A Phase I/II Study of MEDI4736 (Anti-PD-L1 Antibody) in Combination With Olaparib (PARP Inhibitor) in Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Ovarian, Breast, SCLC, Gastric Cancers
Sponsor: AstraZeneca

Revised Clinical Study Protocol 
Drug Substance
Olaparib and MEDI4736
Study Code
D081KC00001
Version
7
Date
17 December 2020
A Phase I/II Study of MEDI4736 (Anti-PD-L1 Antibody) in Combination 
with Olaparib (PARP inhibitor) in Patients with Advanced Solid Tumors
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden

Revised Clinical Study Protocol
Drug Substance Olaparib and MEDI4736
Study Code D081KC00001
Version 7
Date 17 December 2020
2(461)
VERSION HISTORY
Revised Protocol edition 7, 17 December 2020
This amendment is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
The primary change to the protocol has been the removal of the 3 Third Stage Cohorts from 
the study to reflect the current development strategy for the olaparib + MEDI4736 
combination: the BRCAm breast cancer expansion cohort (Module 8; previously detailed in 
Appendix P), the HRRm breast cancer cohort (Module 9; previously detailed in 
Appendix Q), and the triple negative breast cancer triplet cohort (Module 10; previously 
detailed in Appendix R).  As a result, all text referring to these cohorts, including text in the 
Core Protocol and Appendices P to S has been removed. 
The impact of COVID-19 has highlighted the risk to continuity of clinical trials during 
times of study disruption, whether by civil crisis, natural disaster or public health crisis.  
The study mitigation changes described below will only be initiated at a time of study 
disruption.  Study mitigation language is presented in new Section 1.5.1 of the Core 
Protocol, and in the newly-added Appendix P (Changes related to mitigation of study 
disruptions due to cases of civil crisis, natural disaster, or public health crisis). 
Additionally, Section 1.3.5 (Impact on Benefit/Risk from Study Disruptions due to 
Coronavirus Disease 2019) has been added in the context of the COVID-19 pandemic.  
Text has been included throughout the Clinical Study Protocol stating that enrollment into 
the BRCAm ovarian cancer expansion cohort has been terminated after 51 patients had been 
enrolled, and will not continue until the originally planned 80 patients have been enrolled.  
As PARP inhibitors have become standard of care in the first line setting for gBRCAm
patients, the high unmet clinical need in this patient population has reduced.  In addition, as 
a result of the success of PARP inhibitors in this setting, there are limited numbers of PARP 
inhibitor-naïve patients eligible for inclusion in the BRCAm ovarian cancer expansion 
cohort.  Therefore, despite high response rates in this patient population with olaparib and 
MEDI4736 combination treatment as shown in the initial stage gBRCAm ovarian cancer 
cohort, recruitment for the BRCAm ovarian cancer expansion cohort was closed early.  
Additionally, planned interim analyses for the cohort have been removed. 
Due to slow recruitment of the gBRCAm expansion cohort and removal of the Third Stage 
breast cancer cohorts, the final data cut-off has been updated in Section 9.3, and is
anticipated to occur in 2021. Updated text on the final data cut-offs and the closure of the 
clinical database is updated based on current data maturity in Section 9.3 of the Core 
Protocol, and referenced accordingly in Section 9 of each cohort-specific appendix. 
Additional language has been added to Section 9.3 defining the end of study.
The use of blinded independent central review (BICR) for tumor assessments in select 

Revised Clinical Study Protocol
Drug Substance Olaparib and MEDI4736
Study Code D081KC00001
Version 7
Date 17 December 2020
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cohorts is being removed from the protocol, as there is no intent to use data from any 
cohorts as pivotal data for regulatory filings for new indications and these additional 
independent reviews are not required for the scientific evaluation of the study.  This update 
provides consistency between the protocol and the analyses performed on the study for both 
the Initial Stage Cohorts and Second Stage Cohorts (in the gBRCAm ovarian cancer and 
gBRCAm breast cancer cohorts).  As a result, all mention of BICR has been removed from 
the protocol, including the endpoints based on BICR assessments and the requirement for 
an additional scan to confirm Investigator-assessed disease progression, which was 
performed in order to minimize bias in the BICR assessment. 
The status of the study and the clinical development of the study drugs has been updated 
throughout the protocol as appropriate, including: the benefit/risk language for MEDI4736 
and how many patients have received MEDI4736 in clinical studies; the approval status of 
olaparib for different indications and territories, the enrollment status of the study (all 
cohorts have completed enrollment); and a brief summary of the results from Initial Stage 
Cohorts.  
Section 6.8.4 (Specific toxicity management and dose modification information -
MEDI4736) and Section 6.8.5 (MEDI4736 adverse events of special interest) have been 
updated to ensure consistency with current MEDI4736 standards.  Additionally, the toxicity 
management guidelines portal for MEDI4736 was decommissioned at the end of September 
2020, and therefore reference to this website has been removed; this document is provided 
to sites as an annex to the protocol.  Finally, to ensure that the toxicity management 
guidelines are the sole source for the most current information, individual subsections 
describing the management of each MEDI4736 AESI have been deleted as they are 
duplicative to the toxicity management guidelines.
In Section 7.7 of the Core Protocol, the list of prohibited and restricted medications has 
been updated for consistency with the latest guidance for olaparib and MEDI4736.  Table 8 
(Supportive medications) has also been added to give further details of permitted 
medications.  
Updated text on cohort-specific data cut-offs and the closure of the clinical database has 
been modified in Section 9.3 of the Core Protocol and in Section 9 of each cohort appendix.  
The expected date of final cut-off (in 2021) has also been added.
Clarification on order of administration of bevacizumab and MEDI4736 has been 
implemented in Appendix M (Module 6; ovarian cancer triplet cohort), Section 4 Table 3 
(study schedule for the combination therapy treatment period).  A statement on the order of 
infusions for MEDI4736 and bevacizumab has also been repeated in Section 4.2 and 
Section 7.2.1 of Appendix M, and Section 7.2.3 of the Core Protocol. 
Descriptions of myelodysplastic syndrome/acute myeloid leukaemia, an adverse event of 
special interest for olaparib, have been updated to reflect the fact it is now an identified risk, 
and not a potential risk per the latest Olaparib Investigator Brochure.  Changes have been 

Revised Clinical Study Protocol
Drug Substance Olaparib and MEDI4736
Study Code D081KC00001
Version 7
Date 17 December 2020
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made in Section 1.3.1 and Section 6.8 of the Core Protocol. 
Throughout the Core Protocol and Appendices B and D, minor language updates and 
additions have been made to align with current AstraZeneca standards for clinical study 
protocols and to provide additional clarity.  The updates do not mandate changes in the 
procedures of the study.  Sections affected include: Section 3.8(Restrictions), to clarify 
contraception guidance; Section 5.2.1 (Laboratory safety assessments) and Appendix D 
(Actions Required in Cases of Increases in Liver Biochemistry and Evaluation of Hy’s 
Law), for reporting of liver abnormalities; Section 5.2.4.1 (Pulse and blood pressure); 
addition of Section 5.2.5.3 (Pneumonitis/interstitial lung disease), to provide details of 
management and reporting of pneumonitis/interstitial lung disease; Section 6.3.3 (Adverse 
events after the 90-day follow-up period); Section 6.3.12 (Deaths); Section 6.7 (Medication 
error); Section 7.1.1 (MEDI4736), to add language on administration of MEDI4736 to 
patients with body weight ≤ 30 kg; Section 7.2.2 (Olaparib); Section 7.8 (Post study access 
to study treatment); Section 10 (Ethical and regulatory requirements); and Appendix B 
(International Airline Transportation Association 6.2 Guidance Document).
Further minor changes to the protocol include: 

Updates to references in the Core Protocol (Section 11) and Module 5 (Section 11 of 
Appendix L) including their epub status, and to remove some citations no longer 
referenced. 

In Section 4.1 of the Core Protocol text was added stating that ovarian cancer patients in 
the Second Stage Cohorts are exempt from provision of a new biopsy sample even 
when/even if the archival tumor sample is more than 3 years old for consistency with 
other parts of the protocol.
Text referring to HRR testing has been removed from the Core Protocol as this applied only 
to the Third Stage Cohorts (primarily Section 5.6 of the Core Protocol).

Minor typographical corrections and update of paragraph formatting for consistency 
with current AstraZeneca document standards.
Revised Protocol edition 6, 29 November 2019
The primary change to the protocol has been the removal of Toxicity Management 
Guidelines (TMGs) relating to MEDI4736 from the body of the core protocol (Section 6.8),
to be replaced by references to the standalone TMG Annex document available on a website 
and in the Site Master File.  This document contains the latest guidance for dosing 
modification and toxicity management to be followed by Investigators.
In addition, ADA analysis for bevacizumab has been removed.  Due to an oversight, the 

Revised Clinical Study Protocol
Drug Substance Olaparib and MEDI4736
Study Code D081KC00001
Version 7
Date 17 December 2020
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sample collection and analysis for this has not been done thus far and the decision was 
made that this testing is not critical to the study and could be removed as a secondary 
outcome measure for 2 cohorts (the ovarian cancer triplet cohort and the triple negative 
breast cancer triplet cohort).
Changes in each section are summarized below, in addition minor editorial changes to 
clarify language and to correct typos, cross-references, and formatting have also been made 
and are not described in the version history.
Protocol synopsis (Objectives and outcome measure for all cohorts) and Section 2.2 
(Secondary objectives):
!
For secondary objective relating to PK, immunogenicity and pharmacodynamics 
of bevacizumab, reference in objective to immunogenicity and outcome measures 
referring to ADAs for bevacizumab have been removed (applies to triplet cohorts 
only).
Section 1.4 (Study design):
!
In Section 1.4.1, for participants of Review Committee, requirement that the 
study physician will chair the meeting has been removed.
Section 3.8 (Restrictions):
!
Clarification has been added that use of 2 acceptable methods of contraception by 
females of childbearing potential must be started from the time of signature of the 
first informed consent.
Section 5.2.1 (Laboratory safety assessments) and Section 6.3.8 (Elevations in liver 
biochemistry parameters):
!
Clarification has been added that cases of elevated liver biochemistry parameters 
must be reported as SAEs if the criteria for Potential Hy’s Law are met and no 
alternative explanation can be identified.
!
Sampling for bevacizumab ADA analysis has been removed.
Section 6.3.1 (Time period for collection of adverse events):
!
Clarification has been added that AEs will be collected from the time of signature 
of first informed consent.
Section 6.8 (Management of IP-related toxicities):
!
In Sections 6.8.1 (General comments) and 6.8.4 (formerly entitled “MEDI4736”), 
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Revised Clinical Study Protocol
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Study Code D081KC00001
Version 7
Date 17 December 2020
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guidance has been updated in line with the latest AstraZeneca standard template 
language and refers to a standalone TMG Annex maintained within the site 
master file and on a specified website.

Tables 6, 7, 8, and 9, that included dosing modification and toxicity management 
guidelines and followed Section 6.8.6, have been removed.  References to these 
tables have been removed and replaced by references to the TMG Annex in all 
relevant subsections within Section 6.8.
All cohort specific appendices, Section 3.2 (Exclusion criteria):

In exclusion criterion 12, blood malignancy has been additionally specified as an 
exclusion in this criterion.

In exclusion criterion 22, irritable bowel disease has been corrected to 
inflammatory bowel disease.
Appendix M (Module 6: Ovarian cancer triplet cohort):

In Section 5.2 (Safety assessments), number of samples and corresponding total 
volume for olaparib PK samples in Table 5 have been corrected per Table 6 (total 
of 5 samples).
Appendix R (Module 10: Triple negative breast cancer triplet cohort):

In Section 5.2 (Safety assessments), number of samples and corresponding total 
volumes for olaparib PK samples and ADA samples in Table 6 have been 
corrected per Table 7 (total of 5 olaparib PK samples) and Table 8 (total of 
4 ADA samples), respectively.
Revised Protocol edition 5, 16 August 2018
The primary change to the protocol has been the addition of 3 breast cancer cohorts, based on 
the preliminary results from this study, 1 of which is an expansion of the current (gBRCAm) 
breast cancer cohort, 1 of which assesses the olaparib+MEDI4736 combination in HER2-
negative, non BRCAm, HRRm breast cancer patients, and 1 of which assesses the 
olaparib+MEDI4736+bevacizumab combination in triple-negative non BRCAm, non HRRm 
breast cancer patients.
These cohorts have been added as Appendix P (BRCAm breast cancer expansion cohort; 
Module 8), Appendix Q (HRRm breast cancer cohort; Module 9), and Appendix R (triple 
negative breast cancer triplet cohort; Module 10).  In addition, Appendix S has been added; 
Appendix S describes the screening processes for the 3 new cohorts.

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Study Code D081KC00001
Version 7
Date 17 December 2020
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Throughout the whole protocol, the following changes have been made and are applicable to 
the whole study (including cohort-specific appendices):

In the Core Protocol, information and cross-references for the 3 new Third Stage 
Cohorts have been added as appropriate.

The Initial Stage breast cancer cohort is now referred to as the gBRCAm breast 
cancer cohort for clarity as new breast cancer cohorts have been added.

Reference to “modified” RECIST has been removed throughout the protocol, as 
RECIST 1.1 is no longer being modified to require confirmatory scans at 
progression.

“Quintiles” has been replaced with “IQVIA” to reflect the change in company name 
of the Contract Research Organization.

A Statement that “Imaging assessments every 8 weeks are required for patients who 
continue receiving the study drug combination beyond disease progression” has 
been added where appropriate to clarify the imaging requirements of patients who 
have progressed but remain on study treatment.

In addition to the final data cut-off at the end of the study, details have been added 
on when the cut-off for each cohort will occur, and what data may be collected after 
the cohort data cut-off (survival, investigational product dispensing/accountability,
subsequent anticancer treatment, and selected safety data).

Text stating that details of pregnancy tests must be recorded in the patient’s medical 
records has been added for consistency with current AstraZeneca procedures.

For consistency with current AstraZeneca templates and procedures, Section 5.4 
(Pharmacogenetics) in the Core Protocol and all cohort-specific appendices has 
been re-titled “Genetics”, references to pharmacogenetics have been similarly 
altered.  A new Appendix (Appendix C Genetic Research) has been added and 
details of the optional genetics assessments moved to the Appendix.  Addition of 
the Appendix has resulted in re-lettering of all subsequent Appendices.  In Section 
10.2, ethics information for genetics samples and data have been removed and are 
now in Appendix C. 

Increase in the size of visit windows for visits with previous window of ±2 days to 
±3 days at the suggestion of study centers, to allow patients and centers to 
accommodate weekends and national holidays.

A requirement for completion of a specific eCRF page in the event of 
nausea/vomiting during the study treatment period has been removed, as data on 
olaparib and nausea/vomiting are no longer required.

Revised Clinical Study Protocol
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Study Code D081KC00001
Version 7
Date 17 December 2020
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
Text to introduce the optional taking of tumor biopsies at disease progression 
(where patients consent and biopsy is clinically feasible) has been added for all 
cohorts (Core Protocol and cohort-specific appendices).

In treatment period flow charts the following text was added in all cohorts: If an 
unscheduled assessment was performed and the patient has not progressed, every 
attempt should be made to perform the subsequent assessments at their next 
scheduled visit. Imaging assessments are required for patients who continue 
receiving the study drug, including those who continue beyond progressive disease.

In post-treatment flow charts details on the optional taking of tumor biopsies at 
disease progression were added for all cohorts, and it was clarified in the footnotes 
that RECIST 1.1 assessments continue until objective disease progression (ie, 
should continue after clinical progression until objective progression is determined).

Dexamethasone has been added as a moderate CYP3A inducer to be considered in 
exclusion criteria and concomitant medications.

Throughout the protocol it has been clarified that study treatment will continue until 
objective radiological disease progression as per RECIST 1.1 as assessed by the 
Investigator or as long as, in the Investigator’s opinion, they are benefitting from 
treatment and they do not meet any other discontinuation criteria.

It has been clarified that screening (and all) T3 and T4 assessments will only be 
made if TSH is abnormal or if there is a clinical suspicion of an AE related to the 
endocrine system.

Specified that both urine and serum pregnancy tests (previously just serum) are 
suitable for screening and subsequent pregnancy testing (eligibility criteria and 
schedules of assessment).

Update in QTc prolongation exclusion criterion from exclusion of >470 msec to 
>500 msec, consistent with current olaparib guidance, text in the rest of the protocol 
has been made consistent with this change.

Change of exclusion criteria “previous enrollment in the present study” to “previous 
treatment in the present study”, to allow rescreening. 

In the screening flow chart in all cohorts, it is no longer required to wait until 
eligibility is confirmed before any blood samples are taken at screening/baseline (eg 
plasma for circulating soluble factors). 
Changes in each section are summarized below, in addition minor editorial changes to clarify 
language and to correct typos, cross-references, and formatting have also been made and are 
not described in the version history.

Revised Clinical Study Protocol
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Study Code D081KC00001
Version 7
Date 17 December 2020
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Protocol synopsis:

Content was adapted and added to incorporate and describe the 3 new breast cancer 
cohorts (Modules 8 to 10).  

Minor changes were also made to update the synopsis according to the most recent 
AstraZeneca protocol template (including removal of table showing start and 
projected end times of study cohorts).

The tables for primary, secondary, and exploratory objectives were modified to 
increase the clarity of the objectives and endpoints.

Data cut-offs for each cohort are detailed, in addition to the original overall final 
data cut-off.

Details on the sourcing, labeling and storage of bevacizumab have been added to 
the synopsis for information.
Section 1 (Introduction):

Details of regulatory approvals have been updated to the most current information.

A rationale for the addition of the 3 Third Stage Cohorts has been added (new 
subsection: Section 1.2.3).

In Section 1.4 (Study design), diagrams have been updated for clarity and accuracy.

In Section 1.4 (Study design), subsection 1.4.3 (Third Stage Cohorts) has been 
added which details the study design of the Third Stage Cohorts and illustrates the 
BRCA and HRR testing process.

In Section 1.4 (Study design), subsection 1.4.4 (Summary of breast and ovarian 
cancer cohort characteristics) has been added to provide a single summary of cohort 
characteristics for ovarian and breast cancer patients (eg, molecular markers, 
previous treatment lines)

Section 1.5 (Study governance and oversight): information has been moved from 
Section 6.8 to here for consistency with other recent AstraZeneca protocols.  In 
addition, information on study monitoring and review committees has been added.
Section 2 (Study objectives):

The tables for primary, secondary, and exploratory objectives were modified to 
increase the clarity of the objectives and endpoints.
Section 3 (Patient selection, enrollment, randomization, restrictions, discontinuation and 

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withdrawal)

In Section 3 a reference has been added to Section 3.10.1 to highlight new 
information on rescreening of patients.

Section 3.1 and 3.2 (inclusion and exclusion criteria): To improve readability and 
navigation of the protocol, specific cross-references to the inclusion and exclusion 
criteria for each module have been provided, instead of general references to 
module-specific appendices.

In Section 3.3 (Patient enrollment), text has been added stating that patients 
re-enrolled after rescreening will be assigned a new E-code.

Section 3.5.3 (Third Stage Cohorts, new section) has been added and describes 
methods for assigning Third Stage Cohort patients to the different Third Stage 
breast cancer cohorts. 

Section 3.8.1 (Olaparib and CYP3A4): the recommendation not to consume 
grapefruit juice while on olaparib treatment was updated to a prohibition, in line 
with the most recent guidance on olaparib.

Section 3.9.1 (Procedures for discontinuation of a patient from investigational 
product): a sentence stating that data on subsequent anticancer treatment after study 
treatment discontinuation would be collected was added.

In Section 3.10.1 (Screen failures), text has been added describing in what 
circumstances patients can be rescreened. 
Section 4 (Study plan and timing of procedures):

Cross-references to all the schedules of assessments across the study have been 
added to enable faster and easier navigation of the protocol. 

Section 4.1 (Enrollment/screening period): Text has been added stating that the 
screening period for the Third Stage Cohorts can be up to 40 days (to allow for 
Myriad laboratory testing of greater complexity in these cohorts).  Text confirming 
that baseline tumor assessment and pregnancy tests should still occur within 28 days 
prior to study treatment has been added, as well as a statement that if screening 
activities take less than the full time available, patients can start study treatment.
Section 5.1.3 (Central reading of scans)

Text has been added stating that, in the BRCAm ovarian cancer expansion and 
BRCAm breast cancer expansion cohorts, patients who are determined to have 
progressed according to RECIST 1.1 criteria by the Investigator will have 1 
additional RECIST assessment at the next scheduled RECIST visit in order to 

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minimize bias in the blinded independent central review (BICR) assessment in the 
event the Investigator declares objective progression.  This change has also been 
made in the relevant cohort-specific appendices.
Section 5.5.2.3 (Third Stage Cohorts):
!
Text on mandatory archival tumor samples from breast cancer patients in the 3 new 
Third Stage Cohorts has been added. 
Section 5.5.4.1 (Pharmacodynamics: paired tumor biopsies):
!
 
Section 5.5.4.11 (Pharmacodynamics: tumor biopsy at disease progression):
!
 
Section 5.5.5 (Biomarker sample and data management):
!
 
Section 5.6 (BRCA status) and Section 5.6.3 (Third Stage Cohorts)
!
The title and content have been modified to reflect the additional (HRR) screening 
tests required for the Third Stage Cohorts.
Sections 6.1 and 6.2 (Definition of adverse events, Definitions of serious adverse events):
!
Text has been updated to reflect current AstraZeneca standards.
Section 6.3.3 (Adverse events after the 90-day follow-up period):
!
Text has been updated to reflect current AstraZeneca standards.
Section 6.3.10 (New cancers):
!
Text has been updated to reflect current AstraZeneca standards.
Section 6.6 (Pregnancy):
!
A statement that pregnancies discovered before study treatment starts do not need to 
be reported to AstraZeneca, in line with current AstraZeneca standards.
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Section 6.7 (Medication error; new section)

This section added for consistency with current AstraZeneca templates and 
standards, to define a medication error and detail the actions to be taken in the event 
of a medication error.  Subsequent sections were renumbered accordingly. 
Section 6.8.2 (Olaparib, previously Section 6.7.2):

Minor updates were made in the management of anemia for consistency with 
current olaparib guidance.

Updates were made to the management of nausea and vomiting for consistency with 
current olaparib guidance.
Section 6.8.3 (Olaparib adverse events of special interest, previously Section 6.7.3):

Text on the expedited reporting of olaparib adverse events of special interest has 
been removed, for consistency with current AstraZeneca standards.
Section 6.7.8 (Bevacizumab adverse events of special interest)

Section deleted, as there are no adverse events of special interest for bevacizumab.
Section 6.8 (Study governance and oversight)

Information in this section was moved to Section 1.5, and deleted here. 
Section 7.1 (Identity of investigation products)

An error regarding the dosage form and strength of bevacizumab was corrected in 
Table 8 (now Table 10) – the value was changed from 10 mg/kg to 25 mg/mL.
Section 7.2.1 (Olaparib)

Olaparib dose reduction guidance for patients has been updated in line with current 
olaparib guidelines. 
Section 7.5 (Compliance):

Text has been updated to reflect current AstraZeneca standards.
Section 7.7 (Concomitant and other treatment) and Appendix G (Medications to be Avoided 
with Olaparib):

Section 7.7 has been updated and reformatted for consistency with other olaparib 
protocols and current guidance on olaparib.  Information in Appendix G has been 

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moved to Section 7.7, and replaced with a cross-reference to Section 7.7. 

Guidance on olaparib dose reductions when concomitant strong or moderate 
CYP3A inhibitors cannot be avoided has been added in a new table (Table 13). 
Section 7.7.3 (Rescue medication, new section)

A new section with guidance on rescue medication for immune-mediated adverse 
events potentially experienced by patients receiving MEDI4736 has been added.
Section 8.3.1 (Full analysis set):

Text cross-referencing the full analysis set definition for the BRCAm ovarian cancer 
expansion cohort has been deleted, as the definition is the same as for other cohorts.
Sections 8.4.2.5 (Objective response) 8.4.2.6 (Best objective response), 8.4.2.7 (Duration of 
response):

Information on objective response and duration of response were split into 
2 sections (8.4.2.5 and 8.4.2.7, respectively) for consistency with the Statistical 
Analysis Plan. 

Section 8.4.2.6 (Best objective response) was added to define the calculation and 
analysis of best objective response.
Section 9.3 (Study timetable and end of study):

Information has been added to define data cut-offs for each cohort.  In line with 
expected recruitment, clinical response, and reporting, cohorts have been grouped 
into 3 data cut-offs.
Appendix C (Genetic Research, new appendix)

The appendix has been added to hold all information on the optional genetics 
assessments in one place, in accordance with current AZ standard and templates. 
Appendix E (Guidelines for Evaluation of Objective Tumor Response Using RECIST 1.1 
Criteria; previously Appendix D)

Updates were made to reflect the removal of the requirement for confirmatory 
scans. 
Appendix F (Monitoring Plan for Futility and Efficacy; previously Appendix E)

Details of the monitoring plan for futility and efficacy in the 3 new Third Stage 
Cohorts have been added. 

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Appendix G (Medications to be Avoided with Olaparib; previously Appendix F)

Information has been removed from this appendix to Section 7.7 (concomitant 
medications) for clarity, and for consistency with current AZ templates.  To ensure 
Investigators are alerted to the new location, a cross-reference has been placed in 
the appendix. 
In the Initial Stage cohorts, the following changes were made: 

Retrospective BICR analysis of scans in the gBRCAm breast cancer cohort were 
added to Cohort 2.

Cohort schemas have been updated to more clearly represent the cohort design.

Update exclusion criterion relating to previous malignancies for consistency with 
olaparib standards.
In the Second Stage Cohorts, the following changes were made:

Cohort schemas have been updated to more clearly represent the cohort design.

Updated, and clearer, definitions in inclusion/exclusion criteria for prior treatment 
lines.

Updated the creatinine clearance inclusion criterion in line with current olaparib 
standards.

Update exclusion criterion relating to previous malignancies for consistency with 
olaparib standards.

Update (relaxation) of QTc prolongation exclusion criterion in line with current 
olaparib standards.

Modified NOTE 1 in the screening schedules of assessment footnotes to state that 
waivers may be granted to extend the 28 day screening period in order to allow for 
tumor biopsy sample acquisition, scan scheduling, and other screening procedures.

Removal of the Cycle 1, Day 1 RECIST assessment, which was included in error.

(BRCAm ovarian cancer expansion cohort only): text was added indicating that 
patients who are determined to have progressed according to RECIST 1.1 criteria 
by the Investigator will have 1 final RECIST assessment at the next scheduled 
RECIST visit in order to minimize bias in the BICR assessment in the event the 
Investigator declares objective progression.

Details on the tissue requirements for paired biopsies have been added.  Four cores 

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(2 for processing as FFPE blocks and 2 for immediate freezing) should be taken 
where possible.

(Ovarian cancer triplet cohort only): new information on bevacizumab approvals 
and clinical data has been added to Sections 1.1.1.1, 1.1.1.2, and 1.2.3.1.

(Ovarian cancer triplet cohort only): the specification of a bevacizumab vial size of 
400 mg was removed to allow for different local packaging.

Appendix O (BRCA screening process; previously Appendix N): minor updates 
have been made around the use of the Myriad central laboratory and BRCA testing.  
No changes to the screening/testing process have been made.

Section 8.2 of the BRCAm ovarian cancer expansion cohort (definition of full 
analysis set; Module 5) has been deleted as it is not required (definition is the same 
as all other cohorts, and described in Core Protocol). 

Section 1.4 of the ovarian cancer triplet cohort (Module 6; Study Design) and 
Section 1.3 of the ovarian cancer doublet cohort (Module 7; Study Design), the 
point at which DCR is assessed as reported in Figure 1 of each section has been 
corrected from 12 to 24 weeks.
Three new Third Stage Cohorts enrolling breast cancer patients have been added. These are:

The BRCAm breast cancer expansion cohort – Module 8. Detailed in Appendix P.  
Please see the introduction to Appendix P for background information and rationale 
for the cohort.

The HRR breast cancer cohort – Module 9. Detailed in Appendix Q.  Please see the 
introduction to Appendix Q for background information and rationale for the 
cohort.

The triple negative breast cancer triplet cohort – Module 10. Detailed in Appendix 
R.  Please see the introduction to Appendix R for background information and 
rationale for the cohort.

The BRCA and HRR screening processes for the Third Stage Cohorts are detailed 
in Appendix S.

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Revised Protocol edition 4, 12 April 2018
Section 3.8 of the Core Protocol and Section 3.8 of Appendix L (Module 6) were updated to 
include the guidance for duration of use of effective contraception after bevacizumab 
treatment.
Revised Protocol edition 3, 31 January 2018
In this amendment of the protocol, 3 new ovarian cohorts have been added based on 
preliminary results from this study, 1 of which is an expansion of the current gBRCAm ovarian 
cohort.  The 2 other new cohorts will explore the olaparib+MEDI4736 combination in non 
BRCAm ovarian cancer patients with or without the addition of bevacizumab to the 
combination, which is based on recent findings that suggest vascular endothelial growth factor 
(VEGF) therapy can enhance the activity of polyadenosine 5’diphosphoribose (poly [ADP 
ribose]) polymerization (PARP) inhibitors in non BRCAm ovarian patients.
In order to keep the overall protocol organized and easy to reference with the additional 
3 cohorts, the protocol has been restructured so that information specific to each cohort in 
individual “Modules”.  Information applicable across the study is contained in the “Core 
Protocol”.  Within the Core Protocol, the four initial cohorts are now referred to as the “Initial 
Stage Cohorts”, whereas the 3 new ovarian cohorts are referred to as “Second Stage Cohorts”.  
This change has been made to simplify the protocol for Investigators, placing information 
specific to each in 1 section or module of the protocol.
Specific details for the “Initial Stage” cohorts (Modules 1 to 4; Appendices G to J) and the 
“Second Stage Cohorts” (Module 5 to 7; Appendices K to M) have been organized into the 
same basic structure as the Core Protocol to improve ease of reference for sites.
Whole document: Cohort-specific information has typically been removed from the “Core 
Protocol” and moved to the cohorts-specific Modules.  This includes -

Section 1 (Introduction): 

Introductory text (background, rationales, study design) from the previous 
protocol version has been maintained in the Core Protocol, and referred to 
in the cohort-specific Modules as appropriate.

Information on the clinical experience with olaparib and MEDI4736 has 
been updated.

Benefit-risk text for olaparib and MEDI4736 alone and in combination 
has been updated.

The structure of the introduction has been updated to reflect the focus on 

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olaparib+MEDI4736.
∀
Additional introductory text for the Second Stage Cohorts has been 
included in Section 1 of each Module (Appendices K to M).
!
Section 2 (Study objectives): All study objectives for all cohorts of the study are 
presented in Section 2 of the Core Protocol.  The following changes and additions 
have been made: 
∀
For the Initial Stage gBRCAm ovarian cancer cohort, endpoints assessed 
by retrospective independent central review of scans (in addition to 
Investigator assessment) have been added.  Independent central review 
will be used to retrospectively assess the efficacy endpoints for this 
cohort, which are dependent on medical imaging, to verify the results. 
∀
Dose-limiting toxicities are not being collected, so have been removed as
safety endpoints.
∀
Where time points or endpoints differ for Second Stage Cohorts, these 
have been added in, and subheadings added to indicate which endpoints 
apply to which cohorts.
∀
Pharmacokinetic (PK) endpoints have been updated to reflect that 
olaparib PK samples are plasma, not serum (this has been corrected 
throughout the document). 
∀
PK endpoints that are not planned to be reported in the Clinical Study 
Report have been removed; they will be reported separately.
∀
 
 
∀
Exploratory objectives to be described separately from the Clinical Study 
Report have been removed.
!
Section 3 (Patient selection, enrollment, randomization, restrictions, discontinuation 
and withdrawal): 
∀
All inclusion and exclusion criteria have been moved to the 
cohort-specific Modules to provide a single source for each cohort.  
Furthermore, within each Initial Stage Cohort Module, the text not 
relevant to the cohort has been removed (eg, information on BRCA status 
for gastric cancer cohort).  This has not resulted in any changes to the 
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eligibility criteria for the Initial Stage Cohorts.
∀
In Section 3.8 (Restrictions), all information has been maintained in the 
Core Protocol, however information on pregnancy and contraception has 
been updated consistent with the most current appropriate guidelines for 
olaparib
!
Section 4 (Study plan and timing of procedures): The study flowcharts in the Core 
Protocol have been removed, and cohort-specific flowcharts have been added to 
Section 4 of each Module.  Common information remains in Sections 4.1 to 4.3 of 
the Core Protocol, cohort-specific information regarding the screening (with or 
without olaparib run-in), treatment and follow-up periods is included in Sections 4.1 
to 4.3 of each Module.
!
Section 5.1 (Efficacy assessments): The majority of information has been retained 
in the Core Protocol, limited cohort-specific information has been included in 
Section 5.1 of cohort-specific Modules.
!
Section 5.2 (Safety assessments): 
∀
All safety assessment information remains in Section 5.2 of the Core 
Protocol, with the exception of bevacizumab-specific urinalysis 
assessments, which are described in Module 6 of the protocol.
∀
Tables detailing the blood volumes taken in the study have been 
separated out into the cohort-specific Modules (Table 5 in each Module). 
Note: the gBRCAm ovarian cancer cohort blood sample volumes have 
been updated based on the 52-week extension of the follow-up period.  
Where appropriate, blood volume samples not relevant to a specific 
cohort have been removed (eg, CA-125 in gastric cancer cohort).
∀
Information on pregnancy testing has been updated according to the most 
recent guidelines for olaparib.  These changes have been reflected in 
updates to the study schedule table footnotes in the cohort-specific 
appendices (see Table 2 and Table 3 in each Module).
!
Section 5.3 (Pharmacokinetics), Section 5.4 (Pharmacogenetics), and Section 5.5 
(Biomarker analysis):
∀
Sampling schedules are presented in the cohort-specific Modules and 
have been removed from the Core Protocol.  
∀
Information on sample collection, storage, labeling etc has been retained 
in the Core Protocol, as has other information common to all cohorts.  
∀
 
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∀
In Section 5.5.2 (Mandatory archival tumor sample), information on the 
requirements for mandatory tumor samples in the Initial Stage Cohorts 
have been retained in the Core Protocol in new subsection 5.5.2.1.  
Additionally, requirements for these samples for the Second Stage 
Cohorts have been added into the Core Protocol (subsection 5.5.2.2).
!
Section 5.6 (BRCA status): 
∀
Details on whether BRCA status assessment is required has been added to 
each cohort-specific Module.  The information on BRCA testing for the 
breast cancer and gBRCAm ovarian cancer has been retained in the Core 
Protocol (new subsection 5.6.1).
∀
BRCA status testing for the second stage cohorts is referred to in new 
Core Protocol subsection 5.6.2.  The majority of information is presented 
in Appendix N for clarity. 
!
Section 6 (Safety reporting and medical management): All text remains in the Core 
Protocol, additional text specific to bevacizumab is presented in Section 6 of 
Module 6.
∀
Text on olaparib safety monitoring and management has been updated in 
Section 6.7.2 (Olaparib).
∀
Text on MEDI4736 safety monitoring and management has been updated 
in Sections 6.7.5 (MEDI4736 AESI) and 6.7.6 (Immune-related adverse 
events).  Section 6.7.6 contains the most recent toxicity management 
guidelines, as well as a link for Investigators to access current 
information as it is updated.
!
Section 7 (Investigational Product and other treatments): 
∀
All information on olaparib and MEDI4736 has been retained in Section 
7 of the Core Protocol.  Information specific to bevacizumab is presented 
in Section 7 of Module 6.
∀
In Section 7.1.2 (Olaparib), information on dose management for olaparib 
in renal impairment has been updated with the most recent guidance. 
!
Section 8 (Statistical analyses): The majority of information has been retained in 
Section 8 of the Core Protocol.  Additional information regarding the analysis of the 
Second Stage Cohorts has also been included in the Core Protocol.  Sample size 
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calculation information for each cohort has been moved to Section 8.1 in Modules 1 
to 7.  Appendix E (futility and efficacy for Bayesian design) has been updated with 
values for the ovarian cancer triplet and doublet cohorts.

Section 9: (Study and data management by AstraZeneca): Section 9 of the Core 
Protocol has been modified to accurately describe all cohorts.  In Section 9 of each 
Module, information relevant to the start and end of cohorts has been added (eg, the 
fact that Modules 1 to 4 have, at the time of this amendment, been fully enrolled).

Section 10 (Ethical and regulatory requirements): All information has been retained 
in Section 10 of the Core Protocol as it is relevant to all cohorts

Section 11 (List of references): References in the Core Protocol are referenced here.  
Each Module also has a standalone reference list. 
Whole document: Formatting, grammatical and minor editorial changes have been made 
throughout the document.  In addition, changes have been made to section heading numbers 
and table cross-references, where necessary, due to amendments detailed in this document.
Whole document: Three new ovarian cancer cohorts have been added to the study (Modules 5 
to 7; Appendices K to M).  These are: 

A BRCAm ovarian cancer “expansion” cohort (referred to as “BRCAm ovarian 
cancer expansion cohort” in the protocol [Module 5; details in Appendix K]).  
Preliminary results in the initial stage gBRCA mutated ovarian cohort showed a 
12-week disease control rate (DCR) that was in the superiority region. Based on this 
observation, validation of these results is necessary in a larger number of patients.  
Expansion of the current cohort will be the most efficient way to confirm these 
results and improve the confidence in the objective response rate (ORR).  The 
objective for expanding this cohort is to achieve an equal or improved ORR with 
olaparib and MEDI4736 combination compared to that observed in the standard 
chemotherapy setting.  This could provide a potentially more tolerable, 
non-chemotherapy option for patients with platinum-sensitive recurrent (PSR) 
gBRCAm ovarian cancer.  In contrast to other cohorts in this study, the tumor 
assessments for the BRCAm ovarian cancer expansion cohort will undergo BICR in 
addition to review by Investigators (BICR will also be performed on the Initial 
Stage gBRCAm ovarian cancer cohort).

Two non BRCAm ovarian cancer cohorts, 1 of which will receive 
olaparib+MEDI4736+bevacizumab (referred to as “ovarian cancer triplet cohort” in 
the protocol [Module 6; Details in Appendix L]), and 1 of which will receive 
olaparib+MEDI4736 (referred to as “ovarian cancer doublet cohort” in the protocol 
[Module 7; Details in Appendix M]).

The “triplet” cohort will assess the combination of 
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cancer.  Bevacizumab is approved in ovarian cancer.  Additionally, there 
is clinical evidence that combination treatment with PARP inhibitors, 
such as olaparib, and VEGF inhibitors, such as bevacizumab, is 
efficacious and tolerable in ovarian cancer.  Furthermore, preclinical 
evidence shows potential synergistic, antitumor activity with the 
combination
 
and VEGF inhibition.  Please 
see the Introduction of Appendix M for further details.
∀
The “doublet” cohort is of value in assessing the combination of 
MEDI4736+olaparib for the treatment of non BRCAm ovarian cancer 
patients.  Olaparib monotherapy has shown clinical efficacy in the 
non BRCAm population, therefore it is likely that the addition of 
MEDI4736 will enhance the efficacy in this patient population in a 
similar fashion.  Additionally, this cohort will serve to evaluate the
contribution of bevacizumab when comparing the “doublet” combination 
to the “triplet”.
Minimal changes to the design of the Initial Stage Cohorts have been made in this amendment 
(with the exception of extending the duration of follow-up, and adding independent central 
review of scans, for the gBRCAm ovarian cancer cohort, see below).  The design of the 
Second Stage Cohorts differs from that of the Initial Stage Cohorts in the following ways:
!
The Second Stage Cohorts, including the BRCAm ovarian cancer expansion cohort,
have no olaparib monotherapy run-in period; all study treatments 
(olaparib+MEDI4736 ± bevacizumab) will start at the same time.  The hypothesis 
that PARP inhibition induces changes in the tumor microenvironment was tested by 
taking paired biopsies before and after the olaparib monotherapy 4-week run-in 
period in the Initial Stage Cohorts.  Since this question is currently being addressed 
in the data collected from the Initial Stage Cohorts, the Second Stage Cohorts will 
no longer include the olaparib monotherapy 4 week run-in.  By starting the 
combination of olaparib and MEDI4736 together, the efficacy of the combination 
treatment in platinum-sensitive relapsed ovarian cancer can be evaluated.  In 
addition, this dosing schedule more closely represents the intended clinical use 
under investigation.
!
The BRCAm ovarian cancer expansion cohort has ORR as the primary endpoint.  A 
high ORR was seen in the initial gBRCAm ovarian cancer cohort. To confirm this 
observation, ORR was chosen as the primary endpoint for the expansion cohort.
!
The follow-up for the Second Stage Cohorts is 104 weeks (versus 52 for original 
cohorts) after the final patient has started treatment.  This change has been made to 
capture the progression events in the majority of the patients.
!
In Section 6 of Module 6 (Appendix L; ovarian cancer triplet cohort), additional 
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information on adverse events of special interest and measures required for events 
associated with bevacizumab treatment have been added.  Urinalysis assessments 
specific to bevacizumab treatment have also been added. 

In Section 5.5.3 of Modules 6 and 7 (Appendices L & M; ovarian cancer triplet and 
doublet cohorts), information has been added on assessment of free VEGF in this 
module to assess the activity of bevacizumab on this parameter. 
In addition to the new cohorts, and the restructuring of the document to a modular 
presentation, the following changes have been made:

Introductory text (Section 1 and subsections) has been updated with new 
information on the approval status and clinical data available for olaparib and 
MEDI4736.

An additional exclusion criterion has been added for consistency with current 
AstraZeneca standards: Judgment by the Investigator that the patient should not 
participate in the study if the patient is unlikely to comply with study procedures, 
restrictions and requirements.

An additional exclusion criterion has been added to all cohorts for consistency with 
the most recent MEDI4736 information: Female patients who are pregnant or 
breastfeeding or male or female patients of reproductive potential who are not 
willing to employ effective birth control from screening to 90 days after the last 
dose of study treatment. Additionally, pregnancy testing has been added to all 
cohorts for female patients at the 2- and 3-month follow-up visits.

In the breast cancer cohort inclusion criteria (Module 2; Section 3.2), “eligibility of 
breast cancer with bone only disease is a Principal Investigator (PI) decision on an 
individual patient basis” has been deleted, as it conflicts with other information in 
the protocol.

To capture the majority of the disease progression events in the Initial Stage ovarian 
cancer cohort, the follow-up period in this cohort has been extended from 52 to 
104 weeks. 

Retrospective independent central review of radiographic scans has been added in 
the Initial Stage gBRCAm ovarian cancer cohort.  This is in addition to the 
Investigator assessment.

In Section 3.8, definitions of childbearing and post-menopausal women have been 
updated based on most recent AstraZeneca standards for the investigational 
products. The list of acceptable forms of contraception have been updated for the 
same reason.

Section 5.5.5 (Mechanisms of resistance) has been deleted, as tumors at progression 

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are not being taken in the study. 

In Section 7.1 of the Core Protocol, the final column (Manufacturer and supplier) of 
Table 5 has been removed.  This information is kept current in different study 
documents, and has therefore been removed from the protocol. 

The frequency of the safety monitoring informal meetings (“Investigator Calls”) has 
been changed from every 4 to 6 weeks to “as necessary”, based on the experience of 
the safety profile of olaparib+MEDI4736 accumulated to date. 

Guidance on olaparib administration with food has been updated from “with a light 
meal/snack” to “with or without food”. The effect of food on olaparib tablet has 
been investigated. Co-administration with food slowed the rate of absorption, 
however food did not significantly affect the extent of absorption.  Therefore,
olaparib tablets can be given without regard to food.

As a result of updates to the MEDI4736 Investigator’s Brochure, changes were 
made to the Core Protocol. The details are:

Section 6.7.5 (MEDI4736 adverse events of special interest): Myocarditis
and myositis/polymyositis were added as adverse events of special 
interest for MEDI4736.

Section 6.7.6 (Immune-related adverse events): Myocarditis was added to 
the list of possible immune-related adverse events.  Text was also added 
regarding the close monitoring and prompt evaluation of patients with 
pre-existing cardiac disorders in cases of suspected myocarditis.

Table 4 (Dosing modification and toxicity management guidelines for 
immune-mediated, infusion-related and non-immune-mediated reactions 
[MEDI4736]): Details on the dose modifications and toxicity 
management recommended for suspected and biopsy-confirmed 
immune-mediated myocarditis were added.

Section 6.7.5.2 (Diarrhea/Colitis and Intestinal Perforation): This section has been 
added to provide information on observation and management of diarrhea/colitis 
and intestinal perforation. 
Revised Protocol edition 2, 06 September 2016
Changes to the protocol are summarized below:
Whole document: The protocol template was updated for consistency with other AstraZeneca 
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text, and Appendix A (signatures) was removed according to the new template, with other 
Appendices re-lettered accordingly.  Appendices have been formatted for consistency with the 
new template.
Whole document: Formatting, grammatical and minor editorial changes have been made 
throughout the document.  In addition, changes have been made to section heading numbers 
and table cross-references, where necessary, due to amendments detailed in this document.
Protocol synopsis (Study sites and number of patients planned): The number of countries and 
sites the study is being performed at were updated for consistency with the current status of 
the study.  Additionally, the number of patients expected to be enrolled overall in each cohort 
was updated based on the changes to the Bayesian design of the study; the numbers of 
additional and total patients have also been updated accordingly.
Whole document: The definition of the gastric cancer cohort as “ATM-negative” was 
removed throughout the protocol, as the target patient population in this cohort was widened 
to include gastric cancer patients irrespective of ataxia-telangiectasia-mutated (ATM) status 
(for rationale of this change, see changes to Section 1.3.1).
 
 
Protocol synopsis (Study design); Protocol synopsis (Duration of treatment); Section 3.9 
(Discontinuation of investigational product); Section 4.2.4 (previously Section 4.2.5; Duration 
of therapy); Section 5.1.1 (Tumor assessments by CT or MRI scans): Text was added stating 
that clinically stable patients with disease progression identified after olaparib monotherapy 
has started but before receiving combination therapy are permitted to start combination 
therapy if the Investigator believes they may derive benefit from study therapy.  The text was 
added to clarify the status of patients progressing prior to starting combination therapy.  
Where appropriate, text has also been added indicating these patients should be scanned at 
Week 12 (8 weeks after start of combination therapy).
 
 
 
Protocol synopsis (Target patient population): Text was added to clarify the resolution of 
toxicities of prior therapy to Common Terminology Criteria for Adverse Events (CTCAE)
grade ≤1 (except alopecia) is required prior to the start of treatment.
Section 1.2.1 (Rationale for the study design):
!
Text was updated with information on the effects of olaparib in ovarian and gastric 
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cancers from recent studies to provide updated information in the protocol, and to 
support the widening of the gastric cancer cohort from patients with ATM-negative 
tumors to patients who are ATM-positive or -negative.
!
To improve patient accrual in the ovarian cancer cohort, second-line ovarian cancer 
patients are now included in the target population as well as third-line ovarian 
cancer patients.  The text has been updated to reflect this. 
Section 1.3.1 (Olaparib benefit/risk in monotherapy and combination therapy): The section 
was updated to include the recently-reported effects of olaparib in gastric cancer (GOLD 
study) that support the widening of the gastric cancer cohort from patients with ATM-negative 
tumors to patients who are ATM-positive or -negative.  Updated information on the numbers 
of patients to receive olaparib in different settings was also added.
Section 1.3.2 (MEDI4736 benefit/risk): 
 
 
Updated information on the numbers of patients to receive 
MEDI4736 in different settings was also added.
Figure 1 (Study design: Bayesian predictive probability design – Initial Stage Cohorts), 
Appendix E: The Bayesian design and maximum numbers of patients per cohort have been 
modified.  These changes are to amend the study design to demonstrate superiority, rather 
than parity, with standard of care and olaparib monotherapy, and to reflect new learning on 
progression-free survival rates from recent studies.
Section 3.1 (Inclusion criteria for ovarian cancer patients):
!
Text was updated to clarify the requirement for gBRCAm ovarian cancer patients 
with recurrent disease to have relapsed at least 24 weeks after the administration of 
their last platinum treatment.
!
The requirement for ovarian cancer patients to have received at least two previous 
courses of platinum-based therapy has been altered to at least one previous course 
of platinum-based therapy.  This change is intended to improve patient accrual in 
the ovarian cancer cohort.
Section 3.1 (Inclusion criteria for gastric cancer patients): 
!
The requirement that patients be ATM-negative was removed.  This is because a 
recent study (the GOLD study) indicated there was a trend towards a survival 
advantage in the overall gastric cancer population, and so there is no need to select
patients based on ATM status.
!
Due to the removal of ATM-negative status as an inclusion criterion, the 
requirement for prospective ATM testing was also removed.
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
The prohibition of triplet chemo regimens as acceptable first-line treatment for 
gastric cancer patients was removed as this is a common regimen used in clinical 
practice for this patient population.  Text for the same criterion was updated to 
clarify that the first-line treatment regimen much have contained at least a doublet 
5-fluoropyrimidine and platinum based regimen.
Section 3.1 (Inclusion criteria, criterion 2): Text was updated to clarify the relationship 
between the baseline scan and the start of olaparib monotherapy.
Section 3.1 (Inclusion criteria, criterion 6):

The minimum measured creatinine clearance for inclusion was updated from 
>60 mL/min/1.73m2 to ≥51 mL/min/1.73m2.  This change was made to reflect 
updated guidance on olaparib and MEDI4736 with regards to renal function.

The required laboratory values for alanine aminotransferase (serum glutamic-oxalo-
acetic transaminase) and aspartate aminotransferase (serum glutamate pyruvate 
transaminase) in patients with liver metastases was updated from ≤2.5×upper limit 
of normal (ULN) to ≤5.0 ULN to reflect this population’s increased likelihood of 
impaired liver function.
Section 3.1 (Inclusion criteria, criterion 10): The definition of female patients of 
non-childbearing potential was removed and a reference to Section 3.8 added, where an 
updated definition was added.
Section 3.1 (Inclusion criteria, criterion 11; Table 3): As a result of ATM-negative status 
being removed as an inclusion criterion for gastric cancer patients, reference to ATM status 
and resultant sampling requirements were removed, and sample requirements for gastric 
cancer patients were aligned with other cohorts.
Section 3.2 (Exclusion criteria, criteria 1 and 7): The criterion was modified to state that 
estrogen receptor positive or progesterone receptor positive breast cancer patients are allowed 
anti-hormonal treatment for estrogen receptor positive or progesterone receptor positive breast 
cancer until 7 days prior to treatment with olaparib.  This was amended for consistency with 
the prohibition against these treatments in Section 7.7 (Concomitant medications).
Section 3.2 (Exclusion criteria, criterion 1): 

The prohibition on exposure to investigational agents within 30 days or 5 half-lives 
prior to enrollment was changed to 30 days or 5 half-lives prior to starting olaparib
treatment for consistency with language elsewhere in the criterion.

It was clarified that prior receipt of PD-L2 inhibitors is permitted.
Section 3.2 (Exclusion criteria, criterion 6), Section 7.7.1 (Medications that may NOT be 
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inhibitors and inducers. In both sections, text was added to clarify the required washout 
periods for CYP3A inducers enzalutamide and phenobarbital (5 weeks).
Section 3.2 (Exclusion criteria, criterion 8): This criterion excluding patients requiring long 
acting narcotic analgesics was removed for consistency with other, similar AstraZeneca 
studies.  Subsequent criteria have been renumbered accordingly.
Section 3.2 (Exclusion criteria): A new exclusion criterion (number 14) was added excluding 
patients with a history of active primary immunodeficiency.  This change was made for 
consistency with other MEDI4736 studies.
Section 3.2 (Exclusion criteria, criterion 15): The criterion was updated to allow patients with 
controlled brain metastases and clarify the status of patients with spinal cord compression.  
This change was made after discussion with Investigators, and for consistency with other 
olaparib studies.
Section 3.2 (Exclusion criteria, criterion 16): The criterion was rephrased for greater clarity.
Section 3.2 (Exclusion criteria, criterion 21): 

The criterion was modified to allow inclusion of patients with a past or resolved 
hepatitis B infection, and patients positive for hepatitis C virus (HCV) antibody but 
who are negative for HCV RNA as assessed by polymerase chain reaction.  This 
change was made at the request of Investigators.

It was clarified that active tuberculosis infection is not permitted.
Section 3.2 (Exclusion criteria, criterion 22): The wording of the criterion was updated to 
clarify that stable hypothyroidism treated with hormone replacement, and chronic skin 
conditions that do not require systemic treatment, are not criteria for exclusion.
Section 3.2 (Exclusion criteria, additional criteria for BRCAm HER2-negative breast cancer 
patients): The combination of an aromatase inhibitor and palbociclib was added as a treatment 
regimen not considered cytotoxic chemotherapy.  This change was made to clarify that 
palbociclib is not a cytotoxic chemotherapy.
Section 3.5 (Methods for assigning treatment groups): The maximum cohort sample sizes 
were updated, for consistency with the changes to the Bayesian design changes described 
above.
Section 3.8 (Restrictions): The text regarding restrictions for female patients of childbearing 
potential and males with a female partner of childbearing potential was updated to be 
consistent with other MEDI4736 and olaparib studies.  This includes acceptable methods of 
contraception, which are now presented as a list, with Table 4 deleted.  The definitions of 
females of childbearing/non-childbearing potential have also been updated.

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Section 3.8.1 (Restrictions related to olaparib and CYP3A4): A restriction on consumption of 
grapefruit juice whilst receiving olaparib was added for consistency with other olaparib 
studies.
Section 4 (Study plan and timing of procedures): Text was added to clarify that patients can 
continue to receive olaparib+MEDI4736 treatment beyond the 12-month period described in 
Table 5 (previously Table 6).
Section 4 (Study plan and timing of procedures, Table 4 [previously Table 5]): 

The Table and footnotes were updated to reflect the removal of prospective ATM 
testing and the need for written consent for ATM assessment.

Text was added to footnote “c” (previously “d”) clarifying that the scan performed 
during screening/baseline acts as baseline for disease control rate (DCR) 
assessments.  Text was also added clarifying the timing between baseline 
assessments and the start of olaparib treatment.

A footnote (“i”) was added stating that patients positive for hepatitis C virus (HCV) 
antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV 
RNA. This change was made for consistency with the change in exclusion 
criterion 21.

Reference to footnote “k” for “Mandatory whole blood for immunophenotyping by 
flow cytometry (CytoChex and ACD-B tubes)” was removed as the reference was 
not correct.

Text was added to indicate that ovarian cancer patients who have an archival tumor 
sample >3 years old no longer have to provide a new biopsy sample.  A higher 
proportion of ovarian cancer patients have older archival biopsies. This change is to 
increase patient accrual in this population.

Text was deleted regarding ATM testing in gastric cancer patients, as the 
requirement for these patients to be ATM-negative was removed.

Footnote “p” was added to clarify olaparib dosing and the duration of the 
monotherapy treatment period.
Whole document (first mention: Section 4, Table 4 [previously 5]): Where central diagnostic 
testing by Myriad is mentioned, text was added to state “a central laboratory, such as Myriad”, 
to allow central testing to be performed by other certified vendors. 
Section 4 (Study plan and timing of procedures, Table 5 [previously Table 6]): 

Table 6 was re-titled to reflect treatment can continue beyond 12 months.

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
The MEDI4736 PK sample at C1D15 was removed, it was previously included in 
error.

Text was added to footnote “m” clarifying that the scan performed during 
screening/baseline acts as baseline for DCR assessments.
Section 4 (Study plan and timing of procedures, Table 6 [previously Table 7]): The time 
window for the first follow-up visit after discontinuation of investigational product was 
changed from 3 days to 1 week to balance the requirements for follow-up with patient quality 
of life. 
Section 4.2.1 (Dosing regimen): Text was added to clarify olaparib dosing and the duration of 
the monotherapy treatment period.
Section 4.2.2 (Definition of dose-limiting toxicity): This section was deleted as the 
dose-finding phase of the olaparib clinical program is completed.  Events previously captured 
as dose-limiting toxicities (DLTs) will be captured as appropriately-graded AEs, and there is 
now no need to define DLTs.  Subsequent subsections in Section 4.2 have been renumbered.
Section 5.2 (Safety assessments, Table 7 [previously Table 8]): 

The timepoint of first “Whole blood for gene expression (PAXgene-RNA tube)”
sample was corrected from Screening to Week 1, Day 1 for consistency with the 
study schedule.

The number of blood samples for MEDI4736 PK was updated according to changes 
made in Table 8 (previously Table 9). The total volume of these samples and the 
total blood volume overall have been updated accordingly.
Section 5.2.1 (Laboratory safety assessments): 

Text was added to clarify that local laboratory results can be used by Investigators 
for clinical decision making.

Text was added stating hepatitis C viral load is to be performed (patients with 
history of hepatitis C only).
Section 5.2.2 (Physical examination): Text was added to state that urogenital examination is 
not required for breast, gastric or small cell lung cancer cohort patients, as this is not an 
assessment typically performed for these patients.
Section 5.3.1 (Collection of samples and the determination of olaparib concentrations; Table 8 
[previously Table 9]): 

Changes were made to the format of the table to improve clarity.

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!
The pre-dose MEDI4736 sample on Day 15 was deleted, it was previously included 
in error.
!
The reference to Day 29 was corrected to Day 22 (Week 4 Day 1).
Section 5.3.4.3 (Pharmacodynamic samples): This section was deleted as it repeats 
information already provided in Section 5.3.4.2.
Section 5.5.1 (Data and samples for patient selection and eligibility): The requirements for 
prospective ATM testing were removed, consistent with the removal of the requirement for 
gastric cancer patients to be ATM-negative.
Section 5.5.2 (Mandatory tumor sample): 
!
Text was added confirming that tissue blocks may be repatriated on request.
!
Text was added to indicate that ovarian cancer patients who have an archival tumor 
sample >3 years old no longer have to provide a new biopsy sample.  A higher 
proportion of ovarian cancer patients have older archival biopsies, this change is to 
increase patient accrual in this population.
!
Text on gastric tumor samples for ATM testing was removed, consistent with the 
removal of the requirement for gastric cancer patients to be ATM-negative.
Section 5.5.4.1 (Pharmacodynamics: paired tumor biopsies): 
 
 
 
 
 
Section 6.3.3 (Adverse events after the 90-day follow-up period), Section 6.7.3 (Olaparib 
adverse events of special interest) Section 9.3 (Study timetable and end of study): Text was 
removed relating to Investigator’s knowledge of treatment arm, as this is an open-label study.
Section 6.5 (Overdose): Text was added to further clarify that an overdose should be reported 
if 1 or more doses are found to be missing during tablet counts.
Section 6.7.2.1 (Management of hematological toxicity): In Table 11 (previously Table 12), 
the option for patients with an on-study hemoglobin value of <10 but ≥8 g/dL was added to 
the protocol to allow Investigators greater discretion in the best way to manage cases of 
anemia.
Section 6.7.4 (MEDI4736): Repeat text was deleted to improve clarity.
Section 6.7.5 (MEDI4736 adverse events of special interest): Text was updated based on the 
CCI

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most recent knowledge on MEDI4736.
Section 6.7.6 (Immune-related adverse events): Table 13 (previously 14) was updated with 
up-to-date information on MEDI4736 dose modifications and toxicity management guidelines 
for immune-mediated, infusion-related and non-immune-mediated reactions.
Section 7.1.1 (MEDI4736): The text was updated to remove reference to the 1.125 g dose of 
MEDI4736, as dose reduction for MEDI4736 was removed from the study.
Section 7.2.1 (Olaparib): Text was added giving guidance on olaparib dose reductions for 
patients who develop renal insufficiency (determined by creatinine clearance).  This text was 
added for consistency with other current olaparib studies.
Section 7.7 (Concomitant and other treatments); Appendix F: Text was updated to reflect the 
most up-to-date knowledge on the interactions between olaparib and other drugs.
Section 7.7.1 (Medications that may NOT be administered):

A reference to palliative radiotherapy was added in the text to highlight to readers 
where further information can be found on when it is permitted.

Text was updated to reflect the most up-to-date knowledge on the interactions 
between olaparib and other drugs.

Text was added to describe an olaparib dose reduction strategy for patients who 
require strong CYP3A inhibitors to allow them to remain on olaparib treatment 
where possible.
Sections 8.2.1 to 8.2.4 (Sample size estimate and cohort expansion criteria): Median 
progression-free survival estimates, proportions of patients anticipated to be progression-free 
at 12 weeks, target DCR and DCR value considered undesirable have been updated to reflect 
emerging evidence of the latest efficacy associated with the four cancer cohorts.
Section 8.3.3 (Pharmacokinetic analysis set): A new section (Section 8.3.3) was added that 
defines the pharmacokinetic analysis set.
Section 8.6 (Methods for statistical analysis): The 28-week analysis of DCR was identified as 
a result to be presented without 95% CIs.
Section 9.4 (Data management by Quintiles): text on the AstraZeneca genotyping LIMS 
database was updated to reflect current AstraZeneca processes.
Section 11 (References): Ledermann et al 2014 and Ledermann et al 2016 were added to the 
list of references to support changes made elsewhere in the protocol.  Kim et al 2014 and Le et 
al 2015 were deleted as they are no longer cited in the text.
Appendix D (previously E; Guidelines for Evaluation of Objective Tumor Response Using 

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RECIST 1.1 Criteria [Response Evaluation Criteria in Solid Tumors]): This appendix was 
updated to the most recent text appropriate for RECIST 1.1 criteria.
Appendix E (previously F; Monitoring Plan for Futility and Efficacy): This appendix was
updated with values consistent with the amended Bayesian design.
Revised Protocol edition 1, 23 November 2015
Refer to the separate Clinical Study Protocol Amendment document dated 23 November 2015 
for the changes made in Protocol Amendment Number 1.
Edition 1, 9 September 2015
Initial creation

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This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol 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.

Revised Clinical Study Protocol Synopsis
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Study Code D081KC00001
Version 7
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PROTOCOL SYNOPSIS
A Phase I/II Study of MEDI4736 (Anti-PD-L1 Antibody) in Combination 
with Olaparib (PARP inhibitor) in Patients with Advanced Solid Tumors
International Co-ordinating Investigator 
 
 USA
and
 Philadelphia, PA 19104, USA
Study sites and number of patients planned
This modular study will initially be conducted in approximately 7 countries world-wide. 
This study comprises 2 groups (“stages”) of cohorts:
!
Initial Stage Cohorts: a total of 
 have enrolled approximately 30 patients in 
each of 4 exploratory Initial Stage Cohorts (Modules 1 to 4).  These cohorts (Modules 1 to 
4) include patients with relapsed small cell lung cancer (SCLC), germline BRCA mutated 
(gBRCAm) metastatic human epidermal growth factor receptor 2 (HER2)-negative breast 
cancer, gBRCAm platinum-sensitive relapsed ovarian cancer, and gastric cancer.
Enrollment for these cohorts has been completed and data reported in a Clinical Study 
Report (CSR).    
!
Second Stage Cohorts: a total of 
 (including some centers that enrolled patients
in the Initial Stage Cohorts) enrolled patients into 3 exploratory Second Stage Cohorts 
(Modules 5 to 7) that were originally planned to include a total of approximately 
140 ovarian cancer patients overall.  These Second Stage Cohorts (Modules 5 to 7) were 
planned to include patients with BRCAm platinum-sensitive relapsed ovarian cancer 
(n=80), and non BRCAm platinum-sensitive relapsed ovarian cancer (n=30 for each of 
2 cohorts).  Enrollment for these cohorts has been completed; enrollment for the cohort of 
BRCAm platinum-sensitive relapsed ovarian cancer patients was terminated when 51 of 
80 planned patients had been enrolled; see Study Design below for further details.
Each cohort has its own dedicated Module with cohort-specific information.  The Figure 
below illustrates the location of each cohort-specific Module in the protocol. 
Phase of development: I/II
PPD
PPD
CCI
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Location of cohort modules in the protocol
Patient population
Cohort
Location in 
Protocol
Initial 
Stage 
Cohorts
Solid 
tumors
Relapsed SCLC
SCLC cohort; Module 1
Appendix H
gBRCAm HER2-negative 
breast cancer
gBRCAm breast cancer cohort; 
Module 2
Appendix I
gBRCAm platinum-sensitive relapsed 
ovarian cancer
gBRCAm ovarian cancer cohort; 
Module 3
Appendix J
Gastric cancer
Gastric cancer cohort; Module 4
Appendix K
Second 
Stage 
Cohorts
Ovarian 
cancer
BRCAm platinum-sensitive relapsed 
ovarian cancer
BRCAm ovarian cancer expansion 
cohort; Module 5
Appendix L
Non BRCAm platinum-sensitive 
relapsed ovarian cancer
Ovarian cancer triplet cohort; 
Module 6
Appendix M
Ovarian cancer doublet cohort; 
Module 7
Appendix N
Patients in the ovarian cancer triplet cohort (Module 6) will receive olaparib+MEDI4736+bevacizumab treatment. Patients in all other cohorts will receive 
olaparib+MEDI4736.
BRCAm=BRCA mutated; gBRCAm=germline BRCA mutated; SCLC=small cell lung cancer.

Revised Clinical Study Protocol Synopsis
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Study Code D081KC00001
Version 7
Date 17 December 2020
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Study design
This is a Phase I/II open-label, multicenter study to evaluate the safety, tolerability, 
pharmacokinetics (PK) and antitumor activity of MEDI4736 in combination with olaparib in 
patients with advanced solid tumors, selected based on a rationale for response to olaparib. 
Patients in the Initial Stage Cohorts have selected solid tumors and patients in the Second 
Stage Cohorts have ovarian cancer. Ovarian cancer patients enrolled into Module 6 (ovarian 
cancer triplet cohort; Appendix M) will receive bevacizumab treatment in combination with 
MEDI4736+olaparib treatment.
Patients will be poly (adenosine diphosphate-ribose) polymerase (PARP)-inhibitor and 
immunotherapy (IMT)-naïve (defined as no prior exposure to PARP inhibitors or IMT, 
including, but not limited to, other anti-cytotoxic T-lymphocyte-associated protein 4 
[CTLA-4], anti-programmed cell death 1 [PD-1], 
 
monoclonal antibodies, or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways).
In all cohorts, patients should continue to receive study treatment (ie, 
MEDI4736+olaparib±bevaciumab) until objective radiological disease progression as per 
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by the Investigator, 
or as long as, in the Investigator’s opinion, they are benefitting from treatment and they do not 
meet any other discontinuation criteria.
Each cohort will have a specific data cut-off.  The clinical database will close once the doublet 
and triplet Second Stage Cohorts have reached a median value for overall survival.  Patients 
are, however, permitted to continue to receive study treatment beyond the closure of the 
database if, in the opinion of the Investigator, they are continuing to receive benefit from 
treatment.  Patients who remain on study treatment after this timepoint will be monitored 
according to routine clinical practice as defined by the Investigator. At routine clinic visits, 
patients will return used medication packaging and unused medication, and a thorough drug 
accountability assessment will be performed.  However, where local regulations allow, 
patients may be switched from clinical trial supplies to marketed IP in those territories where 
IP is approved for the disease under study.  For these patients, any SAEs which occur on 
treatment or within 90 days of treatment discontinuation will be reported to Patient Safety.  
However, and furthermore, SAEs in patients continuing on olaparib after the end of 
combination treatment, and which occur after the 90-day window has passed, will be reported 
if they fall within 30 days of this latter timepoint (ie, up to 120 days after discontinuation).
CCI

Revised Clinical Study Protocol Synopsis
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Study Code D081KC00001
Version 7
Date 17 December 2020
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Olaparib dose selection was based on the results of an independent study, the National Cancer 
Institute (NCI) Study ESR-14-10366 (hereafter referred to as the “NCI study”; 
Lee et al 2017).  On the basis of these data, the dose of olaparib to be used in this study will be 
the recommended monotherapy dose of 300 mg twice daily (bid).
The safety and tolerability of olaparib 300 mg bid/MEDI4736 1.5 g every 4 weeks (Q4W) 
(hereafter referred to as “Full Dose”) was convincingly supported by the NCI study.  During 
the study a Review Committee will be convened and review pre-specified safety and efficacy 
data at the times specified in the cohort-specific appendices, where applicable. The Committee 
deliberations will consider safety and pertinent tumor assessment data (at a minimum from 
radiologic imaging studies but also other data, such as relevant physical exam findings, etc).  
All serious adverse events (SAEs), adverse events of special interest (AESI), discontinuations, 
dose reductions and dose interruptions will be reviewed, as well as any lesser-grade adverse 
events (AEs) that are considered by the study team to be of particular interest based on 
emerging data from the ongoing safety monitoring and accumulating clinical experience.
Initial Stage Cohorts
Initially, patients were enrolled concurrently into 4 exploratory cohorts (Initial Stage 
Cohorts, Modules 1 to 4), which include:

Patients with relapsed SCLC (“SCLC cohort”) (Module 1; see Appendix H)

Patients with gBRCAm metastatic HER2-negative breast cancer (“gBRCAm breast cancer 
cohort”) (Module 2; see Appendix I)

Patients with gBRCAm platinum-sensitive relapsed ovarian cancer (“gBRCAm ovarian 
cohort”) (Module 3; see Appendix J)

Patients with relapsed gastric cancer (“gastric cancer cohort”) (Module 4; see 
Appendix K)
Patients in Modules 1 to 4 are receiving study treatment of MEDI4736+olaparib.
In the Initial Stage Cohorts, after evaluating disease control rate (DCR) (defined for the Initial
Stage Cohorts as: complete response [CR]+partial response [PR]+stable disease [SD])
evaluated at 12 weeks and selected safety data from the first 10 patients in the cohort, DCR 
will be monitored every 5 patients until the maximum sample size is reached.  If the doses 
used in combination demonstrate evidence of antitumor activity based on DCR, and are 
considered safe and tolerable, then the alternative hypothesis can be accepted at any of these 
interim looks.  If the DCR is such that the null hypothesis will not be able to be rejected at the 
end of the trial then additional screening activities for new patients into that cohort may be 
stopped.

Revised Clinical Study Protocol Synopsis
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Study Code D081KC00001
Version 7
Date 17 December 2020
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To ensure uniform decision making, a Bayesian predictive probability design will be 
consistently employed in the Initial Stage Cohorts.
There will be an initial period of 4 weeks monotherapy treatment with olaparib in order for 
olaparib to induce changes in the tumor microenvironment as a result of DNA damage and 
cell death with release of potential immunogenic antigens.  A proportion of patients 
(minimum of 5 evaluable pairs per cohort) will undergo pre- and post-olaparib treatment 
tumor biopsies to evaluate the tumor microenvironment changes and to identify potential 
biomarkers predictive of activity of the combination.  Clinically stable patients, with objective 
radiological disease progression identified after olaparib monotherapy has started but before 
receiving combination therapy, may start combination therapy if the Investigator believes they 
may derive benefit from study therapy.  These patients should be scanned at 12 weeks 
(8 weeks after start of combination therapy).
In the final analysis of the Initial Stage Cohorts, patients will be evaluated for DCR at 
12 weeks and 28 weeks, objective response rate (ORR), duration of response (DoR), 
progression-free survival (PFS), percentage change from baseline in tumor size at 12 and 
28 weeks, best percentage change from baseline in tumor size, time to study treatment 
discontinuation (TDT), and overall survival (OS) following objective radiological disease 
progression according to RECIST 1.1 as assessed by the Investigator.  Because of the 4-week 
initial run-in period, the counting of weeks is different when referring to dosing and when 
referring to assessment. 
Data from the Initial Stage Cohorts have been reported in a CSR.  In all 4 Initial Stage 
Cohorts, the olaparib + MEDI4736 combination was well-tolerated, and AEs were consistent 
with those seen in olaparib and MEDI4736 monotherapy studies.  In the breast and ovarian 
cancer cohorts, the combination of olaparib and MEDI4736 showed promising antitumor 
activity.  In the SCLC and gastric cancer cohorts the 12-week disease control rate was below 
the pre-specified target, however durable responses were observed in a minority of patients in 
these cohorts.
Second Stage Cohorts
In the second stage of the study (Second Stage Cohorts), additional patients will be enrolled 
in the following cohorts:

Patients with BRCAm platinum-sensitive relapsed ovarian cancer, who will receive study 
treatment with a combination of MEDI4736+olaparib (“BRCAm ovarian cancer expansion 
cohort”) (Module 5; see Appendix L)

Revised Clinical Study Protocol Synopsis
Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
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
Patients with non BRCAm platinum-sensitive relapsed ovarian cancer, who will receive 
study treatment with “triplet” therapy (MEDI4736+olaparib+bevacizumab; “ovarian 
cancer triplet cohort”) (Module 6; see Appendix M)

Patients with non BRCAm platinum-sensitive relapsed ovarian cancer, who will receive 
study treatment with “doublet” therapy (MEDI4736+olaparib; “ovarian cancer doublet 
cohort”) (Module 7; see Appendix N)
Enrollment into the ovarian cancer doublet cohort will only occur after enrollment for the 
ovarian cancer triplet cohort has been completed.  The BRCAm ovarian cancer expansion 
cohort and the ovarian cancer triplet cohort will enroll concurrently. In the Second Stage 
Cohorts, no olaparib run-in period will be included, and all study treatment will start 
concurrently (olaparib+MEDI4736±bevacizumab).
Patients should continue to receive study treatment (ie, MEDI4736+olaparib±bevaciumab) 
until objective radiological disease progression as per RECIST 1.1 as assessed by the 
Investigator or as long as, in the Investigator’s opinion, they are benefitting from treatment 
and they do not meet any other discontinuation criteria.
Enrollment in the Second Stage Cohorts has completed.
BRCAm ovarian cancer expansion cohort 
A cohort of BRCAm ovarian cancer patients will be enrolled in order to confirm the high 
response rate seen in the Initial Stage gRBCAm ovarian cancer cohort, with ORR as the 
primary endpoint. These patients will also be assessed for disease control rate (assessed at 
24 and 56 weeks), PFS, and DoR to get a better understanding of the longer-term efficacy of 
the combination. Additionally, percentage change from baseline in tumor size (at 24 and 
56 weeks), TDT, and OS following objective radiological disease progression according to 
RECIST 1.1 as assessed by the Investigator will be assessed.
Enrollment into the BRCAm ovarian cancer expansion cohort was terminated when 51 of 
80 planned patients had been enrolled.  As PARP inhibitors have become standard of care in 
the first line setting for gBRCAm patients, the high unmet clinical need in this patient 
population has reduced. In addition, as a result of the success of PARP inhibitors in this 
setting, there are limited numbers of PARP inhibitior-naïve patients eligible for inclusion in 
the BRCAm ovarian cancer expansion cohort.  Therefore, despite high response rates in this 
patient population with olaparib and MEDI4736 combination treatment as shown in the initial 
stage gBRCAm ovarian cancer cohort, recruitment for the BRCAm ovarian cancer expansion 
cohort was closed early.

Revised Clinical Study Protocol Synopsis
Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
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Non BRCAm ovarian cancer triplet and doublet cohorts
The safety of the “triplet” treatment regimen will be evaluated in 10 patients after 4 weeks of 
treatment in the ovarian cancer triplet cohort.
In the ovarian cancer triplet and doublet cohorts, DCR (defined as: CR+PR+SD, evaluated at 
24 weeks) and selected safety data will be reviewed after data from 15 evaluable patients from 
each cohort are available, and then again at the maximum sample size (n=30).  If the doses 
used in combination demonstrate evidence of antitumor activity based on DCR, and are 
considered safe and tolerable, then the alternative hypothesis can be accepted at the interim 
looks.  If the DCR is such that the null hypothesis will not be able to be rejected at the end of 
the trial then additional screening activities for new patients into that cohort may be stopped.
Patients will be evaluated for DCR at 24 and 56 weeks, ORR, DoR, PFS, percentage change 
from baseline in tumor size at 24 weeks and 56 weeks, best percentage change from baseline 
in tumor size, TDT, and OS following objective radiological disease progression according to 
RECIST 1.1 as assessed by the Investigator.
To ensure uniform decision making, a Bayesian predictive probability design will be 
consistently employed in the ovarian cancer triplet and doublet cohorts.

Revised Clinical Study Protocol Synopsis
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Study Code D081KC00001
Version 7
Date 17 December 2020
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Objectives and outcome measure for all cohorts
Primary Objectives
Outcome Measures
Initial Stage 
Cohorts
Second Stage Cohorts
BRCAm ovarian 
cancer expansion 
cohort
Ovarian cancer 
triplet and doublet 
cohorts
To assess the effect of MEDI4736 in 
combination with olaparib±bevacizumab 
in patients with selected advanced solid 
tumors
DCR (CR+PR+SD) 
based on 
RECIST 1.1 at 
12 weeks
ORR (CR+PR) 
based on 
RECIST 1.1 
assessed by the 
Investigator
DCR (CR+PR+SD) 
based on RECIST 1.1 
at 24 weeks
To assess the safety and tolerability of 
MEDI4736 in combination with olaparib 
(±bevacizumab) in patients with selected 
advanced solid tumors

AEs, vital signs including blood pressure, pulse, ECG and 
laboratory findings including clinical chemistry and 
hematology. 

irAEs - given the intended mechanisms of action of 
MEDI4736, particular attention will be given to AEs that may 
follow enhanced T-cell activation, or other irAE.

Dose interruptions, dose reductions.

Causes of olaparib and MEDI4736 discontinuation.
NA
NA
Triplet cohort only:
Causes of 
bevacizumab 
discontinuation.
AE=adverse event; BRCAm=Mutated breast cancer susceptibility gene; CR=complete response; DCR=disease 
control rate; ECG=electrocardiogram; irAE=immune-related adverse event; NA=not applicable; ORR=objective 
response rate; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease.
Secondary Objectives
Outcome Measures
Initial Stage Cohorts
Second Stage Cohorts
BRCAm ovarian 
cancer expansion 
cohort
Ovarian cancer triplet and 
doublet cohorts
To investigate the 
preliminary antitumor 
activity of MEDI4736 in 
combination with 
olaparib±bevacizumab in 
patients with selected 
advanced solid tumors

DCR at 28 weeks

ORR (CR+PR) 
based on 
RECIST 1.1

DoR based on 
RECIST 1.1

PFS based on 
RECIST 1.1

Percentage change 
from baseline in 
tumor size at 
12 weeks and 

DCR at 24 weeks 
and 56 weeks

DoR based on 
RECIST 1.1

PFS based on 
RECIST 1.1

Percentage change 
from baseline in 
tumor size at 
24 weeks and 56 
weeks

Best percentage 
change from 

DCR at 56 weeks 

DoR based on 
RECIST 1.1

PFS based on 
RECIST 1.1

ORR (CR+PR) based 
on RECIST 1.1 
assessed by the 
Investigator

Percentage change 
from baseline in tumor 
size at 24 weeks and 

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Study Code D081KC00001
Version 7
Date 17 December 2020
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Secondary Objectives
Outcome Measures
Initial Stage Cohorts
Second Stage Cohorts
BRCAm ovarian 
cancer expansion 
cohort
Ovarian cancer triplet and 
doublet cohorts
28 weeks
!
Best percentage 
change from 
baseline in tumor 
size
!
TDT
!
Overall survival
baseline in tumor 
size
!
TDT
!
Overall survival
56 weeks
!
Best percentage 
change from baseline 
in tumor size
!
TDT
!
Overall survival
To determine plasma 
concentrations of olaparib 
after single and multiple 
dosing when given orally 
to patients alone and in 
combination with 
MEDI4736±bevacizumab. 
To characterize the PK, 
immunogenicity and 
pharmacodynamics of 
MEDI4736 after single 
dosing and multiple dosing 
when given intravenously 
to patients in combination 
with 
olaparib±bevacizumab
!
Serum 
concentrations of 
MEDI4736, 
MEDI4736 
anti-drug antibody 
(ADA).  Plasma 
concentrations of 
olaparib
!
Presence of ADAs 
for MEDI4736
!
!
Serum 
concentrations of 
MEDI4736, 
MEDI4736 
anti-drug antibody 
(ADA).  Plasma 
concentrations of 
olaparib
!
Presence of ADAs 
for MEDI4736
!
Serum concentrations 
of MEDI4736, 
MEDI4736 anti-drug 
antibody (ADA).  
Plasma concentrations 
of olaparib
!
Presence of ADAs for 
MEDI4736
To characterize the PK and 
pharmacodynamics of 
bevacizumab after single 
dosing and multiple dosing 
when given intravenously 
to patients in combination 
with MEDI4736 and 
olaparib
NA
NA
Triplet cohort only:
!
Serum concentrations 
of bevacizumab
 
 
 
 
ADA=anti-drug antibody; BRCAm=Mutated breast cancer susceptibility gene; CR=complete response; 
DCR=disease control rate; DoR=duration of response; NA=not applicable; ORR=objective response rate; 
; PFS=progression-free survival; PK=pharmacokinetic; PR=partial response; 
RECIST=Response Evaluation Criteria in Solid Tumors;
 
TDT=time to study treatment discontinuation.
CCI
CCI
CCI
CCI

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Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
43(461)
CCI

Revised Clinical Study Protocol Synopsis
Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
44(461)
ADA=anti-drug antibody; BRCAm=Mutated breast cancer susceptibility gene; HLA-DR=human leukocyte 
antigen – antigen D related; NA=not applicable; Pd=pharmacodynamic; PD-1=programmed cell death-1; 
CCI

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Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
45(461)
PK=pharmacokinetic; 
 
VEGF=vascular endothelial growth factor.
Target patient population
Males and females aged 18 years and over (19 years or over in South Korea) with 
histologically or cytologically confirmed progressive metastatic or recurrent solid tumor.
To be enrolled in 1 of the Initial Stage Cohorts of the study, only the following tumor types 
were allowed: 
!
gBRCAm ovarian cancer
!
gBRCAm HER2-negative metastatic breast cancer
!
Relapsed SCLC
!
Gastric cancer.
To be enrolled in 1 of the ovarian cancer Second Stage Cohorts of the study, only the 
following tumor types were allowed: 
!
BRCAm ovarian cancer (BRCAm ovarian cancer expansion cohort)
!
non BRCAm ovarian cancer (ovarian cancer triplet and doublet cohorts).
Details of how BRCA status will be determined to enable enrollment into the Second Stage 
Cohorts are presented in Appendix O.
All patients must have at least 1 measurable lesion that can be accurately assessed by baseline 
computed tomography (CT), or by magnetic resonance imaging where CT is contraindicated, 
and which is suitable for repeated assessment as per RECIST 1.1.  Patients must have 
adequate organ and marrow function.  Toxicities of prior therapy (excepting alopecia) should 
be resolved to less than or equal to grade 1 per Common Terminology Criteria for Adverse 
Events (CTCAE) v 4.03 prior to the start of olaparib treatment.
Duration of treatment
In the Initial Stage Cohorts there will be a 4-week olaparib only run-in period (SCLC, gastric 
cancer, gBRCAm breast cancer, and gBRCAm ovarian cancer cohorts; Modules 1 to 4).  In 
contrast, in the Second Stage Cohorts the study drugs will initiate concurrently.
Patients should continue to receive study treatment until objective radiological disease 
progression as per RECIST 1.1 as assessed by the Investigator or as long as, in the 
Investigator’s opinion, they are benefitting from treatment and they do not meet any other 
discontinuation criteria. Clinically stable patients in the Initial Stage Cohorts, with objective 
CCI
CCI

Revised Clinical Study Protocol Synopsis
Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
46(461)
radiological disease progression identified after olaparib monotherapy has started but before 
receiving combination therapy, may start combination therapy if the Investigator believes they 
may derive benefit from study therapy.
After discontinuation of study treatment, the Investigator will be at liberty to define further the 
most appropriate anticancer treatment.  All patients will be followed for disease progression 
and survival until the cohort data cut-off, and may be followed for survival, selected safety, 
investigational product dispensing/accountability, and subsequent anticancer treatment data
after the cohort data cut-off.
Investigational product, dosage, and mode of administration
Olaparib is available as a film-coated tablet containing 150 mg or 100 mg of olaparib.  
Patients will be administered study treatment orally at a dose of 300 mg bid.  The initial dose 
of 300 mg bid will be made up of 2×150 mg tablets bid.  The 100 mg and 150 mg tablets will 
be used to manage dose reductions.
MEDI4736 will be supplied by AstraZeneca as a 500-mg vial for solution for infusion.  The 
solution contains 50 mg/mL MEDI4736, 26 mM histidine/histidine hydrochloride, 275 mM 
trehalose dihydrate, and 0.02% (weight/volume) polysorbate 80; it has a pH of 6.0.  Total 
in-use storage time from needle puncture of MEDI4736 vial to the start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C (36°F to 46°F).  If 
the in-use storage time exceeds these limits, a new dose must be prepared from new vials.  
MEDI4736 does not contain preservatives and any unused portion must be discarded.
Patients will receive MEDI4736 1.5 g Q4W ±3 days via intravenous (IV) infusion.
In the ovarian cancer triplet cohort (Module 6), bevacizumab will be started at a dose of 
10 mg/kg Q2W via IV infusion. Bevacizumab will be sourced locally or centrally supplied by 
AstraZeneca if local sourcing is not feasible.  Bevacizumab should be administered according 
to local prescribing information, including any treatment restrictions, and should be stored 
according to the local label.
For patients in the Initial Stage Cohorts: Treatment with MEDI4736 will commence on 
Cycle 1, Day 1 following the completion of the 4-week olaparib-only run-in period and will 
continue on a Q4W schedule until objective radiological disease progression as per 
RECIST 1.1 as assessed by the Investigator or as long as, in the Investigator’s opinion, they 
are benefitting from treatment and they do not meet any other discontinuation criteria.

Revised Clinical Study Protocol Synopsis
Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
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For patients in Second Stage Cohorts: All study drugs will commence on Cycle 1, Day 1 
and will continue on a 28-day (or 4-week) cycle until objective radiological disease 
progression as per RECIST 1.1 as assessed by the Investigator or as long as, in the 
Investigator’s opinion, they are benefitting from treatment and they do not meet any other 
discontinuation criteria.
Statistical methods
Sample size
All cohorts except BRCAm ovarian cancer expansion cohort
Progression-free survival is the most relevant endpoint for decision making but is difficult to 
determine accurately in a small cohort.  However, there is an approximate relationship 
between PFS and DCR at specified timepoints because patients whose disease has responded 
or is stable cannot have had a disease progression.  For example, if the median PFS of interest 
is 6 months this would suggest that 70% of patients will be progression-free at 3 months, 
assuming an exponential distribution of progression times.  For this reason, the primary 
efficacy endpoint of these cohorts is DCR and this endpoint has been used to define the 
sample size.
Each cohort, excluding the BRCAm ovarian cancer expansion cohort, will be considered as 
individual predictive probability designs as described by Lee & Liu (2008).  These designs are 
based on Bayesian predictive probability and the minimax criterion.  Taking this approach, in 
each cohort, we assume that the response (DCR) has a prior distribution of beta (0.5, 0.5) – a 
Jeffrey’s non-informative prior.  A predictive probability threshold for futility and efficacy is 
set at 10% and 90%, respectively.
For example, in the Initial Stage Cohorts, the selection of a DCR of 70% at 3 months (ie, at 
12 weeks, using the timing conventions used throughout this protocol) to drive decision 
making will give some assurance that a level of PFS of interest is realistic without having to 
wait to actually observe the PFS times.  After evaluating the DCR of the first 10 patients at 
12 weeks it will be monitored after every 5 patients until the maximum sample size is reached.  
In each cohort, the minimum sample size that results in type I and type II error rates under 
0.10 and 0.20 respectively is selected based on the optimization criterion that maximizes the 
power under alternative hypothesis.
In the Second Stage ovarian cancer triplet and doublet cohorts, where patients have no 
olaparib run-in treatment prior to start, DCR will be assessed at 24 weeks with a target of 

Revised Clinical Study Protocol Synopsis
Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
48(461)
80%.  The DCR at 24 weeks will be reviewed after data from 15 evaluable patients from each 
cohort are available, and then again at the maximum sample size (n=30).
If the doses used in combination demonstrate evidence of antitumor activity based on DCR, 
and are considered safe and tolerable, then the alternative hypothesis can be accepted at any of 
these interim looks.  Additionally, if the DCR is such that the null hypothesis will not be able 
to be rejected at the end of the trial the cohort may be stopped for futility at any of the interim 
looks defined above.
Expansion cohort
To confirm the promising results in the Initial Stage gBRCAm ovarian cancer cohort, patients 
will be evaluated for ORR as the primary endpoint in the BRCAm ovarian cancer expansion
cohort.
In the BRCAm ovarian cancer expansion cohort, when the sample size is n=80, a 2-sided 
95.0% confidence interval for a single proportion using the large sample normal 
approximation will extend 0.090 from the observed proportion for an expected proportion of 
0.785.
Outcome measures for analysis
The primary efficacy variable for the Initial Stage Cohorts and the Second Stage triplet and 
doublet ovarian cancer cohorts is DCR.  The DCR is defined as the percentage of patients who 
have at least 1 visit response of CR or PR or have demonstrated SD which is maintained until 
the RECIST 1.1 assessment at 12 weeks (Initial Stage Cohorts) and 24 weeks (ovarian cancer 
triplet and doublet cohorts). 
The primary efficacy variable for the BRCAm ovarian cancer expansion cohort is ORR as 
assessed by the Investigator. 
Other efficacy endpoints include DCR at 24, 28, and 56 weeks, PFS, OS, TDT, ORR, DoR, 
percentage change from baseline in tumor size, and best percentage change from baseline in 
tumor size.  All tumor assessment-related endpoints will be based on radiological response as 
assessed by the Investigator using RECIST 1.1.
All patients who receive at least 1 dose of 1 study drug (olaparib in the Initial Stage Cohorts, 
or any constituent of the combination treatment in the Second Stage Cohorts) and have not 
been excluded from the study for administrative reasons, eg, failing important inclusion 

Revised Clinical Study Protocol Synopsis
Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
49(461)
criteria (a full list will be predefined in the statistical analysis plan), will be included in 
efficacy analyses.  All patients who received at least 1 dose of study drug will be included in 
safety analyses. 
Methods for statistical analysis
The DCR will be summarized (ie, number of patients, %) in each tumor group.  Patients who 
do not complete the DCR assessment at the timepoint of interest (for example, due to drop out 
prior to the assessment) will be considered as a treatment failure.  For all cohorts except the 
BRCAm ovarian cancer expansion cohort, the mean and median of the posterior distribution 
along with the standard deviation and a 90% credible interval around the mean (based on the 
highest posterior density [Lee, 1997]) will be presented.  An exact 90% CI and 1-sided 
p-value will also be presented.
Safety and tolerability will be assessed within each tumor type in terms of AEs, deaths, 
laboratory data, vital signs and ECGs.  These will be collected for all patients.  Appropriate 
descriptive summaries of these data will be presented.
Pharmacokinetic analysis
The PK of olaparib and MEDI4736 will be assessed in all cohorts.  Additionally, the PK of 
bevacizumab will be assessed in the ovarian cancer triplet cohort.
The plasma concentration-time data will be analyzed by non-linear mixed effects modeling in 
order to evaluate the PK characteristics of olaparib alone and in combination with MEDI4736, 
quantify variability in the PK, identify demographic or pathophysiological covariates which 
may explain the observed variability and explore exposure-response relationships.  The 
relationship between exposure to olaparib and MEDI4736 and pharmacodynamics response 
(safety and/or efficacy) will be investigated if deemed appropriate.  Population 
PK/pharmacodynamic results will be reported separately from the CSR.

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Study Code D081KC00001
Version 7
Date 17 December 2020
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CORE PROTOCOL TABLE OF CONTENTS
PAGE
CORE PROTOCOL TABLE OF CONTENTS................................................... 50
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................... 58
1.
INTRODUCTION ............................................................................................. 63
1.1
Background and rationale for conducting this study ........................................... 63
1.1.1
Background........................................................................................................ 63
1.1.1.1
Tumor immunotherapy and programmed cell death-ligand 1.............................. 63
1.1.1.2
Rationale for combination of MEDI4736+olaparib in solid tumors..................... 65
1.1.2
Background on individual investigational products ............................................ 66
1.1.2.1
Olaparib............................................................................................................. 66
1.1.2.2
MEDI4736......................................................................................................... 69
1.1.2.3
Bevacizumab ..................................................................................................... 70
1.1.3
Pre-clinical experience with investigational products ......................................... 71
1.1.4
Clinical experience with investigational products............................................... 71
1.2
Rationale for study design, doses, and control groups......................................... 71
1.2.1
Rationale for the study design: Initial Stage Cohorts .......................................... 71
1.2.2
Rationale for the study design: Second Stage Cohorts ........................................ 71
1.2.3
Selection of doses .............................................................................................. 72
1.2.3.1
Olaparib............................................................................................................. 72
1.2.3.2
MEDI4736......................................................................................................... 72
1.2.3.3
Bevacizumab ..................................................................................................... 73
1.2.4
Patient population .............................................................................................. 73
1.2.4.1
Initial Stage Cohorts........................................................................................... 73
1.2.4.2
Second Stage Cohorts ........................................................................................ 73
1.3
Benefit/risk and ethical assessment .................................................................... 74
1.3.1
Olaparib benefit/risk in monotherapy and combination therapy.......................... 74
1.3.2
MEDI4736 benefit/risk ...................................................................................... 75
1.3.3
Olaparib and MEDI4736 benefit/risk ................................................................. 76
1.3.4
Bevacizumab benefit/risk................................................................................... 77
1.3.5
Impact on Benefit/Risk from Study Disruptions due to Coronavirus 
Disease 2019...................................................................................................... 77
1.4
Study design ...................................................................................................... 77
1.4.1
Initial Stage Cohorts........................................................................................... 78
1.4.2
Second Stage Cohorts ........................................................................................ 82
1.4.3
Summary of ovarian cancer cohort characteristics .............................................. 85
1.5
Study governance and oversight......................................................................... 85
1.5.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil
Crisis, Natural Disaster, or Public Health Crisis.................................................. 86

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2.
STUDY OBJECTIVES...................................................................................... 88
2.1
Primary objectives ............................................................................................. 88
2.2
Secondary objectives.......................................................................................... 89
2.3
Exploratory objectives ....................................................................................... 91
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 93
3.1
Inclusion criteria ................................................................................................ 93
3.2
Exclusion criteria ............................................................................................... 93
3.3
Patient enrollment .............................................................................................. 93
3.4
Procedures for handling incorrectly enrolled patients ......................................... 94
3.5
Methods for assigning treatment groups............................................................. 94
3.5.1
Initial Stage Cohorts........................................................................................... 94
3.5.2
Second Stage Cohorts ........................................................................................ 95
3.6
Methods for ensuring blinding ........................................................................... 95
3.7
Methods for unblinding...................................................................................... 95
3.8
Restrictions........................................................................................................ 95
3.8.1
Olaparib and CYP3A4 ....................................................................................... 98
3.9
Discontinuation of investigational product ......................................................... 98
3.9.1
Procedures for discontinuation of a patient from investigational product ............ 99
3.10
Criteria for withdrawal..................................................................................... 100
3.10.1
Screen failures ................................................................................................. 100
3.10.2
Withdrawal of the informed consent................................................................. 101
3.11
Discontinuation of the study............................................................................. 102
4.
STUDY PLAN AND TIMING OF PROCEDURES......................................... 102
4.1
Enrollment/screening period ............................................................................ 103
4.2
Treatment period.............................................................................................. 104
4.2.1
Dosing regimen................................................................................................ 104
4.2.2
Definition of evaluable patient ......................................................................... 105
4.2.3
Dose modifications .......................................................................................... 105
4.2.4
Duration of therapy.......................................................................................... 105
4.3
Follow-up period.............................................................................................. 106
5.
STUDY ASSESSMENTS................................................................................ 106
5.1
Efficacy assessments........................................................................................ 107
5.1.1
Tumor assessments by CT or MRI scans.......................................................... 107
5.1.2
Tumor evaluation............................................................................................. 108
5.2
Safety assessments........................................................................................... 108

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Study Code D081KC00001
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Date 17 December 2020
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5.2.1
Laboratory safety assessments.......................................................................... 108
5.2.1.1
Hematology ..................................................................................................... 110
5.2.1.2
Coagulation...................................................................................................... 110
5.2.1.3
Clinical chemistry............................................................................................ 111
5.2.1.4
Disease specific tumor marker samples (CA-125) ............................................ 111
5.2.1.5
Urinalysis......................................................................................................... 112
5.2.1.6
Bone marrow or blood cytogenetic samples ..................................................... 112
5.2.2
Physical examination ....................................................................................... 112
5.2.3
ECG................................................................................................................. 112
5.2.4
Vital signs........................................................................................................ 113
5.2.4.1
Pulse and blood pressure.................................................................................. 113
5.2.4.2
Body temperature............................................................................................. 114
5.2.5
Other safety assessments.................................................................................. 114
5.2.5.1
Serum or urine pregnancy test.......................................................................... 114
5.2.5.2
Performance status........................................................................................... 115
5.2.5.3
Pneumonitis/interstitial lung disease................................................................. 115
5.3
Pharmacokinetics ............................................................................................. 116
5.3.1
Collection of samples and the determination of olaparib concentrations ........... 116
5.3.2
Collection of samples and the determination of MEDI4736 concentrations ...... 117
5.3.3
Collection of samples and the determination of bevacizumab 
concentrations.................................................................................................. 117
5.3.4
Collection of samples to measure the presence of ADAs and sPD-L1............... 118
5.3.5
Storage and destruction of pharmacokinetic, ADA and sPD-L1 samples .......... 118
5.3.5.1
Olaparib samples.............................................................................................. 118
5.3.5.2
MEDI4736 samples.......................................................................................... 119
5.3.5.3
Bevacizumab samples...................................................................................... 119
5.4
Genetics........................................................................................................... 119
5.4.1
Collection of genetic samples........................................................................... 119
5.4.2
Storage, re-use and destruction of genetic samples ........................................... 120
5.5
Biomarker analysis........................................................................................... 120
5.5.1
Data and samples for patient selection and eligibility ....................................... 120
5.5.2
Mandatory tumor sample.................................................................................. 120
5.5.2.1
Initial Stage Cohorts......................................................................................... 120
5.5.2.2
Second Stage Cohorts ...................................................................................... 121
5.5.3
Candidate predictive biomarker analyses on mandatory tumor tissue................ 122
5.5.4
Investigational, immunomodulatory biomarker analyses .................................. 122
5.5.4.1
Pharmacodynamics: paired tumor biopsies....................................................... 123
5.5.4.2
Pharmacodynamics: sPD-L1 analyses .............................................................. 123
5.5.4.3
Pharmacodynamics: whole blood for gene expression (PAXgene-RNA) .......... 123
5.5.4.4
Pharmacodynamics: ctDNA in the plasma (Second Stage Cohorts only) .......... 124
5.5.4.5
Pharmacodynamics: circulating soluble factors in the plasma........................... 124
5.5.4.6
Pharmacodynamics: anti-drug antibodies ......................................................... 125
5.5.4.7
Pharmacodynamics: whole blood for immunophenotyping............................... 125
5.5.4.8
Pharmacodynamics: peripheral blood mononuclear cells.................................. 125

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Study Code D081KC00001
Version 7
Date 17 December 2020
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5.5.4.9
Pharmacodynamics: Plasma for free vascular endothelial growth factor 
(ovarian cancer triplet and ovarian cancer doublet cohorts only)....................... 125
5.5.4.10
Pharmacodynamics: Serum for eg angiogenic evaluation (ovarian cancer 
triplet and ovarian cancer doublet cohorts only) ............................................... 125
5.5.4.11
Pharmacodynamics: tumor biopsy at disease progression ................................. 126
5.5.5
Biomarker sample and data management.......................................................... 126
5.5.6
Labeling and shipment of biological samples ................................................... 127
5.5.6.1
Chain of custody of biological samples ............................................................ 127
5.5.7
Withdrawal of informed consent for donated biological samples...................... 127
5.6
BRCA status..................................................................................................... 128
5.6.1
Initial Stage Cohorts: gBRCAm breast cancer cohort and gBRCAm ovarian 
cancer cohort.................................................................................................... 128
5.6.2
Second Stage Cohorts ...................................................................................... 128
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT........................... 129
6.1
Definition of adverse events............................................................................. 129
6.2
Definitions of serious adverse event ................................................................. 129
6.3
Recording of adverse events............................................................................. 129
6.3.1
Time period for collection of adverse events .................................................... 129
6.3.2
Follow-up of unresolved adverse events........................................................... 130
6.3.3
Adverse events after the 90-day follow-up period............................................. 130
6.3.4
Variables.......................................................................................................... 130
6.3.5
Causality collection.......................................................................................... 132
6.3.6
Adverse events based on signs and symptoms.................................................. 132
6.3.7
Adverse events based on examinations and tests .............................................. 132
6.3.8
Hy’s Law ......................................................................................................... 133
6.3.9
Disease progression.......................................................................................... 133
6.3.10
New cancers..................................................................................................... 133
6.3.11
Lack of efficacy ............................................................................................... 133
6.3.12
Deaths.............................................................................................................. 133
6.4
Reporting of serious adverse events ................................................................. 134
6.5
Overdose.......................................................................................................... 135
6.5.1
Overdose of olaparib and/or MEDI4736........................................................... 135
6.5.2
Overdose of bevacizumab ................................................................................ 136
6.6
Pregnancy ........................................................................................................ 136
6.6.1
Maternal exposure............................................................................................ 136
6.6.2
Paternal exposure............................................................................................. 136
6.7
Medication Error.............................................................................................. 137
6.8
Management of IP-related toxicities................................................................. 138
6.8.1
General comments ........................................................................................... 138
6.8.2
Olaparib........................................................................................................... 139
6.8.2.1
Management of hematological toxicity............................................................. 139

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6.8.2.2
Management of non-hematological toxicity...................................................... 141
6.8.3
Olaparib adverse events of special interest ....................................................... 143
6.8.4
Specific toxicity management and dose modification information -
MEDI4736....................................................................................................... 143
6.8.5
MEDI4736 adverse events of special interest ................................................... 144
6.8.6
Bevacizumab ................................................................................................... 146
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................. 146
7.1
Identity of investigational products .................................................................. 146
7.1.1
MEDI4736....................................................................................................... 146
7.1.2
Olaparib........................................................................................................... 148
7.1.3
Bevacizumab ................................................................................................... 148
7.2
Dose and treatment regimens ........................................................................... 148
7.2.1
Olaparib........................................................................................................... 148
7.2.2
MEDI4736....................................................................................................... 149
7.2.3
Bevacizumab ................................................................................................... 150
7.3
Labeling........................................................................................................... 150
7.4
Storage............................................................................................................. 150
7.4.1
Olaparib........................................................................................................... 150
7.4.2
MEDI4736....................................................................................................... 150
7.4.3
Bevacizumab ................................................................................................... 151
7.5
Compliance...................................................................................................... 151
7.6
Accountability.................................................................................................. 151
7.7
Concomitant and other treatments .................................................................... 151
7.7.1
Other concomitant treatment ............................................................................ 155
7.7.2
Bevacizumab-specific guidelines for concomitant treatments........................... 155
7.7.3
Rescue medication ........................................................................................... 156
7.8
Post study access to study treatment................................................................. 156
8.
STATISTICAL ANALYSES........................................................................... 157
8.1
Statistical considerations .................................................................................. 157
8.2
Sample size estimate and cohort expansion criteria .......................................... 157
8.3
Definitions of analysis sets............................................................................... 158
8.3.1
Full analysis set................................................................................................ 158
8.3.2
Safety analysis set............................................................................................ 159
8.3.3
Pharmacokinetic analysis set............................................................................ 159
8.4
Outcome measures for analyses........................................................................ 159
8.4.1
Primary efficacy endpoint ................................................................................ 159
8.4.2
Secondary efficacy endpoints........................................................................... 160
8.4.2.1
Disease control rate at 24, 28, and 56 weeks..................................................... 160
8.4.2.2
Progression-free survival.................................................................................. 160

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8.4.2.3
Overall survival................................................................................................ 161
8.4.2.4
Time to study treatment discontinuation or death ............................................. 161
8.4.2.5
Objective response rate .................................................................................... 161
8.4.2.6
Best objective response .................................................................................... 161
8.4.2.7
Duration of response ........................................................................................ 162
8.4.2.8
Percentage change in tumor size....................................................................... 162
8.4.2.9
Best overall percentage change from baseline in tumor size ............................. 163
8.5
Calculation or derivation of safety variable(s) .................................................. 163
8.6
Methods for statistical analyses........................................................................ 163
8.6.1
Analysis of the primary variable(s)................................................................... 164
8.6.1.1
Disease control rate (Initial Stage, ovarian cancer triplet, and ovarian 
cancer doublet cohorts) .................................................................................... 164
8.6.1.2
Objective response rate (BRCAm ovarian cancer expansion cohort).................. 164
8.6.2
Analysis of the secondary variables.................................................................. 164
8.6.2.1
Progression-free survival, overall survival and time to study treatment 
discontinuation or death ................................................................................... 164
8.6.2.2
Summary of objective response rate................................................................. 164
8.6.2.3
Percentage change in tumor size and best percentage ....................................... 164
8.6.3
Subgroup analysis............................................................................................ 165
8.6.4
Interim analysis................................................................................................ 165
8.6.4.1
Safety review ................................................................................................... 165
8.6.4.2
Continuous monitoring..................................................................................... 165
8.6.5
Sensitivity analysis........................................................................................... 165
8.6.6
Exploratory analysis......................................................................................... 165
8.7
Calculation or derivation of pharmacokinetic variables .................................... 165
8.7.1
Olaparib and MEDI4736.................................................................................. 166
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA....................... 166
9.1
Training of study site personnel ....................................................................... 166
9.2
Monitoring of the study.................................................................................... 166
9.2.1
Source data ...................................................................................................... 167
9.2.2
Study agreements............................................................................................. 167
9.2.3
Archiving of study documents.......................................................................... 167
9.3
Study timetable and end of study...................................................................... 167
9.3.1
Post final data cut off ....................................................................................... 168
9.4
Data management by IQVIA............................................................................ 169
10.
ETHICAL AND REGULATORY REQUIREMENTS..................................... 170
10.1
Ethical conduct of the study ............................................................................. 170
10.2
Patient data protection...................................................................................... 170
10.3
Financial Disclosure......................................................................................... 171
10.4
Ethics and regulatory review ............................................................................ 171

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10.5
Informed consent process................................................................................. 172
10.6
Changes to the protocol and informed consent form......................................... 173
10.7
Audits and inspections ..................................................................................... 173
10.8
Committees structure ....................................................................................... 173
10.9
Dissemination of clinical study data................................................................. 173
10.10
Data quality assurance...................................................................................... 174
10.11
Source documents............................................................................................ 174
10.12
Publication policy ............................................................................................ 175
11.
LIST OF REFERENCES ................................................................................. 175
LIST OF TABLES
Table 1
Summary of ovarian cancer cohort characteristics .................................85
Table 2
Dose reductions for study treatment .................................................... 139
Table 3
Management of anemia ....................................................................... 139
Table 4
Management of neutropenia, leukopenia, and thrombocytopenia......... 140
Table 5
All investigational products for this study ........................................... 146
Table 6
Prohibited medications........................................................................ 152
Table 7
Restricted concomitant medications .................................................... 153
Table 8
Supportive medications ....................................................................... 155
LIST OF FIGURES
Figure 1
Initial Stage Cohorts..............................................................................79
Figure 2
Study design: Bayesian predictive probability design – Initial 
Stage Cohorts........................................................................................81
Figure 3
Second Stage ovarian cancer cohorts.....................................................83
Figure 4
Diagnostic BRCA testing for Second Stage ovarian cancer cohorts........84

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LIST OF APPENDICES
Appendix A
Additional Safety Information............................................................. 182
Appendix B
International Airline Transportation Association 6.2 Guidance 
Document ........................................................................................... 184
Appendix C
Genetic Research ................................................................................ 185
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ...................................................................... 189
Appendix E
Guidelines for Evaluation of Objective Tumor Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid 
Tumors) .............................................................................................. 195
Appendix F
Monitoring Plan for Futility and Efficacy............................................ 207
Appendix G
Medications to be Avoided with Olaparib ........................................... 210
Appendix H
Module 1: Small Cell Lung Cancer Cohort.......................................... 211
Appendix I
Module 2: gBRCAm breast Cancer Cohort........................................... 240
Appendix J
Module 3: gBRCAm Ovarian Cancer Cohort ....................................... 273
Appendix K
Module 4: Gastric Cancer Cohort........................................................ 305
Appendix L
Module 5: BRCAm Ovarian Cancer Expansion Cohort ........................ 336
Appendix M
Module 6: Ovarian Cancer Triplet Cohort 
(Olaparib+MEDI4736+Bevacizumab)................................................. 368
Appendix N
Module 7: Ovarian Cancer Doublet Cohort ......................................... 420
Appendix O
BRCA Screening Process for Second Stage Cohorts ............................ 456
Appendix P
Changes related to mitigation of study disruptions due to cases of 
civil crisis, natural disaster, or public health crisis ............................... 460

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Core Protocol.
Abbreviation or 
special term
Explanation
ADA
Anti-drug antibody
ADL
Activities of daily living
ADP
Adenosine diphosphate
AE
Adverse event
AESI
Adverse event(s) of special interest
ALT (SGOT)
Alanine aminotransferase (serum glutamic-oxalo-acetic transaminase)
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
APTT
Activated partial thromboplastin time
AST (SGPT)
Aspartate aminotransferase (serum glutamate pyruvate transaminase)
ATM
Ataxia telangiectasia mutated (gene or protein)
bid
Twice daily
BICR
Blinded independent central review
BP
Blood pressure
BOR
Best objective response
BRCA
Breast cancer susceptibility gene, ie, BRCA1 and BRCA2
BRCAm
Mutated breast cancer susceptibility gene
BUN
Blood urea nitrogen
CA-125
Cancer antigen 125
CD
Cluster of differentiation
CI
Confidence interval
Cmax
Maximum observed plasma concentration
CR
Complete response
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4

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Abbreviation or 
special term
Explanation
CXCL
C-X-C motif ligand
CYP
Cytochrome P450
DCR
Disease control rate
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid 
DoR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EU
European Union
FDA
Food and Drug Administration
FFPE
Formalin-fixed paraffin-embedded
gBRCAm
Germline mutated breast cancer susceptibility gene
GCIG
Gynecologic Cancer InterGroup
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GMP
Good Manufacturing Practice
Hb
Hemoglobin
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HER2
human epidermal growth factor receptor 2
HIV
Human immunodeficiency virus
HLA-DR
Human leukocyte antigen – antigen D related
HR
Hazard ratio
IB
Investigator’s Brochure
ICF
Informed consent form
IFN
Interferon
IHC
Immunohistochemistry
IL
Interleukin
INR
International normalized ratio 
imAE
Immune-mediated AE
IMT
Immunotherapy

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Abbreviation or 
special term
Explanation
International 
Co-ordinating 
Investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator coordinating the Investigators and/or 
activities internationally. 
IP
Investigational product 
irAE
Immune-related adverse events
IRB
Institutional Review Board
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LFT
Liver function test
LLN
Lower limit of normal
LPFV
Last patient first visit
mAb
Monoclonal antibody
MATE
Multidrug and toxin extrusion
MDS
Myelodysplastic syndrome
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
NE
Not evaluable
NED
No evidence of disease
NSCLC
Non-small cell lung cancer
NTL
Non-target lesion
OAT
Organic anion transporter
OATP
Organic anion transporter polypeptide
OCT
Organic cation transporter
ORR
Objective response rate
OS
Overall survival
P
P interval on the ECG
PARP
polyadenosine 5’diphosphoribose (poly [ADP ribose]) polymerization
PBMC
Peripheral blood mononuclear cells
PCR
Polymerase chain reaction
PD
Progressive disease
PD-1
Anti-programmed cell death 1

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Abbreviation or 
special term
Explanation
PD-L1
Anti-programmed death-ligand 1
Pgp
P-glycoprotein
PFS
Progression-free survival
PI
Principal Investigator 
PK
Pharmacokinetic
PR 
Partial response
PSR
Platinum-sensitive recurrent
Q2W
Every 2 weeks
Q4W
Every 4 weeks
QRS
QRS interval on the ECG
QTc
Heart rate corrected QT interval
QTcF
Heart rate corrected QT interval (Fridericia’s formula)
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RT-QPCR
Reverse transcription quantitative polymerase chain reaction
SAE
Serious adverse event 
SCLC
Small cell lung cancer
SD
Stable disease
sPD-L1
Soluble PD-L1
T3
Tri-iodothyronine
T4
Thyroxine
TBL
Total bilirubin
TDT
Time to study treatment discontinuation
TL
Target lesion
TMGs
Toxicity Management Guidelines
TNF
Tumor necrosis factor
TSH
Thyroid stimulating hormone
Treg
Regulatory T-cells
ULN
Upper limit of normal
US
United States of America
VEGF
Vascular endothelial growth factor
WBDC
Web Based Data Capture

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Abbreviation or 
special term
Explanation
WT
Weight

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1.
INTRODUCTION
Further introductory information can be found in Section 1 of each of the cohort-specific 
Modules (Appendix H to Appendix N). 
1.1
Background and rationale for conducting this study
1.1.1
Background
1.1.1.1
Tumor immunotherapy and programmed cell death-ligand 1
Immune responses directed against tumors are 1 of the body’s natural defenses against the 
growth and proliferation of cancer cells.  However, over time and under pressure from 
immune attack, cancers develop strategies to evade immune-mediated killing allowing them to 
develop unchecked.  One such mechanism involves upregulation of surface proteins that 
deliver inhibitory signals to cytotoxic T-cells.  
 
 which is upregulated in a broad range of cancers with a high 
frequency, with up to 88% expression in some indications.  In a number of these cancers, 
including lung (Mu et al 2011), renal (Krambeck et al 2007; Thompson et al 2005; 
Thompson et al 2006), pancreatic (Loos et al 2008; Nomi et al 2007; Wang et al 2010), and 
ovarian cancer (Hamanishi et al 2007), 
 
 
 
Anti-programmed death-ligand 1 is part of a complex system of receptors and ligands that are 
involved in controlling T-cell activation.  
 
 
 
 
  This results in reduced T-cell activation and fewer 
activated T-cells in circulation.  
 
  This delivers an 
inhibitory signal to those T-cells, preventing them from killing target cancer cells and 
protecting the tumor from immune elimination (Zou and Chen 2008).
Based on in vitro studies, an antibody that blocks the interaction between 
 
 and enhance the cytotoxic 
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activity of antitumor T-cells (Blank et al 2006).  The levels of tumor-infiltrating lymphocytes, 
and more specifically cytotoxic T-cells, have been correlated with improved prognosis in a 
number of cancers including colorectal, melanoma, and lung (Pages et al 2010), suggesting 
that an antitumor immune response is beneficial to patients.  
 
 
Results of several pre-clinical studies using mouse tumor models 
support this hypothesis (Hirano et al 2005; Iwai et al 2002; Okudaira et al 2009;
Zhang et al 2008).  
 
Stimulating an antitumor immune response is a mechanism employed successfully by a 
number of approved cancer therapies.  For example, aldesleukin (Proleukin®), a recombinant 
human interleukin (IL)-2, in renal cancer (Schmidinger et al 2004) and sipuleucel-T 
(Provenge®) in prostate cancer (Madan and Gulley 2011) both directly stimulate immune 
activation.  Ipilimumab (Yervoy®) also stimulates the immune response, but does so by 
blocking the T-cell co-inhibitory molecule, cytotoxic T-lymphocyte-associated protein 4 
(CTLA-4), thereby removing an immunosuppressive signal.
Blocking 
 is an approach similar to CTLA-4 inhibition, but with some distinct 
differences.  First, the expression of CTLA-4 and its ligands is restricted to the hematopoietic 
system and thus, the site of action for molecules targeting CTLA-4 is solely the peripheral 
lymphoid organs.  In contrast,
 is expressed on cells of the hematopoietic system and on 
a range of tumor types.  Therefore, targeting 
 should have additional effects within the 
tumor microenvironment.  Second, CTLA-4 plays an early and critical role in controlling 
T-cell activation.  This is reflected in the phenotype of CTLA-4 knockout mice, which die 
between 3 and 4 weeks of age due to lymphoproliferative disease and tissue destruction.  In 
contrast, 
 acts later in the process of T-cell activation (Fife and Bluestone 2008) and is 
considered less critical to the control of initial T-cell activation.  This is reflected in the 
phenotype of 
 knockout mice, which are viable and have normal T-cell numbers and 
activation levels but show increased T-cell activation in response to antigen and increased 
susceptibility in certain autoimmune models (Dong et al 2002; Latchman et al 2004).  
Similarly, mice lacking PD-1, a 
 receptor, show strain-specific phenotypes that are
milder than those seen in CTLA-4 knockouts (Nishimura et al 1998; Nishimura et al 2001).  
Therefore, inhibition of the 
/PD-1 pathway might be expected to result in less toxicity 
relative to CTLA-4 inhibition.  In support of these findings, recent Phase I clinical studies 
assessing the tolerability of agents targeting PD-1 have demonstrated a toxicity profile that is 
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more favorable than that of CTLA-4 (Brahmer et al 2010; Berger et al 2008;
Wolchok et al 2010; Topalian et al 2012).
1.1.1.2
Rationale for combination of MEDI4736+olaparib in solid tumors
Treatment options for the broad patient populations eligible for enrollment in this study (see 
below for full details), ie, second-line (or later) ovarian cancer, human epidermal growth 
factor receptor 2 (HER2)-negative breast cancer who have already received standard 
therapies, small cell lung cancer (SCLC) who have already received platinum-based 
chemotherapy, and second-line gastric cancer, are limited and frequently require consideration 
of investigational agents.  Molecular selection criteria with the use of an approved cancer 
therapy (olaparib) targeting deoxyribonucleic acid (DNA) damage repair mechanisms will be 
used to provide a rational therapeutic option for the ovarian, breast, and gastric cancer cohorts, 
and this agent will be combined with an immunotherapeutic agent to broaden the therapeutic 
effect of this regimen, based in part on the separate nonoverlapping mechanisms of action of 
the component agents and on the considerations outlined below.
Inhibition of PARP in sensitive tumor cells, for example those carrying mutations in the 
BRCA1 or BRCA2 genes, results in accumulating levels of DNA damage and genomic 
instability, ultimately resulting in cell death (Farmer et al 2005).  Accumulating DNA damage 
has the potential to modify the immunogenicity of tumors through a number of key 
mechanisms:

Triggering of intracellular signaling events that result in the activation of nuclear factor 
kappa B (NFκB) and interferon (IFN) regulatory factor 7 (IRF7).  These transcriptional 
regulators result in the increased production of cytokines and chemokines that have the 
potential to promote antitumor immunity, such as type I IFNs (Chatzinikolaou et al 2014).

Upregulation of surface receptors such as major histocompatibility complex, ligands for 
natural-killer group 2, member D (NKG2D) and inducible T-cell costimulatory ligand 
(ICOSL), which render tumor cells more visible to detection by cytotoxic T-cells 
(Tang et al 2014).

Death of tumor cells and release of antigen, which may help to promote antigen 
presentation and immune priming (Kroemer et al 2012).
In agreement with this hypothesis, olaparib was associated with a significant improvement in 
progression-free survival (PFS) as a maintenance treatment in ovarian cancer 
(Ledermann et al 2014), and recent analyses suggests this may translate into a survival 
advantage (Ledermann et al 2016).
These effects would be expected to help promote an effective antitumor immune response.  In 
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increased DNA damage show evidence of enhanced immune recognition.  For example,
BRCAm tumor cells are associated with higher levels of tumor infiltrating lymphocytes and 
secreting lymphocyte attractants (eg, C-X-C motif ligand [CXCL] 10) and immune 
suppressive ligands such as 
 (Mulligan et al 2014).  The GOLD Phase III study did not 
meet the primary endpoint of overall survival (OS) in advanced gastric cancer patients, in 
either the overall population or patients whose tumor tested negative for ataxia telangiectasia 
mutated (ATM) protein.  While there was a numerical survival trend in the olaparib plus 
paclitaxel arm, it did not meet statistical significance.
Based on this basic biology, the hypothesis to be tested in this study is that increased DNA 
damage triggered through PARP inhibition will result in enhanced antitumor immunity that 
can be further enhanced through combination with an immune checkpoint inhibitor in 
advanced cancers.  This hypothesis is supported by published studies in mouse models of 
cancer, demonstrating that administration of a PARPi to sensitive tumor types results in 
increased T-cell infiltration and activation within tumors (Higuchi et al 2015; 
Huang et al 2015).  In order to test this hypothesis clinically, patients will receive olaparib 
monotherapy for a period of 4 weeks prior to commencing combination treatment.  It is also 
anticipated that MEDI4736 will prolong the duration of response (DoR) to olaparib in patients 
with DNA repair deficient cancers.
The rationale for combining bevacizumab and MEDI4736 with olaparib in the current study is 
discussed in Section 1.1.2 of Module 6 (ovarian cancer triplet cohort).
1.1.2
Background on individual investigational products
1.1.2.1
Olaparib
Olaparib (AZD2281, KU-0059436, Lynparza™) is a potent polyadenosine 5’ diphosphoribose
[poly (ADP ribose)] polymerization (PARP) inhibitor (PARPi; PARP-1, -2, and -3), the 
capsule formation of which was initially approved by Food and Drug Administration (FDA)
as monotherapy in patients with deleterious or suspected deleterious germline breast cancer 
susceptibility gene (BRCA) mutated (as detected by an FDA-approved test) advanced ovarian 
cancer who have been treated with 3 or more prior lines of chemotherapy.
The initial FDA approval for olaparib was mainly based on data from Study 
 
(Study 42) (Kaufman et al 2015); a Phase II non-comparative study in gBRCAm advanced 
tumors, including ovarian cancer using olaparib capsule formulation, 400 mg bd. 
In Study 
 (Study 19; a Phase II, randomized, double-blind, placebo controlled 
multicenter study using olaparib capsule formulation, 400 mg bd), 
 
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In Europe, based on the Study 19 data, olaparib capsules was approved on 16 December 2014 
as a maintenance treatment for patients with PSR BRCAm high grade serous epithelial 
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ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial 
response) to platinum-based chemotherapy (capsule formulation).
In the EU, the tablet formulation of olaparib for the maintenance treatment of adult patients 
with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary 
peritoneal cancer who are in response (complete response [CR] or partial response [PR]) to 
platinum-based chemotherapy has now been approved.
As of November 2020, olaparib has been granted several more additional approvals in ovarian 
cancer:

By the FDA and European Medicines Agency (EMA) for the maintenance treatment of 
adult patients with deleterious or suspected deleterious germline or somatic 
BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or 
primary peritoneal canacer who are in complete or partial response to first line platinum-
based chemotherapy.

By the FDA for treatment of adult patients with gBRCA-mutated advanced ovarian cancer 
who have been treated with three or more prior lines of chemotherapy

By the FDA and EMA for treatment in combination with bevacizumab for the 
maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or 
primary peritoneal cancer who are in complete or partial response to first-line platinum-
based chemotherapy and whose cancer is associated with homologous recombination 
deficiency (HRD)-positive status defined by either:

A deleterious or suspected deleterious BRCA mutation, and/or

Genomic instability
Besides ovarian cancer, olaparib has been studied in other disease indications. The Phase III 
study GOLD did not meet the primary endpoint of OS in advanced gastric cancer patients, in 
either the overall population or patients whose tumor tested negative for ATM protein.  While
there was a numerical survival trend in the olaparib plus paclitaxel arm, it did not meet 
statistical significance (Bang et al 2017).
A Phase III trial (OlympiAD) in patients with metastatic germline BRCA mutated breast 
cancer showed a median progression-free survival significantly longer in the olaparib group 
than that in the standard-therapy group (7.0 months versus 4.2 months; hazard ratio for disease 
progression or death, 0.58; 95% CI: 0.43 to 0.80; p<0.001).  The response rate was 59.9% in 
the olaparib group and 28.8% in the standard-therapy group (Robson et al 2017).  In the 
United States of America (US), an efficacy supplement seeking licensure of the tablets in the 
treatment of HER2-negative metastatic breast cancer, based on the OlympiAD study, was 
approved in 2018; it has also been approved by the EMA.

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As of August 2020, olaparib has also been approved by the FDA and EMA for the 
maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm
metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks 
of a first-line platinum-based chemotherapy regimen, and by the FDA for the treatment of 
adult patients with deleterious or suspected deleterious germline or somatic homologous 
recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer who 
have progressed following prior treatment with enzalutamide or abiraterone, and also 
approved by the EMA for the BRCA 1/2 population.
Olaparib is being evaluated in combination with other anticancer agents, including 
immune-oncology agents.
1.1.2.2
MEDI4736
MEDI4736 (durvalumab, Imfinzi®) is a mAb of the immunoglobulin G1 kappa subclass that 
inhibits binding of 
 to PD-1 and CD80.  It has shown preliminary activity in advanced 
solid tumors.  The mechanism of action of MEDI4736 suggests the potential to combine it 
with a number of targeted anticancer treatments, resulting in either synergistic or additive 
activity in different tumor types.  MEDI4736 was FDA-approved for the treatment of 
advanced urothelial cancer in 2017.
In 2017, MEDI4736 was approved for the treatment of advanced or metastatic urothelial 
carcinoma.  Approval was based on 1 single-arm trial of 182 patients with locally advanced or 
metastatic urothelial carcinoma whose disease progressed after prior platinum-containing 
chemotherapy.  MEDI4736, 10 mg/kg intravenously, was administered every 2 weeks. 
Confirmed objective response rate (ORR) as assessed by BICR per Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1, was 17.0% (95% CI: 11.9 to 23.3).  At the data 
cut-off for the ORR analysis, median response duration was not reached (range: 0.9+ to 
19.9+ months).  
 
 
 
 
  
 
 
 
 
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A recent Phase III trial (PACIFIC) showed a positive result for MEDI4736 after 
chemoradiotherapy in stage III NSCLC.  The median progression-free survival from 
randomization was 16.8 months (95% CI: 13.0 to 18.1) with MEDI4736 versus 5.6 months 
(95% CI: 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 
0.52; 95% CI: 0.42 to 0.65; p<0.001); the 12-month progression-free survival rate was 55.9% 
versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The 
response rate was higher with MEDI4736 than with placebo (28.4% versus 16.0%; p<0.001), 
and the median duration of response was longer (72.8% versus 46.8% of the patients had an 
ongoing response at 18 months). The median time to death or distant metastasis was longer 
with MEDI4736 than with placebo (23.2 months versus 14.6 months; p<0.001) 
(Antonia et al 2017).  Based on the results of the PACIFIC trial, MEDI4736 was approved by 
the FDA for the treatment of stage III non-small cell lung cancer.
 
 
 
 
 
Details on the safety profile of MEDI4736 monotherapy are 
summarized in Section 1.3.2.  Refer to the current MEDI4736 Investigator’s Brochure (IB) for 
a complete summary of non-clinical and clinical information including safety, efficacy and 
pharmacokinetics (PK).
1.1.2.3
Bevacizumab
See Section 1.1.3.1 in Module 6 for background information on bevacizumab. 
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1.1.3
Pre-clinical experience with investigational products
The pre-clinical experience with olaparib and MEDI4736 is fully described in the respective 
current versions of the olaparib and MEDI4736 IBs.
1.1.4
Clinical experience with investigational products
Clinical experience with olaparib and MEDI4736 is described in the current respective 
versions of the olaparib and MEDI4736 IBs.
Clinical experience with bevacizumab can be found in the FDA label. 
1.2
Rationale for study design, doses, and control groups
This open-label, multicenter, Phase I/II study will evaluate the safety, tolerability, PK and 
antitumor activity of MEDI4736 in combination with olaparib (±bevacizumab), in patients 
with metastatic or recurrent solid malignancies with DNA damage repair deficiencies, in 
which there is a rationale for olaparib to be effective and the potential for the combination to 
be more effective than olaparib alone.
1.2.1
Rationale for the study design: Initial Stage Cohorts
While most signal seeking studies utilize a study design focused on using overall response rate 
as a measure of activity, this endpoint does not capture the depth of response which is 
especially important for assessing immunotherapy containing regimens.  For these regimens, 
PFS is a more relevant endpoint for decision making but is difficult to determine accurately in 
a small cohort without a comparator control.  Since PFS is driven by progression events it is 
possible to define a relationship between PFS and disease control rate (which is based on the 
absence of progression) at a given timepoint.  This study has utilized this strategy to define 
target DCR based on historical PFS targets (for standard of care therapy) for each cohort.
The study uses a Bayesian predictive design for each individual cohort which allows for the 
assessment at multiple intervals of the probability that the trial will show a conclusive result at 
the end of the study, given the current information (see Section 8.2 for more details on the 
statistical design).  This design, therefore, allows an assessment of the activity and durability 
of response with relatively small cohort size and even the ability to stop early if futility or 
efficacy.
1.2.2
Rationale for the study design: Second Stage Cohorts
The rationales for the design of the platinum-sensitive ovarian mutated breast cancer 
susceptibility gene (BRCAm) cohort (“BRCAm ovarian cancer expansion cohort”), the 

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platinum-sensitive ovarian non BRCAm cohort treated with 
MEDI4736+olaparib+bevacizumab (“ovarian cancer triplet cohort”), and the 
platinum-sensitive ovarian non BRCAm treated with MEDI4736+olaparib (“ovarian cancer 
doublet cohort”), are described in Section 1.1 of Module 5, Section 1.2 of Module 6, and 
Section 1.1 of Module 7, respectively. 
1.2.3
Selection of doses
1.2.3.1
Olaparib
Use in monotherapy
The approved olaparib tablet dose is 300 mg twice daily (bid).
Use in combination
Dose selection for this study is based on the results of an independent study, the National 
Cancer Institute (NCI) Study 
 (Lee et al 2017).  On the basis of data from this 
study, the dose of olaparib to be used in this study will be the recommended monotherapy 
dose of 300 mg bid.
1.2.3.2
MEDI4736
 
 
 
 
 
 
 
 
 
 
 
Similar findings have been reported by others (Narwal et al 2013; Ng et al 2006;
Wang et al 2009; Zhang et al 2012).  Wang and colleagues investigated 12 monoclonal 
antibodies (mAbs) and found that fixed and body size-based dosing perform similarly, with 
fixed dosing being better for 7 of 12 antibodies (Wang et al 2009).  In addition, they 
investigated 18 therapeutic proteins and peptides and showed that fixed dosing performed 
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better for 12 of 18 in terms of reducing the between-patient variability in 
PK/pharmacodynamics parameters (Zhang et al 2012).
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors.  Given the expectation of similar PK exposure and variability, 
AstraZeneca considered it feasible to switch to fixed dosing regimens.  Based on an average 
body WT of 75 kg, it is planned that a fixed dose of 1.5 g Q4W ±3 days MEDI4736 
(equivalent to 20 mg/kg Q4W) will be administered via intravenous (IV) infusion, in 
combination with olaparib.
1.2.3.3
Bevacizumab
The rationale for selection of the bevacizumab dose in the ovarian cancer triplet cohort is 
presented in Section 1.2 of Module 6.
1.2.4
Patient population
All patients must have at least 1 measurable lesion at baseline that can be accurately measured 
at follow-up assessments.  The primary and secondary efficacy outcome measures will use the 
RECIST 1.1 as assessed by the Investigator, which is a standard tool for measuring response 
in oncology study in solid tumors.
Molecular testing data from an appropriately accredited laboratory will be documented prior 
to a patient commencing treatment in the study.
1.2.4.1
Initial Stage Cohorts
The 4 exploratory Initial Stage Cohorts comprise patients with relapsed SCLC (Module 1, 
Appendix H), germline BRCA mutated (gBRCAm), metastatic HER2-negative breast cancer
(Module 2, Appendix I), gBRCAm platinum-sensitive relapsed ovarian cancer (Module 3, 
Appendix J), and gastric cancer (Module 4, Appendix K).
The scientific rationale for the choice of tumors is discussed in Section 1.1.1.2.
1.2.4.2
Second Stage Cohorts
The 3 exploratory Second Stage Cohorts are comprised of patients with PSR BRCAm ovarian 
cancer (BRCAm ovarian cancer expansion cohort, Module 5, Appendix L), or with PSR non
BRCAm ovarian cancer (ovarian cancer triplet cohort, Module 6, Appendix M; and ovarian 
cancer doublet cohort, Module 7, Appendix N).

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1.3
Benefit/risk and ethical assessment
The following sections include summaries of the potential benefits and risks associated with 
MEDI4736 monotherapy, olaparib monotherapy, and MEDI4736+olaparib combination 
therapy, respectively, prior to the overall benefit/risk assessment.
The benefit/risk and ethical assessment for the non BRCAm ovarian cancer triplet cohort is
described in Section 1.3 of Module 6.
1.3.1
Olaparib benefit/risk in monotherapy and combination therapy
Olaparib was first studied in ovarian cancer where it is now approved as a second-line 
maintenance treatment in an all-comer population, as well as in fourth line treatment in the 
gBRCAm ovarian cancer population.  Clinical trials are ongoing to explore its role in the 
earlier line setting. A positive phase III trial in breast cancer also lead to FDA approval in the 
gBRCAm patient population.  It is clear that olaparib has some activity also in gastric cancer.  
However, the Phase III trial did not show significant superiority in the olaparib arm - likely 
due to the low dose of olaparib that was limited by use of chemotherapy. Combination studies 
in non-chemotherapy setting are being conducted in gastric cancer to explore the olaparib 
activity seen in Phase II and III trials. Phase III trials are ongoing in prostate and pancreatic 
cancers in biomarker selected patient populations. Phase II trials using olaparib as a 
monotherapy and in combination with immunotherapies are ongoing in SCLC.
Regarding toxicity, olaparib has proven to be better tolerated compared with chemotherapy. 
Most adverse events can be managed. The main toxicities are anemia and gastrointestinal 
symptoms, such as nausea and vomiting. Anemia can be managed by dose reductions and 
occasional blood transfusions. The available evidence from across the olaparib clinical 
development programme supports a conclusion that there is reasonable possibility of a causal 
relationship between olaparib and the AE of special interest of myelodysplastic syndrome/ 
acute myeloid leukemia (MDS/AML).  Therefore, should anemia become chronic and severe, 
a rare possibility of these conditions must be ruled out. Gastrointestinal toxicities should be 
managed by aggressive treatment of nausea with commonly used antiemetics. For 
information on all identified and potential risks with olaparib refer to the current version of the 
olaparib IB.
Overall, the studies conducted in olaparib show clinical activity in multiple indications and in 
populations beyond the germline BRCA-mutated population in ovarian cancer. Given the 
clinical activity and tolerable toxicity profile, olaparib may represent an alternative therapeutic 
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provides a less toxic alternative treatment option for patients, possibly making the quality of 
life better for the patients, while maintaining the efficacy.
1.3.2
MEDI4736 benefit/risk
MEDI4736 is joining the increasing number of immune checkpoint inhibitors being studied in 
the treatment of cancer.  It is FDA-approved for the treatment of patients with locally 
advanced or metastatic urothelial carcinoma and in stage III NSCLC. 
MEDI4736 is being studied extensively in multiple indications as a monotherapy and in 
combination with other immunotherapies, as well as with chemotherapy and targeted agents, 
such as olaparib.  It is hypothesized that the antitumor effects of MEDI4736 are durable and 
sometimes occur long after the administration of the immunotherapy has already been 
stopped, making it a desirable partner to combine with agents that have activity upfront.
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune-mediated mechanism and which 
may require more frequent monitoring and/or unique interventions such as 
immunosuppressants and/or endocrine therapy. These immune-mediated effects can occur in 
nearly any organ system.
Risks with MEDI4736 include, but are not limited to, diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper-
and hypo-thyroidism, Type 1 diabetes mellitus and diabetes insipidus), hepatitis/increases in 
transaminases, nephritis/increases in creatinine, rash/dermatitis, myocarditis, 
myositis/polymyositis, infusion-related reactions, hypersensitivity reactions, pancreatitis, 
serious infections, and other rare or less frequent inflammatory events including 
neuromuscular toxicities (eg, myasthenia gravis). 
For information on all identified and potential risks with MEDI4736, please always refer to 
the current version of the MEDI4736 IB.
The overall advantage of MEDI4736 treatment is its tolerable toxicity profile compared with 
that of chemotherapy.  While the immune-related adverse events can potentially be severe, 
they are rare and can be managed with the use of steroids and other immunosuppressants.  It is 
possible that immunotherapies, such as MEDI4736, will become alternative treatment options 
to chemotherapy in many indications, making the quality of life better for the patients with 
incurable cancer.

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1.3.3
Olaparib and MEDI4736 benefit/risk
Despite the many advances in oncology treatment in recent years, chemotherapy remains the 
primary systemic therapy for many advanced cancers.  The toxicities associated with 
chemotherapy can be challenging for patients to tolerate and difficult for physicians to 
manage. The toxicity associated with chemotherapy limits how long patients can be treated 
and ultimately most patients eventually progress while on these therapies.
PARP inhibitors like olaparib have been shown to be effective for patients with BRCA
mutation both as maintenance therapy following chemotherapy (Pujade-Lauraine et al 2017) 
and as a standalone treatment option without chemotherapy (Robson et al 2017).  It has been 
hypothesized that the PARP inhibitor olaparib could be used with immune checkpoint 
inhibition (MEDI4736) as a new potential combination therapy where the increased DNA 
damage caused by PARP inhibition may stimulate the immune microenvironment, which 
could complement and enhance the antitumor activity of an immune checkpoint inhibitor in 
advanced cancers.  If this hypothesis is correct, this combination could bring together the 
activity of PARP inhibitors with the increased durability of responses associated with immune 
checkpoint inhibition which could lead to greater benefit for patients compared with current 
treatment options.  
Based on the known toxicity profiles of olaparib and MEDI4736, the combination should be 
significantly more tolerable than most chemotherapies and preliminary data supports this 
prediction. In the Phase I part of the MEDI-O trial, the combination has been shown to be 
tolerable with promising activity in treating women’s cancers with no dose-limiting toxicities 
observed (Lee et al 2017). Preliminary data from the prostate cancer cohort of the MEDI-O 
study also supports that this combination is well tolerated with encouraging signs of 
preliminary activity (Karzai et al 2017). These results suggest that the olaparib+MEDI4736
combination is tolerable with significantly less toxicity than what would be expected with 
conventional chemotherapy.
The combination of olaparib and MEDI4736 is now being studied extensively across several 
tumor types with almost 250 patients treated in 2 clinical studies (MEDI-O and MEDIOLA).  
While the efficacy results are still pending, preliminary safety data suggests that the 
combination is tolerable.  Given the potential for the combination in multiple advanced tumors 
and the predicted tolerability of the combination, participation in this study should present an 
acceptable benefit:risk consideration for patients with advanced cancers.

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1.3.4
Bevacizumab benefit/risk
See Section 1.3 of Module 6 for the benefit/risk of bevacizumab discussed in the context of 
treatment in combination with olaparib+MEDI4736.
1.3.5
Impact on Benefit/Risk from Study Disruptions due to Coronavirus Disease 
2019
The emergence of the coronavirus 2019-nCoV (COVID-19) pandemic presents a potential 
safety risk for patients and therefore several risk mitigation factors have been implemented in 
this study (see Section 1.5.1 and Appendix P).
1.4
Study design 
This is a Phase I/II open-label, multicenter study to evaluate the safety, tolerability, PK, and 
antitumor activity of MEDI4736 in combination with olaparib in patients with advanced solid
tumors, selected based on a rationale for response to olaparib.
Patients will be PARP-inhibitor and immunotherapy (IMT)-naïve (defined as no prior 
exposure to PARP inhibitors or IMT, including, but not limited to, other anti-CTLA-4, PD-1, 
 or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways).
Safety measures for all cohorts of the study include routine safety monitoring on an ongoing 
basis conducted by AstraZeneca and a formal Review Committee mechanism as described in 
the cohort-specific appendices.
All serious adverse events (SAEs), adverse events of special interest (AESI), discontinuations, 
dose reductions and dose interruptions will be reviewed, as well as any lesser-grade AEs that 
are considered by the study team to be of particular interest (based on emerging data from the 
ongoing safety monitoring and accumulating clinical experience, and other data from external 
sources as indicated).
Patients should continue to receive study treatment until objective radiological disease 
progression as per RECIST 1.1 as assessed by the Investigator or as long as, in the 
Investigator’s opinion, they are benefitting from treatment and they do not meet any other 
discontinuation criteria.  Imaging assessments are required for patients who continue receiving 
the study drug combination beyond disease progression.
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Patients who remain on study treatment after the final data cut-off will be monitored 
according to routine clinical practice as defined by the Investigator (see Section 9.3 for details 
of safety data collection after the final data cut-off).
1.4.1
Initial Stage Cohorts
Enrollment in the Initial Stage Cohorts has completed. Data from the Initial Stage Cohorts 
have been reported in a Clinical Study Report (CSR).  In all 4 Initial Stage Cohorts, the 
olaparib + MEDI4736 combination was well-tolerated, and AEs were consistent with those 
seen in olaparib and MEDI4736 monotherapy studies (Bang et al 2019, Domchek et al 2020, 
Drew et al 2018, Krebs et al 2017, Drew et al 2019).  In the breast and ovarian cancer cohorts, 
the combination of olaparib and MEDI4736 showed promising antitumor activity 
(Domchek et al 2020, Drew et al 2018, Drew et al 2019).  In the SCLC and gastric cancer 
cohorts the 12-week disease control rate was below the pre-specified target, however durable 
responses were observed in a minority of patients in these cohorts (Bang et al 2019, 
Krebs et al 2017).  
In the initial stage of the study, patients were enrolled concurrently into 4 exploratory Initial 
Stage Cohorts, which include patients with:

Relapsed SCLC

gBRCAm metastatic HER2-negative breast cancer

Relapsed gBRCAm platinum-sensitive ovarian cancer

Relapsed gastric cancer
The Initial Stage Cohorts are illustrated in Figure 1.

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Figure 1
Initial Stage Cohorts
Gastric cancer 
cohort
(N=34)
Module 4
gBRCAm ovarian 
cancer cohort 
(N=31)
Module 3
Olaparib + MEDI4736
gBRCAm breast 
cancer cohort 
(N=30)
Module 2
to 
PD
Olaparib + MEDI4736
to 
PD
to 
PD
1-3L metastatic 
breast cancer
gBRCAm, 
HER2-negative
≥2L metastatic 
ovarian cancer
gBRCAm
Platinum-sensitive
2L metastatic 
gastric cancer
Screen
Initial 
Stage 
Cohorts
Olaparib + MEDI4736
SCLC cohort
(N=38)
Module 1
to 
PD
Relapsed
SCLC
Olaparib + MEDI4736
1L, 2L, 3L=first, second, third-line; gBRCAm=germline BRCA mutation; HER2=human epidermal growth factor 
receptor 2; PD=progressive disease; SCLC=small cell lung cancer.
Based on the results of the NCI study (see Section 1.2.3.1; Lee et al 2017), the current study
will start at a dose of olaparib 300 mg bid/MEDI4736 1.5 g Q4W (hereafter referred to as 
“Full Dose”).  Within each cohort, a Review Committee will be convened and will review 
pre-specified safety and efficacy data when the first 10 patients in each cohort have been 
followed for 12 weeks.  The Committee deliberations will consider safety and pertinent tumor 
assessment data (at a minimum from radiologic imaging studies but also other data, such as 
relevant physical exam findings, etc).  All SAEs, AESI, discontinuations, dose reductions and 
dose interruptions will be reviewed, as well as any lesser-grade AEs that are considered by the 
study team to be of particular interest (based on emerging data from the ongoing safety 
monitoring and accumulating clinical experience in the first 10 patients, and other data from 
external sources as indicated).
Participants of the Review Committee discussed above will consist of the Principal 
Investigators (PIs) and/or their delegates, other relevant clinical staff from the sites, a study 
physician and a clinical scientist.  Ad hoc members, such as the Study Pharmacokineticist, 
Study Statistician, Global Safety Physician (or delegate), Study Delivery Leader, NCI study 
team members, a IQVIA representative, and others may also be invited as appropriate.  
Attendance of the Global Safety Physician (or delegate) is required if safety data are 
discussed.  Safety data and pertinent tumor assessment data collected to date (including scans 

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and other data eg, physical examinations if available) will be considered, as will relevant data 
from the NCI study (and efficacy data as appropriate).  
Further specific operating procedures will be described in a separate document.
Additional safety measures include informal meetings (“Investigator Calls”), which will be 
held as necessary while patients are on treatment, with the AstraZeneca study team, the PIs (or 
their delegates), and a representative from IQVIA to provide an ongoing forum in which to 
exchange and update information and to discuss the progress and data from the study.  The 
meetings will focus on the safety and tolerability data, but will not exclude other topics, such 
as efficacy and operational issues, as needed.
To ensure uniform decision making, a Bayesian predictive probability design will be 
consistently employed across the Initial Stage Cohorts (Lee and Liu 2008). 
For the Initial Stage Cohorts, after evaluating DCR (defined as: CR+partial 
response [PR]+stable disease [SD] evaluated at 12 weeks) and selected safety data from the 
first 10 patients in the cohort, DCR will be monitored every 5 patients until the maximum 
sample size is reached.  If the doses used in combination demonstrate evidence of antitumor 
activity based on DCR, and are considered safe and tolerable, then the alternative hypothesis 
can be accepted at any of these interim looks.  If the DCR is such that the null hypothesis will 
not be able to be rejected at the end of the trial, then additional screening activities for new 
patients into that cohort may be stopped.  Figure 2 summarizes, in graphical form, the 
Bayesian predictive probability design for the Initial Stage Cohorts.  For full details, please 
refer to Section 8.2.

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Figure 2
Study design: Bayesian predictive probability design – Initial Stage Cohorts
OVARIAN CANCER
BREAST CANCER
SCLC
GASTRIC CANCER
Target DCR 12 weeks 90%
Target DCR 12 weeks 75%
Target DCR 12 weeks 60%
Target DCR 12 weeks 70%
Treated with olaparib for 4 weeks followed by olaparib+MEDI4736 until objective radiological disease progression a
Eval. 
Pts
Decision 
Futility
Decision 
Efficacy
Eval. 
Pts
Decision 
Futility
Decision 
Efficacy
Eval. 
Pts
Decision 
Futility
Decision 
Efficacy
Eval. 
Pts
Decision 
Futility
Decision 
Efficacy
10
≤5/10
10/10
10
≤3/10
≥9/10
10
≤1/10
≥8/10
10
≤4/10
≥8/10
15
≤10/15
≥14/15
15
≤6/15
≥12/15
15
≤3/15
≥11/15
15
≤7/15
≥12/15
20
≤14/20
≥18/20
20
≤10/20
≥16/20
20
≤6/20
≥13/20
20
≤10/20
≥15/20
25
≤19/25
≥22/25
25
≤15/25
≥19/25
25
≤9/25
≥16/25
25
≤14/25
≥18/25
30
≤24/30
≥26/30
30
≤20/30
≥21/30
30
≤12/30
≥18/30
30
≤17/30
≥21/30
31
≤25/31
≥26/31
35
≤17/35
≥20/35
34
≤21/34
≥22/34
38
≤20/38
≥21/38
DCRb reviewed after 10 evaluable patients and then every 5 patients until maximum sample size reached.  At each review, cohort may be 
stopped for futility or efficacy.  If decision threshold not reached recruitment continues.  Selected safety data included in initial review.
DCR=disease control rate; Eval. Pts=evaluable patients; RECIST=Response Evaluation Criteria in Solid Tumors; SCLC=small cell lung cancer.
a
Per RECIST 1.1 as assessed by the Investigator or as long as, in the Investigator’s opinion, they are benefitting from treatment and they do not meet any 
other discontinuation criteria.  Imaging assessments are required for patients who continue receiving the study drug combination beyond disease 
progression.
b
DCR: defined as complete response (CR)+partial response (PR)+stable disease (SD), evaluated at 12 weeks.

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There will be an initial period of 4 weeks monotherapy treatment with olaparib in the Initial 
Stage Cohorts, in order for olaparib to induce changes in the tumor microenvironment as a 
result of DNA damage and cell death with release of potential immunogenic antigens.  A 
proportion of patients (minimum of 5 evaluable pairs per cohort) will undergo pre- and 
post-olaparib treatment tumor biopsies to evaluate the tumor microenvironment changes and 
to identify potential biomarkers predictive of activity of the combination.
Details on the analysis of DCR, the closing of the clinical database, and the treatment plan 
schematic for the Initial Stage Cohorts are provided in Section 1.1 of Module 1, Section 1.1 of 
Module 2, Section 1.1 of Module 3 and Section 1.1 of Module 4.
1.4.2
Second Stage Cohorts
Enrollment for the Second Stage Cohorts has been completed.  Enrollment of the BRCAm
ovarian cancer expansion cohort was terminated when 51 of 80 planned patients had been 
enrolled.  As PARP inhibitors have become standard of care in the first line setting for 
gBRCAm patients, the high unmet clinical need in this patient population has reduced. In 
addition, as a result of the success of PARP inhibitors in this setting, there are limited numbers 
of PARP inhibitior-naïve patients eligible for inclusion in the BRCAm ovarian cancer 
expansion cohort.  Therefore, despite high response rates in this patient population with 
olaparib and MEDI4736 combination treatment as shown in the initial stage gBRCAm ovarian 
cancer cohort (Drew et al 2019, Drew et al 2018), recruitment for the BRCAm ovarian cancer 
expansion cohort was closed early.
In the second stage of the study, patients were enrolled into 1 of 3 exploratory Second Stage 
Cohorts, which include patients with:

BRCAm PSR ovarian cancer (“BRCAm ovarian cancer expansion cohort”) - Module 5 
(Appendix L)

Non BRCAm PSR ovarian cancer (“ovarian cancer triplet cohort”) - Module 6
(Appendix M)

Non BRCAm PSR ovarian cancer (“ovarian cancer doublet cohort”) - Module 7
(Appendix N)
The Second Stage Cohorts are illustrated in Figure 3.

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Figure 3
Second Stage ovarian cancer cohorts
a
Doublet cohort will be enrolled once triplet cohort enrollment has been completed.
There will be no olaparib run-in treatment period in the Second Stage Cohorts.
2L, 3L=second, third-line; gBRCAm=germline BRCA mutation; HER2=human epidermal growth factor receptor 
2; PD=progressive disease; SCLC=small cell lung cancer.
In addition to other eligibility criteria specified in each Module, assignment to the 3 Second 
Stage Cohorts will depend on the BRCA status of ovarian cancer patients.  For inclusion in the 
BRCAm ovarian cancer expansion cohort, patients must have documented evidence of a 
germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected 
deleterious (known or predicted to be detrimental/lead to loss of function) from either a prior 
local test or Myriad central testing.  For inclusion in the ovarian cancer triplet or doublet 
cohorts, patients must have documented evidence from the Myriad central laboratory
indicating that they do not have a germline mutation in BRCA1 or BRCA2 that is predicted to 
be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of 
function).
Enrollment into the BRCAm ovarian cancer expansion and ovarian cancer triplet cohorts will 
be concurrent, enrollment into the ovarian cancer doublet cohort will only commence once 
enrollment into the ovarian cancer triplet cohort has been completed.  Full details of BRCA
testing for ovarian cancer patients prior to assignment to 1 of the Second Stage Cohorts are 
presented in Appendix O.  
Figure 4 illustrates the BRCA testing steps for the Second Stage Cohorts.

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Figure 4
Diagnostic BRCA testing for Second Stage ovarian cancer cohorts
Testing is shown in grey boxes.  Black boxes indicate how patient is assigned to a cohort as a result of testing/prior knowledge of BRCA status. 
Non BRCAm cohort=ovarian cancer triplet or doublet cohorts.  Enrollment to triplet cohort will be completed before enrollment into the doublet cohort 
commences.
gBRCA=germline BRCA; gBRCAm=germline BRCA mutation; BRCAm=BRCA mutation.

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Details for the dosing and review of safety data for each of the Second Stage Cohorts are
specified in their corresponding Module.
1.4.3
Summary of ovarian cancer cohort characteristics
The ovarian cancer cohorts in this study have a range of defining molecular markers, numbers 
of previous cycles of treatment, and treatment regimens. For clarity, this information is 
summarized below in Table 1.
Table 1
Summary of ovarian cancer cohort characteristics
Initial Stage 
Cohort
Second Stage Cohorts
gBRCAm ovarian 
cancer cohort
BRCAm ovarian 
cancer expansion 
cohort
Ovarian cancer 
triplet cancer 
cohort
Ovarian cancer 
doublet cohort
Module
Module 3
(Appendix J)
Module 5
(Appendix L)
Module 6
(Appendix M)
Module 7
(Appendix N)
Study 
treatment
Olaparib +
MEDI4736 
(with 4-week 
olaparib run-in)
Olaparib +
MEDI4736 
(no run-in)
Olaparib +
MEDI4736 +
bevacizumab 
(no run-in)
Olaparib +
MEDI4736 
(no run-in)
BRCA status
gBRCAm
gBRCAma
Non gBRCAm
Non gBRCAm
Platinum 
classification
Platinum sensitiveb
Platinum sensitiveb
Platinum sensitiveb
Platinum sensitiveb
Other 
eligibility
≥1 prior lines of 
chemotherapy
1 or 2 prior lines of 
chemotherapy
1 or 2 prior lines of 
chemotherapy
1 or 2 prior lines of 
chemotherapy
a
A local test result demonstrating that the patient has gBRCAm will allow only those patients to bypass 
prospective testing. All other patients must undergo prospective testing.  See Appendix O.
b
Defined as at least 24 weeks from completion of last (most recent) platinum treatment to next relapse.
gBRCAm=germline BRCA mutation.
1.5
Study governance and oversight
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators.
In this Phase I/II open-label study, a data monitoring committee was not considered necessary.

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In the Initial Stage Cohorts: 
Within each Initial Stage Cohort, a Review Committee will be convened and will review 
pre-specified safety and efficacy data when the first 10 patients in each cohort have been 
followed for 12 weeks, as described in Section 1.4.1.
Informal meetings (“Investigator Calls”), which will be held as necessary and focus on the 
safety and tolerability data, but will not exclude other topics, such as efficacy and operational 
issues, as needed (see Section 1.4.1).
In the Second Stage Cohorts: 
The cohorts with a Bayesian design (ovarian cancer triplet cohort, ovarian cancer doublet 
cohort) have the same Review Committee approach to review interim safety and efficacy data 
described in Section 1.4.1 for the Initial Stage Cohorts.
In addition, a review committee will review the ongoing safety and efficacy data of patients in 
the BRCAm ovarian cancer expansion cohort (Module 5).
1.5.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil
Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this Clinical Stusy 
Protocol (CSP) and should be implemented only during cases of civil crisis, natural disaster, 
or public health crisis (eg, during quarantines and resulting site closures, regional travel 
restrictions, and considerations if site personnel or study patients become infected with SARS-
CoV-2 or similar pandemic infection) which would prevent the conduct of study-related 
activities at study sites, thereby compromising the study site staff or the patient’s ability to 
conduct the study. The Investigator or designee should contact the study Sponsor to discuss 
whether the mitigation plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study patients, maintain 
compliance with GCP, and minimize risks to study integrity.
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options: 

Obtaining reconsent for the mitigation procedures (note, where allowable in the case of 
verbal reconsent), the Informed Consent Form (ICF) should be signed at the patient’s next 
contact with the study site.

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
Home or Remote visit: Performed by a site qualified Health Care Professional (HCP) or 
HCP provided by a third-party vendor (TPV).

Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.

At-home or Remote Location Investigational Product (IP) administration: Performed by a 
site-qualified HCP, HCP provided by a TPV, or by the patients or the patient caregiver, if 
possible. Additional information related to the visit can be obtained via telemedicine.

At-home or Remote Delivery of olaparib.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix P.

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2.
STUDY OBJECTIVES
2.1
Primary objectives
Primary Objectives
Outcome Measures
Initial Stage Cohorts
Second Stage Cohorts
BRCAm ovarian cancer 
expansion cohort
Ovarian cancer triplet 
and doublet cohorts
To assess the effect of 
MEDI4736 in combination 
with olaparib±bevacizumab 
in patients with selected 
advanced solid tumors
DCR (CR+PR+SD) based 
on RECIST 1.1 at 
12 weeks
ORR (CR+PR) based on 
RECIST 1.1 assessed by 
the Investigator
DCR (CR+PR+SD) based 
on RECIST 1.1 at 
24 weeks
To assess the safety and 
tolerability of MEDI4736 
in combination with 
olaparib (±bevacizumab) in 
patients with selected 
advanced solid tumors

AEs, vital signs including blood pressure, pulse, ECG and laboratory findings 
including clinical chemistry and hematology. 

irAEs - given the intended mechanisms of action of MEDI4736, particular 
attention will be given to AEs that may follow enhanced T-cell activation, or 
other irAE.

Dose interruptions, dose reductions.

Causes of olaparib and MEDI4736 discontinuation.
NA
NA
Triplet cohort only:
Causes of bevacizumab 
discontinuation.
AE=adverse event; BRCAm=Mutated breast cancer susceptibility gene; CR=complete response; DCR=disease 
control rate; ECG=electrocardiogram; irAE=immune-related adverse event; NA=not applicable; ORR=objective 
response rate; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease.

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2.2
Secondary objectives
Secondary Objectives
Outcome Measures
Initial Stage Cohorts
Second Stage Cohorts
BRCAm ovarian cancer 
expansion cohort
Ovarian cancer triplet 
and doublet cohorts
To investigate the 
preliminary antitumor 
activity of MEDI4736 in 
combination with 
olaparib±bevacizumab in 
patients with selected 
advanced solid tumors
!
DCR at 28 weeks
!
ORR (CR+PR) 
based on 
RECIST 1.1
!
DoR based on 
RECIST 1.1
!
PFS based on 
RECIST 1.1
!
Percentage 
change from 
baseline in tumor 
size at 12 weeks 
and 28 weeks
!
Best percentage 
change from 
baseline in tumor 
size
!
TDT
!
Overall survival
!
DCR at 24 weeks 
and 56 weeks
!
DoR based on 
RECIST 1.1
!
PFS based on 
RECIST 1.1
!
Percentage change 
from baseline in 
tumor size at 
24 weeks and 
56 weeks
!
Best percentage 
change from baseline 
in tumor size
!
TDT
!
Overall survival
!
DCR at 56 weeks 
!
DoR based on 
RECIST 1.1
!
PFS based on 
RECIST 1.1
!
ORR (CR+PR) 
based on 
RECIST 1.1 
assessed by the 
Investigator
!
Percentage change 
from baseline in 
tumor size at 
24 weeks and 
56 weeks
!
Best percentage 
change from 
baseline in tumor 
size
!
TDT
!
Overall survival
To determine plasma 
concentrations of olaparib 
after single and multiple 
dosing when given orally to 
patients alone and in 
combination with 
MEDI4736±bevacizumab. 
To characterize the PK, 
immunogenicity and 
pharmacodynamics of 
MEDI4736 after single 
dosing and multiple dosing 
when given intravenously 
to patients in combination 
with olaparib±bevacizumab
!
Serum 
concentrations of 
MEDI4736, 
MEDI4736 
anti-drug 
antibody (ADA).  
Plasma 
concentrations of 
olaparib
!
Presence of 
ADAs for 
MEDI4736
!
!
Serum 
concentrations of 
MEDI4736, 
MEDI4736 anti-drug 
antibody (ADA).  
Plasma 
concentrations of 
olaparib
!
Presence of ADAs 
for MEDI4736
!
Serum 
concentrations of 
MEDI4736, 
MEDI4736 
anti-drug antibody 
(ADA).  Plasma 
concentrations of 
olaparib
!
Presence of ADAs 
for MEDI4736
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Secondary Objectives
Outcome Measures
Initial Stage Cohorts
Second Stage Cohorts
BRCAm ovarian cancer 
expansion cohort
Ovarian cancer triplet 
and doublet cohorts
To characterize the PK and 
pharmacodynamics of 
bevacizumab after single 
dosing and multiple dosing 
when given intravenously 
to patients in combination 
with MEDI4736 and 
olaparib
NA
NA
Triplet cohort only:
!
Serum 
concentrations of 
bevacizumab
 
 
 
 
ADA=anti-drug antibody; BRCAm=Mutated breast cancer susceptibility gene; CR=complete response; 
DCR=disease control rate; DoR=duration of response; NA=not applicable; ORR=objective response rate; 
PFS=progression-free survival; PK=pharmacokinetic; PR=partial response; 
RECIST=Response Evaluation Criteria in Solid Tumors;
; 
TDT=time to study treatment discontinuation.
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2.3
Exploratory objectives  
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ADA=anti-drug antibody; BRCAm=Mutated breast cancer susceptibility gene; HLA-DR=human leukocyte 
antigen – antigen D related; NA=not applicable; Pd=pharmacodynamic; PD-1=programmed cell death-1; 
PK=pharmacokinetic; 
; 
VEGF=vascular endothelial growth factor.
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient enrolled should meet all of the inclusion criteria and none of the exclusion 
criteria for this study.  Under no circumstances can there be exceptions to this rule.  Patients 
can be rescreened once as described in Section 3.10.1.
3.1
Inclusion criteria
Inclusion criteria are presented separately for each cohort in: 
!
Initial Stage Cohorts (enrollment is complete): Module 1 (SCLC cohort), Module 2
(gBRCAm breast cancer cohort), Module 3 (gBRCAm ovarian cancer cohort), and
Module 4 (gastric cancer cohort)
!
Second Stage Cohorts: Module 5 (BRCAm ovarian cancer expansion cohort), Module 6
(ovarian cancer triplet cohort), and Module 7 (ovarian cancer doublet cohort)
3.2
Exclusion criteria
Exclusion criteria are presented separately for each cohort in:
!
Initial Stage Cohorts (enrollment is complete): Module 1 (SCLC cohort), Module 2
(gBRCAm breast cancer cohort), Module 3 (gBRCAm ovarian cancer cohort), and 
Module 4 (gastric cancer cohort)
!
Second Stage Cohorts: Module 5 (BRCAm ovarian cancer expansion cohort), Module 6
(ovarian cancer triplet cohort), and Module 7 (ovarian cancer doublet cohort)
For details on the procedures for withdrawal of incorrectly enrolled patients see Section 3.4 of 
the Core Protocol.
3.3
Patient enrollment
Investigator(s) should keep a record, the patient screening log, of patients who entered 
pre-study screening.
The Investigator(s) will:
1. Obtain signed informed consent from the potential patient before any study specific 
procedures are performed.
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2. Obtain a unique 7-digit enrollment code (E-code), through the Interactive Voice Response 
System (IVRS)/Interactive Web Response System (IWRS).  This number is the patient’s 
unique identifier and is used to identify the patient on the electronic case report forms 
(eCRFs).
3. Determine patient eligibility. See Sections 3.1 and 3.2 of each Module (Appendix H to
Appendix N).
4. Obtain signed informed consent if patient is participating in the genetic research study.
Patient eligibility will be established before treatment.  If a patient discontinues participation 
in the study, then their E-code cannot be reused.  Patients re-enrolled after rescreening will be 
assigned a new E-code (see Section 3.10.1).
3.4
Procedures for handling incorrectly enrolled patients
Patients 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.  Patients 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 as screen failures.
Where a patient does not meet all the eligibility criteria but is incorrectly started on treatment, 
the Investigator should inform the AstraZeneca study physician immediately, and a discussion 
should occur between the AstraZeneca study physician and the Investigator regarding whether 
to continue or discontinue the patient from treatment. The AstraZeneca study physician must 
ensure all decisions are appropriately documented.
3.5
Methods for assigning treatment groups
3.5.1
Initial Stage Cohorts
The 4 exploratory Initial Stage Cohorts will include patients with metastatic or recurrent solid 
tumors, selected based on a rationale for response to olaparib.
Each cohort (tumor types for each cohort are defined in the cohort-specific Inclusion Criteria 
in Modules 1 to 4 [Appendix H to Appendix K]) has 10 patients to be enrolled in the initial 
exploratory phase and a possible maximum size as follows:

gBRCAm ovarian cancer: maximum sample size of 31 patients 

gBRCAm metastatic HER2-negative breast cancer: maximum sample size of 30 patients

Relapsed SCLC: maximum sample size of 38 patients

Gastric cancer: maximum sample size of 34 patients
These cohorts are also depicted in Figure 2.

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3.5.2
Second Stage Cohorts
The 3 Second Stage Cohorts will include patients with metastatic or recurrent solid tumors
(tumor types for each cohort are defined in the cohort-specific Inclusion Criteria in Section 3.1
of Module 5 [BRCAm ovarian cancer expansion cohort], Section 3.1 of Module 6 [ovarian 
cancer triplet cohort], and Section 3.1 of Module 7 [ovarian cancer doublet cohort]), selected 
based on a rationale for response to olaparib in combination with MEDI4736.
Appendix O shows how patients will be assigned to the 3 Second Stage Cohorts based on 
prior knowledge and on-study testing of their BRCA status.  Section 4.1 describes the 
Screening process for the Second Stage Cohorts. 
Each cohort will have a target sample size as follows:

BRCAm PSR ovarian cancer (BRCAm ovarian cancer expansion cohort): 80 patients

Non BRCAm PSR ovarian cancer (ovarian cancer triplet cohort): 30 patients

Non BRCAm PSR ovarian cancer (ovarian cancer doublet cohort): 30 patients
Enrollment in the doublet cohort did not start until enrollment in the triplet cohort was 
completed.  Enrollment in the Second Stage Cohorts has been completed; enrollment of the 
BRCAm ovarian cancer expansion cohort was terminated when 51 of 80 planned patients had 
been enrolled as described in Section 1.4.2.
3.6
Methods for ensuring blinding
Not applicable.  This is an open-label, unblinded study.
3.7
Methods for unblinding
Not applicable.  This is an open-label, unblinded study.
3.8
Restrictions
The following restrictions apply while the patient is receiving study treatment (both 
combination treatment and during olaparib monotherapy) and for the specified times before 
and after:
1.
Female patients of childbearing potential:

Females of childbearing potential who are not abstinent and intend to be 
sexually active with a non-sterilized male partner must use at least 
1 highly effective form of birth control (see list below) and their partners 
must use a male condom. This should be started from the screening 
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and for at least 90 days months after last dose of MEDI4736 and/or 
olaparib (for at least 6 months after last dose of bevacizumab, whichever 
is longer [Module 6 only]).  

Non-sterilized male partners of a woman of childbearing potential must 
use a male condom plus spermicide (condom alone in countries where 
spermicides are not approved) throughout this period. Cessation of birth 
control after this point should be discussed with a responsible physician. 
Periodic abstinence, the rhythm method, and the withdrawal method are 
not acceptable methods of contraception. Total sexual abstinence is an 
acceptable method provided it is the usual lifestyle of the participant.  
Female patients should refrain from breastfeeding throughout this period.  
2.
Male patients:

Non-sterilised male participants (including males sterilised by a method 
other than bilateral orchidectomy, eg, vasectomy) who intend to be 
sexually active with a female partner of childbearing potential must be
using an acceptable method of contraception such as a male condom plus 
spermicide (or a condom alone in countries where spermicides are not 
approved) from the screening period and continuing throughout the 
period of taking study treatment and for at least 90 days after last dose 
of MEDI4736 and/or olaparib (for at least 6 months after last dose of 
bevacizumab, whichever is longer [Module 6 only]) to prevent pregnancy 
in a partner.

Periodic abstinence, the rhythm method, and the withdrawal method are 
not acceptable methods of contraception. Male patients should refrain 
from sperm donation throughout this period.

Vasectomised (ie, sterile) males are considered fertile and should still use 
a male condom plus spermicide as indicated above during the clinical 
study.

Male patients must use a condom plus spermicide (where approved) 
throughout this period when having sexual intercourse with a pregnant 
woman or with a woman of childbearing potential.

Female partners (of childbearing potential) of male patients must also use 
a highly effective method of contraception (see list below) throughout 
this period.
Females of childbearing potential are defined as those who are not surgically sterile (ie, 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal.  

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Women will be considered post-menopausal if they have been amenorrhoeic for 12 months 
without an alternative medical cause. The following age-specific requirements apply:

Women < 50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy and if they have luteinizing hormone and follicle-stimulating hormone levels in 
the post-menopausal range for the institution.

Women ≥ 50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy, or had radiation-induced menopause with last menses > 1 year ago, or had 
chemotherapy-induced menopause with last menses > 1 year ago.
Highly Effective Methods of Contraception
Highly effective methods of contraception, defined as one that results in a low failure rate (ie, 
less than 1% per year) when used consistently and correctly, are described in the list below. 
Note that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills).
Non-hormonal Highly Effective Methods of Contraception (< 1% failure rate): 

Total/True abstinence: When the patient 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 3 months after last dose of MEDI4736 and/or 
olaparib (for at least 6 months after last dose of bevacizumab [Module 6 only]). 

Vasectomized sexual partner PLUS male condom (with participant assurance that 
partner received post-vasectomy confirmation of azoospermia).

Tubal occlusion PLUS male condom 

IUD PLUS male condom.  Provided coils are copper-banded
Hormonal Highly Effective Methods of Contraception (< 1% failure rate):

Combined pill PLUS male condom: Normal and low dose combined oral pills.

Mini pill PLUS male condom: Progesterone based oral contraceptive pill using 
desogestrel: Cerazette (Merck Sharp & Dohme) is currently the only highly efficacious 
progesterone based pill available.

Hormonal shot or injection PLUS male condom: Medroxyprogesterone injection 
(eg, Depo-Provera, Pfizer).

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
Implants PLUS male condom: Etonogestrel-releasing implants (eg, Nexplanon, Merck 
Sharp & Dohme) 

Patch PLUS male condom: Norelgestromin / ethinyl estradiol transdermal system (eg, 
Xulane)

Levonorgestrel-releasing Intrauterine system PLUS male condom (eg, Mirena, Bayer])

Intravaginal devices PLUS male condom: (eg, ethinyl estradiol/etonogestrel-releasing 
intravaginal devices such as NuvaRing, Merck Sharp & Dohme)
In addition, the following conditions apply from screening through 90 days after receipt 
of the final dose of IP:

All patients: Patients should not donate blood while participating in this study and for 
90 days following the last dose of study treatment. 
Restrictions relating to concomitant medications are described in Section 7.7.
3.8.1
Olaparib and CYP3A4

Patients should avoid concomitant use of drugs, herbal supplements and/or ingestion of 
foods known to modulate Cytochrome P450 (CYP)3A4 enzyme activity (see Section 7.7) 
from the time they enter the screening period until 30 days after the last dose of study 
medication.

It is prohibited to consume grapefruit juice while on olaparib therapy.
3.9
Discontinuation of investigational product
Patients may be discontinued from investigational product (IP) in the following situations:

Withdrawal of consent from further treatment with IP:  The patient is, at any time, free to 
discontinue treatment, without prejudice to further treatment.  A patient who discontinues 
treatment is normally expected to continue to participate in the study unless they 
specifically withdraw their consent to further participation in any study procedures and 
assessments (see Section 3.10.2). 

An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing

Any AE that meets criteria for discontinuation as defined in Section 6.

Pregnancy or the intent to become pregnant

Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from study treatment (eg, refusal to adhere to scheduled 
visits)

Initiation of alternative anticancer therapy including another investigational agent

Bone marrow findings consistent with MDS/acute myeloid leukemia (AML)

Objective radiological disease progression according to RECIST 1.1 (unless in the 
Investigator’s opinion the patient is benefitting from the treatment and does not meet any 
other discontinuation criteria as outlined in this section).

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NOTE (for Initial Stage Cohorts only): Clinically stable patients, with objective 
radiological disease progression identified after olaparib monotherapy has started but 
before receiving combination therapy, may start combination therapy if the Investigator
believes they may derive benefit from study therapy. These patients should be scanned at 
12 weeks (8 weeks after start of combination therapy).

Patient is determined to have met 1 or more of the exclusion criteria for study participation 
at study entry and continuing the IP might constitute a safety risk.

An AE related to IP that is ≥Grade 3, with the exception of toxicities that do not meet 
criteria for discontinuation, as defined in Section 6.8.

≥Grade 3 infusion reaction.
3.9.1
Procedures for discontinuation of a patient from investigational product 
At any time, patients are free to discontinue IP or withdraw from the study (ie, IP and 
assessments – see Section 3.10), without prejudice to further treatment.  When a patient 
discontinues treatment for reasons other than disease progression, the AstraZeneca study 
physician should be informed immediately.  A patient that decides to discontinue IP 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).  All AEs will be followed up (see Section 6); all IP 
should be returned by the patient.
By discontinuing from treatment, the patient is not withdrawing from the study.  Patients 
should be followed for progression (if discontinuation in the absence of progression), OS, and 
subsequent anticancer treatment following treatment discontinuation as per the protocol 
schedule.  If a patient is withdrawn from study, see Section 3.10.
Any patient discontinuing IP should be seen at 30 days post-discontinuation for the 
evaluations outlined in the study schedule (see Section 4 of each cohort: SCLC cohort
[Module 1], gBRCAm breast cancer cohort [Module 2], gBRCAm ovarian cancer cohort
[Module 3], gastric cancer cohort [Module 4], BRCAm ovarian cancer expansion cohort
[Module 5], ovarian cancer triplet cohort [Module 6], and ovarian cancer doublet cohort
[Module 7]). 
The patient’s tumor status should be assessed clinically.  After discontinuation of IP, the 
PI/Sub-Investigator will perform the best possible observation(s), test(s) and evaluation(s) as 
well as give appropriate medication and all possible measures for the safety of the patient.  In 
addition, they will record on the eCRF the date of discontinuation, the reasons, manifestation 
and treatment at the time of discontinuation.  If patients discontinue IP, the AstraZeneca 
monitor must be informed immediately.  Patients will be required to attend the treatment 
discontinuation visit.  The patient should return all IP.

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After discontinuation of the IP at any point in the study, all ongoing AEs or SAEs must be 
followed until resolution unless, in the Investigator’s opinion the condition is unlikely to 
resolve due to the patients underlying disease, or the patient is lost to follow-up (see 
Section 6.3.2).  All new AEs and SAEs occurring during the 90 calendar days after the last 
dose of IP must be reported (if SAEs, they must be reported to AstraZeneca within 24 hours as 
described in Section 6.4) and followed to resolution as above.  Patients should be seen at least 
30 days after discontinuing IP to collect and/or complete AE information.  For guidance on 
reporting AEs after the 90-day follow-up period see Section 6.3.3.
Any patient who has not yet shown objective radiological disease progression at withdrawal 
from IP should continue to be followed as per RECIST 1.1 as detailed in Section 5.1.2.
Patients who are permanently discontinued from receipt of IP should also be discontinued in 
IVRS/IWRS.
All patients will be followed for disease progression and survival until the cohort data cut-off, 
and may be followed for survival, selected safety, investigational product 
dispensing/accountability, and subsequent anticancer treatment data after the cohort data 
cut-off (see Section 9.3 for full details).
3.10
Criteria for withdrawal 
Reasons for withdrawal of a patient from the study include:

Voluntary withdrawal by the patient (all patients are free at any time to discontinue their 
participation in the study, without prejudice to further treatment)

Incorrectly enrolled patients, ie, the patient does not meet the required inclusion/exclusion 
criteria for the study

Patient is lost to follow-up

Death
NOTE: If a patient withdraws consent, they will be specifically asked if they are withdrawing 
consent to:

further participation in the study including any further follow-up (eg, survival calls) 

the use of their study-generated data

withdrawal to the use of any samples (see Section 5.5.7)
3.10.1
Screen failures 
Screen failures are patients who do not fulfill the eligibility criteria for the study and therefore 
must not be assigned to treatment.  These patients should have the reason for study withdrawal 

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recorded as ‘Incorrect Enrollment’ (ie, patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for screen failures (not enrolled 
patients).
Patients who were enrolled, screened but not dosed (ie, withdrew from the study prior to 
dosing) may be re-enrolled and re-screened once if, in the opinion of the Investigator, and 
with the agreement of the Study Physician, the reason(s) for earlier withdrawal no longer 
applies.  Patients cannot re-enter the study if dosed and subsequently withdrawn from the 
study.  Patients re-enrolled after rescreening will be assigned a new E-code. 
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.
Patients who withdraw consent for further participation in the study will not receive any 
further IP or further study observation, with the exception of follow-up for survival, which 
will continue until the end of the study unless the patient has expressly withdrawn his or her 
consent to survival follow-up.  Note that the patient may be offered additional tests or tapering 
of treatment to withdraw safely.
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and 
the presence of any AE(s).  The Investigator will follow-up AEs outside of the clinical study.  
If a patient withdraws from participation in the study, then his or her patient identification 
number cannot be reused.  Withdrawn patients will not be replaced.
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed, such that there is insufficient information to determine the 
patient’s status at that time.  Patients who refuse to continue participation in the study, 
including telephone contact, should be documented as “withdrawal of consent” rather than 
“lost to follow-up.”  Investigators should document attempts to re-establish contact with 
missing patients throughout the study period.  If contact with a missing patient is 
re-established, the patient should not be considered lost to follow-up and any evaluations 
should resume according to the protocol.
The vital status of ongoing, withdrawn (from the study) and “lost to follow-up” patients at the 
time of the final analysis for each cohort should be obtained by the site personnel by checking 
the patient notes, hospital records, contacting the patient’s general practitioner and checking 

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publicly available death registries.  In the event that the patient has actively withdrawn 
consent to the processing of their personal data, the vital status of the patient can be obtained 
by site personnel from publicly available resources where it is possible to do so under 
applicable local laws.
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, study patients 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 patient at the time of 
discontinuation of follow-up must be recorded in the eCRF.  All reasons for discontinuation of 
treatment must be documented.
In terminating the study, AstraZeneca will ensure that adequate consideration is given to the 
protection of the patients’ interests.
4.
STUDY PLAN AND TIMING OF PROCEDURES 
The procedures for the screening period (and the 4-week run-in treatment period with olaparib
[Initial Stage Cohorts only]), the combination therapy treatment period, and after a patient has 
completed combination therapy or is discontinued early from treatment are presented in 
Section 4 of each Module (Appendix H to Appendix N).  
Links to the schedules of assessments for Screening (with run-in for Initial Stage Cohorts), 
combination treatment, and after treatment completion/early discontinuation are presented 
below for each Module to allow easy navigation of the document. 
Initial Stage Cohorts (advanced solid tumors)
SCLC cohort 
(Module 1)
Screening and 
run-in: Table 2
Combination therapy 
treatment period: Table 3
After treatmenta: 
Table 4
gBRCAm breast cancer cohort 
(Module 2)
Screening and 
run-in: Table 2
Combination therapy 
treatment period: Table 3
After treatmenta:
Table 4
gBRCAm ovarian cancer cohort 
(Module 3)
Screening and 
run-in: Table 2
Combination therapy 
treatment period: Table 3
After treatmenta:
Table 4
Gastric cancer cohort 
(Module 4)
Screening and 
run-in: Table 2
Combination therapy 
treatment period: Table 3
After treatmenta:
Table 4

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Second Stage Cohorts (ovarian cancer)
BRCAm ovarian cancer expansion cohort 
(Module 5)
Screening:
Table 2
Combination therapy 
treatment period: Table 3
After treatmenta:
Table 4
Ovarian cancer triplet cohort 
(Module 6)
Screening:
Table 2
Combination therapy 
treatment period: Table 3
After treatmenta:
Table 4
Ovarian cancer doublet cohort 
(Module 7)
Screening:
Table 2
Combination therapy 
treatment period: Table 3
After treatmenta:
Table 4
a
Completed combination therapy or is discontinued early from treatment.
Patients can continue to receive study treatment beyond the period specified in each Module, 
as described in Section 4.2.4.
4.1
Enrollment/screening period
The screening period will be up to 28 days for the Initial and Second Stage cohorts.  For all 
cohorts, if all screening procedures are completed and eligibility confirmed earlier than this, 
the screening period can be concluded early as appropriate.  Note that in all cohorts the 
baseline tumor assessment scan should always be within 28 days prior to Cycle 1 Day 1, 
independent of the duration of screening.  Similarly, for female patients of childbearing 
potential, a pregnancy test should be taken within 28 days prior to Cycle 1 Day in all cohorts.
All screening and enrollment procedures will be performed according to the assessment 
schedule presented in Section 4 of each of the Modules (SCLC cohort, gBRCAm breast cancer 
cohort, gBRCAm ovarian cancer cohort, gastric cancer cohort, BRCAm ovarian cancer 
expansion cohort, ovarian cancer triplet cohort, and ovarian cancer doublet cohort).  
Demographic data and other characteristics will be recorded including date of birth or age, 
gender, smoking history, and race/ethnicity, according to local regulations.  A standard 
medical and surgical history will be obtained.  For gastric cancer patients, the history must 
include whether they have had partial or full gastrectomy.
Written informed consent and any locally required privacy act document authorization must 
be obtained prior to performing any protocol-specific procedures, including screening/baseline 
evaluations.  All patients will be required to provide consent to supply an archival tumor 
sample (not more than 3 years old) for entry into this study.  This consent is included in the 
main patient ICF.  Ovarian cancer patients in the Second Stage Cohorts are exempt from 
provision of a new biopsy sample even when/even if the archival tumor sample is more than 
3 years old.
All patients should be consented to the study within 28 days prior to Day 1 of the first dose of 
study drug therapy.

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Screening/baseline evaluations may be performed over more than 1 visit.
For Second Stage Cohorts, the process by which BRCA testing should be performed to 
allocate patients to the correct cohort according to their BRCA status is described in 
Appendix O.  Note that enrollment for the ovarian cancer doublet cohort will commence after 
enrollment is filled for the ovarian cancer triplet cohort.  Enrollment for the BRCAm ovarian 
cancer expansion and ovarian cancer triplet cohorts will be concurrent. 
The timing of vital sign assessments should be such that it allows the blood draw (eg, 
PK blood sample) to occur at the timepoints indicated in Section 5.3 of each of the Modules 
(Appendix H to Appendix N).
At screening, consenting patients are assessed to ensure that they meet eligibility criteria. 
Patients who do not meet these criteria must not be enrolled in the study.
4.2
Treatment period
All procedures to be conducted during the treatment period will be performed according to the 
assessment schedule presented in Section 4 of each of the Modules (SCLC cohort, gBRCAm
breast cancer cohort, gBRCAm ovarian cancer cohort, gastric cancer cohort, BRCAm ovarian 
cancer expansion cohort, ovarian cancer triplet cohort, and ovarian cancer doublet cohort).
Whenever vital signs and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: vital signs and then blood draws.  The timing 
of the vital signs assessments should be such that it allows the blood draw (eg, PK blood 
sample) to occur at the timepoints indicated in in Section 5.3 of each of the Modules (SCLC 
cohort, gBRCAm breast cancer cohort, gBRCAm ovarian cancer cohort, gastric cancer cohort, 
BRCAm ovarian cancer expansion cohort, ovarian cancer triplet cohort, and ovarian cancer 
doublet cohort).
4.2.1
Dosing regimen
In the Initial Stage Cohorts, there will be an initial 4-week period of monotherapy treatment 
with olaparib beginning on Week 1, Day 1 (monotherapy) before starting MEDI4736 on 
Cycle 1 Day 1 (combination therapy), in order for olaparib to induce changes in the tumor 
microenvironment as a result of DNA damage and cell death with release of potential 
immunogenic antigens.  This 4-week period (28 days) represents a set period and the planned 
visit schedule must not be adjusted regardless of the number of missed olaparib doses.

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In the Second Stage Cohorts, the study drugs (MEDI4736+olaparib, or 
MEDI4736+olaparib+bevacizumab) will initiate concurrently on Cycle 1, Day 1 without the 
4-week period of olaparib monotherapy.
Patients will be administered study olaparib treatment orally at a dose of 300 mg bid.  The 
initial dose of 300 mg bid will be made up of 2×150 mg tablets bid.  The 100 mg and 150 mg 
tablets will be used to manage dose reductions.
MEDI4736 dose selection is discussed in Section 1.2.3.2.  Patients will receive MEDI4736 
1.5 g via IV infusion Q4W ±3 days.  Treatment with MEDI4736 will commence on Cycle 1 
Day 1 concurrently with olaparib and will continue on a Q4W schedule until objective 
radiological disease progression as per RECIST 1.1 as assessed by the Investigator or as long 
as, in the Investigator’s opinion, they are benefitting from treatment and they do not meet any 
other discontinuation criteria. 
In the ovarian cancer triplet cohort (Module 6; Appendix M), patients will be administered 
bevacizumab in line with normal clinical practice, with a dose and schedule of 10 mg/kg of 
body weight Q2W ±3 days.  Treatment with bevacizumab will commence on Cycle 1, Day 1 
following administration of olaparib and MEDI4736 therapy.  Bevacizumab will continue on a 
Q2W schedule until objective radiological disease progression as per RECIST 1.1 as assessed 
by the Investigator or as long as, in the Investigator’s opinion, they are benefitting from 
treatment and they do not meet any other discontinuation criteria.
Refer to Section 7.2 of the Core Protocol for additional details on IP administration.
4.2.2
Definition of evaluable patient
An evaluable patient is defined as a patient who has received at least 1 dose of study treatment 
and has not been excluded from the study for administrative reasons, eg, failing important 
inclusion criteria (a full list will be predefined in the Statistical Analysis Plan).
4.2.3
Dose modifications
Please refer to Section 6.8 for details on dose modifications during the treatment period in the 
event of IP-related toxicities.
4.2.4
Duration of therapy
There is no maximum duration for taking study treatment with olaparib.  Patients should 
continue to receive combination treatment until objective radiological disease progression per 

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RECIST 1.1, as assessed by the Investigator or as long as, in the Investigator’s opinion, they 
are benefitting from treatment and they do not meet any other discontinuation criteria.
In the Initial Stage Cohorts, clinically stable patients, with objective radiological disease 
progression identified after olaparib monotherapy has started but before receiving 
combination therapy, may start combination therapy if the Investigator believes they may
derive benefit from study therapy.
After discontinuation of study treatment, the Investigator will be at liberty to define further 
most appropriate anticancer treatment.  All patients will be followed for disease progression 
and survival until the cohort data cut-off, and may be followed for survival, selected safety, 
investigational product dispensing/accountability, and subsequent anticancer treatment data 
after the cohort data cut-off (see Section 9.3 for full details).
4.3
Follow-up period
All procedures to be conducted during the follow-up period will be performed according to 
the assessment schedule presented in Section 4 of each of the Modules
(Appendix H to Appendix N).
Whenever vital signs, electrocardiograms (ECGs), and blood draws are scheduled for the 
same nominal time, the assessments should occur in the following order: ECG, vital signs, and 
then blood draws.  The timing of the first 2 assessments should be such that it allows the blood 
draw (eg, PK blood sample) to occur at the timepoints indicated in Section 5.3 of each of the 
Modules (SCLC cohort, gBRCAm breast cancer cohort, gBRCAm ovarian cancer cohort, 
gastric cancer cohort, BRCAm ovarian cancer expansion cohort, ovarian cancer triplet cohort,
and ovarian cancer doublet cohort).
5.
STUDY ASSESSMENTS  
The Web Based Data Capture (WBDC) 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 ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA).  
The Investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be 
archived at the study site.

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5.1
Efficacy assessments
5.1.1
Tumor assessments by CT or MRI scans
At baseline, the imaging modalities used for assessment should be contrast enhanced 
computed tomography (CT) (magnetic resonance imaging [MRI] where CT is 
contraindicated) scans of the chest, abdomen and pelvis with other regions as clinically 
indicated for the assessment of disease.  Follow-up CT or MRI assessments will cover chest 
(in those patients with disease in the chest or upper abdomen lymphadenopathy at baseline), 
abdomen and pelvis with any other regions imaged at baseline where disease was present.  
Any other sites at which new disease is suspected should also be appropriately imaged.
Radiological examinations performed in the conduct of this study should be retained at site as 
source data.
All treatment decisions will be based on site assessment of scans.  
In the Initial Stage Cohorts, the baseline scan must be performed at screening unless obtained 
within 28 days prior to first dose of olaparib.  Following the baseline tumor assessment, the 
next tumor assessment will be 4 weeks after the first olaparib monotherapy dose and prior to 
the start if the combination therapy and then all subsequent tumor assessments should be 
performed every 8 weeks (±1 week) relative to the date of start of combination therapy, up to 
objective radiological disease progression as defined by RECIST 1.1, and as determined by 
the Investigator.  Patients with objective radiological disease progression identified after 
olaparib monotherapy has started but before receiving combination therapy, who start 
combination therapy (see Section 3.9) should be scanned at 12 weeks (8 weeks after start of 
combination therapy).
In the Second Stage Cohorts, the baseline scan must be performed at screening unless 
obtained within 28 days prior to first dose of study treatment.  Following the baseline tumor 
assessment, the next tumor assessment will be 8 weeks after the first study treatment dose and 
then all subsequent tumor assessments should be performed every 8 weeks (±1 week) relative 
to the date of start of study treatment, up to objective radiological disease progression as 
defined by RECIST 1.1, and as determined by the Investigator.  
If a patient discontinues treatment (and/or receives a subsequent cancer therapy) prior to 
progression then the patient should still continue to be followed until objective disease 
progression as defined by RECIST 1.1.  Imaging assessments are required for patients who 
continue receiving the study drug combination beyond disease progression.  

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It is important to follow the assessment schedule as closely as possible.  If scans are 
performed outside of scheduled visit ±1-week window interval and the patient has not 
experienced disease progression, every attempt should be made to perform the subsequent 
scans at their scheduled timepoints.
5.1.2
Tumor evaluation
RECIST 1.1 will be used to assess patient response to treatment, as assessed by the 
Investigator.  The RECIST 1.1 guidelines for measurable, non-measurable, target and 
non-target lesions (TL and NTL) and the objective tumor response criteria (CR, PR, SD or 
PD) are presented in Appendix E (Eisenhauer et al 2009). 
Categorization of objective tumor response assessment will be based on the RECIST 1.1 
criteria of response: CR, PR, SD and PD.  Target lesion progression will be calculated in 
comparison to when the tumor burden was at a minimum (ie, smallest sum of diameters 
previously recorded on study).  In the absence of progression, tumor response (CR, PR, SD) 
will be calculated in comparison to the baseline tumor measurements obtained before starting 
treatment.  
If the Investigator is in doubt as to whether progression has occurred, particularly with 
response to NTL 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 tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of 1 or more NTLs is usually not 
sufficient to qualify for unequivocal progression status.
5.2
Safety assessments
The total volume of blood that will be drawn from each patient is summarized in Section 5.2 
of Modules 1 to 7 (Appendix H to Appendix N).
5.2.1
Laboratory safety assessments
Blood samples for determination of clinical chemistry and hematology will be taken at the 
times indicated in the assessment schedules and as clinically indicated (see Section 4 of each 
cohort: SCLC cohort [Module 1], gBRCAm breast cancer cohort [Module 2], gBRCAm

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ovarian cancer cohort [Module 3], gastric cancer cohort [Module 4], BRCAm ovarian cancer 
expansion cohort [Module 5], ovarian cancer triplet cohort [Module 6], and ovarian cancer 
doublet cohort [Module 7]).  Additional safety samples may be collected if clinically indicated 
at the discretion of the Investigator.  The date, time of collection and results (values, units, 
levels, and reference ranges) will be recorded on the appropriate eCRF.
All clinical laboratory safety tests, including serum pregnancy tests, will be performed at a 
local laboratory at or near the investigational site.  Local laboratory results can be used for 
clinical decision making. Should these results be contradicted by central laboratory results 
(when obtained), relevant sampling and tests should be repeated.  Sample tubes and sample 
sizes may vary depending on the laboratory method used and routine practice at the site.  
Urine pregnancy tests may be performed at the site using a licensed test (urine or serum 
pregnancy test).  Abnormal clinically significant laboratory results should be repeated as soon 
as possible (preferably within 24 to 48 hours).  
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with TBL ≥2 × ULN may need to be 
reported as SAEs.  Please refer to Appendix D for further instructions on cases of increases in 
liver biochemistry and evaluation of Hy’s Law.
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.  Situations in which laboratory 
safety results should be reported as AEs are described in Section 6.3.
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from study treatment must have further tests performed until the laboratory values have 
returned to Grade 1 or 2, unless these values are not likely to improve because of the 
underlying disease.
Pregnancy tests on either urine (human chorionic gonadotropin [hCG]) or blood (serum 
β-hCG) samples will be performed for pre-menopausal women of childbearing potential as 
specified in the assessment schedule (see Section 4 of each cohort: SCLC cohort [Module 1], 
gBRCAm breast cancer cohort [Module 2], gBRCAm ovarian cancer cohort [Module 3], gastric 
cancer cohort [Module 4], BRCAm ovarian cancer expansion cohort [Module 5], ovarian 
cancer triplet cohort [Module 6], and ovarian cancer doublet cohort [Module 7]).  Tests will be 
performed by the hospital’s local laboratory.  If results are positive, the patient must not start 

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or continue treatment.  In the event of a suspected pregnancy during the study, the test should 
be repeated.  Details of the pregnancy tests must be recorded in the patient’s medical records.
Other safety tests to be performed include assessment for hepatitis B surface antigen, 
hepatitis C antibodies, hepatitis C viral load (for patients with history of hepatitis C only), 
HIV antibodies, thyroid-stimulating hormone (TSH), free tri-iodothyronine (T3), and free 
thyroxine (T4).  Free T3 or free T4 will only be measured if TSH is abnormal or if there is a 
clinical suspicion of an AE related to the endocrine system.
The laboratory variables to be measured are presented in Sections 5.2.1.1 (hematology), 
5.2.1.2 (coagulation), and 5.2.1.3 (clinical chemistry).
5.2.1.1
Hematology
The following hematology variables will be measured:
Hb
Mean cell hemoglobin
Hematocrit
White blood cell count
Platelets
Absolute differential white cell count
Mean cell volume
Neutrophils, lymphocytes, monocytes, eosinophils and 
basophils and absolute neutrophil count or segmented 
neutrophil count and Band forms should be performed at 
each visit and when clinically indicated.  If absolute 
differentials are not available % differentials should be 
provided.
5.2.1.2
Coagulation
The following coagulation variables will be measured:

Activated partial thromboplastin time (APTT) will be performed at screening and if 
clinically indicated  

International normalized ratio (INR) will be performed at screening and if clinically 
indicated, unless the patient is receiving warfarin.  Patients taking warfarin may participate 
in this study; however, it is recommended that prothrombin time (INR and APTT) be 
monitored carefully at least once per week for the first month, then monthly if the INR is 
stable. 
All coagulation test results will be recorded in the eCRF.

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5.2.1.3
Clinical chemistry
The following clinical chemistry parameters will be measured:
Sodium
Lipase
Potassium
Alkaline phosphatase
Calcium
Bicarbonate
Chloride
AST
Magnesium
ALT
Creatinine
Amylase
Total bilirubin a
Urea or blood urea nitrogen
Gamma glutamyltransferase b
Uric acid
Glucose
Total protein
Lactate dehydrogenase
Albumin
a
If total bilirubin is ≥2×ULN (and evidence of Gilbert’s syndrome) then fractionate into 
direct and indirect bilirubin
b
At baseline and as clinically indicated
5.2.1.4
Disease specific tumor marker samples (CA-125)
As part of the routine safety blood samples, cancer antigen-125 (CA-125) will be measured in 
the ovarian cancer cohorts only (see Module 3 [Appendix J], Module 5 [Appendix L], 
Module 6 [Appendix M], and Module 7 [Appendix N]).  Patients in this cohort will supply a 
2-mL blood sample for the assessment of CA-125 status at the beginning of each 28-day 
period prior to the patient receiving study treatment (see Section 4 of each of the cohorts
specific Modules [gBRCAm ovarian cancer cohort, BRCAm ovarian cancer expansion cohort, 
ovarian cancer triplet cohort, and ovarian cancer doublet cohort]). 
It is important to follow the assessment schedule as closely as possible.  If CA-125 assessment 
is performed outside of scheduled visit ±1-week window interval, every attempt should be 
made to assess the CA-125 at the scheduled timepoints.  Patients will be evaluated until 
objective disease progression, based on progressive serial elevation of serum CA-125 
according to the modified Gynecologic Cancer InterGroup (GCIG) criteria. (NOTE: GCIG
criteria is not validated for this study population).
Further assessment of CA-125 post-serological progression will be at the discretion of the 
Investigator according to local clinical practice.

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5.2.1.5
Urinalysis
Urinalysis will be performed in the ovarian cancer triplet cohort as described in Module 6. 
5.2.1.6
Bone marrow or blood cytogenetic samples
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
hematological toxicities as defined in Section 6.8.2.
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic 
analysis and flow cytometry, and a core biopsy for bone marrow cellularity.  If it is not 
possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then 
attempts should be made to carry out the tests on a blood sample.  Full reports must be 
provided by the Investigator for documentation on the Patient Safety database.  These data are 
not required to be entered into eCRF.
5.2.2
Physical examination
Physical examinations will be performed according to the assessment schedules (see Section 4 
in each cohort-specific Module [SCLC cohort, gBRCAm breast cancer cohort, gBRCAm
ovarian cancer cohort, gastric cancer cohort, BRCAm ovarian cancer expansion cohort, 
ovarian cancer triplet cohort, and ovarian cancer doublet cohort).  Full physical examinations 
will include assessments of the head, eyes, ears, nose, and throat and the respiratory, 
cardiovascular, gastrointestinal (GI), breast, urogenital (not required for breast, gastric and 
small cell lung cancer cohort patients), musculoskeletal (including spine and extremities), 
neurological, dermatological, hematologic/lymphatic, and endocrine systems.  Height will be 
measured at screening only.  Targeted physical examinations are to be utilized by the 
Investigator on the basis of clinical observations and symptomatology.  Situations in which 
physical examination results should be reported as AEs are described in Section 6.3.7.
5.2.3
ECG
Resting 12-lead ECGs will be recorded at screening and on Day 1, and as clinically indicated 
throughout the study (see Section 4 in each cohort-specific Module [SCLC cohort, gBRCAm
breast cancer cohort, gBRCAm ovarian cancer cohort, gastric cancer cohort, BRCAm ovarian 
cancer expansion cohort, ovarian cancer triplet cohort, and ovarian cancer doublet cohort).  
All ECGs should be performed once the patient has rested in the supine position for at least 
5 minutes in each case.  ECGs will be recorded at 25 mm/sec.  
At screening, ECGs will be obtained in triplicate (all 3 within a 5-minute time period, at least 
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On Study Day 1, and at other timepoints as clinically indicated, a single ECG will be 
performed. 
Heart rate, P and QRS durations, PR, QT and QTc intervals will be recorded from standard 
lead of the computerized quantitative 12-lead ECG.
In case of clinically significant ECG abnormalities, including a QTcF value >500 msec, 
2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm 
the finding.  
The Investigator or designated physician will review the paper copies of each of the timed 
12-lead ECGs on each of the study days when they are collected.
All ECGs should be assessed by the Investigator as to whether they are clinically significantly 
abnormal / not clinically significantly abnormal.  If there is a clinically significant abnormal 
finding, the Investigator will record it as an AE on the eCRF.  The original ECG traces must 
be stored in the patient medical record as source data.
Situations in which ECG results should be reported as AEs are described in Section 6.3.7.
5.2.4
Vital signs
Height will be assessed at screening only.
Weight will be assessed according to the Study Schedule (see Section 4 in each 
cohort-specific Module [SCLC cohort, gBRCAm breast cancer cohort, gBRCAm ovarian 
cancer cohort, gastric cancer cohort, BRCAm ovarian cancer expansion cohort, ovarian cancer 
triplet cohort, and ovarian cancer doublet cohort) and as clinically indicated at any other time.
Any changes in vital signs should be recorded as an AE, if applicable.  For information on 
how AEs based on changes in vital signs should be recorded and reported, see Section 6.3.7.
5.2.4.1
Pulse and blood pressure
Vital signs (blood pressure [BP], pulse, temperature, and respiratory rate) will be evaluated 
according to the assessment schedules (see Section 4 in each cohort-specific Module [SCLC 
cohort, gBRCAm breast cancer cohort, gBRCAm ovarian cancer cohort, gastric cancer cohort, 
BRCAm ovarian cancer expansion cohort, ovarian cancer triplet cohort, and ovarian cancer 
doublet cohort]).  

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On infusion days, patients will be monitored during and after infusion of IP as presented in the 
bulleted list below. 
Supine BP will be measured using a semi-automatic BP recording device with an appropriate 
cuff size, after the patient has rested for at least 5 to 10 minutes.  BP and pulse will be 
collected from patients before, during, and after each infusion at the following times (based on 
a 60-minute infusion):

Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [ie, the beginning of the infusion])

Approximately 30 minutes during the infusion (halfway through infusion) 

At the end of the infusion (approximately 60 minutes ±5 minutes)

A 1-hour observation period is recommended after the first infusion of MEDI4736.  If no 
clinically significant infusion reactions are observed during or after the first cycle, 
subsequent infusion observation periods can be at the Investigator’s discretion (suggested 
30 minutes after each MEDI4736 infusion).
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow 
the principles as described above or be taken more frequently if clinically indicated.  The date 
and time of collection and measurement will be recorded on the appropriate eCRF.  Additional 
monitoring with assessment of vital signs is at the discretion of the Investigator per standard 
clinical practice or as clinically indicated.  Any clinically significant changes in vital signs 
should be entered onto an unscheduled vital signs eCRF page.
5.2.4.2
Body temperature
Body temperature will be measured in degrees Celsius according to local practice at the times 
indicated in the Study Schedule (see Section 4 in each cohort-specific Module [SCLC cohort, 
gBRCAm breast cancer cohort, gBRCAm ovarian cancer cohort, gastric cancer cohort, BRCAm
ovarian cancer expansion cohort, ovarian cancer triplet cohort, and ovarian cancer doublet 
cohort).
The date of collection and measurement will be recorded on the appropriate eCRF.
5.2.5
Other safety assessments
5.2.5.1
Serum or urine pregnancy test
Pregnancy tests on blood or urine samples will be performed for women of childbearing 
potential within 28 days prior to the start of study treatment and on Day 1 of the study prior to 
commencing treatment, at the time points shown in the assessment tables during study 
treatment and at the 30-day follow-up visit.  Tests will be performed by the hospital’s local 

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laboratory.  Urine pregnancy tests will be performed at schedule visits as presented in 
Section 4 of each cohort-specific Module (SCLC cohort, gBRCAm breast cancer cohort, 
gBRCAm ovarian cancer cohort, gastric cancer cohort, BRCAm ovarian cancer expansion 
cohort, ovarian cancer triplet cohort, and ovarian cancer doublet cohort) during treatment and 
the 90-day follow-up period. If results are positive the patient is ineligible/must be 
discontinued from study treatment immediately.
5.2.5.2
Performance status
The patient’s performance status will be assessed at screening using the upper limit of normal 
(ECOG) performance status scale (see Section 4 in each cohort-specific Module [SCLC 
cohort, gBRCAm breast cancer cohort, gBRCAm ovarian cancer cohort, gastric cancer cohort, 
BRCAm ovarian cancer expansion cohort, ovarian cancer triplet cohort, and ovarian cancer 
doublet cohort); patients must have an ECOG performance status 0-1 to be eligible for 
enrollment.
During the study, the performance status will be assessed at the timepoints in Section 4 of 
each cohort-specific Module, using the ECOG performance status scales.
5.2.5.3
Pneumonitis/interstitial lung disease
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality 
suggestive of pneumonitis/ILD is observed, toxicity management as described in detail in the 
Dosing Modification and Toxicity Management Guidelines (see Section 6.8.2.2 and 
Section 6.8.4) will be applied. If pneumonitis/ILD is suspected, olaparib treatment should be 
interrupted and prompt investigation initiated. If pneumonitis is confirmed, olaparib treatment 
should be discontinued and the patient treated appropriately, and for MEDI4736 the guidance 
in the toxicity management guidelines (TMGs) should be followed. The results of the full
diagnostic workup (including high-resolution computed tomography [HRCT], blood and 
sputum culture, hematological parameters, etc) will be captured in the eCRF. It is strongly 
recommended to perform a full diagnostic workup, to exclude alternative causes such as 
lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary 
hemorrhage. In the presence of confirmatory HRCT scans where other causes of respiratory 
symptoms have been excluded, a diagnosis of pneumonitis (ILD) should be considered and 
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Pneumonitis (ILD) investigation
The following assessments, and additional assessments if required, will be performed to 
enhance the investigation and diagnosis of potential cases of pneumonitis. The results of the 
assessment will be collected.

Physical examination

Signs and symptoms (cough, shortness of breath, and pyrexia, etc) including 
auscultation for lung field will be assessed.

SpO2

Saturation of peripheral oxygen (SpO2)

Other items

When pneumonitis (ILD) is suspected during study treatment, the following markers 
should be measured where possible:
(i)
ILD Markers (KL-6, SP-D) and β-D-glucan
(ii)
Tumor markers: Particular tumor markers which are related to disease 
progression. 
(iii)
Additional Clinical chemistry: CRP, LDH 
5.3
Pharmacokinetics
5.3.1
Collection of samples and the determination of olaparib concentrations
Blood samples (2.0 mL) will be taken for the determination of olaparib in plasma.  The study 
plans in Section 4 of Modules 1 to 7 (SCLC cohort, gBRCAm breast cancer cohort, gBRCAm
ovarian cancer cohort, gastric cancer cohort, BRCAm ovarian cancer expansion cohort, 
ovarian cancer triplet cohort, and ovarian cancer doublet cohort) present the days on which 
olaparib PK samples will be taken for each cohort.  The details of the sampling times are 
presented in Section 5.3.1 of each Module.  The total volume of blood taken during the study 
for olaparib concentration measures is presented in Section 5.2 of each cohort-specific Module 
(Appendix H to Appendix N).
Samples for determination of olaparib in plasma will be analyzed by Covance on behalf of the 
Clinical Bioanalysis Alliance, AstraZeneca, using an appropriate bioanalytical method.

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Samples will be collected, labeled, stored, and shipped as detailed in the Laboratory Manual.  
Full details of the analytical method used will be described in a separate Bioanalytical 
Validation Report.
5.3.2
Collection of samples and the determination of MEDI4736 concentrations
Blood samples (3.5 mL) will be taken for the determination of MEDI4736 in serum.  The 
study plans in Section 4 of Modules 1 to 7 (SCLC cohort, gBRCAm breast cancer cohort, 
gBRCAm ovarian cancer cohort, gastric cancer cohort, BRCAm ovarian cancer expansion 
cohort, ovarian cancer triplet cohort, and ovarian cancer doublet cohort) present the days on 
which samples will be taken for each cohort.  The details of the sampling times are presented 
in Section 5.3.1 of each Module.  The total volume of blood taken during the study for 
MEDI4736 concentration measures is presented in Section 5.2 of each cohort-specific Module 
(Appendix H to Appendix N).
Samples for determination of MEDI4736 concentrations in serum will be analyzed by a 
designated third party on behalf AstraZeneca/MedImmune, using a validated immunoassay 
using a Meso Scale Discovery platform.
Samples will be collected, labeled, stored, and shipped as detailed in the Laboratory Manual.  
Full details of the analytical method used will be described in a separate Bioanalytical 
Validation Report.
5.3.3
Collection of samples and the determination of bevacizumab concentrations
Assessment of bevacizumab PK will only be performed in the ovarian cancer triplet cohort 
(Module 6; Appendix M). 
Blood samples (3.5 mL) will be taken for the determination of bevacizumab in serum.  The 
study plans in Section 4 of Module 6 (Appendix M) present the days on which samples will be 
taken in the ovarian cancer triplet cohort.  The details of the sampling times are presented in 
Section 5.3.1 of Module 6 (Appendix M).  The total volume of blood taken during the study 
for bevacizumab concentration measures is presented in Section 5.2 of Module 6
(Appendix M).
Samples for determination of bevacizumab concentrations in serum will be analyzed by a 
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Samples will be collected, labeled, stored, and shipped as detailed in the Laboratory Manual.  
Full details of the analytical method used will be described in a separate Bioanalytical 
Validation Report.
5.3.4
Collection of samples to measure the presence of ADAs 
The study plans in Section 4 of Modules 1 to 7 (SCLC cohort, gBRCAm breast cancer cohort, 
gBRCAm ovarian cancer cohort, gastric cancer cohort, BRCAm ovarian cancer expansion 
cohort, ovarian cancer triplet cohort, and ovarian cancer doublet cohort) present the days on 
which samples will be taken for each of the Initial Stage Cohorts.  The details of the sampling 
times are presented in Section 5.3.2 of each Module.  At each timepoint, approximately 
3.5 mL blood will be drawn for detection of MEDI4736 ADAs 
 
Samples will be measured for the presence of MEDI4736 ADAs using validated assays.  
Tiered analysis will be performed to include screening, confirmatory, and titer assay 
components, and positive negative cut points previously statistically determined from 
drug-naïve validation samples will be employed.
Samples will be collected, labeled, stored, and shipped as detailed in the Laboratory Manual.  
Full details of the analytical method used will be described in a separate Bioanalytical 
Validation Report.
5.3.5
Storage and destruction of pharmacokinetic, ADA and 
5.3.5.1
Olaparib samples
Olaparib PK samples will be disposed of or destroyed and anonymized by pooling after the 
Bioanalytical Report finalization or 6 months after issuance of the draft Bioanalytical Report 
(whichever is earlier), unless requested for future analyses. 
Additional analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method.  Any results from such analyses may be reported 
separately from the 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 an Assay Validation Report as an Addendum.
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5.3.5.2
MEDI4736 samples
Samples will be archived and then disposed of after a minimum of 5 years from the Biologic 
License Application filing.
For sample processing, handling and shipment refer to the Investigators Laboratory Manual.
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 an Assay Validation Report as an Addendum.
 
 
5.3.5.3
Bevacizumab samples
Bevacizumab PK samples will be disposed of or destroyed and anonymized by pooling after 
the Bioanalytical Report finalization or 6 months after issuance of the draft Bioanalytical 
Report (whichever is earlier), unless requested for future analyses. 
Additional analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method.  Any results from such analyses may be reported 
separately from the 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 an Assay Validation Report as an Addendum.
 
 
5.4
Genetics
5.4.1
Collection of genetic samples
The decision by the patient to participate in the genetic research components of the study is 
entirely optional. 
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NOTE: This section refers to the optional genetic blood sample. The mandatory BRCA gene 
testing on blood samples required for determining eligibility is discussed in Section 5.6.
See Appendix C.
5.4.2
Storage, re-use and destruction of genetic samples
See Appendix C.
5.5
Biomarker analysis 
 
 
 
 
 
 
5.5.1
Data and samples for patient selection and eligibility
The molecular testing data from an appropriately accredited laboratory that must be 
documented prior to a patient commencing treatment in the study is defined for each cohort in 
Section 5.5.1 of each cohort-specific Module (Appendix H to Appendix N). 
5.5.2
Mandatory tumor sample
5.5.2.1
Initial Stage Cohorts
All patients must provide an archival tumor sample (formalin-fixed paraffin-embedded; 
[FFPE]); a tumor tissue block is preferred.  If a tissue block is unavailable, unstained freshly 
cut sections from the tissue block may be submitted.  Specific instructions and guidelines 
regarding sections are provided in the laboratory manual.  Tissue blocks may be repatriated on 
request.
Where taken expressly for the study, tumor samples should be collected via an image-guided 
core needle (18 gauge or larger) or be collected as an excisional or incisional tumor biopsy 
sample. 
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Tumor lesions used for fresh biopsies should not be the same lesions used as RECIST 1.1 
target lesions, unless there are no other lesions suitable for biopsy.  If a RECIST 1.1 target 
lesion is used for biopsy, the lesion must be ≥2 cm in the longest diameter and must be 
biopsied outside of the screening period.
When fresh tissue is obtained, effort should be made to maximize material for downstream 
analyses.  
  
These should be placed in formalin and processed to a single paraffin embedded block.  That 
written, and as a guidance, it is anticipated that 4 passes of a core needle will provide 
sufficient tissue for establishing eligibility and for delivering protocol defined exploratory 
objectives.  Whenever feasible, additional cores 
 
 should be obtained and immediately frozen as described in the Laboratory Manual.  
Please consult the Laboratory Manual for additional information and guidance regarding how 
to split excisional biopsies for downstream purposes.
 
 
 
5.5.2.2
Second Stage Cohorts
Ovarian cancer patients in the Second Stage Cohorts are exempt from provision of a new 
biopsy sample even when/even if the archival tumor sample is more than 3 years old.
All patients must provide a FFPE archival tumor sample at the screening visit, after other 
eligibility criteria are confirmed (see Sections 3.1 and 3.2). Formalin fixed and embedded in 
paraffin tumor tissue blocks are required, but if not available, tissue sections are accepted. At 
least forty (40) unstained sections without cover slips must be submitted to ensure sufficient 
material.  Samples must meet the minimum tumor content and tissue volume as specified in 
the laboratory manual.
If an archival sample is not available a new biopsy may be provided.  Consideration should be 
given to the potential benefit to the patient (should they be eligible for the study) in the 
context of the risk posed by the biopsy procedure.  Tissue biopsy sampling should be 
conducted in accordance with expert guidelines, only by Investigators experiences in 
performing these sampling methods in appropriate clinical settings.  Four cores (2 for 
processing as FFPE blocks and 2 for immediate freezing) should be taken where possible.  
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Further details can be found in Section 5.5.2.1 of the Core Protocol and the Laboratory 
Manual.
Residual tumor and blood (or its derivatives) may be used to evaluate future BRCA/HRR gene 
companion diagnostic tests and for additional exploratory work, to elucidate the mechanism of 
response, understand the mode of action of study treatment, and improve the understanding of 
disease recurrence (including gene mutation status and its role in response).
5.5.3
Candidate predictive biomarker analyses on mandatory tumor tissue
 
 
  
 
 
 
 
 
 
 
 
 
 
5.5.4
Investigational, immunomodulatory biomarker analyses
 
 
 
 
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Additional sample collections and analyses may be completed at select study sites by 
site-specific amendment.  All samples collected for such exploratory analyses will be stored at 
site, a reference laboratory, or at AstraZeneca’s facilities and may be used for subsequent 
research relevant to evaluating response to IMT.
5.5.4.1
Pharmacodynamics: paired tumor biopsies
 
 
 
 
 
 
 
5.5.4.2
Pharmacodynamics: sPD-L1 analyses
Please refer to Section 5.3.4.
5.5.4.3
Pharmacodynamics: whole blood for gene expression (PAXgene-RNA)
 
 
 
 
 
 
 
 
 
 
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5.5.4.4
Pharmacodynamics: ctDNA in the plasma (Second Stage Cohorts only)
 
 
 
5.5.4.5
Pharmacodynamics: circulating soluble factors in the plasma
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
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5.5.4.6
Pharmacodynamics: anti-drug antibodies
Please refer to Section 5.3.4.
5.5.4.7
Pharmacodynamics: whole blood for immunophenotyping 
 
 
5.5.4.8
Pharmacodynamics: peripheral blood mononuclear cells
 
 
 
 
 
 
5.5.4.9
Pharmacodynamics: Plasma for free vascular endothelial growth factor 
(ovarian cancer triplet and ovarian cancer doublet cohorts only)
 
 
 
5.5.4.10
Pharmacodynamics: Serum for eg angiogenic evaluation (ovarian cancer 
triplet and ovarian cancer doublet cohorts only)
 
 
 
  
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5.5.4.11
Pharmacodynamics: tumor biopsy at disease progression
 
 
  
 
5.5.5
Biomarker sample and data management
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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5.5.6
Labeling and shipment of biological samples
The PI will ensure that samples are labeled 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 will not be shipped, and no further 
samples will be taken from the involved patients unless agreed upon with AstraZeneca and 
appropriate labeling, shipment, and containment provisions are approved.
5.5.6.1
Chain of custody of biological samples
A full chain of custody will be maintained for all samples throughout their life cycle.
The PI at each center will keep full traceability of collected biological samples from the 
patients while in storage at the center until shipment or disposal (where appropriate).
The sample receiver will keep full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and will keep documentation of receipt of 
arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, and auditing of external laboratory providers.
Samples retained for further use will be registered by the AstraZeneca Biobank team during 
the entire life cycle.
5.5.7
Withdrawal of informed consent for donated biological samples
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of or destroyed and the action documented.  If samples have already been analyzed, 
AstraZeneca is not obliged to destroy the results of this research.
The PI will ensure that
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AstraZeneca is immediately notified of the patients’ withdrawal of informed consent to the 
use of donated samples

Biological samples from that patient, if stored at the study site, are immediately identified, 
disposed of or destroyed and the action documented

The laboratory(ies) holding the samples is/are immediately informed about the withdrawn 
consent and that samples are disposed of or destroyed, the action is documented, and the 
signed document is returned to the study site

The patient and AstraZeneca are informed about the sample disposal
5.6
BRCA status
Mandatory blood samples are collected to determine BRCA gene mutation status (ovarian 
cancer patients).
5.6.1
Initial Stage Cohorts: gBRCAm breast cancer cohort and gBRCAm ovarian 
cancer cohort
BRCA gene testing for study inclusion purposes in the gBRCAm breast cancer and gBRCAm
ovarian cancer cohorts will be performed on a blood sample taken specifically for that purpose 
and all local guidelines for such genetic testing must be followed.  Patients must have a known 
deleterious or suspected deleterious BRCA mutation to be enrolled into the study; this can be 
either a local laboratory result or a Sponsor-designated central laboratory (such as Myriad) test 
result.  Patients with a suspected (ie, unconfirmed BRCA mutation) will have the blood sample 
taken at the screening visit, after other eligibility criteria are confirmed.  Patients for whom 
BRCA status is already known, should be consented to the study within 28 days prior to Day 1 
of the first dose of olaparib monotherapy and have a blood sample taken for confirmation of 
BRCA status at the Week 1/Day 1 visit.  All patients must provide samples and consent to 
study-related Sponsor-designated central laboratory (such as Myriad) gBRCA status testing, 
and must also have a blood sample taken at the same time for the purpose of developing and 
validating a diagnostic test for BRCA mutations.
5.6.2
Second Stage Cohorts
Patients in the 3 ovarian cancer Second Stage Cohorts will either have BRCAm ovarian cancer 
(BRCAm ovarian cancer expansion cohort; Appendix L), or non BRCAm ovarian cancer 
(ovarian cancer triplet and doublet cohorts; Appendix M and Appendix N, respectively).  
Information on BRCA testing for the Second Stage Cohorts is provided in Appendix O.

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6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section.
6.1
Definition of adverse events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
patient administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils 1 or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability or incapacity

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent 1 of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse events, including SAEs, will be collected from the time of signature of first informed 
consent throughout the treatment period up to and including the 90-day follow-up period.  All 
ongoing and any new AEs/SAEs identified during the 90 calendar days’ follow-up period, 
after the last dose of study medication must be followed to resolution.  After any interim 
analysis, any ongoing AEs/SAEs need to be unlocked and followed for resolution.

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6.3.2
Follow-up of unresolved adverse events
Any SAEs or non-serious AEs that are unresolved at the time of the 90-day follow-up period 
must be followed up to resolution unless the event is considered by the Investigators as 
unlikely to resolve or the patient is lost to follow-up.  AstraZeneca retains the right to request 
additional information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary.
6.3.3
Adverse events after the 90-day follow-up period
For Pharmacovigilance purposes and characterization of SAE, any case of MDS/AML or new 
primary malignancy occurring after the 90-day follow-up period should be reported to 
AstraZeneca, Patient Safety, regardless of Investigator’s assessment of causality.  
Investigators will be asked during the regular follow-up for overall survival if the patient has 
developed MDS/AML or a new primary malignancy and prompted to report any such cases.
At any time after a patient has completed the study, if an Investigator learns of any SAE 
including death, and he/she considers there is a reasonable possibility that the event is causally 
related to the IP, the Investigator should notify AstraZeneca, Patient Safety.
If patients who are gaining clinical benefit are allowed to continue study treatment post-data 
cut-off and/or post-study completion then all SAEs must continue to be collected and reported 
to Patient Safety within the usual timeframe.
Otherwise, after study treatment completion (i.e. after any scheduled post treatment follow-up 
period has ended) there is no obligation to actively report information on new AEs or SAEs 
occurring in former study patients. This includes new AEs/SAEs in patients still being 
followed up for survival but who have completed the post treatment follow-up period 
(90 days).
All ongoing AEs/SAEs and any new AEs/SAEs identified during the 90 calendar days 
follow-up period after last dose of study medication must be followed to resolution unless, in 
the Investigator’s opinion, the condition is unlikely to resolve due to the patient’s underlying 
disease, or the patient is lost to follow-up. AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.
6.3.4
Variables 
The following variables will be collected for each AE:

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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) / combination drug (Yes/No)

Action taken with regard to IP/combination drug

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

AE is serious due to

Date of hospitalization

Date of discharge from hospital

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)

Causality assessment in relation to Other medications 

Description of AE
Severity of the adverse event
For each episode of an AE, all changes to the CTCAE grade attained, as well as the highest 
CTC grade, are to be reported.
It is important to distinguish between seriousness and severity.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Section 6.2.
The grading scales found in the NCI CTCAE v 4.03 will be utilized for all events with an 
assigned CTCAE grading.  For those events without assigned CTCAE grades the 
recommendation is that the CTCAE criteria that convert mild, moderate and severe events into 
CTCAE grades should be used.
A copy of the CTCAE version can be downloaded from the Cancer Therapy Evaluation 
program website (http://ctep.cancer.gov).

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6.3.5
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/comparator/combination drug?’
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 Clinical 
Study Protocol.
6.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF.  When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
6.3.7
Adverse events based on examinations and tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarized in the CSR.  Deterioration as compared to baseline in protocol-mandated 
laboratory values, vital signs and ECGs should therefore only be reported as AEs if 1 of the 
following is met:

Any criterion for an SAE is fulfilled

Causes discontinuation of study treatment

Causes interruption of study treatment

Causes a dose reduction of study treatment

The Investigator believes that the abnormality should be reported as an AE.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible, the reporting Investigator
uses the clinical, rather than the laboratory term (eg, anemia versus low Hb value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).

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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.
6.3.8
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with TBL ≥2 × ULN may need to be 
reported as SAEs.  Please refer to Appendix D for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law.
6.3.9
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the 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.
6.3.10
New cancers
The development of a new primary cancer should be reported as an AE (see Section 6.8.3) and 
would in most cases meet seriousness criteria (with the exception of some non-melanoma skin 
cancers).  New primary cancers are those that are not the primary reason for the administration 
of the study treatment and have developed after the inclusion of the patient into the study.  
They do not include metastases of the original cancer.  Symptoms of metastasis or the 
metastasis itself should not be reported as an AE/SAE, as they are considered to be disease 
progression.
6.3.11
Lack of efficacy
In this study, lack of efficacy (ie, deterioration in the cancer, for which the study treatment(s) 
is being used) is not to be reported as an AE.
6.3.12
Deaths
All deaths that occur during the study, or within the protocol defined 90-day post-study 
follow-up period after the administration of the last dose of study treatment, must be reported 
as follows:

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Death that is clearly the result of disease progression should be reported to the study 
monitor at the next monitoring visit and should be documented in the DEATH eCRF, but 
should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under study, the 
cause of death must be reported as an SAE with a fatal outcome within 24 hours (see 
Section 6.4 for further details).  The report should contain a comment regarding the 
co-involvement of progression of disease, if appropriate, and should assign main and 
contributory causes of death.  This information must be captured in the ‘death eCRF’.
If the death occurred as a result of an event that started post the defined safety follow-up 
period and the event is considered to be due to a late onset toxicity to study drug then it should 
also be reported as an SAE.
Deaths with an unknown cause should always be reported as a SAE.  If performed, a copy of 
the post mortem results should be forwarded to AstraZeneca within 24 hours.
6.4
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.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca, Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs, and within 5 calendar days for follow-up 
information.
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 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day, ie, immediately but no later than 24 hours of when he or she becomes 
aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.

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If the WBDC system is not available, then the Investigator or other study site staff reports a 
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.
The reference document for definition of expectedness/listedness is the IB for MEDI4736 and 
olaparib, the EU Summary of Product Characteristics for olaparib, and the
FDA bevacizumab label.
6.5
Overdose
6.5.1
Overdose of olaparib and/or MEDI4736
Use of IP in doses in excess of that specified in the protocol is considered to be an overdose.  
Olaparib compliance will be assessed by tablet count (see Section 7.5). An overdose should 
be reported if 1 or more doses are found to be missing during the tablet count.  
There is currently no specific treatment in the event of overdose with olaparib or/and 
MEDI4736 and possible symptoms of overdose are not established. 
Olaparib/ MEDI4736 must only be used in accordance with the dosing recommendations in 
this protocol.  Any dose or frequency of dosing that exceeds the dosing regimen specified in 
this protocol should be reported as an overdose. 
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately.

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 on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca, Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.

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6.5.2
Overdose of bevacizumab 
See Appendix M for the overdose instruction for bevacizumab. 
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca, except for:

If the pregnancy is discovered before the study patient has received any study drug
Should pregnancy occur, the physician should discuss with the patient the potential hazard to 
the fetus or potential risk of loss of the pregnancy.
6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the IP should be discontinued 
immediately. 
The outcomes of any conception occurring from the date of the first dose of study medication 
until 90 days after the last dose of study medication must be followed up and documented.
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.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca, Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
6.6.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
90 days following the last dose of IP (refer to Section 3.8).

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Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) occurring from the date of the first dose until 90 days after the last 
dose should, if possible, be followed up and documented.
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the patient’s partner.  Therefore, the local study 
team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant Ethics Committees (EC)/Internal Review Boards (IRB) prior to use.
6.7
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the patient or 
has the potential to cause harm to the patient. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or patient.
Medication error includes situations where an error:

occurred

was identified and intercepted before the patient received the drug

did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the patient

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a solid 
tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong patient received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to patient (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS - including those which lead to 1 of the 
above listed events that would otherwise have been a medication error 

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
Patient accidentally missed drug dose(s) eg, 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 AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.  
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 6.4) and within 30 days for all other 
medication errors.
6.8
Management of IP-related toxicities
In general, the toxicity profiles of MEDI4736 and of olaparib are nonoverlapping, therefore, 
management of toxicities will be per the individual guidelines of the respective agents.  
Pneumonitis is considered to be the most important potential exception.  The management 
guidelines for pneumonitis (see Section 5.2.5.3, Section 6.8.2.2, and Section 6.8.4) integrate 
the guidance provided for these 2 agents.
6.8.1
General comments
The following general guidance should be followed for management of toxicities.

Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity if required).

If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of the assigned IP along with appropriate continuing supportive 
care.  If medically appropriate, dose modifications are permitted.

All dose modifications should be documented with clear reasoning and documentation of 
the approach taken.
All toxicities will be graded according to NCI CTCAE, Version 4.03.

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6.8.2
Olaparib 
Any toxicity observed during the course of the study could be managed by interruption of the 
dose of study treatment or dose reductions.  Repeat dose interruptions are allowed, as 
required, for a maximum of 4 weeks on each occasion.  If the interruption is any longer, the 
study team must be informed.  Study treatment can be dose reduced to 250 mg bid as a first 
step and to 200 mg bid as a second step (Table 2).  If the reduced dose of 200 mg bid is not 
tolerable, no further dose reduction is allowed and study treatment should be discontinued. 
Once dose is reduced, escalation is not permitted (except following concomitant treatment 
with CYP3A4 inhibitors – see Section 7.7).
Table 2
Dose reductions for study treatment
Initial dose
Following re-challenge post-interruption: 
dose reduction 1
Dose reduction 2
300 mg twice daily
250 mg twice daily
200 mg twice daily
6.8.2.1
Management of hematological toxicity
Management of anemia
The management of anemia is presented in Table 3.
Table 3
Management of anemia
Hemoglobin
Action to be taken
Hb <10 but ≥8 g/dL
(CTCAE Grade 2)
First occurrence:
Give appropriate supportive treatment and investigate causality. 
Investigator judgment to continue olaparib with supportive treatment (eg 
transfusion) or interrupt dose for a maximum of 4 weeks. Study treatment 
can be restarted if Hb has recovered to >9 g/dL.
Subsequent occurrences:
If Hb <10 but ≥9 g/dL Investigator judgment to continue with supportive 
treatment (eg transfusion) or dose interrupt (for max of 4 weeks) and upon 
recovery dose reduction to may be considered (250 mg twice daily as a 
first step and to 200 mg twice daily as a second step).
If Hb<9 but ≥8 g/dl, dose interrupt (for max of 4 weeks) until Hb ≥9 g/dl 
and upon recovery dose reduction may be considered (to 250 mg twice 
daily as a first step and to 200 mg twice daily as a second step).

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Hemoglobin
Action to be taken
Hb <8 g/dL
(CTCAE Grade 3)
Give appropriate supportive treatment (eg, transfusion) and investigate 
causality. 
Interrupt olaparib for a maximum of 4 weeks until improved to Hb 
≥9 g/dl.
Upon recovery dose reduce to 250 mg twice daily as a first step and to 
200 mg twice daily as a second step in the case of repeat Hb decrease.
CTCAE=Common Terminology Criteria for Adverse Event; Hb=hemoglobin
Common treatable causes of anemia (eg, iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed.  In some cases,
management of anemia may require blood transfusions.  For cases where patients develop 
prolonged hematological toxicity (≥2-week interruption/delay in study treatment due to CTC 
grade 3 or worse anemia and/or development of blood transfusion dependence), refer to the 
dedicated section below (“Management of prolonged hematological toxicities while on study 
treatment") for the management of these cases. 
Management of neutropenia, leukopenia and thrombocytopenia
The management of neutropenia, leucopenia, and thrombocytopenia is presented in Table 4.
Table 4
Management of neutropenia, leukopenia, and thrombocytopenia
Toxicity
Study treatment dose adjustment
CTCAE Grade 1-2
Investigator judgment to continue treatment or if dose interruption, this 
should be for a maximum of 4 weeks; appropriate supportive treatment 
and causality investigation
CTCAE Grade 3-4
Dose interruption until recovered to CTCAE grade 1 or better for a 
maximum of 4 weeks. If repeat CTCAE grade 3-4 occurrence, dose reduce 
olaparib to 250 mg twice daily as a first step and 200 mg twice daily as a 
second step
bid=twice daily; CTCAE=Common Terminology Criteria for Adverse Events
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by 
the Investigator with close follow-up and interruption of study drug if CTC grade 3 or worse 
neutropenia occurs.
Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not 
recommended, however, if a patient develops febrile neutropenia, study treatment should be 
stopped and appropriate management including G-CSF should be given according to local 

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hospital guidelines. Please note that G-CSF should not be used within at least 24 h (7 days for 
pegylated G-CSF) of the last dose of study treatment unless absolutely necessary.
Platelet transfusions, if indicated, should be done according to local hospital guidelines.
For cases where patients develop prolonged hematological toxicity (≥2-week 
interruption/delay in study treatment due to CTC grade 3 or worse), refer to guidance later in 
this section for the management of this. 
Management of prolonged hematological toxicities while on study treatment
If a patient develops prolonged hematological toxicity such as:

≥2-week interruption/delay in study treatment due to CTC grade 3 or worse anemia and/or 
development of blood transfusion dependence

≥2-week interruption/delay in study treatment due to CTC grade 3 or worse neutropenia 
(ANC <1×109/L)

≥2-week interruption/delay in study treatment due to CTC grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (Platelets 
<50×109/L)
Check weekly differential blood counts including reticulocytes and peripheral blood smear. If 
any blood parameters remain clinically abnormal after 4 weeks of dose interruption, the 
patient should be referred to hematologist for further investigations.  Bone marrow analysis 
and/or blood cytogenetic analysis should be considered at this stage according to standard 
hematological practice.  Study treatment should be discontinued if blood counts do not 
recover to CTC grade 1 or better within 4 weeks of dose interruption.
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should 
be reported as an SAE and full reports must be provided by the Investigator to AstraZeneca 
Patient Safety. Olaparib treatment should be discontinued if patient’s diagnosis of MDS 
and/or AML is confirmed.
6.8.2.2
Management of non-hematological toxicity
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each 
occasion. If the interruption is any longer than this the study monitor must be informed. 
Where toxicity reoccurs following re-challenge with study treatment, and where further dose 
interruptions are considered inadequate for management of toxicity, then the patient should be 
considered for dose reduction or must permanently discontinue study treatment.

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Study treatment can be dose reduced to 250 mg twice daily as a first step and to 200 mg twice 
daily as a second step. Treatment must be interrupted if any NCI-CTCAE grade 3 or 
4 adverse event occurs which the Investigator considers to be related to administration of 
study treatment.
Management of new or worsening pulmonary symptoms 
If new or worsening pulmonary symptoms (eg, dyspnoea) or radiological abnormalities occur 
in the absence of a clear diagnosis, an interruption in study treatment dosing is recommended 
and further diagnostic workup (including a high resolution CT scan) should be performed to 
exclude pneumonitis.
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then study treatment can be restarted, if deemed appropriate by the 
Investigator. If significant pulmonary abnormalities are identified, these need to be discussed 
with the Study Physician.
As pneumonitis is an AESI for MEDI4736, please refer to Section 6.8.4.
Management of nausea and vomiting
Events of nausea and vomiting are known to be associated with olaparib treatment.  These 
events are generally mild to moderate (CTCAE grade 1 or 2) severity, intermittent and 
manageable on continued treatment.  The first onset generally occurs in the first month of 
treatment for nausea and within the first 6 months of treatment for vomiting.  For nausea, the 
incidence generally plateaus at around 9 months, and for vomiting at around 6 to 7 months.
No routine prophylactic antiemetic treatment is required at the start of study treatment, 
however, patients should receive appropriate antiemetic treatment at the first onset of nausea 
or vomiting and as required thereafter, in accordance with local treatment practice guidelines.  
Alternatively, olaparib tablets can be taken with a light meal/snack (ie, 2 pieces of toast or a 
couple of biscuits).
As per international guidance on antiemetic use in cancer patients (European Society for 
Medical Oncology, NCCN), generally a single agent antiemetic should be considered eg, 
serotonin receptor antagonists or dopamine receptor antagonists.  For persistent nausea, 
combination therapy is recommended.

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Interruptions for intercurrent non-toxicity related events
Study treatment dose interruption for conditions other than toxicity resolution should be kept 
as short as possible.  If a patient cannot restart study treatment within 4 weeks for resolution 
of intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with AstraZeneca study physician.
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF. 
Study treatment should be stopped at least 3 days prior to planned surgery.  After surgery 
study treatment can be restarted when the wound has healed.  No stoppage of study treatment 
is required for any needle biopsy procedure.
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
radiation treatment.  Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered.
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, patients 
should be advised to use caution while driving or using machinery if these symptoms occur.
6.8.3
Olaparib adverse events of special interest
Adverse events of special interest are events of scientific and medical interest specific to the 
further understanding of olaparib’s safety profile and require close monitoring and rapid 
communication by the Investigators to AstraZeneca.  Adverse events of special interest for 
olaparib are the Important Identified Risk of MDS/AML, and the Important Potential Risks of 
new primary malignancy (other than MDS/AML) and pneumonitis.
A questionnaire will be sent to any Investigator reporting an AESI, as an aid to provide further 
detailed information on the event. During the study, there may be other events identified as 
AESIs that require the use of a questionnaire to help characterize the event and gain a better 
understanding regarding the relationship between the event and study treatment.
6.8.4
Specific toxicity management and dose modification information - MEDI4736
Comprehensive toxicity management guidelines (TMG) have been developed to assist 
Investigators with the recognition and management of toxicities associated with the use of the 
immune-checkpoint inhibitor MEDI4736 
  These guidelines are applicable 
when MEDI4736 is used alone or is administered concurrently or sequentially with other 
anticancer drugs (ie, antineoplastic chemotherapy, targeted agents), as part of a protocol 
CCI

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specific treatment regimen.  The TMGs provide information for the management of 
immune-mediated reactions, infusion-related reactions, and non-immune mediated reactions 
that may be observed with checkpoint inhibitor monotherapy or combination checkpoint 
inhibitor regimens, with specific instructions for dose modifications (including 
discontinuations) and treatment interventions.  Investigators are advised however to use local 
practice guidelines and consult local references for the management of toxicities observed 
with other cancer treatment. The most current version of the TMGs entitled “Dosing 
Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, 
and Non-Immune Mediated Reactions (MEDI4736) Monotherapy or Combination Therapy 
with Tremelimumab or Tremelimumab Monotherapy” is provided to the investigative site as 
an Annex document and is maintained within the Site Master File.
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered 
potentially immune related.  In addition, there are certain circumstances in which MEDI4736
should be permanently discontinued (see Section 3.9 of this protocol and the Dosing 
Modification and Toxicity Management Guidelines).  Following the first dose of IP, 
subsequent administration of MEDI4736 can be modified based on toxicities observed as 
described in the Dosing Modification and Toxicity Management Guidelines. These guidelines 
have been prepared by the Sponsor to assist the Investigator in the exercise of his/her clinical 
judgment in treating these types of toxicities. These guidelines apply to AEs considered 
causally related to the MEDI4736 therapy regimen by the reporting Investigator.
Dose reductions for MEDI4736 are not permitted. In case of doubt, the Investigator should 
consult with the Study Physician.
6.8.5
MEDI4736 adverse events of special interest
An AESI is an AE of scientific and medical interest specific to understanding of the 
Investigational Product and may require close monitoring. An AESI may be serious or 
non-serious. The rapid reporting of AESIs allows ongoing surveillance of these events in 
order to characterize and understand them in association with the use of this investigational 
product.
Adverse events of special interest for MEDI4736 include but are not limited to events with a 
potential inflammatory or immune-mediated mechanism and which may require more 
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hormone replacement therapy.  The rapid reporting of AESIs allows ongoing surveillance of 
these events in order to characterize and understand them in association with the use of this IP. 
These AESIs are being closely monitored in clinical studies with MEDI4736 monotherapy 
and combination therapy.  An immune-related adverse event (irAE) is defined as an adverse 
event that is associated with drug exposure and is consistent with an immune-mediated 
mechanism of action and where there is no clear alternate etiology.  Serologic, immunologic, 
and histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis.  
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or 
other etiologic causes of the irAE. 
If the Investigator has any questions in regards to an AE being an irAE, the Investigator 
should promptly contact the Study Physician.
AESIs observed with MEDI4736 include:

Diarrhea/colitis 

Intestinal perforations

Pneumonitis

Hepatitis

Endocrinopathies (hypo- and hyper-thyroidism, adrenal insufficiency, 
hypophysitis/hypopituitarism and Type 1 diabetes mellitus)

Rash/dermatitis

Nephritis

Pancreatitis

Myocarditis

Myositis/polymyositis

Neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome

Other inflammatory responses that are rare/less frequent with a potential 
immune-mediated etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis 
and other events involving the eye, skin, hematological and rheumatological events,
vasculitis, non-infectious meningitis and non-infectious encephalitis.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs.
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the MEDI4736 Investigator Brochure (IB).  More specific guidelines for their 
evaluation and treatment are described in detail in the Dosing Modification and Toxicity 
Management Guidelines. These guidelines have been prepared by the Sponsor to assist the 
Investigator in the exercise of his/her clinical judgment in treating these types of toxicities.  

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These guidelines apply to AEs considered causally related to the study drug/study regimen by 
the reporting Investigator.
6.8.6
Bevacizumab
For information on management of bevacizumab-related toxicities, please see Appendix M.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational products
The AstraZeneca Pharmaceutical Technology and Development R&D Supply Chain will 
supply the investigational sites with MEDI4736 and olaparib. Bevacizumab will be sourced 
locally or centrally and should be administered according to local prescribing information, 
including any treatment restrictions (Table 5).
In this study protocol, the term “IP” refers to the treatment regimen (including 
MEDI4736+olaparib, MEDI4736+olaparib+bevacizumab, and olaparib monotherapy).
Table 5
All investigational products for this study
Investigational producta
Dosage form and strength
MEDI4736b
50 mg/mL, solution for infusion
Olaparibb
150 mg and 100 mg tablet
Bevacizumab
25 mg/mL, solution for infusion
a
May be cohort-dependent, please see each cohort-specific appendix.
b
Descriptive information for olaparib and MEDI4736 can be found in the respective olaparib and MEDI4736 
Investigator’s Brochures.
7.1.1
MEDI4736
MEDI4736 will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution.  The solution contains 50 mg/mL MEDI4736, 26 mM histidine/histidine 
hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; 
it has a pH of 6.0.  The nominal fill volume is 10.0 mL.  Investigational product vials are 
stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product should be kept in 
secondary packaging until use to prevent excessive light exposure.
Preparation of MEDI4736 doses for administration with an IV bag

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The dose of MEDI4736 for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique. Total time from needle puncture of the 
MEDI4736 vial to the start of administration should not exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
Infusion solution must be allowed to equilibrate to room temperature prior to commencement 
of administration.
A dose of 1.5 g will be administered using an IV bag containing 0.9% (weight/volume) saline 
or 5% (weight/volume) dextrose, with a final MEDI4736 concentration ranging from 
1 mg/mL to 20 mg/mL and delivered through an IV administration set with a 0.2-μm or 
0.22-μm in-line filter.  Remove a volume of IV solution equivalent to the dose volume of 
MEDI4736 (30.0 mL) from the IV bag prior to addition of MEDI4736.  Next, the 30.0 mL 
dose of MEDI4736 is added to the IV bag such that the final concentration is within 1 to 
20 mg/mL (IV bag volumes 100 to 1000 mL). Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag.
Please note, if a patient’s weight is 30 kg or below the patient should receive weight-based 
dosing equivalent to 20 mg/kg of MEDI4736 once every 4 weeks after consultation between 
Investigator and Study Physician, until the weight improves to >30 kg, at which point the 
patient should start receiving the fixed dosing of MEDI4736 1500 mg once every 4 weeks.
Standard infusion time is 1 hour. However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed.
In the event that either preparation time or infusion time exceeds the time limits outlined, a 
new dose must be prepared from new vials. MEDI4736 does not contain preservatives and 
any unused portion must be discarded.
No incompatibilities between MEDI4736 and polyethylene, polypropylene, polyvinylchloride, 
or polyolefin copolymers have been observed.

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Preparations are to be in accordance with the study-specific drug handling instructions.
7.1.2
Olaparib
Olaparib is available as a film-coated tablet containing 150 mg or 100 mg of olaparib.  
7.1.3
Bevacizumab
For bevacizumab preparation, see Appendix M.
7.2
Dose and treatment regimens
There is no maximum duration of treatment with study treatment.  Patients should continue to 
receive study treatment until objective radiological disease progression as per RECIST 1.1 as 
assessed by the Investigator or as long as, in the Investigator’s opinion, they are benefitting 
from treatment and they do not meet any other discontinuation criteria.  Treatment will be 
supplied as open labeled drug via manual supply once the IVRS/IWRS has been closed.
7.2.1
Olaparib
For all centers, olaparib will be packed in high-density polyethylene bottles with 
child-resistant closures.  The olaparib study treatment will be dispensed to patients.  Each 
dosing container will contain sufficient medication for at least each treatment period plus 
overage.  Multiple bottles of study treatment may be required for dispensing in order to make 
up the desired dose.
Patients will be administered olaparib study treatment tablets orally at a dose of 300 mg bid.  
The initial dose of 300 mg bid will be made up of 2×150 mg tablets bid.  The 100 mg and 
150 mg tablets will be used to manage dose reductions.
All doses of study treatment should be taken at the same times each day approximately 
12 hours apart and with approximately 240 mL of water.  The olaparib treatment tablets 
should be swallowed whole and not chewed, crushed, dissolved or divided.  Study tablets can 
be taken with or without food. On the PK sampling day patients should fast from 1 hour 
before taking the olaparib dose to 2 hours after.
If vomiting occurs shortly after the study treatment tablets are swallowed, the dose should 
only be replaced if all of the intact tablets can be seen and counted.  Should any patient 
enrolled on the study miss a scheduled dose for whatever reason (eg, as a result of forgetting 
to take the tablets or vomiting), the patient will be allowed to take the scheduled dose up to a 
maximum of 2 hours after that scheduled dose time.  If greater than 2 hours after the 

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scheduled dose time, the missed dose is not to be taken and the patient should take their 
allotted dose at the next scheduled time.
Dose Reductions
For guidance on dose reductions for management of AEs refer to Section 6.8.2.  For guidance 
on dose reductions when concomitant strong or moderate CYP3A inhibitors cannot be 
avoided see Section 7.7.
Renal Impairment
If subsequent to study entry and while still on study therapy, a patient’s estimated creatinine 
clearance falls below the threshold for study inclusion (≥51 mL/min), retesting should be 
performed promptly. 
A dose reduction is recommended for patients who develop moderate renal impairment 
(calculated creatinine clearance [CrCl] by Cockcroft-Gault equation or based on a 24-hour 
urine test of between 31 and 50 mL/min) for any reason during the course of the study: the 
dose of olaparib should be reduced to 200 mg twice daily.
Because the CrCl determination is only an estimate of renal function, in instances where the 
CrCl falls to between 31 and 50 mL/min, the Investigator should use his or her discretion in 
determining whether a dose change or discontinuation of therapy is warranted.
Olaparib has not been studied in patients with severe renal impairment (creatinine clearance 
≤30 mL/min) or end-stage renal disease; if patients develop severe impairment or end stage 
disease is it recommended that olaparib be discontinued.
7.2.2
MEDI4736
MEDI4736 should be given at least 1 hour after the patient has taken their olaparib morning 
dose.  Infusion solution must be allowed to equilibrate to room temperature prior to 
commencement of administration.
Following preparation of MEDI4736 (see Section 7.1.1), the entire contents of the IV bag 
should be administered as an IV infusion over approximately 60 minutes (±5 minutes).  
MEDI4736 (1.5 g) will be administered via IV infusion Q4W ±3 days.  Treatment with 
MEDI4736 will commence on Day 1 following confirmation of eligibility and will continue 
on a Q4W schedule until objective radiological disease progression as per RECIST 1.1 as 

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assessed by the Investigator or as long as, in the Investigator’s opinion, they are benefitting 
from treatment and they do not meet any other discontinuation criteria.
A 1-hour observation period is recommended after the first infusion of MEDI4736.  If no 
clinically significant infusion reactions are observed during or after the first cycle, subsequent 
infusion observation periods can be at the Investigator’s discretion (suggested 30 minutes after 
each MEDI4736 infusion). 
7.2.3
Bevacizumab
For bevacizumab dosing, see Appendix M.  Bevacizumab should be administered after the 
MEDI4736 observation period at visits where both drugs are administered.
7.3
Labeling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfill GMP Annex 13 requirements for labeling.  Label 
text will be translated into local language.
Specific dosing instructions will not be included on the label; the site must complete the 
“Patient Dispensing Card” with the details of the dosing instructions at the time of dispensing.
The patient emergency contact details will not be on the label, but can be found in the 
informed consent and the ‘Patient Dispensing Card’.  For emergency purposes the patient 
must be in possession of the emergency contact details at all times.
7.4
Storage
7.4.1
Olaparib
Olaparib should be kept in a secure place under appropriate storage conditions.  The IP label 
on the bottle specifies the appropriate storage.  Storage is also described in the IB.
7.4.2
MEDI4736
The Investigator, or an approved representative (eg, pharmacist), will ensure that all 
MEDI4736 is stored in a secured area, in refrigerated temperatures (2°C to 8°C) and in 
accordance with applicable regulatory requirements.  A temperature log will be used to record 
the temperature of the storage area.  Temperature excursions outside the permissible range 
listed in the clinical supply packaging are to be reported to the monitor upon detection.  A 
calibrated temperature monitoring device will be used to record the temperature conditions in 
the drug storage facility.  Storage conditions stated in the IB may be superseded by the label 

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storage.  Drug product should be kept in secondary packaging until use to prevent excessive 
light exposure.
7.4.3
Bevacizumab
For storage of bevacizumab, see Appendix M.
7.5
Compliance
The administration of all study drugs should be recorded in the appropriate sections of the 
eCRF.
Treatment compliance will be assured by reconciliation of site drug accountability logs.
Patients should be given clear instructions on how and when to take their study treatment.  
Patients will self-administer olaparib.  Study site staff will make tablet counts at regular 
intervals during treatment.  After the tablet count has been performed, the remaining tablets 
will not be returned to the patient but will be retained by the investigative site until 
reconciliation is completed by the study monitor.  All patients must return their bottle(s) of 
olaparib at the appropriate scheduled visit, when a new bottle will be dispensed.  Patients will 
be instructed to notify study site personnel of missed doses.  Dates of missed or held doses 
will be recorded by the patient on their patient diary and by the site staff on the eCRF.
Patients must return all containers and any remaining tablets at the end of the study.
7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
The study site staff will account for all study drugs dispensed to and returned from the patient, 
unused study drugs and for appropriate destruction.  Certificates of delivery, destruction and 
return (as applicable for particular study drug) should be signed. 
7.7
Concomitant and other treatments 
The use of any natural/herbal products or other traditional remedies should be discouraged, 
but use of these products, as well as any medication or vaccine including over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements that the patient is receiving at the 
time of enrollment or receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency

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The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical phase of the study (final study visit).  Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF.
Table 6and Table 7show prohibited and restricted medications, respectively. Table 7also
shows guidanceon dose reductions when concomitant strong or moderate CYP3A inhibitors 
cannot be avoided.  Table 8details permitted supportive medications.  Refer to Section 6.8for 
guidance on management of IP-related toxicities.
From screening onwards, should a patient develop nausea, vomiting and/or diarrhea, then 
these symptoms should be reported as AEs (see Section 6.3) and appropriate treatment of the 
event given.
Table 6
Prohibited medications
Prohibited medication/class of drug:
Anticancer therapy:
Chemotherapy
Immunotherapy
Hormonal therapya
Radiotherapy (except palliative)
Biological therapy
Other novel agents
Any investigational anticancer therapy other than 
those under investigation in this study
Not permitted while the patient is receivingstudy 
medication.
mAbs against CTLA-4, PD-1, or
 other than 
those under investigation in this study
Should not be given concomitantly whilst the patient is on 
study treatment.
Live attenuated vaccines
Live bacterial vaccines
Not permitted while the patient is receiving study 
medication and during the 30 day follow up period. 
An increased risk of infection by the administration of live 
virus and bacterial vaccines has been observed with 
conventional chemotherapy drugs and the effects with 
study medications are unknown.
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Immunosuppressive medications including, but not 
limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumor necrosis 
factor-α blockers
Should not be given concomitantly, or used for 
premedication prior to the MEDI4736 infusions. The 
following are allowed exceptions:
!
Use of immunosuppressive medications for the 
management of IP-related AEs, 
!
Use in patients with contrast allergies.  
!
In addition, use of inhaled, topical, and intranasal 
corticosteroids is permitted.
A temporary period of steroids will be allowed if clinically 
indicated and considered to be essential for the 
management of non-immunotherapy related events 
experienced by the patient (eg, chronic obstructive 
pulmonary disease, radiation, nausea, etc).
EGFR TKIs
Should not be given concomitantly. 
Should be used with caution in the 90 days post last dose 
of MEDI4736. 
Increased incidences of pneumonitis (with third generation 
EGFR TKIs) and increased incidence of transaminase 
increases (with first generation EGFR TKIs) has been 
reported when MEDI4736 has been given concomitantly.
Herbal and natural remedies which may have 
immune-modulating effects
Should not be given concomitantly unless agreed by the 
Sponsor
a
Hormone Replacement Therapy (HRT) is acceptable.
AE, adverse event; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; EGFR TKI, epidermal growth factor 
receptor tyrosine kinase inhibitor; IP, Investigational Product; PD-1, anti programmed cell death 1; 
 
Table 7
Restricted concomitant medications
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which the medication is allowed):
Strong CYP3A inhibitors: eg, itraconazole, 
telithromycin, clarithromycin, boosted protease 
inhibitors, indinavir, saquinavir, nelfinavir, 
boceprevir, and telaprevir
Moderate CYP3A inhibitors: eg, ciprofloxacin, 
erythromycin, diltiazem, fluconazole, and 
verapamil
Strong or moderate CYP3A inhibitors should not be taken 
with olaparib.  If there is no suitable alternative 
concomitant medication then the dose of olaparib should 
be reduced for the period of concomitant administration. 
The dose reduction of olaparib should be recorded in the 
CRF with the reason documented as concomitant CYP3A 
inhibitor use. 
!
Strong CYP3A inhibitors – reduce the dose of olaparib 
to 100 mg twice daily for the duration of concomitant 
therapy with the strong inhibitor and for 5 half lives 
afterwards.
!
Moderate CYP3A inhibitors - reduce the dose of 
olaparib to 150 mg twice daily for the duration of 
concomitant therapy with the moderate inhibitor and 
for 3 half lives afterwards.
!
After the washout of the inhibitor is complete, the 
olaparib dose can be re-escalated.
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Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which the medication is allowed):
Strong CYP3A inducers: eg, phenobarbital, 
phenytoin, rifampicin, rifabutin, rifapentine, 
carbamazepine, nevirapine, enzalutamide, and St 
John’s Wort
Moderate CYP3A inducers: eg, bosentan, 
efavirenz, and modafinil
Strong or moderate CYP3A inducers should not be taken 
with olaparib.
If the use of any strong or moderate CYP3A inducers is 
considered necessary for the patient’s safety and welfare 
this could diminish the clinical efficacy of olaparib.
If a patient requires use of a strong or moderate CYP3A 
inducer then they must be monitored carefully for any 
change in efficacy of olaparib.
CYP3A4 substrates with narrow therapeutic 
margin: eg, cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, sirolimus, tacrolimus 
and warfarin 
Sensitive CYP3A4 substrates: eg, buspirone, 
felodipine, fluticasone, lovastatin, quetiapine, 
saquinavir, sildenafil and simvastatin 
CYP2B6 substrates: eg, bupropion and efavirenz
OATP1B1 substrates: eg, bosentan, 
glibenclamide, repaglinide, statins and valsartan
OCT1, MATE1 and MATE2K substrates: eg, 
metformin
OCT2 substrates: eg, cimetidine and metformin
OAT3 substrates: eg, furosemide and methotrexate
BCRP substrates: eg, methotrexate and 
rosuvastatin
P-gp substrates: eg, simvastatin, pravastatin, 
dabigatran, digoxin and colchicine
Effect of olaparib on other drugs:
Based on limited in vitro data, olaparib may increase the 
exposure to substrates of CYP3A4, BCRP, OATP1B1, 
OCT1, OCT2, OAT3, MATE1 and MATE2K.
Based on limited in vitro data, olaparib may reduce the 
exposure to substrates of 2B6 (and potentially substrates of 
CYP2C9, CYP2C19 and P-gp). The efficacy of some 
hormonal contraceptives may be reduced if co-
administered with olaparib.
Caution should be observed if statins or sensitive CYP3A4 
substrates are co-administered.
Appropriate clinical monitoring is recommended for 
patients receiving P-gp substrates or CYP3A substrates 
with a narrow therapeutic margin concomitantly with 
olaparib.
Anticoagulant therapy
Patients who are taking warfarin may participate in this 
trial; however, it is recommended that INR be monitored 
carefully at least once per week for the first month, then 
monthly if the INR is stable. Non-vitamin K antagonist 
oral anticoagulants (NOACs), subcutaneous heparin and 
low molecular weight heparin may be given concomitantly 
with olaparib and INR monitoring is not required. If 
NOACs are used, it is preferable to avoid CYP3A 
substrates (eg, apixaban and rivaroxaban) if possible.
Palliative radiotherapy
Palliative radiotherapy may be used for the treatment of 
pain at the site of bony metastases that were present at 
baseline, provided the Investigator does not feel that these 
are indicative of clinical disease progression during the 
study period.  Study treatment should be discontinued for a 
minimum of 3 days before a patient undergoes therapeutic 
palliative radiation treatment.  Study treatment should be 
restarted within 4 weeks as long as any bone marrow 
toxicity has recovered.  

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Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which the medication is allowed):
Administration of other anticancer agents
Patients must not receive any other concurrent anticancer 
therapy, including investigational agents, while on study 
treatment. Patients may continue the use of 
bisphosphonates or denosumab for bone disease and 
corticosteroids for the symptomatic control of brain 
metastases provided the dose is stable before and during 
the study and they were started at least 4 weeks prior to 
beginning study treatment. 
CYP=cytochrome P450; CRF= case report form; INR=international normalized ratio; MATE=Multidrug and 
toxin extrusion; OAT=organic anion transporter; OCT=organic cation transporter.
Table 8
Supportive medications
Supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) 
deemed necessary to provide adequate 
prophylactic or supportive care, except for 
those medications identified as “prohibited,” as 
listed above 
To be administered as prescribed by the Investigator
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy 
to non-target lesions, etc])
Should be used, when necessary, for all patients
Inactivated viruses, such as those in the 
influenza vaccine
Permitted
Subsequent therapies for cancer 
Details of first and subsequent therapies for cancer and/or details of surgery for the treatment 
of the cancer, after discontinuation of treatment, will be collected.  
 
 
7.7.1
Other concomitant treatment
Medication other than that described above, which is considered necessary for the patient’s 
safety and well-being, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the eCRF.
7.7.2
Bevacizumab-specific guidelines for concomitant treatments
Details of bevacizumab-specific guidelines and restrictions on concomitant treatments for 
patients in the ovarian cancer triplet cohort can be found in Appendix M.
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7.7.3
Rescue medication
As a result of immune mediated adverse events (imAEs) that could potentially be experienced 
by patients on MEDI4736, steroids and other immunosuppressant rescue medication has to be 
made available to this patient population. The 2 products that fall into the category of 
immunosuppressants are infliximab (eg, for colitis) and mycophenolate (eg, for hepatitis). 
AstraZeneca supply chain will be responsible for sourcing these 2 rescue medications to the 
sites if local regulations prevent the use of infliximab and mycophenolate in this indication, as 
they are considered off-label for management of immunotherapy related toxicities. These 
rescue medications must be receipted, controlled, and administered by the pharmacist and 
stored according to the labeled storage conditions, with temperature excursions reported 
accordingly by the pharmacist.  
Infliximab will be locally sourced by the market where possible.  Where not possible, central 
sourced material will be provided.
Mycophenolate will be locally sourced by the market where possible.  Where not possible, 
central sourced material will be provided.
7.8
Post study access to study treatment
Patients receiving study treatment at the time of study completion (ie, after final data cut-off 
date) may continue to receive study treatment if, in the opinion of the Investigator, they are 
continuing to receive benefit from treatment.
The provision of study drug at study completion may include, but is not limited to, transition 
to a roll-over study, continuous supply within this trial (for example in countries where 
regulatory approval is not obtained for a roll-over study) or switching to commercial drug as 
permitted by local regulations.
After discontinuation of study treatment, the Investigator will be at liberty to define further 
most appropriate anticancer treatment.
Subsequent anticancer treatment is expected to be initiated following the cancer recurrence or 
development of a new cancer.  Information on subsequent PARP inhibitors or other cancer 
therapies should be recorded on the clinical database.
Please refer to the “AstraZeneca Global Standard: Providing Study Drug to Patients Following 
Completion of a Clinical Study.” (http://portalapps.is.astrazeneca.net/azgard-

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components/ldms-
documents/Global_Compliance/Effective/Global%20Standard/LDMS_001_00108183.pdf).
8.
STATISTICAL ANALYSES
8.1
Statistical considerations
All statistical analyses will be performed by IQVIA.
A comprehensive statistical analysis plan will be prepared.  The primary aim of the study is to 
assess the safety, tolerability and antitumor activity of MEDI4736 in combination with 
olaparib (±bevacizumab) in patients with selected advanced solid tumors.
8.2
Sample size estimate and cohort expansion criteria
Progression-free survival is the most relevant endpoint for decision making but is difficult to 
determine accurately in a small cohort.  However, there is an approximate relationship 
between PFS and DCR at specified timepoints because patients whose disease has responded 
or is stable cannot have had a disease progression.  For example, if the median PFS of interest 
is 6 months this would suggest that 70% of patients will be progression-free at 3 months, 
assuming an exponential distribution of progression times.  Therefore, the selection of a DCR 
of 70% at 3 months (ie, at 12 weeks, using the timing conventions used throughout this 
protocol) for the Initial Stage Cohorts to drive decision making would also give some 
assurance that a level of PFS of interest is realistic without having to wait to actually observe 
the PFS times.
For this reason, the primary efficacy endpoint of the study in 6 of the 7 cohorts (ie, except the 
BRCAm ovarian cancer expansion cohort) is DCR, assessed at the following timepoints:

At 12 weeks for the Initial Stage Cohorts

At 24 weeks for the Second Stage ovarian cancer triplet and doublet cohorts
Disease control rate as an endpoint has been used to define the sample size in these cohorts.
Each cohort included into the study, except the BRCAm ovarian cancer expansion cohort, will 
be considered as individual predictive probability designs as described by Lee and Liu 2008.  
These designs are based on Bayesian predictive probability and the minimax criterion.  
Predictive probability is obtained by calculating the probability of a positive conclusion 
(rejecting the null hypothesis) should the trial be conducted to the maximum planned sample 
size given the interim observed data.  In this framework, the chance that the trial will show a 

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conclusive result at the end of the study, given the current information, is evaluated.  Then, the 
decision to continue or to stop the trial can be made according to the strength of the predictive 
probability versus pre-specified decision rules.  For example, if predictive probability is less 
than θL then the trial can be stopped for futility or if the predictive probability is greater than 
θU the null hypothesis can be rejected and the trial stopped for efficacy.  If neither threshold is 
crossed the study continues.  In this study there is interest in decision making based on both 
futility and efficacy therefore both thresholds will be defined with θL set at 10% and θU at 
90%.
Taking the predictive probability approach, in 6 of the 7 cohorts, we assume that the response 
(DCR) has a prior distribution of beta (0.5, 0.5) – a Jeffrey’s non-informative prior.  In the 
Initial Stage Cohorts, after evaluating DCR (at 12 weeks) and selected safety data from the 
first 10 patients in the cohort, DCR will be monitored every 5 patients until the maximum 
sample size is reached.  In the ovarian cancer triplet and doublet cohorts, DCR and selected 
safety data from the first 15 patients in the cohort will be evaluated at 24 weeks.  In each 
cohort the minimum sample size that results in type I and type II error rates under 0.10 and 
0.20 respectively is selected based on the optimization criterion that maximizes the power 
under alternative hypothesis.  The tumor types included and the target DCR in each case are
given below with the monitoring plans summarized in Figure 2 of the Core Protocol, Figure 1
of Appendix M, and Figure 1 of Appendix N, and details in Appendix F. 
The primary efficacy endpoint for the BRCAm ovarian cancer expansion cohort is ORR, and 
this endpoint has been used to define the sample size. 
For all cohorts except the BRCAm ovarian cancer expansion cohort, operating characteristics 
and monitoring plans were calculated using the Predictive Probability Calculation for Phase II 
(PID-535) Version 1.0 available from the biostatistics department at MD Anderson 
(https://biostatistics.mdanderson.org/SoftwareDownload/) (first accessed 07 August 2015).
The details of the sample size estimate for each cohort can be found in Section 8.1 of the 
relevant Module (Appendix H to Appendix N). 
8.3
Definitions of analysis sets
8.3.1
Full analysis set
The full analysis set will include all patients who receive at least 1 dose of study treatment and 
have not been excluded from the study for administrative reasons, eg, failing important 
inclusion criteria (a full list will be predefined in the Statistical Analysis Plan).  The full 
analysis set will be used for all efficacy analyses.

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8.3.2
Safety analysis set
The safety analysis set will consist of all patients who received at least 1 dose of study 
treatment.
8.3.3
Pharmacokinetic analysis set
For the Initial Stage Cohorts, the PK analysis set will include all patients who receive at 
least 1 dose of olaparib and provide evaluable PK profiles for at least 1 treatment period 
(olaparib run-in or olaparib+MEDI4736 combination period).
For the Second Stage Cohorts, the PK analysis set will include all patients who receive at 
least 1 dose of any study treatment (olaparib, MEDI4736, bevacizumab) and provide 
evaluable PK profiles for at least 1 treatment period. 
If a patient has an important protocol deviation that affects the evaluability of the PK profile 
in a treatment period, then the patient will not form part of the PK analysis set for that period 
but may still be included in the PK analysis set for the other period.
8.4
Outcome measures for analyses
At each visit when a tumor evaluation takes place the patient will be assigned a RECIST 1.1 
visit response of CR, PR, SD, PD, not evaluable (NE), no evidence of disease (NED) 
depending on the status of their disease compared to baseline and previous assessments.
8.4.1
Primary efficacy endpoint
The primary efficacy endpoints for the study cohorts are as follows:

Initial Stage Cohorts: DCR at 12 weeks

The DCR is defined as the percentage of patients who have at least 1 visit 
response of CR or PR or have demonstrated SD which is maintained until 
the RECIST 1.1 assessment at 12 weeks.

Ovarian cancer triplet and doublet cohorts: DCR at 24 weeks

The DCR is defined as the percentage of patients who have at least 1 visit 
response of CR or PR or have demonstrated SD which is maintained until 
the RECIST 1.1 assessment at 24 weeks.

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
BRCAm ovarian cancer expansion cohort: ORR

Objective response rate is defined as the number (%) of patients with at 
least 1 visit response of CR or PR, as assessed by the Investigator (see 
Section 8.4.2.5 for further details).  
8.4.2
Secondary efficacy endpoints
8.4.2.1
Disease control rate at 24, 28, and 56 weeks
DCR as defined in Section 8.4.1, but reported at 24, 28, or 56 weeks.
8.4.2.2
Progression-free survival
Progression-free survival based on RECIST 1.1 as assessed by the Investigator is a secondary 
endpoint for all cohorts. 
PFS is defined as the time from start of study treatment (Day 1; either the start of olaparib 
monotherapy for Initial Stage Cohorts or Cycle 1 Day 1 for Second Stage Cohorts) until the 
date of objective radiological disease progression according to RECIST 1.1 or death (by any 
cause in the absence of disease progression) regardless of whether the patient withdraws from 
therapy or receives another anticancer therapy prior to disease progression.  Patients whose
disease has not progressed or who have not died at the time of analysis will be censored at the 
time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.  
However, if the patient has disease progression or dies after 2 or more missed visits, they will 
be censored at the time of the latest evaluable RECIST 1.1 assessment.  If the patient has no 
evaluable visits or does not have a baseline assessment they will be censored at Day 1 of 
olaparib treatment unless they die within 2 tumor assessment visits of treatment start.
The PFS time will always be derived based on scan/assessment dates not visit dates.  All 
scans, not only those planned at weeks 12, 24, 28, and 56 for the DCR analysis, will be taken 
into account for the assessment of PFS.
RECIST 1.1 assessments/scans contributing towards a particular visit may be performed on 
different dates.  The following rules will be applied:
(a)
Date of progression will be determined based on the earliest of the RECIST 1.1 
assessment/scan dates of the component that triggered the progression
(b)
When censoring a patient for PFS the patient will be censored at the latest of the 
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Overall visit assessments will be determined for each assessment (scheduled or unscheduled) 
and will contribute to the derivation of PFS.
Objective progression is defined as at least a 20% increase in the sum of the diameters of the 
target lesions (compared to previous minimum sum) and an absolute increase of >5 mm, or an 
overall NTL assessment of progression or a new lesion. 
8.4.2.3
Overall survival
Overall survival is defined as the time from the start of study treatment (day 1; either the start 
of olaparib monotherapy for Initial Stage Cohorts or Cycle 1 Day 1 for Second Stage Cohorts)
until death due to any cause.  Any patient not known to have died at the time of analysis will 
be censored based on the last recorded date on which they were known to be alive.  See 
Section 3.10.2 for the methods to be used to obtain vital status for patients who are no longer 
in the study.
8.4.2.4
Time to study treatment discontinuation or death
The TDT will be assessed.  TDT is defined as the time from start of study treatment (Day 1; 
either the start of olaparib monotherapy for Initial Stage Cohorts or Cycle 1 Day 1 for Second 
Stage Cohorts) to the earlier of the date of study treatment discontinuation or death.  Any 
patient not known to have died at the time of analysis and not known to have discontinued 
study treatment will be censored based on the last recorded date on which the patient was 
known to be alive. 
8.4.2.5
Objective response rate 
Objective response rate based on RECIST 1.1 as assessed by the Investigator is a secondary 
endpoint in all cohorts, except for the BRCAm ovarian cancer expansion cohort.  Objective 
response rate is defined as the number (%) of patients with at least 1 visit response of CR or 
PR.  Data obtained up until progression, or last evaluable assessment in the absence of 
progression, will be included in the assessment of response rate.  Patients who discontinue 
study treatment without progression, receive a subsequent anticancer therapy and then respond 
will not be included as responders in the ORR.  The denominator used for analysis will be the 
number of patients who received at least 1 dose of investigational treatment for whom 
measurable disease is present at baseline.
8.4.2.6
Best objective response
Best objective response (BOR) is calculated based on the overall visit responses from each 
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has had following enrollment, but prior to starting any subsequent cancer therapy and up to 
and including RECIST progression or the last evaluable assessment in the absence of RECIST 
progression. Categorization of BoR will be based on RECIST using the following response 
categories: CR, PR, SD, NED (applies only to those patients entering the study with no 
disease at baseline), PD and NE. Patients who discontinue treatment without progression, 
receive a subsequent anticancer therapy and then respond will not be included as responders in 
the BOR. The denominator used for analysis will be the number of patients who received at 
least 1 dose of investigational treatment for whom measurable disease is present at baseline. 
For patients who die in the absence of progression and have no evaluable visit responses prior 
to death, BOR will be set to PD. 
8.4.2.7
Duration of response
Duration of Response (DoR) based on RECIST 1.1 as assessed by the Investigator is a 
secondary endpoint for all cohorts.  Duration of Response will be defined as the time from the 
date of first documented response until date of documented progression or death in the 
absence of disease progression, 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 response 
of PR or CR.
If a patient does not progress following a response, then their duration of response will use the 
PFS censoring time.
8.4.2.8
Percentage change in tumor size
The percentage change from baseline in tumor size at 12 and 28 weeks (Initial Stage Cohorts) 
and the percentage change from baseline in tumor size at 24 and 56 weeks (Second Stage 
Cohorts) are based on RECIST 1.1 target lesion measurements taken at baseline and either at 
12 and 28 weeks (Initial Stage Cohorts) or 24 and 56 weeks (Second Stage Cohorts).  Tumor 
size is the sum of the longest diameters of the target lesions.  Target lesions are measurable 
tumor lesions.  Baseline for RECIST 1.1 is defined to be the last evaluable assessment prior to 
starting olaparib treatment.  The percentage change in target lesion tumor size at each 
timepoint will be obtained for each patient taking the difference between the sum of the target 
lesions at each timepoint and the sum of the target lesions at baseline divided by the sum of 
the target lesions at baseline times 100; eg, for Week 12 (Week 12 - baseline) / baseline * 
100).

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8.4.2.9
Best overall percentage change from baseline in tumor size
The best percentage change from baseline in tumor size is based on RECIST 1.1 target lesion 
measurements taken at each RECIST 1.1 assessment.  All measurements up until RECIST 1.1 
progression or the last evaluable assessment in the absence of RECIST 1.1 progression will be 
included in the calculation.
8.5
Calculation or derivation of safety variable(s)
Safety and tolerability will be assessed within each tumor type in terms of AEs, deaths, 
laboratory data, vital signs and ECGs.  These will be collected for all patients.  Appropriate 
summaries of these data, to be described in the Statistical Analysis Plan, will be presented.
8.6
Methods for statistical analyses
For the Initial Stage Cohorts and the Second Stage ovarian cancer triplet and doublet cohorts, 
the primary endpoint is DCR in patients using Investigator assessments per RECIST 1.1.  In 
the BRCAm ovarian cancer expansion cohort, ORR is the primary endpoint.  Each cohort, with 
the exception of the BRCAm ovarian cancer expansion cohort, has been sized to characterize 
the DCR of MEDI4736+olaparib (or MEDI4736+olaparib+bevacizumab, for the ovarian 
cancer triplet cohort).  All formal statistical analysis will be performed on a per cohort basis, 
to test the main hypotheses that the DCR is above the threshold of interest defined for each 
cohort, or in the case of the BRCAm ovarian cancer expansion cohort, test the main hypothesis
that the ORR is above the threshold of interest.
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
cohort.  Continuous variables will be summarized by the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Categorical variables will be 
summarized by frequency counts and percentages for each category.  Unless otherwise stated, 
percentages will be calculated out of the population total for the corresponding treatment arm. 
Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of olaparib for Initial Stage Cohorts, or Cycle 1 Day 1 for Second Stage Cohorts.
All data collected will be listed.  Efficacy and safety data will be summarized on the Efficacy 
and Safety Analysis Sets.
With the exception of DCR at 12, 24, 28, and 56 weeks (which will be presented with 
90% CIs; see Section 8.6.1.1), results will be presented with 95% CIs, unless otherwise stated.

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8.6.1
Analysis of the primary variable(s)
8.6.1.1
Disease control rate (Initial Stage, ovarian cancer triplet, and ovarian cancer 
doublet cohorts)
The DCR will be summarized (ie, number of patients, %) in each tumor group.  Patients who 
do not complete the DCR assessment at the timepoint of interest (for example, due to drop out 
prior to the assessment) will be considered as a treatment failure.  The mean and median of the 
posterior distribution along with the standard deviation and a 90% credible interval around the 
mean (based on the highest posterior density [Lee 1997]) will be presented.  An exact 90% CI 
and 1-sided p-value will also be presented.
8.6.1.2
Objective response rate (BRCAm ovarian cancer expansion cohort)
Objective response rate will be analyzed when all 80 patients have been followed for a 
minimum of 24, 40, 56, 80, and 104 weeks.  For the BRCAm ovarian expansion cohort, at 
n=80, a 2-sided 95% CI for a single proportion using the large sample normal approximation 
will extend 0.090 from the observed proportion, for an expected proportion of 0.785 (eg, 95% 
CI: 69.5% to 87.5%).
8.6.2
Analysis of the secondary variables
8.6.2.1
Progression-free survival, overall survival and time to study treatment 
discontinuation or death
A Kaplan-Meier plot of PFS will be presented for each cohort.  Summaries of the number and 
percentage of patients experiencing a PFS event, and the type of event (RECIST 1.1 or death) 
will be provided along with median PFS.
The estimated PFS rates at specific timepoints (every 6 months to a maximum of 24 months) 
will also be presented.
The analysis will be based on the overall visit assessments (ie, individual tumor measurements 
will not be used) and using all scans regardless of whether they were scheduled or not. 
The analysis will be repeated for OS and TDT.
8.6.2.2
Summary of objective response rate
The ORR will be summarized (ie, number of patients, %) in each tumor group. 
8.6.2.3
Percentage change in tumor size and best percentage
These endpoints will be reported by cohort using summary statistics.

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8.6.3
Subgroup analysis
Not applicable.
8.6.4
Interim analysis
8.6.4.1
Safety review
A formal Safety Review process will be put in place throughout this study.  Please refer to 
Section 1.4 of the Core Protocol and to the cohort-specific Modules for further for details.
8.6.4.2
Continuous monitoring
Within each of the Initial Stage Cohorts, an initial review of DCR and selected safety data will 
take place when 10 patients have been evaluated at 12 weeks.  Patients who do not complete 
the DCR assessment (for example, due to drop out prior to the assessment) will be considered 
as a treatment failure.  Subsequent to the first 10 patients, the DCR will be monitored after 
every 5 patients become evaluable.
In the ovarian cancer triplet and doublet cohorts, an initial review of DCR and selected safety 
data will take place when 15 patients have been evaluated at 24 weeks.  Patients who do not 
complete the DCR assessment (for example, due to drop out prior to the assessment) will be 
considered as a treatment failure.  Subsequent to the first 15 patients, the DCR will be 
monitored again once 30 patients (full cohort) become evaluable.  In addition, the safety of the 
“triplet” treatment regimen will be assessed once n=10 patients have reached 4 weeks of 
treatment in the ovarian cancer triplet cohort.
Full details of these analyses will be included in the statistical analysis plan.  
8.6.5
Sensitivity analysis 
Not applicable.
8.6.6
Exploratory analysis
Not applicable; these endpoints will not be reported in the CSR.
8.7
Calculation or derivation of pharmacokinetic variables
The PK analysis of the plasma concentration data for olaparib will be performed at 
AstraZeneca Research & Development or by a clinical research organization identified by 
AstraZeneca Research & Development.  The actual sampling times will be used in the PK 
calculations.  For each patient providing a complete set of PK samples, non-linear mixed 

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effects modeling will be used to estimate steady state maximum observed plasma 
concentration, area under the curve, and minimum observed plasma concentration.
8.7.1
Olaparib and MEDI4736
 
 
 
 
Bevacizumab
Bevacizumab serum concentrations will be listed and summarized by timepoint. 
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC
system utilized.
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.
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:
!
Provide information and support to the Investigator(s)
!
Confirm that facilities remain acceptable
!
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
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accordance with the Laboratory Manual and that study drug accountability checks are 
being performed

Perform source data verification (a comparison of the data in the eCRFs with the patient’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating patients.  This will require 
direct access to all original records for each patient (eg, clinic charts)

Ensure withdrawal of informed consent to the use of the patient’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the patient.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the center needs information and advice about the study conduct.
9.2.1
Source data
Refer to the CSA for location of source data.
9.2.2
Study agreements
The PI at each/the center should comply with all the terms, conditions, and obligations of the 
CSA, or equivalent, for this study.  In the event of any inconsistency between this Clinical 
Study Protocol and the CSA, the terms of Clinical Study Protocol shall prevail with respect to 
the conduct of the study and the treatment of patients and in all other respects, not relating to 
study conduct or treatment of patients, the terms of the CSA shall prevail.
Agreements between AstraZeneca and the PI should be in place before any study-related 
procedures can take place, or patients are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.3
Study timetable and end of study
The end of the study is defined as the date of the last visit of the last patient occurring when 
all patients have completed study therapy.
In the event that a roll-over or safety extension study is available at the time of the final data 
cut-off and database closure, patients currently receiving MEDI4736 and/or olaparib treatment 
may be transitioned to such a study, and the current study would reach its end. The roll-over 
or safety extension study would ensure treatment continuation with visit assessments per its 
protocol. Any patient proposed to move to such a study would be given a new ICF.

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There will be a data cut-off for each cohort, after which only survival, subsequent anticancer 
treatment, and specific safety data (see below) may be collected in the clinical study database
(see Section 9 of each cohort for cohort-specific details). The data cut-offs will be as follows:
!
For the Initial Stage SCLC, gastric cancer, gBRCAm breast cancer, and gBRCAm ovarian 
cancer cohorts, the data cut-off occurred once all 4 cohorts had reached last patient first 
visit (LPFV) + 2 years and all 4 cohorts had observed a median value for PFS. For the 
Initial Stage gBRCAm ovarian cancer cohort only, once the data cut-off occurred, only 
survival, subsequent anticancer treatment, and safety data will continue to be collected in 
the clinical study database, until the final data cut-off is reached.
!
For the Second Stage Cohorts, the final data cut-off will be once the doublet and triplet 
ovarian cancer cohorts have observed a median value for overall survival. The expansion 
cohort will be analyzed once this data cut-off has occurred.  At this timepoint, the clinical 
study database will close to new data.
9.3.1
Post final data cut off 
Patients are permitted to continue to receive study treatment beyond the closure of the 
database if, in the opinion of the Investigator, they are continuing to receive benefit from 
treatment. Patients who remain on study treatment after this timepoint will be monitored 
according to routine clinical practice as defined by the Investigator. At routine clinic visits, 
patients will return used medication packaging and unused medication, and a thorough drug 
accountability assessment will be performed. 
 
 
For patients who do continue to receive treatment beyond the time of the data cut-off, 
Investigators will continue to report all SAEs to AstraZeneca Patient Safety until 90 days after 
study treatment is discontinued, in accordance with Core Protocol Section 6.4 (Reporting of 
Serious Adverse Events).  
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 
causally related to the IP, the Investigator should notify AstraZeneca, Patient Safety.  
Additionally, as stated in Core Protocol Section 6.3 (Recording of AEs), any SAE or 
non-serious AE that is ongoing at the time of this data cut-off, must be followed up by the 
Investigator for as long as medically indicated.  
The study started in Q2 2016; the final data cut-off is expected to occur in 2021.
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The study may be terminated at individual centers 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 olaparib and MEDI4736.  AstraZeneca reserves the right to close 
the study site or terminate the study at any time for any reason.
9.4
Data management by IQVIA
Data management will be performed by IQVIA, 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.  Medications will be 
classified according to the World Health Organisation (WHO) Drug Dictionary.  
Classification coding will be performed by IQVIA.
The data collected through third party sources will be obtained and reconciled against study 
data.
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.
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.
SAE Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data Management of genotype data
See Appendix C.

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Data associated with human biological samples
 
 
 
Management of external data
Data from external providers (eg, central laboratories) will be validated as appropriate to 
ensure they are consistent with the clinical data and this data will be included in the final 
database.
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 Council for Harmonisation 
(ICH)/GCP, applicable regulatory requirements and the AstraZeneca policy on Bioethics and 
Human Biological Samples.
Regulatory Reporting Requirements for Serious Adverse Events
!
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.
!
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators.
!
For all studies except those utilising medical devices Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary.
!
An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements.
10.2
Patient data protection
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation.
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
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Refer to Appendix C for details of data protection for genetic samples and information.
10.3
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.4
Ethics and regulatory review
An EC/IRB should approve the final study protocol, including the final version of the ICF and 
any other written information and/or materials to be provided to the patients.  The Investigator
will ensure the distribution of these documents to the applicable EC/IRB, and to the study site 
staff.
The opinion of the EC/IRB should be given in writing.  The Investigator should submit the 
written approval to AstraZeneca before enrollment of any patient into the study. 
The EC/IRB should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the EC/IRB annually.
Before enrollment of any patient into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.

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AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, EC/IRB and PIs with safety updates/reports 
according to local requirements.
10.5
Informed consent process
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorised representative and answer all questions regarding the study.  
Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center. 
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative. 
If a patient declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the patient and he/she will not be 
excluded from other aspects of the study.
If a patient’s partner becomes pregnant during or within 90 days after the last dose of study 
treatment, the partner is asked to sign the "Adult Study Informed Consent Form for Pregnant 
Partners of Study Patients" and provide information about the pregnancy accordingly.
The Investigator or authorized designee will explain to each patient the objectives of the 
exploratory research. Patients will be told that they are free to refuse to participate in any 
optional samples or the future use and may withdraw their consent at any time and for any 
reason during the retention period.

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10.6
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the PI and 
AstraZeneca.
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol.
The new version of the Clinical Study Protocol 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 new versions of Clinical Study Protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the Clinical 
Study Protocol to each PI(s).  For distribution to EC/IRB see Section 10.4.
If a change to a Clinical Study Protocol requires a change to a center’s ICF, AstraZeneca and 
the center’s EC/IRB are to approve the revised ICF before the revised form is used. 
10.7
Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an EC/IRB may perform 
audits or inspections at the center, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, 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 center.
10.8
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and 
letters to Investigators.
10.9
Dissemination of clinical study data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com
and http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical study and/or summary of main study results may also be available on 

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other websites according to the regulations of the countries in which the main study is 
conducted.
10.10
Data quality assurance
All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
10.11
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.

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All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and 
evaluation of the study are defined as source documents. Source data are contained in source 
documents (original records or certified copies).
10.12
Publication policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
11.
LIST OF REFERENCES
Antonia et al 2017
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after 
Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 
2017;377(20):1919-29.
Bang et al 2019
Bang YJ, Kaufman B, Geva R, Stemmer S, Hong SH, Lee JS, et al. An open-label, phase II 
basket study of olaparib and durvalumab (MEDIOLA): Results in patients with relapsed 
gastric cancer. J Clin Oncol 2019;37:140.
Bang et al 2017
Bang YJ, Xu RH, Chin K, Lee KW, Park SH, Rha SY, et al. Olaparib in combination with 
paclitaxel in patients with advanced gastric cancer who have progressed following first-line 
therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 
2017;18(12):1637-51.
Berger et al 2008
Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I safety 
and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in 
patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(10):3044-51.

Revised Clinical Study Protocol
Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
176(461)
Blank et al 2006
Blank C, Kuball J, Voelkl S, Wiendl H, Becker B, Walter B, et al. Blockade of PD-L1 
(B7-H1) augments human tumor-specific T-cell responses in vitro. Int J Cancer. 
2006;119(2):317-27.
Brahmer et al 2010
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study 
of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, 
clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 
2010;28(19):3167-75.
Chatzinikolaou et al 2014
Chatzinikolaou G, Karakasilioti I, Garinis GA. DNA damage and innate immunity: links and 
trade-offs. Trends Immunol. 2014;35(9):429-35. 
Domchek et al 2020
Domchek SM, Postel-Vinay S, Im SA, Park YH, Delord JP, Italiano A, et al. Olaparib and 
durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): 
an open-label, multicentre, phase 1/2, basket study. Lancet Oncol. 2020;21(9):1155-1164.
Dong et al 2002
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated 
B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 
2002;8(8):793-800.
Drew et al 2019
Drew Y, Kaufman B, Banerjee S, Lortholary A, Hong SH, Park YH, et al. 1190PD - Phase II 
study of olaparib + durvalumab (MEDIOLA): Updated results in germline BRCA-mutated 
platinum-sensitive relapsed (PSR) ovarian cancer (OC). Ann. Oncol. 2019;30(supplement 
5):v485-486.
Drew et al 2018
Drew Y, de Jonge M, Hong SH, Park YH, Wolfer A, Brown J, et al. An open-label, phase II 
basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA -mutated 
(gBRCA m) platinum-sensitive relapsed (PSR) ovarian cancer (OC). Gynecologic Oncology. 
2018;149:246-247.
Eisenhauer et al 2009
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;45:228-47.
Farmer et al 2005
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the 
DNA repair defect in BRCA mutanT-cells as a therapeutic strategy. Nature. 
2005;434(7035):917-21.

Revised Clinical Study Protocol
Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
177(461)
FDA bevacizumab label
Avastin® (bevacizumab). Solution for intravenous infusion. 2004. Genentech, Inc
Fife and Bluestone 2008
Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the 
CTLA-4 and PD-1 pathways. Immunol Rev. 2008;224:166-82.
Hamanishi et al 2007
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed 
cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of 
human ovarian cancer. Proc Nat Acad Sci U S A. 2007;104(9):3360-5.
Higuchi et al 2015
Higuchi T, Flies DB, Marjon NA, Mantia-Smaldone G, Ronner L, Gimotty PA, et al. CTLA-4 
Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient Ovarian 
Cancer. Cancer Immunol Res. 2015;3(11):1257-68.
Hirano et al 2005
Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and
PD-1 by Monoclonal Antibodies Potentiates Cancer Therapeutic Immunity. Cancer Res. 
2005;65(3):1089-96.
Huang et al 2015
Huang J, Wang L, Cong Z, Amoozgar Z, Kiner E, Xing D, et al. The PARP1 inhibitor BMN 
673 exhibits immunoregulatory effects in a Brca1(-/-) murine model of ovarian cancer. 
Biochem Biophys Res Commun. 2015;463(4):551-6. 
Iwai et al 2002
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor 
cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. 
Proc Natl Acad Sci U S A. 2002;99(19):12293-7.
Karzai et al 2017
Karzai F, Madan RA, Owens H, Hankin A, Couvillon A, Houston ND, et al. A phase II study 
of the anti-programmed death ligand-1 antibody durvalumab (D; MEDI4736) in combination 
with PARP inhibitor, olaparib (O), in metastatic castration-resistant prostate cancer (mCRPC). 
J Clin Oncol 2017;35:6(suppl) 162-162.
Kaufman et al 2015
Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, et 
al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 
mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50.
Keir et al 2008
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol. 2008;26:677-704.

Revised Clinical Study Protocol
Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
178(461)
Krambeck et al 2007
Krambeck AE, Dong H, Thompson RH, Kuntz SM, Lohse CM, Leibovich BC, et al. Survivin 
and B7-H1 are collaborative predictors of survival and represent potential therapeutic targets 
for patients with renal cell carcinoma. Clin Cancer Res. 2007;13(6):1749-56.
Krebs et al 2017
Krebs M, Ross K, Kim S, De Jonge M, Barlesi F, Postel-Vinay S, et al. P1.15-004 An 
open-label, multitumor phase II basket study of olaparib and durvalumab 
(MEDIOLA):Results in patients with relapsed SCLC. J Thorac Oncol 2017;12: S2044-S2045.
Kroemer et al 2012
Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu 
Rev Immunol. 2013;31:51-72. 
Latchman et al 2004
Latchman YE, Liang SC, Wu Y, Chernova T, Sobel RA, Klemm M, et al. PD-L1-deficient 
mice show that PD-L1 on T-cells, antigen-presenting cells, and host tissues negatively 
regulates T-cells. Proc Natl Acad Sci U S A. 2004;101(29):10691-6.
Ledermann et al 2012
Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib 
maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 
2012;366(15):1382-92.
Ledermann et al 2014
Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib 
maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a 
preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial.
Lancet Oncol. 2014;15(8):852-61.
Ledermann et al 2016
Ledermann JA, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Overall 
survival (OS) in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (PSR 
SOC) receiving olaparib maintenance monotherapy: An interim analysis. J Clin Oncol.
2016;34 (suppl; abstr 5501).
Lee et al 2017
Lee JM, Cimino-Mathews A, Peer CJ, Zimmer A, Lipkowitz S, Annunziata CM, et al. Safety 
and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in 
Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial 
Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, 
Phase I Study. J Clin Oncol. 2017;35(19):2193-2202.
Lee 1997
Lee PM. Bayesian statistics: an introduction. 1997. New York: John Wiley & Sons.

Revised Clinical Study Protocol
Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
179(461)
Lee and Liu 2008
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clin Trials. 
2008;5(2):93-106.
Loos et al 2008
Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, et al. Clinical significance 
and regulation of the costimulatory molecule B7-H1 in pancreatic cancer. Cancer Lett. 
2008;268(1):98-109.
Madan and Gulley 2011
Madan RA, Gulley JL. Sipuleucel-T: harbinger of a new age of therapeutics for prostate 
cancer. Expert Rev Vaccines. 2011;10(2):141-50.
Mu et al 2011
Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer 
may contribute to poor prognosis and tumor cells immune escape through suppressing tumor 
infiltrating dendritic cells maturation. Med Oncol. 2011;28(3):682-8.
Mulligan et al 2014
Mulligan JM, Hill LA, Deharo S, Irwin G, Boyle D, Keating KE, et al. Identification and 
validation of an anthracycline/cyclophosphamide-based chemotherapy response assay in 
breast cancer. J Natl Cancer Inst. 2014;106(1):djt335.
Narwal et al 2013
Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an 
investigational anti-interferon-alpha monoclonal antibody, in systemic lupus erythematosus. 
Clin Pharmacokinet. 2013;52(11):1017–27.
Ng et al 2006
Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab 
in cancer patients based on population pharmacokinetic analysis. Pharm Res. 
2006;23(6):1275–84.
Nishimura et al 1998
Nishimura H, Minato N, Nakano T, Honjo T. Immunological studies on PD-1 deficient mice: 
implication of PD-1 as a negative regulator for B cell responses. Int Immunol. 
1998;10(10):1563-72.
Nishimura et al 2001
Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune 
dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291(5502):319-22.
Nomi et al 2007
Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151-7.

Revised Clinical Study Protocol
Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
180(461)
Okudaira et al 2009
Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, et al. Blockade of B7-
H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. Int J Oncol. 
2009;35(4):741-9.
Pages et al 2010
Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautès-Fridman C, Fridman WH. Immune 
infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene. 
2010;29(8):1093-1102.
Park et al 2010
Park J, Omiya R, Matsumura Y, Sakoda Y, Kuramasu A, Augustine MM, et al. B7-H1/CD80 
interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood. 
2010;116(8):1291-8.
Powles et al 2017
Powles T, O'Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, et al. 
Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: 
Updated Results From a Phase 1/2 Open-label Study. JAMA Oncol. 2017;3(9):e172411.
Pujade-Lauraine et al 2017
Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT5, Oza AM, et al. Olaparib 
tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer 
and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-
controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274-84.
Robson et al 2017
Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for Metastatic 
Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 
2017;377(6):523-33.
Schmidinger et al 2004
Schmidinger M, Hejna M, Zielinski CC. Aldesleukin in advanced renal cell carcinoma. Expert 
Rev Anticancer Ther. 2004;4(6):957-80.
Tang et al 2014
Tang ML, Khan MK, Croxford JL, Tan KW, Angeli V, Gasser S. The DNA damage response 
induces antigen presenting cell-like functions in fibroblasts. Eur J Immunol. 
2014;44(4):1108-18.
Tarhini 2013
Tarhini A. Immune-Mediated Adverse Events Associated with Ipilimumab CTLA-4 Blockade
Therapy: The Underlying Mechanisms and Clinical Management. Scientifica (Cairo).
2013;2013:857519.

Revised Clinical Study Protocol
Drug Substance Olaparib and MEDI4736 
Study Code D081KC00001
Version 7
Date 17 December 2020
181(461)
Thompson et al 2005
Thompson RH, Gillett MD, Chevillem JC, Lohsem CM, Dongm H, Webster WS, et al. 
Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. 
Cancer. 2005;104(10):2084-91.
Thompson et al 2006
Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor 
B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term 
follow-up. Cancer Res. 2006;66(7):3381-5.
Topalian et al 2012
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 
2012;366(26):2443-54.
Wang et al 2010
Wang L, Ma Q, Chen X, Guo K, Li J, Zhang M. Clinical significance of B7-H1 and B7-1 
expressions in pancreatic carcinoma. World J Surg. 2010;34(5):1059-65.
Wang et al 2009
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based 
dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 
2009;49(9):1012-24.
Wolchok et al 2010
Wolchok JD, Weber JS, Hamid O, Lebbé C, Maio M, Schadendorf D, et al. Ipilimumab 
efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA 
subtype from four trials. Cancer Immun. 2010;10:9.
Zhang et al 2008
Zhang C, Wu S, Xue X, Li M, Qin X, Li W, et al. Anti-tumor immunotherapy by blockade of 
the PD-1/PD-L1 pathway with recombinant human PD-1-IgV. Cytotherapy. 
2008;10(7):711-9.
Zhang et al 2012
Zhang S, Shi R, Li C, Parivar K, Wand DD. Fixed dosing versus body size-based dosing of 
therapeutic peptides and proteins in adults. J Clin Pharmacol. 2012;52(1):18–28.
Zou and Chen 2008
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev 
Immunol. 2008;8(6):467-77.

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