Conditions: Ovarian, Fallopian Tube, Peritoneal Cancer, P53 Mutation
Keywords: Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 95
Healthy volunteers: no

Brief summary:
Adavosertib in combination with carboplatin, paclitaxel, gemcitabine, or PLD.

Detailed description:
This is an open-label, four-arm lead-in safety and efficacy study in which adavosertib will be combined in four separate treatment arms as follows: adavosertib plus gemcitabine (Arm A); adavosertib plus weekly paclitaxel (Arm B); adavosertib plus carboplatin (Arm C); and adavosertib plus PLD (Arm D). A subset of patients will be evaluated for the safety assessment of each treatment arm.

The adavosertib plus paclitaxel arm (Arm B) will enrol approximately 30 additional patients at selected sites as part of a further efficacy evaluation based on emerging data that suggests clinical activity.

In addition, the adavosertib plus carboplatin arm (Arm C) will enrol approximately 23 patients overall at selected sites as part of a further efficacy evaluation based on emerging data that suggests clinical activity.

To further optimise the dosing schedule of adavosertib in Arm C, a safety expansion arm (referred to as Arm C2) of approximately 12 additional patients will be enrolled at selected sites to explore emerging pre-clinical and clinical data that suggest that prolonged adavosertib exposure may increase the clinical activity.

Arms:
arm 1: Adavosertib (175 mg PO) will be taken on Days 1-2, 8-9, and 15-16. Gemcitabine 800 mg/m² will be administered IV on days 1, 8, and 15 of each 28 day cycle. arm 2: Five doses of adavosertib (225 mg PO BID) will be taken in approximate 12 hour intervals over 2.5 days weekly (Days 1-3, 8-10, and 15-17). Weekly paclitaxel 80 mg/m² IV will be administered according to institutional standards on Day 1, 8, and 15 of each 28 day cycle. arm 3: Arm C: Five doses of adavosertib (225 mg PO BID) will be taken in approximate 12 hour intervals over 2.5 days (Days 1-3). Carboplatin AUC 5 IV will be administered according to institutional standards on Day 1 of each 21-Day cycle.

Arm C2: Five doses of adavosertib (225 mg PO BID) 2.5 days per dosing week (QW), on Weeks 1 (D1-3), 2 (D8-10) and 3 (D15-17), or on Weeks 1 (D1-3) and 2 (D8-10) ( 2 weeks on followed by 1 week off.) Carboplatin AUC 5 IV will be administered according to institutional standards on Day 1 of each 21 day cycle. arm 4: Five doses of adavosertib (175 mg or 225 mg) will be taken in approximate 12 hour intervals over 2.5 days (Days 1, 2, and 3) of each 28-day cycle. PLD will administered IV on Day 1 of each cycle.

Interventions: intervention 1: Adavosertib intervention 2: Paclitaxel intervention 3: Carboplatin intervention 4: Gemcitabine intervention 5: PLD
Intervention descriptions: intervention 1: Adavosertib will be taken as oral capsules with water, approx. 2 hours before or 2 hours after food. intervention 2: Paclitaxel will be administered as a 1-hour IV infusion (± 10 minutes) at a dose of 80 mg/m2 according to institutional standards on Days 1, 8, and 15 of each 28 Day cycle.

Patients should be pre-medicated with corticosteroids, diphenhydramine and/or H2 antagonists according to institutional standards. intervention 3: Carboplatin, at a dose calculated to produce an AUC of 5 will be administered by intravenous infusion according to institutional standards on Day 1 of each 21 Day cycle. The carboplatin dose will be calculated using the Calvert Formula based on the patient's glomerular filtration rate (GFR) which is estimated by using the creatinine clearance. intervention 4: Gemcitabine 800 mg/m² will be administered IV on Days 1, 8, and 15 of each 28-Day cycle. intervention 5: PLD (pegylated liposomal doxorubicin) 40 mg/m² IV will be given on Day 1 of each 28-Day cycle.

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol 
Drug Substance
AZD1775
Study Code
D6010C00004
Version
10  
Date
05 September 2018
A Multicentre Phase II Study of AZD1775 plus Chemotherapy in 
Patients with Platinum-Resistant Epithelial Ovarian, Fallopian 
Tube, or Primary Peritoneal Cancer
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden.
EudraCT:  2015-000886-30


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VERSION HISTORY
Version 10.0, 05 September 2018 (Amendment 9)
Changes to the protocol are summarised below:
!
Specified that patients still receiving AZD1775 after the primary data cut-off will have 
a Final Protocol Visit (FPV) occurring at their next scheduled visit focused on 
capturing safety information. Following the FPV, patients may continue to receive 
treatment with AZD1775 ± chemotherapy as deemed appropriate by the Investigator 
(see Table 2, footnote ‘bb’, Table 3, footnote ‘cc’, and Section 4.4). The end-of-study 
treatment visit is not required for patients continuing treatment after the FPV.
!
Amended Section 5.6 to add clarification about optional tumour biopsies.
!
Clarified that blood samples and optional tumour biopsies for exploratory biomarker 
research will be collected at treatment discontinuation due to disease progression for 
subjects that continue taking AZD1775 ± chemotherapy after the FPV (see Section 
5.6).
!
Clarified how SAEs will be reported after the FPV (see Section 6.4.1 and Section 6.5).
!
Clarified that after the FPV pregnancies will be monitored while patients are on 
treatment and for 30 days after their final dose of AZD1775 ±chemotherapy (Section 
6.7).
!
Clarified that after the FPV, drug accountability information must continue to be 
collected until the patient discontinues treatment. In addition, patients must continue to 
be monitored for all SAEs, overdoses and pregnancies while receiving 
AZD1775 ± chemotherapy.  SAEs and pregnancy test results will be collected for
30 days following the patient’s last dose of AZD1775 ± chemotherapy (see Sections 4.4 
and 9.3).
!
Clarified that all safety data collected after the primary analysis and up to (and 
including) the last of the FPVs will be listed and/or summarised as appropriate (see 
Sections 8.6 and 9.3).
!
Other miscellaneous minor changes throughout (corrections to typos, formatting, etc.).
Version 9.0, 14 February 2018 (Amendment 8)
Changes to the protocol are summarised below:
!
Dose modification guidance for haematological events for patients receiving AZD1775 
plus chemotherapy has been updated in Section 6.9.1, Table 2, and Table 3.
!
Table 20, Table 21, and Table 22 have been replaced with the new Table 20 illustrating 
the new dose modification guidance.


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Version 8.0, 19 June 2017 (Amendment 7)
Changes to the protocol are summarised below:
!
Increased number of sites to reflect addition of 6 new sites to trial. 
!
Inclusion of allowable prior treatment regimens changed from 2 to 2-4.
!
Updated text in Synopsis and Section 1.2 about enrolling 23 patients overall to Arm C.
!
Deleted text in Synopsis about following patients 12 months after database lock.
!
Clarified inclusion and exclusion criteria.
!
Applicable sections of the protocol have been updated to reflect the current 
Investigator’s Brochure (IB), 11 January 2017.  Specifically: 
∀
updated the number of patients exposed to AZD1775 thus far 
∀
clarified language in the following sections: benefit/risk, non-haematologic toxicity 
dose modifications, diarrhoea, overdose 
∀
Addition of exclusion criteria: AZD1775 should not be given to patients who have 
a history of Torsades de pointes unless all risk factors that contributed to Torsades 
have been corrected.  AZD1775 has not been studied in patients with ventricular 
arrhythmias or recent myocardial infarction. 
!
Updated Objectives in Synopsis and Section 2 to include all chemotherapy regimens.
!
Updated tumour response section language; removed text regarding ‘Best Regimen’; 
updated CIs for PFS medians.
!
Schedule of collection of cfDNA modified in Tables 2 and 3 and Section 5.6 for Arms 
B and C (Arms A and D closed to enrollment).
!
In Appendix E, definition of ‘total/true abstinence’ has been expanded, in order to align 
with changes to UK protocol required by MHRA.
!
Changed abbreviated version of Sarah Cannon Development Innovations to 
‘Innovations’.
!
Other miscellaneous minor changes throughout (corrections to typos, formatting, etc.). 
Version 7.0, 20 January 2017 (Amendment 6)
Changes to the protocol are summarised below:
!
Due to emerging data, approximately 30 additional patients will be enroled in an 
expansion of Arm B (AZD1775 and paclitaxel).  Patients will be enroled through 
selected sites.
!
Approximately 12 additional patients will be treated within the expansion of AZD1775 
and carboplatin (Arm C2) at selected sites.


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Version 7.0, 20 January 2017 (Amendment 6)
!
Mandatory AZD1775 pharmacokinetic samples will be collected from patients in 
AZD1775 and paclitaxel efficacy expansion and the AZD1775 and carboplatin 
expansion (see Table 14).
!
In addition to the collections described in the study plan table(s), another cfDNA 
sample will be collected from patients on Cycle 2 Day 1 (see Section 5.6).
!
An optional pharmacogenetic sample will be collection from all patients (see Section 
5.5). 
!
Triplicate ECGs will be obtained as described at baseline/screening.  In addition, 
triplicate ECGs taken 2-5 minutes apart will be required prior to starting each new 
treatment cycle (see Section 5.2.3).
!
Applicable sections of the protocol have been updated to reflect the current Project 
Specific Safety Requirements (PSSR) 10 November 2016.  Specifically, exclusion of 
Seville grapefruit and juices, triplicate ECGs prior to beginning each study treatment 
cycle, and guidelines for retaking missed doses of AZD1775.
!
Approximately 97 patients will be enrolled in the safety and efficacy portions of the 
study at completion.
!
Patient must be ≥18 years of age to be included in the study.  This criterion was 
removed in error in the last protocol amendment.
!
In CSP Amendment 5, the Section 5.6.1 Plasma Pharmacogenetics was moved to 
Section 5.5.  Amendment 5 incorrectly stated the section was expanded when it was 
moved and the content was reduced. 
!
Clarifications for improved readability, references updated, and minor grammatical 
errors corrected.
Version 6.0, 17 August 2016 (Amendment 5)
Changes to the protocol are summarised below:
!
This Clinical Study Protocol (CSP) has been extensively modified as indicated in the 
redlined version, as the contents from the previous protocol have been placed into a 
new template.
!
Applicable sections of the protocol have been updated to reflect the current AZD1775 
Investigator Brochure (IB) information throughout [updated safety information based 
on cut-off of November 11, 2015; updated information on contraception use and sperm 
freezing; language on nausea and diarrhoea].
!
Section 5.5 has been expanded to describe the collection and use of data for 
pharmacogenetic research.
!
Additional areas have been updated to harmonise with the new template for 
consistency.


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Version 6.0, 17 August 2016 (Amendment 5)
!
Removed references to pegylated liposomal doxorubicin (PLD) expansion cohort of 
Arm D, which is not moving forward
!
Clarifications for improved readability, references updated, and minor grammatical 
errors corrected.
Version 5.0, 04 December 2015 (Amendment 4)
Primary reasons for amendment:
!
To stop enrolment into the following treatment arms: AZD1775 + paclitaxel and 
AZD1775 + gemcitabine, beyond the safety cohorts
!
To add an AZD1775 + Doxil treatment arm for evaluating safety and efficacy of this 
combination in advanced ovarian, fallopian tube, or primary peritoneal cancer patients
!
To update the study design by not performing the randomisation for enrolling patients 
in the treatment arms
!
TP53 mutations are so prevalent in the eligible patient population, that requiring proof 
of these mutations prior to enrolment is no longer necessary in the amended protocol.  
However, mutational analysis of tumour samples will be performed for all patients, in a 
retrospective manner.
!
The study objectives have been updated to align with the updated study design
!
Correction of minor consistency errors and clarifications for readability.
Version 4.0, 29 June 2015 (Amendment 3)
Amendment 3 changed the restrictions and the inclusion criteria for the study.  This 
amendment also identified corrections to the edition numbering to bring it back into 
alignment.
!
Clarified number of allowable prior treatment regimens, types of treatment and stage of 
disease; women of child bearing potential inclusion criteria updated
!
Included and clarified information presented in study plan
!
Clarified dosing instructions and harmonised them with other treatment schedules


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Version 3.0, 18 May 2015 (Amendment 2)
Amendment 2 provided additional clarification and guidance for this study, including:
!
Allowing patients in that had received prior adjuvant therapy
!
Reducing starting dose of gemcitabine from 1000 mg/m2 to 800 mg/m2
!
Adding windows for collection times
!
Providing better dose modification guidance, dose-limiting toxicity (DLT) clarification, 
tumour assessments clarification
Version 2.0, 06 October 2014 (Amendment 1)
Amendment 1 provided additional clarification and guidance for the conduct of this study.  
Additional dose-limiting criteria were included to part 1 of the study (grade 3 
thrombocytopenia with bleeding as a haematologic DLT), the AZD1775 dosing schedule 
was changed to be administered concurrently with chemotherapy, the 48-hour gap or delay 
in administering AZD1775 was removed, and visit windows were clarified in the Study 
Plan tables.
Version 1.0, 12 August 2014 (Original Clinical Study Protocol)
Initial approved protocol.
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol (CSP) has been subject to a peer review according to 
AstraZeneca Standard procedures.  The CSP is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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PROTOCOL SYNOPSIS
A Multicentre Phase II Study of AZD1775 plus Chemotherapy in 
Patients with Platinum-Resistant Epithelial Ovarian, Fallopian 
Tube, or Primary Peritoneal Cancer
Principal Investigator:
 
Study site(s) and number of subjects planned
Approximately 97 patients will be enrolled at 32 global investigational sites.
Study period
Phase of development
Estimated date of first subject enrolled
Q4 2014
2
Estimated date of last subject completed
Q4 2018
2
Study design
The aim of this study is to evaluate the safety and tolerability of AZD1775 when combined 
with either gemcitabine, paclitaxel, carboplatin, or PLD in patients with platinum resistant 
ovarian cancer. The research hypothesis for the AZD1775 drug development programme is 
that administration of AZD1775 combined with chemotherapy in women with platinum-
resistant ovarian, fallopian tube, or primary peritoneal carcinoma experience improved 
progression-free survival compared to women receiving chemotherapy alone.  This study is 
being conducted to understand the dose level, dosing schedule, safety, and tolerability of 
AZD1775 combined with chemotherapy agents such that they can be subsequently studied for 
improvement in efficacy.
This is an open-label, four-arm lead-in safety and efficacy study in which AZD1775 will be 
combined in four separate treatment arms as follows:  AZD1775 plus gemcitabine (Arm A); 
AZD1775 plus weekly paclitaxel (Arm B); AZD1775 plus carboplatin (Arm C); and 
PPD


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AZD1775 plus PLD (Arm D [See Figure 1]).  A subset of patients will be evaluated for the 
safety assessment of each treatment arm (see Section 7.2.3.1). 
The AZD1775 plus paclitaxel arm (Arm B) will enrol approximately 30 additional patients at 
selected sites as part of a further efficacy evaluation based on emerging data that suggests 
clinical activity.
The AZD1775 plus carboplatin arm (Arm C) will enrol approximately 23 patients overall at 
selected sites as part of a further efficacy evaluation based on emerging data that suggests 
clinical activity.
To further optimise the dosing schedule of AZD1775 in Arm C, a safety expansion arm 
(referred to as Arm C2) of approximately 12 additional patients will be enrolled at selected 
sites to receive carboplatin AUC 5 IV on Day 1 of a 21 day cycle in combination with 
AZD1775 BID for 2.5 days per dosing week (QW), on Weeks 1 (D1-3), 2 (D8-10) and 3 
(D15-17), or on Weeks 1 (D1-3) and 2 (D8-10) (2 weeks on followed by 1 week off).  These 
additional weeks of AZD1775 dosing are meant to explore emerging pre-clinical and clinical 
data that suggest that prolonged AZD1775 exposure may increase the clinical activity.  
Initially, 6 patients will be enrolled in a 3-weekly AZD1775 dosing cycle; if 1 patient or less 
experiences a DLT during Cycle 1, then an additional 6 patients will be enrolled for a total of 
12 patients.  However, if 2 or more of the first 6 patients experience a DLT then the AZD1775 
dosing may be modified to 2 weeks on followed by 1 week off.  All decisions which include 
but are not limited to cohort dosing, dose escalation or de-escalation will be reviewed by the 
Safety Review Team (SRT).
Modified PK assessments will be obtained to harmonise and accommodate the investigation 
of alternative dose levels and/or schedules.


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Objectives
Primary Objective:
Outcome Measure:
To evaluate the objective response rate (ORR) of 
AZD1775 in combination with gemcitabine, 
carboplatin, paclitaxel, or PLD in patients with 
platinum-resistant epithelial ovarian, fallopian tube, 
or primary peritoneal cancer 
The primary endpoint of this study is ORR for the arms 
included in the efficacy assessment, defined as the 
proportion of patients achieving a complete or partial 
tumour response according to Response Evaluation Criteria 
in Solid Tumours (RECIST) v1.1 (Eisenhauer et al 2009).
Secondary Objectives:
Outcome Measures:
To evaluate the duration of response (DoR) of 
AZD1775 in combination with gemcitabine, 
carboplatin, paclitaxel, or PLD
DoR, defined as the time from first documented tumour 
response until the date of documented progression or death 
from any cause.
To evaluate the safety and tolerability of AZD1775 
in combination with paclitaxel, gemcitabine, 
carboplatin or PLD in patients with platinum-
resistant epithelial ovarian, fallopian tube, or 
primary peritoneal cancer 
Treatment emergent adverse events (TEAEs), serious 
adverse events (SAEs), and deaths; clinically significant 
changes in safety-related laboratory parameters according 
to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE v4.03) and abnormal 
vital signs.
To evaluate the disease control rate (DCR) of 
AZD1775 in combination with carboplatin, 
paclitaxel, gemcitabine, or PLD in patients with 
platinum-resistant epithelial ovarian, fallopian tube, 
or primary peritoneal cancer  
DCR, defined as the proportion of patients achieving a 
complete response (CR), partial response (PR), or stable 
disease (SD) according to RECIST v1.1 criteria.
To evaluate the Cancer Antigen-125 (CA-125) 
response of AZD1775 in combination with 
carboplatin, paclitaxel, gemcitabine, or PLD in 
patients with platinum-resistant epithelial ovarian, 
fallopian tube, or primary peritoneal cancer.
Gynecologic Cancer Intergroup (GCIG) CA-125 response, 
defined as the proportion of patients achieving a 50% 
reduction in CA-125 levels from baseline, if baseline level 
is ≥2 x the upper limit of normal (ULN) within 2 weeks 
prior to starting treatment.  Response must be confirmed 
and maintained for at least 28 days.
To characterise the pharmacokinetics (PK) of 
AZD1775 plus carboplatin, AZD1775 plus 
paclitaxel, AZD1775 plus PLD, and AZD1775 plus 
gemcitabine
Plasma PK parameters of AZD1775 plus carboplatin, 
AZD1775 plus paclitaxel, AZD1775 plus gemcitabine, and 
AZD1775 plus PLD
To assess the drug interaction between AZD1775 
plus carboplatin, AZD1775 plus paclitaxel, 
AZD1775 plus gemcitabine, and AZD1775 plus 
PLD  
Plasma PK parameters of AZD1775 plus carboplatin, 
AZD1775 plus paclitaxel, AZD1775 plus gemcitabine, and 
AZD1775 plus PLD


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Exploratory Objectives:
Outcome Measures:
To identify genetic alterations in breast cancer 
genes 1 and 2 (BRCA1 and BRCA2) and other 
relevant genes, including TP53, from analysis of 
archived or fresh tumour tissue collected at 
baseline, and to determine if the presence of a 
genetic alteration is predictive of clinical outcomes. 
Molecular analysis of tumour tissue samples will be 
reviewed and correlated with clinical data.
To analyse changes in plasma circulating free 
tumour DNA (cfDNA) over time, from baseline, to 
restaging, and at disease progression.  (This 
exploratory analysis will be reported separately 
from the Clinical Study Report [CSR].) 
Blood samples will be collected to analyse cfDNA 
concentrations and molecular alterations.
To obtain preliminary estimates of the overall 
survival (OS) and progression-free survival (PFS) 
of AZD1775 in combination with gemcitabine, 
paclitaxel, carboplatin, or PLD.
OS, defined as the time from first dose to death from any 
cause, and progression-free survival (PFS), defined as the 
time from first dose to the first documentation of disease 
progression (according to RECIST v1.1 criteria) as 
determined by the Investigator or death from any cause, 
whichever comes first.
To collect and store deoxyribonucleic acid (DNA) 
for future research into genes/genetic variations that 
may influence PK or response to AZD1775 (i.e., 
absorption, distribution, metabolism, excretion, 
safety and efficacy) and/or susceptibility to the 
development of cancers.
Correlation of genetic polymorphisms with variation in 
PK, safety or response observed in subjects treated with 
AZD1775.
Data generated may be reported separately and may also 
form part of a pooled analysis with other AZD1775 
studies.
Target subject population
Target subject population consists of females aged 18 years or older with platinum-resistant, 
high-grade serous (HGS) epithelial ovarian, fallopian tube, or primary peritoneal cancer who 
progressed within 6 months of completing (but without progression during) at least 4 cycles of 
a first-line platinum-containing regimen for Stage III/IV disease, and had no more than 2-4
prior treatment regimens for Stage III/IV disease (investigational, chemotherapy, hormonal, 
biologic, or targeted therapy).  
Duration of treatment
Patients will be allowed to continue on therapy as long as they have no limiting toxicity or 
disease progression, have not withdrawn from the study, and are considered by the 
Investigator to still be receiving clinical benefit.  
Investigational product, dosage and mode of administration
AZD1775 is available as dry-filled capsules containing 25 or 100 mg of drug substance
AZD1775 will be provided by AstraZeneca.  Additional information about the investigational 
product (IP) may be found in the Investigator’s Brochure (IB).


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Commercially available gemcitabine 800 mg/m2 IV will be infused over approximately 
30 minutes or according to institutional standards.  Refer to the gemcitabine package insert for 
additional information.
Commercially available paclitaxel will be administered as a 1-hour IV infusion (± 10 
minutes) at a dose of 80 mg/m2 according to institutional standards.  Patients should be pre-
medicated with corticosteroids, diphenhydramine and/or H2 antagonists according to 
institutional standards (see Section 7.7).  Refer to the paclitaxel package insert for additional 
information.
Carboplatin, at a dose calculated to produce an area under the curve (AUC) of 5 mg/mL min, 
will be administered by IV infusion according to institutional standards.  The carboplatin dose 
will be calculated using the Calvert Formula based on the patient’s glomerular filtration rate 
(GFR) which is estimated by using the creatinine clearance (CrCl).  Refer to the carboplatin 
package insert for additional information.
Commercially available pegylated liposomal doxorubicin (PLD) (40 mg/m2) will be 
administered by IV infusion on Day 1 of each 28-day Cycle.  PLD should be administered at 
an initial rate of 1 mg/min to minimize the risk of infusion reactions.  If no infusion related 
reactions occur, the rate of infusion can be increased to complete administration over 1 hour.  
A bolus injection or undiluted solution should not be administered.  PLD should not be mixed 
with any other drug. Refer to the package insert for additional information.
Statistical methods
Sample size calculations for Arm C of the study are based upon testing a primary endpoint of 
ORR according to RECIST v1.1. In order to test the null hypothesis of an ORR of 10% versus 
an alternative hypothesis with an ORR of 30%, 23 patients are required in order to have 85% 
power to test the null hypothesis using a one-sided exact binomial test at the 0.10 significance 
level.  The null hypothesis will be rejected if at least 5 responses are observed from 23 
patients.
The Part C2 expansion will enrol approximately 12 patients to assess a weekly AZD1775 
dosing regimen in combination with carboplatin in a 3 week cycle. Initially, 6 patients will be 
enrolled in a 3-weekly AZD1775 dosing cycle; if 1 patient or less experiences a DLT during 
Cycle 1, then an additional 6 patients will be enrolled for a total of 12 patients.  However, if 2 
or more of the first 6 patients experience a DLT then the AZD1775 dosing schedule will be 
shortened to 2 weeks on and 1 week off.   
The AZD1775 plus paclitaxel arm (Arm B) will enrol approximately 30 additional patients.  
Historical response rates using weekly paclitaxel in platinum-resistant and refractory ovarian 
cancer are in the region of 20% to 40% (Pignata et al 2015, Lortholary et al 2011, McNeish et 


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al 2014).  The following examples give an indication of the level of precision that will be 
achieved in the paclitaxel treated patients.
If the observed response rate is 30% (9/30), the 2-sided 80% confidence interval (CI) will be 
(18%, 43%).  If the observed response rate is 50% (15/30), the 2-sided 80% CI will be (36%, 
63%).  For decision making, ORR will be considered in addition to the observed safety and 
tolerability data and the other efficacy endpoints.
  


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY........................................................................................................... 2
PROTOCOL SYNOPSIS...................................................................................................... 7
TABLE OF CONTENTS.................................................................................................... 13
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.......................................... 19
1.
INTRODUCTION............................................................................................ 22
1.1
Background and rationale for conducting this study .......................................... 24
1.1.1
The p53 signalling pathway .............................................................................. 24
1.1.2
AZD1775.......................................................................................................... 24
1.1.2.1
AZD1775 clinical experience............................................................................ 26
1.1.3
Rationale for conducting this study................................................................... 29
1.2
Rationale for study design, doses and control groups ........................................ 29
1.3
Benefit/risk and ethical assessment ................................................................... 30
1.4
Study Design .................................................................................................... 32
2.
STUDY OBJECTIVES..................................................................................... 34
2.1
Primary objective.............................................................................................. 34
2.2
Secondary objectives ........................................................................................ 34
2.3
Exploratory objectives ...................................................................................... 35
3.
SUBJECT SELECTION, ENROLMENT, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL................................................. 35
3.1
Inclusion criteria............................................................................................... 35
3.2
Exclusion criteria.............................................................................................. 37
3.3
Subject enrolment ............................................................................................. 38
3.3.1
Optional Pharmacogenetic (PGx) research ........................................................ 39
3.4
Procedures for handling incorrectly enrolled subjects........................................ 39
3.5
Methods for assigning treatment groups............................................................ 39
3.5.1
TP53 testing...................................................................................................... 40
3.6
Methods to ensure blinding............................................................................... 40
3.7
Methods for unblinding..................................................................................... 40
3.8
Restrictions....................................................................................................... 40
3.9
Discontinuation of investigational product........................................................ 40
3.9.1
Procedures for discontinuation of a subject from investigational product .......... 41
3.10
Criteria for withdrawal...................................................................................... 41
3.10.1
Screen failures .................................................................................................. 42
3.10.2
Withdrawal of the informed consent ................................................................. 42
3.10.3
Lost to follow-up .............................................................................................. 42
3.11
Discontinuation of the study ............................................................................. 42


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4.
STUDY PLAN AND TIMING OF PROCEDURES ......................................... 43
4.1
Screening period............................................................................................... 58
4.2
Treatment period............................................................................................... 58
4.3
Follow-up period .............................................................................................. 58
4.4
Final Protocol Visit and Beyond ....................................................................... 59
5.
STUDY ASSESSMENTS................................................................................. 59
5.1
Efficacy assessments......................................................................................... 60
5.2
Safety assessments............................................................................................ 62
5.2.1
Laboratory safety assessments .......................................................................... 62
5.2.2
Physical examination ........................................................................................ 64
5.2.3
ECG ................................................................................................................. 64
5.2.4
CA-125 tumour markers ................................................................................... 64
5.2.5
Other safety assessments – ECHO or MUGA.................................................... 65
5.3
Pharmacokinetics.............................................................................................. 65
5.3.1
Collection of samples........................................................................................ 65
5.3.2
Determination of drug concentration................................................................. 66
5.3.3
Storage and destruction of pharmacokinetic samples......................................... 70
5.4
Pharmacodynamics........................................................................................... 70
5.4.1
Collection of samples........................................................................................ 70
5.5
Pharmacogenetics ............................................................................................. 70
5.5.1
Background and rationale ................................................................................. 70
5.5.2
Pharmacogenetic research objectives ................................................................ 70
5.5.3
Genetic Research Plan and Procedures.............................................................. 71
5.5.4
Discontinuation of patients from this genetic research....................................... 71
5.5.5
Collection of pharmacogenetic samples ............................................................ 71
5.5.6
Storage, re-use and destruction of pharmacogenetic samples............................. 71
5.5.7
Ethical and Regulatory Requirements ............................................................... 72
5.5.8
Informed consent .............................................................................................. 72
5.5.9
Patient data protection....................................................................................... 72
5.5.10
Data management ............................................................................................. 73
5.5.11
Statistical Methods and Determination of Sample Size...................................... 73
5.6
Biomarker analysis ........................................................................................... 73
5.6.1
Circulating free tumour DNA samples .............................................................. 73
5.6.2
Optional tumour biopsies .................................................................................. 74
5.6.3
Storage, re-use and destruction of biological samples........................................ 74
5.6.4
Labelling and shipment of biological samples................................................... 74
5.6.5
Chain of custody of biological samples............................................................. 74
5.6.6
Withdrawal of Informed Consent for donated biological samples...................... 75
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................ 75
6.1
Data collection of safety-related study variables................................................ 76
6.1.1
Adverse events of special interest related to AZD1775...................................... 76
6.2
Definition of adverse events.............................................................................. 76
6.3
Definitions of serious adverse event.................................................................. 76


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6.4
Recording of adverse events ............................................................................. 76
6.4.1
Time period for collection of adverse events..................................................... 76
6.4.2
Follow-up of unresolved adverse events............................................................ 77
6.4.3
Variables .......................................................................................................... 77
6.4.4
Causality collection........................................................................................... 78
6.4.5
Adverse events based on signs and symptoms................................................... 78
6.4.6
Adverse events based on examinations and tests ............................................... 79
6.4.7
Hy’s Law.......................................................................................................... 79
6.4.8
Disease progression .......................................................................................... 79
6.4.9
New cancers ..................................................................................................... 80
6.4.10
Handling of deaths............................................................................................ 80
6.5
Reporting of serious adverse events .................................................................. 80
6.6
Overdose .......................................................................................................... 82
6.7
Pregnancy......................................................................................................... 82
6.7.1
Maternal exposure ............................................................................................ 82
6.8
Medication error ............................................................................................... 83
6.9
Management of IP related toxicities / Dose Reductions..................................... 84
6.9.1
Dose modifications due to haematologic toxicity .............................................. 86
6.9.2
Non-haematologic toxicity dose modifications.................................................. 88
6.9.3
Non-haematologic toxicity management guidelines .......................................... 93
6.9.3.1
Diarrhoea.......................................................................................................... 93
6.9.3.2
Nausea and vomiting ........................................................................................ 93
6.9.3.3
Febrile neutropenia ........................................................................................... 94
6.9.3.4
Motor neuropathy or muscle weakness.............................................................. 94
6.9.3.5
Dose modifications for infusion reactions ......................................................... 94
6.10
Study governance and oversight........................................................................ 95
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS.................. 95
7.1
Identity of investigational product(s)................................................................. 95
7.2
Dose and treatment regimens ............................................................................ 96
7.2.1
AZD1775.......................................................................................................... 96
7.2.2
Chemotherapy................................................................................................... 96
7.2.2.1
Gemcitabine...................................................................................................... 96
7.2.2.2
Paclitaxel.......................................................................................................... 97
7.2.2.3
Carboplatin....................................................................................................... 97
7.2.2.4
Pegylated liposomal doxorubicin (PLD)............................................................ 98
7.2.3
Lead-in safety and efficacy selection................................................................. 98
7.2.3.1
Arms A, B, & C - First 6 patients and Arm D-First 12 patients.......................... 99
7.2.4
Definition of dose-limiting toxicity (DLT)...................................................... 100
7.2.4.1
Reporting a DLT............................................................................................. 100
7.2.5
Evaluation of Efficacy .................................................................................... 101
7.2.6
Restaging during treatment ............................................................................. 101
7.2.7
End of study treatment visit ............................................................................ 101
7.3
Labelling ........................................................................................................ 101
7.4
Storage ........................................................................................................... 102


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7.5
Compliance..................................................................................................... 102
7.6
Accountability ................................................................................................ 102
7.7
Concomitant and other treatments................................................................... 102
7.7.1
Permitted concomitant medications................................................................. 102
7.7.2
Restricted concomitant medications................................................................ 103
7.7.3
Prohibited concomitant medications................................................................ 104
7.7.4
Palliative radiotherapy .................................................................................... 105
7.7.5
Other concomitant treatment........................................................................... 105
8.
STATISTICAL ANALYSES BY ASTRAZENECA....................................... 106
8.1
Statistical considerations................................................................................. 106
8.2
Sample size estimate....................................................................................... 106
8.3
Definitions of analysis sets.............................................................................. 106
8.3.1
All patients set................................................................................................ 106
8.3.2
Full analysis set .............................................................................................. 107
8.3.3
PK analysis set................................................................................................ 107
8.3.4
CA-125 analysis set ........................................................................................ 107
8.4
Outcome measures for analyses ...................................................................... 107
8.4.1
Calculation or derivation of efficacy variable(s).............................................. 107
8.4.1.1
Tumour response rate...................................................................................... 107
8.4.1.2
Progression-free survival ................................................................................ 108
8.4.1.3
Overall survival .............................................................................................. 108
8.4.1.4
Changes in tumour size................................................................................... 109
8.4.1.5
Duration of response....................................................................................... 109
8.4.2
Calculation or derivation of safety variable(s)................................................. 109
8.4.2.1
Exposure to investigational product ................................................................ 109
8.4.2.2
Adverse events, laboratory changes, vital signs............................................... 109
8.4.2.3
Other significant adverse events (OAE) .......................................................... 109
8.4.3
Calculation or derivation of pharmacokinetic variables in plasma ................... 109
8.5
Pharmacokinetics/Pharmacodynamic Analysis................................................ 110
8.6
Methods for statistical analyses....................................................................... 110
8.6.1
Lead-in safety and efficacy selection............................................................... 110
8.6.2
Lead-in safety dose-limiting toxicities............................................................. 111
8.6.3
Objective response rate................................................................................... 111
8.6.4
Disease control rate......................................................................................... 111
8.6.5
CA-125 response rate...................................................................................... 111
8.6.6
Safety analysis................................................................................................ 111
8.6.7
Changes in target lesion.................................................................................. 111
8.6.8
Demographic and baseline data....................................................................... 111
8.6.9
Exposure......................................................................................................... 112
8.6.10
Progression-free survival ................................................................................ 112
8.6.11
Overall survival .............................................................................................. 112
8.6.12
Duration of response....................................................................................... 112
8.6.13
Exploratory biomarker analysis....................................................................... 112


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9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
REPRESENTATIVE...................................................................................... 112
9.1
Training of study site personnel ...................................................................... 112
9.2
Monitoring of the study................................................................................... 113
9.2.1
Source data..................................................................................................... 113
9.2.2
Study agreements............................................................................................ 113
9.2.3
Archiving of study documents ........................................................................ 113
9.3
Study timetable and end of study .................................................................... 114
9.4
Data management by AstraZeneca or delegate ................................................ 114
10.
ETHICAL AND REGULATORY REQUIREMENTS.................................... 115
10.1
Ethical conduct of the study............................................................................ 115
10.2
Subject data protection.................................................................................... 116
10.3
Ethics and regulatory review........................................................................... 116
10.4
Informed consent ............................................................................................ 117
10.5
Changes to the protocol and informed consent form........................................ 117
10.6
Audits and inspections .................................................................................... 118
11.
LIST OF REFERENCES................................................................................ 119
LIST OF TABLES
Table 1
Study Plan: Arm A (AZD1775 plus Gemcitabine) ................................... 44
Table 2
Study Plan: Arm B (AZD1775 plus Weekly Paclitaxel) ........................... 47
Table 3
Study Plan: Arm C and C2 (AZD1775 plus Carboplatin) ......................... 51
Table 4
Study Plan: Arm D (AZD1775 plus PLD)................................................ 55
Table 5
Laboratory Safety Variables..................................................................... 63
Table 6
Lead-in PKs: Arm A gemcitabine and AZD1775 cycle 1 ......................... 66
Table 7
Lead-in PKs: Arm B paclitaxel and AZD1775 cycle 1 ............................. 67
Table 8
Lead-in and Expansion PKs: Arm C carboplatin and AZD1775 Cycle 1, 
Day 1....................................................................................................... 67
Table 9
Lead-in and Expansion PKs: Arm C Carboplatin and AZD1775, Cycle 3, 
Day 3....................................................................................................... 67
Table 10
Lead-in PKs: Arm D PLD and AZD1775 (PK for PLD only), Cycle 1, 
Day 1....................................................................................................... 68
Table 11
Lead-in PKs: Arm D PLD and AZD1775 (PKs for PLD only), 
Additional Cycle 1 time points................................................................. 68
Table 12
Lead-in PKs: Arm D PLD and AZD1775 (PKs for AZD1775), Cycle 1 
Day 3....................................................................................................... 69


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Table 13
Lead-in PKs: Arm D PLD and AZD1775, Alternate cycles starting from 
Cycle 3 .................................................................................................... 69
Table 14
AZD1775 Sparse PKs for Arm B Efficacy and Arm C2 Safety 
Expansions .............................................................................................. 69
Table 15
AZD1775 Dose Level Reductions for Toxicity ........................................ 85
Table 16
Gemcitabine Dose Level Reductions for Toxicity .................................... 85
Table 17
Weekly Paclitaxel (28-Day Cycle) Dose Level Reductions for Toxicity... 86
Table 18
Carboplatin Dose Level Reductions for Toxicity...................................... 86
Table 19
PLD Dose Level Reductions for Toxicity................................................. 86
Table 20
Management of haematological toxicity in patients receiving AZD1775 
plus chemotherapy................................................................................... 86
Table 21
AZD1775 dose modifications for QTc interval prolongation.................... 89
Table 22
Non-Haematologic Toxicity Dose Modification and Management ........... 89
Table 23
Additional Non-Haematologic Toxicity Dose Modification and 
Management for PLD (arm D only) ......................................................... 92
LIST OF FIGURES
Figure 1
AZD1775 treatment arms and dosing schedules....................................... 32
LIST OF APPENDICES
Appendix A
Additional Safety Information................................................................ 124
Appendix B
International Airline Transportation Association (IATA) 6.2 Guidance 
Document .............................................................................................. 126
Appendix C
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 127
Appendix D
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumours).. 132
Appendix E
Definition of Women of Childbearing Potential and Acceptable 
Contraceptive Methods.......................................................................... 143
Appendix F
Stages of Heart Failure – New York Heart Association Classification.... 145
Appendix G
Disallowed Medications and Medications to be Administered with 
Caution.................................................................................................. 146


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this Clinical Study Protocol.
Abbreviation or special 
term
Explanation
AE
Adverse event (see definition in Section 6.2)
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC
Area under the curve
BCRP
Breast cancer resistance protein
BRCA½1/2  
Breast cancer gene ½1/2
CA-125
Cancer Antigen-125
CBC
Complete blood count
cfDNA
Circulating free tumour DNA
CI
Confidence interval
CR
Complete response
CrCl
Creatinine clearance
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
DCR
Disease control rate
DLT
Dose-limiting toxicity
DoR
Duration of response
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
ECHO
Echocardiography
ECOG
Eastern Cooperative Oncology Group (Performance Status)
eCRF
Electronic case report form
FAS
Full analysis set
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FPV
Final protocol visit


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Abbreviation or special 
term
Explanation
GCIG
Gynecologic Cancer Intergroup
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GOG
Gynecologic Oncology Group
HGS
High-grade serous
IB
Investigator Brochure
ICH
International Conference on Harmonisation
Innovations
Sarah Cannon Development Innovations
IP
Investigational Product 
MM
Medical monitor
MRI
Magnetic resonance imaging
MUGA
Multiple uptake gated acquisition scan
NCI
National Cancer Institute
NE
Non-evaluable
NSCLC
Non-small-cell-lung cancer
NTL
Non-target lesion
NYHA
New York Heart Association
OAE
Other significant adverse event (see definition in Section 8.4.2.3)
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PDx
Pharmacodynamics
PET
Positron-emission tomography
PFS
Progression-free survival
P-gp
P-glycoprotein
PI
Principal Investigator 
PK
Pharmacokinetic
PLD
Pegylated liposomal doxorubicin
PO
By mouth
PR
Partial response
QTc
Corrected QT interval
RECIST
Response Evaluation Criteria in Solid Tumours
RR
Response rate
SAE
Serious adverse event (see definition in Section 6.3)


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Abbreviation or special 
term
Explanation
SD
Stable disease
SDV
Source data verification
SRT
Safety review team
TEAE
Treatment-emergent adverse events
TL
Target lesion
ULN
Upper limit of normal
WNL
Within normal limits
WoCBP
Women of childbearing potential  


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1.
INTRODUCTION
Ovarian cancer accounts for 5% of cancer-related deaths among women in the United States 
according to the American Cancer Society.  Diagnosis of 21,980 new cases and 14,270 deaths 
were estimated in 2014 (SEER Research Data).  Although the death rate for ovarian cancer 
has been stable for the last 10 years it remains the cause of more cancer deaths of the female 
reproductive system than any other.  Fallopian tube cancer and primary peritoneal cancer are 
grouped with ovarian cancer because of their similar prognostic features.  Though less 
frequently diagnosed, these two female-reproductive cancers are known to respond to the 
same types of treatment and have similar histologic features as ovarian cancer (Bloss et al 
1993; Schneider et al 2000).  
Systemic chemotherapy with a platinum-based regimen (carboplatin or cisplatin with/without 
paclitaxel) following surgical debulking, has markedly improved the long-term survival of 
patients with advanced stage ovarian cancer.  However, patients who experience disease 
recurrence within 6 months of completing treatment (defined as platinum-resistant) have a 
poorer prognosis than platinum-sensitive patients and require subsequent treatment options in 
order to extend survival and preserve quality of life.  Platinum-resistant patients may benefit 
from retreatment with platinum-based therapy administered in a dose-dense fashion (Pignata 
et al 2015, Pinato et al 2013, Kavanagh et al 1995, and Bozas et al. 2007).  It may be possible 
to overcome platinum resistance by combining platinum with other compounds.  Carboplatin 
is approved by the Food and Drug Administration (FDA) for patients previously treated with 
cisplatin.  The Gynecologic Oncology Group (GOG) conducted a series of studies in patients 
with platinum-resistant disease (Naumann and Coleman 2011).  In one GOG study, a response 
rate (RR) of 21% was observed in 47 platinum- and paclitaxel-resistant ovarian cancer 
patients receiving weekly paclitaxel (80 mg/m2/week) until disease progression.  Previous 
treatment for this group of patients included standard paclitaxel once every three weeks 
(Markman et al 2006).  Platinum-resistant ovarian malignancies are frequently treated with 
single agents such as topotecan, paclitaxel, oral etoposide or pegylated liposomal doxorubicin 
(PLD) with RRs ranging between 5% and 15%.  Gemcitabine demonstrated activity in 8/51 
patients with platinum and taxane refractory ovarian cancer.  Four patients experienced 
significant cancer antigen-125 (CA-125) blood level declines (≥75%) and 4 patients achieved 
partial remissions of measureable disease.  Three week on/1 week off cycles of single agent 
gemcitabine were administered.  Ten patients received the initial starting dose of gemcitabine 
1250 mg/m2, 35 patients were initiated at a reduced dose of 1000 mg/m2 and 6 patients were 
started at 800 mg/m2 because of toxicity (Markman et al 2002).  The median duration of 
response (DoR) was 4 months.  Physician decision as to which agent to administer is usually 
based upon toxicity, tumour response and quality of life (Pignata et al 2015, Pinato et al 
2013).


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Gemcitabine is recognized for its ability to initiate cell death, and has been FDA approved for 
relapsed ovarian cancer when combined with carboplatin (refer to package insert).  Two Phase 
II trials administering single-agent gemcitabine weekly for 3 weeks, followed by 1-week rest 
(1250 mg/m2 – 1000 mg/m2) to platinum/ paclitaxel-refractory or -resistant ovarian patients 
demonstrated RRs of 16% and 17%, respectively.  These RRs were consistent with other 
Phase 2 study responses seen in platinum-resistant patients (Markman et al 2002 , D’Agostino 
et al 2003).  
A recent report from a Phase II clinical trial indicated that patients receiving AZD1775 plus 
paclitaxel and carboplatin combination had greater progression-free survival (PFS) compared 
to patients receiving only paclitaxel and carboplatin (Oza et al 2015).  
Another study report indicated that, AZD1775 in combination with carboplatin is well 
tolerated and shows promising anti-tumour activity in patients with p53 mutated ovarian 
cancer who are refractory or resistant to standard first line therapy (Leijen et al 2015). 
Anti-tumour activity of doxorubicin against epithelial ovarian cancer has been subsequently 
proven in clinical trials (A’Hern and Gore 1995; Ozols et al 1980).  Despite its potent 
antineoplastic activity, clinical use of doxorubicin has been limited by its associated side 
effects, in particular haematological toxicity and irreversible cardiac damage.  
Recently there has been increasing attention on PLD (Gabizon 2001), which is a formulation 
of liposomal doxorubicin that is coated in polyethylene glycol (PEG).  The PEG coating 
creates a hydrophilic barrier that protects the liposomes from detection by the
reticuloendothelial system and increases the time that the active drug remains in circulation, 
which reduces the rate at which the active drug is broken down (Gabizon 2001) and makes it 
less toxic to heart muscle.  The size of the liposomes prevents PLD from entering tissues with 
tight capillary junctions, such as the heart and gastrointestinal tract; therefore it causes less 
toxicity compared with non-modified doxorubicin, while leading to increased concentrations 
within the tumour (Waterhouse et al 2001).  In 1999 it was first approved for platinum-
refractory ovarian cancer and then received full approval for platinum-sensitive recurrent 
disease in 2005.  The main toxicities associated with PLD are nausea, palmar-plantar 
erythema or hand-foot syndrome (HFS-redness and soreness of palms of hands and soles of 
feet), stomatitis and myelosuppression (Janssen-Cilag 2011).  
Pegylated liposomal doxorubicin (PLD, e.g. Doxil® and Caelyx®) class of agents are 
approved for treating patients with ovarian cancer for whom the disease has progressed or 
recurred after treatment with platinum-based chemotherapy.  In this study, the safety of PLD 
in combination with AZD1775 will be tested in some patients.


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1.1
Background and rationale for conducting this study
1.1.1
The p53 signalling pathway
It is important to understand the molecular signature of tumours in order to improve 
therapeutic approaches and better manage refractory and recurrent ovarian cancer.  One of the 
most important molecular aberrations in oncogenesis is related to protein 53 (p53) a tumour 
suppressor encoded by the TP53 gene.  In normal cells, wild-type p53 plays a pivotal role in 
DNA damage repair and cell cycle arrest as well as helping to trigger apoptosis in response to 
genotoxic stress (Vogelstein et al 2000).  P53 deficiency leads to diminished DNA-repair 
capability; and germline TP53 mutations are associated with early-onset cancers such as Li-
Fraumeni and Li-Fraumeni-like syndromes (Hainaut and Hollstein 2000).  Somatic TP53
mutations are common in many forms of human cancer, as well.  Aberrant p53 function and/or 
p53 deficiency is particularly important in ovarian cancer, where the overwhelming majority 
of patients demonstrate mutations in TP53 (Vang et al 2009; Kurman and Shih 2010; 
TCGARN 2011).  These mutations are heterogeneous, presenting a very complex scenario for 
an effective drug development strategy; and it is becoming increasingly apparent that tumour-
associated mutations in the p53 signalling pathway can induce biological responses beyond 
that of simple loss of function.  Mutant p53 proteins may acquire oncogenic properties that 
promote invasion, metastasis, proliferation, and cell survival.
Since p53 is a key regulator of the G1 cell-cycle check point, p53-deficient cells 
predominantly depend on the S or G2 checkpoint for the repair of damaged cells.  Therefore, 
blocking the G2-checkpoint may selectively sensitize p53-deficient cells to DNA-damaging 
anticancer therapeutics while sparing normal tissue from toxicity.  WEE1 is a protein tyrosine 
kinase that selectively phosphorylates the Tyr15 residue on cyclin-dependent kinase 1 
(CDK1), inhibiting the transition from G2 into mitosis, preventing cells with damaged DNA 
from proliferating, so DNA repair can occur (Parker and Piwnica-Worms 1992; Igarashi et al 
1991; Watanabe et al 1995; McGowan and Russell 1993).  
Evaluation of tumour-associated mutations in the tumour suppressor TP53 has indicated that 
while most mutations abrogate p53 protein function, a small fraction of these mutations are 
not predicted to abrogate it’s function.  Therefore, a list of TP53 mutations has been generated 
that are known or predicted to have a deleterious impact on p53 function.  This list represents 
approximately 87% of known TP53 mutations in ovarian cancer, and will be used to 
determine retrospectively the TP53 mutation status of the tumour tissue being collected for 
this clinical study.  
1.1.2
AZD1775
AZD1775 is a highly selective, adenosine-triphosphate (ATP) competitive, small-molecule 
inhibitor of the WEE1 kinase that sensitises tumour cells to cytotoxic agents and is being 
developed for the treatment of advanced solid tumours and p53 pathway deficient 


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malignancies.  Inhibition of the DNA damage checkpoint kinase WEE1 potentiates genotoxic 
chemotherapies by abrogating cell-cycle arrest and eliminating the opportunity for proper 
DNA repair to occur.  From a therapeutic standpoint, inhibition of checkpoint kinases that 
mediate cell-cycle arrest may force tumour cells to continue cell division before chemically 
induced DNA damage is repaired, eventually causing apoptosis or mitotic catastrophe 
(Medema and Macurek 2012).  
The primary objective of the clinical development of AZD1775 is to test it as a 
chemosensitising drug in combination with a cytotoxic agent (or combination of agents) for 
treatment of advanced solid tumours.  In vitro experiments demonstrate that AZD1775 has 
synergistic cytotoxic effects when administered in combination with various DNA damaging 
agents that have divergent mechanisms of action.  In studies with matched ovarian cell lines 
(p53 WT and shRNA p53 knockdown), AZD1775 enhanced cell death induction by 
gemcitabine in p53-deficient but not in p53 positive control cells.  AZD1775 also 
demonstrates synergistic effects on cell death induction when used in combination with 
cisplatin and carboplatin in a p53-dependent manner.  Cervical cancer cells with HPV induced 
inactivation of p53 demonstrated chemosensitisation to cisplatin and topotecan by AZD1775. 
The ability of AZD1775 to affect tumour growth as monotherapy or to enhance the anti-
tumour effects of gemcitabine, carboplatin, cisplatin, capecitabine, 5-fluorouracil, and gamma 
irradiation was evaluated in immunocompromised host animals bearing human xenograft 
tumours.
The anti-tumour effect of AZD1775 dosed as monotherapy was investigated in the A427 non-
small-cell lung cancer (NSCLC) nude mouse xenograft model.  Daily treatment with 
AZD1775 led to 51% tumour regression (n=10) and mean body weight loss did not exceed 5% 
over the course of the study.  AZD1775 single agent treatment also led to tumour growth 
inhibition in additional xenograft models: 92% TGI (Day 28) in SKMES1 model of NSCLC, 
13% regression (Day 11) in LoVo colorectal cancer model and 64% TGI (Day 19) in NCI-
H2122 NSCLC.
The anti-tumour effect of AZD1775 in combination with gemcitabine was investigated in the 
WiDr (human colorectal adenocarcinoma) nude rat xenograft model.  Several schedules of 
gemcitabine + AZD1775 were explored.  A 10 mg/kg dose of AZD1775 significantly 
enhanced the anti-tumour effect of gemcitabine in WiDr tumours with % treated/control 
(T/C) = -2%.
The anti-tumour effect of AZD1775 in combination with carboplatin was investigated in the 
HeLa-luc (human cervical adenocarcinoma) nude rat xenograft model.  AZD1775 dose-
dependently enhanced the anti-tumour effect of carboplatin tumours with %T/C = 85, 39 and 
28% at doses of 10, 20 and 30 mg/kg, respectively.


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The anti-tumour effect of AZD1775 in combination with cisplatin was also investigated in the 
HeLa-luc model.  These experiments showed dose-dependently enhanced the anti-tumour 
effect of cisplatin with %T/C = -5 and -16% at doses of 10 and 20 mg/kg respectively, 
compared to carboplatin (or cisplatin) alone (X% T/C).
AZD1775 enhanced the anti-tumour efficacy of 5-FU and capecitabine when used in 
combination with these agents, as well; and experiments with nude mouse xenograft models 
of A549 (p53 wild type) and Calu-6 (p53 null) NSCLC cell lines showed enhanced anti-
tumour growth effect of radiotherapy preferentially in p53 mutant xenograft tumours.  Please 
refer to the AZD1775 Investigator Brochure (IB) for more detailed information regarding 
these experiments and findings.
PLD is an anthracycline topoisomerase II inhibitor approved for treatment of patients with 
ovarian cancer who have failed on platinum-based chemotherapy.  AZD1775 has been 
reported to potentiate cytotoxic effects of doxorubicin in vitro (Hirai et al 2010).  This report 
supports the rationale of assessing the safety of doxorubicin in combination with AZD1775 as 
a potential therapeutic approach.
1.1.2.1
AZD1775 clinical experience
AZD1775 has been and is being evaluated in several clinical studies, including both phase I 
and phase II studies in a variety of combinations and tumour settings (AZD1775 (MK-1775) 
IB).  These include:
!
PN001 (NCT 00648648) (except for Part 3):  a first-time-in-patients (FTIP), Phase I, 
dose-escalation study evaluating AZD1775 both as monotherapy and combination therapy 
with gemcitabine, cisplatin, or carboplatin in adult patients with advanced solid tumours
!
PN005 (NCT 01047007):  a Phase I, dose-escalation study evaluating AZD1775 as 
monotherapy (Part 1), combination therapy with 5-FU (Part 2), and combination therapy 
with 5-FU plus cisplatin (Part 3) in adult Japanese patients with advanced solid tumours 
was terminated early due to portfolio prioritization in oncology at Merck after 3 patients 
had been enrolled in Part 1 and 8 patients had been enrolled in Part 2.  Part 3 was not 
initiated.
!
PN008 (NCT 01076400):  a Phase I/IIa, dose-escalation study evaluating AZD1775 in 
combination with topotecan plus cisplatin in adult patients with cervical cancer was 
terminated early due to portfolio prioritization in oncology at Merck after 7 patients had 
been enrolled in the dose-escalation part of the study.  Phase IIa was not initiated.
In Study PN001 (NCT 00648648), of 176 evaluable patients who received AZD1775 (either 
single or multiple doses) as monotherapy or in combination with gemcitabine, cisplatin, or 
carboplatin, a partial response (PR) (confirmed and unconfirmed) was observed in 17 (9.7%) 
patients, and stable disease (SD) was observed in 94 (53.4%) patients (AZD1775 (MK-1775) 
IB).  Nine patients received AZD1775 monotherapy.  Single ascending doses of AZD1775 up 
to 1300 mg were well tolerated; the maximum tolerated dose (MTD) was not evaluated.


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In Study PN005 (NCT 01047007), patients in Part 1 received single-cycle twice-daily (BID) 
dosing of AZD1775 for 5 days as monotherapy.  A cohort of 3 patients was enrolled at the 
starting dose level of AZD1775 65 mg BID and no serious adverse events (SAEs) were 
experienced.  
An ongoing study (NCT 01748825) sponsored by the National Cancer Institute (NCI) Cancer 
Therapy Evaluation Program, in collaboration with AstraZeneca, is investigating AZD1775 
monotherapy.  The MTD for monotherapy treatment in patients with advanced refractory solid 
tumours was found to be 225 mg BID x 5 on Weeks 1 and 2 of a 3-week schedule.  Paired 
biopsies were obtained from 5 patients on this dose and schedule.  The biopsies showed that a 
decrease in pCDC2 was observed in the post-treatment biopsy in 3 of the biopsy pairs with an 
average of 80% reduction.  The same biopsies were analysed for increases in γH2AX, an 
indicator of DNA damage.  Three of the 5 biopsy pairs showed a post-treatment increase in 
γH2AX, with an average of 404% induction observed in these 4 biopsy pairs.  This study is 
also evaluating a once daily (QD) schedule for monotherapy starting at a 200 mg dose.  
Twenty-five patients have been enrolled for the BID schedule and 3 for the QD schedule.
As of 11 November 2016, a total of approximately 551 patients have been exposed to 
AZD1775 in AstraZeneca-sponsored or Merck-sponsored clinical studies.  In addition, 350
patients have also received AZD1775 as part of AstraZeneca’s externally-sponsored scientific 
research.  These patients have received single doses per cycle as high as 1300 mg of 
AZD1775 as monotherapy, 325 mg of AZD1775 as a single-dose in combination with 
chemotherapy, and 325 mg BID in a multiple-dose regimen in combination with 
chemotherapy.  Please refer to the current version of the AZD1775 IB.
The most common adverse events (AEs) observed in studies of AZD1775 combined with 
chemotherapy include blood and lymphatic disorders, (i.e., thrombocytopenia, neutropenia, 
leukopenia, anaemia, febrile neutropenia), gastrointestinal disorders (i.e., diarrhoea, vomiting, 
nausea, abdominal pain, and constipation), and blood investigations (haematology and serum 
chemistries).  Other reported safety concerns include electrocardiogram (ECG) QT 
prolongation, fatigue, influenza like illness, malaise, mucosal inflammation, myalgia, 
palpitations, pruritus, pyrexia, rash, rash maculopapular, skin lesion, stomatitis, tachycardia, 
loss of weight.
The single-dose maximum tolerated dose (MTD) of AZD1775 was 200 mg in combination 
with gemcitabine and/or cisplatin.  Dose-limiting toxicities (DLTs) tended to be 
haematological in nature in the gemcitabine group and constitutional in the cisplatin group.  
The single-dose MTD for the combination with carboplatin was 325 mg of AZD1775.  DLTs 
in this group were related to serum chemistry. 
Hematologic DLTs were most commonly observed in the multiple-dose AZD1775 
combination treatment groups with gemcitabine and cisplatin.  An MTD of AZD1775 in 


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combination with gemcitabine was established with an interim dose of 50 mg BID on Day 1, 
25 mg BID on Day 2, and 25 mg on Day 3.  An attenuated once daily for 2 day schedule in 
combination with gemcitabine continues under investigation.  Two DLTs (grade 3 febrile 
neutropenia and grade 3 aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) increase) were observed at 200 mg once daily for 2 days with the regimen in 
combination with gemcitabine.  The dose was adjusted to 175 mg once daily for 2 days, and 
one DLT has been reported to date.  The MTD for combination with cisplatin has been 
exceeded at the 250 mg dose level, and tolerability of the MTD at 200 mg BID has been 
confirmed.  DLTs observed in the multiple-dose carboplatin combination have been both 
haematological and constitutional in nature.  The multiple-dose MTD in combination with 
carboplatin is AZD1775 225 mg BID.
The MTD for AZD1775 in combination with 5-FU was not reached due to early study 
termination.  DLTs of encephalopathy and hyponatraemia were observed in the AZD1775 
20 mg BID in combination with 1000 mg/m2 5-FU treatment group.
Triplet-based therapy was administered in the study PN004, AZD1775, carboplatin, and 
paclitaxel.  The starting dose of 225 mg AZD1775 (BID for 5 total doses) in Part 1 was 
generally well tolerated.  One patient experienced a DLT in the first six patients treated and 
the dose remained at 225 mg BID 2.5 days.  A total of 15 patients were treated, with 3 DLTs 
being reported (grade 3 and 4 febrile neutropenia and grade 4 thrombocytopenia).  The study 
expanded to Part 2 and is ongoing.  Other toxicities were generally blood and lymphatic 
system disorders and gastrointestinal.  
For the combination of AZD1775 with topotecan plus cisplatin in study PN008, toxicities 
were generally haematological and gastrointestinal in nature.  No unexpected toxicities were 
observed.  
In study PN009 and the premarket formulation substudy to PN001 (both combining 2.5-day 
BID dosing of AZD1775 with carboplatin) there were no appreciable differences in toxicity 
from the ones observed in the carboplatin arm of study PN001.  However, increased 
haematological toxicity was observed, which is considered to be a function of a drug-drug 
interaction with aprepitant (which was administered as anti-nausea medication in these 
studies).
Preliminary pharmacokinetic (PK) analyses revealed that co-administration of AZD1775 and 
aprepitant results in a ~60% increase of AZD1775 exposure.
Available preliminary efficacy data are encouraging, with confirmed PRs in patients 
participating in the two ovarian trials, as well as the phase I trial in solid tumours.  Several 
studies are ongoing (AZD1775 (MK-1775) IB).


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1.1.3
Rationale for conducting this study
The purpose of this study is to find a new alternative treatment for platinum-resistant TP53-
mutated high-grade serous (HGS) ovarian cancer patients.  AZD1775 has demonstrated 
efficacy in two ongoing ovarian carcinoma studies (PN004 and PN009) combined with either 
carboplatin alone or carboplatin and paclitaxel.  
The platinum-resistant HGS ovarian patient presents unique treatment challenges.  TP53
mutations in HGS ovarian cancer occur in 80-96% of patients.  In one report, TP53 mutations 
were reported in 96% of 316 HGS ovarian cancer patients using high-throughput technology 
(TCGARN 2011).  In the current study, archival tumour samples will be required to confirm 
TP53 mutation status, in a retrospective manner.
The current study is an open-label, four-arm, lead-in safety and efficacy study of gemcitabine, 
paclitaxel, carboplatin or PLD in combination with AZD1775.   
This study is intended to provide important safety and efficacy data for administering 
AZD1775 in combination with chemotherapy (gemcitabine, carboplatin, weekly paclitaxel, or 
PLD).  
1.2
Rationale for study design, doses and control groups
The aim of this study is to evaluate the safety and tolerability of AZD1775 when combined 
with either gemcitabine, paclitaxel, carboplatin, or PLD in patients with platinum resistant 
ovarian cancer. The research hypothesis for the AZD1775 drug development programme is 
that administration of AZD1775 combined with chemotherapy in women with platinum-
resistant TP53 mutated ovarian, fallopian tube, or primary peritoneal carcinoma experience 
improved PFS compared to women receiving chemotherapy alone.  This study is being 
conducted to understand the dose level, dosing schedule, safety, and tolerability of AZD1775 
combined with chemotherapy agents such that they can be subsequently studied for 
improvement in efficacy.
This is an open-label, four-arm lead-in safety and efficacy study in which AZD1775 will be 
combined in four separate treatment arms as follows:  AZD1775 plus gemcitabine (Arm A); 
AZD1775 plus weekly paclitaxel (Arm B); AZD1775 plus carboplatin (Arm C); and 
AZD1775 plus PLD (Arm D [See Figure 1]).  A subset of patients will be evaluated for the 
safety assessment of each treatment arm (see Section 7.2.3.1).  The dose/schedules for 
AZD1775 and paired chemotherapeutic agents that will be used in the lead in safety/expansion 
are presented below:  
Arm A (AZD1775 175 mg PO daily days (D)1-2, 8-9, 15-16 + gemcitabine 1000 mg/m2 IV 
D1, 8, 15 q28D); 


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Arm B (AZD1775 225 mg PO BID x 5 doses D1-3, 8-10, 15-17 + paclitaxel 80 mg/m2 IV D1, 
8, 15 q28D);   
Arm C (AZD1775 225 mg PO BID x 5 doses D1-3 + carboplatin AUC 5 IV D1 q21D) 
Arm D (AZD1775 175 or 225 mg PO BID x 5 doses D1-3 + PLD 40 mg/m2 IV D1 q28D) 
The AZD1775 plus paclitaxel arm (Arm B) will enrol approximately 30 additional patients at 
selected sites as part of a further efficacy evaluation based on emerging data that suggests 
clinical activity.
The AZD1775 plus carboplatin arm (Arm C) will enrol approximately 23 patients overall at 
selected sites as part of a further efficacy evaluation based on emerging data that suggests 
clinical activity.
To further optimise the dosing schedule of AZD1775 in Arm C, a safety expansion arm 
(referred to as Arm C2) of approximately 12 additional patients will be enrolled at selected 
sites to receive carboplatin AUC 5 IV on Day 1 of a 21 day cycle in combination with 
AZD1775 BID for 2.5 days per dosing week (QW), on Weeks 1 (D1-3), 2 (D8-10) and 3 
(D15-17), or on Weeks 1 (D1-3) and 2 (D8-10) (2 weeks on followed by 1 week off).  These 
additional weeks of AZD1775 dosing are meant to explore emerging pre-clinical and clinical 
data that suggest that prolonged AZD1775 exposure may increase the clinical activity.  
Initially, 6 patients will be enrolled in a 3-weekly AZD1775 dosing cycle; if 1 patient or less 
experiences a DLT during Cycle 1, then an additional 6 patients will be enrolled for a total of 
12 patients.  However, if 2 or more of the first 6 patients experience a DLT then the AZD1775 
dosing may be modified to 2 weeks on followed by 1 week off.  All decisions which include 
but are not limited to cohort dosing, dose escalation or de-escalation will be reviewed by the 
Safety Review Team (SRT).
Modified PK assessments will be obtained to harmonize and accommodate the investigation 
of alternative dose levels and/or schedules.
1.3
Benefit/risk and ethical assessment
The investigation of AZD1775 in this patient population appears acceptable based upon the 
non-clinical profile and emerging clinical data.  The lead-in safety and efficacy phase of the 
study will be risk minimising with safety and medical monitoring, PK assessments, and Safety 
Review Team (SRT) involvement.  Overall the benefit/risk assessment supports the 
administration of AZD1775 to patients with platinum-resistant ovarian, fallopian tube, or 
primary peritoneal carcinoma.


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Based on the safety data from the completed AZD1775 clinical studies and preliminary data 
from ongoing studies, adverse drug reactions to AZD1775 monotherapy include: anaemia, 
neutropenia, thrombocytopenia, QTc prolongation, gastrointestinal events such as dyspepsia, 
diarrhoea, nausea, and vomiting (with or without dehydration or serum electrolyte decreases), 
as well as decreased appetite.  In addition, the following events are also considered expected 
during treatment with AZD1775 in combination with cytotoxic chemotherapy: febrile 
neutropenia, leukopenia, stomatitis, asthenia, fatigue, mucosal inflammation, and myalgia. 
Based on information emerging during the clinical development programme of AZD1775, 
potential risks with AZD1775 monotherapy include asthenia/fatigue, febrile neutropenia, 
gastrointestinal haemorrhage, lymphopenia/lymphocyte count decreased, leukopenia/WBC 
count decreased, myalgia, stomatitis, sepsis and transaminases elevation.  Gastrointestinal 
haemorrhage and sepsis are described in further detail in the current IB.
In addition, the following events are also considered potential risks for AZD1775 in 
combination with cytotoxic chemotherapy: tachycardia and pancytopenia.
Refer to the IB for AZD1775 for information on the potential benefits and assessment of 
potential and known risks.  


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1.4
Study Design 
Figure 1
AZD1775 treatment arms and dosing schedules
Arm A – AZD1775 (2 Days On/5 Days Off) plus Gemcitabine 
Week 1
Week 2
Week 3
Week 4
Cycle = 28 Days
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
28
26
27
28
Arm A
AZD1775 
PO Daily  
X
X
X
X
X 
X
Gemcitabine
X
X
X
Arm A (AZD1775 175 mg PO daily days (D)1-2, 8-9, 15-16 + gemcitabine 1000 mg/m2 IV D1, 8, 15 q28D)
Arm B – AZD1775 (2.5 Days/Weeks 1, 2 and 3) plus Paclitaxel
Week 1
Week 2
Week 3
Week 4
Cycle = 28 Days
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
28
26
27
28
Arm B
3/4 dosing (5 doses/2.5 days)
AZD1775 
PO BID   
X
X
X
X
X
X
X
X
X
Paclitaxel
X
X
X
Arm B (AZD1775 225 mg PO BID x 5 doses D1-3, 8-10, 15-17 + paclitaxel 80 mg/m2 IV D1, 8, 15 q28D)
Arm C – AZD1775 (2.5 Days/Week 1) plus Carboplatin
Week 1
Week 2
Week 3
Cycle = 21 Days
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Day 1-3 (5 doses/2.5 days)
AZD1775 
PO BID (5 doses) 
X
X
X
Carboplatin  
X
Arm C (AZD1775 225 mg PO BID x 5 doses D1-3 + carboplatin AUC 5 IV D1 q21D) 


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Arm C2 – AZD1775 (2.5 Days/Weeks 1, 2, and 3) plus Carboplatin
Week 1
Week 2
Week 3
Cycle = 21 Days
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Arm C2
3/4 dosing (5 doses/2.5 days)
AZD1775 
PO BID (5 doses) 
X
X
X
X
X
X
X
X
X
Carboplatin  
X
Arm C2 (AZD1775 on weeks 1 (D1-3), 2 (D8-10) and 3 (D15-17) over 2.5 days plus carboplatin AUC 5 IV on Day 1 or AZD1775 on weeks 1 (D1-3) and 2 (D8-10) over 2.5 
days.)
Arm D – AZD1775 (2.5 Days/Week 1) plus PLD
Week 1
Week 2
Week 3
Week 4
Cycle = 28 Days
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
28
26
27
28
Arm D
Day 1-3 (5 doses/2.5 days)
AZD1775 
PO BID (5 
doses)
X
X
X
PLD 
X
Arm D (AZD1775 175 or 225 mg PO BID x 5 doses D1-3 + PLD 40 mg/m2 IV D1 q28D) 


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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To evaluate the objective response rate (ORR) of 
AZD1775 in combination with carboplatin,  
paclitaxel, gemcitabine, or PLD in patients with 
platinum-resistant epithelial ovarian, fallopian tube, 
or primary peritoneal cancer 
The primary endpoint of this study is ORR for the arms 
included in the efficacy assessment, defined as the 
proportion of patients achieving a complete or partial 
tumour response according to Response Evaluation Criteria 
in Solid Tumours (RECIST) v1.1 (Eisenhauer et al 2009).
2.2
Secondary objectives
Secondary Objectives:
Outcome Measures:
To evaluate the DoR of AZD1775 in combination 
with gemcitabine, PLD, carboplatin or paclitaxel 
DoR, defined as the time from first documented tumour 
response until the date of documented progression or death 
from any cause.
To evaluate the safety and tolerability of AZD1775 
in combination with paclitaxel, gemcitabine, 
carboplatin or PLD in patients with platinum-
resistant epithelial ovarian, fallopian tube, or 
primary peritoneal cancer  
Treatment emergent adverse events (TEAEs), serious 
adverse events (SAEs), and deaths; clinically significant 
changes in safety-related laboratory parameters according 
to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE v4.03) and abnormal 
vital signs.
To evaluate the disease control rate (DCR) of 
AZD1775 in combination with carboplatin, 
paclitaxel, gemcitabine, or PLD in patients with 
platinum-resistant epithelial ovarian, fallopian tube, 
or primary peritoneal cancer  
DCR, defined as the proportion of patients achieving a 
complete response (CR), partial response (PR), or stable 
disease (SD) according to RECIST v1.1 criteria.
To evaluate the Cancer Antigen-125 (CA-125) 
response of AZD1775 in combination with 
carboplatin, paclitaxel, gemcitabine or PLD in 
patients with platinum-resistant epithelial ovarian, 
fallopian tube, or primary peritoneal cancer.
Gynaecologic Cancer Intergroup (GCIG) CA-125 
response, defined as the proportion of patients achieving a 
50% reduction in CA-125 levels from baseline, if baseline 
level is ≥2 x the upper limit of normal (ULN) within 2 
weeks prior to starting treatment.  Response must be 
confirmed and maintained for at least 28 days.
To characterise the PK of AZD1775 plus 
carboplatin, AZD1775 plus paclitaxel, AZD1775 
plus PLD, and AZD1775 plus gemcitabine
Plasma PK parameters of AZD1775 plus carboplatin, 
AZD1775 plus paclitaxel, AZD1775 plus PLD, and 
AZD1775 plus gemcitabine
To assess the drug interaction between AZD1775 
plus carboplatin, AZD1775 plus paclitaxel, 
AZD1775 plus gemcitabine, and AZD1775 plus 
PLD  
Plasma PK parameters of AZD1775 plus carboplatin, 
AZD1775 plus paclitaxel, AZD1775 plus gemcitabine, and 
AZD1775 plus PLD


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2.3
Exploratory objectives  
Exploratory Objectives:
Outcome Measures:
To identify genetic alterations in breast cancer 
genes 1 and 2 (BRCA1 and BRCA2) and other 
relevant genes, including TP53, from analysis of 
archived or fresh tumour tissue collected at 
baseline, and to determine if the presence of a 
genetic alteration is predictive of clinical outcomes. 
Molecular analysis of tumour tissue samples will be 
reviewed and correlated with clinical data.
To analyse changes in plasma circulating free 
tumour DNA (cfDNA) over time, from baseline, to 
restaging, and at disease progression.  (This 
exploratory analysis will be reported separately 
from the Clinical Study Report [CSR].) 
Blood samples will be collected to analyse cfDNA 
concentrations and molecular alterations.
To obtain preliminary estimates of the overall 
survival (OS) and progression-free survival (PFS) 
of AZD1775 in combination with gemcitabine, 
PLD, carboplatin or paclitaxel 
OS, defined as the time from first dose to death from any 
cause, and progression-free survival (PFS), defined as the 
time from first dose to the first documentation of disease 
progression (according to RECIST v1.1 criteria) as 
determined by the Investigator or death from any cause, 
whichever comes first
To collect and store DNA for future research into 
genes/genetic variations that may influence PK or 
response to AZD1775 (i.e., absorption, distribution, 
metabolism, excretion, safety and efficacy) and/or 
susceptibility to the development of cancers.
Correlation of genetic polymorphisms with variation in 
PK, safety or response observed in subjects treated with 
AZD1775.
Data generated may be reported separately and may also 
form part of a pooled analysis with other AZD1775 
studies.
3.
SUBJECT SELECTION, ENROLMENT, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL 
Each subject 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.
3.1
Inclusion criteria
For inclusion in the study subjects should fulfil the following criteria:
1
Has read and understands the informed consent form (ICF) and has given written IC prior 
to any study specific procedures.
2
Histologic or cytologic diagnosis of epithelial ovarian, fallopian tube, or primary 
peritoneal cancer.   


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3
Progressed within 6 months of completing at least 4 cycles of a first-line platinum-
containing regimen for Stage III/IV disease.  Patients with refractory disease (progression 
during platinum-containing therapy) are ineligible.
4
No more than 2-4 prior treatment regimens for Stage III/IV disease defined as 
investigational, chemotherapy, hormonal, biologic, or targeted therapy. 
5
Prior doxorubicin (or other anthracyclines) at a cumulative dose of ≤360 mg/m2 or 
cumulative epirubicin dose of ≤ 720 mg/m2 (calculated using doxorubicin equivalent 
doses: 1 mg doxorubicin = 1 mg PLD = 0.3 mg mitoxantrone = 0.25 mg idarubicin).  
Subjects without any prior anthracycline exposure can also be included (applies to Arm D 
only).
6
At least 1 measurable lesion according to RECIST v1.1.
7
Any prior palliative radiation therapy must be completed at least 7 days prior to start of 
study treatment and patients must have recovered from any acute adverse effects prior to 
start of study treatment.  
8
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0-1.
9
Baseline laboratory values within 7 days of starting study drugs as follows:
!
Absolute neutrophil count (ANC) ≥1500/μL
!
Hemoglobin (Hgb) ≥9 g/dL with no blood transfusions in the past 28 days
!
Platelets ≥100,000/μL
!
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x 
ULN or ≤5 x ULN if known hepatic metastases.
!
Serum bilirubin within normal limits (WNL) or ≤1.5 x the ULN in patients with 
liver metastases; or total bilirubin ≤3.0 x ULN with direct bilirubin WNL in 
patients with well documented Gilbert’s Syndrome.
!
Serum creatinine ≤1.5 x ULN OR measured creatinine clearance (CrCl) 
≥45 mL/min as calculated by the Cockcroft-Gault method (confirmation of 
creatinine clearance is only required when creatinine is >1.5 x institutional 
ULN):
CrCl (glomerular filtration rate [GFR]) = (140-age) x (weight/kg) x (0.85 [female])
(72 x serum creatinine mg/dL)
10 Left ventricular ejection fraction (LVEF) WNL of the institution, as determined by 
multiple uptake gated acquisition (MUGA) or echocardiography (ECHO) (applies to Arm 
D only).
11 Female patients who are not of childbearing potential and fertile female patients of 
childbearing potential who agree to use adequate contraceptive measures from 2 weeks 
prior to the study and until 1 month after study treatment discontinuation, who are not 
breastfeeding, and who have a negative serum or urine pregnancy test within 3 days prior 
to start of study treatment (see Appendix E).  
12 Predicted life expectancy ≥12 weeks.


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13 Must be ≥18 years of age.
14 Willingness and ability to comply with study and follow-up procedures.
3.2
Exclusion criteria
Subjects should 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 enrolment in the present study
3
Participation in another clinical study with an investigational product during the last 28 
days
4
Use of a study drug (approved or investigational drug therapy) ≤21 days or 5 half-lives 
(whichever is shorter) prior to the first dose of study treatment.  For study drugs for which 
5 half-lives is ≤21 days, a minimum of 10 days between termination of the study drug and 
administration of study treatment is required.
5
Major surgical procedures ≤28 days of beginning study treatment, or minor surgical 
procedures ≤7 days.  No waiting required following port-a-cath placement, or any other 
central venous access placement.
6
No other (chemotherapy, immunotherapy, hormonal anti-cancer therapy, radiotherapy 
[except for palliative local radiotherapy]), biological therapy or other novel agent is to be 
permitted while the patient is receiving study medication 
7
Grade >1 toxicity from prior therapy (except alopecia or anorexia).
8
Inability to swallow oral medication.  Note: Patient may not have a percutaneous 
endoscopic gastrostomy (PEG) tube or be receiving total parenteral nutrition (TPN).
9
Known malignant central nervous system (CNS) disease other than neurologically stable, 
treated brain metastases – defined as metastasis having no evidence of progression or 
haemorrhage after treatment for at least 2 weeks (including brain radiotherapy).  Must be 
off any systemic corticosteroids for the treatment of brain metastases for at least 14 days 
prior to enrolment.
10 Patient has had prescription or non-prescription drugs or other products (i.e. grapefruit 
juice) known to be sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow 
therapeutic index, or to be moderate to strong inhibitors or inducers of CYP3A4, which 
cannot be discontinued 2 weeks prior to Day 1 of dosing and withheld throughout the 
study until 2 weeks after the last dose of study drug.  (See Appendix G).  
11 Caution should be exercised when inhibitors or substrates of P-gP, substrates of CYP1A2 
with a narrow therapeutic range, sensitive substrates of CYP2C19 or CYP2C19 substrates 
with a narrow therapeutic range are administered with AZD1775.  


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12 Transporter studies (in vitro) have shown that AZD1775 is an inhibitor of breast cancer 
resistance protein (BCRP).  Please refer to Appendix G for use of BCRP substrates.
13 Herbal medications should be discontinued 7 days prior to the first dose of study 
treatment.  Please see Section 7.7.3 on prohibited concomitant medications and 
Appendix G for further details.
14 Any known hypersensitivity or contraindication to the components of study treatment 
(AZD1775, doxorubicin, paclitaxel, or carboplatin [and cisplatin]).
15 Any of the following cardiac diseases currently or within the last 6 months as defined by 
New York Heart Association (NYHA) ≥ Class 2 
!
Unstable angina pectoris
!
Congestive heart failure 
!
Acute myocardial infarction
!
Conduction abnormality not controlled with pacemaker or medication
!
Significant ventricular or supraventricular arrhythmias (patients with chronic 
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are 
eligible).
16 AZD1775 should not be given to patients who have a history of Torsades de pointes 
unless all risk factors that contributed to Torsades have been corrected.  AZD1775 has not 
been studied in patients with ventricular arrhythmias or recent myocardial infarction.
17 Corrected QT interval (QTc) >470 msec at study entry or congenital long QT syndrome.  
QTc interval will be calculated using Fridericia's formula (per institutional standards) 
obtained from 3 ECGs performed 2-5 minutes apart at study entry.
18 Pregnant or lactating
19 Serious active infection at the time of enrolment, or another serious underlying medical 
condition that would impair the ability of the patient to receive study treatment.
20 Presence of other active cancers, or history of treatment for invasive cancer within the last 
3 years.  Patients with Stage I cancer who have received definitive local treatment within 
the last 3 years, and whom are considered unlikely to recur, are eligible.  All patients with 
previously treated in-situ carcinoma (i.e., non-invasive) are eligible, as are patients with 
prior non-melanoma skin cancers.
21 Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol.
For procedures for withdrawal of incorrectly enrolled subjects, see Section 3.4.
3.3
Subject enrolment 
Investigator(s) should keep a record, the subject screening log, of subjects who entered pre-
study screening.


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The Investigator(s) will:
1
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed.  Obtain study identifier according to the instructions provided 
in the Study Reference Manual.
2
Assign the patient a unique enrolment number/code.
3
Determine subject eligibility. See Sections 3.1 and 3.2.
If a subject withdraws from participation in the study, then his/her enrolment code cannot be 
reused.
3.3.1
Optional Pharmacogenetic (PGx) research 
For inclusion in the optional exploratory PGx research, patients must provide informed 
consent for pharmacogenetic research.
Exclusion from this pharmacogenetic research may be for any of the exclusion criteria 
specified in the main study or any of the following:
!
Previous allogenic bone marrow transplant
!
Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection.
If a patient declines to participate in the optional exploratory pharmacogenetic research, there 
will be no penalty or loss of benefit to the patient.  The patient will not be excluded from other 
aspects of the study.
3.4
Procedures for handling incorrectly enrolled subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  Subjects who 
are enrolled, but subsequently found not to meet all the eligibility criteria must not be initiated 
on treatment, and must be withdrawn from the study.
Where a subject does not meet all the eligibility criteria but is enrolled in error, or incorrectly 
started on treatment, the Investigator should inform the Medical Monitor (MM) immediately, 
and a discussion should occur between the MM and the Investigator regarding whether to 
continue or discontinue the patient from treatment. The MM must ensure all decisions are 
appropriately documented.
3.5
Methods for assigning treatment groups
This is an open-label study and no randomisation details are required.


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3.5.1
TP53 testing
TP53 mutations are so prevalent in the eligible patient population that requiring proof of these 
mutations prior to enrolment is no longer necessary in the amended protocol.  Retrospective 
TP53 mutation assessments will be performed centrally from archival tumour tissue.  A full 
report that includes all of the genes present on the gene panel will subsequently be made 
available to Investigators upon request.
Refer to the Laboratory Manual for complete instructions.  
3.6
Methods to ensure blinding
The study is open-label; therefore, blinding procedures are not applicable.
3.7
Methods for unblinding
This is open-label; therefore, unblinding procedures are not applicable.
3.8
Restrictions
Please see Appendix G for information regarding concomitant medications that are prohibited 
or should be avoided while receiving AZD1775 and chemotherapy.  Additional restrictions 
include the following:
!
Women of childbearing potential (WoCBP) may be included only if acceptable 
contraception is in place for two weeks before study entry, for the duration of the study 
and for one month after the last dose of AZD1775 (see Appendix E for definitions of non-
childbearing potential and acceptable contraceptive methods).
!
WoCBP defined as: Women between menarche and menopause who have not been 
permanently or surgically sterilized and are capable of procreation.
!
WoCBP receiving paclitaxel chemotherapy may be included in the study only if 
acceptable contraception is in place for 2 weeks before study entry, for the duration of the 
study and for at least 6 months after the last dose of paclitaxel treatment.
!
All WoCBP must have a negative pregnancy test within 3 days of starting study treatment 
and confirmed prior to the start of study treatment on the first day of dosing.  WoCBP 
must have a negative pregnancy test prior to starting each new treatment cycle and at the 
end-of-treatment visit (EOT).  
3.9
Discontinuation of investigational product
Subjects may be discontinued from investigational product (IP) in the following situations:
!
Subject decision.  The subject is at any time free to discontinue treatment, without 
prejudice to further treatment
!
Adverse Event
!
Confirmed disease progression
!
Pregnancy


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!
Patient is lost to follow-up
!
Severe non-compliance with the study protocol 
!
Development of any study specific criteria for discontinuation 
!
Investigator decision.
3.9.1
Procedures for discontinuation of a subject from investigational 
product 
At any time, subjects are free to discontinue IP or withdraw from the study (i.e., IP and 
assessments – see Section 3.10), without prejudice to further treatment.  A subject that decides 
to discontinue investigational 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).  Adverse events will be 
followed up (see section 6), and all study drugs should be returned by the subject.
If a subject is withdrawn from study, see Section 3.10.
3.10
Criteria for withdrawal 
Reasons for withdrawal from the study:
!
Withdrawal of consent
!
Death
!
Incorrectly enrolled or treated patient
!
AE
!
Patient is lost to follow-up
If a patient wishes to withdraw her consent to both treatment and study assessments, they 
should be asked if they are willing to continue with survival follow-up (which can be 
conducted by telephone).  If a patient wishes to withdraw her consent to further participation 
in the study entirely, including survival follow-up, this should be clearly documented in the 
patient medical record and in the electronic case report form (eCRF).
The status of ongoing, withdrawn (from the study) and “lost to follow-up” patients at the time 
of analysis should be obtained by the site personnel by checking the patient’s medical record 
and 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 still be obtained by site 
personnel from publicly available resources where it is possible to do so under applicable 
local laws.


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3.10.1
Screen failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be enrolled.  These patients should have the reason for study withdrawal 
recorded as ‘Incorrect Enrolment’ (i.e., patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for screen failures (not enrolled
patients).
3.10.2
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (IP 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 subject withdraws from participation in the study, then her enrolment code cannot be 
reused. Withdrawn patients will not be replaced unless they withdraw in Cycle 1 of the Part 1 
lead-in safety cohort.
3.10.3
Lost to follow-up
Patients will be considered lost to follow-up only if contact was lost and could not be re-
established by the time the study is completed, and there is insufficient information to 
determine the patient’s status at that time.  Note: 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.  If a patient withdraws from participation in the study, then 
their patient number cannot be reused.
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial subjects are placed at 
undue risk because of clinically significant findings that:
!
meet individual stopping criteria or are otherwise considered significant 
!
are assessed as causally related to study drug, 
!
are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the electronic case report form (eCRF). All 
reasons for discontinuation of treatment must be documented.


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In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests.
4.
STUDY PLAN AND TIMING OF PROCEDURES 


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Table 1
Study Plan: Arm A (AZD1775 plus Gemcitabine) 
Screena
AZD1775 and Chemotherapy (Cycle = 28-days)
Restage Every 
2 Cyclesk
(±7 days)
End of 
Study 
Treatment 
Visit 
(30 Day 
FU)l
(±2 days)
Follow-Up
Lead-In Safety 
Cycle 1
Cycles 2 and Beyond
PFSm
(±7 
days)
Survival 
FUn
(±7 days)
Assessments 
Baseline   D1
D8
D15
D1 
(±2 days)
D8/15
(±2 days)
Informed consent
X
Archival tumour sampleb
X
Medical/surgical history
X
Physical Examination
X
X
X
X
ECOG performance status
X
X
X
X
Vital signsc
X
X
X
X
Hematology 
X
X
X
X
X
X
X
Clinical Chemistryd
X
X
X
X
Coagulation (PT or INR with PTT)e
X
Urinalysis
X
Pregnancy test (urine or serum)g
X
Xg
Xg
X
Triplicate 12-Lead ECGf
X
Xf
PK sample collectionp (Lead-in) 
Xp
Xp
cfDNAq (Plasma sample)
X
X
X
Xq
Xq
CA-125 (Serum sample)r
Xo
Xo
Xo
Xo
Tumour assessments (RECIST 
v1.1) 
X
X
Xw
Xx
CT Scan/MRI of the Chesti
X
Xh,j,k
Xw
Xx
CT Scan/MRI of the Abdomen and 
Pelvisi
X
Xh,j,k
Xw
Xx
Optional tumour biopsy sample 
Xv
Xv
Concomitant medication review
X
X
X
X
Adverse event assessment
X
X
X
X
X
X
X
Survival status
X
Xn
Dispense AZD1775s  
Review/Collect Dosing Diaryu 
X
X
X
Xs,u
X
Gemcitabine administrationt
X
X
X
X
X


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a
The physical examination, vital signs, medical history (capture previous treatment medications and response to each prior treatment regimen), concomitant 
medications (recorded ≤14 days prior to trial entry), ECOG PS, complete blood count (CBC) with differential and platelets, clinical chemistry, urinalysis, 
and 12-lead ECG should be done ≤7 days prior to initiation of treatment.  However, if any of these initial examinations are required at Cycle 1 Day 1 and 
are obtained within 3 days prior to the initiation of treatment they do not have to be repeated.  CA-125 should be done within 14 days prior to the initiation 
of treatment.  Scans to document evaluable disease (i.e., tumour measurement) should be performed ≤28 days prior to initiation of treatment and should be 
performed as close to the start of treatment as possible.  
b
All patients must provide a tumour sample (archival) for TP53 testing and other exploratory biomarkers by a central laboratory (see Section 5.6).    
c
Vital signs (resting heart rate, blood pressure, temperature and weight) at the Screening visit will include height.  After Screening, height will not be 
measured. Vital signs and weight will be obtained prior to chemotherapy administration according to institutional practice.  
d
Clinical chemistry will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase (ALP), AST, 
ALT, total bilirubin, total protein, lactate dehydrogenase (LDH), phosphorus, and albumin.  
e
Coagulation performed at baseline only (PT or INR with PTT) should be done ≤7 days prior to initiation of treatment.  Repeat at the beginning of every 
cycle if patient on Coumadin.
f
QTc interval will be calculated using Fridericia's formula (as calculated per institutional standards) obtained from 3 ECGs 2-5 minutes apart at study entry 
(see Section 3.2). In addition, patients will have triplicate 12-lead ECGs performed 2-5 minutes apart at the beginning of each treatment cycle. 
g
Pregnancy tests will only be performed in women of childbearing potential (WoCBP) within 3 days of starting study treatment and confirmed prior to start 
of study treatment on the first day of dosing.  WoCBP must have a negative pregnancy test prior to starting each new treatment cycle and at the end-of-
treatment visit (see Section 3.8).
h
Patients will be restaged after every 2 cycles (every 8 weeks [±7 days]).  Patients with progressive disease (PD) or unacceptable toxicity should be 
discontinued from the study; patients with SD or response to therapy will continue treatment.
i
Computed tomography (CT) scans/magnetic resonance imaging (MRI) of the chest and abdomen and pelvis are required at baseline and every 2 cycles (8 
weeks).
j
The same method of assessment and the same technique must be used to characterize each identified and reported lesion at baseline and during subsequent 
imaging procedures. Patients continuing study treatment beyond 1 year may have the tumour imaging assessments expanded to every 3 cycles (12 weeks 
[±7 days]).
k
Patients without evidence of undue toxicity may continue treatment with study drugs until disease progression occurs as long as they are achieving clinical 
benefit and desire to continue therapy.  
l
The End of Study Treatment Visit will be performed 30 days after the last dose of study treatment or prior to the beginning of new therapy.  Reassessments 
for toxicity, disease progression, and survival will be performed 30 days from last treatment dose (see Section 7.2.7).  Tumour assessments will be repeated 
at the end of study treatment visit if they have not been performed within the past 2 cycles (3 cycles for patients on study for >1 year).
m
Post follow-up for patients without disease progression at the time of study drug discontinuation should include repeat CT scan(s) and CA-125 (if 
applicable) until disease progression has been observed.  The patient will be followed every 3 months (±1 week) from the date of the last tumour assessment 
and assessment of response, until death or until the study is terminated by the sponsor.    
n
Patients with documented disease progression will be followed every 3 months (±1 week) for survival status (e.g., date and cause of death).  Patients may be 
contacted during outpatient visits or by telephone.  All post study therapies and dates of administration will be collected.
o
CA-125 serum sample collected at baseline (within 14 days prior to first study treatment), Day 1 of each cycle, and end-of-study treatment visit (see Section 
5.2.4).   


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p
The 6 patients in the lead-in safety group will have limited plasma PK samples collected pre-and post AZD1775 dosing (see Table 6 and Section 5.3.1).  PK 
samples will be collected at the following time points:  Cycle 1 Day 1 - 2 samples will be collected pre AZD1775 and gemcitabine administration (this 
collection may be done the previous day).  Two samples will be collected at 30 minutes post AZD1775 morning dosing (once the gemcitabine infusion 
ends), and at 1, 2, and 4 hours.  One sample will be collected at 6 hours and at the end of the first day, ideally around 8 hours post AZD1775 dosing.  On 
Cycle 2 Day 1, samples will be collected at 2 hours and 3-4 hours after AZD1775 dosing.  On Cycle 3 Day 1, 30 minutes to1 hour and 2 hours after 
AZD1775 dosing, Cycle 3 Day 2 after AZD1775 is dosed, and Cycle 4 Day 1 before AZD1775 dosing and 2 hours after dosing occurs.  Refer to the 
Laboratory Manual.
q
Collection of cfDNA to explore the genetic tumour markers in plasma correlation with markers in tumour samples and to monitor for the emergence of 
resistance is mandatory at baseline, restaging, end-of-treatment and progression for all patients.  A baseline plasma sample will be required followed by 
subsequent single plasma samples at the time of each restaging, end-of-treatment and progression.  Plasma samples will be collected in an EDTA tube and 
processed according to the Laboratory Manual.  See Section 5.6 for more information.
r
Patients with elevated CA-125 levels that can be monitored for response will be assessed according to the GCIG CA-125 response criteria in addition to 
RECIST v1.1.  An additional sample will be collected for tumour response monitoring.  Patients can be evaluated according to CA-125 only if they have a 
pre-treatment sample that is at least twice the upper limit of normal (ULN) and within 2 weeks prior to starting treatment (see Section 5.1).
s
AZD1775 (175 mg by mouth [PO]) will be taken once a daily on Days 1-2, 8-9 and 15-16.  AZD1775 should be taken approximately 2 hours before or 2 
hours after food.
t
Gemcitabine 800 mg/m2 IV will be administered according to institutional standards on Days 1, 8, and 15 of each 28 day cycle.  
u
Review and document AZD1775 dosing compliance with the patient at the beginning of each new treatment cycle when study drug is dispensed.
v
Optional tumour biopsy samples will be requested from patients at the time of disease progression.  Informed consent must be obtained from any patient 
who agrees to provide tissue for this optional testing.  
w
The end of study treatment visit tumour assessments do not need to be repeated if they were done during the previous 2 cycles (3 cycles if patient was on 
study for >1 year).
x
Follow-up assessments start 12 weeks from the last date tumour and response assessments were performed.


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Table 2
Study Plan: Arm B (AZD1775 plus Weekly Paclitaxel) 
Screena
AZD1775 and Chemotherapy (Cycle = 28-
days)
Restage 
Every 2 
Cyclesk
(±7 days)
End of 
Study 
Treatment 
Visit 
(30 Day 
FU)l
(±2 days)
Follow-Up
FPVbb
Lead-In Safety 
Cycle 1
Cycles 2 and Beyond
PFSm
(±7 
days)
Survival 
FUn
(±7 
days)
Assessments 
Baseline   
D1
D8
D15
D1 
(±2 
days)
D8/15
(±2 days)
Informed consent
X
Archival tumour sampleb
X
Medical/surgical history
X
Physical Examination
X
X
X
X
X
ECOG performance status
X
X
X
X
X
Vital signsc
X
X
X
X
X
Haematologyaa
X
X
X
X
X
X
X
X
Clinical Chemistryd
X
X
X
X
X
X
X
X
Coagulation (PT or INR with 
PTT)e
X
Urinalysis
X
Pregnancy test (urine or serum)g
X
Xg
Xg
Xg
Xg
Triplicate 12-Lead ECGf
X
X
Xf
Xf
PK sample collectionp  
Xp,q
Xp
Sparse PK sample collectionq 
See Table 14
See Table 14
Optional PGx blood samplez
X
cfDNAr (Plasma sample)
Xr
Xr
Xr
Xr
Xr
Xr
CA-125 (Serum sample)s
Xo
Xo
Xo
Xo
Xo
Tumour assessments (RECIST 
v1.1) 
Xs
X
Xx
Xy
CT Scan/MRI of the Chesti
X
Xh,j,k
Xx
Xy
CT Scan/MRI of the Abdomen 
and Pelvisi
X
Xh,j,k
Xx
Xy
Optional tumour biopsy sample 
Xw
Xw
Xw
Concomitant medication review
X
X
X
X
X
Adverse event assessment
X
X
X
X
X
X
X
X
Survival status
X
Xn
Dispense AZD1775t  
Review/Collect Dosing Diaryv 
X
X
X
Xt,v
X
X
X
Paclitaxel administrationu
X
X
X
X
X
X


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a
The physical examination, vital signs, medical history, (capture previous treatment medications and response to each prior treatment regimen), concomitant 
medications (recorded ≤14 days prior to trial entry), ECOG PS, complete blood count (CBC) with differential and platelets, clinical chemistry, urinalysis, 
and 12-lead ECG should be done ≤7 days prior to initiation of treatment.  However, if any of these initial examinations are required at Cycle 1 Day 1 and 
obtained within 3 days prior to the initiation of treatment they do not have to be repeated.  CA-125 should be done within 14 days prior to initiation of 
treatment.  Scans to document evaluable disease (i.e., tumour measurement) should be performed ≤28 days prior to initiation of treatment and should be
performed as close to the start of treatment as possible. 
b
All patients must provide a tumour sample (archival) for TP53 testing and other exploratory biomarkers by a central laboratory (see Section 5.6).    
c
Vital signs (resting heart rate, blood pressure, temperature and weight) at the Screening visit will include height.  After Screening, height will not be 
measured.  Vital signs and weight will be obtained prior to chemotherapy administration according to institutional practice at screening, on Day 1 of each 
cycle visit, at the end-of-study treatment visit, and the final protocol visit (FPV).
d
Clinical chemistry will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, ALP, AST, ALT, total bilirubin, 
total protein, lactate dehydrogenase (LDH), phosphorus, and albumin.  
e
Coagulation performed at baseline only (PT or INR with PTT) should be done within ≤7 days prior to the initiation of treatment.  Repeat at the beginning of 
every cycle if patient on Coumadin.
f
QTc interval will be calculated using Fridericia's formula (as calculated per institutional standards) obtained from 3 ECGs 2-5 minutes apart at study entry 
(see Section 3.2). In addition, patients will have triplicate 12-lead ECGs performed 2-5 minutes apart at the beginning of each treatment cycle including the 
FPV.  
g
Pregnancy tests will only be performed in WoCBP within 3 days of starting study treatment and confirmed  prior to start of study treatment on the first day 
of dosing.  WoCBP must have a negative pregnancy test prior to starting each new treatment cycle and at the end-of-treatment visit (see Section 3.8), and at
the FPV.
h
Patients will be restaged after every 2 cycles (every 8 weeks [±7 days]).  Patients with PD or unacceptable toxicity should be discontinued from study
treatment; patients with SD or response to therapy will continue treatment.
i
CT scans/MRIs of the chest and abdomen and pelvis are required at baseline and every 2 cycles (8 weeks).  
j
The same method of assessment and the same technique must be used to characterize each identified and reported lesion at baseline and during subsequent 
imaging procedures.  Patients continuing study treatment beyond 1 year may have the tumour imaging assessments expanded to every 3 cycles (12 weeks 
[±7 days]).
k
Patients without evidence of undue toxicity may continue treatment with study drugs until disease progression occurs as long as they are achieving clinical 
benefit and desire to continue therapy.  
l
The End of Study Treatment Visit will be performed 30 days after the last dose of study treatment or prior to the beginning of new therapy. Reassessments 
for toxicity, disease progression, and survival will be performed 30 days from last treatment dose (see Section 7.2.7).  Tumour assessments will be repeated 
at the end of study treatment visit if they have not been performed within the past 2 cycles (3 cycles for patients on study for >1 year). The end-of-study 
treatment visit is not required for patients continuing treatment after the FPV.
m
Post follow-up for patients without disease progression at the time of study drug discontinuation should include repeat CT scan(s) and CA-125 (if 
applicable) until disease progression has been observed.  The patient will be followed every 8 weeks (±1 week) from first dose (every 12 weeks for patients 
on study >1 year) until progression, death or until the study is terminated by the sponsor.  
n
Patients with documented disease progression will be followed every 3 months (±1 week) for survival status (e.g., date and cause of death).  Patients may be 
contacted during outpatient visits or by telephone.  All post study therapies and dates of administration will be collected.
o
CA-125 serum sample collected at baseline (until 14 days prior to first study treatment), Day 1 of each cycle, at the end-of-study treatment visit, and the 
FPV (see Section 5.2.4).     


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p
The 6 patients in the lead-in safety group will have limited plasma PK samples collected pre-and post AZD1775 dosing (see Table 7 and Section 5.3.1).  PK 
samples will be collected at the following time points:  Cycle 1 Day 1 - 2 samples will be collected at each of the following time points:  before AZD1775 
and paclitaxel administration (this collection may be done the day before), 1 sample at 30 minutes post AZD1775 morning dosing, 2 samples (once the 
paclitaxel infusion stops) at 1, 2, 4, and 6 hours post AZD1775 dosing and at the end of the first day, ideally around 8 hours from AZD1775 dosing.  On 
Cycle 2 Day 1, samples will be collected at 2 hours and 3-4 hours after AZD1775 dosing.  On Cycle 3 Day 1, 30 minutes to1 hour and 2 hours after 
AZD1775 dosing, Cycle 3 Day 2 after AZD1775 is dosed, and Cycle 4 Day 1 before AZD1775 dosing and 2 hours after dosing occurs.  Refer to the 
Laboratory Manual.  
q
Efficacy Expansion:  Mandatory sparse AZD1775 PKs will be collected from patients pre-dose, post-dose 1 hour and post-dose 2-4 hours to be collected on 
Day 3 or Day 10 or Day 17 on Cycle 1, 3, 5 and 7 (see Table 14).  Paclitaxel ONLY PKs will be collected described in Table 7 during Cycle 1 (before 
paclitaxel administration (this collection may be done the day before), 1 samples (once the paclitaxel infusion stops) at 1, 2, 4, and 6 hours post AZD1775 
dosing and at the end of the first day, ideally around 8 hours.
r
Collection of cfDNA to explore the genetic tumour markers in plasma correlation with markers in tumour samples and to monitor for the emergence of 
resistance is mandatory at baseline, Cycle 2 Day 1, Day 1 of every odd-numbered cycle (Cycles 3, 5, etc.), end-of-treatment and progression for all patients.
Patients continuing treatment after the FPV will have a cfDNA sample collected if the patient discontinues treatment due to disease progression. Plasma 
samples will be collected in an EDTA tube and processed according to the Laboratory Manual. See Section 5.6 for more information.
s
Patients with elevated CA-125 levels that can be monitored for response will be assessed according to the GCIG CA-125 response criteria in addition to 
RECIST v1.1.  An additional sample will be collected for tumour response monitoring.  Patients can be evaluated according to CA-125 only if they have a 
pre-treatment sample that is at least twice the ULN and within 2 weeks prior to starting treatment (see Section 5.1).
t
Five doses of AZD1775 (225 mg PO BID) will be taken in approximate 12 hour intervals over 2.5 days weekly (Days 1-3, 8-10 and 15-17).  AZD1775 
should be taken approximately 2 hours before or 2 hours after food. Beyond the FPV, patients may continue to receive AZD1775 if they are deriving 
clinical benefit, in the opinion of the Investigator, and not fulfilling any of the discontinuation criteria.
u
Weekly paclitaxel 80 mg/m2 IV will be administered according to institutional standards on Days 1, 8 and 15 of each 28 day cycle. After the FPV, patients 
will continue to receive paclitaxel 80 mg/m2 IV until disease progression, or until they no longer derive clinical benefit, or until they fulfil any 
discontinuation criteria, in the opinion of the Investigator. Drug accountability information must continue to be collected in patient source documents until 
the patient discontinues the treatment.  
v
Review and document AZD1775 dosing compliance with the patient at the beginning of each new treatment cycle when study drug is dispensed.   
w
Optional tumour biopsy samples will be requested from patients that discontinue treatment due to disease progression. Informed consent must be obtained 
from any patient who agrees to provide tissue for this optional testing, including patients that continue after the FPV.
x
The end of study treatment visit tumour assessments do not need to be repeated if they were done during the previous 2 cycles (3 cycles if patient was on 
study for >1 year).
y
Follow-up assessments every 8 weeks (±1 week) from first dose (every 12 weeks for patients on study >1 year) until progression, death, or until the study is 
terminated by the sponsor.
z
An optional PGx sample will be collected from consenting patients.  If not collected at Cycle 1 Day 1, the PGx sample may be collected at any visit until the 
last study visit (see Section 3.3).
aa
Complete blood counts (CBC) will be obtained for all patients at the beginning of each treatment week and reviewed prior to dose administration.  If 
haematologic toxicity occurs, treatment should be held and ANC and platelets should be monitored at least weekly.  Patients should be managed as 
medically indicated.  Treatment should not be resumed until recovery to Grade 1 (ANC ≥1.5 x 109/L or 1,500/μL; platelets ≥75,000/μL) (see Section 6.9.1
for further information).


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bb
The Final Protocol Visit (FPV) applies only to those patients who will be receiving AZD1775 ± chemotherapy after the time of primary data cut-off meant 
for the preparation of the CSR. The FPV should occur at the next scheduled visit following implementation of the Revised Protocol Edition 10. Beyond the 
FPV, patients may continue to receive AZD1775 ± chemotherapy if they are deriving clinical benefit, in the opinion of the Investigator, and not fulfilling 
any of the discontinuation criteria.  Drug accountability information must continue to be collected in patient source documents until the patient discontinues 
the treatment. After the FPV, SAEs, drug accountability, overdoses and pregnancy test results will be collected while the patient is receiving 
AZD1775 ± chemotherapy.  The EOT visit is not required for patients continuing treatment after the FPV.  SAEs and pregnancy test results will be 
collected for 30 days following the patient’s last dose of AZD1775 ± chemotherapy. 


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Table 3
Study Plan: Arm C and C2 (AZD1775 plus Carboplatin)  
Screena
AZD1775 and Chemotherapy (Cycle = 21-
days)
Restage 
Every 2 
Cyclesk
(±7 days)
End of 
Study 
Treatment 
Visit 
(30 Day 
FU)l
(±2 days)
Follow-Up
FPVcc
Lead-In Safety 
Cycle 1
Cycles 2 and Beyond
PFSm
(±7 
days)
Survival 
FUn
(±7 
days)
Assessments 
Baseline   
D1
D8
D15
D1 
(±2 
days)
D8
(±2 
days)
D15
(±2 
days)
y
Informed consent
X
Archival tumour sampleb
X
Medical/surgical history
X
Physical Examination
X
X
X
X
X
ECOG performance status
X
X
X
X
X
Vital signsc
X
X
X
X
X
Hematologybb
X
X
X
X
X
X
X
X
X
Clinical Chemistryd
X
X
X
X
X
X
X
X
X
Coagulation (PT or INR with 
PTT)e
X
Urinalysis
X
Pregnancy test (urine or serum)g
X
Xg
Xg
X
Xg
Triplicate 12-Lead ECGf
X
X
Xf
Xf
PK sample collectionp (Lead-in)
Xp
Sparse PK collectionq
See Table 14
See Table 14
cfDNAr (Plasma sample)
Xr
Xr
Xr
Xr
Xr
Xr
Optional PGx blood sample
Xaa
CA-125 (Serum sample)s
Xo
Xo
Xo
Xo
Xo
Tumour assessments (RECIST 
v1.1) 
X
X
Xx
Xy
CT Scan/MRI of the Chesti
X
Xh,j,k
Xx
Xy
CT Scan/MRI of the Abdomen 
and Pelvisi
X
Xh,j,k
Xx
Xy
Optional tumour biopsy sample 
Xw
Xw
X
Concomitant medication review
X
X
X
X
X
Adverse event assessment
X
X
X
X
X
X
X
X
X
Survival status
X
Xn


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Screena
AZD1775 and Chemotherapy (Cycle = 21-
days)
Restage 
Every 2 
Cyclesk
(±7 days)
End of 
Study 
Treatment 
Visit 
(30 Day 
FU)l
(±2 days)
Follow-Up
FPVcc
Lead-In Safety 
Cycle 1
Cycles 2 and Beyond
PFSm
(±7 
days)
Survival 
FUn
(±7 
days)
Assessments 
Baseline   
D1
D8
D15
D1 
(±2 
days)
D8
(±2 
days)
D15
(±2 
days)
y
Dispense AZD1775t
Review/Collect Dosing 
Diaryv 
X
X
X
Xs,u
X
X
X
X
Carboplatin administrationu
X
X
X
a
The physical examination, vital signs, medical history (capture previous treatment medications and response to each prior treatment regimen), concomitant 
medications recorded ≤14 days prior to trial entry, ECOG PS, complete blood count (CBC) with differential and platelets, clinical chemistry, urinalysis, and 
12-lead ECG should be done ≤7 days prior to initiation of treatment.  However, if any of these initial examinations are required at Cycle 1 Day 1 and are 
obtained within 3 days prior to the initiation of treatment they do not have to be repeated.  CA-125 should be done within 14 days prior to the initiation of 
treatment.  Scans to document evaluable disease (i.e., tumour measurement) should be performed ≤28 days prior to initiation of treatment and should be 
performed as close to the start of treatment as possible. 
b
All patients must provide a tumour sample (archival) for TP53 testing and other exploratory biomarkers by a central laboratory (see Section5.6).   
c
Vital signs (resting heart rate, blood pressure, temperature, and weight) at the Screening visit will include height.  After Screening, height will not be 
measured.  Vital signs and weight will be obtained prior to chemotherapy administration according to institutional practice at screening, on Day 1 of each 
cycle visit, at the end-of-study treatment visit, and the final protocol visit (FPV).
d
Clinical chemistry will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, ALP, AST, ALT, total bilirubin, 
total protein, albumin, lactate dehydrogenase (LDH), phosphorus, and magnesium.  
e
Coagulation performed at baseline only (PT or INR with PTT) should be done ≤7 days prior to initiation of treatment.  Repeat at the beginning of every 
cycle if patient on Coumadin.
f
QTc interval will be calculated using Fridericia's formula (as calculated per institutional standards) obtained from 3 ECGs 2-5 minutes apart at study entry 
(see Section 3.2). In addition, patients will have triplicate 12-lead ECGs performed 2-5 minutes apart at the beginning of each treatment cycle. 
g
Pregnancy tests will only be performed in WoCBP ( within 3 days of starting study treatment and confirmed prior to start of study treatment on the first day 
of dosing.  WoCBP must have a negative pregnancy test prior to starting each new treatment cycle and at the end-of-treatment visit (see Section 3.8), and at 
the FPV.
h
Patients will be restaged after every 2 cycles (every 6 weeks [±7 days]).  Patients with PD or unacceptable toxicity should be discontinued from study
treatment; patients with SD or response to therapy will continue treatment.
i
CT scans/MRIs of the chest and abdomen and pelvis are required at baseline and every 2 cycles (6 weeks).  
j
The same method of assessment and the same technique must be used to characterize each identified and reported lesion at baseline and during subsequent 
imaging procedures.  Patients continuing study treatment beyond 1 year may have the tumour imaging assessments expanded to every 3 cycles (9 weeks [±7 
days]).
k
Patients without evidence of undue toxicity may continue treatment with study drugs until disease progression occurs as long as they are achieving clinical 
benefit and desire to continue therapy.


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l
The End of Study Treatment Visit will be performed 30 days after the last dose of study treatment or prior to beginning a new therapy.  Reassessments for 
toxicity, disease progression, and survival will be performed 30 days from last treatment dose (see Section 7.2.7).  Tumour assessments will be repeated at 
the end of study treatment visit if they have not been performed within the past 2 cycles (3 cycles for patients on study for >1 year). The end-of-study 
treatment visit is not required for patients continuing treatment after the FPV.
m
Post follow-up for patients without disease progression at the time of study drug discontinuation should include repeat CT scan(s) and CA-125 (if 
applicable) until disease progression has been observed.  The patient will be followed every 6 weeks (±1 week) from first dose (every 9 weeks for patients 
on study >1 year) until progression, death or until the study is terminated by the sponsor.  
n
Patients with documented disease progression will be followed every 3 months (±1 week) for survival status (e.g., date and cause of death).  Patients may be 
contacted during outpatient visits or by telephone.  All post study therapies and dates of administration will be collected.
o
CA-125 serum sample collected at baseline (within 14 days prior to first study treatment), Day 1 of each cycle, at the end-of-study treatment visit, and the 
FPV.   
p
The patients in the lead-in safety and expansion group will have limited plasma PK samples collected pre-and post AZD1775 dosing (see Table 8 and 
Section 5.3.1).  These will not be collected during Part C2.  PK samples will be collected at the following time points:  Cycle 1 Day 1 - 2 samples will be 
collected at each of the following time points:  before AZD1775 and carboplatin administration (this collection may be done the day before), 2 samples will 
be collected 30 minutes post AZD1775 dosing, once the carboplatin infusion stops 2 samples will be collected at 1, 2, 4, and 6 hours from AZD1775 dosing 
and at the end of the first day, ideally around 8 hours from AZD1775 dosing (Table 8).  On Cycle 3 Day 3, AZD1775 and carboplatin PK samples will be 
collected before AZD1775 dosing (pre-dose).  On Cycle 3 Day 3, another carboplatin PK sample will be collected 30 minutes after AZD1775 dosing 
(Table 9).  Refer to the Laboratory Manual.  
q
Part C2 Safety Expansion: Mandatory sparse PKs will be collected from patients pre-dose, post-dose 1 hour and post-dose 2-4 hours to be collected on Day 
3 or Day 10 or Day 17 on Cycle 1, 3, 5 and 7 (see Table 14).  Refer to the Laboratory Manual. 
r
Collection of cfDNA to explore the genetic tumour markers in plasma correlation with markers in tumour samples and to monitor for the emergence of 
resistance is mandatory at baseline, Cycle 2 Day 1, Day 1 of every odd-numbered cycle (Cycles 3, 5, etc.), end-of-treatment and progression for all patients.  
Patients continuing treatment after the FPV will have a cfDNA sample collected at the time of disease progression. Plasma samples will be collected in an 
EDTA tube and processed according to the Laboratory Manual. See Section 5.6 for more information.
s
Patients with elevated CA-125 levels that can be monitored for response will be assessed according to the GCIG CA-125 response criteria in addition to 
RECIST v1.1.  An additional sample will be collected for tumour response monitoring.  Patients can be evaluated according to CA-125 only if they have a 
pre-treatment sample that is at least twice the ULN and within 2 weeks prior to starting treatment (see Section 5.1).
t
Five doses of AZD1775 (225 mg PO BID) will be taken in approximate 12 hour intervals over 2.5 days. AZD1775 should be taken approximately 2 hours 
before or 2 hours after food.  See Table 15 for starting doses per arm, as well as dose level reductions for toxicity.  Beyond the FPV, patients may continue 
to receive AZD1775 if they are deriving clinical benefit, in the opinion of the Investigator, and not fulfilling any of the discontinuation criteria. Drug 
accountability information must continue to be collected in patient source documents until the patient discontinues the treatment.
u
Carboplatin area under the curve (AUC) 5 mg/mL min IV will be administered according to institutional standards on Day 1 of each 21-day cycle.  After the 
FPV, patients will continue to receive carboplatin area under the curve (AUC) 5 mg/mL min IV until disease progression, or until they no longer derive 
clinical benefit, or until they fulfil any discontinuation criteria, in the opinion of the Investigator. Drug accountability information must continue to be 
collected in patient source documents until the patient discontinues the treatment.
v
Review AZD1775 dosing compliance with the patient at the beginning of each new treatment cycle when study drug is dispensed. 
w
Optional tumour biopsy samples will be requested from patients that discontinue treatment due to disease progression.  Informed consent must be obtained 
from any patient who agrees to provide tissue for this optional testing, including patients that continue after the FPV.  


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x
The end of study treatment visit tumour assessments do not need to be repeated if they were done during the previous 2 cycles (3 cycles if patient was on 
study for >1 year).
y
Follow-up assessments every 6 weeks (±1 week) from first dose (every 9 weeks for patients on study >1 year), until progression, death, or until the study is 
terminated by the sponsor.
z
Patients receiving AZD1775 weekly as part of the safety expansion will need to return to the clinic on Days 1, 8 and 15 for the first 2 cycles.  After 
completing Cycle 2 patients will not be required to return to the clinic on Day 15 of each subsequent cycle unless instructed by the Study Doctor.  
aa
An optional PGx sample will be collected from consenting patients.  If not collected at Cycle 1 Day 1, the PGx sample may be collected at any visit until the 
last study visit (see Section 3.3).
bb
Complete blood counts (CBC) will be obtained for all patients at the beginning of each treatment week and reviewed prior to dose administration.  If 
haematologic toxicity occurs, treatment should be held and ANC and platelets should be monitored at least weekly.  Patients should be managed as 
medically indicated.  Treatment should not be resumed until recovery to Grade 1 (ANC ≥1.5 x 109/L or 1,500/μL; platelets ≥75,000/μL) (see Section 6.9.1
for further information).
cc
The Final Protocol Visit (FPV) applies only to those patients who will be receiving AZD1775 ± chemotherapy after the time of primary data cut-off meant 
for the preparation of the CSR. The FPV should occur at the next scheduled visit following implementation of the Revised Protocol Edition 10. Beyond the 
FPV, patients may continue to receive AZD1775 ± chemotherapy if they are deriving clinical benefit, in the opinion of the Investigator, and not fulfilling 
any of the discontinuation criteria.  Drug accountability information must continue to be collected in patient source documents until the patient discontinues 
the treatment. After the FPV, SAEs, drug accountability, overdoses and pregnancy test results will be collected while the patient is receiving 
AZD1775 ± chemotherapy.  The EOT visit is not required for patients continuing treatment after the FPV.  SAEs and pregnancy test results will be 
collected for 30 days following the patient’s last dose of AZD1775 ± chemotherapy. 


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Table 4
Study Plan: Arm D (AZD1775 plus PLD) 
Screena
AZD1775 and Chemotherapy (Cycle = 28-
days)
Restage 
Every 2 
Cyclesk
(±7 days)
End of 
Study 
Treatment 
Visit 
(30 Day 
FU)l
(±2 days)
Follow-Up
Lead-In Safety 
Cycle 1
Cycles 2 and Beyond
PFSm
(±7 
days)
Survival 
FUn
(±7 
days)
Assessments 
Baselin
e   
D1
D
8
D15
D1 
(±2 
days)
D8/15
(±2 days)
Informed consent
X
Archival tumour sampleb
X
Medical/surgical history
X
Physical Examination
X
X
X
X
ECOG performance status
X
X
X
X
Vital signsc
X
X
X
X
Haematology 
X
X
X
X
X
X
X
Clinical Chemistryd
X
X
X
X
Coagulation (PT or INR with 
PTT)e
X
Urinalysis
X
Pregnancy test (urine or serum)g
X
Xg
Xg
Xg
12-Lead ECGf
X
X
Xf
ECHO or MUGAp
X
Xp
PK sample collectionq (Lead-in)
Xq
Xq
cfDNAr (Plasma sample)
X
X
Xr
Xr
CA-125 (Serum sample)o,s
Xo,s
Xo,s
Xo,s
Xs
Tumour assessments (RECIST 
v1.1) 
X
X
Xw
Xx
CT Scan/MRI of the Chesti
X
Xh,j,k
Xx
Xy
CT Scan/MRI of the Abdomen 
and Pelvisi
X
Xh,j,k
Xx
Xy
Optional tumour biopsy samplew
Xw
Xw
Concomitant medication review
X
X
X
X
Adverse event assessment
X
X
X
X
X
X
X
Survival status
X
Xn
Dispense AZD1775t  
Review/Collect Dosing Diaryu 
X
X
X
X t,u
X
X
PLD administrationv
X
X


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a
The physical examination, vital signs, medical history (capture previous treatment medications and response to each prior treatment regimen), concomitant 
medications (recorded ≤14 days prior to trial entry), ECOG PS, complete blood count (CBC) with differential and platelets, clinical chemistry, urinalysis, 
and 12-lead triplicate ECG should be done ≤7 days prior to initiation of treatment.  However, if any of these initial examinations are required at Cycle 1 Day 
1 and are obtained within 3 days prior to the initiation of treatment they do not have to be repeated.  If an ECG is done ≤7 days prior to initiation of 
treatment, then it does not need to be repeated pre-dose on C1D1.  CA-125 should be done within 14 days prior to the initiation of treatment.  Scans to 
document evaluable disease (i.e., tumour measurement) should be performed ≤28 days prior to initiation of treatment and should be performed as close to 
the start of treatment as possible.  
b
All patients must provide an archival tumour for TP53 testing and other exploratory biomarkers by a central laboratory(see Section 5.6).    
c
Vital signs (resting heart rate, blood pressure, temperature and weight) at the Screening visit will include height.  After Screening, height will not be 
measured.  Vital signs and weight will be obtained prior to chemotherapy administration according to institutional practice.  
d
Clinical chemistry will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, ALP, AST, ALT, total bilirubin, 
total protein, lactate dehydrogenase (LDH), phosphorus, and albumin.  
e
Coagulation performed at baseline only (PT or INR with PTT) should be done ≤7 days prior to initiation of treatment.  Repeat at the beginning of every 
cycle if patient on Coumadin.
f
QTc interval will be calculated using Fridericia's formula (as calculated per institutional standards) obtained from 3 ECGs 2-5 minutes apart at study entry 
(see Section 3.2). An ECG will be collected at baseline to calculate the QTc interval and confirm eligibility (see Section 3.2). Thereafter, patients will have 
triplicate ECG on C1D1 (pre-dose, 2 and 4 hr post-dose) and C1D3 (pre-dose, and 2 hours and 4 hours post-dose) and on C3D3 (pre-dose only).  In 
addition, patients will have triplicate 12-lead ECGs performed 2-5 minutes apart at the beginning of each treatment cycle.
g
Pregnancy tests will only be performed in WoCBP within 3 days of starting study treatment and confirmed prior to start of study treatment on the first day 
of dosing.  WoCBP must have a negative pregnancy test prior to starting each new treatment cycle and at the end-of-treatment visit (see Section 3.8).
h
Patients will be restaged after every 2 cycles (every 8 weeks [±7 days]).  Patients with PD or unacceptable toxicity should be discontinued from the study; 
patients with SD or response to therapy will continue treatment.
i
CT scans/MRIs of the chest and abdomen and pelvis are required at baseline and every 2 cycles (8 weeks).      
j
The same method of assessment and the same technique must be used to characterise each identified and reported lesion at baseline and during subsequent 
imaging procedures.  Patients continuing study treatment beyond 1 year may have the tumour imaging assessments expanded to every 3 cycles (12 weeks 
[±7 days]).
k
Patients without evidence of undue toxicity may continue treatment with study drugs until disease progression occurs as long as they are achieving clinical 
benefit and desire to continue therapy.  
l
The End of Study Treatment Visit will be performed 30 days after the last dose of study treatment or prior to the beginning of new therapy.  Reassessments 
for toxicity, disease progression, and survival will be performed 30 days from last treatment dose (see Section 7.2.7).  Tumour assessments will be repeated 
at the end of study treatment visit if they have not been performed within the past 2 cycles (3 cycles for patients on study for >1 year).
m
Post follow-up for patients without disease progression at the time of study drug discontinuation should include repeat CT scan(s) and CA-125 (if 
applicable) until disease progression has been observed.  The patient will be followed every 3 months (±1 week) from the date of the last tumour assessment 
and assessment of response, until death or until the study is terminated by the sponsor.    
n
Patients with documented disease progression will be followed every 3 months (±1 week) for survival status (e.g., date and cause of death).  Patients may be 
contacted during outpatient visits or by telephone.  All post study therapies and dates of administration will be collected.
o
CA-125 serum sample collected at baseline (within 14 days prior to first study treatment), Day 1 of each cycle, and end-of-study treatment visit (see Section 
5.1).  


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p
Left ventricular cardiac function (e.g. MUGA or echocardiogram [ECHO]) will be assessed at baseline, every 6 cycles or as clinically indicated based on 
prior anthracycline exposure and clinical symptoms.  End of treatment assessment should be done for patients who receive at least 3 cycles of treatment and 
have not had an ECHO done in the past three months.  
q
All patients will have limited plasma PK analysis.  Samples will be collected as follows:
PK samples for PLD will be collected on Cycle 1, Day 1: 0 (pre-dose), and 0.5, 1, 2, 6, 24 h, 48 h, 7d and 14d after infusion start (Table 10 and Table 11); 
Additional PK samples for PLD will be collected pre-dose & 1 hour post-dose time point on Day 1 of alternate cycles, starting from Cycle 3 (Cycles 3, 5, 7 
etc.) (Table 13).  PK samples for AZD1775 will be collected on Cycle 1 Day 3 (0, 1, 2, 4, 6, and approximately 8 hrs post-dose) (Table 12) 
Additional PK samples for AZD1775 will be collected pre-dose on Day 3 on alternate cycles, starting from Cycle 3 (Cycles 3, 5, 7 etc.) (Table 13).
r
Collection of cfDNA to explore the genetic tumour markers in plasma correlation with markers in tumour samples and to monitor for the emergence of 
resistance is mandatory at baseline, Cycle 2 Day 1, restaging, end-of-treatment and progression for all patients.  Plasma samples will be collected in an 
EDTA tube and processed according to the Laboratory Manual.  See Section 5.6 for more information.
s
Patients with elevated CA-125 levels that can be monitored for response will be assessed according to the GCIG CA-125 response criteria in addition to 
RECIST v1.1.  An additional sample will be collected for tumour response monitoring.  Patients can be evaluated according to CA-125 only if they have a 
pre-treatment sample that is at least twice the ULN and within 2 weeks prior to starting treatment (see Section 5.1
t
Five doses of AZD1775 (175 mg or 225 mg PO) will be taken within 3 consecutive days (at least 12 hours apart).  AZD1775 should be taken approximately 
2 hours before or 2 hours after food.
u
Review and document AZD1775 dosing compliance with the patient at the beginning of each new treatment cycle when study drug is dispensed.  
v
PLD 40 mg/m2 IV will be administered according to institutional standards on Days 1 of each 28 day cycle.
w
Optional tumour biopsy samples will be requested from patients at the time of disease progression.  Informed consent must be obtained from any patient 
who agrees to provide tissue for this optional testing.  
x
The end of study treatment visit tumour assessments do not need to be repeated if they were done during the previous 2 cycles (3 cycles if patient was on 
study for >1 year).
y
Follow-up assessments start 12 weeks from the last date tumour and response assessments were performed.


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4.1
Screening period
Procedures will be performed according to the Study Plan.  At screening, consenting subjects 
are assessed to ensure that they meet eligibility criteria. Subjects who do not meet these 
criteria must not be enrolled in the study.  
4.2
Treatment period
A patient is defined as being on-study if they are continuing to have any study data collected, 
if the patient is receiving study specific treatment, is being followed for efficacy after 
discontinuation of protocol specific treatment, or is in follow-up.  Descriptions of the 
procedures for this period are included in the Study Plan. 
4.3
Follow-up period
Patients discontinuing study treatment should be scheduled for an end-of-treatment (EOT) 
visit, approximately 30 days after the study drug is permanently discontinued unless the 
patient withdraws consent.
Approximately 30 days after the last treatment, patients will return to the clinic for a follow-
up assessment.  The primary purpose of this visit is to follow-up any AEs ongoing at the time 
of discontinuation and to assess any new AEs that may have occurred since discontinuation.  
Any AE, SAE, abnormal laboratory findings that are ongoing at the time of study treatment 
discontinuation or any new events within 30 days of last study treatment, must be followed up 
to resolution or until the event becomes stable (or returns to baseline) or is unlikely to resolve 
further in the opinion of the Investigator.
Patients who discontinue study treatment prior to the occurrence of disease progression will be 
followed every 8 weeks (±1 week) from first dose (every 12 weeks for patients on study >1 
year), until progression, death, or until study is terminated by sponsor.  The exception is for 
Arm C, which will be followed every 6 weeks (±1 week) from first dose (every 9 weeks for 
patients on study >1 year), until progression, death, or until the study is terminated by the 
sponsor.
Patients with documented disease progression will be followed every 3 months for survival 
status (e.g., date and cause of death) for up to 2 years, death, or until time of final data 
collection for the progression-free survival analysis, whichever comes first.  Patients may be 
contacted during outpatient visits or by telephone.  Information pertaining to the type and 
dates of administration of post-study therapy will be collected when available.


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4.4
Final Protocol Visit and Beyond
The Final Protocol Visit (FPV) requirement applies only to those patients who will be 
receiving AZD1775 ± chemotherapy after the time of primary data cut-off meant for the 
preparation of the CSR.
Any patients receiving AZD1775 ± chemotherapy at the time of the primary data cut-off will 
complete a FPV, which should occur at the next scheduled visit following implementation of 
the Revised Protocol Edition 10.
Beyond the FPV, patients may continue to receive AZD1775 ± chemotherapy if they are 
deriving clinical benefit, in the opinion of the Investigator, and not fulfilling any of the 
discontinuation criteria.  Combining AZD1775 with a different anti-cancer therapy is not 
allowed.  Such patients are to be treated as deemed appropriate by the Investigator to ensure 
continued safety monitoring of the patient while receiving the investigational product.  It is 
recommended to continue observing ongoing patients at the frequency indicated within the 
study plans as described in Table 2, Table 3 and Table 4.  Restrictions regarding concomitant 
medications (refer to Section 7.7.2) will be followed while the patient is receiving 
AZD1775 ± chemotherapy.  A change in AZD1775 ± chemotherapy dose/schedule 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.  
After the FPV, SAEs, drug accountability, overdoses and pregnancy test results will be 
collected while the patient is receiving AZD1775 ± chemotherapy.  
If a patient is no longer receiving benefit from AZD1775 ± chemotherapy beyond the FPV in 
the opinion of the treating physician, then the study drug should be stopped.  The Investigator 
will inform AstraZeneca when a patient discontinues the study drug.  Patients must return 
unused medication when they discontinue treatment.  In addition, provided that a patient gives 
proper informed consent, a plasma isolation (cfDNA) blood sample and optional tumour 
biopsy for future biomedical research should be obtained at the time of 
AZD1775 ± chemotherapy discontinuation, if due to disease progression.  SAEs and 
pregnancy test results will be collected for 30 days following the patient’s last dose of 
AZD1775 ± chemotherapy. 
5.
STUDY ASSESSMENTS
The Sarah Cannon Development Innovations, LLC (Innovations) Trial Master electronic data 
capture (EDC) system will be used for data collection and query handling.  The Investigator 
will ensure that data are recorded on the eCRFs as specified in the study protocol and in 
accordance with the instructions provided.
The Investigator must ensure the accuracy, completeness, and timeliness of the data recorded 
and of the provision of answers to data queries according to the Clinical Study Agreement 


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(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
Tumour assessments
RECIST v1.1 criteria will be used to assess patient response to treatment by PFS, ORR and 
DCR.  The RECIST v1.1 guidelines for measurable, non-measurable, target lesions (TLs) and 
non-target lesions (NTLs) and the objective tumour response criteria (CR, PR, SD or 
progression of disease) are presented in Appendix E.
The same method of assessment of tumour burden used at baseline (CT scans or magnetic 
resonance imaging [MRI] of the chest and abdomen/pelvis) must be used at each subsequent 
follow-up assessment (see Table 1 – Table 4).  CT scan or MRI of chest and abdomen/pelvis 
are mandatory and must be repeated every 2 cycles.  Patients will be assessed for biochemical 
response (CA-125) at baseline, Day 1 of each cycle, at the end of study treatment visit and the 
FPV.  
Following the baseline assessment, efficacy for all patients will be assessed by objective 
tumour assessments after start of treatment until objective disease progression as defined by 
RECIST v1.1 or withdrawal from study.  For patients in Arm C, objective tumour assessments 
will be done every 6 weeks (± 1 week) (2 cycles).  For patients in Arms A, B, and D, objective 
tumour assessments will be done every 8 weeks (±1 week) (2 cycles). 
Categorisation of objective tumour response assessment will be based on the RECIST v1.1 
criteria of response: CR (complete response), PR (partial response), SD (stable disease) and
PD (progression of disease).  Target lesion progression will be calculated in comparison to 
when the tumour burden was at a minimum (i.e. smallest sum of longest diameters previously 
recorded on study).  In the absence of progression, tumour response (CR, PR, or SD) will be 
calculated in comparison to the baseline tumour measurements obtained before starting 
treatment.
If the Investigator is in doubt as to whether progression has occurred, particularly with regard 
to NTLs or the appearance of a new lesion, it is advisable to continue treatment until 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 tumour burden has increased sufficiently to merit 


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discontinuation of therapy.  A modest ‘increase’ in the size of one or more NTLs is usually 
not sufficient to quality for unequivocal progression status.
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
study plan in Table 1, Table 2, Table 3, or Table 4.  Patients will be assessed by standard 
criteria.  For the purposes of this study, patients should be evaluated for radiographic tumour 
response every six or eight weeks (±1 week [cycle length dependent]).  The same method of 
assessment and the same technique should be used to characterize each identified and reported 
lesion at baseline and throughout the study.  Overall tumour response and progression will be 
calculated according to RECIST 1.1 (see Appendix E), at the designated time points.  Patients 
continuing study treatment beyond one year may have tumour assessments expanded to be 
repeated every 9 or 12 weeks instead of every 6 or 8 weeks.
Tumour status will be compared to baseline and confirmation of response will be evaluated by 
physical examination, anatomic imaging measurement, and performance status.
Patients with elevated CA-125 levels that can be monitored for response will be assessed 
according to the GCIG CA-125 response criteria in addition to RECIST v1.1. 
GCIG Criteria
The GCIG has agreed criteria for defining response and progression of ovarian carcinoma 
which use the serum marker CA-125 and the situations where these criteria should be used.  
The GCIG recommends that for trials of relapsed ovarian cancer the following definition for 
response according to CA-125 be used in addition to RECIST v1.1 response criteria (Rustin et 
al 2011).
Evaluation of Response according to CA-125
Definition of response:  A response according to CA-125 has occurred if there is at least a 
50% reduction in CA-125 levels from a pre-treatment sample. The response must be 
confirmed and maintained for at least 28 days.  Patients can be evaluated according to CA-125 
only if they have a pre-treatment sample that is at least twice the ULN and within 2 weeks 
prior to starting treatment.
To calculate CA-125 responses accurately, the following rules apply: 
∀
Intervening samples and the 28-day confirmatory sample must be less than or equal 
to (within an assay variability of 10%) the previous sample.
∀
Variations within the normal range of CA-125 levels will not interfere with the 
response definition. 
∀
For each patient, it is preferred that the same assay method be used, and the assay 
must be tested in a quality-control scheme.


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∀
Patients are not evaluable (NE) by CA-125 if they have received mouse antibodies 
(unless the assay used has been shown not to be influenced by HAMA [1, 2]) or if 
there has been medical and/or surgical interference with their peritoneum or pleura 
during the previous 28 days.  If assessing therapy that includes two treatment 
modalities for relapse (e.g., surgery and chemotherapy), any CA-125 response results 
from both treatments modalities.  CA-125 cannot distinguish between the effects of 
the two treatments.
The date when the CA-125 level is first reduced by 50% is the date of the CA-125 response. 
To calculate RRs, an intent-to-treat analysis should be used that includes all patients with an 
initial CA-125 level of at least twice the ULN as eligible and evaluable.  In addition, as a 
separate analysis, those patients who have both a CA-125 response and whose CA-125 level 
falls to within the normal range, can be classified as CA-125 complete responders.  Patients 
who have a fall of CA-125 to within the normal range but whose initial CA-125 was less than 
twice the ULN, have not had a CA-125 response and cannot therefore be classified as a CA-
125 complete responder.
5.2
Safety assessments
A physical examination, medical history (to capture previous treatment medications and 
response to each prior treatment regimen), concomitant medications recorded (including ≤14 
days prior to trial entry), ECOG PS, complete blood count (CBC) with differential and 
platelets, clinical chemistry, and 12-lead ECG should be done at screening, at the beginning of 
each treatment cycle, and at the FPV according to the study plan.  Assessments at other time 
points are indicated in the study plan. 
Vital signs (resting heart rate, blood pressure, temperature) and weight will be recorded at 
screening and at times shown in the study plan. 
The following are AZD1775 project related assessments that should be carried out in addition 
to any standard protocol monitoring such as routine haematology/biochemistry, vital signs, 
and physical examinations.
5.2.1
Laboratory safety assessments
Blood samples for determination of clinical chemistry, haematology, coagulation, and PK will 
be performed at the times indicated in the Study Plan (Table 1-Table 4) and PK assessment 
schedule (Table 6-Table 13).
Additional safety samples may be collected as clinically indicated and 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.


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The clinical chemistry and haematology will be performed at the local laboratory. Sample 
tubes and sample sizes may vary depending on laboratory method used and routine practice at 
the study centre. 
The following laboratory variables will be measured as a minimum (some of these variables 
may be measured at baseline only):
Table 5
Laboratory Safety Variables
Clinical chemistry
Haematology
Serum (S)/Plasma (P)-Albumin
Blood (B)-Haemoglobin
S/P-ALT
B-Leukocyte count
S/P-AST
B-Absolute leukocyte differential count:
S/P-Alkaline phosphatase (ALP)
Neutrophils
S/P-Bilirubin, total
Lymphocytes
S/P-Calcium
Monocytes
S/P-Creatinine
Basophils
S/P-Glucose
Eosinophils
S/P-CO2
B-Platelet count
S/P-Phosphorus
S/P-Potassium
Coagulation
S/P-Sodium
PT/INR/PTT
S/P-Chloride
S/P-Total protein
Serum or Urine Pregnancy Test
S/P-BUN
Urinalysis
S-Lactate dehydrogenase (LDH)
Urine dipstick (pH, specific gravity, blood, protein 
and glucose)
Pre-menopausal women of childbearing potential must have a negative urine or serum 
pregnancy test within 3 days prior to starting study treatment on Day 1, and a confirmatory 
test will be performed before treatment at the start of each cycle, at the EOT visit, and the 
FPV. In the event of suspected pregnancy during the study, the test should be repeated and, if 
positive, the patient discontinued from study treatment immediately.
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  Any clinically significant abnormal laboratory values should be 
repeated as clinically indicated and recorded on the eCRF. The laboratory results should be 
signed and dated and retained at centre as source data for laboratory variables.  For 


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information on how AEs based on laboratory tests should be recorded and reported, see 
Section 6.4.
NB. In case a subject shows an AST or ALT ≥3xULN AND total bilirubin ≥ 2xULN please 
refer to Appendix C, ‘Actions required in cases of combined increase of Aminotransferase and 
Total Bilirubin – Hy’s Law’, for further instructions.
5.2.2
Physical examination
A complete physical examination will be performed and include an assessment of the 
following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal (including
spine and extremities) and neurological systems. 
If new or aggravated physical findings imply deterioration compared with baseline, the 
finding should be reported as an AE (Section 6.4).  Performance status will be assessed using 
the ECOG performance status criteria.
5.2.3
ECG
An ECG will be performed at baseline as indicated in the Study Plans.  QTc interval will be 
calculated using Fridericia's formula (per institutional standards) obtained from 3 ECGs 
performed 2-5 minutes apart at study entry.  Thereafter, triplicate 12-lead ECGs will be 
performed 2-5 minutes apart prior dosing on Day 1 of each treatment cycle and the FPV.
Attention should be paid to any detected increases in QTc interval.  Patients who develop a 
single resting value of QTc interval of >470 msec/female or a shift from baseline of 60 ms 
should stop taking AZD1775.  Dosing can be resumed at a reduced dose (see Section 6.9.2) 
after return of the resting QTc interval to pre-treatment status has been confirmed and 
correction of possible electrolyte imbalance has been made.
Monitoring of QTc, checking and correction of abnormal electrolyte levels and renal function 
are advised, especially in case of severe/prolonged diarrhoea.  If QTc increases markedly from 
baseline, but stays below the above limits, a cardiologist’s advice should be sought.
The concomitant use of ondansetron (known to prolong the QTc interval in rare cases, per 
labelling) should be taken into account when interpreting QTc changes.
5.2.4
CA-125 tumour markers
Serum samples will be collected for CA-125 tumour markers on all patients at baseline 
(within 14 days prior to Cycle 1 Day 1), Day 1 of each cycle, end-of-study treatment visit, and 
the FPV.  The CA-125 analysis will be performed by a local laboratory.  Patients with 
elevated CA-125 levels that can be monitored for response will be assessed according to the 
GCIG CA-125 response criteria in addition to RECIST v1.1. 


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5.2.5
Other safety assessments – ECHO or MUGA
For patients participating in the AZD1775 and PLD combination cohort (Arm D), left 
ventricular cardiac function (ECHO or MUGA) will be assessed at baseline, every 6 cycles or 
as clinically indicated based on prior anthracycline exposure and clinical symptoms.  End of 
treatment assessment should be done for patients who receive at least 3 cycles of treatment 
and have not had an ECHO done in the past three months. 
5.3
Pharmacokinetics
5.3.1
Collection of samples
All patients in each treatment arm will have PK plasma samples collected according to Table 
6–Table 14.  
Objectives for the collection of PKs from the lead-in safety and expansion group patients are:
!
To characterise the exposure of all analytes in the lead-in safety group   to confirm no 
change in exposure
!
To characterise the exposure of all analytes to help determine the cause of any adverse 
effects observed in the safety cohort
!
To assess the drug interaction between AZD1775 plus carboplatin, AZD1775 plus 
paclitaxel, AZD1775 plus gemcitabine, and AZD1775 plus PLD
!
To provide exposure data for AZD1775 which can be included with that from other 
studies for overall population PK (POPPK) analysis to help understand the PKs of the 
compound and identify covariates. 
During Cycle 1, the PK collection schedule will vary with the treatment arm reflecting the 
different PKs of the 4 chemotherapeutic agents (see Table 6, Table 7, Table 8, Table 10, Table 
11, Table 12, and Table 13).  AZD1775 will be given at the start of each cycle, which also 
defines the start of PK sampling for all analytes.  The chemotherapeutic agent infusion will 
start at the same time AZD1775 is dosed.  PK collections for additional cycles are presented in 
Table 9 and Table 13).
The following information will be recorded each time a PK sample is collected:
∀
Date and actual time of the PK sample collection
∀
Date and time of the AZD1775 dose preceding PK collection
∀
Date and time of the start and end of infusion of the relevant chemotherapeutic agent
∀
Time and date of last meal 


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If a patient’s dosing regimen is altered, the PK sampling regimen will be appropriately 
amended to characterise PK profiles.  Equivalent PK samples will be required if an additional 
lead-in safety/expansion cohort is necessary.
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
5.3.2
Determination of drug concentration
Samples for determination of AZD1775 concentrations in plasma will be analysed by 
Covance on behalf of AstraZeneca using an appropriate bioanalytical method.  Additional 
analyses may be conducted on the biological samples to further investigate the presence 
and/or identity of drug metabolites.  Full details of the analytical method used will be 
described in a separate bioanalytical report.  The data may be compared by visual inspection 
to broadly compare exposure to historic monotherapy or other data.  The analysis of the PK 
samples may be expedited if tolerance, safety or other issues are suspected to be related to, or 
have caused changes in the exposure of AZD1775.  From a PK modelling perspective, this 
data will be used for pooling with PK data collected from other AZD1775 studies in order to 
perform a population PK analysis using non-linear mixed effects modelling.  This data
together with safety and pharmacodynamics (PDx) data may be used as part of a future 
exploratory PK/PDx analysis which will be reported separately from the CSR.
Plasma concentrations of gemcitabine (and 2’Difluoro-2’2’-deoxyuridine), paclitaxel, total 
platinum, and total doxorubicin will be analysed by Covance on behalf of AstraZeneca and 
used to compare exposure and PKs to published data.  Other drug related components may be 
measured if required.
Table 6
Lead-in PKs: Arm A gemcitabine and AZD1775 cycle 1 
Time (h) post AZD1775 
dose
0a
0.5c
1c
2d
4d
6d
end of 
dayb,d
Swallow AZD1775
X
Start gemcitabine IV
X
Stop gemcitabine IV
X
PK sample for 
gemcitabine
X
X
X
X
X
PK sample for AZD1775
X
X
X
X
X
X
X
h = hour, IV = intravenous infusion
a
PK sample may be collected the day before dosing.
b
Collection time optional, collect as late as possible at the end of the first day, ideally around 8 hours post 
dose.
c
±5 minutes.
d
±15 minutes. 


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Table 7
Lead-in PKs: Arm B paclitaxel and AZD1775 cycle 1  
Time (h) post 
AZD1775 dose
0a
0.5 c
1c
2 d
4 d
6 d
end of 
dayb, d
Swallow AZD1775
X
Start paclitaxel IV
X
Stop paclitaxel IV
X
PK sample for 
paclitaxele
X
X
X
X
X
X
PK sample for 
AZD1775
X
X
X
X
X
X
X
h = hour, IV = intravenous infusion
a
PK sample may be collected the day before dosing.
b
Collection time optional, collect as late as possible at the end of the first day, ideally around 8 hours post 
dose.
c
±5 minutes.
d
±15 minutes. 
e
Efficacy expansion:  PKs will be collected only for paclitaxel according to this schedule.  AZD1775 PKs 
will not be collected according to this schedule but will follow the sparse collections described in Table 14.   
Table 8
Lead-in and Expansion PKs: Arm C carboplatin and AZD1775 Cycle 1, 
Day 1
Time (h) post 
AZD1775 dose
0a
0.5 c
1c
2 d
4 d
6 d
end of 
dayb d,
Swallow AZD1775
X
Start Carboplatin IV
X
Stop Carboplatin IV
X
PK sample for total 
platinum
X
X
X
X
X
X
X
PK sample for 
AZD1775
X
X
X
X
X
X
X
h = hour, IV = intravenous infusion
a
PK sample may be collected the day before dosing.
b
Collection time optional, collect as late as possible at the end of the first day, ideally around 8 hours post 
dose.
c
±5 minutes.
d
±15 minutes. 
Table 9
Lead-in and Expansion PKs: Arm C Carboplatin and AZD1775, Cycle 
3, Day 3 
Time (h) pre-dose
Cycle 3+  
Day 3a, b
Cycle 3+ a, b
Day 3 a, b
Pre-dose
0.5h
PK samples for AZD1775
X


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a
Alternate cycles, starting with Cycle 3 (e.g. Cycles 3, 5, 7 etc.)
b
±15 minutes. 
Table 10
Lead-in PKs: Arm D PLD and AZD1775 (PK for PLD only), Cycle 1, 
Day 1 
Time (h) post 
infusion
0a
0.5 b
1b
2
6
Swallow AZD1775
X
Start PLD IV
X
PK sample for PLD
X
X
X
X
X
a
±5 minutes.
b
±15 minutes. 
Table 11
Lead-in PKs: Arm D PLD and AZD1775 (PKs for PLD only), 
Additional Cycle 1 time points 
Time (h) post
infusion
Cycle 1
Day 2a, b
Cycle 1
Day 3 a, c
Cycle 1
Day 8 a, d
Cycle 1
Day 15 a, e
PK sample for PLD
X
X
X
X
a
± 1 hour
b 
24 hours post-infusion 
c 
48 hours post-infusion 
d 
7 days post-infusion 
e 
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Table 12
Lead-in PKs: Arm D PLD and AZD1775 (PKs for AZD1775), Cycle 1 
Day 3 
Time (h) post 
0a
1c
2c
4d
6d
end of
dayb,d
Swallow AZD1775
PK sample for AZD1775
X
X
X
X
X
X
a
PK sample may be collected the day before dosing.
b
Collection time optional, collect as late as possible at the end of the first day, ideally around 8 hours post 
dose.
c
±5 minutes.
d
±15 minutes. 
Table 13
Lead-in PKs: Arm D PLD and AZD1775, Alternate cycles starting from 
Cycle 3  
Time (h) pre-dose
Cycle 3+  
Day 1a, b
Cycle 3+ a, b
Day 1 a, b
Cycle 3+
Day 3a, b
Pre-dose
1h
Pre-dose
PK sample for PLD
X
X
PK samples for AZD1775
X
a
Alternate cycles, starting with Cycle 3 (e.g. Cycles 3,5,7 etc.)
b
±15 minutes. 
Table 14
AZD1775 Sparse PKs for Arm B Efficacy and Arm C2 Safety 
Expansions  
Cycle 1
Cycle 3
Cycle 5
Cycle 7
Day
Day 3 or 10 or 17
Day 3 or 10 or 17
Day 3 or 10 or 17
Day 3 or 10 or 17
AZD1775 Pre-dose
X
X
X
X
AZD1775 1-hour 
post-dose
X
X
X
X
AZD1775 2-4 
hours post-dose
X
X
X
X
Sparse PKs will be collected from all patients in the Arm B efficacy expansion and Arm C2 
safety expansion as described below.  The collection of these PKs is mandatory.  


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5.3.3
Storage and destruction of pharmacokinetic samples
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or six 
months after issuance of the draft Bioanalytical Report (whichever is earlier), unless requested 
for future analyses. Any pharmacokinetic sample remaining after analysis for AZD1775 may 
be used for exploratory drug-drug interaction (DDI), metabolite, or biomarker analyses.  Any
results from such analyses may be reported separately from the CSR.
Additional analyses may be conducted on the anonymised, pooled PK samples to further 
evaluate and validate the analytical method. Any results from such analyses may be reported 
separately from the 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.
Any residual back-up PK samples will be disposed of after the CSR is finalized.  
5.4
Pharmacodynamics
5.4.1
Collection of samples
Pharmacodynamic samples will not be taken during the study.
5.5
Pharmacogenetics
5.5.1
Background and rationale
AstraZeneca intends to perform genetic research in the AZD1775 clinical development 
programme to explore how genetic variations may affect the clinical parameters associated 
with AZD1775 when combined with chemotherapy.  Collection of DNA samples from 
populations with well-described clinical characteristics may lead to improvements in the 
design and interpretation of clinical trials and, possibly, to genetically guided treatment 
strategies.  Future research may suggest other genes or gene categories as candidates for 
influencing not only response to AZD1775 but also susceptibility to or evolution of ovarian 
cancer/cancer studies, for which AZD1775 is being evaluated.  Thus, this genetic research 
may involve study of additional un-named genes or gene categories, but only as related to 
disease susceptibility to or evolution of ovarian cancer/cancer studies, and drug action.
5.5.2
Pharmacogenetic research objectives
The objective of this research is to collect and store DNA for future exploratory research into 
genes/genetic variation that may influence response (e.g., distribution, metabolism, safety, 
tolerability and efficacy) to AZD1775, as well as susceptibility to disease evolution of ovarian 
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The benefits of being able to explore associations between genes and clinical outcomes within 
the AZD1775 programme are potentially many, and include:
!
Analysis of genes that may affect efficacy, safety, and tolerability of AZD1775 when 
combined with chemotherapy (for example, but not limited to, drug metabolising 
enzymes and drug transporters).
!
Genetic research into genes that may contribute to the development or evolution of, or 
susceptibility to ovarian cancer/cancer studies.
5.5.3
Genetic Research Plan and Procedures
Selection of genetic research population
Patients will be asked to participate in this genetic research.  Participation is voluntary and if a 
patient declines to participate there will be no penalty or loss of benefit.  The patient will not 
be excluded from any other aspect of the main study.
5.5.4
Discontinuation of patients from this genetic research
Patients may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study.  Voluntary discontinuation will 
not prejudice further treatment.
5.5.5
Collection of pharmacogenetic samples
The patient’s consent to participate in the pharmacogenetic research components of the study 
is optional; however, for inclusion in this optional research, patients must provide informed 
consent.  
The blood sample (approximately 10 mL) for genetic research will be obtained from the 
patients at screening, prior to their first dose of study drug.  Although genotype is a stable 
parameter, early sample collection is preferred to avoid introducing bias through excluding 
patients who may withdraw due to an adverse event (AE); such patients would be important to 
include in any genetic analysis.  If for any reason the sample is not drawn prior to the first 
dose of study drug, it may be taken at any visit until the last study visit.  Only one sample 
should be collected per patient for genetic research during the study. 
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual.
5.5.6
Storage, re-use and destruction of pharmacogenetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 15 
years from the date of the Last Patient’s Last Visit, after which they will be destroyed.  DNA 
is a finite resource that may be used up during analyses.  The results of any further analyses 


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will be reported either in the Clinical Study Report itself or as an addendum, or separately in a 
scientific report or publication.
For all samples the DNA will be extracted from the blood sample.  The DNA sample will be 
assigned a unique number replacing the information on the sample tube. Thereafter, the DNA 
sample will be identifiable by the unique DNA number only.  The DNA number is used to 
identify the sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated contract laboratory.  No personal details identifying the individual will be available 
to any person (AstraZeneca employee or contract laboratory staff working with the DNA.)
The samples and data for genetic analysis in this study will be single coded.  The link between 
the patient enrolment/randomisation code and the DNA number will be maintained and stored 
in a secure environment, with restricted access within the Clinical Genotyping Group 
Laboratory Information Management System (LIMS) at AstraZeneca.  The link will be used 
to identify the relevant DNA samples for analysis, facilitate correlation of genotypic results 
with clinical data, allow regulatory audit and to trace samples for destruction in the case of 
withdrawal of consent when the patient has requested disposal/destruction of collected 
samples not yet analysed.
5.5.7
Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 10.
5.5.8
Informed consent
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study the patient must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the patient and the originals filed at the study centre.  The 
principal investigator(s) is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely discontinue from the genetic aspect of the study at 
any time.
5.5.9
Patient data protection
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.
Extra 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 both the genetic data and the personal identifiers of a patient.  For example, in the case of 


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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.
5.5.10
Data management
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or third party contracted 
to work with AstraZeneca to analyse the samples.
The results from this genetic research may be reported in the CSR for the main study, or in a 
separate report as appropriate.
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
5.5.11
Statistical Methods and Determination of Sample Size
The number of patients that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A statistical 
analysis plan will be prepared where appropriate.
5.6
Biomarker analysis 
The patient’s consent to the use of donated biological samples is mandatory.  
Biological samples (e.g., archived tumour samples and cfDNA) will be collected and may be 
analysed for exploratory biomarkers to assess correlations with disease activity, effects of 
study drug, clinical outcomes and toxicity.
5.6.1
Circulating free tumour DNA samples
Collection of cfDNA is mandatory at baseline, Cycle 2 Day 1, Day 1 of every odd-numbered 
cycle (Cycles 3, 5, etc.), end-of-study treatment visit, and at treatment discontinuation due to 
progression for all patients continuing treatment after the FPV in order to explore the genetic 
tumour markers in plasma, correlate with markers in tumour samples and to monitor for the 
emergence of resistance.  A baseline plasma sample will be required and subsequent plasma 
samples collected as described in the Laboratory Manual.  This exploratory analysis will be 
reported separately from the Clinical Study Report (CSR). 


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5.6.2
Optional tumour biopsies
Optional tumour biopsies during this study will be requested from consenting patients with 
easily accessible tumours who discontinue treatment due to disease progression including 
from consenting patients that continue treatment after the FPV.
The tumour biopsy procedure will be performed by core needle, under radiological guidance, 
or surgically if the site of disease is superficial and palpable or visible.  It is mandated that the 
core biopsy be removed directly from the tumour in situ and not cored from a surgically 
removed tumour.  This is to ensure the best possible quality of the biopsy, as the 
blood/nutrient supply to the tumour is not disrupted prior to biopsy collection.  
All tumour biopsies will be collected, stored, and shipped as detailed in the Laboratory 
Manual.
Any residual samples remaining after analysis will be retained for any potential subsequent 
retrospective analysis of other response related and/or cancer related biomarkers.  It is not 
intended that data derived from residual sample analysis will be reported in the CSR.
Informed consent must be obtained from any patient who agrees to provide tissue for tumour 
tissue sample testing.
5.6.3
Storage, re-use and destruction of biological samples
Samples will be stored for a maximum of 15 years from the date of the Last Subject’s Last 
Visit, 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.
5.6.4
Labelling and shipment of biological samples
The Principal Investigator (PI) 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 B, ‘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 subject unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved.
5.6.5
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.


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The PI at each centre keeps full traceability of collected biological samples from the subjects 
while in storage at the centre until shipment or disposal (where appropriate) and keeps 
documentation of receipt of arrival.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment.
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.
5.6.6
Withdrawal of Informed Consent for donated biological samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of some of the biological samples is an optional part of the study, then the 
subject may continue in the study.
The PI:
!
Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca
!
Ensures that biological samples from that subject, 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 subject 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.
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.


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6.1
Data collection of safety-related study variables 
6.1.1
Adverse events of special interest related to AZD1775
There are no AESI for AZD1775 which require additional data collection.
6.2
Definition of adverse events
An AE 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 (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., 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 study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.3
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient hospitalisation or prolongation of existing hospitalisation 
!
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 jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol (CSP).
6.4
Recording of adverse events
6.4.1
Time period for collection of adverse events
Adverse events will be collected throughout the study, from informed consent until 30 days 
after the end of the last investigational product administration. 
SAEs will be recorded from the time of informed consent and should be reported to the 
Innovations Safety Department as described in Section 6.5.  After the FPV, patients will 
continue to be monitored for all SAEs, overdoses and pregnancies while receiving 
AZD1775 ± chemotherapy and for 30 days after the last dose of AZD1775 ± chemotherapy.


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Following discontinuation of study treatment, SAEs considered related to study procedures
should continue to be collected while patients are followed-up for disease progression.
For each patient who discontinues study treatment for a reason other than disease progression:
∀
Follow-up information on all ongoing AEs should continue to be collected until the 
survival follow-up.
∀
SAEs considered related to study procedures must continue to be collected and 
reported using standard SAE timelines and process until the end of progression 
follow-up (i.e., disease progression).
∀
All deaths must continue to be collected after progression and during the survival 
follow-up.
6.4.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the eCRF. 
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s) at the end of the study, if judged necessary.
If an Investigator learns of any SAEs, including death, at any time after a patient has 
completed the study and he/she considers there is a reasonable possibility that the event is 
related to AZD1775, the Investigator should notify Innovations.
6.4.3
Variables 
The following variables will be collect for each AE:
!
AE (verbatim)
!
The date when the AE started and stopped
!
CTCAE grade and changes in CTCAE grade  
!
Whether the AE is serious or not
!
Investigator causality rating against the IP (yes or no)
!
Action taken with regard to IP
!
Outcome.
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for serious AE
!
Date Investigator became aware of serious AE
!
Reason AE is serious  
!
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!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)
!
Causality assessment in relation to other medication
!
Causality assessment in relation to module-specific combination treatments
!
Description of AE.
The grading scales found in the revised NCI CTCAE v4.03 will be utilized for all events with 
an assigned CTCAE grading.  For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria should be utilized that converts mild, moderate and 
severe events.  A copy of the CTCAE version 4.03 can be downloaded from the Cancer 
Therapy Evaluation Program website (http://ctep.cancer.gov).
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 6.3.  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 a SAE.  On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE.  
6.4.4
Causality collection
The Investigator will assess causal relationship between 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 the IP?’
For SAEs causal relationship will also be assessed for other 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 A to the CSP.
6.4.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient, reported in response to an open question from 
the study personnel 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.  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.


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They do not include metastases of the original cancer.
6.4.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
CSR.  Deterioration as compared to baseline in protocol-mandated laboratory values, vital 
signs and ECG should therefore only be reported as AEs if they fulfil any of the SAE criteria 
or are the reason for discontinuation of the study treatment unless clearly due to the 
progression of disease under study.
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 (e.g., anaemia versus low haemoglobin 
value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Deterioration of a laboratory value 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.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment.
6.4.7
Hy’s Law
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 x ULN and total bilirubin ≥ 2 x ULN may need to be 
reported as SAEs.  Please refer to Appendix C for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law.
6.4.8
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied.  It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease.  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.


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Events including diagnosis or signs and symptoms or the abnormal results of an investigation 
including those leading to hospitalization, which constitute or result from: 
(a) ‘unequivocal progression’ (i.e., representative of overall disease status change, not a 
single lesion increase) of non-measurable/non-target disease, 
or
(b) progression of malignancy under study (target disease)as determined per RECIST 1.1 
criteria, should not be reported as AEs or SAEs.  
Progression of the malignancy under study, including signs and symptoms of 
progression, should not be reported as a serious adverse events. Hospitalizations due 
to signs and symptoms of disease progression should not be reported as serious 
adverse events.
6.4.9
New cancers
The development of a new cancer should be regarded as an AE and will generally meet at 
least one of the serious criteria. New cancers are those that are not the primary reason for the 
administration of the study treatment and have been identified after the patient’s inclusion in 
this study. They do not include metastases of the original cancer.
6.4.10
Handling of deaths
All deaths that occur during the study or within the follow-up period after the administration 
of the last dose of study treatment must be reported as follows:
!
Death which is unequivocally due to disease progression should be communicated to the 
study monitor at the next monitoring visit and should be documented in the eCRF 
module, but should not be reported as a SAE during the study.
!
Where death is not clearly due to progression of the disease under study the AE causing 
the death should be reported by entering into the WBDC system as an SAE within 24 
hours.  The report should contain a comment regarding the co-involvement of progression 
of disease, if appropriate, and should assign a single primary cause of death together with 
any contributory causes.
!
Death with an unknown cause should always be reported as an SAE but every effort 
should be made to establish a cause of death.  A post-mortem may be helpful in the 
assessment of the cause of death, and if performed a copy of the post-mortem results 
(with translation of important parts into English) should be reported in an expedited 
fashion to an AstraZeneca representative within the usual timeframes. 
6.5
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF. For patients continuing after the 


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FPV (see Section 4.4), SAEs should be determined per protocol and must continue to be 
reported via the standard pharmacovigilance process (on paper) as stated below.  For medical 
emergencies, see below.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate Innovations Safety Department, the  AstraZeneca representative within one 
day i.e., immediately but no later than 24 hours of when he or she becomes aware of it.
The designated Innovations representative works with the Investigator to ensure that all the 
necessary information is provided within 24 hours of investigator awareness.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform Innovations
representatives of any follow-up information on a previously reported SAE within one 
calendar day i.e., immediately but no later than 24 hours of when he or she becomes aware 
of it.
SAE information will be sent via secure e-mail connection or via fax.  The Innovations Safety 
Department standard paper SAE Report with supporting relevant source documents (e.g. 
history and physical [H&P], hospital discharge summary, autopsy report when available, 
results of relevant diagnostic tests completed to evaluate the event) will be attached and sent 
via:
!
Secure email (Innovations SAE mailbox: 
 
!
or by 
!
Fax (Innovations safety fax number: 
Transmission of the SAE Report Form should be confirmed by the site personnel submitting 
the report.
Follow-up information for SAEs and information on non-serious AEs that become serious 
should also be reported to the Innovations Safety Department as soon as it is available; these 
reports should be submitted using the Innovations SAE Report Form.  The detailed SAE 
reporting process will be provided to the sites in the SAE reporting guidelines contained in the 
trial reference manual.
The appointed study Medical Monitor works with the Investigator to ensure that all necessary 
information is provided to the Innovations Safety Department within 24 hours of 
Investigator awareness.  
Investigators must report SAEs and follow-up information to their responsible Institutional 
Review Board (IRB) according to the policies of each responsible IRB.  For fatal or life-
PPD
PPD


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threatening AEs for which important or relevant information is missing, active follow-up is 
undertaken immediately.   
AstraZeneca or their representative will provide Regulatory Authorities, Ethics Committees 
(ECs), IRBs and PIs with clinical safety updates/reports according to local requirements. 
6.6
Overdose
A dose of AZD1775 in excess of that specified according to the protocol will constitute an 
overdose.  There is currently no known antidote to AZD1775, and the treatment of overdose 
should be supportive for the underlying symptoms.  To date, there has been one patient who 
has experienced an overdose with AZD1775 which was associated with adverse events.
Overdoses with non-AZ products used in combination or comparative studies should be 
managed according to the product label.  
Such overdoses should be recorded as follows:
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose of AZD1775 occurs in the course of the study, then the Investigator or other 
site personnel will inform the Innovations Safety Department immediately, or no later than 
24 hours of when he or she becomes aware of it.
The Innovations Safety Department 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 6.5.  
For other overdoses, reporting must occur within 24 hours.
6.7
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to the Innovations Safety 
Department.  After the FPV, pregnancies will be monitored while patients are on treatment 
and for 30 days after their final dose of AZD1775 ± chemotherapy.
6.7.1
Maternal exposure
If a subject becomes pregnant during the course of the study, IP should be discontinued 
immediately.  Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP 
under study may have interfered with the effectiveness of a contraceptive medication.  
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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) should be followed up and documented 
even if the subject 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 Innovations Safety Department representatives within 1 day (i.e., 
immediately but no later than 24 hours) of when he or she becomes aware of it.
!
The designated Innovations Safety Department 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 6.5) and within 30 days for 
all other pregnancies.
The same timelines apply when outcome information is available.
6.8
Medication error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for the study drug(s) 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 has:
!
occurred
!
was identified and intercepted before the patient received the drug
!
did not occur, but circumstances were identified that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error e.g., medication prepared incorrectly, even if it was not actually given to 
the patient
!
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
!
Drug not taken as indicated e.g., tablet dissolved in water when it should be taken as a 
solid tablet
!
Drug not stored as instructed e.g., kept in the fridge when it should be at room 
temperature
!
Wrong patient received the medication 


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!
Wrong drug administered to patient
Examples of events that do not require reporting as medication errors in clinical studies: 
!
Patient accidentally missed drug dose(s) e.g., forgot to take medication
!
Accidental overdose (will be captured as an overdose)
!
Patient 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 Innovations representatives within 1 day, i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.  The Innovations representative works 
with the Investigator to ensure that all relevant information is completed within 1 to 5 calendar 
days if there is an SAE associated with the medication error (see Section 6.3) and within 30 
days for all other medication errors.
6.9
Management of IP related toxicities / Dose Reductions
Toxicity will be assessed utilizing the NCI CTCAE v4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf), 
unless otherwise specified.  
The DLT evaluations (see Section 7.2.4) will be used to assess the first 6 patients during 
Cycle 1.  Toxicity occurring in patients beyond Cycle 1 of the Part 1 lead-in safety phase will 
be graded and the appropriate dose modification or supportive care will be administered to 
decrease the signs and symptoms thereof according to this section.  
Dose adjustments will be based on the organ system exhibiting the greatest degree of toxicity.  
Dose reductions or holds and initiation of supportive care are allowed as clinically indicated 
by the treating physician.  A maximum of 2 dose reductions for the AZD1775 and 
chemotherapy will be allowed.  For patients experiencing toxicity while taking AZD1775 over 
2.5 days weekly the Investigator should contact the Medical Monitor to discuss alternative 
dosing frequencies.  Patients requiring >2 dose reductions of these drugs will be discontinued 
from the study drug and chemotherapy.  
Brief treatment or visit delays (±7 days) for public holidays or weather conditions do not 
constitute a protocol violation but should be recorded in the eCRF.


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Any patient requiring a toxicity-related dose delay of more than 28 days from the intended day 
of the next scheduled dose must be discontinued from the study unless there is approval from 
the MM for the patient to continue.
The AZD1775 and chemotherapy dose level reductions for Arms A, B, C and D are presented 
in Table 15, Table 16, Table 17, Table 18, and Table 19.  
Table 15
AZD1775 Dose Level Reductions for Toxicity 
Arm
AZD1775 
Starting Dose
AZD1775
-1 level
AZD1775 
-2 level
Arm Aa,
175 mg QD
125 mg QD
100 mg QD
(2 doses over 2 
consecutive days)
(2 doses over 2 
consecutive days)
(2 doses over 2 
consecutive days)
Arm Bb, Cc, and Dd,e
225 mg BID
(5 doses over 2.5 days)
175 mg BID 
(5 doses over 2.5 days)
125 mg BID 
(5 doses over 2.5 days)
Arm C2f
225 mg BID
(5 doses over 2.5 days) 
weekly
175 mg BID
(5 doses over 2.5 days) 
weekly
125 mg BID (5 doses 
over 2.5 days weekly)
a
AZD1775 once daily for 2 days on Days 1-2, 8-9, and 15-16.
b
AZD1775 twice daily taken in 12 hour intervals over 2.5 days on Days 1-3, 8-10, and 15-17 of each 28-Day 
cycle.
c
AZD1775 twice daily taken in 12 hour intervals over 2.5 days on Days 1-3 of each 21-day cycle.
d
AZD1775 twice daily taken in 12 hour intervals over 2.5 days on Days 1-3 of each 28-Day cycle
e
If DLTs are encountered during the lead-in safety portion the SRT may decrease AZD1775 to the next 
lowest dose level and  new -1 and -2 dose levels would be:  Arm A (100 mg and 75 mg) and Arms B and C 
(125 mg and 100 mg) respectively.  A formal protocol amendment will be generated should the dose levels 
change.
f
AZD1775 twice daily taken in 12-hour intervals over 2.5 days on Days 1-3, 8-10, and 15-17.  If the initial 
dose reduction from 225 mg BID to 175 mg BID is intolerable, patient may further dose reduce to 125 mg 
BID over 2.5 days weekly or reduce frequency of dosing e.g., Days 1-3 and 8-10 of each 21 day cycle or 
Days 1-3 only of each 21 day cycle after discussion with Medical Monitor.  
Dose level reductions for gemcitabine are shown below.
Table 16
Gemcitabine Dose Level Reductions for Toxicity
Gemcitabinea
Starting Dose
Gemcitabine 
-1 level
Gemcitabine 
-2 level
800 mg/m2
600 mg/m2
400 mg/m2
a
Gemcitabine is administered on Days 1, 8 and 15 of each 28-day cycle.
Dose level reductions for weekly paclitaxel, 28-day schedule are shown in Table 17.


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Table 17
Weekly Paclitaxel (28-Day Cycle) Dose Level Reductions for Toxicity
Paclitaxela
Starting Dose
Paclitaxel
-1 level
Paclitaxel
-2 level
80 mg/m2
60 mg/m2
50 mg/m2
a
Paclitaxel is administered on Days 1, 8 and 15 of each 28-day cycle.
Table 18
Carboplatin Dose Level Reductions for Toxicity
Carboplatina
Starting Dose
Carboplatin 
-1 level
Carboplatin 
-2 level
Safety and efficacy
AUC 5
AUC 4
AUC 3
a
Carboplatin is administered on Day 1 of each 21-day cycle.
Table 19
PLD Dose Level Reductions for Toxicity
Arm
PLDa Starting Dose
PLD -1 Dose Level
D
40 mg/m2
30 mg/m2
a
PLD is administered on Day 1 of each 28-day cycle.
6.9.1
Dose modifications due to haematologic toxicity
Complete blood counts (CBC) will be obtained for all patients at the beginning of each 
treatment week and reviewed prior to dose administration.  If hematologic toxicity occurs (see
Table 20), treatment should be held and ANC and platelets should be monitored at least 
weekly.  Patients should be managed as medically indicated.
Treatment should not be resumed until recovery to Grade 1 (ANC ≥1.5 x 109/L or 1,500/μL; 
platelets ≥75,000/μL).
Table 20
Management of haematological toxicity in patients receiving AZD1775 
plus chemotherapy
Blood Neutrophil and Platelet Counts and AZD1775/Chemotherapy Action 
Neutrophil count
Action 
AZD1775
Action 
chemo
2nd
event
Action 
AZD177
5
Action 
chemo
3rd
event
Action 
AZD1775
Action 
chemo
Grade 2 <1.5-1.0 x 
109/L
Hold
Resume at 
same dose
Hold
Resume at 
same dose
Hold
Resume
at DL-1
Hold
Resume 
at same 
dose
Hold
Resume at 
DL-2
Hold 
Resume at 
DL-1
Grade 3 <1.0-0.5 x 
109/L
Hold
Resume at 
DL-1
Hold
Resume at 
same dose
Hold
Resume 
at DL-2
Hold
Resume 
at DL-1
Hold
Resume at 
DL-2
Hold
Resume at 
DL-2


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Blood Neutrophil and Platelet Counts and AZD1775/Chemotherapy Action 
Grade 3 <1.0-0.5 x 
109/L with 
documented 
infection and/or 
fever
Hold
Resume at 
DL-1
Hold
Resume at 
DL-1
Hold
Resume 
at DL-2
Hold
Resume 
at DL-2
Hold
Contact 
Medical 
Monitor
Hold
Contact 
Medical 
Monitor
Grade 4 <0.5 x 
109/L
Hold
Resume at 
DL-1
Hold
Resume at 
DL-1
Hold
Resume 
at DL-2
Hold
Resume 
at DL-2
Discontinu
e and 
follow for 
disease 
progressio
n
Discontin
ue and 
follow for 
disease 
progressio
n
Grade 4 Febrile 
neutropenia or 
Grade 4 Infection 
with neutropenia
Discontinu
e and 
follow for 
disease 
progressio
n
Discontinu
e and 
follow for 
disease 
progressio
n


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Platelet count
Action 
AZD1775
Action 
chemo
2nd
event
Action 
AZD177
5
Action 
chemo
3rd
event
Action 
AZD1775
Action 
chemo
Grade 2 75,000-
50,000/μL
Hold
Resume at 
same dose
Hold
Resume at 
same dose
Hold
Resume 
at DL-1
Hold
Resume 
at same 
dose
Hold
Resume at 
DL-1
Hold
Resume at 
DL-1
Grade 3 50,000-
25,000/μL
Hold
Resume at 
DL-1
Hold
Resume at 
same dose
Hold
Resume 
at DL-2
Hold
Resume 
at DL-1
Hold
Resume at 
DL-2
Hold
Resume at 
DL-2
Grade 4 
<25,000/μL 
without any 
evidence of 
bleeding
Hold
Resume at 
DL-1
Hold
Resume at 
DL-1
Hold
Resume 
at DL-2
Hold
Resume 
at DL-2
Discontinu
e and 
follow for 
disease 
progressio
n
Discontin
ue and 
follow for 
disease 
progressio
n
Thrombocytopenic 
haemorrhage 
(gross occult 
bleeding) 
associated with 
platelet count 
<50,000/μL (≥ 
Grade 3)
Discontinu
e
Discontinu
e
Please consider using G-CSF in the event of severe neutropenia or febrile neutropenia 
according to institutional standards.
No more than two dose reductions will be allowed for any patient.  Patients requiring further 
dose reduction due to toxicity must discontinue study treatment.  Dose re-escalation is not 
allowed.  If the patient has concurrent neutropenia and thrombocytopenia, please follow the 
most conservative guidance in Table 20 and discuss with the MM as needed.
If haematologic parameters do not recover within 28 days, the patient should be removed from 
the study treatment.
6.9.2
Non-haematologic toxicity dose modifications
Substantial acute toxicities should be managed as medically indicated and with temporary 
suspension of investigational product, as appropriate.  Dose reductions or holds and initiation 
of supportive care are allowed as clinically indicated by the treating physician.
Dose reductions of AZD1775 should be considered if the toxicity is considered to be related to 
AZD1775 (i.e. in monotherapy studies or in combination studies) if the relationship cannot be 
wholly attributed to the combination agent (each combination agent should be considered on 
an individual basis). Dose re-escalation is not permitted.  


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In general, if a patient experiences a Grade 1/Grade 2 non-haematological toxicity, no dose 
modification is required (except QTc prolongation; see table below).  If a patient experiences 
a Grade 3 or Grade 4 toxicity which is not attributable to the disease or disease-related 
processes under investigation, dosing will be interrupted and/or the dose reduced, and 
supportive therapy administered as required.  Any patient who develops a Grade 3 or 4 
non-haematologic toxicity (during the lead-in safety and efficacy portion after completing 
Cycle 1) that does not resolve to ≤ Grade 1 within 21 days should be removed from the study 
treatment, unless approved by the Medical Monitor.  However, if the Investigator determines 
that the non-haematologic toxicity was due to one study drug and not the other, treatment with 
the remaining study drug may continue as clinically appropriate.
Table 21
AZD1775 dose modifications for QTc interval prolongation
Electrocardiogram QT corrected interval prolonged
QTc Value
AZD1775
QTc 450-480 ms (males) or 
470-480 (females)
Hold. Once QTc interval has returned to pretreatment 
status and correction of possible electrolyte imbalance has 
been made, resume at next lower dose level.
QTc 481-500 ms
Hold. Seek cardiologist advice.
QTc ≥ 501 ms 
Discontinue treatment.  Seek cardiologist advice
Shift from baseline of ≥ 
60ms
Discontinue treatment.  Seek cardiologist advice.
Based upon the maximum non-haematologic toxicities experienced during the previous cycle, 
dose adjustments for subsequent cycles are to be made according to the criteria defined in 
Table 15-19, unless specified per unique toxicities noted below:
Table 22
Non-Haematologic Toxicity Dose Modification and Management
CTCAE v4.03
Gemcitabine
Paclitaxel
Carboplatin
PLD
AZD1775 
Grade 0 - 2
No dose 
modification
No dose 
modification
No dose 
modification
No dose 
modification
No dose 
modification
Grade 3b,c,d
Holda
Holda
Holda
Holda
Holda
Grade 4b
Hold until 
toxicity 
resolves to 
Grade ≤1.  
Resume with 1 
dose level 
reduction
Hold until 
toxicity 
resolves to 
Grade ≤1.  
Resume with 1 
dose level 
reduction
Hold until 
toxicity resolves 
to Grade ≤1.  
Resume with 1 
dose level 
reduction
Hold until 
toxicity 
resolves to 
Grade ≤1.  
Resume with 1 
dose level 
reduction
Hold until 
toxicity 
resolves to 
Grade ≤1.  
Resume with 1 
dose level 
reduction


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CTCAE v4.03
Gemcitabine
Paclitaxel
Carboplatin
PLD
AZD1775 
Second repeat 
incidence of 
Grade 3 or 4 
toxicity
(except nausea, 
vomiting, 
fatigue, malaise, 
lethargy, 
anorexia, 
alopecia)
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
Hepatic
Grade 1-2
No dose 
modification
No dose 
modification
No dose 
modification
No dose 
modification
No dose 
modification
Grade 3 or 4
(manifested as 
elevations in 
ALT, AST, ALP 
or bilirubin)
Hold until 
resolves to 
Grade ≤1 or 
baseline, then 
resume 
gemcitabine 
with a 1 level 
dose 
reduction.  If 
not resolved 
within 28 days 
discontinue 
gemcitabine.
Hold until 
resolves to 
Grade ≤1 or 
baseline, then 
resume   
paclitaxel with 
a 1 level dose 
reduction.  If 
not resolved 
within 28 days 
discontinue   
paclitaxel.
Hold until 
resolves to 
Grade ≤1 or 
baseline, then 
resume 
carboplatin with 
a 1 level dose 
reduction.  If not 
resolved within 
28 days 
discontinue 
carboplatin.
Hold until 
resolves to 
Grade ≤1 or 
baseline, then 
resume PLD 
with a 1 level 
dose reduction.  
If not resolved 
within 28 days 
discontinue 
PLD.
Hold until 
resolves to 
Grade ≤1 or 
baseline, then 
resume study 
drug with a 1 
level dose 
reduction.  If 
not resolved 
within 28 days 
discontinue 
study drug.
Diarrhea or 
Mucositis
Grade 3 or 4 (or 
requiring 
hospitalization)
Holda
Holda
Holda
Holda
Holda
Renal


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CTCAE v4.03
Gemcitabine
Paclitaxel
Carboplatin
PLD
AZD1775 
Grade ≥ 2
Holda
Hold until 
resolves to 
Grade ≤1 or 
baseline, then 
resume   
paclitaxel with 
a 1 level dose 
reduction.  If 
not resolved 
within 28 days
discontinue 
paclitaxel or 
reduce 1 dose 
level.
If AE reoccurs 
after 1 dose 
level 
reduction, 
reduce a 
second dose 
level once AE 
recovers to 
Grade ≤1.
Hold until 
resolves to 
Grade ≤1 or 
baseline, then 
resume 
carboplatin with 
a 1 level dose 
reduction.  If not 
resolved within 
28 days 
discontinue 
carboplatin.
Holda
Holda
Neurotoxicity
Grade 1
No dose 
modification
No dose 
modification
No dose 
modification
No dose 
modification
No dose 
modification
Grade 2
No dose 
modification
Hold until 
toxicity 
resolves to 
Grade ≤1.  
Resume with 1 
dose level 
reduction.
Hold until 
toxicity resolves 
to Grade ≤1.  
Resume with 1 
dose level 
reduction.
No dose 
modification
No dose 
modification
Grade 3 or 4
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
Discontinue 
treatment
a
Hold until toxicity resolves to ≤ Grade 1, and then resumed at the same dose with no modification. 
b
Dose reduction for nausea and vomiting should be made only if Grade 3 or Grade 4 toxicity occurs in spite of 
maximum anti-emetics.
c
For a Grade 3 pulmonary embolism, the dose should be held but the subsequent doses do not have to be 
reduced 1 dose level, at the Investigator’s discretion.   
d
Grade 3 electrolyte value(s) (i.e., hypokalaemia), do not require a dose reduction once the electrolyte is 
≤Grade 1.  


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Table 23
Additional Non-Haematologic Toxicity Dose Modification and 
Management for PLD (arm D only)
Toxicity
Dose Adjustment
Hand-Foot Syndrome (HFS)
Grade 1: Mild erythema, swelling, or 
desquamation not interfering with daily 
activities
If no previous Grade 3 or 4 HFS: no dose adjustment.
If previous Grade 3 or 4 HFS: delay dose up to 2 weeks, then 
decrease dose by 25%.
Grade 2: Erythema, desquamation, or swelling 
interfering with, but not precluding normal 
physical activities; small blisters or ulcerations 
less than 2 cm in diameter
Delay dosing up to 2 weeks or until resolved to Grade 0-1.
Discontinue PLD if no resolution after 2 weeks.
If resolved to Grade 0-1 within 2 weeks:
° And no previous Grade 3 or 4 HFS: continue treatment at 
previous dose.
° And previous Grade 3 or 4 toxicity: decrease dose by 25%.
Grade 3: Blistering, ulceration, or swelling 
interfering with walking or normal daily 
activities; cannot wear regular clothing
Delay dosing up to 2 weeks or until resolved to Grade 0-1,
then decrease dose by 25%.
Discontinue PLD if no resolution after 2 weeks.
Grade 4: Diffuse or local process causing 
infectious complications, or a bed ridden state 
or hospitalization
Delay dosing up to 2 weeks or until resolved to Grade 0-1,
then decrease dose by 25%.
Discontinue PLD if no resolution after 2 weeks.
Stomatitis
Grade 1: Painless ulcers, erythema, or mild 
soreness
If no previous Grade 3 or 4 toxicity: no dose adjustment.
If previous Grade 3 or 4 toxicity: delay up to 2 weeks then 
decrease dose by 25%.
Grade 2: Painful erythema, edema, or ulcers, 
but can eat
Delay dosing up to 2 weeks or until resolved to Grade 0-1.
Discontinue PLD if there is no resolution after 2 weeks.
If resolved to Grade 0-1 within 2 weeks:
-And no previous Grade 3 or 4 stomatitis: resume treatment at 
previous dose.
-And previous Grade 3 or 4 toxicity: decrease dose by 25%.


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Toxicity
Dose Adjustment
Grade 3: Painful erythema, edema, or ulcers, 
and cannot eat
Delay dosing up to 2 weeks or until resolved to Grade 0-1. 
Decrease dose by 25% and return to original dose interval.
If after 2 weeks there is no resolution, discontinue PLD.
Grade 4: Requires parenteral or enteral supportDelay dosing up to 2 weeks or until resolved to Grade 0-1. 
Decrease dose by 25% and return to original dose interval.
If after 2 weeks there is no resolution, discontinue PLD.
6.9.3
Non-haematologic toxicity management guidelines
6.9.3.1
Diarrhoea
Due to frequent reports of diarrhoea with AZD1775 administration, vigorous anti-diarrhoeal 
treatment loperamide (lmodium) is required at the first onset of diarrhoea according to 
American Society of Clinical Oncology (ASCO) guidelines.  Patients should be instructed to 
take oral loperamide (Imodium) 4 mg at the first onset of diarrhoea and then 2 mg every 2 
hours until diarrhoea-free for at least 12 hours. The first dose of loperamide could be lowered 
to 2 mg if the diarrhoea is recurrent and if, in the opinion of the treating physician, the 
diarrhoea is not severe.
Patients should be instructed to notify the Investigator or research staff of the occurrence of 
bloody or black stools, symptoms of dehydration, fever, inability to take liquids by mouth, and 
inability to control diarrhoea within 24 hours of using loperamide (Imodium) or other 
prescribed anti-diarrhoeal medications.
If diarrhoea is severe (i.e., requiring IV rehydration) and/or associated with fever or severe 
neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed.  Patient with 
severe diarrhoea or any diarrhoea associated with severe nausea or vomiting should be 
hospitalized for IV hydration and correction of electrolyte imbalances.
6.9.3.2
Nausea and vomiting
All patients receiving oral AZD1775 are required to receive premedication for preventing 
nausea and vomiting prior to each AZD1775 dose regardless of the protocol schedule or dose. 
The regimen described below should be instituted immediately for these symptoms:
!
All patients must receive a 5-HT3 antagonist, e.g., ondansetron (Zofran) 8 mg PO BID or 
granisetron (Kytril) 1 mg PO BID prior to each dose of AZD1775.  Additional doses of 5-
HT3 antagonist may be used if needed.  In addition, dexamethasone 4 mg PO will be 
given as a minimum with each AZD1775 dose, on the first day of every 3-5 day dosing 


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period, unless contraindicated or not well tolerated.   Dexamethasone may be continued 
on further days of dosing, potentially at a lower dose.  Dexamethasone or the 5-HT3 
antagonist may be given by IV, as needed.
!
Aprepitant (Emend) and fosaprepitant are not permitted due to known drug-drug 
interactions.
!
Promethazine (Phenergan], prochlorperazine (Compazine), and benzodiazepine may still 
be used as additional adjunctive treatments during AZD1775 therapy.
!
Patients should be strongly encouraged to maintain liberal oral fluid intake.
!
Suitable alternative medications may be used, with adequate justification, in those studies 
where the use of any of the above medications might interfere with other study 
procedures or are deemed insufficient.
6.9.3.3
Febrile neutropenia
Patients experiencing febrile neutropenia with significant symptoms should be managed in a 
hospital setting according to standard procedures, with the urgent initiation of IV antibiotic 
therapy.  Patients with febrile neutropenia without symptoms should be managed according to 
standard guidelines.
6.9.3.4
Motor neuropathy or muscle weakness
Any onset of > Grade 2 motor neuropathy or > Grade 2 muscle weakness should be evaluated 
by an electromyogram to rule out the possibility of chronic inflammatory demyelinating 
polyneuropathy (CIDP).  With a diagnosis of CIDP the patient should be discontinued from 
study treatment.
6.9.3.5
Dose modifications for infusion reactions
Infusion reactions (e.g. rash, urticaria, erythema, pruritus, bronchospasm, and hypotension) 
can occur with the agents used in this study.  There is increased risk of a reaction with 
carboplatin, paclitaxel and PLD.  Carboplatin and PLD must be discontinued in patients 
experiencing a Grade 3 or 4 infusion reaction during treatment.
To identify the grade of a reaction, refer to the list below adapted for the General Disorders 
and Administration Site Conditions section of the NCI CTCAE v4.03:
Grade 1: Mild transient reaction; infusion interruption not indicated; intervention not 
indicated.
Grade 2: Therapy or infusion interruption indicated but responds promptly to symptomatic 
treatment (e.g., antihistamines, non-steroidal anti-inflammatory drugs [NSAIDs], 
narcotics, IV fluids indicated for ≤24 hours).
Grade 3: Prolonged (e.g., not rapidly responsive to symptomatic mediation and/or brief 
interruption of infusion); recurrence of symptoms following initial improvement; 


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hospitalization indicated for other clinical sequelae.  Note: any infusion that is 
interrupted and not resumed within the visit will be considered a Grade 3 reaction.
Grade 4: Life-threatening consequences; urgent intervention indicated.
6.10
Study governance and oversight
A Safety Review Team (SRT) will be established by Innovations for this study.  Reviewers 
may include the study PI, MM, Principal Biostatistician, Safety Director, Safety Lead, Clinical 
Data Analyst, Clinical Project Manager, and Sponsor representatives.  The roles and 
responsibilities of the SRT and the MM are described in the Dose Escalation Plan.  
The SRT will review all available safety data on the first 6 evaluable lead-in safety patients 
completing Cycle 1 DLT evaluation from each Part 1 treatment arm.  The SRT will review the 
frequency and severity of AEs of the 6 lead-in safety patients and will compare to published 
data for similar regimens administered in this setting.  The frequency of additional safety 
reviews will be determined by the SRT based on the early safety reviews.  Accrual will not be 
halted while the review is being conducted unless 2 patients experience a DLT in a treatment 
arm.  If safety signals arise from this review, the SRT may recommend discontinuation of 
enrolment to a treatment arm or a change to the dose and/or schedule of AZD1775.  If fewer 
than 2 of the 6 evaluable patients experience a DLT in a treatment arm then enrolment to that 
arm will continue for evaluation of efficacy. 
The MM will monitor the safety of individual patients during the entire AE reporting period 
(i.e., from the first administration of AZD1775 through 30 days after completion of study 
treatment).  In addition, the MM will conduct the safety review to preserve the integrity of the 
study.  MM duties may include, but not limited to the following:
!
Perform periodic reviews of all safety data for individual patients.  These listings will 
include: demographic characteristics, general medical history (including concurrent 
illnesses), disease history, clinical laboratory data (serum chemistry, haematology), any 
AEs requiring study drug interruption or discontinuation, and AEs (all grades).
!
Perform continued monitoring of Grade 3 and higher adverse events and SAEs on an 
ongoing basis for all patients.
Please refer to the Dose Escalation Plan for additional details.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
AstraZeneca will supply AZD1775 capsules for oral use.  The capsules will be supplied in 
high-density polyethylene (HDPE) bottles, which sufficiently protect the drug from light.  The 
different capsule strengths (see table below) should not be combined in the same bottle at any 
time.  Additional information about the IP may be found in the IB.


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Investigational product
Dosage form and strength
AZD1775
25 mg, 50 mg, 75 mg, or 100 mg capsules
7.2
Dose and treatment regimens
7.2.1
AZD1775  
AZD1775 will be taken with 8 ounces of water, approximately 2 hours before or 2 hours after 
food.  The administration schedules for AZD1775 and chemotherapy will differ in the arms.    
If a patient missed a dose according to schedule, the dose should be taken as soon as possible, 
but not more than 6 hours after the missed dose was scheduled.  If greater than 6 hours, the 
missed dose should be skipped and the patient should take the next dose when scheduled.  If 
the patient missed the 5th dose of the cycle (single dose taken on Day 3 of dosing), the dose 
should be taken as soon as possible. 
If vomiting occurs after the patient takes the AZD1775, the patient should be instructed not to 
retake the dose, but to wait until the next scheduled dose of AZD1775.  If vomiting persists, 
the patient should contact the Investigator.  
AZD1775 dosing compliance should be reviewed with the patient at the beginning of each 
new treatment cycle when study drug is dispensed.  All patients will be required to complete a 
Dosing Diary, which must be returned to the clinic for review at each visit.  The patient should 
be instructed to record each date and time the dose(s) were taken on the dosing diary.  If a 
dose is missed, the reason must be noted in the diary.  A copy of the Dosing Diary is provided 
in the study reference materials.  In addition, patients should be advised to return any unused 
AZD1775 in the original bottles, in addition to returning any empty bottles.
All study drugs must be kept in a secure place under appropriate storage conditions.  The IP 
label on the bottle and the IB specifies the appropriate storage.
7.2.2
Chemotherapy
7.2.2.1
Gemcitabine 
800 mg/m2 IV Days 1, 8 and 15 every 28 days
Commercially available gemcitabine 800 mg/m2 IV will be infused over approximately 
30 minutes or according to institutional standards.  
Refer to the gemcitabine package insert for additional information.


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7.2.2.2
Paclitaxel 
80 mg/m2 IV Days 1, 8 and 15 every 28 days
Commercially available paclitaxel will be administered as a 1-hour IV infusion (± 10 minutes) 
at a dose of 80 mg/m2 according to institutional standards.  
Patients should be pre-medicated with corticosteroids, diphenhydramine and/or H2 antagonists 
according to institutional standards (see Section 7.7).  
Refer to the paclitaxel package insert for additional information.
7.2.2.3
Carboplatin  
Area Under the Curve (AUC) 5 IV Day 1 every 21 days
Carboplatin, at a dose calculated to produce an AUC of 5 will be administered by intravenous 
infusion according to institutional standards.  
The carboplatin dose will be calculated using the Calvert Formula based on the patient’s GFR 
which is estimated by using the CrCl.  
Calvert Formula: Carboplatin dose (mg) = target AUC x (GFR + 25)
The FDA has recommended that physicians consider capping the dose of carboplatin for the 
desired exposure (AUC) to avoid potential toxicity due to overdosing for all laboratories using 
the IDMS-derived serum creatinine measurements.  Therefore the maximum dose of 
carboplatin should be based on a CrCl no greater than 125 mL/min for patients with normal 
renal function.  In these, carboplatin can be safely dosed according to the instructions in the 
drug’s labelling.  
Refer to US FDA, Center for Drug Evaluation and Research website:  
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/
ucm228974.htm for more specific guidelines.
Cockcroft-Gault Formula: 
CrCl (GFR) = [(140 – age) x (wt in kg)] x (0.85 for female)
                     
(72 x serum creatinine [mg/dL])
Patients may receive prophylactic anti-emetic therapy for moderately emetogenic 
chemotherapy according to institutional standards, excluding aprepitant (Emend), (see 
Section 7.7).  
Refer to the carboplatin package insert for additional information.


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7.2.2.4
Pegylated liposomal doxorubicin (PLD)  
Commercially available PLD (40 mg/m2) will be administered on Day 1 of each 28-day Cycle.  
PLD should be administered at an initial rate of 1 mg/min to minimize the risk of infusion 
reactions.  If no infusion related reactions occur, the rate of infusion can be increased to 
complete administration over 1 hour.  A bolus injection or undiluted solution should not be 
administered.  PLD should not be mixed with any other drug.
Refer to the package insert for additional information.
7.2.3
Lead-in safety and efficacy selection
A lead-in safety and efficacy phase will be implemented to establish safety and tolerability 
and to thereafter evaluate efficacy.  
AZD1775 schedules and paired chemotherapeutic agents are presented below:  
Arm A (AZD1775 plus gemcitabine):
AZD1775 (175 mg PO) will be taken once a day on Days 1-2, 8-9 and 15-16.  Gemcitabine 
800 mg/m2 will be administered by intravenous infusion according to institutional standards 
on Days 1, 8, and 15 of each 28 day cycle.  AZD1775 should be taken approximately 2 hours 
before or 2 hours after food.
Arm B (AZD1775 plus weekly paclitaxel):
Five doses of AZD1775 (225 mg PO BID) will be taken in approximate 12 hour intervals over 
2.5 days weekly (Days 1-3, 8-10 and 15-17).  Weekly paclitaxel 80 mg/m2 IV will be 
administered according to institutional standards on Days 1, 8 and 15 of each 28 day cycle.  
AZD1775 should be taken approximately 2 hours before or 2 hours after food.
Arm C (AZD1775 plus carboplatin):
Five doses of AZD1775 (225 mg PO BID) will be taken in approximate 12 hour intervals over 
2.5 days (Days 1-3). AZD1775 should be taken approximately 2 hours before or 2 hours after 
food. Carboplatin AUC 5 IV will be administered according to institutional standards on Day 
1 of each 21 day cycle.  
Arm C2 Safety Expansion
Patients will receive carboplatin AUC 5 IV on Day 1 of a 21 day cycle in combination with 
AZD1775 BID for 2.5 days per dosing week (QW), on Weeks 1 (D1-3), 2 (D8-10) and 3 
(D15-17), or on Weeks 1 (D1-3) and 2 (D8-10) (2 weeks on followed by 1 week off).  
Initially, 6 patients will be enrolled in a 3-weekly AZD1775 dosing cycle; if 1 patient or less 
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12 patients.  However, if 2 or more of the first 6 patients experience a DLT then the AZD1775 
dosing may be modified to 2 weeks on followed by 1 week off.  
All decisions which include but are not limited to cohort dosing, dose escalation or de-
escalation will be reviewed by the Safety Review Team (SRT).
Arm D (AZD1775 plus PLD):
Two dose levels of AZD1775 will be tested with 40 mg/m2 PLD.  The starting dose of 
AZD1775 of this combination arm will be 175 mg, which will be escalated to 225 mg, if the 
lower dose is tolerated.
Five doses of AZD1775 (175 mg or 225 mg) will be taken in approximate 12 hour intervals 
over 2.5 days on week 1 (Days 1, 2 and 3) of each 28-day cycle.  PLD will be administered on 
Day 1 of each cycle.
Alternative dose levels/cohorts and dosing schedules which may be informed by emerging 
pre-clinical and clinical data, including the tolerability data, may be evaluated before the 
MTD/RP2 dose is defined.  Modified PK assessments would be obtained to harmonize and 
accommodate the investigation of alternative dose levels and/or schedules.
7.2.3.1
Arms A, B, & C - First 6 patients and Arm D-First 12 patients
An SRT will assess the safety and tolerability of the first 6 patients in each arm by incidence 
and severity of AEs after a minimum of 1 treatment cycle as determined by NCI CTCAE 
v4.03 and the occurrence of pre-defined dose-limiting toxicities (DLTs).  Patients must 
complete Cycle 1 safety evaluations, and return to the study centre for Cycle 2 Day 1 
evaluations to be considered evaluable for the 6 patient lead-in safety cohort unless a DLT 
occurs prior to completion of Cycle 1.  The responsibilities and general procedures of the SRC 
are described in Section 6.10.
Lead-in safety patients will be considered non-evaluable (NE) and will be replaced if:
!
They are enrolled, but not treated with study drug(s)
!
They discontinue from the study prior to completing all safety evaluations without 
experiencing a DLT during Cycle 1
Non-evaluable patients will not be counted toward the lead-in safety cohort for total DLT 
evaluation.
Patients may continue on study as long as they are benefiting, have no evidence of disease 
progression, and do not meet any criteria for discontinuation or withdrawal. 


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7.2.4
Definition of dose-limiting toxicity (DLT)
Toxicity will be assessed utilizing the NCI CTCAE v4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE), unless otherwise specified.  
Dose limiting toxicities thought to be related to the study drug during the lead-in safety phase 
will be defined as any of the following toxicities not attributable to the disease or disease-
related processes under investigation, which occur from the first dose of study treatment up to 
the last day of Cycle 1 (first 28 days [Arm A, Arm B and Arm D] or first 21 days [Arm C]), 
and that meets at least 1 of the hematologic or non-hematologic criteria below: 
!
Grade 4 haematological toxicity present for more than 7 days including:  
!
Infection with febrile neutropenia
!
Grade 3 thrombocytopenia associated with haemorrhage
!
Non-haematological toxicity ≥ Grade 3 
!
Any other toxicity that is clinically significant and/or unacceptable, does not respond to 
supportive care, results in a disruption of dosing schedule of more than 7 days, or is 
judged to be a DLT by the Investigator in collaboration with the MM.  
A DLT excludes:
!
Alopecia of any grade
!
Isolated laboratory changes of any grade without clinical sequelae or clinical significance
If appropriate the DLT observation period can be expanded by up to 2 weeks in case of 
treatment delay due to study drug-related AEs.  A treatment combination will be considered 
non-tolerated if 2 or more of up to 6 evaluable patients experience a DLT in the lead-in safety 
cohort.  If the initial dose or schedule of the treatment combination is not tolerated, patient 
enrolment to the treatment combination will be stopped and either the combination will be 
taken no further or the dose level or schedule of AZD1775 may be adjusted to evaluate safety 
in a second 6 patient cohort at the next lower dose level or revised schedule.  The DLT 
criterion applies to only the lead-in safety patients during Cycle 1.  Lead-in safety patients 
continuing treatment beyond Cycle 1 will have dose modifications applied according to 
Section 6.8.  
If fewer than 2 out of 6 patients experience a DLT in a treatment arm then enrolment may
continue for evaluation of efficacy.  
7.2.4.1
Reporting a DLT 
Any DLT occurring in a patient in the lead-in safety cohort during Cycle 1 must be reported to 
the MM by the Investigator or designee within 24 hours of first knowledge, and to the 
Innovations Safety Department as an SAE when appropriate (see Section 6.5).  


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7.2.5
Evaluation of Efficacy 
Once the AZD1775 plus carboplatin arm is evaluated as safe and tolerated by the SRT, this 
arm will continue enrolling until 23 patients have been evaluated for efficacy (i.e., tumour 
response).  At least 5 of the 23 patients must achieve an objective tumour response according 
to RECIST v1.1 for the treatment arm to be considered as sufficiently efficacious.
The AZD1775 plus paclitaxel arm will enrol approximately 30 additional patients. For 
decision making, ORR will be considered in addition to the observed safety and tolerability 
data and the other efficacy endpoints.
If there are tolerability challenges with the delivery of the initial planned treatment in this 
particular arm, revised dose levels or schedules of AZD1775 and/or the chemotherapy agent 
may be considered.  Such revisions will be documented and communicated in writing to the 
Investigator and the Institutional Review Board (IRB).
7.2.6
Restaging during treatment 
Tumour assessments will be performed at Screening (within 28 days of first dose) as outlined 
in the Study Plan and then every 2 cycles (6 weeks [±7 days] or 8 weeks [±7 days]) depending 
upon the treatment arm, for the first 12 months and every 3 cycles (9 weeks or 12 weeks)
thereafter until objective disease progression as defined by RECIST v1.1.  
Patients will be eligible to continue treatment as long as they are benefiting, have no evidence 
of disease progression, and do not meet any criteria for discontinuation or withdrawal. 
7.2.7
End of study treatment visit
Patients are allowed to continue treatment until disease progression, until the patient is 
discontinued due to unacceptable toxicity, or until a decision to discontinue treatment by the 
patient or Investigator.  After withdrawal from or completion of protocol treatment, patients 
must be followed for any new AEs for 30 calendar days after the last dose of study drug or 
until new therapy.
The end of study treatment visit will be performed 30 days from last treatment dose or prior to 
new therapy.  At the end of study treatment visit the patient will be assessed for toxicity, 
disease progression, and survival according to the Study Plans in Table 1 –Table 4
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.


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7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  The IP 
label on the bottle specifies the appropriate storage.
7.5
Compliance
The administration of all study drugs (including IPs) should be recorded in the appropriate 
sections of the eCRF.
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 
subject.
The study personnel at the investigational site will account for all study drugs received at the 
site, unused study drugs and for appropriate destruction.  Certificates of delivery, destruction 
and return should be signed. 
7.7
Concomitant and other treatments 
All concomitant medications taken within 14 days before the first dose of study medication 
and 30 days after the last dose of study medication should be recorded.  Concomitant 
medications must be recorded in the appropriate sections of the eCRF.
7.7.1
Permitted concomitant medications
Supportive Medication/Class of drug:
Usage:
Anti-emetics (excluding aprepitant [Emend] and 
fosaprepitant)
Premedication with anti-emetics is mandatory (excluding 
aprepitant [Emend] and fosaprepitant) 
Loperamide (Imodium)
Loperamide (Imodium) is required at the first onset of 
diarrhoea according to ASCO guidelines (see Section 
6.9.3.1).


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Medications including but not limited to the 
following:
•
Bisphosphonates and receptor activator of 
nuclear factor kappa-B ligand (RANKL) 
inhibitors (e.g. denosumab).
•
Patients requiring therapeutic warfarin or 
coumadin-derivative anticoagulants will be 
monitored with INR and Prothrombin Time 
(PT) as clinically indicated.
•
Low molecular weight heparin, rivaroxaban, 
or equivalent anticoagulant therapy is 
permitted where clinically indicated.
•
Patients may receive treatment with megestrol 
acetate when prescribed for appetite 
stimulation.
Medications may be administered for maintenance of 
existing conditions prior to study enrolment or for a new 
condition that develops while on study.
Prophylactic hematopoietic growth factors
Hematopoietic growth factors may be used to treat 
neutropenia as indicated by the current American Society 
of Clinical Oncology (ASCO) or Institutional guidelines, 
but should not be used as a substitute for the appropriate 
dose reductions/delays as specified in Section 6.8.   
7.7.2
Restricted concomitant medications
The following treatments and the medications listed below, as listed in Appendix G, should be 
used with caution while in this study.  Any further questions regarding concomitant treatments 
should be referred to the MM.
Restricted Medication/Class of drug:
Usage:
In vitro data suggests that AZD1775 may also be a 
weak reversible inhibitor of CYP2C19.
Caution should be exercised with concomitant 
administration of AZD1775 and agents that are sensitive 
substrates of CYP2C19, or substrates of this enzyme with 
narrow therapeutic range.
Refer to Appendix G for a list of sensitive substrates of 
CYP2C19, or substrates of this enzyme with narrow 
therapeutic range
AZD1775 has been shown to be a weak inducer of 
CYP1A2 in vitro with a maximum measured 
response between donors of 39.9% to 93.1% (at 10 
μM) and 18.6% to 32.5% (at 5 μM) of the positive 
control omeprazole (50 μM), respectively.  Given 
the nature of the AZD1775 dosing schedule, 
however, the risk of induction in the clinic is 
considered low.  
Be initially vigilant when using substrates of CYP1A2 with 
a narrow therapeutic range.


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Restricted Medication/Class of drug:
Usage:
Inhibitors or substrates of P-gp.  
In vitro studies have shown that AZD1775 may be a 
substrate and inhibitor for human P-glycoprotein (P-gp).
Caution should be exercised when agents that are inhibitors 
or substrates of P-gp are administered concomitantly with 
AZD1775 (see Appendix G).
Aminoglycosides
Caution must be exercised with the concomitant use of 
aminoglycosides in keeping with the treatment guidelines 
for carboplatin.
Gemfibrozil and Rifampin
Caution must be exercised with the concomitant use of 
Gemfibrozil (strong CYP2C8 inhibitor) and Rifampin
(strong CYP2C8 inducer) for patients receiving paclitaxel 
in this study.
BCRP substrates with narrow therapeutic index
Recent in vitro transporter studies have shown AZD1775 
to be an inhibitor of BCRP (IC50 5.1 μM).  This finding is 
particularly relevant for drugs administered orally where 
exposure is normally limited by BCRP-mediated efflux, in 
particular some statins, such as rosuvastatin. Other drugs 
where the disposition is mediated via BCRP should be 
administered with caution, dose modification considered, 
or substituted by an alternative drug.
Metformin
AZD1775 has been shown to be an inhibitor of MATE1 
and MATE2K transporters.  A drug interaction with 
substrates of either transporter cannot be ruled out, the 
most important substrate known to date being metformin.
7.7.3
Prohibited concomitant medications
Prohibited Medication/Class of drug:
Additional Information
Anticancer agents other than the study medications
If such agents are required for a patient, then the patient 
must first be withdrawn from the study treatment.
Monoclonal antibodies against PD-1, PD-L1, and 
PD-L2, CXCR2 inhibitors, and therapeutic 
anticancer vaccines
May not be administered through 90 days after the last 
dose of study drug.


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Prohibited Medication/Class of drug:
Additional Information
Concomitant treatment with aprepitant and 
fosaprepitant is not allowable per protocol until 
further evaluation.
Potent or moderate inhibitors or inducers of 
CYP3A4, sensitive CYP3A4 substrates, and 
CYP3A4 substrates with a narrow therapeutic 
window should be avoided until additional data on 
drug-drug interaction becomes available.  See 
Appendix G for a list.
No formal clinical drug interaction studies have been 
performed with AZD1775.  An exploratory assessment of 
the effect of aprepitant on AZD1775 exposure in oncology 
patients suggests that there is a drug interaction between 
AZD1775 and aprepitant, as exposure to AZD1775 
increased by ~60% when aprepitant was co-administered 
with AZD1775.  The observed increase in AZD1775 
exposure is likely the result of CYP3A4 inhibition by 
aprepitant.  This increase in exposure is statistically 
significant.  At the selected MTDs, this increase may also 
be of clinical importance.  
Grapefruit, Seville oranges and their products (e.g., 
juice, marmalade, etc.)
As grapefruit and Seville oranges are known to contain 
moderate inhibitors of CYP3A4, these fruits or their 
products (including marmalade, juice, etc.) should be 
avoided while taking AZD1775.
Herbal preparations/medications are not allowed 
throughout the study.  These herbal medications 
include, but are not limited to:  St. John’s wort, 
kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, and ginseng.  
Patients should stop using these herbal medications 7 days 
prior to first dose of AZD1775.
Administration of substances known to prolong 
ECG QTc
The potential risk of concomitant use of AZD1775 with 
ondansetron (known to prolong the QTc interval) should be 
taken into account.
7.7.4
Palliative radiotherapy
Patients may receive palliative radiotherapy during the trial only for local pain control, and 
only if in the opinion of the treating Investigator the patient does not have progressive disease 
(PD).  The radiation field cannot encompass a TL.  Radiation to a TL is considered PD and the 
patient should be removed from study treatment.
7.7.5
Other concomitant treatment
Medication other than that described above, which is considered necessary for the subject’s 
safety and well-being, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the eCRF.


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8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
A comprehensive description of the statistical analyses and related activities for this study will 
be documented in a statistical analysis plan (SAP) which will be finalized prior to DBL.  Note 
that data will be presented separately from the two parts of the study.
8.2
Sample size estimate
Sample size calculations for Arm C of the study are based upon testing a primary endpoint of 
ORR according to RECIST v1.1. In order to test the null hypothesis of an ORR of 10% 
versus an alternative hypothesis with an ORR of 30%, 23 patients are required in order to have 
85% power to test the null hypothesis using a one-sided exact binomial test at the 0.10 
significance level.  The null hypothesis will be rejected if at least 5 responses are observed 
from 23 patients.
The Part C2 expansion will enrol approximately 12 patients to assess a weekly AZD1775 
dosing regimen in combination with carboplatin in a 3 week cycle. Initially, 6 patients will be 
enrolled in a 3-weekly AZD1775 dosing cycle; if 1 patient or less experiences a DLT during 
Cycle 1, then an additional 6 patients will be enrolled for a total of 12 patients.  However, if 2 
or more of the first 6 patients experience a DLT then the AZD1775 dosing schedule will be 
shortened to 2 weeks on and 1 week off. .  
The AZD1775 plus paclitaxel arm (Arm B) will enrol approximately 30 additional patients.  
Historical response rates using weekly paclitaxel in platinum-resistant and refractory ovarian 
cancer are in the region of 20% to 40% (Pignata et al 2015, Lortholary et al 2011, McNeish et 
al 2014).  The following examples give an indication of the level of precision that will be 
achieved in the paclitaxel treated patients.
If the observed response rate is 30% (9/30), the 2-sided 80% confidence interval (CI) will be 
(19%, 43%).  If the observed response rate is 50% (15/30), the 2-sided 80% CI will be (37%, 
63%).  For decision making, ORR will be considered in addition to the observed safety and 
tolerability data and the other efficacy endpoints.
8.3
Definitions of analysis sets
8.3.1
All patients set
The All Patients Set will include all patients who have signed the informed consent form (i.e. 
screening failures plus patients enrolled).  The All Patients Set will be used to describe the 
patient disposition. 


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8.3.2
Full analysis set
The Full Analysis Set (FAS) will include all patients who received at least one (non-zero) 
dose of study treatment.  Information using this population will be tabulated by treatment arm 
unless otherwise indicated.  This population will be used for the primary analyses of the 
efficacy and safety endpoints.
8.3.3
PK analysis set
Pharmacokinetics will be summarised as per the PK analysis set.
The PK analysis set will include all dosed patients who had at least one measurable plasma 
concentration collected post-dose which was obtained without any protocol deviation, 
violation, or events thought to significantly affect the PK.
All plasma concentration data for AZD1775, paclitaxel, carboplatin, gemcitabine and PLD, 
and derived PK parameters will be summarised and presented according to AstraZeneca 
standards.  This will be described in the SAP.
8.3.4
CA-125 analysis set
The CA-125 Analysis Set will consist of all dosed patients with a pre-treatment serum sample 
showing CA-125 ≥ 2 x ULN within 2 weeks before starting treatment.  The CA-125 Analysis 
Set will be used to evaluate response according to GCIG CA-125 response criteria.
8.4
Outcome measures for analyses
8.4.1
Calculation or derivation of efficacy variable(s)
8.4.1.1
Tumour response rate
Patients will undergo regular tumour assessments until documented objective disease 
progression as defined by RECIST v1.1 (Eisenhauer et al 2009). At each restaging visit the 
RECIST data for a patient will be assigned a response of CR, PR, SD, or PD depending on the 
status of the disease compared with baseline and previous assessments (see Appendix D).  
The objective response rate (ORR) is defined as the number of the patients with a confirmed 
best overall response of CR or PR divided by the number of patients in the FAS for whom 
measureable disease is present at baseline.  Similarly, the disease control rate (DCR) is 
defined as the percentage of FAS patients with a best overall response of CR, PR or SD. 
Progression of TLs will be calculated in comparison with what the tumour burden was at a 
minimum (i.e., smallest sum of diameters previously recorded on study).  In the absence of 
progression, tumour response (CR, PR, or SD) will be calculated in comparison to the baseline 
tumour measurements obtained before starting treatment.


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If a patient has had a tumour assessment that 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).
For TL measurements, if ≤1/3 of the TL sizes are missing (either NE or not read, or the scan 
was not done) then a scaling up rule will be applied as follows:
!
If ≤1/3 of lesions recorded at baseline are missing, then the results will be scaled up 
(based on the nadir sizes) 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-missing 
lesions to the nadir sum of diameters excluding the lesions that are missing and 
determining at what rate the lesions are changing) 
!
If >1/3 of lesions recorded at baseline are missing, then the TL response will be NE.  
However, if the sum of non-missing TL diameters would result in PD (i.e., if using a 
value of 0 for missing lesions the sum of diameters has still increased by >20% or more 
compared with the smallest sum of diameters on study and has an absolute increase ≥5 
mm) PD takes precedence over NE.
!
A visit response of CR will not be allowed if any of the TL data are missing.
8.4.1.2
Progression-free survival 
Progression-free survival is defined as the time from 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 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.  
If the patient progresses or dies after two or more missed 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.  
Progression-free survival will be derived based on scan/assessment dates not visit dates.  If 
RECIST assessments/scans contributing towards a particular visit are performed on different 
dates then the date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression.  With regard to censoring, a patient will be censored 
at the latest of the dates contributing to a particular overall visit assessment. 
8.4.1.3
Overall survival
Overall survival 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 the analysis will be censored based on the 
last recorded date on which the patient was known to be alive.


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8.4.1.4
Changes in tumour size
Percent changes in tumour size from baseline will also be determined for patients with 
measurable disease at baseline and is derived at each visit as the % change in the sum of the 
diameters of TLs. % change = [(post baseline TL sum – baseline TL sum) / baseline TL sum] 
*100.
8.4.1.5
Duration of response
Duration of response is defined as the time from the date of first documented response until 
the date of documented progression or any cause death.  In the case where a patient does not 
progress following response, the DoR censoring time will be the same as the PFS censoring 
time.
8.4.2
Calculation or derivation of safety variable(s)
8.4.2.1
Exposure to investigational product
The total time on study treatment, as well as total exposure to study treatment and the amount 
delivered relative to the intended amount will be summarised.  The number of patients with 
pauses and reductions and the dose intensities of AZD1775, gemcitabine, paclitaxel, and 
carboplatin will also be summarised.
8.4.2.2
Adverse events, laboratory changes, vital signs
Safety profiles will be assessed in terms of AEs and laboratory data, vital signs, and ECG data 
that will be collected for all patients.
8.4.2.3
Other significant adverse events (OAE)
During the evaluation of the AE data, the MM will review the list of AEs that were not 
reported as SAEs and other adverse events (OAEs).  Based on the expert’s judgement, 
significant AEs of particular clinical importance may, after consultation with the Medical 
Science Director, be considered OAEs and reported as such in the CSR.  A similar review of 
laboratory/vital signs/ECG data will be performed for identification of OAEs.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment.
8.4.3
Calculation or derivation of pharmacokinetic variables in plasma
Pharmacokinetic analysis of plasma for AZD1775, gemcitabine, paclitaxel, carboplatin and 
PLD concentration data will be performed by Covance on behalf of AstraZeneca.  Real time 
PK analysis will be conducted prior to each cohort, as appropriate.  The actual sampling times 
will be used in the parameter calculations and PK parameters will be derived using standard 
non-compartmental methods.


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Where possible the following PK parameters will be determined using non-compartmental 
analysis: 
!
Maximum plasma concentration (Cmax) obtained directly from the observed concentration 
versus time data
!
Time to maximum plasma concentration (tmax) obtained directly from the observed 
concentration versus time data
!
Area under the plasma concentration-time curve from zero to the time of the last 
measurable concentration (AUC0-t) calculated by linear up/log down trapezoidal 
summation
!
Area under the plasma concentration time curve from zero to 8 or 10 hours (AUC(0-8/10)) 
calculated by linear up/log down trapezoidal summation 
!
Terminal half-life (t½). Visual assessment will be used to identify the terminal linear 
phase of the concentration-time profile
!
C(8/10 hr), concentration at 8/10 hr time point
!
Ctrough
Additional PK parameters may be determined if deemed appropriate.
8.5
Pharmacokinetics/Pharmacodynamic Analysis
The plasma concentration data for AZD1775 may be analysed using a population PK 
approach, which may include exploring the influence of covariates on PK, if the data allows.  
A population PDx approach will be used to investigate the relationship between PK and 
selected primary, secondary and/or exploratory endpoints, where deemed appropriate.  Results 
may be reported separately from the CSR for the main study.  The PK, PDx, demographic, 
safety and tumour response data collected in this study may also be combined with similar 
data from other studies and explored using population PK and/or PK-PDx methods.  The 
results of any such analyses will be reported separately from the CSR.
8.6
Methods for statistical analyses
A comprehensive description of the statistical analyses and related activities for this study will 
be documented in a statistical analysis plan (SAP) which will be finalized prior to DBL.  
The study will have a primary cut-off date for the CSR (see Section 9.3).  Following the 
primary analysis data cut-off, no further statistical analysis of the data will be conducted.  All 
safety data collected after the primary analysis and up to (and including) the last of the FPVs 
will be listed and/or summarised as appropriate.  
8.6.1
Lead-in safety and efficacy selection
There will be no formal statistical comparisons made between the four treatment arms.


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8.6.2
Lead-in safety dose-limiting toxicities
In the first six evaluable patients of each treatment arm the number of patients experiencing a 
DLT will be reported, based on DLT observations during the first cycle of treatment.  If 2 or 
more patients experience a DLT within an individual treatment arm then the treatment arm 
will be considered as not tolerated.  Consideration may be given to opening a second cohort of 
six patients at a reduced dose or different schedule of AZD1775 at the discretion of the Study 
Review Team (see Section 6.10).  
8.6.3
Objective response rate
In each treatment arm deemed tolerated after the initial lead-in safety the ORR (according to 
RECIST v1.1) will be computed and presented together will the exact 90% CI, using the 
method of Clopper and Pearson (Clopper and Pearson 1934).    
8.6.4
Disease control rate
In each treatment arm deemed tolerated after the initial lead-in safety the DCR will be 
computed and presented together will the exact 90% CI, using the method of Clopper and 
Pearson.  
8.6.5
CA-125 response rate
In each treatment arm deemed tolerated after the initial lead-in safety the CA-125 RR will be 
computed according to GCIG criteria and presented together with the exact 90% CI, using the 
method of Clopper and Pearson.   
8.6.6
Safety analysis
The following minimum data summaries will be presented by treatment arm using the Full 
Analysis Set:
!
Treatment-emergent adverse events of any CTCAE grade – summarised by MedDRA 
preferred term and system organ class and CTCAE grade
!
SAEs
!
Deaths summarised by primary cause 
!
Laboratory parameters (haematology and chemistry), vital signs, ECG data and 
concomitant medications will be summarized appropriately
8.6.7
Changes in target lesion
The absolute and percentage changes in TL tumour size will be summarised using descriptive 
statistics and presented for each time point by treatment arm.  
8.6.8
Demographic and baseline data
Baseline characteristics of the patients, including demography, medical history and disease 
characteristics will be listed for each patient and summarised by treatment arm.


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8.6.9
Exposure
Exposure to all components of study treatment (AZD1775 and chemotherapy), i.e., total 
amount of study drug received, will be listed and summarised for all patients and by treatment 
arm.  Total exposure, time on study drug, and dose intensity will be summarised, along with 
the number and percentage of patients with at least one dose interruption and at least one dose 
reduction.  Reason for discontinuation of study treatment will be summarised.
8.6.10
Progression-free survival
Medians with the 90% CIs will be calculated from the Kaplan-Meier analyses. The CIs will be 
calculated using the Brookmeyer and Crowley method (Brookmeyer and Crowley 1982). 
Kaplan-Meier curves will be produced to provide a visual description of PFS.
8.6.11
Overall survival
Overall survival will be presented and analysed using equivalent methods to those described 
for PFS.
8.6.12
Duration of response 
Informational summaries and Kaplan Meier plots, without formal statistical comparisons, will 
be produced.
8.6.13
Exploratory biomarker analysis
The number and proportion of patients having a genetic alteration in each of the following 
markers at baseline will be presented: TP53, BRCA1 and BRCA2.  Note that additional 
markers may be considered and will be summarised if deemed relevant.  
The relationship between clinical outcomes and the presence of genetic alterations in each 
marker will be summarised where appropriate as specified in the SAP.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
REPRESENTATIVE
9.1
Training of study site personnel
Before the first subject is entered into the study, an AstraZeneca or Innovations representative 
will review and discuss the requirements of the CSP and related documents with the 
investigational staff and also train them in any study specific procedures and the EDC 
system(s) utilised.
The PI will ensure that appropriate training relevant to the study is given to all of these staff, 
and that any new information relevant to the performance of this study is forwarded to the 
staff involved.


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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 or Innovations representative will have regular contacts 
with the study site, including visits to:
!
Provide information and support to the Investigator(s)
!
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 CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed
!
Perform source data verification (SDV, a comparison of the data in the CRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating subjects. This will 
require direct access to all original records for each subject (e.g., clinic charts)
!
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
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.
9.2.1
Source data
Refer to the CSA for location of source data.
9.2.2
Study agreements
The PI at each/the centre 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 CSP and the 
CSA, the terms of CSP shall prevail with respect to the conduct of the study and the treatment 
of subjects and in all other respects, not relating to study conduct or treatment of subjects, 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 subjects are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the CSA.


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9.3
Study timetable and end of study
The study is expected to start in Q4 2014 and to end by Q4 2018.
There will be a data cut-off for preparation of a CSR.  Any patients still receiving 
AZD1775 ± chemotherapy at the time of the primary data cut-off will complete an FPV, 
which should occur at the next scheduled visit following implementation of the CSP Version 
10.  Refer to Section 4.4 for further information regarding the FPV.
After this point, patients may continue to receive study drug as long as they are continuing to 
derive benefit from treatment as judged by the Investigator and do not have disease 
progression or unmanageable drug-related toxicity.  Patients continuing on study drug beyond 
the FPV (see Section 4.4) will continue to be monitored for all SAEs, overdoses and 
pregnancies while receiving AZD1775 ± chemotherapy. SAEs and pregnancy test results will 
be collected for 30 days after the last dose of the investigational products and should be cared 
for according to local clinical practice.  Investigators must report SAEs and pregnancies
directly to the AstraZeneca representative in accordance with Section 6.5, and continue to 
maintain study drug accountability as long as patients are receiving treatment with the study 
drug.  
The Part B efficacy expansion and Part C2 safety expansion will be conducted at selected 
investigator sites.  The study may be terminated at individual centres if the study procedures 
are not being performed according to Good Clinical Practice (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 AZD1775.
9.4
Data management by AstraZeneca or delegate
Data management will be performed by Innovations, 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 WHO Drug Dictionary.  Classification coding will be 
performed by AstraZeneca or Innovations.
The data collected through third party sources will be obtained and reconciled against study 
data.
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 AstraZeneca or delegate


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Data queries will be raised for inconsistent, impossible 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 from eCRF are produced and reconciled with the Patient Safety 
database and/or the investigational site. 
Data Management of genotype data
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or third party contracted
to work with AstraZeneca to analyse samples.  The results from this genetic research will be 
reported separately from the CSR for the main study.  Some or all of the clinical datasets from 
the main study may be merged with the genetic data in a suitable secure environment separate 
from the clinical database.
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca.
Management of external data
Data Management determines the format of the data to be received from external vendors and 
coordinates the flow of data to an external environment or clinical database (if applicable). 
Data Management will ensure that the data collection tool (e.g., IWRS, etc.) will be tested / 
validated as needed. 
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 International Conference on Harmonisation 
(ICH)/GCP, applicable regulatory requirements and the AstraZeneca policy on Bioethics and 
Human Biological Samples.


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10.2
Subject 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 subjects, 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 subject. In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a subject’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate.
10.3
Ethics and regulatory review
An Ethics Committee (EC) or 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 subjects.  The Investigator will ensure the distribution of these documents 
to the applicable EC, 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 enrolment of any subject into the study. 
The EC/IRB should approve all advertising used to recruit subjects 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 enrolment of any subject 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, ECs, IRBs, and PIs with safety 
updates/reports according to local requirements.


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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 IP.  AstraZeneca will provide 
this information to the PI so that he/she can meet these reporting requirements.
10.4
Informed consent
The PI(s) at each centre will:
!
Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study
!
Ensure each subject is notified that they are free to discontinue from the study at any time
!
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided
!
Ensure each subject 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 subject
!
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the informed consent form that is approved by an EC.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the Medical Science 
Director 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 ECs/IRBs see Section 10.3.
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s EC/IRB are to approve the revised Informed Consent Form before the revised 
form is used. 


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If local regulations require, any administrative change will be communicated to or approved 
by each EC/IRB.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an EC may perform 
audits or inspections at the centre, including SDV.  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, analysed, and 
accurately reported according to the protocol, (GCP), guidelines of the ICH, and any 
applicable regulatory requirements.  The Investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the centre.


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Appendix A
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
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?


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!
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.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.


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Appendix B
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.  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 
!
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
!
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 C
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 (AEs) and Serious Adverse Events (SAEs) according to the 
outcome of the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication  irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law (HL)
AST or ALT ≥ 3x ULN  together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:


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!
ALT ≥ 3xULN
!
AST ≥ 3xULN
!
TBL ≥ 2xULN
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any 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) by the central laboratory
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original local 
laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:
!
Determine whether the patient meets PHL criteria (see Definitions within this Appendix 
for definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)
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 Definitions within 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 CSP.
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:


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!
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Actions Required When Potential Hy’s Law Criteria are Met Before and 
After Starting Study Treatment)
!
Notify the AstraZeneca representative who will then inform the central Study Team 
The MM 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 MM. 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 MM) 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 MM 
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
!
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:


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!
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 with liver metastases 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 in  
# 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 MM 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.


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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 e.g. 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 Actions Required When Potential 
Hy’s Law Criteria are Met Before and After Starting Study Treatment?
If No: follow the process described in Potential Hy’s Law Criteria met 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 MM 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 D
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 RECIST 1.1 Guidelines (Eisenhauer et al 2009) 
for the D6010C00004 study with regards to Investigator assessment of tumour burden 
including protocol-specific requirements for this study.
Definition of measurable, non-measurable, target and non-target lesions
Patients with measurable and non-measurable disease at baseline should be included in Part A 
of the study.  Only patients with measurable disease at baseline should be included in Part B 
of the study.  Measurable disease is defined by the presence of at least one measurable lesion 
which has not been previously irradiated. 
Measurable:
A 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) with CT or 
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 to <15mm short axis at baseline*).
!
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.
!
Previously irradiated lesions**
!
Skin lesions assessed by clinical examination***
!
Brain metastasis***
* Nodes with <10mm short axis are considered non-pathological and should not be recorded 
or followed as NTL.
**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 
Non-Target Lesions (NTL) at baseline and followed up as part of the NTL assessment.


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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 below, and those 
excluded from tumour assessments for this study are highlighted, with the rationale provided.
Summary of methods of assessments
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 Scan
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. 


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In the D6010C00004 study it is recommended that CT examinations of the chest, abdomen, 
and pelvis will be used to assess tumour burden at baseline and follow-up visits.  CT 
examination with intravenous (IV) 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 D6010C00004 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 D6010C00004 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 D6010C00004 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 D6010C00004 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 D6010C00004 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 D6010C00004 study tumour markers will not be used for tumour response assessments 
as per RECIST 1.1.
Cytology and histology
In the D6010C00004 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 SD.  


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In such circumstances, the cytology is necessary to differentiate between response/SD (an 
effusion may be a side effect of the treatment) and PD (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 baseline 
assessment.  
In the D6010C00004 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 Scans
In the D6010C00004 study fluorodeoxyglucose 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 FDG uptake* 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.
* A positive FDG-PET scan lesion should be reported only when an uptake greater than twice 
that of the surrounding tissue is observed.
TUMOUR RESPONSE EVALUATION
Schedule of evaluation
Baseline assessments should encompass chest, abdomen and pelvis and should additionally 
investigate areas that may be involved based on signs and symptoms of individual patients and 
should be performed no more than 28 days before the start of study treatment.  Follow-up 
assessments will be performed every 2 cycles +/- 1 week window interval after start of 
treatment until objective disease progression as defined by RECIST 1.1 or withdrawal from 
study.  Any other sites at which new disease is suspected should also be adequately imaged at 
follow-up.


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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 (TA)
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 
millimeters.  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 > 5mm, 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 two or more parts, then record the sum of the diameters of those parts. 
!
If two or more TL merge then the sum of the diameters of the combined lesion should be 
recorded for one 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 5mm should be assigned.  If an accurate measure can be given, this should be 
recorded, even if it is below 5mm.
!
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 e.g. radiotherapy, embolisation, surgery etc., during 
the study, the size of the TL should still be provided where possible.


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Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumour visit 
response for TL.
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
Progressive 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 
5mm.
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 PD criteria, PD overrides NE as a TL response
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.
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 one or more NTL 
Progression (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.


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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.
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 SD or PR in TLs, 
the overall tumour 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.
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: i.e. 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
Symptomatic deterioration is not a descriptor of an objective response: it is 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 below.


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Overall visit response
Target lesions
Non-Target lesions
New Lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
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, NA = not applicable (only relevant if there were no NTLs at 
baseline).
CONFIRMATION OF RESPONSE
In the D6010C00004 study, imaging for confirmation of response (CR or PR) should be 
performed at next scheduled visit (certainly no less than 4 weeks) following the date the 
criteria for response were first met.
SPECIFICATIONS FOR RADIOLOGICAL IMAGING
These notes are recommendations for use in clinical studies.  The use of standardized 
protocols for CT and MRI allows comparability both within and between different studies, 
irrespective of where the examination has been undertaken.
CT Scans
CT scans of the chest, abdomen, and pelvis should be contiguous throughout all the anatomic 
region of interest.
The most critical CT image acquisition parameters for optimal tumour evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval.
Anatomic coverage: Optimal anatomic coverage for most solid tumours is the chest, 
abdomen and pelvis. Coverage should encompass all areas of known predilection for 


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metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual patients.  Because a lesion later 
identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, careful consideration should be given to the extent of 
imaging coverage at baseline and at subsequent follow-up time points.  This will enable better 
consistency not only of tumour measurements but also identification of new disease.
IV contrast administration: Optimal visualisation and measurement of metastases in solid 
tumours requires consistent administration (dose and rate) of IV contrast as well as timing of 
scanning.  Typically, most abdominal imaging is performed during the portal venous phase 
and (optimally) about the same time frame after injection on each examination.  An adequate 
volume of a suitable contrast agent should be given so that the metastases are demonstrated to 
best effect and a consistent method is used on subsequent examinations for any given patient.  
It is very important that the same technique be used at baseline and on follow- up 
examinations for a given patient.  For patients who develop contraindications to contrast after 
baseline contrast CT is done, the decision as to whether non-contrast CT or MRI (enhanced or 
non-enhanced) should be performed should also be based on the tumour type, anatomic 
location of the disease and should be optimised to allow for comparison to the prior studies if 
possible.  Each case should be discussed with the radiologist to determine if substitution of 
these other approaches is possible and, if not, the patient should be considered NE from that 
point forward.  Care must be taken in measurement of TLs on a different modality and 
interpretation of non-target disease or new lesions, since the same lesion may appear to have a 
different size using a new modality.  Oral contrast is recommended to help visualise and 
differentiate structures in the abdomen. 
If iodine contrast media is medically contraindicated at baseline or at any time during the 
course of the study then the recommended methods are:  CT thoracic examination without 
contrast and abdominal and pelvis MRI with contrast.  If MRI cannot be performed then CT 
without IV contrast is an option for the thorax, abdomen and pelvis examination.  For brain 
lesions assessment, MRI is the preferred method. 
Slice thickness and reconstruction interval: It is recommended that CT scans be performed 
at 5mm contiguous slice thickness and this guideline presumes a minimum 5 mm thickness in 
recommendations for measurable lesion definition.  Exceptionally, particular institutions may 
perform medically acceptable scans at slice thicknesses greater than 5 mm.  If this occurs, the 
minimum size of measurable lesions at baseline should be twice the slice thickness of the 
baseline scans.
All window settings should be included in the assessment, particularly in the thorax where 
lung and soft tissue windows should be considered.  When measuring lesions, the TL should 
be measured on the same window setting for repeated examinations throughout the study.  All 


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images from each examination should be included in the assessment and not “selected” 
images of the apparent lesion.
MRI Scans
MRI has excellent contrast, spatial and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity 
and measurement.  Furthermore, the availability of MRI is variable globally.  The modality 
used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  Generally, axial imaging of the abdomen and 
pelvis with T1 and T2 weighted imaging along with gadolinium-enhanced imaging should be 
performed.  The field of view, matrix, number of excitations, phase encode steps, use of fat 
suppression and fast sequences should be optimised for the specific body part being imaged as 
well as the scanner utilised.  It is beyond the scope appendix to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts and diseases.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans.  Body scans should be performed with breath-hold scanning 
techniques if possible.
For these reasons, CT is the imaging modality of choice.
FDG-PET Scans
FDG-PET has gained acceptance as a valuable tool for detecting, staging and restaging several 
malignancies.  If  FDG-PET scans are included in a protocol, an FDG uptake period of 60 min 
prior to imaging has been decided as the most appropriate for imaging of  patients with 
malignancy.  Whole-body acquisition is important since this allows for sampling of all areas 
of interest and can assess if new lesions have appeared thus determining the possibility of 
interval progression of disease.  Images from the base of the skull to the level of the mid-thigh 
should be obtained 60 min post injection.  PET camera specifications are variable and 
manufacturer specific, so every attempt should be made to use the same scanner, or the same 
model scanner, for serial scans on the same patient.  Whole-body acquisitions can be 
performed in either 2- or 3-dimensional mode with attenuation correction, but the method 
chosen should be consistent across all patients and serial scans in the clinical trial.
PET/CT Scans
At present, low dose or attenuation correction CT portions of a combined PET–CT are of 
limited use in anatomically based efficacy assessments and it is therefore suggested that they 
should not be substituted for dedicated diagnostic contrast enhanced CT scans for tumour 
measurements by RECIST 1.1.  In exceptional situations, if a site can document that the CT 
performed as part of a PET–CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast) then the CT portion of the PET–CT can be used for RECIST measurements.  


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However, this is not recommended because the PET portion of the CT introduces additional 
data that may bias an Investigator if it is not routinely or serially performed.
REFERENCES
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R.  New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer
45 (2009) 228-247


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Appendix E
Definition of Women of Childbearing Potential and 
Acceptable Contraceptive Methods
DEFINITION OF WOMEN OF CHILDBEARING POTENTIAL
Women of Child Bearing Potential (WoCBP) - Women between menarche and menopause 
who have not been permanently or surgically sterilized and are capable of procreation.
Women NOT of Childbearing Potential - Women who are permanently or surgically 
sterilized or postmenopausal (definitions below):
Permanent sterilisation includes hysterectomy and/or bilateral oophorectomy and/or bilateral 
salpingectomy but excludes bilateral tubal occlusion.  Tubal occlusion is considered a highly 
effective method of birth control but does not absolutely exclude possibility of pregnancy.  
(The term occlusion refers to both occluding and ligating techniques that do not physically 
remove the oviducts).
!
Women who have undergone tubal occlusion should be managed on trials as if they are of 
WoCBP (e.g. undergo pregnancy testing etc. as required by the study protocol).
!
Women will be considered postmenopausal if they are amenorrheic for 12 months 
without an alternative medical cause.  The following age-specific requirements apply:
!
Women under 50 years old will be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and with LH and FSH levels in the post-menopausal range.
!
Women over 50 years of age will be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments.
ACCEPTABLE CONTRACEPTION METHODS
Highly effective method of birth control is defined in Note 3 in ICH Guidance M3 
(Nonclinical Safety Studies for the conduct of Human Clinical trials for Pharmaceuticals) as 
one that results in a low failure rate (e.g. less than 1 percent per year) when used consistently 
and correctly.
The following methods of highly effective contraception are considered acceptable.
Note that women should have been stable on their chosen method of birth control for a 
minimum of 2 weeks before entering the trial.  Generic names and examples of trade names 
are given.  As trade names may vary, Investigators should check the generic name of any 
contraception to ensure suitability.
Acceptable contraception methods are:


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!
Total sexual abstinence:  abstinence is only acceptable as ‘total/true abstinence’ when the 
subject refrains from any form of sexual intercourse and this is in line with their usual 
and/or preferred lifestyle; this must continue for the total duration of the trial and for at 
least 1 month after the last dose of AZD1775 for patients who do not receive paclitaxel, 
and for at least 6 months after the last dose of paclitaxel treatment for patients on the 
paclitaxel arm.
!
Vasectomised sexual partner plus male condom (with participant assurance that partner 
received post-vasectomy confirmation of azoospermia)
!
Tubal occlusion plus male condom
!
Intrauterine Device (IUD) - provided coils are copper-banded, plus male condom
!
Intra-uterine system (IUS) Levonorgestrel Intrauterine System (e.g., Mirena), plus male 
condom
!
Medroxyprogesterone injections (Depo-Provera) plus male condom
!
Etonogestrel implants (e.g., Implanon, Norplan) plus male condom
!
Normal and low dose combined oral contraceptive pills, plus male condom
!
Norelgestromin / ethinylestradiol transdermal system plus male condom
!
Intravaginal device (e.g. ethinylestradiol and etonogestrel ) plus male condom
!
Cerazette (desogestrel) plus male condom.  Cerazette is currently the only highly 
efficacious progesterone based pill
UNACCEPTABLE CONTRACEPTION METHODS
The following methods are considered not to be highly effective and are therefore not 
acceptable contraceptive methods in AstraZeneca clinical trials:
!
Triphasic combined oral contraceptives (COCs)
!
All progesterone only pills except, Cerazette
!
All barrier methods, if intended to be used alone
!
Non-copper containing Intrauterine Devices (IUDs)
!
Fertility awareness methods (e.g, calendar, ovulation, symptothermal, post-ovulation 
methods)
!
Coitus interruptus


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Appendix F
Stages of Heart Failure – New York Heart Association 
Classification
The Stages of Heart Failure – New York Heart Association Classification
Class I (Mild)
No limitation of physical activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, or dyspnoea (shortness of breath).
Class II (Mild)
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, or dyspnoea.
Class III (Moderate)
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary physical 
activity results in fatigue, palpitation, or dyspnoea.
Class IV (Severe)
Unable to carry out any physical activity without discomfort.  Symptoms of cardiac 
insufficiency at rest. If any physical activity is undertaken, physical discomfort is increased.
Reference
The Criteria Committee of the New York Heart Association. Nomenclature and criteria for 
diagnosis of diseases of the heart and great vessels. 9th ed. Boston (MA): Little, Brown & Co; 
1994:253-256.


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Appendix G
Disallowed Medications and Medications to be Administered 
with Caution
Formal drug-drug interaction studies have not yet been performed with AZD1775, therefore, 
the potential for drug-drug interaction described in this protocol are based on findings from in 
vitro studies and clinical experience.
In vitro data has shown that AZD1775 is metabolised predominantly by CYP3A4, with an 
FMO3 and/or FMO5 component.  As a result, there is potential for the exposure of AZD1775 
to be affected by drugs which inhibit or induce the metabolism of CYP3A4.  In the clinic, co-
administration of AZD1775 with the moderate CYP3A4 inhibitor, aprepitant, resulted in a 
40% increase in the plasma levels of AZD1775.  Drugs known to be moderate to strong 
inhibitors/inducers of CYP3A4 are therefore prohibited for use in the current study, including 
aprepitant.  
In vitro data suggests that AZD1775 may be a weak reversible inhibitor of CYP2C19 (IC50 12 
μM).  Caution should therefore be exercised when AZD1775 is co-administered with agents 
that are sensitive substrates of CYP2C19, or substrates of this enzyme with a narrow 
therapeutic range.
Based on in vitro studies, AZD1775 has been shown to be a weak reversible inhibitor (IC50 14 
μM) and a time-dependent inhibitor of CYP3A4 (Kinact 0.061/min, Ki 6.04 μM).  The full 
impact of the time dependent inhibition is currently unknown, however, modelling data has 
predicted an 8-10 fold increase in the exposure of sensitive CYP3A4 substrates when 
administered with AZD1775 (250 mg BID for 5 doses).  To date, no significant DDI effects 
have been reported in the clinic that may be related to the TDI finding.  However, sensitive 
CYP3A4 substrates or substrates of CYP3A4 with a narrow therapeutic window are 
prohibited.
AZD1775 has been shown to be a weak inducer of CYP1A2 in vitro (39% increase in activity 
of positive control).  Given the nature of the AZD1775 dosing schedule, however, the risk of 
induction in the clinic is considered low.  No specific precautions are recommended at this 
time, except to be initially vigilant when using substrates of CYP1A2 with a narrow 
therapeutic range.
Transporter studies (in vitro) have shown that AZD1775 is both a substrate and inhibitor (IC50
20 μM) of P-gp.  Maximum impact of these finding is likely to occur for drugs administered 
orally at the same time as AZD1775.  Caution should therefore be exercised when agents that 
are inhibitors or substrates of P-gp are administered concomitantly with AZD1775.
Recent in-vitro transporter studies have shown AZD1775 to be an inhibitor of BCRP (IC50 5.1 
μM).  This finding is particularly relevant for drugs administered orally where exposure is 


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normally limited by BCRP-mediated efflux, in particular some statins, such as rosuvastatin.  
Other drugs where the disposition is mediated via BCRP should be administered with caution, 
dose modification considered or substituted by an alternative drug. 
Use of metformin should be used with caution in this study as recent in vitro transporter data 
have shown AZD1775 is an inhibitor of Multidrug and Toxin Extruder 1 (MATE1) and 
MATE2K.
Caution should be used when administering drugs that are substrates of these transporters (e.g. 
cimetidine, acyclovir, fexofenadine) as the clinical relevance of AZD1775 inhibition of the 
MATE pathway is not known in these compounds.
Herbal preparations/medications can be substrates, inhibitors and inducers, similar to any 
registered medication.  Herbal preparations are therefore not allowed throughout the study.  
These herbal medications include, but are not limited to: St. John’s wort, kava, ephedra (ma 
huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and 
ginseng.  
In addition, any other drugs should be avoided at the Investigator’s discretion if, in their 
opinion, the co-administration with AZD1775 may increase the risk of a clinically significant 
drug interaction.
A list of the main CYP3A4 substrates, inhibitors (strong and moderate) and inducers, 
CYP2C19 substrates, P-gp substrates and inhibitors and BCRP substrates are shown below.  
This is not an exhaustive list and further details can be found at Expert Opin. Drug Metab. 
Toxicol. (2013) 9(6):737-751.   


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CYP3A4 Inhibitors
Strong
Boceprevir
Clarithromycin
Cobicistat (GS-9350)
Conivaptan
Danoprevir
Elvitegravir
Fosamprenavir
Grapefruit juice
Idelalisib
Indinavir
Itraconazole
Ketoconazole
LCL161
Lopinavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Tipranavir
Troleandomycin
Voriconazole
Moderate
ACT-178882
Amprenavir
Aprepitant
Atazanavir
Casopitant
Ciprofloxacin
Crizotinib 
Darunavir
Dronedarone
Diltiazem
Erythromycin
FK1706
Fluconazole 
Fosamprenavir
Imatinib
Ledipasvir
Lomitapide
Netupitant
Schisandra sphenanthera
Tofisopam
Verapamil
Grapefruit
Seville oranges


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Weak
Almorexant 
Alprazolam 
AMD070
Amiodarone
Amlodipine
Atorvastatin 
Azithromycin 
Berberine
Bicalutamide
Blueberry juice 
Chlorzoxazone 
Cilostazol
Cimetidine
Clotrimazole
Cranberry juice
Cyclosporine
Daclatasvir 
Delavirdine
Everolimus
Faldaprevir
Fluvoxamine
Fosaprepitant (IV)
Ginkgo
Goldenseal
GSK1292263
GSK2248761
Isoniazid
Ivacaftor
Lacidipine 
I Linagliptin
Lomitapide
M100240
Nilotinib
Oral contraceptives 
Pazopanib
Peppermint oil
Propiverine 
Ranitidine 
Ranolazine
Resveratrol
Roxithromycin
Seville orange juice 
Simeprevir
Sitaxentan
Suvorexant
Tabimorelin
Tacrolimus
Teriflunomide
Ticagrelor
Tipranavir/ritonavir
Tolvaptan
Zileuton
CYP3A4 Inducers (Strong and Moderate)
Avasimibe
Bosentan
Carbamazepine 
Efavirenz
Enzalutamide 
Etravirine
Genistein 
Lersivirine 
Lopinavir 
Mitotane 
Modafinil 
Nafcillin 
Phenobarbital 
Phenytoin 
Rifabutin
Rifampin
Ritonavir 
Semagacestat 
St John's Wort
Thioridazine 
Tipranavir


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CYP3A4 Inducers (Weak)
Amprenavir 
Aprepitant 
Armodafinil 
AZD 7325
Bexarotene 
Boceprevir 
Brivaracetam 
Clobazam 
Danshen 
Dexamethasone 
Echinacea 
Eslicarbazepine
Garlic 
Gingko 
Ginseng 
Glycyrrhizin 
LCL161
Methylprednisolone 
Nevirapine 
Oritavancin 
Oxcarbazepine 
PA-824
Pleconaril 
Prednisone 
Quercetin 
Raltegravir 
Ritonavir
Rufinamide 
Sorafenib 
Stribild 
Telaprevir 
Terbinafine 
Ticagrelor 
Ticlopidine
Topiramate
Troglitazone  
Vemurafenib 
Vicriviroc and ritonavir
Vinblastine


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CYP3A and CYP3A4 Sensitive Substrates or Substrates with a Narrow Therapeutic 
Range
ABT-384
Alfentanil
Aprepitant
Alfuzosin
Almorexant
Alpha-Dihydroergocryptine
Amiodarone
Aplaviroc
Aprepitant
Astemizole
Atazanavir
Atorvastatin
Avanafil
Bexarotine
BIRL 355
Bortezomib
Bosutinib
Brecanavir
Brotizolam
Budesonide
Buspirone
Capravirine
Carbamazepine
Casopitant
Cisapride, 
Conivaptan
Cyclophosphamide
Cyclosporine
Danoprevir
Darifenacin
Darunavir
Dasatinib
Dihydroergotamine
Disopyramide
Dronedarone
Docetaxol
Dofetilide
Doxorubicin
Ebastine
Eletriptan
Elvitegravir
Eplerenone
Ergotamine
Erlotinib 
Etoposide
Everolimus
Felodipine
Fentanyl
Fluticasone
Gefitinib
Halofantrine
Ibrutinib
Ifosfamide
Imatinib
Indinavir
Ironotecan 
Ivacaftor
Ixabepilone
L-771,688
Lapatinib
Levomethadyl (LAAm)
Lomitapide
Lopinavir
Lovastatin
Lurasidone
Maraviroc, 
Midazolam
Midostaurin
Mosapride
Neratinib
Nilotinib
Nisoldipine
Paclitaxel
Pazopanib
Perospirone
Pimozide
Propafenone
Propofol
Quetiapine
Quinidine
Ranolazine
Ridaforolimus
Romidepsin
Saquinavir 
Sildenafil 
Simeprevir
Simvastatin 
Sirolimus
Tacrolimus
Temsirolimus
Terfenadine 
Ticagrelor
Theoophylline
Thioridazine
Thiotepa
Tilidine
Tipranavir
Tolvaptan 
Triazolam 
Tretinoin
Ulipristal
Vardenafil
Vicriviroc
Voclosporin


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CYP2C19 Sensitive Substrates or Substrates with a Narrow Therapeutic Range
Diazepam
Gliclazide
Lansoprazole 
(R)-Lansoprazole 
(S)-Lansoprazole 
(S)-Mephenytoin
(R)-Mephobarbital
Omeprazole
(R)-Omeprazole
Pantoprazole
(+)-Pantoprazole
Rabeprazole
Tilidine
CYP1A2 Sensitive Substrates or Substrates with a Narrow Therapeutic Range
Alosetron
Caffeine
Duloxetine
Melatonin
Ramelteon
Tacrine 
Theophylline
Tizanidine
P-gp Substrates
Colchicine
Digoxin
Fexofenadine
Indinavir
Paclitaxel
Topotecan
Vincristine
If a patient requires initiation of digoxin during the study, or is already receiving treatment 
with digoxin, monitoring of digoxin levels is recommended according to local practice (as the 
levels of digoxin may increase).  Monitoring of digoxin levels is also recommended when the 
patient has completed dosing with study treatment (as the levels of digoxin may then 
decrease).
P-gp Inhibitors (Strong)
Cyclosporine
Elacridar
Erythromycin
Itraconazole


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Ketoconazole
LY335979Quinidine
Ritonavir
Valspodar
Verapamil
BCRP Substrates
Daunorubicin
Doxorubicin
Rosuvastatin
Sulfasalazine
Topotecan


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d6010c00004-csp-amendment-10
Document Title:
D6010C00004 Clinical Study Protocol Amendment 10
Document ID:
Doc ID-003908528
Version Label:
2.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
13-Sep-2018 07:56 UTC
Management Approval
11-Sep-2018 07:15 UTC
Author Approval
12-Sep-2018 09:18 UTC
Management Approval
12-Sep-2018 08:42 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD

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Sarah Cannon Research Institute 
 
 
A Multicentre Phase II Study of AZD1775 plus Chemotherapy 
in Patients with Platinum-Resistant Epithelial Ovarian, 
Fallopian Tube, or Primary Peritoneal Cancer 
 
 
Statistical Analysis Plan 
(v5.0)
Protocol Number: D6010C00004 (GYN49) 
 
 
 
 
 
 
 
 
 


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Prepared by: 
 
 
 
06/07/2018
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SCRI Development Innovations 
Date 
 
 
Approved by: 
 
 
 
06/07/2018
06:30 PM EDT
SCRI Development Innovations 
Date 
 
 
 
 
 
 
06/07/2018
10:59 AM EDT
AstraZeneca 
Date 
 
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Table of Contents 
Table of Contents .............................................................................................................................. 3
Glossary .............................................................................................................................................. 6
Modification History .......................................................................................................................... 8
1
Introduction............................................................................................................................. 11
1.1
Objectives ....................................................................................................................... 11
1.1.1 Primary Objective ...................................................................................................... 11
1.1.2 Secondary Objectives ............................................................................................... 11
1.1.3 Exploratory Objectives ............................................................................................. 12
1.2
Study Design .................................................................................................................. 12
1.2.1 Lead-in safety and efficacy expansion................................................................... 12
1.2.2 Treatment Groups ..................................................................................................... 13
1.3
Statistical Considerations ............................................................................................. 14
1.3.1 Sample Size Justification ......................................................................................... 14
1.4
Timing of Analysis.......................................................................................................... 14
1.4.1 Safety Analysis........................................................................................................... 14
1.4.2 Final Analyses ............................................................................................................ 14
1.5
Responsibilities ............................................................................................................... 15
1.6
Analysis Software .......................................................................................................... 15
2
Definition of Analysis Sets .................................................................................................... 15
2.1
All Patients Set ............................................................................................................... 15
2.2
Full Analysis Set ............................................................................................................. 15
2.3
DLT Analysis Set ............................................................................................................ 16
2.4
CA-125 Analysis Set ...................................................................................................... 16
2.5
Biomarker Analysis Set................................................................................................. 16
2.6
PK Analysis Set .............................................................................................................. 16
3
Efficacy Parameters / Endpoints .......................................................................................... 17
3.1
Tumor Response ............................................................................................................ 17
3.1.1 Evaluation of Best Overall Response ..................................................................... 19


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3.1.2 CA-125 Response ...................................................................................................... 20
3.2
Efficacy Endpoints.......................................................................................................... 20
3.2.1 Primary Efficacy Parameter / Endpoint ................................................................. 20
3.2.2 Secondary Efficacy Parameters / Endpoints ......................................................... 20
3.2.3 Exploratory Efficacy Parameters/Endpoints .......................................................... 21
4
Safety Parameters / Endpoints ............................................................................................ 22
4.1
Adverse Events .............................................................................................................. 22
4.2
Laboratory Parameters ................................................................................................. 23
5
Pharmacokinetic Parameters / Endpoints .......................................................................... 23
5.1
Treatment of Concentrations Below the Limit of Quantification in PK Analysis . 24
5.2
Anomalous Values ......................................................................................................... 24
6
Statistical Methods ................................................................................................................. 25
6.1
Definition of Dates / Days / Cycles ............................................................................ 25
6.1.1 Deriving Study Day and Cycle Day ........................................................................ 25
6.1.2 Assigning Treatment Cycle Number ....................................................................... 25
6.1.3 Baseline ....................................................................................................................... 25
6.2
Descriptive Statistics ..................................................................................................... 25
6.3
Trial Subjects .................................................................................................................. 25
6.3.1 Patient Disposition and Accountability................................................................... 26
6.3.2 Important Protocol Deviations ................................................................................ 27
6.4
Baseline Data ................................................................................................................. 28
6.4.1 Demography ............................................................................................................... 28
6.4.2 Medical History........................................................................................................... 28
6.4.3 Disease History .......................................................................................................... 28
6.4.4 Prior anti-cancer therapy ......................................................................................... 29
6.4.5 Height, Weight and Vital Signs at baseline........................................................... 30
6.4.6 EJECTION FRACTION ASSESSMENTS .................................................................... 30
6.4.7 Laboratory Parameters at baseline ........................................................................ 30
6.5
Efficacy Analysis............................................................................................................. 31
6.5.1 Primary Endpoint ....................................................................................................... 31


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6.5.2 Secondary Endpoints ................................................................................................ 31
6.5.3 Exploratory Endpoints .............................................................................................. 32
6.6
Safety Analysis ............................................................................................................... 32
6.6.1 Exposure ..................................................................................................................... 33
6.6.2 Adverse Events .......................................................................................................... 34
6.6.3 Laboratory Data ......................................................................................................... 36
6.6.4 Electrocardiographic Assessments ......................................................................... 37
6.6.5 Vital Signs ................................................................................................................... 38
6.6.6 ECOG Performance Status ....................................................................................... 38
6.6.7 Physical Examinations .............................................................................................. 38
6.7
Concomitant Medications ............................................................................................. 38
6.8
Biomarker Analysis ........................................................................................................ 39
6.9
Pharmacokinetic Analysis ............................................................................................. 39
6.9.1 Descriptive Statistics for PK Data Summaries ..................................................... 39
6.9.2 Presentation of Pharmacokinetic Concentration and Parameter Data ............. 40
6.10
Further Anti-Tumor Therapy ........................................................................................ 42
7
References ............................................................................................................................... 42
8
Appendices .............................................................................................................................. 43
8.1
Appendix 1: List of Tables, Figures and Listings...................................................... 43
8.1.1 Tables and Figures .................................................................................................... 43
8.1.2 Listings ........................................................................................................................ 44
8.2
Appendix 2: Overall Visit Responses.......................................................................... 45
 
 
 
 


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Glossary
AE 
Adverse Event 
ALT 
Alanine Transferase 
AST 
Aspartate Transaminase  
AUC 
Area Under The Curve from time zero extrapolated to 
infinity 
AUC(0-t) 
Area under the concentration-time curve from zero up to 
a definite time 
BLQ 
Below the Limit of Quantification 
BSA 
Body Surface Area 
C(8hr) 
Observed plasma concentration at 8 hours after 
administration 
C(max) 
Observed maximum plasma concentration after 
Administration 
Ctrough 
Observed trough plasma concentration 
CLss/F 
Apparent total body clearance after multiple doses 
following extravascular administration  
CA-125 
Cancer Antigen-125 
CL 
Total body clearance after intravascular adminstration 
CR 
Complete Response 
CRF 
Case Report Form 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DLT 
Dose Limiting Toxicity 
DoR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
GCIG  
Gynaecologic Cancer Intergroup 
ICH 
International Committee for Harmonisation 
ITT 
Intent-To-Treat 
Ǌz 
Terminal Elimination Rate Constant 
LLOQ 
Lower Limit of Quantification 
LOQ 
Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MR 
Metabolite:Parent Ratio 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NQ 
Not Quantifiable 
ORR 
Overall Response Rate 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PLD 
Pegylated liposomal doxorubicin 
PP 
Per Protocol 
PR 
Partial Response 
Rac 
Accumulation Ratio 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 
SD 
Stable Disease 
SRT 
Safety Review Team 
TEAE 
Treatment Emergent Adverse Event 
tmax 
Time to reach Cmax 
t½Ǌz 
Half Life associated with terminal slope of a semi-
logarithmic concentration-time curve 
UNK 
Unknown 
Vss/F 
Apparent volume of distribution at equilibrium after oral 
administration 
WHO 
World Health Organisation 


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Modification History 
Unique Identifier 
for SAP Version 
Date of SAP 
Version 
Author 
Changes from the 
Previous Version 
1.0 
14 July 2015
 
 
2.0 
08 March 2016 
 
Updates to align 
with Amendment 4 
Updated Statistician  
Updated Director 
Biostatistics  
Updated 
 
 title to 
 
 
Removed 
references to 
randomization 
Added coagulation 
CTCAE gradable 
measures 
Clarified 
concomitant 
medications section 
Added additional PK 
information 
3.0 
27SEP2016 
 
Revised definitions 
of analysis sets 
Updated endpoint 
definitions and 
statistical methods 
Added AstraZeneca 
statistician approval 
4.0 
13July2017 
 
Updated Signature 
Lines due to new 
project personnal  
Updated to align 
with wording in the 
PPD
PPD
PPD
PPD
PPD
PPD


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amended clinical 
study protocol 
version 8.0, for 
example: 
objectives, study 
design, sample size 
justification, PK and 
timings of safety 
analysis. 
Provided further 
details on timings of 
the final analysis of 
the study.  
Updated definition 
of tumour response 
to align with the 
clinical study 
protocol and 
provided further 
detail on RECIST 
derivations ie 
added/expanded 
BOR, ORR, DCR and 
PFS sections. 
Updated the 
protocol deviations 
section to important 
protocol deviations 
of focus that will 
impact the 
interpretation of 
efficacy and safety 
Added further 
details on the 
analysis of genetic 
alterations   
 
5.0 
07JUN2018 
 
Updated Signature 
Lines due to new 
project personnal  
Added DLT Analysis 
Set Definition 
Removed condition 
to exclude patients 
with non-
PPD


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measurable disease 
from ORR and DOR 
calculations 
Added list of TFLs in 
Appendix 8.1 
 


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1
Introduction 
As per ICH E9 guidelines (ICH.org),) the purpose of this document is to provide a more 
technical and detailed elaboration of the principal features of the analysis described in 
the D6010C00004 (GYN49) study protocol, “A Multicentre Phase II Study of AZD1775 
plus Chemotherapy in Patients with Platinum-Resistant Epithelial Ovarian, Fallopian 
Tube, or Primary Peritoneal Cancer”, and to include detailed procedures for executing the 
statistical analysis of the study endpoints and other collected data.  
 
The Statistical Analysis Plan (SAP) is based on the working Clinical Study Protocol (CSP) 
dated 14 February 2018, Version 9 and electronic Case Report Form (eCRF) version 10.0 
dated 16MAR2018. In particular, the SAP is based on the planned analysis specification 
as written in CSP Section 8. Any further amendments to the protocol or eCRF may 
necessitate an update to the SAP.  
 
Results of the analyses described in this SAP will be included in the final Clinical Study 
Report (CSR). Any post-hoc or unplanned analyses performed to provide results for 
inclusion in publications or other reports but not identified in this prospective SAP will be 
clearly identified in the relevant documents. 
1.1
Objectives 
The overall objectives of this study are to assess the efficacy and safety of treatment 
with AZD1775 in combination with chemotherapy for patients with platinum-resistant 
epithelial ovarian, fallopian tube, or primary peritoneal cancer. Four separate 
chemotherapy agents will be considered: paclitaxel, gemcitabine, carboplatin and PLD 
(Pegylated liposomal doxorubicin). This is an open-label, four-arm lead-in safety and 
efficacy study. 
1.1.1
Primary Objective 
The primary objective is to evaluate the objective response rate (ORR) of AZD1775 in 
combination with carboplatin, paclitaxel, gemcitabine, or PLD in patients with platinum-
resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. 
 
1.1.2
Secondary Objectives 
The secondary objectives are to: 
 
•
evaluate the duration of response (DOR) of AZD1775 in combination with paclitaxel, 
gemcitabine, carboplatin, or PLD in patients with platinum-resistant epithelial 
ovarian, fallopian tube, or primary peritoneal cancer 
 
•
evaluate the safety and tolerability of AZD1775 in combination with paclitaxel, 
gemcitabine, carboplatin, or PLD in patients with platinum-resistant  
epithelial ovarian, fallopian tube, or primary peritoneal cancer 
 
•
evaluate the disease control rate (DCR) of AZD1775 in combination with 


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paclitaxel, gemcitabine, carboplatin, or PLD in patients with platinum-resistant 
epithelial ovarian, fallopian tube, or primary peritoneal cancer 
 
•
evaluate the Cancer Antigen-125 (CA-125) response of AZD1775 in combination 
with paclitaxel, gemcitabine, carboplatin, or PLD in patients with platinum-resistant 
epithelial ovarian, fallopian tube, or primary peritoneal cancer 
 
x
to characterize the PK of AZD1775 in combination with paclitaxel, gemcitabine, 
carboplatin, and PLD 
 
x
to assess the drug interaction between AZD1775 plus paclitaxel, AZD1775 plus 
gemcitabine, AZD1775 plus carboplatin, and AZD1775 plus PLD 
 
1.1.3
Exploratory Objectives 
The exploratory objectives of this study are to: 
 
•
identify genetic alterations in breast cancer gene 1 and 2 (BRCA1 or BRCA2) and 
other relevant genes, including TP53, from analysis of archived or fresh tumour 
tissue collected at baseline and to determine if the presence of a genetic alteration is 
predictive of clinical outcomes.  
 
•
analyse changes in plasma circulating free tumour DNA (cfDNA)  
over time, from baseline, to restaging, and at disease progression.  (This exploratory 
analysis will be reported separately from the Clinical Study Report [CSR].) 
 
•
obtain preliminary estimates of the overall survival (OS) and progression-free 
survival (PFS) of AZD1775 in combination with gemcitabine, paclitaxel, carboplatin or 
PLD. 
 
•
To collect and store DNA for future research into genes/genetic variations that may 
influence PK or response to AZD1775 (i.e., absorption, distribution, metabolism, 
excretion, safety and efficacy) and/or susceptibility to the development of cancers. 
(This exploratory analysis will be reported separately from the Clinical Study Report 
[CSR].) 
 
1.2
Study Design 
1.2.1
Lead-in safety and efficacy expansion 
This is an open-label, four-arm lead-in safety and efficacy study in which AZD1775 will 
be combined with chemotherapy in four separate arms: AZD1775 plus gemcitabine (Arm 
A); AZD1775 plus weekly paclitaxel (Arm B); AZD1775 plus carboplatin (Arm C); and 
AZD1775 plus PLD (Arm D). 
The AZD1775 plus paclitaxel arm (Arm B) will enrol approximately 30 additional patients 
at selected sites as part of a further efficacy evaluation based on emerging data that 
suggests clinical activity. 


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The AZD1775 plus carboplatin arm (Arm C) will enrol approximately 23 patients overall 
at selected sites as part of a further efficacy evaluation based on emerging data that 
suggests clinical activity. 
To further optimise the dosing schedule of AZD1775 in Arm C, a safety expansion arm 
(referred to as Arm C2) of approximately 12 additional patients will be enrolled at 
selected sites to receive carboplatin AUC 5 IV on Day 1 of a 21 day cycle in combination 
with AZD1775 BID for 2.5 days per dosing week (QW) on Weeks 1, 2 and 3, or on 
Weeks 1 and 2 (2 weeks on followed by 1 week off). 
1.2.2
Treatment Groups 
The AZD1775 schedules and paired chemotherapeutic agents are presented below in 
Arms A, B, C and D: 
 
Arm A (AZD1775 plus gemcitabine): 
AZD1775 (175 mg PO) will be taken once a day on Days 1-2, 8-9 and 15-16. 
Gemcitabine 800 mg/m2 (per CSP amendment 2) will be administered by intravenous 
infusion according to institutional standards on Days 1, 8, and 15 of each 28-day cycle. 
AZD1775 should be taken approximately 2 hours before or 2 hours after food. 
 
Arm B (AZD1775 plus weekly paclitaxel): 
Five doses of AZD1775 (225 mg PO BID) will be taken in approximate 12 hour intervals 
over 2.5 days weekly (Days 1-3, 8-10 and 15-17). Weekly paclitaxel 80 mg/m2 IV will be 
administered according to institutional standards on Days 1, 8 and 15 of each 28 day 
cycle. AZD1775 should be taken approximately 2 hours before or 2 hours after food. 
 
Arm C (AZD1775 plus carboplatin): 
Five doses of AZD1775 (225 mg PO BID) will be taken in approximate 12 hour intervals 
over 2.5 days (Days 1-3). Carboplatin AUC 5 IV will be administered according to 
institutional standards on Day 1 of each 21 day cycle. AZD1775 should be taken 
approximately 2 hours before or 2 hours after food. 
 
Arm C2 (AZD1775 plus carboplatin): 
Five doses of AZD1775 (225 mg PO BID) for 2.5 days per dosing week (QW), on Weeks 
1 (D1-3), 2 (D8-10) and 3 (D15-17), or on Weeks 1 (D1-3) and 2 (D8-10) (2 weeks on 
followed by 1 week off).  Carboplatin AUC 5 IV will be administered according to 
institutional standards on Day 1 of each 21 day cycle. AZD1775 should be taken 
approximately 2 hours before or 2 hours after food. 
Arm D (AZD1775 plus PLD): 
Two dose levels of AZD1775 will be tested with 40 mg/m2 PLD. The starting dose of 
AZD1775 of this combination arm will be 175 mg, which will be escalated to 225 mg, if 
the lower dose is tolerated. 
Five doses of AZD1775 (175 mg or 225 mg) will be taken in approximate 12 hour 
intervals over 2.5 days on week 1 (Days 1, 2 and 3) of each 28-day cycle. PLD will be 
administered on Day 1 of each cycle. 


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1.3
Statistical Considerations 
1.3.1
Sample Size Justification 
Sample size calculations for Arm C of the study are based upon testing a primary 
endpoint of ORR according to RECIST v1.1. In order to test the null hypothesis of an 
ORR of 10% versus an alternative hypothesis with an ORR of 30%, 23 patients are 
required in order to have 85% power to test the null hypothesis using a one-sided exact 
binomial test at the 0.10 significance level. The null hypothesis will be rejected if at least 
5 responses are observed from 23 patients.  
 
The Part C2 expansion will enrol approximately 12 patients to assess a weekly AZD1775 
dosing regimen in combination with carboplatin in a 3 week cycle. Initially, 6 patients will 
be enrolled in a 3-weekly AZD1775 dosing cycle; if 1 patient or less experiences a DLT 
during Cycle 1, then an additional 6 patients will be enrolled for a total of 12 patients. 
However, if 2 or more of the first 6 patients experience a DLT then the AZD1775 dosing 
schedule will be shortened to 2 weeks on and 1 week off.   
 
The AZD1775 plus paclitaxel arm (Arm B) will enrol approximately 30 additional 
patients. Historical response rates using weekly paclitaxel in platinum-resistant and 
refractory ovarian cancer are in the region of 20% to 40% (Pignata et al 2015, 
Lortholary et al 2011, McNeish et al 2014). The following examples give an indication of 
the level of precision that will be achieved in the paclitaxel treated patients. 
 
If the observed response rate is 30% (9/30), the 2-sided 80% confidence interval (CI) 
will be (18%, 43%). If the observed response rate is 50% (15/30), the 2-sided 80% CI 
will be (36%, 63%). For decision making, ORR will be considered in addition to the 
observed safety and tolerability data and the other efficacy endpoints. 
1.4
Timing of Analysis 
1.4.1
Safety Analysis  
A review of safety data by the Safety Review Team (SRT) will take place on the the first 
six evaluable patients completing the Cycle 1 DLT evaluation. Refer to the protocol for 
further details, including the roles and responsibilities of the SRT. 
Note, the SRT will include (but are not limited to): 
x
Innovations Medical Monitor 
x
Innovations Safety Lead 
x
Clinical Project Manager 
x
AstraZeneca representative 
 
1.4.2
Final Analyses 
An administrative interim analysis of ORR will take place after all patients in the 
paclitaxel arm (Arm B) have completed at least two RECIST follow-up assessments (i.e. 
4months). At this time, DoR, PFS and safety/tolerability will also be summarised.  


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The CSR will report the analysis of all primary and secondary endpoints (including 
updated ORR and DoR, DCR, PFS, OS, and PK). This analysis will take place 
approximately 8 months after the last subject has started the first dose of 
AZD1775+paclitaxel, to allow responding patients to have a DoR greater than 6 months.  
 
Note, updates as addenda to the CSR will be undertaken to summarise information 
collected in other treatment arms if they are not fully recruited and have had chance to 
complete 2 cycles of treatment (ie first tumour assessment) at the time the full CSR is 
reported.  
 
1.5
Responsibilities 
The safety and final statistical analyses of the D6010C00004 (GYN49) study will be 
performed by the SCRI Development Innovations assigned Statistical Programming team 
under the guidance of the Trial Statistician and according to this SAP. 
 
After completion, final evaluation, and sign-off of the final clinical study report (CSR), all 
applicable data sets, outputs, programs, and specification documents will be transferred 
to the Sponsor for archival.  
 
Pharmacokinetics analysis will be performed by Early Clinical Biometrics PK, Covance, 
Inc., Madison, WI on behalf of AstraZeneca. 
 
1.6
Analysis Software 
Statistical analyses will be performed using SAS® version 9.3 or higher. PK analyses will 
be performed using Phoenix WinNonlin Version 6.3 or higher. 
 
2
Definition of Analysis Sets 
The following analysis sets may be used in this study. There will be a review prior to 
database lock to determine the inclusion/exclusion of subjects in each analysis set. The 
use of the analysis sets in the statistical analyses is shown in Table 1. 
2.1
All Patients Set 
The All Patients Set will include all subjects who have signed the informed consent form 
(i.e. screening failures plus subject’s enroled and treated).  The All Patients Set will be 
used to list the patient accountability and patient deaths on study.   
2.2
Full Analysis Set 
The Full Analysis Set (FAS) will include all patients who received at least one (non-zero) 
dose of study treatment. Information using this population will be tabulated by 


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treatment arm unless otherwise indicated. This population will be used for the primary 
analyses of the efficacy and safety endpoints. 
2.3
DLT Analysis Set 
The DLT Analysis set will include the first 6 patients in Arms A, B, C, and C2 and the first 
12 patients in Arm D.  Patients must receive at least 75% of the AZD1775 dose (at least 
9 of 12 doses) and complete the minimum safety evaluation requirements during the 
first 21 days of treatment or who experienced a DLT during the first 21 days of 
treatment regardless of the amount of drug received.
 
2.4
CA-125 Analysis Set 
The CA-125 Analysis Set will consist of all dosed subjects with a pre-treatment serum 
sample showing CA-125  2 x Upper Limit of Normal (ULN) within 2 weeks before 
starting treatment. The CA-125 Analysis Set will be used to evaluate response according 
to Gynaecologic Cancer Intergroup (GCIG) CA-125 response criteria (Rustin et al 2011). 
2.5
Biomarker Analysis Set  
The Biomarker Analysis Set (BMS) for molecular markers analysis in tumor tissue will 
include all subjects who have consented to and provided a valid tumor tissue sample. 
2.6
PK Analysis Set 
The formal PK analysis will include all patients who receive at least one dose of the 
AZD1775/chemotherapy combination treatment and have at least one measurable 
plasma concentration, obtained without any protocol deviation, violation, or events 
thought to significantly affect the PK. 
 


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Table 1: Use of Analysis Sets in Statistical Analyses 
Class of 
endpoint/variable 
Population 
ALL 
FAS 
BMS 
PK 
DLT 
Accountability 
X 
 
 
 
 
Primary endpoint  
 
X 
 
 
 
Secondary efficacy 
endpoints*
 
X 
Disposition 
 
X 
 
 
 
Safety variables  
 
X 
 
 
 
Dose Limiting Toxicities 
 
X 
Demographic/baseline 
variables
X
Biomarker variables 
 
 
X 
 
 
Pharmacokinetic 
 
 
 
X 
 
* CA-125 response will use the CA-125 analysis set 
3
Efficacy Parameters / Endpoints 
3.1
Tumor Response 
Patients will undergo regular tumour assessments until documented objective disease 
progression as defined by RECIST v1.1 (Eisenhauer et al 2009). At each restaging visit 
the RECIST data for a patient will be assigned a response of CR, PR, SD, or PD 
depending on the status of the disease compared with baseline and previous 
assessments. 
Progression of Target Lesions (TL) will be calculated in comparison with what the tumour 
burden was at a minimum (i.e., smallest sum of diameters previously recorded on 
study). In the absence of progression, tumour response (CR, PR, or SD) will be 
calculated in comparison to the baseline tumour measurements obtained before starting 
treatment.  
If a patient has had a tumour assessment that cannot be evaluated, then the patient will 
be assigned a visit response of non-evaluable (NE) (unless there is evidence of 
progression in which case the response will be assigned as PD).  
For TL measurements, if 1/3 of the TL sizes are missing (either not evaluable or not 
read, or the scan was not done) then a scaling up rule will be applied as follows:  
x
If 1/3 of lesions recorded at baseline are missing, then the results will be scaled up 
(based on the nadir sizes) 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-missing lesions to the nadir sum of diameters excluding the lesions that are 
missing and determining at what rate the lesions are changing)  
x
If >1/3 of lesions recorded at baseline are missing, then the target lesion response 
will be NE. However, if the sum of non-missing target lesion diameters would result 
in PD (i.e., if using a value of 0 for missing lesions the sum of diameters has still 


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increased by >20% or more compared with the smallest sum of diameters on study 
and has an absolute increase 5 mm) PD takes precedence over NE.  
x
A visit response of CR will not be allowed if any of the TL data are missing.  
 
Progression of non-target lesions is outlined below: 
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 
 
 
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 tumour. 
 
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. 
 
A new lesion indicates progression so the overall visit response will be PD irrespective of 
the TL and NTL response. 
 


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Note, the overall visit response and RECIST outcomes (ie ORR, PFS, etc..) will be 
programmatically derived using TL, NTL and New lesion information from the site 
investigator data. See Appendix 2 for how overall visit responses will be assigned.  The 
investigator reported overall visit response at each visit will be listed only. 
3.1.1
Evaluation of Best Overall Response 
The best overall response per subject will be derived as the best response recorded from 
the start of treatment until documented objective disease progression as defined by 
RECIST v1.1.  
 
The following rules will be used to determine the best objective response in each patient, 
assuming Assessment 1 is Baseline/Pre-treatment tumor assessment, and assessments 
are performed every 8 weeks (± 1 week), with the exception of the carboplatin arm 
which are performed every 6 weeks (± 1 week).  In the case of stable disease, 
measurements should have met the stable disease criteria for a minumum interval of 7 
weeks (8 weeks minus the 7-day visit window) following the start of treatment for all 
arms, with the exception of the carboplatin arm with a minimum interval of 5 weeks (6 
weeks minus the 7-day visit window). 
Assessment 2 
Assessment 3 
Assessment 4 
Best Overall Response 
PD 
- 
- 
PD 
CR, PR, SD 
PD 
- 
SD 
UNK 
PD 
- 
PD 
CR, PR or SD 
UNK 
PD or UNK 
SD 
SD or UNK 
CR, PR or SD 
PD 
SD 
UNK 
UNK 
PD 
PD 
PR 
SD(1) 
 
 
PD 
SD 
PR 
CR or PR(2) 
PD or UNK 
PR 
PR 
SD 
PR(2) 
PR 
PR 
UNK 
PR(2) 
PR 
CR 
CR(2) 
PD 
CR 
CR 
UNK 
CR(2) 
CR 
(1) Only if the increase in diameter from Assessment 2 to Assessment 3 does not qualify 
for PD 


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(2) Assessment occurred at least 4 weeks after initial CR/PR 
3.1.2
CA-125 Response  
Serum samples will be collected for CA-125 tumour markers on all subjects at baseline 
(within 14 days prior to Cycle 1 Day 1), Day 1 of each cycle, and at the end-of-study 
treatment visit.  
 
To be evaluated according to CA-125, subjects must have a baseline sample that is at 
least twice the ULN and within 2 weeks prior to starting treatment. 
For subjects in the CA-125 analysis set, CA-125 response is defined as a 50% reduction 
in CA-125 levels from the baseline sample. The response must be confirmed and 
maintained for at least 28 days. For subjects who have both a CA-125 response and 
whose CA-125 level falls to within the normal range, can be classified as CA-125 
complete responders. 
3.2
Efficacy Endpoints 
3.2.1
Primary Efficacy Parameter / Endpoint 
Objective Response Rate (ORR) is the proportion of patients with a confirmed best 
overall response of complete response (CR) or partial response (PR).  
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 
discontinue treatment without progression, 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. 
 
3.2.2
Secondary Efficacy Parameters / Endpoints 
3.2.2.1 Disease Control Rate 
Disease Control Rate (DCR) = Proportion of patients with a best overall response of 
CR, PR, or SD. 
The denominator is the number of subjects in the full analysis set (FAS) and includes 
subjects with best overall response of NE. 
 


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3.2.2.2 Duration of Response 
Duration of response is defined as the time from the date of first documentation of 
response (CR or PR, which is subsequentyly confirmed) to the date of documentation of 
disease progression or death in the absence of disease progression (i.e date of PFS 
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. 
In the case where a patient does not progress following response, the duration of 
response censoring time will be the same as the PFS censoring time. 
 
 
3.2.2.1 CA-125 Response Rate 
The CA-125 Response Rate is defined as the proportion of subjects in the evaluable CA-
125 population achieving a CA-125 response (see Section 3.1.2). The denominator is the 
number of subjects in the CA-125 Analysis Set. 
 
3.2.3
Exploratory Efficacy Parameters/Endpoints 
3.2.3.1 Progression Free Survival (PFS) 
Progression-free survival (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 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. If the patient progresses or dies after two 
or more missed visits, the patient will be censored at the time of the latest evaluable 
RECIST assessment.  For example, 18 weeks (i.e. 2 x 8 weeks + 1 week for an early 
assessment + 1 week for a late assessment = 18 weeks) for all arms with the exception 
of the carboplatin arm which will be 14 weeks (i.e. 2 x 6 weeks + 1 week for an early 
assessment + 1 week for a late assessment = 14 weeks). 
 
If the patient has no evaluable visits or does not have baseline data they will be 
censored at day 1 unless they die within two visits of baseline (16 weeks plus 1 week 
allowing for a late assessment within the visit window for all arms except carboplatin 
which will use 12 weeks plus 1 week). 
 
PFS (in days) is calculated as:  
(Date of death or documented Progression or Censoring) – (Date of first dose) +1 
 
Equivalently, PFS (in months) is calculated as:  
12 X ((Date of death or documented Progression or Censoring) – (Date of first dose) 
+1)/365.25 
 


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Progression-free survival will be derived based on scan/assessment dates not visit dates. 
If RECIST assessments/scans contributing towards a particular visit are performed on 
different dates then the date of progression will be determined based on the earliest of 
the dates of the component that triggered the progression. With regard to censoring, a 
patient will be censored at the latest of the dates contributing to a particular overall visit 
assessment. 
 
3.2.3.2 Overall survival (OS) 
Overall survival is defined as the time from the date of first dose until death due to any 
cause.  Any subject not known to have died at the time of analysis will be censored 
based on the last recorded date on which the subject was known to be alive.   
 
4
Safety Parameters / Endpoints 
4.1
Adverse Events 
An AE 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 (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged 
liver), or the abnormal results of an investigation (e.g. 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 study treatment has been 
administered. 
 
The term AE is used to include both serious and non-serious AEs. 
AEs will be graded using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Event (CTCAE), version 4.03, whenever possible. The AE reporting 
period for safety surveillance begins when the subject is included into the trial (date of 
first signature of informed consent) and continues through the trial’s post treatment 
follow-up period. 
 
All AEs (serious and non-serious) will be considered treatment emergent AEs (i.e. TEAEs) 
except AEs recorded with an onset date prior to the first day of dosing (unless a 
worsening of the event is recorded after first dosing date, in which case the event will be 
counted as TEAE).  Patients will be followed for Adverse Events for 30 days after their 
last dose or until new cancer therapy is started. 
 
A serious adverse event is an AE occurring during any study phase (i.e. run-in, 
treatment, washout, and follow-up) that fulfils one or more of the following criteria: 
x
Results in death 
x
Is immediately life-threatening 
x
Requires in-patient hospitalisation or prolongation of existing hospitalisation  


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x
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 
x
Is a congenital abnormality or birth defect in the offspring of the treated patient 
x
Is an important medical event that may jeopardise 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 A to the Clinical Study 
Protocol (CSP). 
 
Adverse events will be graded using the NCI-CTCAE version 4.03 where applicable, or 
using the 5-point severity scale: 
 
NCI-CTCAE Grade 
Severity scale 
1 
Mild 
2 
Moderate 
3 
Severe 
4 
Life-Threatening 
5 
Fatal 
  
In grading the adverse events the worst grade observed is to be reported. Adverse 
events will be coded using MedDRA, version 17.1 or higher. 
 
4.2
Laboratory Parameters 
Laboratory toxicity grading will be derived from the laboratory values using NCI-CTCAE 
version 4.03, where applicable.  Laboratory results collected on the eCRF will be 
converted to standard units and compared to the JAMA reference ranges (reference) for 
the purpose of grading.  Laboratory parameters that do not have corresponding toxicity 
grades will be identified as normal; abnormal, high; or abnormal, low, based on standard 
reference ranges. 
 
5
Pharmacokinetic Parameters / Endpoints 
Blood samples will be collected for assessment of AZD1775, gemcitabine, paclitaxel, 
carboplatin and PLD pharmacokinetics at the times outlined in the clinical study protocol. 
Note, sparse PK will be collected from all patients in the Arm B efficacy expansion and 
Arm C2 safety expansion.  
 
The PK Analysis Set will be used in all PK analyses. 
 


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Actual blood sampling times post dosing will be used in calculation of PK parameters. If 
actual sampling time is missing, nominal time may be used with sponsor approval. 
Concentrations will be used as supplied by the analytical laboratory for PK analysis. The 
units of concentration and resulting PK parameters, with the amount or concentration in 
the unit, will be presented as they are received from the analytical laboratory.The PK 
parameters will be calculated using non-compartmental methods with plasma 
concentrations of AZD1775 and chemotherapy agents . As data permit, the following 
parameters will be determined: 
AZD1775: Cmax, dose-normalized Cmax, C8hr, tmax, tlast, AUC(0-t), dose-normalized AUC(0-t). 
Gemcitabine and metabolite dFdU: Cmax, tmax, AUC(0-t), tlast, metabolite:parent ratio [ MR 
AUC(0-t)] 
Paclitaxel: Cmax, tmax, AUC(0-t), tlast, AUC, t½Ǌz, CL, Vz, and Vss 
Carboplatin: Cmax, tmax, AUC(0-t), tlast, AUC, t½Ǌz, CL, Vz, and Vss 
PLD: Cmax, tmax, AUC(0-t), tlast, AUC, t½Ǌz, CL, Vz, and Vss  
 
Cmax, C8hr, tmax, and tlast will be obtained directly from the plasma concentration-time 
profiles.  If Cmax occurs at more than one time point, tmax will be assigned to the first 
occurrence of Cmax.  Where possible the terminal elimination rate constant (Ǌz) will be 
calculated by log linear regression of the terminal portion of the concentration-time 
profiles when there are sufficient data, and t½Ǌz will be calculated as ln2/Ǌz.  AUC(0-t)Zill 
be calculated using the linear up/ log down trapezoidal rule. CL will be determined from 
the ratio of dose/AUC.  Vz will be determined from CL divided by Ǌz, as appropriate. Vss 
will be determined as CL multiplied by MRT 
5.1
Treatment of Concentrations Below the Limit of Quantification in 
PK Analysis 
Plasma concentrations that are below the limit of quantification (BLQ) prior to 
administration of the first dose and up to the first measurable concentration will be set 
to zero. Any other time points will be set to missing. Any deviation from this will be 
justified and documented in the PK Analyis Notes. 
If consecutive BLQ concentrations are followed by quantifiable concentrations in the 
terminal portion of the concentration curve, these quantifiable values will be excluded 
from the PK analysis unless there is a scientific rationale not to do so, which will be 
documented in the PK Analysis Notes. 
5.2
Anomalous Values 
If a value is considered to be anomalous due to being inconsistent with the expected 
pharmacokinetic profile, it may be appropriate to exclude this point from the 
pharmacokinetic analysis.  However, the exclusion of data must have strong justification 
and will be documented in the PK Analysis Notes and study report. 
BLQ values occurring between two quantifiable concentrations may be considered 
anomalous depending on the route of administration and the characteristics of the drug. 


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6
Statistical Methods 
All analyses will be performed on data entered into the study database to a data cut-off 
date agreed by the study team in advance of the interim and final analyses (see Section 
1.4). 
6.1
Definition of Dates / Days / Cycles 
6.1.1
Deriving Study Day and Cycle Day 
x
Day 1  = Date of first Treatment in a patient 
x
Study Day  
 
= Study Date – Date of First Treatment + 1;  if study date is on or after date of 
Date of First Treatment or  
= Study Date – Date of First Treatment; if study date is before date of Date of 
First Treatment 
x
Cycle Day = Cycle Date – Date of Treatment in current cycle + 1 
6.1.2
Assigning Treatment Cycle Number 
x
Cycle n begins when the patient starts the n-th course of treatment. 
 
x
Adverse Events that occur on the same date as the n-th course of infusion will be 
assigned to cycle n. Laboratory values taken on the same date as the n-th course 
of infusion will be assigned to cycle n-1, as the samples are usually taken before 
the treatment. 
6.1.3
Baseline 
Baseline will be the last assessment of the variable under consideration prior to the 
intake of the first dose of investigational product.  
 
6.2
Descriptive Statistics 
Binary and ordinal variables will be presented as frequencies and percentages. 
Continuous variables will be presented with the number of values, mean, standard 
deviation, median, minimum and maximum values, and number of missing values. 
Graphical data may also be presented where appropriate. 
 
Unless specified otherwise, all summary tables will be presented by treatment arm and 
for all subjects.   
 
6.3
Trial Subjects 
The subsections in this section include specifications for reporting subject disposition and 
treatment/study discontinuations. Additionally procedures for reporting protocol 
deviations are provided. 


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6.3.1
Patient Disposition and Accountability 
A primary table will provide the overall summary of the analyses sets using ALL subjects 
who signed the ICF: 
 
x
Subjects Consented  
x
Subjects Consented to Tumor Sample Biopsies 
x
Subjects Enroled 
x
Subjects Treated 
x
Subjects in the Full analysis set  
x
Subjects in the CA-125 analysis set  
x
Subjects in the Biomarker analysis set 
x
Subjects in the PK analysis set 
 
Number of subjects in each category will be presented. This table will be presented for 
all subjects and by treatment arm, where appropriate.  
A second summary table will provide the overall summary of subjects with treatment 
ongoing, treatment discontinued and reason off-treatment, together with the number of 
subjects still on study, discontinued study and reason off-study:  
 
x
Subjects with AZD1775 treatment ongoing 
x
Subjects with Chemotherapy treatment ongoing 
x
Subjects with AZD1775 treatment discontinuation and reason 
x
Subjects with Chemotherapy treatment discontinuation and reason 
x
Subjects still on study 
x
Subjects with study discontinuation and reason 
 
Subjects in the FAS Population will be classed as ‘on-treatment’ if they have had one 
dose of study medication and either of the ‘AZD1775 End of Treatment’ or 
‘Chemotherapy End of Treatment’ eCRF pages is not completed or date of last dose of 
AZD1775 or Chemotherapy is after the study cut-off date for the analysis.  Any subject 
with completion of the AZD1775 End of Treatment eCRF page will be classed as off 
AZD1775 treatment, and the corresponding reason will be recorded on the eCRF.  Any 
subject with completion of the Chemotherapy End of Treatment eCRF pages will be 
classed as off Chemotherapy treatment, and the corresponding reason will be recorded 
on the eCRF. The number and percentages of subjects in each category will be presented 
by treatment arm. 
 
The listing of patient eligibility will include all subjects who signed ICF (i.e. including 
screening failures).  The listing will include the following information: patient number, 
country/age/sex, date of informed consent, whether meets inclusion/exclusion criteria 
(yes/no), type of criteria failed, failed criteria number, protocol version enroled, whether 
the patient enrolled (yes/no), enrolment comment, assigned treatment arm, and 
planned doses of AZD1775 and chemotherapy. 
 


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A second listing giving the patient overview will include the following information: patient 
number, treatment arm, dosing cohort (if relevant), country/age/sex, date of informed 
consent, consented to tumor sample biopsies (yes/no), date consented to tumor sample 
biopsies, date of enrolment, date of first dose, date of last dose, number of cycles 
received, flag (yes/no) for the Full, CA-125, Biomarker and PK Analysis Set. 
 
6.3.2
Important Protocol Deviations 
A table summarizing the important protocol deviations, along with the number and 
percentage of subjects in each will be presented (based on FAS).  Minor protocol 
deviations are not expected to affect the treatment response.  A listing detailing the 
important protocol deviations for each enrolled subject will be also presented. 
 
The following general categories will be considered important protocol deviations and will 
be programmatically derived from the eCRF data:  
 
x
Patients entered but who did not receive study treatment (Deviation 1).  
x
Patients who deviate from key entry criteria per the Clinical Study Protocol (CSP) 
(Deviation 2).  
o
Histologic or cytologic diagnosis of epithelial ovarian, fallopian tube, or 
primary peritoneal cancer (Inclusion criteria 2).  
o
Progressed within 6 months of completing at least 4 cycles of a first-line 
platinum containing regimen for Stage III/IV disease. Patients with 
refractory disease (progression during platinum-containing therapy) are 
ineligible (Inclusion criteria 3).  
o
No more than 2-4 prior treatment regimens for Stage III/IV disease 
defined as investigational, chemotherapy, hormonal, biologic, or targeted 
therapy (Inclusion criteria 4). 
o
At least 1 measurable lesion according to RECIST v1.1 (Inclusion criteria 
6). 
o
Predicted life expectancy 12 weeks (Inclusion criteria 12).  
x
Baseline RECIST scan > 42 days before start date of treatment (Deviation 3).  
x
No baseline RECIST 1.1 assessment on or before date of first dose (Deviation 4).  
x
Received other systemic anti-cancer agents whilst on study treatment (Deviation 
5).  
Patients who receive the wrong treatment at any time will be included in the full analysis 
set as described in section 2. During the study, decisions on how to handle errors in 
treatment dispensing (with regard to continuation/discontinuation of study treatment or, 
if applicable, analytically) will be made on an individual basis with written instruction 
from the study team leader and/or statistician.  
The important protocol deviations will be listed and summarised by treatment group. 
Deviation 1 will lead to exclusion from the full analysis set. None of the other deviations 
will lead to patients being excluded from the analysis sets described in section 2 (with 
the exception of the PK analysis set, if the deviation is considered to impact upon PK).  
In addition to the programmatic determination of the deviations above, other study 
deviations captured from the CRF module for inclusion/exclusion criteria will be tabulated 


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and listed. Any other deviations from monitoring notes or reports will be reported in an 
appendix to the CSR. 
 
6.4
Baseline Data 
The following subsections describe the specifications for the baseline characteristics. All 
baseline data will be tabulated and listed using the full analysis set by treatment arm, 
unless otherwise stated. No formal statistical testing to compare the treatment groups 
will be performed on the baseline variables.  
 
Data will be summarised by treatment arm and for all subjects. In all listings the 
treatment arm the subject was enroled in will be identified. 
6.4.1
Demography  
The demography table will summarize the following variables by treatment arm: 
  
x
Sex (Female, Male) 
x
Age (in years at enrolment), Age Categories:  <65, 65 
x
Race (White/Caucasian, Black or African American, American Indian or Alaskan 
Native, Asian, Native Hawaiian or Other Pacific Islander, Other) 
x
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown) 
x
ECOG Performance Status (0, 1, 2, 3 or 4) 
 
The listing of demographic data will include the following information: patient number, 
treatment arm, date of enrolment, date of birth, age, gender, race, ethnicity. 
 
6.4.2
Medical History 
Data collected on Medical History will be listed, including the MedDRA v17.1 or higher 
Preferred Term and whether the condition is ongoing.  
 
Note that Medical History will be coded using MedDRA v17.1 or later. 
6.4.3
Disease History 
The disease history table will summarize the following variables by treatment arm: 
 
x
Time from first positive biopsy for the disease to enrolment (weeks) 
x
Local or Regional recurrence (Yes, No) 
x
Time from Local/Regional recurrence to enrolment (weeks) 
x
Distant metastases (Yes, No) 
x
Time from distant metastases to enrolment (weeks) 
x
Tumor histology 


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x
Histological Grade 
x
TNM stage T at initial diagnosis 
x
TNM stage N at initial diagnosis 
x
TNM stage M at initial diagnosis 
x
Stage at initial diagnosis 
 
A second table will summarise the sites of metastatic disease at study entry by 
treatment arm: 
 
•
Presence of metastatic sites (Yes, No) 
•
Number of sites (0, 1, 2, >2) 
•
Sites of disease 
 
A detailed listing of the specified disease characteristics will also be provided, including 
all relevant data (as collected on the eCRF). 
 
6.4.4
Prior anti-cancer therapy 
Prior anti-cancer therapy including prior systemic therapy, prior radiotherapy and prior 
surgery will be summarised for all subjects.  The prior systemic therapy table will 
summarize the following variables: 
 
•
Prior systemic therapy for disease (Yes, No) 
•
Time from end of most recent prior regimen to enrolment (weeks) 
•
Number of prior regimens (0, 1, 2) 
•
Best overall response to most recent prior regimen (CR, PR, Non CR/Non PD, SD, PD, 
NE, NA) 
•
Reason most recent prior regimen ended (completed planned treatment course, 
progressive disease, toxicity, other) 
 
A listing detailing all prior regimens will also be presented and will include medication, 
start and end dates, disease setting, best overall response and reason therapy ended. 
Prior systemic therapy will be coded using WHO Drug. 
 
The prior radiotherapy table will summarize the following variables: 
 
•
Prior radiotherapy (Yes, No) 
•
Number of sites irradiated (0, 1, 2, >2) 
•
Time from end of most recent prior radiotherapy to enrolment (weeks) 
 
A listing detailing all prior radiotherapy will also be presented and will include site(s) 
irradiated, total dose (Gy), start and end dates. 
 


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The prior surgery table will summarize the following variables: 
 
•
Prior surgery (Yes, No) 
•
Number of prior surgeries (0, 1, 2, >2) 
•
Time from most recent prior surgery to enrolment (weeks) 
 
A listing detailing all prior surgeries will also be presented and will include type and date 
of surgery  
 
Prior radiotherapy and surgery will be coded using MedDRA v17.1 or later. 
 
6.4.5
Height, Weight and Vital Signs at baseline 
The vital signs table at baseline will summarise the following variables by treatment 
arm: 
 
•
Height (cm) 
•
Weight (kg) 
•
Pulse rate (beats/min) 
•
Systolic BP (mmHg) 
•
Diastolic BP (mmHg) 
•
Temperature (degrees Celsius) 
x
Body surface area (m2) 
 
6.4.6
EJECTION FRACTION ASSESSMENTS 
LVEF will be collected at screening, every 6 cycles and as clinically indicated for patients 
consenting to the PLD arm only.  MUGA and ECHO results will be listed. 
 
6.4.7
Laboratory Parameters at baseline 
The laboratory parameters at baseline table will be summarised in the haematology and 
chemistry shift from baseline tables by treatment arm and include the following 
variables: 
•
Baseline CTCAE grade for each relevant parameter (missing, Grade 0, Grade 1, 
Grade 2, Grade 3, Grade 4) 
 
•
Hematology parameters will include: red blood cells, hemoglobin, haematocrit, 
platelets, white blood cells, granulocytes, neutrophils, basophils, eosinophils, 
lymphocytes, monocytes, ANC. 
 


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•
Chemistry parameters will include: Albumin, SGPT/ALT, SGOT/AST, Alkaline 
Phosphatase, Calcium, Carbon Dioxide, Chloride, Creatinine, Glucose, Potassium, 
Sodium, Total Protein, Total Bilirubin, Blood Urea Nitrogen. 
 
•
Coagulation parameters will include: Prothrombin Time, Activated Partial 
Thromboplastin Time, Prothrombin Intl. Normalized Ratio. 
 
•
Urinalysis parameters will include: Blood, Protein, Glucose, Ketones, Leukocytes, 
Specific Gravity, pH. 
 
6.5
Efficacy Analysis 
6.5.1
Primary Endpoint 
The ORR (according to RECIST v1.1) will be computed in each treatment arm. An exact 
two-sided 80%/95% CI for the ORR will be computed using the method of Clopper and 
Pearson. Best overall response will also be summarised. 
The Investigator reported tumor response per time point will be listed, including the % 
change from baseline and % change from nadir in sum of longest diameters of target 
lesions. Listings of target lesions and non-target/new lesions will also be presented.  
A Waterfall-Plot of Best Percent Change in Sum of Longest Diameters from baseline will 
be generated with each patient’s best percentage change in TL tumour size as a separate 
bar, with the bars ordered from the largest increase to the largest decrease and each 
treatment arm highlighted in a different colour. A reference line at the –30% and +20% 
change in TL tumour size level will be added to the plots, which corresponds with the 
definition of ‘partial’ response and ‘progressive disease’. The scale in these plots will be 
fixed to be from -100 to 100 to avoid presenting extreme values. Values that are capped 
as a result of this restriction to the scale are marked. 
Additionally, ‘spider’ plots will be produced for each treatment group. The line plots will 
depict each patient’s percentage change in TL tumour size as a line over time and the 
patients best overall response status will be indicated, as well as whether they had a 
genetic alterations of interest including (but not restricted to) BRCA1,  BRCA2 and 
CCNE1. A reference line at the –30% and +20% change in TL tumour size level will be 
added to the plots, which corresponds with the definition of ‘partial’ response and 
‘progressive disease’. 
6.5.2
Secondary Endpoints 
The variables for the secondary endpoints follow: DCR, DoR, CA-125 Reponse and CA-
125 Complete Response  
 
6.5.2.1 Disease Control Rate 
DCR will be computed in each treatment arm. An exact two-sided 80%/95% confidence 
interval for the DCR will be computed using the method of Clopper and Pearson. 
 
6.5.2.2 Duration of Response 


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Duration of Response will be analysed the same as Progression-free Survival, see 
Section 6.5.3.1 below. 
 
6.5.2.3  CA-125 Response Rate 
The number and percentage of subjects who do and do not achieve a CA-125 response 
and a CA-125 complete response will be presented based upon the CA-125 analysis set. 
 
In each treatment arm deemed tolerated after the initial lead-in safety the CA-125 RR 
and CA-125 Complete RR will be computed and presented together with the exact 
80%/90% CI, using the method of Clopper and Pearson. 
 
The CA-125 response per time point will be listed, including the % change from baseline. 
A Waterfall-Plot of Best Percent Change in CA-125 level from baseline will be generated 
with each patient’s best percentage change in CA-125 level presented as a separate bar, 
with the bars ordered from the largest increase to the largest decrease and each 
treatment arm highlighted in a different colour.  
 
Additionally, ‘spider’ plots will be produced overall and for each treatment group. This 
depicts each patient’s percentage change in CA-125 as a line over time and the patients 
CA-125 response status will be indicated. A reference line at the –50% CA-125 level will 
be added to the plots, which corresponds with the definition of CA-125 response. 
 
6.5.3
Exploratory Endpoints 
6.5.3.1 Progression Free Survival 
Kaplan-Meier curves will be produced to provide a visual description of the time-to-event 
variables in each treatment arm.  
 
Medians of PFS (in months) as well as 25th and 75th percentiles with the 80%/95% 
confidence intervals will be calculated from the Kaplan-Meier analyses. The confidence 
intervals will be calculated using the Brookmeyer and Crowley method. 
 
In addition, the proportion of patients event-free at 3, 4, 5, 6, 9 and 12 months will also 
be presented by treatment. 
Progression free survival times will be listed for each subject. 
 
6.5.3.2 Overall Survival 
Overall Survival will be analysed the same as Progression-free Survival. The proportion 
of patients surviving at 6, 12, and 18 months will also be presented by treatment. 
 
6.6
Safety Analysis 
The current section describes the specifications for the safety parameters analyses. 


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All safety analyses will be performed using the FAS population, unless otherwise 
specified. Analyses will be presented by treatment arm, as treated. 
6.6.1
Exposure  
Exposure to AZD1775 and Chemotherapy will be summarised by treatment arm in the 
following ways: 
x
Time on study (months) 
x
Time on AZD1775 treatment (months) 
x
Time on Chemotherapy (months) 
x
Total number of initiated cycles 
x
Cumulative actual dose of AZD1775 (mg) 
x
Cumulative actual dose of Chemotherapy (mg) 
x
Relative dose intensity of AZD1775 (%) 
x
Relative dose intensiy of Chemotherapy (%) 
 
In a second table the number of patients and cycles with dose reduction and dose 
interruptions with the reasons for such dose modifications, will be summarised by 
treatment arm. An additional table will be generated to summarise the duration of 
Chemotherapy treatment infusion per cycle.  
 
Listings of treatment administration, treatment modifications and infusion duration will be 
provided.  
 
6.6.1.1 Definition of terms related to Treatment Administration 
6.6.1.1.1Infusion Duration 
Infusion Duration (Minutes) = End Time of Infusion – Start Time of Infusion 
 
6.6.1.1.2Dose Calculations 
The Carboplatin dose will be calculated by the site using the Calvert Formula based on 
the patient’s glomerular filtration rate (GFR) which is estimated by using the CrCl. 
 
6.6.1.1.2.1
Total exposure 
Total (or intended) exposure of study treatment 
x
Total (or intended) exposure = min(last dose date where dose > 0mg, date of 
death, date of data cut off) – first dose date + 1 
 
The total exposure calculation makes no adjustment for any dose reductions that may 
have occurred. 
 
Exposure will also be measured by the number of cycles started. A cycle corresponds to 
a period of 28 days (21 days for carboplatin). If a cycle is prolonged due to toxicity, this 


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should still be counted as one cycle. A cycle will be counted if treatment is started even if 
the full dose is not delivered. 
 
6.6.1.1.2.2
Relative Dose Intensity 
Relative dose intensity (RDI) is the percentage of the actual dose delivered relative to 
the intended dose through to treatment discontinuation.  
x
RDI = 100% * d/D, where d is the actual cumulative dose delivered up to the 
earlier of progression (or a censoring event) or the actual last day of dosing and 
D is the intended cumulative dose up to the earlier of progression (or a censoring 
event) or the actual last day of dosing. 
x
If a patient received the planned dose at the scheduled time at every cycle, then 
RDI = 100%. 
 
6.6.2
Adverse Events 
AEs will be graded using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Event (CTCAE), version 4.03, whenever possible.  The AE reporting 
period for safety surveillance begins when the subject is included into the trial (date of 
first signature of informed consent) and continues through the trial’s post treatment 
follow-up period, defined as 30 days after last trial drug administration. AEs leading to 
permanent discontinuation are those events with action taken regarding study drug is 
“Drug withdrawn” (as recorded on the AEs CRF page). 
 
All AEs (serious and non-serious) will be considered treatment emergent AEs (i.e. TEAEs) 
except AEs recorded with an onset date prior to the first day of dosing (unless a 
worsening of the event is recorded after first dosing date, in which case the event will be 
counted as TEAE) or with an onset date >30 days after last dose of treatment.  Tables 
will summarise only TEAEs and TESAEs as applicable, but all AEs and SAEs will be listed 
in the listing documents. 
 
The AE tables will include the number and percentage of subjects with at least one TEAE, 
by MedDRA primary System Organ Class (SOC) (sorted by decreasing SOC frequencies 
within the Overall Total (treatment group) column) and by preferred term (PT) (sorted 
by decreasing PT frequencies within SOC), and by treatment arm, unless otherwise 
stated.  For counts by subject, subjects experiencing the same preferred term more than 
once will be counted once within each system organ class and once within each preferred 
term for each treatment group, or overall.  Percentages will be calculated as a proportion 
of the number of subjects in the full analysis set reporting events, and not the number of 
events. 
In the event of a missing TEAE start date, the following conventions will be 
implemented: 
•
If the day of the month is missing, the day will be set to the first day of the month.  
If the day and the month are both missing, then the date will be set to January 1st.  
If this imputed date is prior to the first administration of the IMP, or if the entire 
onset date is missing, the date of first administration of treatment will be used to 
replace the onset date.  However, if it is clear from the recorded month or year that 


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the TEAE started prior to the first study treatment administration, then the day and / 
or month will be imputed as described above. 
•
In the event of missing relationship, the TEAE will be considered to be “related”.  
   
All Adverse Events 
The overall summary of AE table will include the following summaries, displayed by 
treatment arm and for all subjects: 
•
TEAEs, Classified as NCI CTCAE Grade 
•
AZD1775-Related TEAEs, Classified as NCI CTCAE Grade 
•
Chemotherapy-Related TEAEs, Classified as NCI CTCAE Grade 
•
Serious TEAEs 
•
AZD1775-Related Serious TEAEs 
•
Chemotherapy-Related Serious TEAEs 
•
Serious TEAEs leading to death 
•
AZD1775-Related Serious TEAEs leading to death 
•
Chemotherapy-Related Serious TEAEs leading to death 
•
TEAEs leading to AZD1775 treatment discontinuation 
•
TEAEs leading to AZD1775 dose reduction 
•
TEAEs leading to AZD1775 treatment interruption 
•    TEAEs leading to Chemotherapy treatment discontinuation 
•    TEAEs leading to Chemotherapy dose reduction 
•    TEAEs leading to Chemotherapy treatment interruption 
 
For the Lead-in safety phase, a DLT table will be generated showing the number of 
subjects experiencing a DLT together with the total number of DLTs by DLT category as 
specified in the CSP (Section 7.2.4). A listing will also be provided.  These outputs will 
utilize the DLT analysis set. 
  
The following AE tables will also be generated: 
•
TEAEs, by SOC, PT and Worst NCI CTCAE Grade  
•
TEAEs by Preferred Term 
•
AZD1775-Related TEAEs, by SOC, PT and Worst Grade 
•
AZD1775-Related TEAEs by Preferred Term 
•
Chemotherapy-Related TEAEs, by SOC, PT and Worst Grade 
AZD1775-Related and Chemotherapy-Related adverse events are those events with 
relationship to study therapy reported by the investigator as ‘yes’.  
The listings of AEs will also be provided with the relevant information. 
 
Serious Adverse Events 
The following summary tables will be produced: 
•
Serious TEAEs, by SOC and PT   
•
Serious TEAEs by Preferred Term 
•
AZD1775-Related Serious TEAEs by Preferred Term 


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•
AZD1775-Related Serious TEAEs by SOC and PT 
•
Chemotherapy-Related Serious TEAEs by SOC and PT 
 
The listings of SAEs will also be provided with the relevant information. 
 
Deaths  
The following summary table will be produced by treatment arm: 
•
Summary of Deaths 
 
The death data will be ascertained from the dedicated Death CRF form.  
 
6.6.3
Laboratory Data 
For hematology and biochemical toxicity, patients with at least one laboratory 
assessment during the study treatment will be included in the analyses.  
Assuming laboratory data on C1D1 were performed before first day administration of 
study therapy, the evaluations collected prior to (and including) C1D1 will be reported as 
baseline data. The evaluations collected after (and including) C1D8 will be reported as 
on-treatment.  All laboratory tables will be restricted to the on-study measurements at 
protocol specified time points (no unscheduled visits).  The laboratory listings will 
however include all measurements (whether on-treatment or not).  
The analysis population for each laboratory parameter will be restricted to the treated 
subjects who had the laboratory test performed.  
The worst grade per subject is defined as the highest CTC grade among the on-study 
evaluations. This applies to hematology and chemistry evaluations which can be graded 
per NCI-CTCAE. 
The following laboratory assessments will be performed according to the schedule of 
assessments: 
•
Hematology profile, including red blood cells, hemaglobin, haematocrit, platelets, 
white blood cells, granulocytes, neutrophils, basophils, eosinophils, lymphocytes, 
monocytes, ANC 
• 
Serum chemistry profile, including BUN, creatinine, AST, ALT, total bilirubin, total 
protein, albumin, alkaline phosphatase, sodium, chloride, potassium, calcium, 
glucose, LDH, phosphorus, carbon dioxide and magnesium (for carboplatin only). 
x
Coagulation, including prothrombin time, Activated Partial Thromboplastin Time and 
Prothrombin Intl. Normalized Ratio 
x
Urinalysis, including blood, protein, glucose, ketones, leukocytes, specific gravity and 
pH. 
 
The required laboratory parameters will be summarized by treatment arm. For 
laboratory assessments that are repeated then the first value will be used in the 
summary statistics.     
Local Laboratory Conversion Factors 
Local laboratories will provide data for this study – conversions will be done to convert to 
SI units and will be compared to the JAMA reference ranges. 


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Shifts in Laboratory Results from Baseline 
The CTC gradable laboratory parameters will be tabulated using the shift from baseline 
in the worst CTC grade, by treatment arm. Parameters with both hyper and hypo grades, 
will be separated accordingly. 
 
CTC gradable parameters 
•
Hematology: shift from baseline in the CTC grade.   The CTC gradable hematology 
parameters are: White Blood Cells; Haemoglobin; Platelets; Lymphocytes; 
Neutrophils. 
•
Serum chemistry: shift from baseline in the CTC grade.   The CTC gradable chemistry 
parameters are: Total Bilirubin; AST; ALT; Albumin; Alkaline Phosphatase; Calcium; 
Creatinine; Glucose; Potassium; Sodium; Magnesium (for carboplatin only). 
•
Coagulation: shift from baseline in the CTC grade.  The CTC gradable coagulation 
parameters are: prothrombin time and Activated Partial Thromboplastin Time. 
Non-CTC gradable parameters 
•
Hematology: Red Blood Cells; Haematocrit; Granulocytes; Basophils; Eosinophils; 
Monocytes. 
•
Serum chemistry: Total Protein; Blood Urea Nitrogen; Chloride; Carbon Dioxcide; 
LDH; Phosphorus. 
•
Coagulation: Prothrombin Intl. Normalized Ratio. 
 
The listings (hematology and chemistry separately), will include all the laboratory 
parameters as available in the data base (including laboratory tests codes as “Other”) 
with the corresponding relevant information. All laboratory data will be listed and values 
outside the normal ranges will be flagged.   
 
Liver Related abnormalities 
Liver related abnormalities occurring while on study treatment will be tabulated using 
the following criteria: 
x
3x-, 5x-, 10x-, and 20xULN elevations of AST, ALT, and either ALT or AST 
x
Any elevations of total bilirubin to >2xULN 
x
Any elevations of ALP >1.5xULN 
x
Elevation of AST or ALT (>3xULN) and bilirubin (>1.5xULN, >2xULN), at any time 
point 
 
6.6.4
Electrocardiographic Assessments 
Triplicate ECGs are performed at baseline and at the beginning of each treatment cycle. 
The baseline ECG value per subject will be the last one recorded prior to, or pre-dose on 
the first dosing date. 
 
In Arm D the ECG will performed at baseline and thereafter, patients will have triplicate 
ECG on C1D1 (pre-dose, 2 and 4 hr post-dose) and C1D3 (predose, and 2 hours and 4 
hours post-dose) and on C3D3. 


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A table summarizing clinically significant ECG findings will be presented by treatment 
arm and for all subjects in the FAS.  The listings with ECG overall qualitative conclusion 
per time point and the abnormal ECG findings will be provided. 
6.6.5
Vital Signs 
Systolic and diastolic blood pressure, pulse rate, temperature, weight and body surface 
area will be collected at Screening, and then on Day 1 of each treatment cycle prior to 
chemotherapy administration. The time window for the assessment of vital signs is ±2 
days.  Measurements will also be taken at the end of treatment visit. Height will only be 
collected at the screening visit.  
 
Summaries of absolute and change from baseline cacluations will be presented at each 
protocol timepoint by treatment arm based upon the FAS.  
 
All data collected for vital signs will be listed.  
6.6.6
ECOG Performance Status 
ECOG PS is collected for all patients at screening, prior to the first dose of study 
treatment on day 1 of each cycle and at the end of study treatment visit.  
 
ECOG PS will be summarised by treatment arm and for all subjects at each timepoint. 
Values will be included in the vital signs listing. 
6.6.7
Physical Examinations 
Physical Examination will take place a screening, day 1 of each cycle, at the end of study 
treatment and during follow-up visits. Only the date of the exam will be recorded and 
reported with vital signs.   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. 
6.7
Concomitant Medications 
World Health Organization (WHO) Drug Dictionary March 2014 will be used for coding 
medication terms.  Medications taken 28 day prior to the first dose of study medication 
through 30 days following the last dose of study medication will be summarized 
(frequency and percentage of patients) by ATC level 4 and preferred name.  Multiple 
unique drugs will be counted once per patient.  The summary will be ordered by 
decreasing total frequency of use.  Medication start and stop dates will be compared to 
the date of first dose of study medication to allow medications to be classified as either 
prior or concomitant.   
Medications that start and stop within 28 days prior to the date of first dose of study 
drug will be classified as “prior”.  If a medication starts within 28 days before the date of 
first dose of study drug and stops on or after the date of first dose of study medication, 
then the medication will be classified as “concomitant”.  Additionally, medications will be 
classified as “concomitant” if they have a start date on or after the date of first dose of 
study drug and overlap with administration of the study drug.  If a medication starts 


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within 30 days after the last dose of study drug, then the medication will be classified as 
“post-treatment”.  Partial dates will be handled as follows in the summary tables:  
Missing day only (assume Day 1 of each respective month), missing month and/or year 
will be considered missing in the summarization.  If partial dates do not allow for 
accurate categorization of a medication, it will be assumed to be ‘concomitant’.  A 
summary table for concomitant medications only will be provided (no prior or post-
treatment).   
Any concomitant medications taken by a patient that are explicitly disallowed by the 
protocol will be flagged in the listings.   
Individual subject details will be fully listed, and will include the name of the concomitant 
medication, the start and end date, indication, prophylaxis, prior/concomitant/post-
treatment status, and whether the medication is ongoing at the time of analysis.  
6.8
Biomarker Analysis 
Biomarker data will be provided by an external vendor (Foundation Medicine). This data 
will be converted into a SAS dataset for generation of outputs for inclusion in the CSR.  
 
The presence or absence of genetic alterations will be summarised by gene. This data 
will be summarised using counts and percentages and will make use of the Biomarker 
Analysis Set.  
 
A listing of relevant genetic data as provided by Foundation Medicine will be provided. 
6.9
Pharmacokinetic Analysis 
PK Plasma concentrations of AZD1775 and Chemotherapy agents will be summarised 
and listed, as appropriate.  
6.9.1
Descriptive Statistics for PK Data Summaries 
The following summary statistics will be presented for plasma concentrations at each 
time point and derived PK parameters: AUC(0-t), AUC, Cmax, C8hr, and dose normalized 
Cmax, and dose normalized AUC(0-t): 
•
Number of observations 
•
The geometric mean (gmean) calculated as exp[μ], where μ is the sample mean of 
the data on a logarithmic scale 
•
Coefficient of variation (CV), calculated as 100*¥[exp(s2) – 1], where s is the 
standard deviation of the data on a log-scale 
•
Gmean ± standard deviation (SD) (calculated as exp[μ ± s]) 
•
Arithmetic mean calculated using untransformed data 
•
SD calculated using untransformed data 
•
Median 
•
Minimum 
•
Maximum 


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The following summary statistics will be presented for MR, CL, Vz, Vss, and t1/2Ǌz: 
•
Number of observations 
•
Arithmetic mean 
•
SD 
•
Median 
•
Minimum 
•
Maximum 
 
For tmax and tlast only: Number of observations, Median, Minimum, and Maximum will be 
presented in summary tables. 
 
6.9.2
Presentation of Pharmacokinetic Concentration and Parameter Data 
All plasma concentration data and PK parameters for AZD1775 and chemotherapy agents 
will be listed. 
Plasma concentrations below the lower limit of quantification (LLOQ) will be reported as 
not quantifiable (NQ) with the LLOQ defined in the TFLs.  
For calculation of descriptive statistics for plasma concentrations: 
•
If, at a given time point, 50% or less of the plasma concentrations are NQ, the 
gmean, CV, geometric SD, arithmetic mean and SD will be calculated by substituting 
the limit of quantification (LOQ) for values which are NQ. 
•
If more than 50%, but not all, of the concentrations are NQ, the gmean, CV, 
geometric SD, arithmetic mean and SD will be reported as not calculable (NC). The 
maximum value will be reported from the individual data, and the minimum and 
median will be set as NQ. 
•
If all the concentrations are NQ, the gmean and arithmetic mean will be reported as 
NQ and the CV, geometric SD and SD as NC. 
The number of values above LLOQ will be reported for each time point along with the 
total number of collected values. 
Three observations >LLOQ are required as a minimum for a plasma concentration or PK 
parameter to be summarised.  Two values will be presented as a minimum and 
maximum with the other summary statistics as NC. 
Plasma concentrations of AZD1775 and chemotherapy agents will be summarized by 
nominal time point and visit for each treatment group. PK parameters will be presented 
according to the conventions listed in the table below. 
Table 1: Conventions for Reporting PK Parameters  
Parameter 
Reporting in Summary Tablesa 
Listings 
AUC(0-t) 
gmean/CV/gmeanSD/mean/SD/med = 4 s.f. 
min/max = 3 s.f. 
3 s.f. 
AUC 
gmean/CV/gmeanSD/mean/SD/med = 4 s.f. 
3 s.f. 


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min/max = 3 s.f. 
CL 
mean/SD/med = 4 s.f. 
min/max = 3 s.f. 
3 s.f. 
C8hr 
gmean/CV/gmeanStD/mean/SD/med = 4 s.f. 
min/max = 3 s.f. 
same s.f. as supplied 
from bioanalysis 
Cmax 
gmean/CV/gmeanStD/mean/SD/med = 4 s.f. 
min/max = 3 s.f. 
same s.f. as supplied 
from bioanalysis 
Dose 
normalized 
AUC(0-t) 
gmean/CV/gmeanSD/mean/SD/med = 4 s.f. 
min/max = 3 s.f. 
3 s.f. 
Dose 
normalized 
Cmax 
gmean/CV/gmeanSD/mean/SD/med = 4 s.f. 
min/max = 3 s.f. 
3 s.f. 
MR AUC(0-t) 
mean/SD/med = 4 s.f. 
min/max = 3 s.f. 
3 s.f. 
t1/2Ǌz 
mean/SD/med = 4 s.f. 
min/max = 3 s.f. 
3 s.f. 
tmax 
med = 2 d.p. 
min/max = 2 d.p. 
2 d.p. 
tlast 
med = 2 d.p. 
min/max = 2 d.p. 
2 d.p. 
Vz 
mean/SD/med = 4 s.f. 
min/max = 3 s.f. 
3 s.f. 
Vss 
mean/SD/med = 4 s.f. 
min/max = 3 s.f. 
3 s.f. 
a N number included in summary table for all parameters as whole numbers. 
d.p. decimal places 
s.f. significant figures 
The concentration data for AZD1775 and chemotherapy agents will also be displayed 
graphically. Displays will include individual subject plasma concentration versus time 
profiles, on both the linear and log-scales, and the gmean concentration (±SD) versus 
time profiles, stratified by treatment group. For consistency, the same plasma 
concentration values are used in the mean data graphs as those given in the descriptive 
statistics summary table for each time point. 
 
A preliminary assessment of the effect of chemotherapy agents on AZD1775 PK will be 
conducted. The geometric mean AUC(0-t) values for AZD1775 following coadministration 
of AZD1775+chemotherapy agent will be compared to the geometric mean AUC(0-t) 
values for AZD1775 following monotherapy of AZD1775. Since AZD1775 was not 
administered as monotherapy in study D6010C00004, the preliminary data from studies 
D6015C00001, D6015C00003, and/or PN001 will be used for this preliminary 
assessment of drug interaction. 
 


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6.10
Further Anti-Tumor Therapy 
A table of the number and percentage of subjects who have received systemic anti-
cancer therapy for the disease after discontinuing protocol treatment will be presented 
by treatment arm using the FAS. The time from treatment discontinuation to first 
subsequent systemic therapy will also be summarised.  
A listing of further systemic therapy, radiotherapy and surgical intervention will also be 
provided.  
 
7
References 
x
Brookmeyer R and Crowley J. A confidence interval for the median survival time. 
Biometrics, 1982;38:29-41 
 
x
Clopper C and Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika 26: 404-413, 1934. 
 
x
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumors; revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2): 228-247 
 
x
Ellis S, Carroll KJ, Pemberton K. Analysis of duration of response in oncology trials. 
Contemporary Clinical Trials 2008; 29: 456-465. 
 
x
Lortholary A, Largillier R, Weber B, Gladieff L, Alexandre J, Durando X, Slama B, et 
al.  Weekly paclitaxel as a single agent or in combination with carboplatin or weekly 
topotecan in patients with resistant ovarian cancer: the CARTAXHY randomised phase 
II trial from Groupe d’Investigateurs Nationaux pour I’Etude des Cancers Ovariens 
(GINECO). Annals of oncology. 2011 May: mdr149. 
 
x
McNeish IA< Ledermann JA, Webber L, James L, Kaye SB, Hall M, Hall G, Clamp A, et 
al. A randomised, placebo controlled trial of weekly paclitaxel and saracatinib 
(AZD0530) in platinum-resistant ovarian, fallopian tube or primary peritoneal cancer. 
Annals of Oncology. 2014 Oct 1;25(10):1988-95 
 
x
SAS Institute Inc. (2001): The SAS System, Version 8.2. Cary, NC. SAS Institute Inc. 
 
x
Pignata S, Lorusso D, Scambia G, Sambatoraro D, Tamberi S, Cinieri S, et al. 
Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum alone for 
platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): a 
randomised, open-label, phase 2 trial. The Lancet Oncology. 2015 May 31; 
15(5):561-8. 
x
Rustin GJS, et al. Definitions for response and progression in ovarian cancer clinical 
trials incorporating RECIST v1.1 and CA-125 agreed by the Gynecological Cancer 
Intergroup (CGIG). Int J Gynecol Cancer 2011;21: 419-423. 


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8
Appendices 
8.1
Appendix 1: List of Tables, Figures and Listings 
8.1.1
Tables and Figures 
 
Table 11.1.1 Patient Disposition 
Table 11.1.2 Important Protocol Violations 
Table 11.1.3 Patient Accountability 
Table 11.1.4 Patient Demographics 
Table 11.1.5 Vital Signs at Baseline 
Table 11.1.6 Summary of Genetic Alterations 
Table 11.1.7 Prior Systemic Therapy for Disease 
Table 11.1.8 Prior  Radiotherapy for Disease 
Table 11.1.9 Prior Surgery for Disease 
Table 11.1.10 Disease History 
Table 11.1.11 Sites of Disease at Study Entry 
Table 11.1.12 Concomitant Medications 
Table 11.1.13 Further Anti-Tumour Therapy 
Table 11.2.1.1 Progression Free Survival via RECIST v1.1 
Table 11.2.1.2 Progression Free Survival via RECIST v1.1 (investigator assessment) 
according to genetic alteration status 
Figure 11.2.1.3 Progression-free survival, Kaplan-Meier plot 
Table 11.2.1.4 Overall Response Rate and Disease Control Rate via RECIST v1.1 
Table 11.2.1.5 Overall Response Rate & Disease Control Rate via RECIST v1.1 
(investigator assessment) according to genetic alteration status 
Table 11.2.1.6 Duration of Response 
Figure 11.2.1.7 Duration of Response, Kaplan-Meier plot 
Figure 11.2.1.8.1 Best Percent Change in Sum of Longest Diameters of Target Lesions - 
Waterfall Plot 
Figure 11.2.1.8.2 Best Percent Change in Sum of Longest Diameters of Target Lesions - 
Waterfall Plot by Cohort 
Figure 11.2.1.9.x Spider Plot of % Change in Tumour Size 
Figure 11.2.1.9.x Spider Plot of % Change in Tumour Size 
Table 11.2.1.10 Overall Survival 
Figure 11.2.1.11 Overall Survival, Kaplan-Meier plot 
Table 11.2.1.12 CA-125 Response Rate via Gynecological Cancer Intergroup Guidelines 
Figure 11.2.1.13.1 Waterfall Plot of Best Percent Change in CA-125 
Figure 11.2.1.13.1 Waterfall Plot of Best Percent Change in CA-125 by Cohort 
Figure 11.2.1.14.x Spider Plot of Change in CA-125 
Table 11.2.1.15.1 Summary of Plasma AZD1775 Concentration 
Table 11.2.1.15.2 Summary of Plasma Concentrations of Chemotherapy Agents 
Table 11.2.1.15.3 Summary of PLD Concentration - Additional Cycle 1 Time Points 


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Figure 11.2.1.16.x Individual AZD1775 plasma concentrations (<<unit>>) of 
AZD1775[a] versus time for AZD1775<dose>+Chemotherapy<dose> on Cycle 1 Day 
1[b]* 
Figure 11.2.1.17.x Geometric mean (+/- GSD) plasma concentrations (unit) of 
AZD1775[a] versus time on Cycle 1 Day 1 
Table 11.2.1.18.1 Summary of Plasma AZD1775 PK Parameters 
Table 11.2.1.18.2 Summary of Plasma Chemotherapy Agents PK Parameters 
Table 11.3.1.1 Time on Treatment and Exposure 
Table 11.3.1.2 Duration of Chemotherapy Infusion By Cycle 
Table 11.3.1.3 Treatment Modifications 
Table 11.3.2.1 Adverse Events Overview 
Table 11.3.2.2 All Treatment Emergent Adverse Events by SOC, PT and Worst Grade 
Table 11.3.2.3 All Treatment Emergent Adverse Events by PT 
Table 11.3.2.4 AZD1775 Related TEAE by SOC, PT and Worst Grade 
Table 11.3.2.5 AZD1775 Related TEAE by PT 
Table 11.3.2.6 Chemotherapy Related TEAE by SOC, PT and Worst Grade 
Table 11.3.2.7 Chemotherapy Related Serious TEAEs by SOC and PT 
Table 11.3.2.8 Dose Limiting Toxicity Overview 
Table 11.3.2.9 Summary of Deaths 
Table 11.3.4.1 Serious TEAEs by SOC and PT 
Table 11.3.4.2 Serious TEAEs by PT 
Table 11.3.4.3 AZD1775 Related Serious TEAEs by SOC and PT 
Table 11.3.4.4 AZD1775 Related Serious TEAEs by PT 
Table 11.3.7.1.1.x Laboratory tests - Summary over time 
Table 11.3.7.1.2  Haematology and clinical chemistry, CTCAE grade change from 
baseline to maximum on treatment (Safety analysis set) 
Table 11.3.7.1.3  Clinical chemistry, CTCAE grade change from baseline to maximum on 
treatment for electrolytes (Safety analysis set) 
Table 11.3.7.1.4 Summary of Elevated AST, ALT, Total Bilirubin and Alkaline Phosphate 
Table 11.3.8.1.1 Vital Signs Summary over time 
Table 11.3.8.1.2 Vital Signs Change from Baseline Summary over time  
Table 11.3.8.1.3 ECOG PS Summary over time 
Table 11.3.8.1.4 Summary of Electrocardiogram Tests 
 
8.1.2
Listings 
Appendix 12.2.1.1 Date Informed Consent Form was Signed 
Appendix 12.2.1.2 Eligibility 
Appendix 12.2.2.1 Subjects with Important Protocol Deviations 
Appendix 12.2.4.1 Demographic and Baseline Characteristics 
Appendix 12.2.4.2.1 Medical History and Current Medical Conditions 
Appendix 12.2.4.2.2 Disease History 
Appendix 12.2.4.2.3Prior Systemic Therapy 


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Appendix 12.2.4.2.4 Prior Rradiotherapy 
Appendix 12.2.4.2.5 Prior Surgery for the Disease 
Appendix 12.2.4.3 Concomitant medication on entry and during the study 
Appendix 12.2.4.4 Biomarker Results 
Appendix 12.2.4.5.1 Anti-tumour therapies after study treatment 
Appendix 12.2.4.5.2 Post Discontinuation Radiotherapy 
Appendix 12.2.4.5.3 Post Discontinuation Surgery 
Appendix 12.2.5.1 Administration of investigational product, AZD1775  
Appendix 12.2.5.2 Administration of investigational product, Chemotherapy  
Appendix 12.2.6.1 Overall Response via RECIST 1.1 
Appendix 12.2.6.2.1 Target lesion data 
Appendix 12.2.6.2.2 Non-target lesion data 
Appendix 12.2.6.2.3 Progression-Free Survival  
Appendix 12.2.6.2.4 CA-125 Response 
Appendix 12.2.6.3.1 Pharmacokinetic parameters, AZD1775 
Appendix 12.2.6.3.2 Pharmacokinetic parameters, Chemotherapy 
Appendix 12.2.6.3.3.x Lambda_z Related PK Parameter Results for <analyte> 
Appendix 12.2.6.4.1 Drug concentration data, AZD1775 
Appendix 12.2.6.4.2 Drug concentration data, Chemotherapy 
Appendix 12.2.7.1 Adverse Events 
Appendix 12.2.7.2 Serious Adverse Events 
Appendix 12.2.7.3 Dose Limiting Toxicities 
Appendix 12.2.7.4 Deaths 
Appendix 12.2.8.1.1 Individual laboratory measurement - haematology 
Appendix 12.2.8.1.2 Individual laboratory measurement - chemistry 
Appendix 12.2.8.1.3 Individual laboratory measurement - coagulation 
Appendix 12.2.9.1 Individual vital signs data 
Appendix 12.2.10.1 Electrocardiogram data 
Appendix 12.2.10.2 Ejection Fraction Assesments 
8.2
Appendix 2: Overall Visit Responses 
Target Response 
Non-target 
Response 
New Lesions 
Overall Response 
at this 
assessment 
CR 
CR 
NO 
CR = Complete 
Response 
CR 
NA 
NO 
NA 
CR 
NO 
CR 
NonCR/NonPD  
NO 
PR = Partial 
Response 
CR 
NE 
NO 
PR 
NA 
NO 


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PR 
CR 
NO 
PR 
NonCR/NonPD 
NO 
PR 
NE 
NO 
NA 
NonCR/NonPD  
NO 
NonCR/NonPD 
SD 
NA 
NO 
SD = Stable 
disease 
SD 
CR 
NO 
SD 
NonCR/NonPD 
NO 
SD 
NE 
NO 
PD 
ANY 
YES or NO 
PD = Progressive 
Disease 
ANY 
PD 
YES or NO 
ANY 
ANY 
YES 
NE 
NA 
NO 
NE = Not 
Evaluable 
NE 
NonCR/NonPD 
NO 
NE 
CR 
NO 
NE 
NE 
NO 
NA 
NE 
NO 
NA 
NA 
NO 
NA = Not 
Assessed