be exhaustive so that data recorded at any timepoint has the 
potential to be summarised.   Inclusion within the time window should be based on the 
actual date and not the intended date of the visit.
!
All unscheduled visit data should have the potential to be included in the summaries.
!
The window for the visits following baseline will be constructed in such a way that the 
upper limit of the interval falls half way between the two visits (the lower limit of the 
first post-baseline visit will be Day 2). If an even number of days exists between two 
consecutive visits then the upper limit will be taken as the midpoint value minus 1 day.  
For example, the visit windows for CA-125 data (with 8 weeks between scheduled 
assessments) are:
-
Day 57, visit window 2 – 84
-
Day 113, visit window 85 – 140
-
Day 169, visit window 141 – 196, etc
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Data up to and including 30 days after last dose of either IP will be considered on 
treatment and presented by scheduled visit except for PRO data which will be reported 
as follow-up visit; thereafter data will be assigned to a post-treatment visit category.
!
For summaries showing the maximum or minimum values, the maximum/minimum 
value recorded will be used (regardless of where it falls in an interval). 
!
For visit based summaries
%
If there is more than one value per patient within a time window then the closest 
value to the scheduled visit date should be summarised, or the earlier, in the event 
the values are equidistant from the nominal visit date. .  Note: in summaries of 
extreme values all post baseline values collected are used including those 
collected at unscheduled visits regardless of whether or not the value is closest to 
the scheduled visit date  
%
To prevent very large tables or plots being produced that contain many cells with 
meaningless data, for each treatment group, visit data should only be summarised 
if the number of observations is greater than the minimum of 20 and  > 1/3 of 
patients dosed, 
!
Baseline will generally be the last value obtained prior to the first dose of study 
medication. Alternatively, if two visits are equally eligible to assess patient status at 
baseline (e.g., screening and baseline assessments both on the same date prior to first 
dose with no washout or other intervention in the screening period), the average can be 
taken as a baseline value.  For non-numeric laboratory tests (i.e. some of the urinalysis 
parameters) where taking an average is not possible then the best value would be taken 
as baseline as this is the most conservative.  In the scenario where there are two 
assessments on day 1, one with time recorded and the other without time recorded, the 
one with time recorded would be selected as baseline. Where data are summarised 
over time, study day will be calculated in relation to date of first treatment
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4.2
Analysis methods
4.2.1
Patient disposition and data sets analysed
Patient disposition will be listed and summarised and will include the number and percentage of 
patients:
!
Screened i.e. those patients who received an E-code.
!
Enrolled. i.e. those who were confirmed as eligible for the study and signed informed 
consent. 
!
Treated.
!
Patients ongoing study treatment at the data cut-off.
!
Included in each analysis set (full, evaluable for response, PK).
In addition, the number and percentage of patients discontinuing treatment and reasons for 
discontinuing will be presented.
4.2.2
Protocol deviations
All important protocol deviations will be listed and summarised for the full analysis set.  All 
important protocol deviations will be defined by the study team and identified before database 
lock.
4.2.3
Demographic and other baseline characteristics
Demographic and baseline patient characteristics will be summarised for the full analysis set. If 
the sizes of other analysis sets are different from the FAS then the demographic and baseline 
characteristics tables will be repeated for the relevant analysis sets. Standard descriptive statistics 
will be presented for the continuous variables of:
!
Age (years).
!
Weight (kg).
!
Height (cm).
!
Body mass index (kg/m2) [calculated as (weight/height2) where weight is in kg and height 
is in m].
The total counts and percentages of patients will be presented for the categorical variables of:
!
Age group (years) (grouped as <50, >=50-<65,≥= 65-<75, >=75).
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!
Race.
!
Ethnic group.
!
Stage of disease.
!
Germline BRCA status.
!
1st sensitivity to first platinum line calculated as <6, 6-<12, >=12 months from date of 
completing first-line platinum-based chemotherapy to date of progression
!
2nd sensitivity to the last platinum line calculated as <6, 6-<12, >=12 months from date 
of last receipt of platinum-based chemotherapy to date of progression 
!
Ascites at baseline.
!
Histology
!
ECOG performance status at baseline
!
gBRCA classification at study entry
!
suspected sBRCAm status
!
Patients carrying a tumor deleterious or suspected deleterious variant in homologous 
recombination repair (HRR) associated genes 
4.2.4
Medical history
Disease related medical history and relevant surgical history will be coded using MedDRA 
(version 17.0 or later).  The number and percentage of patients with any disease related medical 
history or relevant surgical history will be summarised for the full analysis set by system organ 
class (SOC) and preferred term (PT) for each cohort and overall.
4.2.5
Concomitant medications (prior, during, post treatment with IP) 
Medications received prior to, concomitantly, or post study IPs will be coded using the 
AstraZeneca Drug Dictionary Anatomical Therapeutic Chemical (ATC) Classification codes.
The period of study treatment is defined as the period in which a patient is receiving either of the 
IPs. Olaparib and cediranib should be initiated and stopped at the same time, however if this 
doesn’t occur then the date of the first and last dose of either IP will be used to define the period 
of study treatment. 
Prior medications, concomitant and post-treatment medications are defined as follows:
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!
Prior medications are those taken prior to screening with a stop date prior to the first dose 
of study treatment.
!
Concomitant medications are those with a stop date on or after the first dose date of study 
treatment (and could have started prior to or during treatment).
!
Post treatment medications are those with a start date after the last dose date of study 
treatment.
All medications other than anti-cancer medications will be collected until 30 days after the last 
dose of study treatment. Anti-cancer medications will be collected as part of survival follow-up 
until the end of the study.
A summary of disallowed medications taken by the patients during the study treatment will be 
produced.
4.2.5.1
Previous anti-cancer treatment modalities
All prior anti-cancer therapies will be summarised for the full analysis set. 
Treatments will be grouped by ATC code and summarised by line of therapy individually and
grouped (3, >=4). In addition a similar summary will be presented where treatments are grouped 
as platinum and non-platinum based.
The time from most recent disease progression until first dose of first IP will be summarised. 
Where partial dates are given and only day is missing, the last day of the month will be imputed, 
otherwise if month or year is missing then the entire date will be regarded as missing and not 
included in the summary.
In addition all prior anti-cancer therapies will also be summarised by the medically reviewed 
categories:
a.
Platinum containing regimen (excluding bevacizumab or PARPi containing)
b.
Platinum containing regimen with PARPi maintenance
c.
Platinum in combination with bevacizumab
d.
Other bevacizumab containing regimen 
e.
PARPi monotherapy regimen
f.
Any other PARPi containing regimen
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g.
Any other chemotherapy regimen (including immunotherapy; excluding platinum, 
bevacizumab, or PARPi containing)
h.
Hormonal agent
i.
Investigational agent
4.2.5.2
Concomitant anti-cancer medications and radiotherapy 
Concomitant anti-cancer medications during treatment are not allowed by the protocol. 
4.2.5.3
Post treatment anti-cancer medications and radiotherapy
All post treatment anti-cancer medications and surgical procedures will be summarised for the 
full analysis set. 
In addition all post treatment anti-cancer medications will be summarised by the medically 
reviewed categories in section 4.2.5.1.
4.2.6
Treatment exposure
Exposure to Cediranib, Olaparib, and the combination of Cediranib and Olaparib will each be 
summarised separately. Two criteria will be used to summarise and plot the combination of 
Cediranib and Olaparib:
1. The period of treatment will include the first date either IP was initiated till the last date 
either IP was discontinued. An interruption to both IPs will be considered an interruption 
for this summary.
2. The period of treatment will include the first date the combination was taken till the last 
date the combination was taken. An interruption to either IP will be considered an 
interruption for this summary.
An overall summary of total treatment duration and actual treatment duration will be presented. 
The Relative dose intensity (RDI) and cumulative exposure over time will also be included. 
A summary of duration of therapy at starting dose and each level of dose reduction will be 
created for each of cediranib and olaparib. 
The number of patients who ended on each possible dose combination will be summarised along 
with the number of patients who took each combination at least once.
Dose reductions will be summarised using a bar chart where each individual patient is 
represented by two bars, one for cediranib and one for olaparib. The bars represent the dose level 
over time, including any interruptions, and indicate whether a reduction has taken place. The plot 
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will also show whether a discontinuation or discontinuation due to death has occurred, and 
whether treatment was ongoing at data cut-off.
Treatment interruptions, dose reductions, and the duration of interruptions (any) will be 
summarised for both cediranib and olaparib. 
4.2.7
Efficacy 
Tables, figures and listings will be summarised according to the analysis sets for the relevant 
variable as detailed in Table .   
4.2.7.1
Analysis of the primary efficacy variable ORR
The primary analysis of ORR will be based on ICR assessments of tumor response using the 
EFR analysis set.  
The number of responders (confirmed CR or PR) will be modelled using a binomial distribution 
with a neutral Beta(1/3,1/3) prior distribution on the rate.
The mean and median of the posterior distribution of ORR will be presented, along with the 
standard deviation and a 95% credible interval around the mean (based on the highest posterior 
density [Lee, 1997]).  The observed ORR by ICR will also be presented with 95% exact (Clopper 
Pearson) confidence intervals.
The posterior probabilities of the ORR being larger than 15, 20 and 24% will be also computed.  
To further characterize the response rate, the posterior probability of showing unacceptable 
(<15%), low (>15-20%), moderate (>20-24%) or substantial (>24%) efficacy will be presented.
Summaries of the number of patients with best response in each of the follow categories will be 
presented: CR, PR, SD, PD and Non-Evaluable (NE).  The number of patients with an 
unconfirmed CR or PR will be presented as a sub-category of SD. For the interim analysis the 
CR (PR) category will be split into confirmed CR (PR) and unconfirmed CR (PR).
4.2.7.2
Analysis of the secondary efficacy variable(s)
DoR
Duration of response in responding patients will be summarized and the number (%) of 
responding patients with a duration of response >3; >6; >9; >12 months will be presented.  
A Kaplan Meier plot and median duration of response with 95% CI (calculated from the 
Kaplan-Meier plot) will be presented.  
Further plots showing the duration of response in responding patients will be presented as 
appropriate. For example, a plot showing a horizontal bar for each patient for the duration of 
response which are ordered from longest to shortest response. Any patients who are censored 
will have an arrow at the end of the bar to indicate response is on-going.
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The time to onset of response from first dose will also be summarised using the median 
calculated using the Kaplan-Meier method. The number and percentage of responding patients 
with an onset by 6, 12, 18 and 24 weeks will be summarised.
DCR
DCR will be presented together with 95% exact (Clopper Pearson) confidence intervals. 
PFS
The progression status at the time of the PFS analysis will be summarised, including the number 
and percentage of patients who progressed due to RECIST progression or due to death, those 
who did not progress due to being progression free or due to being lost to follow up, and those 
who have withdrawn consent. The number of patients censored on Day 1 will also be reported.
PFS will be displayed using a Kaplan Meier plot. The median time to event (calculated from the 
Kaplan-Meier plot), and the proportion of patients without an event at 3, 6, 12, and 18 months 
will be summarized. 
OS
A summary of the number and percentage of patients who have died, are still in survival follow-
up, are lost to follow-up and have withdrawn consent will be presented.
When there is sufficient data (>20 events), OS will be displayed using a Kaplan-Meier plot.  The 
number of events, median time to event (calculated from the Kaplan-Meier plot), and the 
proportion of patients without an event at 3, 6, 12 and 18 months will be summarized. 
Time to discontinuation of study treatment or death (TDT)
TDT will be displayed using a Kaplan-Meier plot.  The number of events, median time to event 
(calculated from the Kaplan-Meier plot), and the proportion of patients without an event at 3, 6, 
12, and 18 months will be summarized.
4.2.7.3
Sensitivity analysis
ORR, DCR, DoR and PFS will be re-analyzed at the time of the primary analysis using the 
investigator assessment of tumor response instead of ICR assessment, as sensitivity analyses.  
ORR and exact 95% CI (Clopper Pearson) will be presented for the following:
!
ORR by investigator assessment.  The numerator (number of confirmed responses) 
will be based on RECIST as per investigator assessment and the denominator will be 
based on the full analysis set
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!
ORR for both confirmed and unconfirmed responses based on ICR assessment.  The 
numerator will include unconfirmed responses in addition to confirmed responses and 
the denominator will be based on the EFR set.
Sensitivity analyses of PFS, DoR and DCR using the investigators assessment of RECIST will 
be performed in an analogous manner to those using the ICR described in Section 4.2.7.2 above.
In addition, ORR and BOR using the ICR will be summarised for the FAS.
For patients where measurable disease at baseline is not confirmed by the ICR and who 
therefore appear in the sensitivity analysis using FAS, but not the primary analysis set (evaluable 
for response), a detailed description of the reasons for being considered not evaluable will be 
described in the CSR. 
A further comparison of each type of overall objective response (CR, PR, SD, PD, NE or without 
measureable disease at baseline) between investigator and ICR will be presented using the full 
analysis set. Details for the patients identified as responders by ICR and not by the investigator, 
as well as by the investigator and not by ICR will be given.
The concordance between response as assessed by ICR and by investigator with the full analysis 
set will be summarised by cross-tabulation of the number and percentage of patients with:
!
Response declared by investigator and ICR
!
Response declared by investigator but not ICR
!
Response declared by ICR but not investigator
!
No response declared by both investigator and ICR
The overall concordance rate will be calculated as the total number of agreements between 
investigator and ICR divided by the total sample size. 
4.2.7.4
Subgroup analysis
The analyses of ORR, DCR, DoR, PFS at the time of the primary analyses and OS at the time of 
the final analysis will be repeated in the following subgroups of patients:
1. patients carrying a somatic deleterious or suspected deleterious variants in either of the 
BRCA genes (BRCA1 or BRCA2) identified with current and potential future tumor based 
BRCA mutation assays
2. patients who don’t carry a somatic deleterious or suspected deleterious variants in either 
of the BRCA genes (BRCA1 or BRCA2) identified with current and potential future tumor 
based BRCA mutation assays
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3. patients identified as having a deleterious or suspected deleterious variants in HRR-
associated genes identified with current and potential future HRR gene mutation assays
4. patients identified as not having a deleterious or suspected deleterious variants in HRR-
associated genes identified with current and potential future HRR gene mutation assays
5. Patients in either group 1 or 3, (if the number in group 1 or 3 separately is small [less than 
10]) 
6. Patients not in group 1 or 3 (if the number in group 1 or 3 separately is small [less than 
10])  
If a subgroup has <10 patients then the subgroup will not be analyzed and a listing including 
response status will be produced instead.
4.2.7.5
Exploratory endpoints
Biomarkers 
The following biomarkers may be analyzed using plots and descriptive summary statistics.
!
Biomarker of potential HRDs, including genomic scarring, BRCA1 methylation, and 
other genes that might modify HRD.
!
Biomarkers of gene expression signature for angioimmune/angio/immune/metabolic 
categorization
!
Angiogenic biomarkers such as VEGF-A, C, D; sVEGFR2, Tie2, Ang1, 2; leptin; IL6 
The exploratory biomarker analyses will be reported separately to the CSR.
4.2.8
PROs
Patients without a baseline PRO assessment will not be included in summaries of PRO 
endpoints.
4.2.8.1
PRO-CTCAE
Data from the PRO-CTCAE will be summarised for those patients with evaluable data. The 
number (%) of patients with each level of response for each PRO-CTCAE item at baseline and 
over time will be summarised. 
4.2.8.2
EORTC QLQ- C30 and EORTC QLQ- OV28
The EORTC-QLQ-C30 and EORTC-QLQ-OV28 questionnaires will be summarized.  
Descriptive statistics of absolute scores and change from baseline of all subscales will be 
presented and plots will be generated as appropriate to interpret changes over time.  
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Proportions of patients who had a best observed change of improved, stayed the same or 
deteriorated whilst on treatment (excluding follow-up) for all subscales (symptom and 
functioning scales) will be presented.  A 10 point change in score will be used as cut-off point.  
Improved will be defined as the number (%) of patients with two assessments at least 18 days 
apart (i.e. 21 days allowing a visit window of 3 days) which showed a clinically meaningful 
improvement (a decrease from baseline score ≥10) in that symptom from baseline.  The quantity 
and impact of missing data will be evaluated.  If warranted, some investigation of HRQoL data 
by whether patients are still taking study drug will be performed. 
Symptom Improvement Rate at 8 weeks
For dyspnea, pain and constipation from QLQ-C30 and abdominal/GI symptoms from QLQ-
OV28, the symptom improvement rate at 8 weeks (follow-up data will be excluded) will be 
defined as the number (%) of patients showing a clinically meaningful improvement (a decrease 
from baseline score >=10; Osoba et al 2005) in that symptom from baseline. The denominator 
will consist of a subset of the FAS population who have a baseline symptom score >=10. A 95% 
confidence interval for the symptom improvement rate will be constructed using the Clopper-
Pearson method.
4.2.9
Safety and tolerability
Safety and tolerability data will be presented using summaries and descriptive statistics.
The safety analysis set will be used for all safety and tolerability tables, figures and listings 
except where expressly noted.
For change from baseline summaries for vital signs, laboratory data, LVEF, the baseline value 
will be the latest result obtained prior to the start of investigational product.
The denominator used in laboratory summaries will only include evaluable patients, in other 
words those who had sufficient data to have the possibility of an abnormality. For example:
!
If a CTCAE criterion involves a change from baseline, evaluable patients would have 
both a pre-dose and at least 1 post-dose value recorded.
!
If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient need only have 1 post dose-value recorded.
The denominator in vital signs data should include only those patients with recorded data.
REACT
To enable continuing assessment of the safety profile of the cediranib and olaparib combination, 
and toxicity management for study patients, a data visualisation tool (e.g., REACT) will be used.
No efficacy data (RECIST response; progression status) will be included. The “CONCERTO 
principles for use of REACT” document will describe appropriate access to and use of the tool.
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AEs
All AE data will be listed individually by patient.  Any AE occurring before treatment with 
either IPs will be included in the data listings and flagged but will not be included in the 
summary tables of AEs.  
An overview table will summarise the number and percentage of patients with at least one of the 
following AEs where patients with more than one AE in a particular category are counted only 
once in that category:
!
Any AE
!
Any AE causally related to either IP, listed separately
!
Any AE of CTCAE grade 3 or higher
!
Any AE of CTCAE grade 3 or higher, causally related to either IP, listed separately
!
Any AE with outcome of death
!
Any AE with outcome = death, causally related to either IP, listed separately
!
Any SAE (including events with outcome=death)
!
Any SAE (including events with outcome=death), causally related to either IP, listed 
separately
!
Any SAE leading to discontinuation of either IP, listed separately Any AE leading to 
discontinuation of either IP, listed separately
!
Any AE leading to discontinuation of either IP, listed separately, causally related to either 
IP, listed separately
!
Any AE leading to dose interruption
!
Any AE leading to dose reduction
!
Any AE leading to dose modification (interruption and/or reduction)
!
Any other significant AE (if applicable)
The number and percentage patients reporting each AE will be summarised, by SOC (sorted 
alphabetically) and PT (sorted by descending overall total) The following summaries will be 
produced:
!
AEs by SOC and PT.
!
AEs by maximum reported CTCAE grade, by SOC and PT.
!
AEs of CTCAE grade 3 or higher, by SOC and PT.
!
AEs causally related by IP, by SOC and PT.
!
AEs leading to hospitalisation, by SOC and PT.
!
AEs leading to dose interruption, by SOC and PT.
!
AEs leading to dose reduction, by SOC and PT. 
!
AEs with outcome of death, by SOC and PT.
!
AEs with outcome of death, causally related by IP, by SOC and PT.
!
SAEs by SOC and PT.
!
SAEs causally related by IP, by SOC and PT.
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!
AEs leading to discontinuation of either IP (listed separately), by SOC and PT.
!
OAEs by SOC and PT (if applicable).
In the above summaries, patients with more than one AE within a particular SOC are counted 
only once for that SOC.  Similarly, patients with more than one AE within a particular PT are 
counted only once that PT.  For summaries by maximum reported CTCAE grade with multiple 
AEs within a particular SOC or PT will be counted under the category of their most severe AE 
within that SOC or PT.
A summary of deaths will be provided, detailing deaths due to disease only, deaths where AE 
outcome is death only or both.
AEs of special interest
The AESIs for Cediranib are as follows: PRES, arterial thromboembolic events, and the 
Important Potential Risks: symptomatic left ventricular dysfunction and cardiac failure; 
nephrotic syndrome; renal thrombotic microangiopathy, liver failure, and (per eCRF) diarrhea, 
fatigue, hypertension and nausea.  The AESIs for Olaparib are as follows: potential risks of 
MDS/AML, new primary malignancy (other than MDS/AML) and pneumonitis.
Grouped summary tables of certain MedDRA preferred terms will be produced and may also 
show the individual preferred terms which constitute each AESI grouping. Groupings will be 
based on preferred terms provided by the medical team prior to DBL, and a listing of the 
preferred terms in each grouping will be provided.
Summaries of the above-mentioned grouped AE categories will include number (%) of patients 
who have:
!
At least one AESI presented by outcome
!
At least one AESI causally related to either study medication separately 
!
At least one AESI leading to discontinuation of either study medication separately
A summary of total duration (days) of AESI will be provided for events which have an end date 
and this will be supported by summaries of ongoing AESIs at death and, separately, at data cut-
off.
To reflect the particular interest in diarrhoea, fatigue, hypertension, and nausea, life tables and 
prevalence plots will be produced for these AEs.
In addition as all CTCAE grade changes for diarrhoea, fatigue, hypertension, and nausea will be 
recorded, a plot will be generated for each AE which shows the AE grade over time for each 
patient.
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Laboratory evaluations
All laboratory data recorded in the eCRF will be listed.  If any additional analyses to those in 
Table 7 are also recorded then these will be listed only.  Out-of-reference range values will be 
flagged as high (H) or low (L) in the listings.
For clinical chemistry and haematology, numerical summaries will be generated which include 
the mean, standard deviation, median, minimum value, maximum value, and lower and upper 
quartiles at each visit in which laboratory values are taken. Plots of both the maximum post-
baseline ALT and AST versus the maximum post-baseline total bilirubin, expressed as multiples 
of their upper limit of reference range will be produced. 
As a primary interpretation of potential drug induced liver injury, outputs related to patients with 
liver function tests (LFTs) that meet biochemical criteria for Hy’s Law and with elevations of 
LFTs will be produced. Biochemical criteria for Hy’s Law are defined as any situation where a 
study patient has an increase in both AST or ALT ≥ 3×ULN and TBL ≥ 2×ULN, irrespective of 
ALP, at any point during the study. The elevations do not have to occur at the same time or 
within a specified time frame. 
For all patients who meet the criteria for potential Hy’s Law, a plot of AST, ALT, ALP and total 
bilirubin over time will be produced. 
The proportion of patients who met GCIG criteria for CA-125 progression (any of the criteria, 
and each criterion individually) will be summarised by visit. The time to CA-125 progression 
will be presented using a Kaplan Meier plot and the median time to CA-125 progression (from 
the Kaplan Meier) calculated. Patients without CA-125 progression will be censored at their 
latest lab evaluation visit.
Vital signs
Absolute values and change from baseline will summarised, overall and by visit. The minimum, 
maximum, and most recent measurement will also be listed. Plots of observed and changes in 
vital sign variables data may be generated to illustrate the data.
Physical examination
Abnormalities identified from physical examination will be captured as AEs.  
4.2.10
PK
PK data will be analysed and reported separately from the CSR, along with other studies as part 
of a pooled population PK analysis.
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5.
INTERIM ANALYSES
An interim futility analysis will take place after 20 evaluable (by Investigator assessment) 
patients are recruited and have had opportunity to be observed for at least 4 months, and datasets 
required are clean. The primary endpoint of the interim futility analysis will be the number of 
responders using the investigators assessment of RECIST 1.1. The study may be stopped for 
futility if there are less than 4 responders out of the first 20 patients in which case the predictive 
probability of observing 30 responders or more at the end of trial is ≤4.6%. 
A summary of the ORR will be presented for the interim population, along with a two-way table 
illustrating the concordance of the baseline scans between local assessment and ICR with respect 
to whether there was measurable disease at baseline. 
For the purposes of the interim analyses a responder is defined as a patient with measurable 
disease at baseline, with at least one confirmed or unconfirmed visit response of CR or PR.
No formal outputs beyond assessment of ORR, and concordance of the population with ICR, are 
planned to be generated at the interim analysis.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
CSP version 5 mentions “For dyspnea, pain and constipation from QLQ-C30 and abdominal/GI 
symptoms from QLQ-OV28, the symptom improvement rate at 8 weeks will be defined as the 
number (%) of patients showing a clinically meaningful improvement (a decrease from baseline 
score >10)”. This is an error and the decrease from baseline score should be >=10.
7.
REFERENCES
Fisch et al 2015. Bayesian Design of Proof-of-Concept Trials. Therapeutic Innovation
& Regulatory Science, 2015, Volume 49(1) 155-162
Kerman, J. Neutral noninformative and informative conjugate beta and gamma prior 
distributions. Electronic Journal of Statistics, 2011, Volume 5; 1450-1470.
Aghajanian C, Goff B, Nycum LR, Wang Y, Husain A, Blank S. Independent radiologic
review: bevacizumab in combination with gemcitabine and carboplatin in recurrent ovarian
cancer. Gynecol Oncol. 2014; 133(1):105-10.
Rustin, G, et al. Definitions for Response and Progression in Ovarian Cancer Clinical Trials 
Incorporating RECIST 1.1 and CA 125 Agreed by the Gynecological Cancer Intergroup (GCIG). 
International Journal of Gynecological Cancer, 2011; 21:419-423.
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Osoba D, Bezjak A, Brundage M, Zee B, Tu D, Pater J; Quality of Life Committee of the NCIC
CTG: Analysis and interpretation of health-related quality-of life data from clinical trials: Basic 
approach of The National Cancer Institute of Canada Clinical Trials Group. Eur J Cancer 2005; 
41:280-287
Eisenhauer, E. et al. New response evaluation criteria in solid tumours: revised RECIST 
guideline. European Journal of Cancer, 2009; 45(2):228-47
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8.
APPENDIX
8.1
Appendix A
AZ project-specific normal range for laboratory tests
Test
Gender
SI Unit
Lower Limit 
of Normal 
Range
Upper Limit 
of Normal 
Range
Albumin
M and F
g/L
32
56
Alkaline phosphatase
M and F
U/L
20
130
ALT
M and F
U/L
0
50
AST
M and F
U/L
0
45
CA125
M and F
U/mL
0
55
Calcium
M and F
mmol/L
2.2
2.6
Creatinine
M and F
umol/L
53
120
Magnesium
M and F
mmol/L
0.70
1.00
Phosphate
M and F
mmol/L
0.8
1.4
Potassium
M and F
mmol/L
3.5
5.0
Sodium
M and F
mmol/L
136
145
T4, free
M and F
pmol/L
10
30
Total Bilirubin
M and F
umol/L
2
21
Total Protein
M and F
g/L
60
80
TSH
M and F
mU/L
0.5
5.0
Urea
M and F
mmol/L
2.5
6.7
APTT
M and F
sec
25
35
Haemoglobin
M
g/L
135
180
Haemoglobin
F
g/L
120
160
Leucocytes
M and F
10**9/L
4.4
11.3
Neutrophils
M and F
10**9/L
1.8
7.8
Platelets
M and F
10**9/L
150
450
Prothrombin time
M and F
sec
10.5
14.5
Protein (24hr)
M and F
mg/24 h
0
199
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