Clinical trial NCT02937818
Conditions: Platinum Refractory Extensive-Stage Small Cell Lung Carcinoma
Keywords: Platinum Refractory Extensive-Stage Carcinoma, Small Cell Lung Platinum Refractory Extensive-Stage Oat Cell Carcinoma of Lung Platinum Refractory Extensive-Stage Oat Cell Lung Cancer Platinum Refractory Extensive-Stage Small Cell Cancer Of The Lung Platinum Refractory Extensive-Stage Small Cell Lung Cancer
Sponsor: AstraZeneca
Start date: 2016-11-28; Completion date: 2023-11-27
Enrollment: 72 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study design This is a Phase II, open-label, multi-drug, multi-center, multi-arm, signal-searching study in patients with extensive-stage small-cell lung cancer (SCLC) who have refractory or resistant disease from prior platinum-based chemotherapy.

Detailed description:
This study is modular in design, allowing evaluation of the preliminary efficacy, safety, tolerability, and immunogenicity of novel combinations of immunotherapies and/or deoxyribonucleic acid (DNA) damage repair inhibitors in patients with platinum refractory or resistant extensive-stage-disease SCLC. Patients who have progressive disease (PD) during first-line platinum-based chemotherapy (platinum refractory) or PD within 90 days after completing first-line platinum-based chemotherapy (platinum resistant) will be enrolled to the study. The primary objective of the study is to assess the preliminary efficacy of each treatment arm based on objective response rate (ORR).

This study consists of a number of arms (sub-studies), each evaluating the efficacy, safety, and tolerability of a specific agent or combination. This study was initially open with 2 arms (Arms A and B), and additional arms may open, provided there is compelling rationale for the combination and safe and tolerable doses and schedules have been determined from ongoing Phase I studies. There are 2 pre-defined arms:

A. Durvalumab + tremelimumab followed by durvalumab monotherapy B. AZD1775 + carboplatin (CBDP)

Further arm was added in amendment 3:

C. AZD6738 + olaparib Amendment #4 was updated with possibility to allow expansion of any arm, to a total of 40 eligible subjects, based on Review Committee assessment of data from the first 20 subjects (from Stage 1 and Stage 2). Currently Arm A will enroll 20 additional patients into expansion.

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Durvalumab and Tremelimumab intervention 2: AZD1775 and carboplatin (CBPT) intervention 3: AZD6738 and olaparib
Intervention descriptions: intervention 1: Durvalumab + tremelimumab via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 months (4 cycles) followed by durvalumab monotherapy via IV infusion q4w, starting on Week 16 until PD, or for other discontinuation criteria. intervention 2: AZD1775 twice daily (oral) for 2.5 days from Day 1 + CBDP area under the curve 5 (Day1) (IV); every 3 weeks. intervention 3: AZD6738 once a day (oral) for 7 days from Day 1 + olaparib twice a day(oral) for 28 days from Day 1, every 4 weeks

Protocol documents:
Prot_000.pdf: 
Protocol number: D419QC00002 
Document title: A Phase II, Open-Label, Multi-Arm Study to   
Determine the Preliminary Efficacy of Novel Combinations of 
Treatment in Patients with Platinum Refractory Extensive-Stage 
Small-Cell Lung Cancer (BALTIC) 
NCT number: NCT02937818 
Version number: 5.0 
Date of the document: 16 January 2020 


The following Amendment(s) and Administrative Changes have been made to this protocol since the date of 
preparation:
Amendment No.
Date of Amendment
Local Amendment No:
Date of Local Amendment
1
01Jul2016
2
30 Mar2017
3
15Dec 2017
4
25June 2018
5
16Jan2020
Administrative 
Change No.
Date of Administrative 
Change
Local Administrative 
Change No.
Date of Local 
Administrative Change
Clinical Study Protocol 
Drug Substance
Durvalumab (MEDI4736), 
tremelimumab, AZD1775, 
carboplatin, olaparib, 
ceralasertib (AZD6738)
Study Code
D419QC00002
Version
05
Date
16Jan2020
EudraCT Number
2016-001202-42
A Phase II, Open-Label, Multi-Arm Study to Determine the Preliminary 
Efficacy of Novel Combinations of Treatment in Patients with Platinum 
Refractory Extensive-Stage Small-Cell Lung Cancer (BALTIC)
Sponsor:
AstraZeneca AB, 151 85 Södertälje, Sweden


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
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VERSION HISTORY
Version 05, 16Jan2020
The following changes were incorporated into version 05 of the protocol:

Sections on durvalumab and tremelimumab monotherapies and combined therapy 
updated as per current IBs in Appendix A. Sections updated: 2.7.2.1, 2.7.2.2, 
2.7.2.3 and 7.6

Dosing Modification and Toxicity Management Guidelines for durvalumab and 
tremelimumab separated from Appendix A (i.e. Arm A study protocol). Sections 
updated: 6.2.3, 7.5, (Section 7.5.2 added), and Appendix A1 (removed from 
Appendix A) 

Removal of the requirement to collect PK samples after Cycle 6 in Arm C. Sections 
updated: Appendix C Table 3 (schedule of assessments) and Section 7.2

Haematological parameters for ongoing treatment, and guidance for dose 
modifications revised as per updated Cerelasertib guidance. Sections updated: 
Appendix C, Section 8.4 (Dose modification and management of investigational 
product toxicities)

Photosensitivity added to restrictions in Appendix C.  Section updated: Appendix 
C, Section 5.5.4

Study drug name AZD6738 supplemented or replaced with ceralasertib across the 
protocol.
Version 04 , 25June 2018
The following changes were incorporated into version 04 of the protocol:

Protocol synopsis and Section 2.2.1 Rationale for study design were updated to 
allow expansion of any arm, to a total of 40 eligible subjects, based on Review 
Committee assessment of data from the first 20 subjects.

 
 
 
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
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
Synopsis Statistical Methods section and Section 9.2 Sample Size Estimate of 
Master protocol updated to correct typos, include a row in the table for 40 subjects
and remove the column for 
.

Rationale for study design updated in Section 2.2.1 to clarify that the decision-
making for moving to Stage II and expansion of arms will be a Review Committee
assessment of the first 20 subjects, based on the totality of the data considering 
benefit-risk assesment.

Figure 1 study design diagram updated to include Arm A expansion.

Section 2.3 benefit-risk updated with 6 and 12 months OS data.

Figure 2 of study design updated to include Arm A expansion.

Information updated on exploratory objectives in Section 3.4 for consistency with 
synopsis.

Inclusion criteria from Section 4.1 and exclusion criteria from Section 4.2 were 
deleted and added to criteria section in each arm appendix.

Section 4.5 Methods for assigning treatment groups updated to clarify that parallel 
recruitment is allowed.

Information added to Section 6.1 to clarify how to follow up if patients discontinue 
study treatment prior to PD.

Section 6.2.1 Laboratory safety assessments has been updated to remove lists of 
variables measured as these are fully described in the individual arms.

Section 6.2.5 Other safety assessments has been moved to Appendix for Arm A.

 
 
 

Section 7.9 Study governance and oversight updated to clarify the role of Review 
Committee in decision-making 

Section 9.3.2 evaluable set definition has been deleted, including a sentence about 
replacing subjects (information on replacement has now been mentioned earlier in 
CSP).

Wording describing expansion added to Section 9.5 Methods for statistical analyses.
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
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
Section 9.5.8 Analysis following expansion added to explain there is no need for 
further interim analysis in that group of patients and describe planned sensitivity 
analysis.

Section 10.3 Study timetable and end of study updated to be consistent with 
predicted end of trial as described in clinicaltrials.gov

Wording was updated through protocol to streamline document, provide 
clarifications and make more user-friendly (e.g. clarified “study treatment 
commencement” instead of “study start”; provided references to appropriate 
appendix; corrected typos; renumbered tables etc)

Appendix A Section 2.5 Rationale for study design, doses, and control groups 
updated to include scientific rationale for expanding Arm A.

Appendix A Section 2.6 Durvalumab and tremelimumab dose and treatment 
regimen justification updated with latest data and durvalumab IB.

Appendix A Figure 1 updated to reflect addition of Expansion patients

Appendix A Section 4.1 and Section 4.2 updated to contain a complete set of 
inclusion and exclusion criteria. Mandatory provision of archival or fresh tumour 
sample added as an eligibility criterion for Arm A.

Appendix A Table 2 Schedule of assessments updated to remove biomarker samples 
that are not collected (e.g. 
), added (e.g. 
) and tighten requirements for 
tumour biopsy material. Footnotes updated to clarify that some samples are not 
required in the expansion group (including PK, anti-drug antibodies (ADA) and 
mRNA).

Appendix A Table 3 Schedule of assessments (post-discontinuation) updated 
regarding PK samples to clarify not required for expansion group.

Appendix A Section 6 Study assesments updated to include laboratory variables and 
other safety assessments instead of these being in master protocol, and vital signs 
moved to Section 6.2 safety assessments.

Appendix A section 6.3
 
.

Appendix B Section 3.4 updated to remove 
 as not relevant at this time.

Appendix B Section 4.1 and Section 4.2 updated to contain a complete set of 
inclusion and exclusion criteria.
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
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
Updates added to Appendix B Table 1 to reflect updates of protocol structure and to
to remove need to collect 
 Footnote added to highlight the need to check 
haematology results prior to each cycle.

Addition of footnote e in Appendix B Table 1 regarding availability of haematology 
results prior to dosing of each cycle.

Appendix B section 6.1 Safety Assessments updated with the complete set of 
laboratory variables, moved from master protocol.

Appendix B Section 7.3.1 updated with clarification to the dose modification 
guidance for haematological events with current safety guidance regarding 
AZD1775 plus carboplatin.

Addition of Hepatitis B, C and HIV testing into Appendix C Table 3 Schedule of 
assessment for olaparib + AZD6738 combination therapy. RECIST schedule 
corrected to include the 12 week scan. Footnotes amended to remove redundant 
nausea and vomiting eCRF.

Appendix C Section 7.4.5 and Table 3 updated to reflect the wording on optional 
exploratory genetic sample informed consent form, consistent with current 
durvalumab template.

Appendix C Section 9.7.2 updated to reflect information included in latest olaparib 
IB (edition 15).

Appendix F (RECIST) Section 4.1 Schedule of evaluation: wording amended from 
“confirmatory scan” to “follow up scan” and deleted sentence describing 
continuation of study drug past progression until confirmation, as it only applies to 
Arm A, which is fully described in Section 5 of this appendix.

 

List of References moved to Appendix K
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
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Version 03,  15 December 2017
The following changes were incorporated into version 3.0 of the protocol:

Treatment Arm C added to protocol – subprotocol for this Arm is included in 
APPENDIX  C

Appropriate section, figures and tables of this protocol updated to reflect addition of 
Arm C

Changes related to the numbering of Sections and naming of Appendices updated to 
indicate the separation of treatment Arms 

Table of content updated to reflect changes in numbering and naming of Appendices 
throughout the protocol

Minor editorial changes of a typographical nature made throughout the protocol for 
consistency and clarity.  Several references to sections were updated for consistency 
across the protocol. 

Clarification to interim analysis description was added in Synopsis section to clarify 
the action taken in event of a decision to close Arm after stage 1

List of References updated to reflect all added references. All references moved to 
Appendix J

Exploratory objective and specification for Arms was added to Section 3.4, Study 
Objectives

Information to refer to Arm specific criteria added to Section 4.1. and 4.2

Clarification added to Section 4.9 on discontinuation of investigational product

Information added in Section 4.10.2 regarding possible replacement of withdrawn 
patients

Clarification was added in Section 4.10.3 on consent withdrawal

Addition of Section 6.2.5 regarding Other Safety Assessments

Information in Section 6.6.1.3 added on collection and processing of 
 
samples

Section 7.3.1, Time period for collection of adverse events, revised to address events 
post the defined safety follow-up period
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
7 (296)

Section 7.3.2, Follow-up of unresolved adverse events, revised to align with current 
IB

Information updated in Section 7.9 on study governance and oversight

Information on Safety Analysis Set updated in table 9.3 and section 9.3.2

Information added in section 9.3.1 to provide definition of evaluable patients

Section 9.5.1 added to provide more clarity on clarity on Primary Analysis including 
OS analysis

Clarification on patients included in safety and efficacy analyses added to Section 
9.5.7

Addition of timelines for publishing of safety and efficacy analyses added to Section 
9.5.7

Information updated in section 10.4 on data management

Information updated in Section 11.3 on ethics and regulatory review 

Appendix A, Sections 2.2, 2.3, 2.4, 2.6.4, 2.6.5.1, 2.7.2, 4.6, 7.5, 7.6 and 8.1 content 
updated to align with current IBs

Information added to Appendix A, Section 2.8 to provide clarity on study design for 
Arm A

Additional clarification added to inclusion criteria regarding fulfilment of criteria in 
Appendix A, Section 4.1. 

Clarification added to inclusion criterion 5 in Appendix A, section 4.1 on 
prohibition of use of granulocyte-colony stimulating factor for neutrophils raising 
during screening 

Information regarding sample collection for biomarker analysis in Appendix A, 
section 6.2. added

Clarification on sample disposition and timing of pharmacokinetic/ADA samples 
added to Appendix A, section 6.5

Appendix A, Section 8.1.2 updated to clarify product storage

Information updated in Appendix A, section 8.2.1 regarding re-consenting of 
patients 


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
8 (296)

Updated Appendix A Table 7 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) to version from 1 Nov 2017

Information added to Appendix B Section 2.6 to provide clarity on study design for 
Arm B

Additional information added regarding exclusion criterion 8 in Appendix B section 
4.2

Additional information regarding sample collection for biomarker analysis added in 
Appendix B section 6.4

Information was added to Appendix B Section 7.2.2 regarding paternal exposure

Appendix B Section 7.3 updated to reflect latest PSSR

Content moved from Appendix B2 to Appendix A Table 7 as the is common to all 
treatment arms. Duplicative parts related only to Arm B removed as already 
described in Appendix B section 8.7.1

Additional information added in Appendix G regarding acceptable contraceptive 
methods
Version 02, 30 March 2017

The following changes were incorporated into version 2.0 of the protocol:Minor 
editorial changes of a typographical nature were made throughout the protocol for 
consistency and clarity.  Several references to sections were updated for accuracy. 

Changes related to the numeration were made for the majority of sections for 
consistency with the current protocol templates for durvalumab   and AZD1775.

Minor clarifications were made throughout the protocol for consistency with the 
current protocol templates for durvalumab and AZD1775.

Clarification added regarding the number of patients to be enrolled in Synopsis, 
Section 1 and Section 2.4.

Addition of the timelines between progression and enrolment  to target population in 
Synopsis


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
9 (296)

Changes related to weigh based dosing for patients whose weight falls to 30kg or 
below in Synopsis, Sections 2.6.1, 2.6.4, 2.6.6, 2.8, 8.1.1, 8.2.

Minor clarification added to inclusion criteria 3 regarding stage at initial diagnosis.

Clarification added to inclusion criteria 4 regarding the timelines between 
progression and enrolment  

Information added to Section 5 Study plan and timing of procedures regarding 
relevant assessments. 

Change related to the time of validity of laboratory samples between screening and 
baseline was from 7 days to 3 days in Section 6.2.1.

Addition of Partial thromboplastin time into Table 2 “Hematology variables to be 
measured”.

Information added to Section 6.2.3. Resting 12-lead ECGs regarding additional ECG 
monitoring for Arm B

Minor clarification added to Section 7.6 Overdose

Information added regarding sensitivity analysis in Section 9.5

Information updated on number of patients who received durvalumab in Section 2.2, 
2.4

Additional information added on Study D4190C00006 Section 2.6.3.1

Additional information added on Rationale for four cycles of combination therapy 
followed by durvalumab monotherapy Section 2.6.4.

Removal of Section 12.7.1.2 Tremelimumab as there will be no tremelimumab 
monotherapy in the trial.

Information added to Sections 2.7.2, 2.7.2.1, 2.7.2.2 and 2.7.2.3 regarding identified 
and potential risks for durvalumab, tremelimumab and durvalumab + tremelimumab.

Information on blood donation was added to Section 4.6.

Additional information added on intravaginal devices for contraception to Appendix 
A Table 1.

Information added to Section 5 regarding reasons for potential dosing delay.


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
10 (296)

Information added on Coagulation (PT/INR/PTT) requirements to Appendix A 
Table 2.

Addition of footnote q that specifies the time of sample collection to Appendix A 
Table 2.

Removal of footnote j from Appendix A Table 3 as this is for post discontinuation 
PK.

Information added to Section 6.1 regarding ORR and confirmation of progression.

Information added to Section 7.5 regarding  Dosing Modification and Toxicity 
Management Guidelines for patients with new or worsening pulmonary symptoms.

Information added to Section 7.5.1 regarding etiologic causes of the imAE.

Additional clarification and information added to Section 7.6 regarding AESIs.

Additional information added to Section 8.1.1 regarding durvalumab administration.

Additional information added to Section 8.1.2 tremelimumab administration.

Information added to Section 8.2.1 regarding progression during treatment.

Information added to Appendix A Table 7 regarding Herbal and natural remedies as 
prohibited medication.

Amendment of Appendix A1 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) to version from 19 Aug 2016.

Amendment of  Section 2.5.2.1 regarding identified and potential risks for 
AZD1775.

Clarification added to Section 4.1, inclusion criteria 4 regarding Cockcroft-Gault 
method GFR calculation.

Clarification added to Section 4.2, exclusion criteria 10, and Section 8.7.1 regarding 
use of sensitive substrates of CYP3A4.

Section 4.2, exclusion criteria 15 was moved under exclusion criteria 14.

Addition of History of Torsades de pointes as exclusion criteria 15 to Section 4.2.

Additional information added to Section 4.5 regarding AZD1775 dosing. 


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
11 (296)

Addition of a section regarding Patients with a history of Torsades de pointes to the 
Restrictions Section 4.5.2. 

Addition of ECG assessments on Cycle 1, Cycle 2 and Cycle 3 and beyond 
Appendix B Table 1. Adjustment of the text of footnote C in Appendix B Table 1 
according to this change.

Addition of  Safety assessments and ECG to Section 6.

Addition of Electrocardiogram QT corrected interval prolonged to Appendix B 
Table .

Clarification added to section 7.3.3.3 Nausea and vomiting regarding aprepitant 
[Emend] and fosaprepitant.

Addition of Section 7.3.3.6 QTc prolongation.

Clarification added to Appendix B Figure 2 AZD1775 + carboplatin therapy dosing 
schedule.

Addition of Section 8.7.3 Substances known to prolong the ECG QTc interval.

Clarification added to Section Appendix B2 regarding the administration of 
AZD1775 with substances known to prolong the ECG QTc interval is not 
recommended and a list of medicines with a known risk of Torsades de pointes is 
provided.

Additional information added to Appendix F Confirmation of progression.

Appendix 3 Definition of Women of Childbearing Potential and Acceptable 
Contraceptive Methods was  renamed to Appendix G

Appendicies 1 for section A and 1 and 2 for section B were renamed to Appendix A 
Table 7, Appendix B1New York Heart Association Criteria

, and Appendix B2 respectively
Version 01, 01 July 2016
Initial creation


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
12 (296)
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol 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.


Clinical Study Protocol Synopsis
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
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1.
PROTOCOL SYNOPSIS
A Phase II, Open-Label, Multi-Arm Study to Determine the Preliminary 
Efficacy of Novel Combinations of Treatment in Patients with Platinum 
Refractory Extensive-Stage Small-Cell Lung Cancer 
International Coordinating Investigator: Dr. med. Niels Reinmuth, Gauting, Germany
Study site(s) and number of patients planned
This study will enroll up to 40 eligible patients in each arm at approximately 30 sites using a 
2-stage approach to recruitment, with the potential for expansion depending on data from the 
first 20 subjects.  The study initially opened with 2 arms; additional treatment arms can be 
opened in a modular manner when a compelling rationale for the combination and a safe and 
tolerable dose has been provided.  The total number of patients will depend on full enrolment 
of individual arms as well as the total number of treatment arms in the study.
Study period
Phase of development
Estimated date of first patient enrolled
Q3 2016
II
Estimated date of last patient completed
Q1 2021
II
Study design
This is a Phase II, open-label, multi-drug, multi-center, multi-arm, signal-searching study in 
patients with extensive-stage small-cell lung cancer (SCLC) who have refractory or resistant 
disease from prior platinum-based chemotherapy.  This study will evaluate the preliminary 
efficacy, safety, tolerability, and immunogenicity of novel combinations of immunotherapies 
and/or deoxyribonucleic acid (DNA) damage repair inhibitors in patients with platinum 
refractory or resistant extensive stage-disease SCLC.
Patients who have progressive disease (PD) during first-line platinum-based chemotherapy 
(platinum refractory) or PD within 90 days after completing first-line platinum-based 
chemotherapy (platinum resistant) will be enrolled to the study. 
The primary objective of the study is to assess the preliminary efficacy of each treatment arm 
based on objective response rate (ORR). Tumor assessment will be performed by Investigators 
either every 6 or 8 weeks ± 1 week depending on the treatment arm (relative to the date of 
initiation of study treatment) until confirmed objective disease progression (as defined by 
Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST 1.1]). 
RECIST 1.1 measurements will be used to programmatically derive the primary variable of 
ORR and secondary variables of duration of response (DoR), disease control rate (DCR), time 
to response (TTR), and progression-free survival (PFS).  ORR (complete response [CR] or 


Clinical Study Protocol Synopsis
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
14 (296)
partial response [PR]) should be confirmed preferably at the next scheduled visit and not less 
than 4 weeks after the visit when the response was last observed.  There is no planned central 
review of scans.
This study will consist of a number of arms (sub-studies), each evaluating the efficacy, safety, 
and tolerability of a specific agent or combination. 
At study commencement, there were 2 pre-defined arms:
A. Durvalumab (MEDI4736)  + tremelimumab followed by durvalumab monotherapy 
B. AZD1775 + carboplatin (CBDP)
A further arm was added in version 3
C. Ceralasertib (AZD6738) + olaparib.
Conduct of the study within these arms are detailed in Appendix A (Arm A), Appendix B 
(Arm B) and Appendix C (Arm C).
Study Objectives
Primary Objective:
Outcome Measure:
To assess the preliminary efficacy of each 
treatment arm in terms of ORR
ORR using Investigator assessments according to 
RECIST 1.1
Secondary Objective:
Outcome Measure:
To further assess the preliminary efficacy of 
each treatment arm in terms of DoR, DCR, 
TTR, PFS, and overall survival (OS)
DoR, DCR, TTR, and PFS using Investigator 
assessments according to RECIST 1.1
OS
To assess the pharmacokinetics (PK) of novel 
combination treatments (Arm A (stage 1 and 2 
only), Arms B and C only)
Concentration of novel combination treatments in 
blood 
Safety Objective:
Outcome Measure:
To assess the safety and tolerability profile of 
each treatment arm
Adverse events (AEs); physical examinations; vital 
signs, including blood pressure and pulse; 
electrocardiograms; and laboratory findings, 
including clinical chemistry, hematology, and 
urinalysis


Clinical Study Protocol Synopsis
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
15 (296)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Study Protocol Synopsis
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
16 (296)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Target patient population
Male or female patients aged 18 years or older with histologically or cytologically 
documented extensive disease (American Joint Committee on Cancer Stage IV SCLC [T any, 
N any, M1 a/b]) at initial diagnosis and who have demonstrated PD either during first-line 
platinum-based chemotherapy (platinum refractory) or within 90 days of completing first-line 
platinum-based chemotherapy (platinum resistant), and a minimum life expectancy of 
8 weeks.  Patients should be enrolled within 90 days of progression in order to be accepted 
into the study. Refer to the specific sub-protocol for World Health Organization performance 
status requirements.
Duration of treatment
Unless specific treatment discontinuation criteria are met, all patients will continue therapy 
until disease progression.
Follow up of patients post discontinuation of study treatment
Patients who have discontinued treatment due to toxicity, symptomatic deterioration, or 
clinical progression, or who have commenced subsequent anticancer therapy, will be followed 
up until confirmed disease progression and for survival.  
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Clinical Study Protocol Synopsis
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
17 (296)
Survival
All patients will be followed monthly for survival for the first 3 months of the follow-up 
period and then every 2 months thereafter. 
Investigational product, dosage and mode of administration
Specific information for each combination therapy arm are provided in the relevant 
sub-protocols Appendices (A, B and C). Additional information on the molecules is included 
from completed Phase I studies.
Summary of therapy arms in this version of the CSP:
ARM A
Patients enrolled in the durvalumab+ tremelimumab arm followed by the durvalumab 
monotherapy arm will receive
•
Durvalumab 1500 mg + tremelimumab 75 mg via intravenous (IV) infusion every 4 
weeks (q4w), starting on Week 0, for up to a total of 4 doses/cycles followed by durvalumab 
monotherapy 1500 mg via IV infusion q4w, starting 4 weeks after completion of the 4th cycle 
of combination therapy until PD, or for other discontinuation criteria. If a patient’s weight 
falls to 30 kg or below (≤30 kg), then the patient should receive weight-based dosing after 
discussion between Investigator and Study Physician, until the weight improves to >30 kg, at 
which point the patient should start receiving the fixed dosing of durvalumab 1500 mg and 
tremelimumab 75 mg Q4W (during the combination phase of treatment). The equivalent 
weight based doses to the fixed doses are 20 mg/kg of durvalumab and 1 mg/kg 
tremelimumab Q4W.
ARM B
Patients enrolled in the AZD1775 + CBDP arm will receive
•
AZD1775 225 mg twice daily (oral) for 2.5 days from Day 1 + CBDP area under the 
curve 5 (Day1) (IV); every 3 weeks
ARM C
Patients enrolled in the ceralasertib + olaparib arm will receive
•
ceralasertib 160 mg QD PO between Days 1 to 7 + olaparib 300 mg BID PO between 
Days 1 to 28 days continuously; q4w until PD.
Statistical methods
The primary objective of this study is to assess the preliminary efficacy of each treatment arm 
in terms of ORR by Investigator assessment according to RECIST 1.1.


Clinical Study Protocol Synopsis
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
18 (296)
ORR (per RECIST 1.1 as assessed by site Investigator) is defined as the number (%) of 
patients with a confirmed CR or confirmed PR and will be based on all evaluable patients and 
will be estimated for each treatment arm with corresponding 2-sided 95% exact confidence 
intervals (CIs).
The table below shows the 2-sided exact 95% confidence intervals (CI) for the ORR of a 
treatment arm at each stage of the study, assuming the observed ORR is 
% or 
%:
ORR
%
%
Stage 1 (10 patients)
(
%, 
%)
(
%
%)
Stage 2 (20 patients in total)
(
%, 
%)
(
%, 
%)
Expansion cohort (40 patients in total)
(
%, 
%)
(
%, 
5%)
Secondary efficacy variables include DoR, DCR, TTR, PFS, and OS.  Efficacy data will be 
summarized and analyzed based on the Full Analysis Set.  
An interim analysis will be conducted on each arm after stage 1 (first 10 patients).  The Data 
cut off (DCO) for the interim analysis will take place approximately 12 weeks after the 10th
eligible patient has initiated treatment.  If there are 
 responders, then there is a low 
posterior probability of achieving ORR of at least 
% in 20 patients and no further patients 
will be recruited to the arm.  If there are 
 responders out of 10, then an additional 10 
patients will be recruited and the final estimate of ORR will be based on 20 patients.  If there 
are  or more responders out of 10 patients, then it will be regarded as strong efficacy and 
recruitment may be stopped in that specific arm.  The posterior probability of having at leas
 
responders in 20 patients for 
 responders in 10 patients is shown below.
%
%
%
If the decision is made to progress to stage 2 and treat a further 10 subjects in that arm, the 
primary analysis of ORR will occur approximately 12 weeks after the last patient in stage 2 
has initiated treatment.  All study endpoints will be analyzed at this time. 
If the decision is made to close the Arm at the interim analysis the Sponsor will determine the 
appropriate length of follow up to ensure sufficient data collection for the primary analysis in 
that Arm. 
If a decision is made to further expand any given arm (and treat a further 20 patients, to a 
maximum total of 40 eligible patients), the primary analysis of ORR will occur approximately 
12 weeks after the last patient in the expansion group has initiated treatment. All study 
endpoints will be analyzed at this time.
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Clinical Study Protocol Synopsis
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
19 (296)
Safety data will be evaluated on an ongoing basis and will be summarized descriptively and 
will not be formally analyzed. 
All Review Committee decision making (including the decision whether to recommend 
opening Stage II or to expand the arm) will be based on the totality of the data available at the 
time, considering the benefit-risk assessment.


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
20 (296)
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................................1
VERSION HISTORY..........................................................................................................2
1.
PROTOCOL SYNOPSIS................................................................................... 13
TABLE OF CONTENTS................................................................................................... 20
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................................... 36
2.
INTRODUCTION ............................................................................................. 39
2.1
Background and rationale for conducting this study ........................................... 39
2.1.1
Immunotherapies ............................................................................................... 41
2.1.2
Immunotherapies in SCLC................................................................................. 41
2.1.3
DNA damage and repair mechanisms in SCLC .................................................. 43
2.1.4
DNA damage and immunogenicity .................................................................... 43
2.2
Rationale for study design, doses, and control groups......................................... 44
2.2.1
Rationale for study design.................................................................................. 44
2.2.2
Rationale of the study for specific agents ........................................................... 45
2.2.3
Rationale for study endpoints............................................................................. 45
2.2.4
Background, rationale, and risk benefit information on specific agents............... 46
2.3
Benefit/risk and ethical assessment .................................................................... 46
2.3.1
Summary benefit/risk statement ......................................................................... 46
2.4
Study design ...................................................................................................... 47
3.
STUDY OBJECTIVES...................................................................................... 49
3.1
Primary objective............................................................................................... 49
3.2
Secondary objectives.......................................................................................... 49
3.3
Safety objectives................................................................................................ 49
3.4
Exploratory objectives ....................................................................................... 49
4.
PATIENT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL.................... 51
4.1
Inclusion criteria ................................................................................................ 51
4.2
Exclusion criteria ............................................................................................... 51
4.3
Patient enrollment and randomization ................................................................ 51
4.4
Procedures for handling incorrectly enrolled or randomized patients.................. 52


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
21 (296)
4.5
Methods for assigning treatment groups............................................................. 52
4.6
Methods for ensuring blinding ........................................................................... 53
4.7
Methods for unblinding...................................................................................... 53
4.8
Restrictions........................................................................................................ 53
4.9
Discontinuation of investigational product ......................................................... 53
4.9.1
Procedures for discontinuation of a patient from investigational product ............ 54
4.9.2
Assessments following discontinuation of investigational product...................... 54
4.10
Criteria for withdrawal....................................................................................... 55
4.10.1
Screen failures ................................................................................................... 55
4.10.2
Withdrawal of the informed consent................................................................... 55
4.10.3
Survival status for withdrawn consent and lost to follow-up patients.................. 56
4.11
Discontinuation of the study............................................................................... 57
5.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 57
6.
STUDY ASSESSMENTS.................................................................................. 57
6.1
Efficacy assessments.......................................................................................... 58
6.1.1
Survival assessments.......................................................................................... 59
6.2
Safety assessments............................................................................................. 59
6.2.1
Laboratory safety assessments............................................................................ 59
6.2.2
Physical examination ......................................................................................... 60
6.2.3
Resting 12-lead ECG ......................................................................................... 60
6.2.4
Vital signs.......................................................................................................... 61
6.3
Other assessments.............................................................................................. 61
6.3.1
WHO/ECOG performance status........................................................................ 61
6.4
Pharmacokinetics ............................................................................................... 61
6.4.1
Collection of samples......................................................................................... 61
6.4.2
Determination of drug concentration.................................................................. 61
6.4.3
Storage and destruction of pharmacokinetic samples.......................................... 62
6.5
Pharmacodynamics ............................................................................................ 62
6.5.1
Collection of samples......................................................................................... 62
6.6
Biomarker analysis............................................................................................. 62
6.6.1
Exploratory biomarkers...................................................................................... 63
6.6.2
Management of biomarker data.......................................................................... 64
6.6.3
Storage, re-use, and destruction of biological samples........................................ 64
6.6.4
Labeling and shipment of biological samples ..................................................... 64
6.6.5
Chain of custody of biological samples .............................................................. 64
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
22 (296)
6.6.6
Withdrawal of informed consent for donated biological samples........................ 65
7.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 65
7.1
Definition of adverse events............................................................................... 65
7.2
Definitions of serious adverse event ................................................................... 65
7.3
Recording of adverse events............................................................................... 66
7.3.1
Time period for collection of adverse events ...................................................... 66
7.3.2
Follow-up of unresolved adverse events............................................................. 66
7.3.2.1
Post-study events ............................................................................................... 66
7.3.3
Variables............................................................................................................ 66
7.3.4
Causality collection............................................................................................ 68
7.3.5
Relationship to protocol procedures ................................................................... 68
7.3.6
Adverse events based on signs and symptoms.................................................... 68
7.3.7
Adverse events based on examinations and tests ................................................ 69
7.3.8
Hy’s Law ........................................................................................................... 69
7.3.9
Disease progression............................................................................................ 69
7.3.10
New cancers....................................................................................................... 70
7.3.11
Deaths................................................................................................................ 70
7.4
Reporting of serious adverse events ................................................................... 70
7.5
Adverse events of special interest....................................................................... 71
7.6
Overdose............................................................................................................ 71
7.7
Pregnancy .......................................................................................................... 72
7.7.1
Maternal exposure.............................................................................................. 72
7.7.2
Paternal exposure............................................................................................... 72
7.8
Management of investigational product-related toxicities ................................... 73
7.9
Study governance and oversight......................................................................... 73
8.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 73
8.1
Identity of investigational product(s).................................................................. 73
8.1.1
Duration of treatment ......................................................................................... 73
8.1.2
Follow up of patients post discontinuation of study drug.................................... 73
8.2
Dose and treatment regimens ............................................................................. 74
8.3
Labeling............................................................................................................. 74
8.4
Storage............................................................................................................... 74
8.5
Compliance........................................................................................................ 74
8.6
Accountability.................................................................................................... 74
8.7
Concomitant and other treatments ...................................................................... 74
8.7.1
Other concomitant treatment .............................................................................. 75
8.8
Post-study access to study treatment................................................................... 75


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
23 (296)
9.
STATISTICAL ANALYSES BY ASTRAZENECA.......................................... 75
9.1
Statistical considerations .................................................................................... 75
9.2
Sample size estimate .......................................................................................... 75
9.3
Definitions of analysis sets................................................................................. 76
9.3.1
Full Analysis Set................................................................................................ 76
9.3.2
PK Analysis Set ................................................................................................. 76
9.4
Outcome measures for analyses.......................................................................... 77
9.4.1
Calculation or derivation of efficacy variables.................................................... 77
9.4.1.1
RECIST 1.1-based endpoints ............................................................................. 77
9.4.1.2
Primary endpoint (objective response rate)......................................................... 77
9.4.1.3
Secondary endpoints .......................................................................................... 77
9.4.2
Calculation or derivation of safety variables....................................................... 79
9.4.2.1
Adverse events................................................................................................... 79
9.4.2.2
Safety assessments............................................................................................. 80
9.4.3
Calculation or derivation of patient-reported outcome variables ......................... 80
9.4.4
Calculation or derivation of pharmacokinetic variables ...................................... 81
9.4.4.1
Population pharmacokinetics and exposure-response/safety analysis.................. 81
9.4.4.2
Pharmacokinetic analysis ................................................................................... 81
9.4.6
Calculation or derivation of pharmacogenetic variables...................................... 81
9.5
Methods for statistical analyses.......................................................................... 81
9.5.1
Primary analysis................................................................................................. 82
9.5.2
Analysis of the primary variable(s)..................................................................... 82
9.5.3
Analysis of the secondary variable(s) ................................................................. 82
9.5.3.1
Duration of response .......................................................................................... 82
9.5.3.2
Disease control rate............................................................................................ 82
9.5.3.3
Time to response................................................................................................ 83
9.5.3.4
Progression-free survival.................................................................................... 83
9.5.3.5
Overall survival.................................................................................................. 83
9.5.4
Safety data ......................................................................................................... 83
9.5.5
Pharmacokinetic data ......................................................................................... 83
9.5.7
Interim analysis.................................................................................................. 84
9.5.8
Analysis following expansion ............................................................................ 84
10.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA......................... 84
10.1
Training of study site personnel ......................................................................... 84
10.2
Monitoring of the study...................................................................................... 85
10.2.1
Source data ........................................................................................................ 85
10.2.2
Study agreements............................................................................................... 86
10.2.3
Archiving of study documents............................................................................ 86
10.3
Study timetable and end of study........................................................................ 86
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
24 (296)
10.4
Data management by AstraZeneca ..................................................................... 86
11.
ETHICAL AND REGULATORY REQUIREMENTS....................................... 87
11.1
Ethical conduct of the study ............................................................................... 87
11.2
Patient data protection........................................................................................ 87
11.3
Ethics and regulatory review .............................................................................. 87
11.4
Informed consent ............................................................................................... 88
11.5
Changes to the protocol and informed consent form........................................... 89
11.6
Audits and inspections ....................................................................................... 89
APPENDIX A ARM A: DURVALUMAB (MEDI4736) + TREMELIMUMAB 
SUB-PROTOCOL ............................................................................................. 90
1.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................... 90
2.
INTRODUCTION ............................................................................................. 93
2.1
Background and rationale for conducting this study ........................................... 93
2.2
Durvalumab (MEDI4736).................................................................................. 94
2.3
Tremelimumab................................................................................................... 95
2.4
Durvalumab in combination with tremelimumab................................................ 95
2.5
Rationale for study design, doses, and control groups......................................... 96
2.5.1
Rationale for opening expansion cohort.............................................................. 96
2.6
Durvalumab and tremelimumab dose and treatment regimen justification .......... 96
2.6.1
Durvalumab + tremelimumab combination therapy dose rationale...................... 96
2.6.2
Durvalumab + tremelimumab combination therapy 
pharmacokinetics/Pharmacodynamics data......................................................... 97
2.6.3
Clinical data....................................................................................................... 98
2.6.3.1
Study D4190C00006.......................................................................................... 98
2.6.3.2
Study D4190C00010.......................................................................................... 99
2.6.4
Rationale for four cycles of combination therapy followed by durvalumab 
monotherapy.................................................................................................... 100
2.6.5
Durvalumab monotherapy dose rationale ......................................................... 100
2.6.5.1
Durvalumab monotherapy Pharmacokinetic/Pharmacodynamic data................ 100
2.6.5.2
Clinical experience with durvalumab ............................................................... 101
2.6.6
Rationale for fixed dosing of durvalumab and tremelimumab........................... 101
2.6.7
Rationale for study endpoints........................................................................... 102
2.7
Benefit/risk and ethical assessment .................................................................. 102
2.7.1
Potential benefits.............................................................................................. 103
2.7.1.1
Durvalumab ..................................................................................................... 103
2.7.1.2
Durvalumab + tremelimumab.......................................................................... 103
2.7.2
Identified and potential risks ............................................................................ 104
2.7.2.1
Durvalumab ..................................................................................................... 104


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
25 (296)
2.7.2.2
Tremelimumab................................................................................................. 105
2.7.2.3
Durvalumab + tremelimumab.......................................................................... 105
2.7.3
Overall benefit risk .......................................................................................... 106
2.8
Study design .................................................................................................... 106
3.
STUDY OBJECTIVES.................................................................................... 107
3.1
Primary objective............................................................................................. 107
3.2
Secondary objectives........................................................................................ 107
3.3
Safety objectives.............................................................................................. 107
3.4
Exploratory objectives ..................................................................................... 107
4.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL.................. 108
4.1
Inclusion criteria .............................................................................................. 108
4.2
Exclusion criteria ............................................................................................. 110
4.3
Patient enrollment and randomization .............................................................. 113
4.4
Procedures for handling incorrectly enrolled or randomized patients................ 113
4.5
Methods for assigning treatment groups........................................................... 113
4.6
Restrictions...................................................................................................... 113
4.7
Discontinuation of investigational product ....................................................... 115
4.7.1
Assessments following discontinuation of investigational product.................... 115
4.8
Criteria for withdrawal..................................................................................... 115
4.9
Discontinuation of the study............................................................................. 116
5.
STUDY PLAN AND TIMING OF PROCEDURES......................................... 116
5.1
Enrollment/screening period ............................................................................ 125
5.2
Treatment period.............................................................................................. 125
5.3
Follow-up period.............................................................................................. 125
6.
STUDY ASSESSMENTS................................................................................ 126
6.1
Efficacy assessments........................................................................................ 126
6.2
Safety assessments........................................................................................... 128
6.2.1
Laboratory safety assessments.......................................................................... 128
6.2.2
Vital Signs ....................................................................................................... 129
6.2.3
Other Safety Assessments ................................................................................ 130
6.3
Biomarker analysis........................................................................................... 131
6.4
Pharmacokinetic and Immunogenicity analysis ................................................ 132
6.5
Storage and destruction of pharmacokinetic/ADA samples............................... 132


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
26 (296)
7.
SAFETY REPORTING AND MEDICAL MANAGEMENT........................... 132
7.1
Reporting of adverse events ............................................................................. 132
7.2
Reporting of serious adverse events ................................................................. 133
7.3
Pregnancy ........................................................................................................ 133
7.3.1
Paternal exposure............................................................................................. 133
7.4
Overdose.......................................................................................................... 133
7.5
Management of investigational product-related toxicities ................................. 133
7.5.1
Durvalumab and durvalumab + tremelimumab................................................. 134
7.5.2
Toxicity Management Guidelines..................................................................... 134
7.6
Adverse events of special interest..................................................................... 135
7.6.1
Immune-related adverse events ........................................................................ 136
8.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................. 137
8.1
Identity of investigational product(s)................................................................ 137
8.1.1
Durvalumab ..................................................................................................... 137
8.1.2
Tremelimumab................................................................................................. 138
8.2
Dose and treatment regimens ........................................................................... 139
8.2.1
Duration of treatment and criteria for treatment through progression................ 140
8.3
Labeling........................................................................................................... 142
8.4
Storage............................................................................................................. 142
8.5
Compliance...................................................................................................... 142
8.6
Accountability.................................................................................................. 142
8.7
Concomitant and other treatments .................................................................... 142
8.8
Post Study Access to Study Treatment ............................................................. 144
9.
STATISTICAL ANALYSES BY ASTRAZENECA........................................ 144
9.2
Adverse events................................................................................................. 144
9.3
Study and data management by AstraZeneca.................................................... 145
10.
ETHICAL AND REGULATORY REQUIREMENTS..................................... 145
APPENDIX B
ARM B: AZD1775 + CARBOPLATIN SUB-PROTOCOL ................... 147
1.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS....................... 147
2.
INTRODUCTION ........................................................................................... 150
2.1
Background and rationale for conducting this study ......................................... 150
2.2
AZD1775......................................................................................................... 150
2.3
Carboplatin ...................................................................................................... 151
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
27 (296)
2.4
Rationale for study design, doses, and control groups....................................... 151
2.4.1
AZD1775 in combination with CBDP.............................................................. 151
2.4.2
Clinical experience with AZD1775 .................................................................. 151
2.4.3
Pharmacokinetic and pharmacodynamic data ................................................... 153
2.4.5
Rationale for study endpoints........................................................................... 154
2.5
Benefit/risk and ethical assessment .................................................................. 154
2.5.1
Potential benefits.............................................................................................. 155
2.5.1.1
AZD1775......................................................................................................... 155
2.5.1.2
CBDP .............................................................................................................. 155
2.5.1.3
AZD1775 + CBDP........................................................................................... 155
2.5.2
Identified and potential risks ............................................................................ 155
2.5.2.1
AZD1775......................................................................................................... 155
2.5.2.2
CBDP .............................................................................................................. 155
2.5.2.3
AZD1775 + CBDP........................................................................................... 156
2.5.3
Summary benefit: risk statement ...................................................................... 156
2.6
Study design .................................................................................................... 156
3.
STUDY OBJECTIVES.................................................................................... 158
3.1
Primary objective............................................................................................. 158
3.2
Secondary objectives........................................................................................ 158
3.3
Safety objectives.............................................................................................. 158
3.4
Exploratory objectives ..................................................................................... 158
4.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL.................. 158
4.1
Inclusion criteria .............................................................................................. 158
4.2
Exclusion criteria ............................................................................................. 161
4.3
Patient enrollment and randomization .............................................................. 163
4.3.1
Procedures for handling incorrectly enrolled or randomized patients................ 163
4.4
Methods for assigning treatment groups........................................................... 163
4.5
Restrictions...................................................................................................... 163
4.5.1
Women of childbearing potential ..................................................................... 164
4.5.2
Patients with a history of Torsades de pointes .................................................. 164
4.6
Discontinuation of investigational product ....................................................... 164
4.7
Criteria for withdrawal..................................................................................... 164
4.8
Discontinuation of the study............................................................................. 164
5.
STUDY PLAN AND TIMING OF PROCEDURES......................................... 165
5.1
Enrollment/screening period ............................................................................ 173
CCI


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
28 (296)
5.2
Treatment period.............................................................................................. 173
5.3
Follow-up period.............................................................................................. 173
6.
STUDY ASSESSMENTS................................................................................ 173
6.1
Safety Assessments.......................................................................................... 173
6.1.1
Laboratory safety assessments.......................................................................... 173
6.1.2
ECG................................................................................................................. 175
6.2
Pharmacokinetics ............................................................................................. 176
6.2.1
Collection of blood pharmacokinetic samples................................................... 176
6.3
Efficacy Analysis............................................................................................. 176
6.4
Biomarker analysis........................................................................................... 177
7.
SAFETY REPORTING AND MEDICAL MANAGEMENT........................... 177
7.1
Reporting of adverse events ............................................................................. 177
7.1.1
Time period for collection of adverse events .................................................... 177
7.1.2
Follow-up of unresolved adverse events........................................................... 177
7.1.3
Reporting of serious adverse events ................................................................. 178
7.1.4
Post study events.............................................................................................. 178
7.2
Pregnancy ........................................................................................................ 179
7.2.1
Maternal exposure............................................................................................ 179
7.2.2
Paternal exposure............................................................................................. 179
7.3
Dose modifications and management of investigational product-related
toxicities .......................................................................................................... 179
7.3.1
Dose modifications due to hematologic-related adverse events......................... 180
7.3.2
Dose modifications due to non-hematologic related adverse events.................. 182
7.3.3
Non-hematologic toxicity management guidelines ........................................... 184
7.3.3.1
Gastrointestinal system disorders ..................................................................... 184
7.3.3.2
Diarrhea........................................................................................................... 184
7.3.3.3
Nausea and vomiting........................................................................................ 185
7.3.3.4
Motor neuropathy or muscle weakness............................................................. 185
7.3.3.5
Dose modifications for infusion reactions......................................................... 185
7.3.3.6
QTc prolongation............................................................................................. 186
8.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................. 186
8.1
Identity of investigational product(s)................................................................ 186
8.1.1
AZD1775......................................................................................................... 187
8.1.2
Carboplatin ...................................................................................................... 187
8.2
Dose and treatment regimens ........................................................................... 188
8.3
Labeling........................................................................................................... 188
8.4
Storage............................................................................................................. 188
8.5
Compliance...................................................................................................... 188


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
29 (296)
8.6
Accountability.................................................................................................. 189
8.7
Concomitant and other treatments .................................................................... 189
8.7.1
Prohibited concomitant medications................................................................. 189
8.7.2
Prohibited concomitant medications:  CBDP.................................................... 190
8.7.3
Substances known to prolong the ECG QTc interval........................................ 191
8.7.4
Other concomitant treatment ............................................................................ 191
9.
STATISTICAL ANALYSES BY ASTRAZENECA........................................ 191
9.1
Adverse events................................................................................................. 191
9.2
Study and data management by Astrazeneca .................................................... 191
10.
ETHICAL AND REGULATORY REQUIREMENTS..................................... 191
APPENDIX B1
NEW YORK HEART ASSOCIATION CRITERIA............................. 192
APPENDIX  C
ARM C: CERALASERTIB (AZD6738) + OLAPARIB SUB-
PROTOCOL.................................................................................................... 193
1.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS....................... 193
2.
INTRODUCTION ........................................................................................... 196
2.1
Background and rationale for conducting this study ......................................... 196
2.2
Ceralasertib...................................................................................................... 197
2.3
Olaparib........................................................................................................... 198
2.4
Rationale for study design, doses, and control groups....................................... 199
2.4.1
Ceralasertib in combination with olaparib ........................................................ 199
2.4.2
Clinical experience with ceralasertib ................................................................ 199
2.4.3
Ceralasertib pharmacokinetic and pharmacodynamic data................................ 201
2.4.4
Clinical experience with olaparib ..................................................................... 202
2.4.4.1
Description of selected adverse reactions associated with olaparib 
monotherapy.................................................................................................... 204
2.4.4.2
Adverse events of special interest for olaparib.................................................. 205
2.4.5
Ceralasertib + olaparib combination therapy dose rationale.............................. 205
2.4.6
Rationale for study endpoints........................................................................... 206
2.5
Benefit/risk and ethical assessment .................................................................. 206
2.5.1
Potential benefits.............................................................................................. 206
2.5.1.1
Ceralasertib...................................................................................................... 206
2.5.1.2
Olaparib........................................................................................................... 207
2.5.1.3
Ceralasertib + olaparib ..................................................................................... 207
2.5.2
Identified and potential risks ............................................................................ 207
2.5.2.1
Ceralasertib...................................................................................................... 207
2.5.2.2
Olaparib........................................................................................................... 208
2.5.2.3
Ceralasertib + olaparib ..................................................................................... 208
2.5.2.4
Summary benefit:risk statement ....................................................................... 209
3.
STUDY DESIGN............................................................................................. 209


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
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4.
STUDY OBJECTIVES.................................................................................... 210
4.1
Primary objective............................................................................................. 210
4.2
Secondary objectives........................................................................................ 210
4.3
Safety objectives.............................................................................................. 210
4.4
Exploratory objectives ..................................................................................... 210
5.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL.................. 210
5.1
Inclusion criteria .............................................................................................. 210
5.2
Exclusion criteria ............................................................................................. 212
5.3
Patient enrollment and randomization .............................................................. 216
5.3.1
Procedures for handling incorrectly enrolled or randomized patients................ 216
5.4
Methods for assigning treatment groups........................................................... 216
5.5
Restrictions...................................................................................................... 216
5.5.1
Food Restrictions ............................................................................................. 216
5.5.2
Foetal risk ........................................................................................................ 216
5.5.3
Concomitant treatments.................................................................................... 217
5.5.3.1
Women of childbearing potential ..................................................................... 217
5.5.4
Photosensitivity................................................................................................ 217
5.6
Discontinuation of investigational product ....................................................... 217
5.7
Criteria for withdrawal..................................................................................... 217
5.8
Discontinuation of the study............................................................................. 218
6.
STUDY PLAN AND TIMING OF PROCEDURES......................................... 218
6.1
Enrollment/screening period ............................................................................ 225
6.2
Treatment period.............................................................................................. 225
6.3
Follow-up period.............................................................................................. 225
7.
STUDY ASSESSMENTS................................................................................ 226
7.1.1
Physical examination ....................................................................................... 226
7.1.2
Vital signs........................................................................................................ 226
7.1.2.1
Supine blood pressure and pulse rate................................................................ 226
7.1.2.2
Body temperature............................................................................................. 226
7.1.3
ECG................................................................................................................. 226
7.1.4
Laboratory safety assessment ........................................................................... 227
7.1.5
Bone marrow or blood cytogenetic samples ..................................................... 228
7.2
Pharmacokinetics ............................................................................................. 228
7.2.1
Collection of pharmacokinetic samples ............................................................ 228
7.2.2
Determination of drug concentration in pharmacokinetic samples .................... 229
7.3
Efficacy Analysis............................................................................................. 229


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
31 (296)
7.4
Biomarker analysis........................................................................................... 230
 
.............................................................................................. 230
7.4.2
Collection of peripheral blood for pharmacodynamic biomarker analysis......... 231
7.4.3
Collection of archival tumour samples ............................................................. 231
7.4.4
Collection of fresh biopsy samples................................................................... 231
7.5
Biological sampling procedures ....................................................................... 232
7.5.1
Volume of blood.............................................................................................. 232
7.5.2
Handling, storage and destruction of biological samples................................... 232
7.5.2.1
Pharmacokinetic samples ................................................................................. 233
7.5.2.2
Samples for exploratory research ..................................................................... 233
7.5.3
Labelling and shipment of biohazard samples .................................................. 233
7.5.4
Withdrawal of informed consent for donated biological samples...................... 233
8.
SAFETY REPORTING AND MEDICAL MANAGEMENT........................... 234
8.1
Reporting of adverse events ............................................................................. 234
8.1.1
Time period for collection of adverse events .................................................... 234
8.1.2
Follow-up of unresolved adverse events........................................................... 234
8.1.3
Reporting of serious adverse events ................................................................. 234
8.1.4
Post study events.............................................................................................. 235
8.2
Pregnancy ........................................................................................................ 235
8.2.1
Maternal exposure............................................................................................ 235
8.2.2
Paternal exposure............................................................................................. 235
8.3
Overdose of either olaparib or ceralasertib ....................................................... 235
8.4
Dose modifications and management of investigational product related 
toxicities .......................................................................................................... 236
8.4.1
Dose Reduction: Ceralasertib + Olaparib Combination .................................... 236
8.4.2
Management of Haematological Toxicities for Ceralasertib and Olaparib 
Combination .................................................................................................... 238
8.4.2.1
Management of Anemia................................................................................... 238
8.4.2.2
Management of neutropenia, leukopenia and thrombocytopenia for 
ceralasertib plus olaparib combination.............................................................. 239
8.4.2.3
Management of prolonged haematological toxicities while on study 
treatment.......................................................................................................... 240
8.4.2.4
Management of non-haematological toxicity for ceralasertib and olaparib........ 241
8.4.2.5
Management of new or worsening pulmonary symptoms ................................. 243
8.4.2.6
Renal Impairment............................................................................................. 243
8.4.2.7
Management of nausea and vomiting ............................................................... 243
8.4.2.8
Interruptions for intercurrent non-toxicity related events .................................. 244
9.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................. 244
9.1
Identity of investigational product(s)................................................................ 244
9.1.1
Ceralasertib...................................................................................................... 244
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
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9.1.2
Olaparib........................................................................................................... 245
9.2
Dose and treatment regimens ........................................................................... 245
9.3
Labeling........................................................................................................... 246
9.4
Storage............................................................................................................. 246
9.5
Compliance...................................................................................................... 246
9.6
Accountability.................................................................................................. 246
9.7
Concomitant and other treatments .................................................................... 246
9.7.1
Medications that may NOT be administered..................................................... 247
9.7.2
Effect of olaparib on other drugs...................................................................... 248
9.7.3
Anticoagulant Therapy..................................................................................... 249
9.7.4
Anti-emetics/Anti-diarrhoeals .......................................................................... 249
9.7.5
Palliative radiotherapy ..................................................................................... 249
9.7.6
Administration of other anti-cancer agents ....................................................... 249
9.7.7
Subsequent therapies for cancer ....................................................................... 249
9.7.8
Other concomitant treatment ............................................................................ 249
10.
STATISTICAL ANALYSES BY ASTRAZENECA........................................ 249
10.1
Adverse events................................................................................................. 250
10.2
Study and data management by AstraZeneca.................................................... 250
11.
ETHICAL AND REGULATORY REQUIREMENTS..................................... 250
APPENDIX D
INTERNATIONAL AIRLINE TRANSPORTATION 
ASSOCIATION 6.2 GUIDANCE DOCUMENT ............................................. 251
APPENDIX E
ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY’S LAW............................... 252
APPENDIX F
GUIDELINES FOR EVALUATION OF OBJECTIVE TUMOR 
RESPONSE USING RECIST 1.1 CRITERIA (RESPONSE 
EVALUATION CRITERIA IN SOLID TUMORS)......................................... 257
1.
INTRODUCTION ........................................................................................... 257
2.
DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET, 
AND NON-TARGET LESIONS...................................................................... 257
3.
METHODS OF ASSESSMENT ...................................................................... 258
4.
TUMOR RESPONSE EVALUATION ............................................................ 261
5.
CONFIRMATION OF PROGRESSION.......................................................... 265
6.
SPECIFICATIONS FOR RADIOLOGICAL IMAGING ................................. 267
APPENDIX G
DEFINITION OF WOMEN OF CHILDBEARING POTENTIAL 
AND ACCEPTABLE CONTRACEPTIVE METHODS .................................. 270


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
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1.
DEFINITION OF WOCBP AND WOMEN NOT OF CHILDBEARING 
POTENTIAL ................................................................................................... 270
2.
ACCEPTABLE CONTRACEPTION METHODS........................................... 270
APPENDIX H
ADDITIONAL SAFETY INFORMATION........................................... 273
APPENDIX I
DISALLOWED MEDICATIONS AND MEDICATIONS TO BE 
ADMINISTERED WITH CAUTION .............................................................. 275
APPENDIX  K LIST OF REFERENCES......................................................................... 284
LIST OF TABLES
Table 1 Summary of outcome variables and analysis populations.......................................76
Appendix A Table 1
Highly effective methods of contraception (less than 1% 
failure rate per year)..................................................................... 115
Appendix A Table 2
Schedule of assessments for durvalumab  + tremelimumab 
combination therapy, and durvalumab  monotherapy 
treatment period........................................................................... 117
Appendix A Table 3
Schedule of assessments: completed/discontinued treatment 
with durvalumab + tremelimumab combination therapy, and 
durvalumab  monotherapy ........................................................... 122
Appendix A Table 4 Laboratory - clinical chemistry........................................................ 128
Appendix A Table 5 Laboratory – hematology................................................................. 129
Appendix A Table 6 Laboratory – urinalysis.................................................................... 129
Appendix A Table 7
Prohibited concomitant medications for Arm A ........................... 143
Appendix A Table 8
Rescue/supportive medication for Arm A .................................... 144
Appendix B Table 1
Schedule of assessments for AZD1775 + Carboplatin 
combination therapy .................................................................... 166
Appendix B Table 2 Laboratory - clinical chemistry ........................................................ 174
Appendix B Table 3 Laboratory – hematology................................................................. 175
Appendix B Table 4 Laboratory – urinalysis .................................................................... 175
Appendix B Table 5
PKs: Carboplatin and AZD1775 .................................................. 176
Appendix B Table 6
AZD1775 dose level reductions for toxicity................................. 180
Appendix B Table 7
CBDP dose level reductions for toxicity ...................................... 180
Appendix B Table 8
Hematologic dose modifications and management....................... 180
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
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Appendix B Table 9
Non-hematologic toxicity dose modification and management..... 182
Appendix C Table 1 
Cumulative number of patients exposed to ceralasertib plus 
olaparib in Study D5330C00004.................................................. 200
Appendix C Table 2
Adverse Drug Reactions reported in Clinical Trials with 
Olaparib....................................................................................... 203
Appendix C Table 3
Schedule of assessment for olaparib + ceralasertib 
(AZD6738) combination therapy ................................................. 219
Appendix C Table 4
Laboratory safety assessment....................................................... 227
Appendix C Table 5 
Cohort C Guidance for dose reductions for ceralasertib and 
olaparib* ..................................................................................... 237
Appendix C Table 6 
Day 1 Haematologic dose modifications and management for 
ceralasertib plus olaparib combination ......................................... 238
Appendix C Table 7 
Management of anemia for ceralasertib plus olaparib 
combination................................................................................. 238
Appendix C Table 8 
Management of neutropenia, leukopenia and and 
thrombocytopenia ....................................................................... 240
Appendix C Table 9
Summary of guidance on the management of non-
haematologic toxicity for ceralasertib and olaparib ...................... 242
Appendix F Table 1
Summary of methods of assessment............................................. 259
Appendix F Table 2
Evaluation of TLs........................................................................ 263
Appendix F Table 3
Evaluation of non-target lesions................................................... 264
Appendix F Table 4
Overall visit response .................................................................. 265
LIST OF FIGURES
Figure 1
Staged recruitment design..............................................................45
Figure 2
Overall study design ......................................................................48
Appendix A Figure 1
Arm A Study design .................................................................... 107
Appendix A Figure 2
Durvalumab + tremelimumab combination therapy dosing 
schedule....................................................................................... 140
Appendix B Figure 1
Study design................................................................................ 157
Appendix B Figure 2
AZD1775 + carboplatin therapy dosing schedule......................... 188
Appendix C Figure 1
The anti-tumour effect of the ceralasertib and olaparib................ 197
Appendix C Figure 2
Study design............................................................................... 209


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
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Appendix C Figure 3
Ceralasertib + olaparib therapy dosing schedule........................... 246


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ALP
Alkaline phosphatase
AST
Aspartate aminotransferase
BRCA
Breast cancer susceptibility gene
CBDP
Carboplatin
CI
Confidence interval
CR
Complete response
CRF
Case report form (electronic/paper)
CSP
Clinical study protocol
CSR
Clinical Study Report
CT
Computed tomography
CTLA-4
Cytotoxic T-lymphocyte-associated antigen 4
CTCAE
Common Terminology Criteria for Adverse Event
CXCL
C-X-C motif ligand
DCO 
Data cut off
DCR
Disease control rate
DDR
DNA damage repair
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid 
DoR
Duration of response
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
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Date 16Jan2020
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Abbreviation or 
special term
Explanation
EDC
Electronic Data Capture
eCRF
Electronic case report form
ED
Extensive-stage disease
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose positron emission tomography
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HL
Hy’s Law
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IFN
Interferon
imAE
Immune mediated adverse event
IMP
Investigational Medicinal Product
International 
Coordinating 
Investigator
If a study is conducted in several countries the International Coordinating 
Investigator is the Investigator coordinating the Investigators and/or 
activities internationally. 
IP
Investigational product 
IRB
Institutional Review Board
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
NCI
National Cancer Institute
NE
Not evaluable
NSCLC
Non-small-cell lung cancer


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
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Abbreviation or 
special term
Explanation
NTL
Non-target lesions
ORR
Objective response rate
OS
Overall survival
PARP
Poly(ADP-ribose) polymerase
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PET
Positron emission tomography
PFS
Progression-free survival
PHL
Potential Hy’s Law
PK
Pharmacokinetic(s)
PR
Partial response
q4w
Every 4 weeks
QTcF
Heart rate corrected QT interval (Fridericia’s formula)
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
SAE
Serious adverse event 
SAP
Statistical analysis plan
SCLC
Small-cell lung cancer
SD
Stable disease
T3
Triiodothyronine
T4
Thyroxine
TBL
Total bilirubin
TIL
Tumor-infiltrating lymphocyte
TL
Target lesion
TSH
Thyroid-stimulating hormone
TTR
Time to response
ULN
Upper limit of normal
US
United States
WHO
World Health Organization
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
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Date 16Jan2020
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2.
INTRODUCTION
2.1 Background and rationale for conducting this study
Small-cell lung cancer (SCLC) represents approximately 13% of all newly diagnosed lung 
cancers (Puglisi et al 2010).  SCLC is perhaps the most aggressive form of the disease, 
distinguishable from non-small-cell lung cancer (NSCLC) by its rapid doubling time, high 
growth fraction, early dissemination, and frequent association with distinct paraneoplastic 
syndromes.  It is strongly associated with tobacco smoking and is also associated with an 
extremely high mutation rate. 
A 2-stage system dividing patients into limited and extensive-stage disease (ED) was 
developed in 1973 by the United States (US) Veteran’s Administration Lung Cancer Study 
Group, and this is the most commonly employed system in clinical practice.  Limited disease 
was defined as tumor tissue that could be encompassed in a single radiation port, and ED was 
defined as any tumor that extended beyond the boundaries of a single radiation port.  At 
present, limited disease is identified in approximately 30% of patients, and ED is identified in 
approximately 70% of patients.  Prognosis for patients with ED is poor; surgery is not usually 
an option in ED because of the inability of local excision to control systemic disease, leaving 
chemotherapy as the primary treatment modality.  Without treatment, survival is a matter of 
weeks (Green et al 1969); with treatment, median overall survival (OS) is <10 months, and for 
patients with Stage IV disease, the 5-year survival rate is approximately 2% (FDA Guidance 
2011, Foster et al 2011, Rossi et al 2012). 
In terms of treatments, combination chemotherapies are the current standard of care for 
ED-SCLC and have remained largely unchanged for the past 2 decades.  SCLC is highly 
responsive to first-line platinum-based chemotherapy.  However, despite high initial response 
rates of up to 70% with a standard of 4 to 6 cycles of doublet chemotherapy 
(platinum + etoposide [ETOPOPHOS®]) (Rossi et al 2012), SCLC typically recurs within 1 
year after treatment in the vast majority of patients (Ardizzoni 2004).
It is estimated that 80% of patients with limited stage and almost all patients with ED-SCLC 
relapse or experience disease progression (Clark and Ihde 1998).  Most patients will relapse 
within 2 years and die from systemic metastases (Asai et al 2014).  
Patients who receive a platinum-based treatment can be empirically divided into “refractory,” 
“resistant,” and “sensitive” on the basis of response to first-line chemotherapy (Califano et al
2012).  Patients who have disease that progresses through first-line treatment are categorized 
as having refractory disease, while those who show initial response to treatment but whose 
disease progresses within 3 months of completing chemotherapy are categorized as having 
resistant disease.  The sensitive subgroup includes those patients who have a relapse-free 
interval of at least 3 months from completion of treatment.  The proportion of patients with 
refractory, resistant, and sensitive disease is approximately 20%, 35%, and 45%, respectively.  
Despite this classification of patients with refractory, resistant, and sensitive disease, in 
clinical studies, the term “refractory” has been used to include patients who have disease that 
progresses through first-line treatment and those who show an initial response to treatment but 


Clinical Study Protocol
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whose disease progresses within 3 months of completing chemotherapy (ie, refractory and 
resistant).
Single-agent topotecan (HYCAMTIN®; both intravenous [IV] and oral formulations) is the 
only drug approved as second-line treatment for recurrent SCLC in the US, European Union 
(EU), and Japan (IV formulation only in Japan).  Amrubicin (CALSED®) is also approved for 
use in Japan but currently not in any other country. It is important to note that while there 
have been multiple studies to underpin the approval of topotecan in patients with sensitive 
disease, the approval for topotecan for patients with refractory disease is based on 1 single 
study where the comparator arm was best supportive care (O’Brien et al 2006).  In this study, 
topotecan was shown to extend survival from 13.9 to 25.9 weeks with greater symptom 
control.
A recent meta-analysis of more than 1300 SCLC patients treated with topotecan concluded 
that topotecan treatment in patients with refractory disease (classed as progression that 
occurs within 90 days post completion of first-line chemotherapy, ie, both refractory and 
resistant disease) is associated with poor outcomes; pooled analysis reported objective 
response rate (ORR) of 5% and a 12-month survival rate of just 9% (Horita et al 2015).  
Treatment is often associated with significant hematological toxicity (~69% patients 
experience Grade 3/4 neutropenia, as an example), calling into question the true benefit:risk 
assessment for this treatment option.
A number of targeted agents have been investigated in SCLC, mostly in unselected 
populations, but with disappointing results (Asai et al 2014).  
There remains a significant unmet medical need for patients with refractory/resistant 
ED-SCLC; as highlighted above, approximately 95% of patients fail to respond to single-
agent topotecan, which is the only currently approved available treatment in most countries. 
The mechanisms that underpin the high rate of relapse in SCLC are still poorly understood; 
the disease’s rapid progression and the lack of available tissue for translational research mean 
that there has been little progress in this area.  If focus is placed on the available information 
that SCLC is associated with high mutation burden and genomic instability together with data 
to suggest enhanced deoxyribonucleic acid (DNA) repair mechanisms could be a resistance 
mechanism (Tapia and DiazPadilla- 2013), it can be hypothesized that agents that harness the 
immune system together with agents that affect DNA repair could prove beneficial in this 
disease setting.  As such, this umbrella study aims to test multiple agents that fall into 2 main 
categories, ie, those that harness the immune system and those that affect DNA repair. 
SCLC is also an ideal clinical setting for the exploratory study of the evolution of tumor 
genetics in patients with SCLC because the high levels of 
 in 
this tumor histology are both prognostic (Huang et al 2014) and allow genetic analysis 
through “liquid biopsies” (Hodgkinson et al 2014).
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
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Date 16Jan2020
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Novel therapies are needed to improve clinical outcomes in both extending survival for those 
patients who initially respond to treatment with chemotherapy, as well as those who ultimately 
progress following treatment with chemotherapy.
2.1.1
Immunotherapies 
It is increasingly understood that cancers are recognized by the immune system, and, under 
some circumstances, the immune system may control or even eliminate tumors (Du Bois et al 
2003, Dunn et al 2004).  The connection between cancer and the immune system was first 
uncovered nearly 100 years ago, long before an in-depth knowledge of the intricate workings 
of the immune system existed (Cancer Research Institute 2003).  Failure of immune 
surveillance of preneoplastic lesions and micrometastases is a key step in cancer development.  
Individuals with chronic immunosuppression show higher rates of cancer.  This observation 
led to the hypothesis that sporadic cancers among immunocompetent individuals are likely to 
be minimally immunogenic, allowing for passive escape from immune surveillance.  Recent 
data suggest that this may be an oversimplification.  Some sporadic tumors are highly 
immunogenic but actively suppress the local immune environment through the production of 
immunosuppressive cytokines (Shields et al 2010).  As such, the local tumor environment is 
likely a highly dynamic environment where most tumors grow and metastasize through 
adaptive responses that modulate antitumor immunity.
The complexity and redundancy of the immune system offer multiple targets that may be 
manipulated to maximize the body’s inherent immune response to a tumor.  This immune 
response may be augmented by direct stimulation of effector cells, increased antigen 
presentation leading to indirect stimulation of effector cells, or blockade of 
immunosuppressive factors or cells (Monti et al 2005).
Tumor-infiltrating lymphocytes (TILs) have the capacity to control the growth of many types 
of cancers (Gooden et al 2011).  Most tumors show infiltration by TILs, but tumors modulate 
the local microenvironment through surface expression or release of inhibitory molecules.  
Engagement of TIL cell surface receptors with these inhibitory ligands leads to a 
dysfunctional immune response, causes T-cell exhaustion, and facilitates tumor progression 
(Baitsch et al 2012, Crespo et al 2013).  Novel monoclonal antibodies (mAbs) that block these 
inhibitory receptors have shown significant clinical activity across a number of tumor types 
(Brahmer et al 2010, Hodi et al 2010, Robert et al 2011, Topalian et al 2012, Wolchok et al
2009).  Specifically, blockade of immune checkpoint signaling (through cytotoxic 
T-lymphocyte-associated antigen 4 [CTLA-4], programmed cell death 1 [PD-1], and 
programmed cell death ligand 1 [PD-L1]) has shown clinical activity not only in 
conventionally immune-responsive tumors, such as melanoma and renal cell carcinoma, but 
also in NSCLC (Brahmer et al 2010, Brahmer et al 2012, Topalian et al 2012), prostate cancer 
(Harzstark and Small 2010, Slovin et al 2013), mesothelioma (Calabrò et al 2013), and other 
solid tumors (Brahmer et al 2010, Brahmer et al 2012, Gordon et al 2013).
2.1.2
Immunotherapies in SCLC
During the last decade, there has been a progressively increased interest in studying the 
therapeutic potential of immunotherapies for different types of tumors.  In particular, 


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nonclinical and clinical studies have indicated that blockade of immune checkpoints 
(PD-1/PD-L1 and CTLA-4) can have a positive effect on antitumor immunity.  One potential 
strategy is to combine these non-redundant and potentially synergistic single-agent 
immunotherapies together, thereby producing an additive improvement in tumor response 
(Larkin et al 2015, Postow et al 2015).
Patients with SCLC may be particularly susceptible to immunotherapies given the high 
mutational burden of this disease (SCLC has the 5th highest level of mutations of all human 
cancers; Alexandrov et al 2013) and the likely high antigen release following the responses 
that are often observed in this indication with frontline chemotherapy.  SCLC is associated 
with multiple mutations in oncogene and tumor-suppressor pathways, the most prevalent 
being almost universal loss of tumor protein 53 and retinoblastoma protein (Salgia and 
Skarkin 1998).  Such abnormalities predispose the tumor to uncontrolled proliferation, 
reduced apoptosis, and a reliance on DNA damage repair (DDR) pathways.  In addition to 
these mutations, chromosomal abnormalities are found in the majority of patients with SCLC, 
and microsatellite instability is also common (Merlo et al 1994, Chen et al 1996).  As such, 
SCLC presents with a high degree of genomic instability and chromosomal abnormality 
(Massari et al 2015).  Genomic instability, driven by mismatch repair deficiency, has been 
shown in recent studies to be a potential driver of response to checkpoint inhibition (Le et al 
2015), likely because such deficiency leads to high mutational burden.  Several recent studies 
analyzing data from different tumor types have demonstrated a correlation between mutational 
burden and response to checkpoint inhibitors targeting both PD-1 (Rizvil 2015) and CTLA-4 
(Snyder et al 2014, Van Allen et al 2015). 
Although no such correlative studies have included SCLC, given the high mutational load and 
genomic instability seen in these tumors, one can hypothesize that this same class of agents 
would also prove beneficial in this disease setting.
This is supported by encouraging clinical activity reported with this class of agents in both 
first-line and second-line settings in patients with SCLC, both as monotherapy and in 
combination.  Recent studies, specifically in the platinum refractory/resistant SCLC setting, 
have also shown promise.  The ongoing KEYNOTE-028 study (NCT02054806) has recently 
reported that pembrolizumab (KEYTRUDA®; anti-PD-1 mAb) showed 35% ORR and 40% 
disease control rate (DCR) in patients with PD-L1-positive, recurrent SCLC.  Responses 
appear to be durable, with 6 out of 7 responders ongoing as of March 2015 (Ott et al 2015).  
Nivolumab (OPDIVOR®) as monotherapy or in combination with ipilimumab (YERVOY®; 
anti-CTLA-4 mAb) has also been investigated in relapsed SCLC, with preliminary promising 
results of 18% and 32.6% ORR, respectively.  Furthermore, DCR was 38% for nivolumab as 
monotherapy versus 54% for nivolumab in combination with ipilimumab.  Median survival 
data have also been recently reported in this study; nivolumab alone had an OS of 4.4 months 
(n=40) versus 8.2 months (n=46) for nivolumab in combination with ipilimumab (Antonia
2015).  Taken together, these preliminary data are very encouraging when comparing to 
pooled analysis for single-agent topotecan, which demonstrated a typical ORR of 5% and a 
12-month survival rate of 9% (Horita et al 2015) in this refractory setting.


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AstraZeneca is also investigating the use of durvalumab + tremelimumab combination therapy 
for the treatment of cancer.  The development of durvalumab in combination with 
tremelimumab was initiated in Study D4190C00006 (NSCLC) and Study D4190C00010 (in a 
range of tumor types, including SCLC).  Preliminary data from these studies suggested that 
this 
  Based on 
 from these studies, further exploration of the 
benefit/risk of the durvalumab + tremelimumab combination therapy in SCLC is warranted.
2.1.3
DNA damage and repair mechanisms in SCLC
Although exact mechanisms of drug resistance remain to be elucidated, it seems to be a 
multi-factorial process with pivotal roles for altered expression of genes encoding proteins 
involved in drug transport and DDR mechanisms.  Moreover, clinically observed platinum 
resistance (in ovarian carcinoma) is associated with 1) decreased cellular accumulation of 
drug in tumor cells, 2) augmented drug inactivation, 3) increased DNA repair, and 4) tolerance 
to DNA damage (Kurzeder et al 2006). 
Proteomic profiling across >30 SCLC cell lines and 12 primary SCLC tumors has identified 
high expression of E2F transcription factor 1-regulated proteins, including enhancer of zeste 
homolog 2, DNA repair and apoptosis proteins, and poly(ADP-ribose) polymerase (PARP) 1 
as potential targets in SCLC based on their differential dysregulated expression (Byers et al 
2012).  Given the similarity of SCLC to ovarian carcinoma in terms of initial sensitivity to 
platinum and the proven clinical utility of PARP inhibitors in that setting, this study further 
explored the effects of PARP inhibition on SCLC cell lines.  They found that they were as 
sensitive as breast cancer susceptibility gene (BRCA)-mutated breast and ovarian cell lines, 
and that sensitivity was correlated with increased expression of PARP (Wainberg et al 2014) 
Recently they have presented the first clinical evidence of a single-agent PARP inhibitor in 
platinum-resistant SCLC with BMN673 with initial data from 25 patients demonstrating a 
25% DCR (complete response [CR] + partial response [PR] + stable disease [SD] >24weeks). 
Taken together, there may be a role for agents that inhibit DNA repair in SCLC.
2.1.4
DNA damage and immunogenicity 
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 and interferon (IFN) regulatory factor 7.  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, and inducible T-cell costimulatory ligand, which render 
tumor cells more visible to detection by cytotoxic T cells (Tang et al 2014).
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Death of tumor cells and release of antigen, which may help to promote antigen presentation 
and immune priming (Kroemer et al 2012).
These effects would be expected to help promote an effective antitumor immune response.  In 
keeping with this hypothesis, several tumor types with genetic defects expected to lead to 
increased DNA damage show evidence of enhanced immune recognition.  For example, 
BRCA tumor cells are associated with higher levels of TILs and secreting lymphocyte 
attractants (eg, C-X-C motif ligand [CXCL] 10) and immune-suppressive ligands such as 
PD-L1 (Mulligan et al 2014).  Similarly, ataxia telangiectasia mutated-negative gastric tumors 
are associated with higher levels of microsatellite instability, which is itself associated with 
higher response rates to immunotherapy in colorectal cancer (Kim et al 2014, Le et al 2015).
Similarly, modification of the pathways involved in controlling DNA damage through use of 
selective inhibitors has been shown to have beneficial effects on the immune system 
non-clinically.  For example, Wee1 inhibition, through AZD1775, has been demonstrated to 
increase the capacity of T cells to induce tumor cell lysis (Hamilton et al 2014), while PARP 
inhibition has been shown to synergize with CTLA-4 blockade and promote release of IFNγ in 
a mouse model of BRCA-deficient ovarian cancer (Higuchi et al 2015).
2.2 Rationale for study design, doses, and control groups
2.2.1
Rationale for study design
This is an exploratory, signal-searching study with multiple arms with a primary endpoint of 
ORR.  Experimental arms may open concurrently and recruit up to 40 eligible patients.  
Enrollment into any given arm on the study will be sequential and follow a staged design; 
each arm will initially enroll a minimum of 10 patients (see Figure 1 Staged recruitment 
design).  After the initial 10 eligible patients are treated on each arm and assessed for a 
minimum of 12 weeks, an interim analysis will be performed, which will determine whether 
recruitment should expand to the second stage (an additional 10 patients for a total of 20 
patients) for that specific arm or stop. The Sponsor Review Committee (see Section 7.9) may 
decide to enroll additional patients to replace any patients who do not meet the key inclusion 
criteria at each stage. If the results of the primary ORR analysis from the completed 2nd stage 
of any arm are encouraging the Review Committee could decide to recommend adding up to 
an additional 20 eligible subjects (for a total of 40 eligible patients) into an expansion cohort 
to further explore the findings. 
All Review Committee decision points (including the decision whether to recommend opening 
Stage II or to expand the arm) will be based on the totality of the data available at the time, 
considering the benefit-risk assessment.
This design allows rapid assessment of a given treatment by directly measuring the treatment 
effect on the tumor with no/minimal impact on enrollment to the study overall.  As discussed 
in Section 2.1, the response rate in the refractory/resistant setting for ED-SCLC is poor with 
current therapies.  The interim assessment of efficacy in 10 patients not only facilitates an 
early stop if patients are deriving no benefit (e.g. 0/10 responses) but could also prompt early 


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closure if promising efficacy is observed (>3/10 responses).  For more details on the proposed 
interim analysis, see Section 9.5.7.
Figure 1
Staged recruitment design
This study was opened with 2 arms initially (A and B) and was amended with version 3 to
add Arm C in the original modular design where multiple treatment arms of novel
combination therapies can be added and opened. Each new therapy will have a defined dose 
and schedule based on earlier studies investigating that combination, as well as a clear 
rationale for the expected efficacy in this setting. Please refer to each specific arm(s) for this 
information. 
2.2.2
Rationale of the study for specific agents
Please see specific study arm appendices for rationale on specific agents.

Appendix A: Arm A (durvalumab + tremelimumab followed by durvalumab 
monotherapy) 

Appendix B: Arm B (AZD1775 + carboplatin [CBDP]) 

Appendix C: Arm C (AZD6738 + olaparib)
2.2.3
Rationale for study endpoints
The primary aim of this study is to determine the preliminary efficacy of novel combinations 
of anti-cancer agents in patients with refractory or resistant ED-SCLC.  The primary endpoint 
of the study is ORR by Investigator assessment according to Response Evaluation Criteria in 
Solid Tumors, version 1.1 (RECIST 1.1).  ORR measures direct effects on tumors and has 
been widely used as the endpoint in early clinical development for decades.  A meta-analysis 
of 14 studies in 12567 patients with advanced NSCLC submitted to the Food and Drug 
Administration (FDA) between 2003 and 2013 demonstrated a strong patient-level association 


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between response and progression-free survival (PFS) and OS (Blumenthal et al 2015).  The 
FDA has used ORR as the endpoint for accelerated approval of breakthrough novel therapies.
2.2.4
Background, rationale, and risk benefit information on specific agents 
See the following appendices for information on specific agents and the scientific rationale 
supporting the combinations for investigation in each arm:

Appendix A: Arm A (durvalumab + tremelimumab followed by durvalumab 
monotherapy):

Appendix B: Arm B (AZD1775 + carboplatin [CBDP])

Appendix C: Arm C (AZD6738 + olaparib)
2.3 Benefit/risk and ethical assessment
As described in Section 2.1, the prognosis of refractory or resistant SCLC is very poor.  
Single-agent topotecan is the only drug approved as second-line treatment for recurrent SCLC 
in most countries.  A meta-analysis has shown that topotecan has limited activities in this 
setting, with an ORR of 5%, 6 month OS rate of 37% and 12 month OS rate of 9% (Horita et 
al 2015).  Therefore, there is a significant unmet medical need for improving treatment 
outcome and provide more treatment options to patients with refractory or resistant ED-SCLC. 
The benefit/risk and ethical assessments that are specific to each arm of the Clinical study 
protocol (CSP) are described in the relevant section of each specific arm appendix.  
The monitoring and management of the potential risks are discussed in Section 7.  Refer to the 
relevant Investigator’s Brochure (IB) and arm for each agent used for more information on the 
potential benefits of each agent and an assessment of the potential and known risk.
2.3.1
Summary benefit/risk statement
There remains a significant unmet medical need for patients with refractory/resistant 
ED-SCLC; as highlighted above, approximately 95% of patients fail to respond to single-
agent topotecan, which is the only currently approved available treatment in most countries. 
The mechanisms that underpin the high rate of relapse in SCLC are still poorly understood; 
the disease’s rapid progression and the lack of available tissue for translational research mean 
that there has been little progress in this area.  
The study design aims to minimize potential risks in several ways. Firstly, by minimizing the 
number of subjects exposed to study drugs, via the  staged recruitment process. Second, the 
protocol includes safety monitoring in excess of standard of care monitoring, with the intent of 
protecting subjects involved in the study. Furthermore, there is specific guidance for 
Investigators for each arm to support optimal management of those risks deemed to be most 


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likely or serious. Potential benefits of each combination in patients with refractory/resistant 
ED-SCLC are unknown at this time; however, non-clinical and clinical data to date have 
showed acceptable safety profile and anti-tumor activity for the agents proposed in this study 
(see specific sub-protocol Appendices for more information). 
Thus, the benefit/risk assessment for this Phase II study is acceptable.  
2.4 Study design
This is a Phase II, open-label, multi-drug, multi-center, multi-arm study to determine the 
preliminary efficacy of novel combinations of treatment in patients with ED-SCLC who have 
refractory or resistant disease, defined as patients who progress during first-line 
platinum-based chemotherapy or those who progress within 90 days after completing first-line 
platinum-based chemotherapy. 
This multi-arm study initially opened with 2 arms (Arms A and B), and an additional arm 
(Arm C) was added in version 3;additional arms may be opened provided there is compelling 
rationale for the combination and a safe and tolerable dose and schedule have been determined 
from ongoing Phase I studies (Figure 2).
The 3  experimental arms are:

Arm A (durvalumab + tremelimumab followed by durvalumab monotherapy) -
Appendix A

Arm B (AZD1775 + CBDP) -Appendix B

Arm C (AZD6738 + olaparib) - APPENDIX  C
Each arm will have its own sub-protocol to include study information specific to that arm. 
Each arm is independent, and any signal observed in 1 arm will not have an impact on the 
other arm in the study.  Please refer to each sub-study appendix for the relevant study 
flowchart.


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Figure 2
Overall study design
ED-SCLC  Extensive-stage disease small-cell lung cancer; ORR  Objective response rate; OS  Overall survival; PFS  Progression-free survival.


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3.
STUDY OBJECTIVES
All objectives will be evaluated for all patients, unless otherwise indicated.  Please also refer 
to relevant sub-protocol appendix for objectives applicable to particular arm of the study (eg, 
Appendix A for Arm A).
3.1 Primary objective
Primary Objective:
Outcome Measure:
To assess the preliminary efficacy of each 
treatment arm in terms of ORR
ORR using Investigator assessments according to 
RECIST 1.1
3.2 Secondary objectives
Secondary Objective:
Outcome Measure:
To further assess the preliminary efficacy of 
each treatment arm in terms of duration of 
response (DoR), DCR, time to response (TTR), 
PFS, and OS
DoR, DCR, TTR, and PFS using Investigator 
assessments according to RECIST 1.1
OS
To assess the pharmacokinetics (PK) of novel 
combination treatments (Arm A, stages 1 and 2 
only, Arm B and Arm C)
Concentration of novel combination treatments in 
blood
3.3 Safety objectives
Safety Objective:
Outcome Measure:
To assess the safety and tolerability profile of 
each treatment arm
Adverse events (AEs); physical examinations; vital 
signs, including blood pressure and pulse; 
electrocardiograms (ECGs); and laboratory 
findings, including clinical chemistry, hematology, 
and urinalysis
3.4 Exploratory objectives
 
 
 
 
 
 
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4.
PATIENT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL
Each patient must meet all of the sub protocol inclusion criteria  and exclusion criteria  for this 
study. Please refer to Appendix  A, B or C for inclusion/exclusion criteria specific to each 
individual arm of the study.
4.1 Inclusion criteria 
Please refer to Appendix  A (Arm A Inclusion criteria), B (Arm B Inclusion criteria) or C
(Arm C inclusion criteria) for inclusion criteria for each individual arm of the study.
4.2 Exclusion criteria
Please refer to Appendix  A (Arm A Exclusion criteria), B (Arm B Exclusion criteria) or C
(Arm C Exclusion criteria) for exclusion criteria for each individual arm of the study.
4.3 Patient enrollment and randomization
Investigator(s) should keep a record, the patient screening log, of patients who entered 
screening.
At screening/baseline (Days -28 to -1), the Principal Investigator, or suitably trained delegate, 
will:
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1. Obtain signed informed consent from the potential patient or their guardian/legal 
representative before any study-specific procedures are performed.  If laboratory or 
imaging procedures were performed for alternate reasons prior to signing consent, these 
can be used for screening purposes with consent of the patient.  However, all screening 
laboratory and imaging results must have been obtained within 28 days of enrollment.
2. Obtain a unique 7-digit enrollment number (E-code) through the Interactive Voice 
Response System (IVRS)/Interactive Web Response System (IWRS) into the following 
format “E#”.
3. Determine patient eligibility.  See Section 4 and specific treatment sub-protocol (please 
check the specific arm appendix for details).
Patients will begin treatment on Day 1.  Patients must not be treated unless all eligibility 
criteria have been met.  
There is no randomization in the study.
If a patient withdraws from participation in the study, then his or her enrollment code cannot 
be reused, and they cannot re-enter the study.  Withdrawn patients will not be replaced.
4.4 Procedures for handling incorrectly enrolled or randomized patients
Patients who fail to meet the eligibility criteria must 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.
When a patient is started on study treatment and is later found to not meet all the eligibility 
criteria (e.g. during routine monitoring), the Investigator should inform the AstraZeneca Study 
Physician immediately. A discussion should occur between the AstraZeneca Study Physician 
and the Investigator regarding whether to continue or discontinue the patient from treatment 
based on risk/benefit assessment. The AstraZeneca Study Physician must ensure all decisions 
are appropriately documented.
4.5 Methods for assigning treatment groups
At baseline, patients who satisfy all the inclusion and exclusion criteria to participate in a 
particular treatment arm will be enrolled sequentially in that treatment arm. If they do not 
fulfil the criteria for one arm but satisfy all the criteria for another ongoing arm of the study 
then they may be enrolled into the arm for which they are most suitable.
Every effort should be made to minimize the time between enrollment and starting study 
treatment.
Patients cannot enroll into more than 1 arm.  For example, if a patient is enrolled into Arm A 
and experiences PD, he or she cannot enroll into another sub-study of this protocol.


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4.6 Methods for ensuring blinding
Not applicable, as study is open label. 
4.7 Methods for unblinding 
Not applicable, as study is open label. 
4.8 Restrictions
Please refer to the specific sub-study appendix (eg, Appendix A for Arm A) for specific 
restrictions applicable to each arm of the study.
4.9 Discontinuation of investigational product
An individual patient will not receive any further IP if any of the following occur in the 
patient in question:

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 4.10.2).

Any AE that meets criteria for discontinuation as defined in the Dosing 
Modification and Toxicity Management Guidelines (see study-specific information 
in sub-protocols).  Note that this is arm specific; this would not impact enrollment 
into the other arms in the study.

Initiation of alternative anticancer therapy including another investigational agent.

AEs that, in the opinion of the Investigator or the Sponsor, contraindicate further 
dosing.  Note that this is arm specific; this would not impact enrollment into the 
other arms in the study. 

Confirmed PD per RECIST 1.1 and Investigator determination that the patient is no 
longer benefiting from treatment with IP.

Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (eg, refusal to adhere to 
scheduled visits).

Patients incorrectly initiated on study treatment (eg, patient is determined to have 
met 1 or more of the exclusion criteria for study participation at study entry and 
continuing investigational therapy might constitute a safety risk)

Pregnancy or intent to become pregnant.


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Should any of this occur, the patient will not receive any further IP.
If the patient is discontinued from study treatment, the scheduled study visits, data collection, 
and procedures should continue according to this study protocol until study closure of the arm 
the patient is participating in.  Alternatively, if the patient does not agree to this option, a 
modified follow-up through methods such as regular telephone contacts or a contact at study 
closure should be arranged, if agreed to by the patient and in compliance with local data 
privacy laws/practices (see Section 4.9.2).
4.9.1
Procedures for discontinuation of a patient from investigational product
At any time, patients are free to discontinue IP without prejudice to further treatment. A 
patient who decides to discontinue IP will always be asked about the reason(s) for 
discontinuation and the presence of any AEs. If possible, they will be seen and assessed by an 
Investigator(s). AEs will be followed up (see Section 7). The AstraZeneca Study Physician 
should be notified of any ongoing AE that may delay treatment or necessitate permanent 
discontinuation of treatment.
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment. Patients who are 
permanently discontinued will enter the follow-up period (see specific arm appendix for 
details).
All patients will be followed for survival until the end of the study.
Patients who decline to return to the site for evaluations should be contacted by telephone as 
an alternative.
Any patient who discontinues study treatment for reasons other than objective disease 
progression should have tumor assessments performed as scheduled until confirmed objective 
disease progression is documented or death occurs, unless consent is withdrawn.
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IVRS/IWRS.
If a patient is withdrawn from the study, see Section 4.10.
4.9.2
Assessments following discontinuation of investigational product
Patients who are permanently discontinued from receiving IP will remain in the study and will 
be followed per the study plan (see the relevant arm sub-protocol) for safety, including the 
collection of any protocol-specified blood specimens, unless consent is withdrawn or the 
patient is lost to follow-up or enrolled in another clinical study.  All patients will be followed 
for survival (please see follow-up tables for each specific study arm).  Patients who decline to 
return to the site for evaluations will be offered follow-up by phone.  However, patients who 
discontinue due to an AE will need to attend all protocol-specified visits, and all assessments 
will be conducted as scheduled.


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All patients who have any Grade 3 or 4 laboratory values at the time of discontinuation must 
have further tests performed, and the results must be recorded on the appropriate electronic 
case report form (eCRF) until the laboratory values have returned to Grade 1 or 2, unless these 
values are not likely to improve because of the underlying disease.
At discontinuation, all ongoing study-related toxicities and serious adverse events (SAEs) 
must be followed until resolution unless, in the Investigator’s opinion, the condition is 
unlikely to resolve due to the patient’s underlying disease.
All SAEs occurring for up to the pre-defined time period after the last dose of study treatment 
must be recorded in the eCRF.  See the relevant appendices for the pre-defined time period for 
collection of SAEs for specific agents.
Drug- or study procedure-related SAEs must be captured until the patient completes the 
follow-up period following discontinuation of study drug (due to confirmed progression of 
disease) or is permanently withdrawn from the study.  Both the patient and the physician will 
be asked about the subsequent treatment the patient receives during the follow-up period per 
the study plan.
4.10 Criteria for withdrawal
4.10.1
Screen failures 
Screen failures are patients who do not fulfil the eligibility criteria for the study, and therefore 
must not be treated with study drug or progress any further on the study. These patients should 
have the reason for study withdrawal recorded as “eligibility criteria not fulfilled” (ie, patient 
does not meet the required inclusion/exclusion criteria). This reason for study withdrawal is 
only valid for screen failures (not enrolled patients who commence on study treatment). 
Patients are not allowed to be rescreened. 
4.10.2
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 their 
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) and the presence of 
any AE.  If possible, they will be seen and assessed by an Investigator.  The Investigator will 
follow up AEs outside of the clinical study.
If a patient withdraws from participation in the study, then his or her enrollment code cannot 
be reused.  Withdrawn patients may be replaced following discussion between AstraZeneca 
Study Physician and AstraZeneca Study Statistician.


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If consent is withdrawn, the patient will not receive any further study treatment or further 
study observation.  The patient will be specifically asked if they are withdrawing consent to:

Further participation in the study including any further follow-up (eg, survival calls)

Withdrawal of consent to the use of their study-generated data

Withdrawal to the use of any samples
Note that the patient may be offered additional tests or tapering of treatment to withdrawal for 
safety and will be offered follow-up by phone.  If a patient wishes to withdraw their consent to 
further participation in the study, including survival follow-up (by phone), this should be 
clearly documented in the patient notes and in the clinical study database.
Regardless of the reason for termination, all data available for the patient up to the time of 
discontinuation of follow-up must be recorded in the eCRF.  All reasons for discontinuation of 
treatment must be documented.
4.10.3
Survival status for withdrawn consent and lost to follow-up patients
In order to support key end points of PFS and OS analyses, the survival status of all patients in 
the full analysis and the safety analysis sets should be re-checked. This includes those patients 
who withdrew consent or are classified as “lost to follow up.”    
• Lost to Follow up: site personnel should check hospital records, the patients’ current 
physician, and a publicly available death registry (if available) to obtain a current survival 
status in the 7 days following data cutoff.  (The applicable CRF modules will be updated.)
• In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient can be obtained by site personnel from publicly 
available death registries (if available) where it is possible to do so under applicable local laws 
to obtain a current survival status in the 7 days following data cutoff.  (The applicable CRF 
modules will be updated.)
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.
Note: Patients who refuse to continue all participation in the study, including study team 
phone contact with their clinician to obtain follow up, 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.


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4.11 Discontinuation of the study
Specific arms in this study may be stopped if, in the judgment of AstraZeneca, study patients 
are placed at undue risk because of clinically significant findings that meet any of the 
following criteria:

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.
Note that this is arm specific; this would not impact enrolment into the other arms in the study 
as each arm would be considered separately.
In terminating any particular sub-study, or the entire study, the Sponsor will ensure that 
adequate consideration is given to the protection of the patients’ interests.
5.
STUDY PLAN AND TIMING OF PROCEDURES 
The study plan for each arm of the study will be included in the appropriate arm appendix.  
Please consult the appendix for the sub-study in which patients are enrolled (eg, Appendix A
for Arm A).  See Figure 2 for the study flow chart.
For all treatment arms
•
Tumor efficacy (RECIST) assessment dates are not affected by dose delays and remain 
as originally scheduled, as they are based on the date of initiation of study therapy.
•
All other scheduled assessments must be performed relative to the start of the dosing 
cycle such that all laboratory procedures, etc required for dosing should be performed within 3 
days prior to dosing. See individual arm appendix for details of all scheduled assessments.
6.
STUDY ASSESSMENTS
A Web-Based Data Capture 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.  The 
Investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be archived 
at the study site.


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The study assessments described here are applicable to all arms in the study.  Please refer to 
the corresponding sections of each specific modular appendix (eg, Appendix A for Arm A) for 
study assessments that are specific to each arm of the study.
6.1 Efficacy assessments
This study will evaluate the primary endpoint of ORR as determined by Investigator 
assessment according to RECIST 1.1 criteria.  Efficacy assessments of PFS, TTR, DoR, and 
DCR will be derived (by AstraZeneca) using Investigator RECIST 1.1 assessments.  In 
addition, OS will be determined as a secondary efficacy endpoint.
Tumor assessments use images from CT (preferred) or MRI, each preferably with IV contrast,
of the chest, abdomen, and pelvis, collected during screening/baseline and at regular (follow-
up) intervals during study treatment.  Any other areas of disease involvement should be 
additionally imaged based on the signs and symptoms of individual patients.
The RECIST 1.1 guidelines (Appendix F) provide a method of assessment of change in tumor 
burden in response to treatment. Screening/Baseline imaging should be performed no more 
than 28 days before start of study treatment and ideally should be performed as close as 
possible to and prior to the start of study treatment. The RECIST 1.1 assessments of baseline 
images identify target (defined and measurable) and non-target lesions.  Each lesion (and any 
new lesion) is evaluated in subsequent on-treatment follow-up images. This allows 
determination of follow-up target lesion response, non-target lesion response, and overall 
timepoint tumor responses (CR, PR, SD, PD, or not evaluable [NE]).
Efficacy for all patients (all arms) will be assessed on images collected either every 6 or 
8 weeks ± 1 week until confirmed objective disease progression or when the patient has been 
taken off-study.  It is important to follow the assessment schedule as closely as possible (refer 
to the study plans in each arm [screening and treatment period, and follow-up]).  If an 
unscheduled imaging assessment is performed and the patient has not progressed, every 
attempt should be made to perform the subsequent assessments at his or her next regularly 
scheduled imaging visit.
According to RECIST 1.1, objective tumor response (CR or PR) should be confirmed 
preferably at the next scheduled imaging visit and not less than 4 weeks after the visit when 
the response was last observed.
Patients who have discontinued treatment due to toxicity or symptomatic deterioration, 
clinical progression, or who have commenced subsequent anticancer therapy will be followed 
up with tumor assessments until RECIST 1.1-defined PD or until death (whichever comes 
first) and followed for survival.
For the immunotherapy arm only, a follow-up scan is requested following an overall timepoint 
assessment of progression by RECIST 1.1, preferably at the next scheduled imaging visit and 
no earlier than 4 weeks after the previous assessment of PD in the absence of clinically 
significant deterioration.  Treatment will continue between the initial assessment of 


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progression and confirmation for progression. If a patient discontinues treatment (and/or 
receives a subsequent anticancer therapy) after the initial assessment of progression, then the 
patient should continue to be followed with scheduled imaging until confirmed objective 
disease progression. 
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
study plan of the relevant arm appendix.
6.1.1
Survival assessments
Following treatment discontinuation, assessments for survival must be made monthly for the 
first 3 months and then every 2 months thereafter.  Survival information may be obtained via 
telephone contact with the patient or the patient’s family, or by contact with the patient’s 
current physician.  The details of first and subsequent therapies for cancer, after 
discontinuation of treatment, will be collected.  
In addition, patients on treatment or in survival follow-up will be contacted following the data 
cut-off for the primary analysis and all subsequent survival analyses to provide complete 
survival data.  These contacts should generally occur within 7 days after the data cut-off.
6.2 Safety assessments
6.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the times indicated in the study plan (see the specific section of the relevant 
arm appendix).  Please also refer to the Laboratory Manual.
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a 
licensed clinical laboratory according to local standard procedures.  Sample tubes and sample 
sizes may vary depending on the laboratory method used and routine practice at the site.  
Pregnancy tests may be performed at the site using a licensed test (urine or serum pregnancy 
test).  Clinically significant abnormal laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection, and results (values, units, and reference ranges) will 
be recorded on the appropriate eCRF.
Laboratory tests do not need to be repeated at baseline if the baseline visit is within 3 days of 
the screening sample.  The date of each collection will be recorded in the appropriate eCRF.
The laboratory variables to be measured are presented in the relevant appendix (eg, Appendix 
A for Arm A).


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Additionally, a urine/serum sample will be collected from all women of childbearing potential 
at screening and before the first dose for a pregnancy test in all combination arms.
If a patient shows an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
≥3× upper limit of normal (ULN) or total bilirubin ≥2× ULN, refer to Appendix E for further 
instructions on cases of increases in liver biochemistry and evaluation of Hy’s Law.  These 
cases should be reported as SAEs if, after evaluation, they meet the criteria for a Hy’s Law 
case or if any of the individual liver test parameters fulfil any of the SAE criteria.  
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 7.3.7.
All patients who have any Common Terminology Criteria 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 Common Terminology Criteria Grade 1 
or 2, unless these values are not likely to improve because of the underlying disease.
6.2.2
Physical examination
Physical examinations will be performed according to the assessment schedules (see 
individual arm appendix).  Full physical examinations will include assessments of the head, 
eyes, ears, nose, and throat and the respiratory, cardiovascular, gastrointestinal, urogenital, 
musculoskeletal, 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 7.3.7.
6.2.3
Resting 12-lead ECG
Resting 12-lead ECGs will be recorded at screening, at the commencement of each treatment 
cycle for patients in Arms B and C (see Appendix B section 5 and Appendix C.), and as 
clinically indicated throughout the study (see relevant arm appendix). ECGs should be 
obtained after the patient has been in a supine position for 5 minutes and recorded while the 
patient remains in that position.
In case of clinically significant ECG abnormalities, including a heart rate corrected QT 
interval (Fridericia’s formula) (QTcF) value >470 ms or a shift from baseline of ≥ 60ms, 
2 additional 12 lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm 
the finding.  
Situations in which ECG results should be reported as AEs are described in Section 7.3.7.


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6.2.4
Vital signs
Semi-supine blood pressure, pulse, temperature, and respiration rate will be measured after 
10-minute rest.  Assessments will be performed at the visits as shown in the study plan (see 
the appropriate section of the relevant arm appendix) and below.
Situations in which vital signs results should be reported as AEs are described in 
Section 7.3.7.  For any AEs of infusion reactions, vital signs values should be entered into the 
case report form (CRF).
6.3 Other assessments
6.3.1
WHO/ECOG performance status
WHO/ECOG performance status will be assessed at the times specified in the assessment 
schedules (see relevant arm appendix) based on the following:
0. Fully active; able to carry out all usual activities without restrictions.
1. Restricted in strenuous activity, but ambulatory and able to carry out light work or work of 
a sedentary nature (eg, light housework or office work).
2. Ambulatory and capable of self-care, but unable to carry out any work activities; up and 
about more than 50% of waking hours.
3. Capable of only limited self-care; confined to bed or chair more than 50% of waking hours.
4. Completely disabled; unable to carry out any self-care and totally confined to bed or chair.
Any significant change from baseline or screening must be reported as an AE.
6.4 Pharmacokinetics
Please refer to the relevant arm appendix for details of PK requirements that are required on 
an investigational product basis (eg, Appendix A for Arm A).
6.4.1
Collection of samples
Blood samples for determination of study drug in serum will be obtained according to the 
assessment schedules (see relevant arm appendix).  
6.4.2
Determination of drug concentration
Samples for determination of drug concentration in serum will be analyzed by a designated 
third party on behalf of AstraZeneca using an appropriate bioanalytical method.  Full details 
of the analytical method used will be described in a separate bioanalytical report.


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6.4.3
Storage and destruction of pharmacokinetic samples
PK samples will be disposed of after the Bioanalytical Report finalization or 6 months after 
issuance of the draft Bioanalytical Report (whichever is earlier), unless requested for future 
analyses.
PK samples may be disposed of and destroyed or anonymized by pooling.  Additional 
analyses may be conducted on the anonymized, pooled PK samples to further evaluate and 
validate the analytical method.  Results from such analyses may be reported separately from 
the Clinical Study Report (CSR).
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Validation Report.
Any residual back-up PK samples may be used for future exploratory biomarker research (in 
this case, residual back-up PK samples will be shipped to AstraZeneca Biobank; see details in 
the Laboratory Manual).
6.5 Pharmacodynamics
6.5.1
Collection of samples
Blood (mandatory) and archival tumor samples (if available) for exploratory biomarker 
analyses will be obtained according to the schedules presented in each arm.  Details for 
collection, volumes, storage, and shipment of biologic samples are presented in a separate 
Laboratory Manual. 
Please see Section 6.6.1.
6.6 Biomarker analysis 
By participating in this study, the patient consents to the collection and use of donated 
biological samples as described here.  Samples will be obtained from all screened patients.
Biological samples (eg, archived tumor samples) will be collected and may be analyzed for 
exploratory biomarkers to assess correlations with disease activity, effects of study drug, 
clinical outcomes, and toxicity.
Samples will be obtained according to the assessment schedules provided in each arm.
Details for collection, volumes, storage, and shipment of biologic samples are presented in a 
separate Laboratory Manual.
All samples collected for biomarker analyses will be stored at the study site, a reference 
laboratory, or at AstraZeneca facilities and may be used for subsequent research relevant to 
evaluating biological and/or clinical response as described in the exploratory analyses section.


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The results may be pooled with biomarker data from other studies to evaluate biological 
responses across indications and to compare results in monotherapy versus combination 
settings.
6.6.1
Exploratory biomarkers
The exploratory biomarker plan is described by sample type below.
.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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6.6.2
Management of biomarker data
The biomarker data will have unknown clinical significance. AstraZeneca will not provide 
biomarker research results to patients, their family members, any insurance company, an 
employer, clinical study Investigator, general physician, or any other third party, unless 
required to do so by law.  The patient’s samples will not be used for any purpose other than 
those described in the study protocol.
Individual patients will not be identified in any report or publication resulting from this work.  
The data and results of this research may be reviewed with collaborators and published, but 
neither the patient’s name nor any other personal identifiers will appear in any publication or 
report.
6.6.3
Storage, re-use, and destruction of biological samples
Samples will be stored for a maximum of 15 years from the date of the Last Patient Last Visit, 
after which they will be destroyed.  Summaries and analyses for exploratory biomarkers will 
be documented in a separate analysis plan and will be reported outside the CSR in a separate 
report.  The results of this biomarker research may be pooled with biomarker data from other 
studies involving the agents tested in this study to generate hypotheses to be tested in future 
research.
6.6.4
Labeling and shipment of biological samples
The Principal Investigator ensures 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 D, International Airline Transportation Association 6.2 Guidance Document.
Any samples identified as Infectious Category A materials are not shipped, and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labeling, shipment, and containment provisions are approved.
6.6.5
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator 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) and keeps documentation of receipt of arrival.
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 keeps documentation of receipt of 
arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites, and auditing of external laboratory providers.


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Samples retained for further use are registered in the AstraZeneca Biobank during the entire 
life cycle.
6.6.6
Withdrawal of informed consent for donated biological samples
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of or destroyed and the action will be documented.  If samples are already analyzed, 
AstraZeneca is not obliged to destroy the results of this research.
The Principal Investigator will:

Ensure that AstraZeneca is immediately notified of the patients’ withdrawal of 
informed consent to the use of donated samples

Ensure that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of, or destroyed and the action is documented

Ensure that 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

Ensure that the patient and AstraZeneca are informed about the sample disposal
7.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
7.1 Definition of adverse events
An AE is the development of an undesirable medical condition (other than progression of the 
malignancy under evaluation) or the deterioration of a pre-existing medical condition 
following or during exposure to a pharmaceutical product, whether or not considered causally 
related to the product.  An undesirable medical condition can be symptoms (eg, nausea, chest 
pain), signs (eg, tachycardia, enlarged liver), or the abnormal results of an investigation (eg, 
laboratory findings, ECG).  In clinical studies, an AE can include an undesirable medical 
condition occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
7.2 Definitions of serious adverse event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, or 
follow-up) that fulfils 1 or more of the following criteria:

Results in death


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
Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent 1 of the outcomes listed above
For further guidance on the definition of an SAE, see Appendix H.
7.3 Recording of adverse events
7.3.1
Time period for collection of adverse events
AEs and SAEs will be recorded from the time of informed consent, throughout the treatment 
period, and up to the follow-up period (see relevant arm appendix for number of days after the 
last dose of study treatment).
7.3.2
Follow-up of unresolved adverse events
During the course of the study, all AEs and SAEs should be proactively followed 
up for each patient for as long as the event is ongoing. Every effort should be 
made to obtain a resolution for all events, even if the events continue after the 
patient has discontinued study drug or the study has completed.
Any AEs that are unresolved at the patient’s last visit in the study are followed up 
by the Investigator for as long as medically indicated but without further 
recording in the eCRF. AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary.
7.3.2.1
Post-study events
After the patient has been permanently withdrawn from the study, there is no 
obligation for the Investigator to actively report information on new AEs or SAEs 
occurring in former study patients after the arm-designated number of days.  
However, if an Investigator learns of any SAEs, including death, at any time after 
the patient has been permanently withdrawn from study, and he or she considers 
there is a reasonable possibility that the event is related to study treatment, the 
Investigator should notify AstraZeneca, Patient Safety, or its representative.
7.3.3
Variables 
The following variables will be collected for each AE:


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
AE (verbatim)

The date and time when the AE started and stopped

The maximum Common Terminology Criteria for Adverse Event (CTCAE) grade 
reported

Changes in CTCAE grade (report only the maximum CTCAE grade for each calendar 
day)

Whether the AE is serious or not

Investigator causality rating against the study treatment (yes or no)

Action taken with regard to study treatment

Administration of treatment for the AE

Whether AE caused patient’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date Investigator became aware of the SAE

Seriousness criteria

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Whether an autopsy was performed

Causality assessment in relation to study procedure(s)

Causality assessment in relation to other medication, as explained in Section 7.3.4

Description of AE


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The grading scales found in the revised National Cancer Institute (NCI) CTCAE version 4.03 
will be used for all events with an assigned CTCAE grading.  For those events without 
assigned CTCAE grades, the recommendation in the CTCAE criteria that converts mild, 
moderate, and severe events into CTCAE grades should be used.  A copy of the CTCAE 
version 4.03 can be downloaded from the Cancer Therapy Evaluation Program website 
(http://ctep.cancer.gov).
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity, whereas seriousness is defined by the criteria in Section 7.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Section 7.2.  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 7.2.
7.3.4
Causality collection
The Investigator will assess causal relationships between the 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 Investigational Product?”
For SAEs, a 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 H.
7.3.5
Relationship to protocol procedures
The Investigator is also required to provide an assessment of the relationship of SAEs to 
protocol procedures on the SAE report form.  This includes both non-treatment-emergent (ie, 
SAEs that occur prior to the administration of IP) and treatment-emergent SAEs.  A protocol-
related SAE may occur as a result of a procedure or intervention required during the study (eg, 
blood collection).  The following guidelines should be used by Investigators to assess the 
relationship of SAEs to the protocol:

Protocol related: The event occurred due to a procedure or intervention that was 
described in the protocol for which there is no alternative etiology present in the 
patient’s medical record.

Not protocol related: The event is related to an etiology other than the procedure or 
intervention that was described in the protocol.  The alternative etiology must be 
documented in the study patient’s medical record.
7.3.6
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 personnel, “Have you had any health problems since the previous visit/you 


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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.
7.3.7
Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests and vital signs will be summarized in the 
CSR.  Deterioration as compared to baseline in protocol-mandated laboratory values and vital 
signs should, therefore, only be reported as AEs if they fulfil any of the SAE criteria or are the 
reason for discontinuation of treatment.
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 term rather than the laboratory term (eg, anemia versus low hemoglobin 
value).
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s).
Deterioration of a laboratory value that 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.
7.3.8
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3× ULN or total bilirubin ≥2× ULN may need to be 
reported as SAEs.  Please refer to Appendix E for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law.
7.3.9
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the study treatment 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 that are unequivocally due 
to disease progression should not be reported as an AE during the study.


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7.3.10
New cancers
The development of a new cancer should be regarded as an SAE.  New primary cancers are 
those that are not the primary reason for the administration of the study treatment and have 
been identified after the patient’s inclusion in this study.
7.3.11
Deaths
All deaths that occur during the study treatment period or within the protocol-defined 
follow-up period after the administration of the last dose of study treatment must be reported 
as follows:

Deaths that are clearly the result of disease progression should be reported to the 
Study Monitor/Physician at the next monitoring visit and should be documented in 
the eCRF in the Statement of Death page.  It should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of disease under study, 
the AE causing the death must be reported to the study monitor as an SAE within 
24 hours.  It should also be documented in the Statement of Death page in the 
eCRF.  The report should contain a comment regarding the co-involvement of PD, 
if appropriate, and should assign main and contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE.  It should also 
be documented in the Statement of Death page in the eCRF.  A post-mortem maybe 
helpful in the assessment of the cause of death, and if performed, a copy of the 
post-mortem results should be forwarded to AstraZeneca Patient Safety or its 
representative within the usual timeframes.
Deaths occurring after the protocol-defined safety follow-up period after the administration of 
the last dose of study drug should be documented in the Statement of Death page.  If the death 
occurred as a result of an event that started after 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.
7.4 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 and submitted as described in 
each arm.  
If any SAE occurs in the course of the study, then Investigators or other site personnel will 
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 will work with the Investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 


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1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel will 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).
Please refer to the arm-specific Safety Reporting Guidelines.  The AstraZeneca representative 
will advise the Investigator/study site personnel how to proceed.  AstraZeneca or their 
representative will provide regulatory authorities, Ethics Committees (ECs), and Principal 
Investigators with clinical safety updates/reports according to local requirements.
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study.  A medical emergency usually 
constitutes an SAE and is to be reported as such.
7.5 Adverse events of special interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
the understanding of the study treatment and may require close monitoring and rapid 
communication by the Investigator to the Sponsor.  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 the individual investigational 
products.
Please see the relevant arm appendix for applicable AESIs.
7.6 Overdose
Use of any agent studied in doses in excess of that specified in the protocol or arms is 
considered to be an overdose.  There is currently no specific treatment in the event of 
overdose of any of these agents, and possible symptoms of overdose are not established.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE arms in the eCRF and on the Overdose eCRF for that arm.

An overdose without associated symptoms is only reported on the Overdose eCRF 
for that arm.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
Investigators or other site personnel should inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.


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For overdoses associated with an SAE, the standard reporting timelines apply; see Section 7.4.  
For other overdoses, reporting must occur within 30 days.
7.7 Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:
Pregnancy discovered before the study patient has received any study drugs.
7.7.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study treatment 
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 to5 
calendar days for SAEs (see Section 7.4) and within 30 days for all other pregnancies.
The same timelines apply when information on the outcome of the pregnancy is available.
The PREGREP arm in the eCRF is used to report the pregnancy, and the PREGOUT is used 
to report the outcome of the pregnancy.
7.7.2
Paternal exposure 
Please see specific arm for the required time for male patients to refrain from fathering a child, 
donating sperm during the study, or details of reporting outcomes of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital 
abnormality) occurring from the date of the first dose of study medication.
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 informed consent form (ICF) template in line with local 
procedures and submit it to the relevant ECs/Institutional Review Boards (IRBs) prior to use.


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7.8 Management of investigational product-related toxicities
Please refer to the relevant section (eg, Section 7.5 for Arm A) for specific toxicity 
management guidelines applicable to each arm of the study.  
All toxicities will be graded according to NCI CTCAE version 4.03 (see study-specific 
sub-protocols).  
7.9 Study governance and oversight
A Review Committee, which includes the Principal Investigator, the AstraZeneca Study 
Physician, and statisticians, will convene after the first 10 patients are enrolled onto each arm 
to assess whether the arm should continue to accrue or stop recruitment based on an interim 
analysis including ORR (see section 9.5.7). The recommendation of the Review Committee
will be discussed at a clinical project level before endorsement.
If the decision is made to open stage 2 of a particular arm the Review Committee will review 
the results of the primary analysis for the first 20 subjects after completion of 12 weeks follow 
up. Based on the totality of the data and the benefit-risk assessment the Review Committee 
may recommend expansion of that arm. The recommendation of the Review Committee will 
be discussed at a clinical project level before endorsement.
No Steering Committee and/or Scientific Advisory Committee will be used in this study.  
There is an internal AstraZeneca BALTIC Study Team to oversee the global operational and 
medical monitoring aspects of the study. The safety of all subjects in the BALTIC study is 
closely monitored on an ongoing basis by this team in consultation with AstraZeneca Patient 
Safety and clinical teams responsible for the individual products under investigation in each 
arm.  Issues identified will be addressed; for instance, this could involve amendments to the 
study protocol and letters to Investigators.  
8.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
8.1 Identity of investigational product(s)
Please refer to the relevant appendix (eg, Appendix A for Arm A) for specific IP information 
applicable to each arm of the study.  
8.1.1
Duration of treatment
Unless specific treatment discontinuation criteria are met, all patients will continue therapy 
until disease progression.
8.1.2
Follow up of patients post discontinuation of study drug
Please refer to the relevant appendix (eg, Appendix A for Arm A) for specific information 
applicable to each arm of the study. 


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8.2 Dose and treatment regimens
Please refer to the relevant arm appendix (eg, Appendix A for Arm A) for specific dose and 
treatment regimens.
8.3 Labeling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 and regulatory requirements of 
each country participating in the study.  The labels will be translated into local languages 
where applicable as required by local regulations.  Labels will be provided as either 
singlepanel labels or as multi-language booklet labels.  
The patient emergency contact details and patients’ dosing instructions will not be on the 
labels but can be found in the informed consent and the “Patient Information Card.”  For 
emergency purposes, the patient must be in possession of the emergency contact details at all 
times.
Please see the relevant arm appendix (eg, Appendix A for Arm A) for specific labeling 
information.
8.4 Storage
All study medications should be kept in a secure place under appropriate storage conditions.  
The IP label on the pack/bottle/carton will specify the appropriate storage.  Storage is also 
described in the IB of each product and in the IP Handling Instruction  
8.5 Compliance
The administration of all study drugs (including IPs) should be recorded in the appropriate 
sections of the CRF.
8.6 Accountability
The study drug provided for this study will be used only as directed in the study protocol.
Study site personnel will account for all study drugs received at the site, unused study drugs, 
and study drugs for appropriate destruction.  Certificates of delivery, destruction, and/or return 
should be signed.
8.7 Concomitant and other treatments 
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical treatment phase of the study including the 
follow-up period following the last dose of treatment.  Any concomitant medication(s), 
including herbal preparations, taken during this time will be recorded in the eCRF.  
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator.


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Restricted, prohibited, and permitted concomitant medications are described in the relevant 
arm appendix.  
8.7.1
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the CRF.
8.8 Post-study access to study treatment
Patients are permitted to receive study treatment until confirmed progression.  AstraZeneca 
may continue to provide open-label drugs to patient, if such becomes available. 
After discontinuation of study treatment, the Investigator will be at liberty to define further 
most appropriate anti-cancer treatment.
9.
STATISTICAL ANALYSES BY ASTRAZENECA
9.1 Statistical considerations
All statistical analyses will be performed by AstraZeneca or its representatives.  The analyses 
will be descriptive, and no inferential analysis will be performed based on statistical tests. 
A comprehensive statistical analysis plan (SAP) will be prepared and finalized within 
3 months of enrollment of the first patient, and any subsequent amendments will be 
documented, with final amendments completed prior to reporting of the data. 
9.2 Sample size estimate
This study will enroll up to 40 eligible patients in each treatment arm.  Stage 1 will initially 
enroll a minimum of 10 patients; after a minimum of 12 weeks an interim analysis will be 
performed, which will determine whether recruitment should expand to the second stage (an 
additional 10 patients for a total of 20 eligible patients) or stop.  If the results of the primary
ORR from the completed 2nd stage are encouraging the Review Committee could recommend
expansion to add up to an additional 20 eligible subjects (for a total of 40 eligible patients), to 
further explore the findings.
The table below shows the 2-sided exact 95% confidence intervals (CI) for the ORR of a 
treatment arm at each stage of the study, assuming the observed ORR is 
% or 
%:
ORR
%
Stage 1 (10 patients)
(
%, 
%)
(
%, 
%)
Stage 2 (20 patients in total)
(
%, 
%)
(
%, 
%)
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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ORR
%
%
Expansion (40 patients in total)
(
%, 
%)
(
%, 
%)
9.3 Definitions of analysis sets
Definitions of the analysis sets for each outcome variable are provided in Table 1.
Table 1 Summary of outcome variables and analysis populations
Outcome variable
Population
Efficacy data
ORR, DoR, DCR, TTR, PFS and OS
Full Analysis Set 
Demography
Full Analysis Set 
PK data
PK Analysis Set
Safety data
Exposure
Full Analysis Set
AEs
Full Analysis Set
Laboratory measurements
Full Analysis Set
Vital signs
Full Analysis Set
ECGs
Full Analysis Set
AE  Adverse Event; DCR  Disease control rate; DoR  Duration of response; ECG  Electrocardiogram; 
ORR  Objective response rate; OS  Overall survival; PFS  Progression-free survival; PK  Pharmacokinetic; 
TTR  Time to response.
9.3.1
Full Analysis Set
The Full Analysis Set (FAS) will include all treated patients. Patients who were enrolled but 
did not subsequently go on to receive IP are not included in the FAS.  
9.3.2
PK Analysis Set
All patients who received at least 1 dose of study treatment per the protocol for whom any 
post-dose data are available and who do not violate or deviate from the protocol in ways that 
would significantly affect the PK analyses will be included in the PK Analysis Set.  The 
population will be defined by the Study Physician, Pharmacokineticist, and Statistician prior 
to any analyses being performed.
CCI
CCI
CCI
CCI
CCI
CCI


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9.4 Outcome measures for analyses
9.4.1
Calculation or derivation of efficacy variables
The analysis of the primary endpoint, ORR, and the analyses of the secondary endpoints, 
DoR, DCR, TTR, and PFS, will be based on site Investigator assessment using RECIST 1.1.  
In addition, OS will also be evaluated.
9.4.1.1
RECIST 1.1-based endpoints 
Investigator RECIST 1.1-based assessments
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations.  This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy.
At each visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, 
PR, SD, or PD depending on the status of their disease compared with baseline and previous 
assessments.  Baseline will be assessed within the 28 days prior to enrollment.  If a patient has 
had a tumor assessment that cannot be evaluated, then the patient will be assigned a visit 
response of NE (unless there is evidence of progression, in which case the response will be 
assigned as PD). 
Please refer to Appendix F for the definitions of CR, PR, SD, and PD.
9.4.1.2
Primary endpoint (objective response rate) 
ORR (per RECIST 1.1 as assessed by the site Investigator) is defined as the number (%) of 
patients with a confirmed objective response of CR or PR and will be based on patients in the 
evaluable set.
A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 visit and 
confirmed by repeat imaging not less than 4 weeks after the visit when the response was first 
observed with no evidence of progression between the initial and CR/PR confirmation visit.  
Therefore, data obtained up until progression, or the last evaluable assessment in the absence 
of progression, will be included in the assessment of ORR.  Any patient who discontinues 
treatment without progression, receives a subsequent therapy, and then responds will not be 
included as responders in the ORR.
For sensitivity analysis, ORR may be assessed using the RECIST 1.1 site Investigator tumor 
data following a modification where any objective progression requires confirmation.  
Therefore, data obtained up until confirmed progression, or the last evaluable assessment in 
the absence of a confirmed progression, may be included in the assessment of ORR.  Note that 
the response may be after an unconfirmed progression.
9.4.1.3
Secondary endpoints
Secondary efficacy variables include DoR, DCR, TTR, PFS, and OS.  Efficacy data will be 
summarized and analyzed based on the FAS.   


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Duration of response
DoR (per RECIST 1.1 as assessed by the site Investigator) will be defined as the time from the 
date of first documented response (which is subsequently confirmed) until the first 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 RECIST 1.1 
PFS endpoint. 
The time of the initial response will be defined as the latest of the dates contributing toward 
the first visit response of CR or PR.  If a patient does not progress following a response, then 
their DoR will be censored at the PFS censoring time.  DoR will not be defined for those 
patients who do not have documented response (which is subsequently confirmed).
Sensitivity analyses of DoR may be performed based on Investigator assessment according to 
RECIST 1.1 modified for confirmation of progression.
Disease control rate
DCR at 12 weeks is defined as the percentage of patients who have a best objective response 
of CR or PR in the first 13 weeks (to allow for a late assessment within the assessment 
window) or who have demonstrated SD for a minimum interval of 11 weeks (to allow for an 
early assessment within the assessment window) following the start of study treatment.  
DCR will be determined programmatically based on RECIST 1.1 using site Investigator data 
and all data up until the first progression event.
Sensitivity analyses of DCR may be performed based on Investigator assessment according to 
RECIST 1.1 modified for confirmation of progression.
Time to response
TTR (per RECIST 1.1 as assessed by the Investigator) is defined as the time from the date of 
first dose until the first date of documented response (which is subsequently confirmed).  The 
date of first documented response should coincide with that used for the RECIST 1.1 DoR 
endpoint.  TTR will not be defined for those patients who do not have documented response 
(which is subsequently confirmed). 
Progression-free survival
PFS (per RECIST 1.1 as assessed by the site Investigator) will be defined as the time from the 
date of first dose until the date of objective disease progression or death (by any cause in the 
absence of progression) regardless of whether the patient withdraws from therapy or receives 
another anticancer therapy prior to progression.
Patients who have not progressed or died at the time of analysis will be censored at the time of 
the latest date of assessment from their last evaluable RECIST 1.1 assessment.  However, if 
the patient progresses or dies after 2 or more missed visits, the patient will be censored at the 


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time of the latest evaluable RECIST 1.1 assessment.  If the patient has no evaluable visits or 
does not have baseline data, they will be censored at Day 1 unless they die within 2 visits of 
baseline.
The PFS time will always be derived based on scan/assessment dates not visit dates.
RECIST 1.1 assessments/scans contributing toward a particular visit may be performed on 
different dates.  The following rules will be applied:

Date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression on the first set of scans that indicates 
progression.

When censoring a patient for PFS, the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment.
Sensitivity analyses of PFS may be performed based on Investigator assessment according to 
RECIST 1.1 modified for confirmation of progression.
Overall survival
OS is defined as the time from the date of first dose until death due to any cause.  Any patient 
not known to have died at the time of analysis will be censored based on the last recorded date 
on which the patient was known to be alive. 
Note: Survival calls will be made in the week following the date of data cut-off for the 
analysis, and if patients are confirmed to be alive or if the death date is post the data cut-off 
date, these patients will be censored at the date of data cut-off.  Death dates may be found by 
checking publicly available death registries.
9.4.2
Calculation or derivation of safety variables
9.4.2.1
Adverse events
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, laboratory 
data, vital signs, ECGs, and exposure.  These will be collected for all patients.  Data from all 
cycles of treatment will be combined in the presentation of safety data.  “On treatment” will 
be defined as assessments between date of start dose and the time period specified in each 
specific study arm following discontinuation of IP (please see relevant arm appendix for 
assessment time periods).  For AEs, on treatment (or treatment-emergent AEs) will be defined 
as any AEs that started after dosing or prior to dosing and that worsens following exposure to 
the treatment.
AEs observed for the time period specified in each specific study arm following 
discontinuation of study treatment or until the initiation of the first subsequent therapy 
following discontinuation of treatment (whichever occurs first) will be used for the reporting 
of the AE summary tables.  This will more accurately depict AEs attributable to study 


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treatment only, as a number of AEs up to the time period specified in each specific study arm 
following discontinuation of the study agents are likely to be attributable to subsequent 
therapy.  However, to assess the longer term toxicity profile, AE summaries will also be 
produced containing AEs observed up until the time period specified in each specific study 
arm following discontinuation of the study agents (ie, without taking subsequent therapy into 
account).  Any events in this period that occur after a patient has received further therapy for 
cancer (following discontinuation of study treatment) will be flagged in the data listings.
A separate data listing of AEs occurring more than until the time period specified in each 
specific study arm after discontinuation of IP will be produced.  These events will not be 
included in AE summaries.
9.4.2.2
Safety assessments
For the change from baseline summaries for vital signs, laboratory data, ECGs, and physical 
examination, the baseline value will be the latest result obtained prior to the start of study 
treatment.  
The QTcF will be derived during creation of the reporting database using the reported ECG 
values (RR and QT).
QTcF=QT/RR^ (1/3) where RR is in seconds
Corrected calcium will be derived during creation of the reporting database using the 
following formulas:
Corrected calcium (mmol/L)=Total calcium (mmol/L)+([40-albumin (G/L)]×0.02).
The denominator used in laboratory summaries will only include evaluable patients, in other 
words, those who had sufficient data to have the possibility of an abnormality.  
For example:

If a CTCAE criterion involves a change from baseline, evaluable patients would 
have both a pre-dose and at least 1 post-dose value recorded.

If a CTCAE criterion does not consider changes from baseline, to be evaluable, the 
patient need only have 1 post dose-value recorded.
The denominator in vital signs data should include only those patients with recorded data.
9.4.3
Calculation or derivation of patient-reported outcome variables
Not applicable.


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9.4.4
Calculation or derivation of pharmacokinetic variables
9.4.4.1
Population pharmacokinetics and exposure-response/safety analysis
No population pharmacokinetics and exposure-response/safety analysis is planned for this 
study given the small number of patients in each arm. However the PK, pharmacodynamics, 
demographic, safety, and efficacy data collected in this study may also be combined with 
similar data from other studies and explored using population PK and/or PK-
pharmacodynamic methods. See the individual arm sub-protocol appendix (e.g. Appendix A 
for Arm A) for details of the PK analysis planned in that arm. 
9.4.4.2
Pharmacokinetic analysis
PK concentration data and summary statistics will be tabulated.  Individual and mean blood 
concentration time profiles will be generated.  PK parameters will be determined using 
standard non-compartmental methods.  The following PK parameters will be determined after 
the first and steady-state doses: peak and trough concentration (as data allow).  Samples below 
the lower limit of quantification will be treated as missing in the analyses.
9.4.5
 
 
9.4.6
Calculation or derivation of pharmacogenetic variables
Not applicable.
9.5 Methods for statistical analyses
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment arm.  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 IP, except for efficacy variables.  For efficacy variables, baseline is defined as 
the last visit prior to first dose of study treatment.
All data collected will be listed.  Efficacy and safety data will be summarized and analyzed 
based on the FAS. As a sensitivity analysis, efficacy data may also be summarized/analyzed in 
a subgroup of FAS for patients without important protocol deviations. PK data will be 
summarized and analyzed based on the PK Analysis Set. 
If the results of final ORR from the completed 2nd stage of any arm are encouraging the 
Review Committee could recommend expansion to add up to an additional 20 eligible subjects 
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Study Code D419QC00002
Version05 
Date 16Jan2020
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into that arm to further explore the findings (for a total of 40 eligible patients). Refer to 
Section 9.5.8 for information on the statistical analysis performed for the expansion cohort.
9.5.1
Primary analysis
The primary analysis of ORR will occur approximately 12 weeks after the last patient has 
initiated treatment. This is planned to ensure the data cut off for ORR analysis follows the 12 
week RECIST assessment for the last subject to be treated. However, in the situation where 
this scan does not occur due to this subject having experienced another progression event (e.g. 
death) the primary analysis DCO will be when all subjects have been followed for at least 12 
weeks or until death if this is earlier. All study endpoints will be analyzed at this time 
including OS. The Sponsor will determine at that time whether any further follow up for OS 
would be required. 
If the decision is made to close the Arm at the interim analysis the Sponsor will determine the 
appropriate length of follow up to ensure sufficient data collection for the primary analysis in 
that Arm. 
9.5.2
Analysis of the primary variable(s)
For the primary endpoint, ORR will be estimated with 95% exact CIs separately for each 
treatment arm.  The primary analysis will be based on the programmatically derived ORR 
based on RECIST 1.1 based on site Investigator assessments, and using all scans regardless of 
whether they were scheduled or not.  A sensitivity analysis will be performed on 
programmatically derived ORR (RECIST 1.1 modified for confirmation of progression) to 
determine if there is any difference when using progression confirmation rules.  The primary 
analysis population for ORR will be the FAS.  
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR).  The number (%) of patients with a confirmed response and the number 
(%) of patients with a single visit response (ie, an unconfirmed response) will also be 
presented.
9.5.3
Analysis of the secondary variable(s)
9.5.3.1
Duration of response
Kaplan-Meier plots of DoR based on the site Investigator assessment of RECIST 1.1 will be 
presented for each treatment arm if appropriate.  Median DoR will also be summarized.  Only 
patients who have a confirmed response will be included in this summary table. 
9.5.3.2
Disease control rate
The DCR based on the site Investigator assessment of RECIST 1.1 will be summarized (ie, 
number of patients [%] for each treatment arm at 3 months). 


Clinical Study Protocol
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Study Code D419QC00002
Version05 
Date 16Jan2020
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9.5.3.3
Time to response
The TTR based on the site Investigator assessment of RECIST 1.1 will be summarized (ie, 
number of patients [%] based on the number of responders for each treatment arm) by the 
scheduled assessment timepoint that the response was first observed.  Additionally, 
descriptive summary statistics (ie, minimum, maximum, median, Q1, and Q3) will also be 
presented.  Only patients who have a confirmed response will be included in this summary 
table. 
9.5.3.4
Progression-free survival
Kaplan-Meier plots of PFS will be presented for each treatment arm.  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 for each treatment. 
9.5.3.5
Overall survival
Kaplan-Meier plots will be presented by treatment arm.  Summaries of the number and 
percentage of patients who have died, those still in survival follow-up, those lost to follow-up, 
and those who have withdrawn consent will be provided along with the median OS for each 
treatment arm. 
9.5.4
Safety data
Safety and tolerability data will be presented separately for each treatment arm using the FAS.
Data from all cycles will be combined in the presentation of safety data.  AEs (both in terms 
of Medical Dictionary for Regulatory Activities [MedDRA] preferred terms and CTCAE 
grade) will be listed individually by patient.  The number of patients experiencing each AE 
will be summarized by CTCAE grade.  Additionally, data presentations of the rate of AEs per 
person-years at risk may be produced.  
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, vital signs, and ECGs.  Exposure to IP will be summarized.  Time on study, IP 
dose delays/interruptions, and dose reductions will also be summarized.  At the end of the 
study, appropriate summaries of all safety data will be produced as defined in the SAP. 
9.5.5
Pharmacokinetic data
PK concentration data will be listed for each patient and each dosing day (where data allow), 
and a summary will be provided for all evaluable patients in the PK Analysis Set.
9.5.6
 
 
 
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
84 (296)
 
9.5.7
Interim analysis
An interim analysis will be conducted on each arm. This will assess ORR in all evaluable 
patients in that arm, to determine whether to progress to stage 2 of the arm.  The DCO for the 
interim analysis will take place approximately 12 weeks after the 10th patient has initiated 
treatment.  If there are 
 responders, then there is a low posterior probability of achieving 
ORR of at least 
% in 20 patients and the Review Committee may decide that no further 
patients will be recruited to the arm.  If there are 
 responders out of 10, then an 
additional 10 patients will be recruited and the final estimate of ORR will be based on 20 
patients.  If there ar
r more responders out of 10 patients, then it will be regarded as strong 
efficacy and the Review Committee may decide to stop recruitment into the particular arm. 
The posterior probability of having at leas
 responders in 20 patients for 
 responders in 
10 patients is shown below.
9.5.8
Analysis following expansion
If the Review Committee decides to recommend expansion of any given arm (for a maximum 
total of 40 eligible patients),  no further interim analysis will be conducted and the entire 
expansion cohort (additional 20 patients) will be recruited with no break. Primary analysis
will be ORR of all subjects recruited to the individual arm (i.e. 1st and 2nd stage cohorts plus 
the expansion cohort) after 12 weeks follow up of the last patient dosed in that arm. However, 
a sensitivity analysis may be performed to analyze the cohorts separately due to potential 
changes in population (e.g. due to differences in the 1st line therapy) between recruitment of 
the initial 2 cohorts and the expansion cohort of that arm.
10.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
10.1 Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca representative or delegate will 
review and discuss the requirements of the CSP and related documents with the 
investigational staff and also train them in any study-specific procedures (including those 
listed in the Laboratory Manual) and the Electronic Data Capture (EDC(s)) used.
The additional requirements for the collection of the patients’ samples for the biomarker 
research will also be made clear.
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
85 (296)
The Principal Investigator 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 Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).
10.2 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 CRFs, that biological samples are handled in 
accordance with the Laboratory Manual, and that study drug accountability checks 
are being performed

Perform source data verification (a comparison of the data in the CRFs 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.
10.2.1
Source data
Refer to the Clinical Study Agreement for location of source data.
The Head of the study site and the Principal Investigator/Investigator will cooperate for 
monitoring and audit by AstraZeneca and accept inspection by the IRB or regulatory 
authorities.  All study documents such as raw data will be open for direct access to source data 
at the request of the monitor and the auditor of AstraZeneca, the IRB, or regulatory 
authorities.
The monitor will verify data from the eCRFs against source data before the Principal 
Investigator signs the eCRFs to ensure accuracy and completeness of documentation and to 
ensure that the Principal Investigator has submitted the eCRFs to AstraZeneca. 


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
86 (296)
10.2.2
Study agreements
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement or equivalent for this study.  In the event of any 
inconsistency between this CSP and the Clinical Study Agreement, the terms of the CSP shall 
prevail with respect to the conduct of the study and the treatment of patients, and in all other 
respects, not relating to study conduct or treatment of patients, the terms of the Clinical Study 
Agreement shall prevail.
Specific reference to requirements relating to the biomarker research will be included in the 
study agreement(s).
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place or before patients are enrolled.
10.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement.
10.3 Study timetable and end of study
The end of the study is defined as “the last visit of the last patient undergoing the study.”  The 
study is expected to start in Q3 2016 and to end by Q1 2021.
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 too slow.  
AstraZeneca may also terminate the entire study or individual sub-studies prematurely if 
concerns for safety arise within this study or in any other study with agents used in any of the 
sub-study arms.
10.4 Data management by AstraZeneca 
Data management will be performed by a chosen vendor according to the Data Management 
Plan.  AEs and medical/surgical history will be classified according to the terminology of the 
latest version of the MedDRA.  Medications will be classified according to the AstraZeneca 
Drug Dictionary.  All coding will be performed by the Medical Coding Team at the 
AstraZeneca Data Management Center.
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 


Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceraasertib (AZD6738)
Study Code D419QC00002
Version05 
Date 16Jan2020
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responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, signed, and locked for a specific arm, a clean file 
will be declared and the final database will be locked for that arm.
Serious adverse event reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data management of genotype data
Not applicable.
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca.
11.
ETHICAL AND REGULATORY REQUIREMENTS
11.1 Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonization 
(ICH)/GCP, applicable regulatory requirements, and the AstraZeneca policy on Bioethics and 
Human Biological Samples.
11.2 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.
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician, or any other third party, unless 
required to do so by law.
11.3 Ethics and regulatory review
An EC or 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 or IRB and to 
the study site staff.
The opinion of the EC or IRB should be given in writing.  The Investigator should submit the 
written approval to AstraZeneca before enrollment of any patient into the study. 


Clinical Study Protocol
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Study Code D419QC00002
Version05 
Date 16Jan2020
88 (296)
The EC or 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 or IRB 
annually.
Before enrollment of any patient into any arm of the study, the final study protocol for that 
arm of the study, including the final version of the ICF, should be approved by the national 
regulatory authority or a notification to the national regulatory authority should be provided, 
according to local regulations.
AstraZeneca will handle the distribution of these documents to the national regulatory 
authorities.
AstraZeneca will provide regulatory authorities, ECs or IRBs, and Principal Investigators 
safety updates or reports according to local requirements.
Each Principal Investigator is responsible for providing the EC or IRB with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the IP.  
AstraZeneca will provide this information to the Principal Investigator so that he or she can 
meet these reporting requirements.
11.4 Informed consent
The Principal Investigator(s) at each center will:

Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, and possible risk and benefit of the study

Ensure each patient is notified that they are free to discontinue from the study at any 
time

Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided

Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study

Ensure the original signed ICF(s) is/are stored in the Investigator’s Study File

Ensure a copy of the signed ICF is given to the patient

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the ICF that is approved by an EC or IRB


Clinical Study Protocol
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Study Code D419QC00002
Version05 
Date 16Jan2020
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11.5 Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and, where required, in a new version of the study 
protocol (revised CSP).
The amendment is to be approved by the relevant EC or IRB and, if applicable, the national 
regulatory authority, before implementation.  Local requirements are to be followed for 
revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator.  For distribution to EC or IRB, see Section 11.3.
If a protocol amendment requires a change to a center’s ICF, AstraZeneca and the center’s EC 
or IRB are to approve the revised ICF before the revised form is used. 
If required by local regulations, any administrative change will be communicated to or 
approved by each EC or IRB.
11.6 Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an EC or 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 to 
determine if data were recorded, analyzed, and accurately reported according to the protocol, 
GCPs, ICH guidelines, and any applicable regulatory requirements.  The Investigator will 
contact AstraZeneca immediately if contacted by a regulatory agency about an inspection at 
the center.


Clinical Study Protocol Appendix A
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Version 04
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APPENDIX A ARM A: DURVALUMAB 
(MEDI4736) + TREMELIMUMAB SUB-PROTOCOL
1.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or special 
term
Explanation
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
anti-HBc
Anti-Hepatitis B core
AST
Aspartate aminotransferase
AUC
Area under the plasma drug concentration-time curve
AUCss
Area under the plasma drug concentration-time curve at steady state
B7-H1
B7 homolog 1
BP
Blood pressure
C
Cycle
CD
Cluster of differentiation
CL
Clearance
Cmax,ss
Maximum plasma concentration at steady state
CR
Complete response
CRF
Case report form (electronic/paper)
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated antigen 4
Ctrough,ss
Median trough concentration at steady state
DCR
Disease control rate
DNA
Deoxyribonucleic acid 
DoR
Duration of response
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Abbreviation or special 
term
Explanation
Durva
Durvalumab (MEDI4736)
ECG
Electrocardiogram
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
ECOG
Eastern Cooperative Oncology Group
ED-SCLC
Extensive stage small-cell lung cancer
EOT
End of treatment
EU
Endotoxin unit
FDA
Food and Drug Administration
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HPV+
Human papilloma virus-positive
IB
Investigator’s Brochure
IHC
Immunohistochemistry
IFN 
Interferon
International 
Coordinating 
Investigator
If a study is conducted in several countries the International Coordinating 
Investigator is the Investigator coordinating the Investigators and/or 
activities internationally. 
IP
Investigational product 
imAE
Immune-mediated adverse event
irAE
Immune-related adverse event
IV
Intravenous
LFT
Liver function test
mAb
Monoclonal antibody
ORR
Overall response rate
OS
Overall survival
NCI
National Cancer Institute
NSCLC
Non-small-cell lung cancer
PD
Progressive disease
PD-1
Programmed cell death 1


Clinical Study Protocol Appendix A
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Study Code D419QC00002
Version 04
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Abbreviation or special 
term
Explanation
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PFS
Progression-free survival
PK
Pharmacokinetic(s)
PR
Partial response
q2w
Every 2 weeks
q3w
Every 3 weeks
q4w
Every 4 weeks
q8w
Every 8 weeks
q12w
Every 12 weeks
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
RNA
Ribonucleic acid
SAE
Serious adverse event 
SCLC
Smallcell- lung cancer
SD
Stable disease
sPD-L1
Soluble programmed death ligand-1
STS
Softtissue- sarcoma
T3
Triiodothyronine
T4
Thyroxine
TB
Tuberculosis
TNBC
Triple Negative Breast Cancer
TKI
Tyrosine kinase inhibitor
TNF
Tumor necrosis factor
Treme
Tremelimumab
TSH
Thyroid stimulating hormone
TTR
Time to response
ULN
Upper limit of normal
USP
United States Pharmacopeia
US
United States
WHO
World Health Organization
w/v
Weight/volume


Clinical Study Protocol Appendix A
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Study Code D419QC00002
Version 05
Date 16Jan2020
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2.
INTRODUCTION
2.1 Background and rationale for conducting this study
Study D419QC00002 is an open-label, multi-center, multi-arm, Phase II study in patients with 
extensive-stage small cell lung cancer (ED-SCLC) who have refractory or resistant disease, 
defined as patients who progress during first-line chemotherapy or those who progress within 
90 days after completing first-line chemotherapy.  Study D419QC00002 is modular in design, 
allowing evaluation of the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity 
of different combinations of novel anticancer agents in patients with refractory or resistant 
ED-SCLC and will consist of a number of study arms, each evaluating the safety and 
tolerability of a specific combination. 
Arm A in Study D419QC00002 investigates the efficacy, safety, and tolerability of 
intravenous (IV) treatment with durvalumab (MEDI4736) in combination with tremelimumab 
followed by durvalumab monotherapy until disease progression in patients with ED-SCLC.
It is increasingly understood that cancers are recognized by the immune system, and, under 
some circumstances, the immune system may control or even eliminate tumors (Du Bois et al 
2003, Dunn et al 2004).  
Programmed cell death ligand 1 (PD-L1) [B7 homolog 1 (B7-H1), cluster of differentiation 
(CD) 274] is part of a complex system of receptors and ligands that is involved in controlling 
T-cell activation.  In normal tissue, PD-L1 is expressed on T-cells, B lymphocytes (B-cells), 
dendritic cells, macrophages, mesenchymal stem cells, bone marrow-derived mast cells, as 
well as various non-hematopoietic cells (Keir et al 2008).  The normal function of PD-L1 is to 
regulate the balance between T-cell activation and tolerance through interaction with 
2 receptors, programmed cell death 1 (PD-1, CD279) and CD80 (B7-1).  PD-L1 is also 
expressed by tumors and acts at multiple sites to help tumors evade detection and elimination 
by the host immune system.  Interactions between the receptors and ligands result in reduced 
T-cell activation and fewer activated T-cells in the circulation.  In the tumor 
microenvironment, PDL1 expressed on tumor cells binds to PD-1 on activated T-cells 
reaching the tumor and this delivers an inhibitory signal to those T-cells, preventing them 
from killing the target tumor cells, and thus protecting the tumor from immune elimination 
(Zou and Chen 2008). 
PD-L1 is expressed in a broad range of cancers with a high frequency of up to 88% in some 
types of cancer.  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 cancers (Hamanishi et al 2007), the 
expression of PD-L1 is associated with reduced survival and an unfavorable prognosis.  In 
ovarian cancer, for example, the 5-year survival rate in patients with low levels of PD-L1 was 
80.2% compared with 52.6% in patients with high levels of PD-L1 (Hamanishi et al 2007).  In 
lung cancer, only 20% of patients with tumors expressing PD-L1 survived for more than 
3 years compared with 49% of patients with tumors lacking PD-L1 (Mu et al 2011).  


Clinical Study Protocol Appendix A
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Study Code D419QC00002
Version 05
Date 16Jan2020
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The levels of tumor-infiltrating cells, and more specifically cytotoxic T-cells, have been 
correlated to improved prognosis in a number of cancers including colorectal, melanoma, and 
lung cancers (Pages et al 2010), suggesting that an anti-tumor immune response is beneficial 
to patients.  
Binding of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) to its target ligands (CD80 
and CD86) provides a negative regulatory signal, which limits T-cell activation.  Anti-
CTLA-4 inhibitors antagonize the binding of CTLA-4 to CD80/86 ligands and enhance 
human T-cell activation as demonstrated by increased cytokine (interleukin-2 and interferon 
[IFN] gamma) production in vitro in whole blood or peripheral blood mononuclear cell 
cultures (Tarhini and Kirkwood 2008).  In addition, blockade of CTLA-4 binding to CD80/86 
by anti-CTLA-4 antibodies results in markedly enhanced T-cell activation and antitumor 
activity in animal models, including killing of established murine solid tumors and induction 
of protective antitumor immunity.  Therefore, it is expected that treatment with an anti-CTLA-
4 antibody will lead to increased activation of the human immune system, increasing 
antitumor activity in patients with solid tumors.
Pre-clinical data has now been added to with a wealth of clinical data showing that blockade 
of negative regulatory signals to T-cells such as CTLA-4 and PD-L1 has promising clinical 
activity.  Ipilimumab (YERVOY®) was granted United States (US) Food and Drug 
Administration (FDA) approval for the treatment of metastatic melanoma and is currently 
under investigation for several other malignancies whilst nivolumab (OPDIVOR®) and 
pembrolizumab (KEYTRUDA®), two anti-PD-1 agents, were granted US FDA and European 
Medicines Agency approval for the treatment of a number of malignancies including 
metastatic melanoma and squamous and non-squamous cell non-small-cell lung cancer 
(NSCLC).  In addition there is data from agents in the anti-PD-1/PD-L1 class showing clinical 
activity in a wide range of tumor types.
2.2 Durvalumab (MEDI4736)
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with 
PD-1 on T cells and CD80 (B7.1) on immune cells (IC). It is being developed by 
AstraZeneca/MedImmune for use in the treatment of cancer (MedImmune is a wholly owned 
subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca 
throughout this document.) The proposed mechanism of action (MOA) for durvalumab is 
interference in the interaction of PDL1 with PD1 and CD80 (B7.1). Blockade of PD-
L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including 
those that may result in tumor elimination. In vitro studies demonstrate that durvalumab 
antagonizes the inhibitory effect of PD-L1 on primary human T cells resulting in the restored 
proliferation of IFN-γ (Stewart et al 2015). In vivo studies have shown that durvalumab 
inhibits tumor growth in xenograft models via a Tcelldependent mechanism (Stewart et al 
2015). Based on these data, durvalumab is expected to stimulate the patient’s antitumor 
immune response by binding to PDL1 and shifting the balance toward an antitumor 
response. Durvalumab has been engineered to reduce antibody-dependent cellular cytotoxicity 
and complement-dependent cytotoxicity.


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
95 (296)
To date, durvalumab has been given to more than 6000 patients as part of ongoing studies 
either as monotherapy or in combination with other anticancer agents. Details on the safety 
profile of durvalumab monotherapy are summarized in sections 2.6.5 and 2.7.1.1. Refer to the 
current durvalumab Investigator’s Brochure (IB) for a complete summary of non-clinical and 
clinical information including safety, efficacy and PK. 
2.3 Tremelimumab
Tremelimumab is a human immunoglobulin (Ig)G2 mAb that is directed against CTLA-4; 
cluster of differentiation [CD]152), a cell surface receptor that is expressed primarily on 
activated T cells and acts to inhibit their activation. Tremelimumab completely blocks the 
interaction of human CTLA-4 with CD80 and CD86, resulting in increased release of 
cytokines (interleukin [IL]-2 and interferon [IFN]-γ) from human T cells, peripheral blood 
mononuclear cells and whole blood (Tarhini and Kirkwood 2008).Tremilimumab is being 
developed by AstraZeneca for use in the treatment of cancer.
To date, tremelimumab has been given to more than 1500 patients, either as monotherapy or 
in combination with other anticancer agents. Details on the safety profile are summarized in 
section 2.7.2.2. Refer to the current tremelimumab IB for a complete summary of non-clinical 
and clinical information including safety, efficacy and PK.
In cancer immunotherapy, agents that have limited therapeutic effects as single agents can be 
powerful when combined.  Combining immunotherapy agents has been shown to result in 
improved response rates relative to those in monotherapy.  Furthermore, responses appeared 
to be rapid, deep, and durable (Wolchok et al 2013).
2.4 Durvalumab in combination with tremelimumab
Targeting both PD-1 and CTLA-4 pathways may have an additive or synergistic activity 
(Pardoll 2012) because the mechanisms of action of CTLA-4 and PD-1 are nonredundant.  
Recent results from clinical studies evaluating the efficacy of nivolumab (PD-1 inhibitor) and 
ipilimumab- (CTLA-4 inhibitor) in untreated melanoma patients have shown significant 
improvement in survival with this combination, which is especially more pronounced in 
patients who have PD-L1 negative tumors (Larkin et al 2015, Postow et al 2015). 
AstraZeneca is also investigating the use of durvalumab + tremelimumab combination therapy 
for the treatment of cancer. 
The development of durvalumab in combination with tremelimumab was initiated in Study 
D4190C00006 (in NSCLC; hereafter referred to as Study 6) and Study D4190C00010 (in a 
range of tumor types, including smallcell lung cancer (SCLC); hereafter referred to as 
Study 10).  Preliminary data from these studies suggested this combination improves clinical 
outcomes in patients with advanced cancer.  Based on promising early efficacy and safety data 
from these studies, further exploration of the benefit-risk of the durvalumab and 
tremelimumab combination in SCLC is warranted.


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
96 (296)
To date, more than 1000 patients have received the combination using a number of doses and 
dosing schedules. Details on the safety profile of durvalumab + tremelimumab combination 
therapy are summarized in section 2.7.1.2. Refer to the current editions of the durvalumab and 
tremelimumab IBs for a complete summary of non-clinical and clinical information including 
safety, PK and efficacy.
2.5 Rationale for study design, doses, and control groups
The rationale for conducting this study is in Section 2.2 of the master protocol.
The rationale for the unmet medical need in refractory or resistant ED-SCLC is described in 
Section 2.2.1 of the master protocol.  The rationale for the specific study design aspects of 
Arm A is described below.
2.5.1
Rationale for opening expansion cohort
A total of 21 platinum refractory or resistant ED-SCLC patients have received durvalumab 
1500 mg + tremelimumab 75 mg via IV infusion q4w, for up to a total of 4 doses/cycles, 
followed by durvalumab monotherapy 1500 mg IV infusion q4w until PD in stages 1 and 2 of 
the present study (D419QC00002).  
 
 
  
, therefore the data did not support moving directly to a Phase III 
study.  
 
 
 
 
 
 
 
Based on the initial review of the survival data the Review Committee recommended to open 
an expansion cohort (an additional 20 patients, for a total of 40 eligible patients), to further 
explore the findings. This recommendation was endorsed by the Clinical Project Team.
2.6 Durvalumab and tremelimumab dose and treatment regimen 
justification
2.6.1
Durvalumab + tremelimumab combination therapy dose rationale
The durvalumab + tremelimumab combination therapy doses and regimen selected for this 
study are based on the goal of selecting an optimal combination dose of durvalumab and 
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Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
97 (296)
tremelimumab that would yield sustained target suppression (soluble programmed death ligand-1 
[sPD-L1]), demonstrate promising efficacy, and have an acceptable safety profile.  
Patients enrolled in Arm A will receive:
Durvalumab 1500 mg + tremelimumab 75 mg via IV infusion every 4 weeks (q4w), starting 
on Week 0, for up to a total of 4 doses/cycles followed by durvalumab monotherapy 1500 mg 
via IV infusion q4w, starting after completion of the 4th cycle of combination treatment, until 
progressive disease (PD) and Investigator confirmation that the patient is no longer receiving 
clinical benefit from the treatment. If a patient’s weight falls to 30 kg or below (≤30 kg), then 
the patient should receive weight-based dosing after discussion between Investigator and 
Study Physician, until the weight improves to > 30 kg, at which point the patient should start 
receiving the fixed dosing of durvalumab 1500 mg Q4W and 75mg tremelimumab Q4W 
(during the combination phase of treatment). The equivalent weight based doses to the fixed 
doses are 20 mg/kg of durvalumab and 1mg/kg tremelimumab Q4W.
2.6.2
Durvalumab + tremelimumab combination therapy 
pharmacokinetics/Pharmacodynamics data
As of 28 February 2017, a total of 379 patients with advanced NSCLC have been treated in 
Study D4190C00006. Various dose combinations were explored, with doses of tremelimumab 
ranging from 
 mg/kg and doses of durvalumab  ranging from 
 mg/kg.
An approximately dose-proportional increase in PK exposure (maximum plasma 
concentration and area under the plasma drug concentration-time curve from time 0 to Day 
28) of both durvalumab and tremelimumab was observed over the dose range of 
mg/kg 
durvalumab q4w and 
 mg/kg tremelimumab q4w. Exposures following multiple doses 
demonstrated accumulation consistent with PK parameters estimated from the first dose. The 
observed PK exposures of durvalumab and tremelimumab following combination were 
consistent with respective monotherapy data, indicating no PK interaction between these 2 
agents.
patients were ADA positive for anti-durvalumab antibodies post-treatment. 
 
patients was ADA positive for anti-tremelimumab antibodies post-treatment. No clear 
relationship between ADA and the dose of either durvalumab or tremelimumab was observed. 
No obvious association between ADA and safety or efficacy was observed.
Target engagement for durvalumab was assessed using suppression of free sPD-L1 in serum. 
Following treatment with the durvalumab and tremelimumab combination, complete sPD-L1 
suppression (surrogate for PD-L1 targeting) was observed in almost all patients over the dose 
range of 
 mg/kg durvalumab q4w or q2w. No clear dose-dependent changes in sPD-L1 
were identified over the dose range of 
 mg/kg durvalumab q4w or q2w.
Monotonic increases in pharmacodynamic activity were observed with increasing doses of
tremelimumab relative to the activity observed in patients treated with durvalumab 
monotherapy.
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Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
98 (296)
There was evidence of augmented pharmacodynamic activity relative to durvalumab 
monotherapy with combination doses containing mg/kg tremelimumab, including both the 
mg/kg durvalumab plus mg/kg tremelimumab combinations.
2.6.3
Clinical data
2.6.3.1
Study D4190C00006
In Study D4190C00006 various dose combinations have been explored, with doses of 
tremelimumab ranging from 
mg/kg and doses of durvalumab ranging from 
 
mg/kg.  Tremelimumab was given on a q4w schedule while durvalumab was explored in 
both a q4w and q2w schedule, with the goal of identifying the dose combination that best 
optimizes the risk:benefit profile in an acceptable range of PK and pharmacodynamic values.
Patients treated with doses of tremelimumab above mg/kg had a 
 rate of adverse 
events (AEs), including discontinuations due to AEs, serious adverse events (SAEs), and 
severe AEs.  Between the 
mg/kg durvalumab + mg/kg tremelimumab and 
mg/kg durvalumab +
mg/kg tremelimumab cohorts treated at the q2w schedule, the 
number of patients reporting any AE, ≥Grade 3 AEs, SAEs, and treatment-related AEs was 
 in the 
mg/kg durvalumab + mg/kg tremelimumab cohort than the 
mg/kg durvalumab +
mg/kg tremelimumab cohort.  A similar pattern was noted in the 
q4w regimens, suggesting that, as the dose of tremelimumab increased above mg/kg, a 
 rate of treatment related events may be anticipated.  Further, the SAEs frequently 
attributed to immunotherapy, pneumonitis, colitis, and other immune-mediated events, were 
more commonly seen in cohorts using either or 
mg/kg of tremelimumab compared to the 
mg/kg dose cohorts.  Together, these data suggest that a combination using a tremelimumab 
dose 
mg/kg appeared to 
 the rate of toxicity when combined with durvalumab.  
As a result, all combination doses utilizing either the or 
mg/kg doses of tremelimumab 
were eliminated in the final dose selection.
In contrast, cohorts assessing higher doses of durvalumab with a constant dose of 
tremelimumab did not show an increase in the rate of AEs.  The data suggested that increasing 
doses of durvalumab may not impact the safety of the combination as much as the 
tremelimumab dose.  Further, safety data between the 
and 
mg/kg cohorts were similar, 
with no change in safety events with increasing dose of durvalumab .
In Study D4190C00006, of all treatment cohorts, the cohort of patients treated in the 
mg/kg durvalumab +
mg/kg tremelimumab group had a tolerable safety profile, but still 
showed 
 evidence of clinical activity.  
 were reported in this 
cohort.  Preliminary clinical activity of the durvalumab (MEDI4736) and tremelimumab 
combination did not appear to change with increasing doses of tremelimumab.  The 
and 
mg/kg durvalumab q4w cohorts demonstrated objective responses at all doses of 
tremelimumab, and increasing doses of tremelimumab did not provide deeper or more rapid 
responses. Efficacy data suggested that the 
mg/kg durvalumab +
mg/kg tremelimumab 
dose cohort may demonstrate 
 clinical activity to other dose combinations.  Of the 
patients in this cohort, there wa
 patient (
%) with a complete response (CR)
patients 
%) with partial response (PR), patients 
%%) with stable disease (SD)
 patient 
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Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
99 (296)
%) with an unconfirmed PR and patients 
%) with PD.  
 patients were not 
evaluable for response.
All together, the data suggested that a 
mg/kg durvalumab + mg/kg tremelimumab dose 
combination should be selected for further development.  
Refer to the current durvalumab Investigator’s Brochure for a complete summary of non-
clinical and clinical information on the durvalumab + tremelimumab combination, including 
safety, efficacy and pharmacokinetics.  
2.6.3.2
Study D4190C00010
Study D4190C00010 is a Phase 1 study of durvalumab  in combination with tremelimumab in 
patients with advanced solid tumors. 
As of a cutoff date of 10 March 2017, a total of 320 immunotherapy-naive subjects with 
advanced solid tumors have been treated in this study.  Of these subjects
 have received 
durvalumab at 
mg/kg q2w for 12 months in combination with tremelimumab mg/kg q4w 
for 7 doses and then every 12 weeks (q12w) for 2 doses.  Included amongst the subjects 
receiving durvalumab at 
mg/kg q4w for 12 months in combination with tremelimumab 
mg/kg q4w for 7 doses and then q12w for 2 doses (n=45) were 30 subjects in the small-cell 
lung cancer cohort. 
Overall, AEs (all grades, regardless of causality) reported in 
% subjects by 
 
order of frequency, were fatigue,, nausea, diarrhoea, pruritus, anemia, vomiting, deceased 
appetite, constipation, abdominal pain, dyspnea, pyrexia, back pain , , , , andhyponatraemia.  
The treatment-related AEs (all grades) reported in 
% of patients, were fatigue, pruritus, 
diarrhoea, nausea, rash maculo-papular and hypothyroidism. A total of 
% of patients had 
treatment-related Grade 3 or 4 AEs. The most common treatment-related Grade 3 or 4 AE 
were lipase increased, amylase increased, colitis and diarrhoea. SAEs were reported in 
 
patients (
%); treatment-related SAEs were reported in 
% of patients. The most 
frequent treatment-related SAEs were colitis and diarrhoea. A total of 
 patients (
%) 
experienced events with a 
 outcome; 
 of which were attributed to underlying disease 
and considered by the investigator as not related to durvalumab and tremelimumab. Two 
deaths were due to treatment-related AEs (pulmonary haemorrhage and colitis).
As of 20 October 2017, a total of 30 patients with SCLC received study treatment in Study 10.  
19 of these patients were platinum resistant/refractory.  
 patients reported ≥1 treatment-
related AE; the most common were fatigue and pruritus
 patients had grade 3/4 treatment-
related AEs. 
patients discontinued due to treatment-related AEs and there wer
 
treatment-related deaths.
Confirmed ORR was 
% (
), including 3 platinum 
resistant/refractory patients (1 CR with 2 prior therapies, 2 PR each with 1 prior treatment). 
Disease control rate at 16 weeks was 
% (
). Median PFS was 
 months 
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Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
100 (296)
(
), median OS was 
 months (
), and 12-month OS rate was 
Refer to the current durvalumab IB for a complete summary of non-clinical and clinical 
information on the durvalumab + tremelimumab combination, including safety, efficacy, and 
PK.
2.6.4
Rationale for four cycles of combination therapy followed by durvalumab 
monotherapy
Long-term follow up on melanoma patients treated with ipilimumab, an anti-CTLA-4-
targeting antibody (dosed every 3 weeks [q3w] for 4 doses and then discontinued), shows that 
patients responding to ipilimumab derive long-term benefit, with a 3-year overall survival 
(OS) rate of approximately 22%.  Furthermore, the survival curve in this population reached a 
plateau at 3 years and was maintained through 10 years of follow up (Brahmer et al 2014, 
Schadendorf et al 2013).
Data from Study D4190C00006 (Phase I trial in NSCLC patients using the combination of 
durvalumab and tremelimumab) also show an approximately dose-proportional 
 in PK 
exposure for durvalumab over the dose range of 
 mg/kg durvalumab Q4W or Q2W. 
(For further information on PK observations in Study 006, please see the current IB).
The observed durvalumab PK data from the combination study were well in line with the 
predicted monotherapy PK data (5th median and 95th percentiles) for a Q4W regimen.
The durvalumab + tremelimumab combination regimen will be administered q4w for up to a 
total of 4 doses/cycles followed by durvalumab monotherapy q4w, until PD and Investigator 
confirmation that the patient is no longer receiving clinical benefit from the treatment, or for 
other discontinuation criteria.  Note that patients whose weight falls to 30 kg or below will not 
receive fixed-dosing, instead this will switch to weight based dosing; equivalent to 
mg/kg 
durvalumab and mg/kg tremelimumab. 
2.6.5
Durvalumab monotherapy dose rationale  
A durvalumab ) dose of 
mg/kg q4w is supported by in vitro data, non-clinical activity, 
clinical PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients 
with advanced solid tumors and from a Phase I trial performed in Japanese patients with 
advanced solid tumor (D4190C00002).
2.6.5.1
Durvalumab monotherapy Pharmacokinetic/Pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 
mg/kg q2w or 
mg/kg q3w, durvalumab exhibited non-linear (dose 
dependent) PK consistent with target-mediated drug disposition.  The PK approached linearity 
a
mg/kg q2w, suggesting near complete target saturation (membrane-bound and sPD-L1), 
and further shows that the durvalumab administration frequency can be adapted to a particular 
regimen given the linearity seen at doses higher than mg/kg.  The expected half life with 
dose
mg/kg q2w is approximately 21 days.  A dose-dependent suppression in peripheral 
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Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
101 (296)
sPD-L1 was observed over the dose range studied, consistent with engagement of durvalumab 
with PD-L1.  A 
 level of immunogenicity has been observed.  No patients have 
experienced 
 disease following exposure to durvalumab (for further 
information on immunogenicity, please see the current durvalumab IB).
A population PK model was developed using the data from Study 1108 at doses of 0.1 to 
10 mg/kg q2w or 15 mg/kg q3w (Fairman et al 2014).  Multiple simulations indicate that a 
similar overall exposure is expected following both 
mg/kg q2w and 
mg/kg q4w 
regimens, as represented by AUCss (4 weeks).  Median Cmax,ss is expected to be higher with 
mg/kg q4w (
fold) and median Ctrough,ss is expected to be higher with 
mg/kg q2w 
(
-fold).
Clinical activity with the 
mg/kg q4w dosing regimen is anticipated to be consistent with 
mg/kg q2w with the proposed similar dose of 
mg/kg q4w expected to:

Achieve complete target saturation in majority of patients.

Account for anticipated variability in PK, pharmacodynamics, and clinical activity 
in diverse cancer populations.

Maintain sufficient PK exposure in case of anti-drug antibody (ADA) impact.

Achieve PK exposure that yielded maximal antitumor activity in animal models.
Given the similar Area under the plasma drug concentration-time curve (AUC) and modest 
differences in median peak and trough levels at steady state, the observation that both 
regimens maintain complete sPD-L1 suppression at trough level, and the available clinical 
data, the 
mg/kg q4w and 
mg/kg q2w regimens are expected to have similar efficacy and 
safety profiles, supporting further development with a dose of 
mg/kg q4w.  
2.6.5.2
Clinical experience with durvalumab 
Refer to the current durvalumab IB for a complete summary of clinical information including 
safety, efficacy, and PK at the 20 mg/kg q4w regimen.
2.6.6
Rationale for fixed dosing of durvalumab and tremelimumab
A population PK model was developed for durvalumab using monotherapy data from a 
Phase I study (Study 1108; N=292; doses=
mg/kg to 
mg/kg q2w or 
mg/kg q3w; solid 
tumors).  Population PK analysis indicated only minor impact of body weight on the PK of 
durvalumab (coefficient of 
).  The impact of body weight-based (
mg/kg q2w) and 
fixed dosing (
mg q2w) of durvalumab was evaluated by comparing predicted steady-state 
PK concentrations (5th, median and 95th percentiles) using the population PK model.  A fixed 
dose of 
mg was selected to approximate 
mg/kg (based on median body weight of 
~75 kg).  A total of 1000 patients were simulated using body weight distribution of 40 kg to 
120 kg.  Simulation results demonstrate that body weight-based and fixed dosing regimens 
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Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
102 (296)
yield similar median steady state PK concentrations with slightly less overall between-patient 
variability with fixed dosing regimen.  
Similarly, a population PK model was developed for tremelimumab using data from Phase I 
through Phase III studies (N = 654; doses =
 mg/kg to 15 mg/kg q4w or every 90 days; 
metastatic melanoma) [Wang et al 2014].  A population PK model indicated minor impact of 
body weight on PK of tremelimumab (coefficient of ≤0.5).  The body weight-based (1 mg/kg 
q4w) and fixed-dosing (75 mg/kg q4w; based on median body weight of ~75 kg) regimens 
were compared using predicted PK concentrations (5th, median, and 95th percentiles) using a 
population PK model in a simulated population of 1000 patients with body weight distribution 
of 40 kg to 120 kg.  Similar to durvalumab , simulations indicated that both body weight-
based and fixed-dosing regimens of tremelimumab yielded similar median steady state PK 
concentrations with slightly less between-patient variability with fixed dosing regimen.
Similar findings have been reported by others (Ng et al 2006, Wang et al 2009, Zhang 
et al 2012, Narwal et al 2013).  Wang and colleagues investigated 12 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 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 low 
dosing errors.  Given the expectation of similar PK exposure and variability, it was considered 
feasible to switch to a fixed dosing regimen.  Based on average body weight of 75 kg, a fixed 
dose of 1500 mg q4w durvalumab (equivalent to 
mg/kg) and a fixed dose of 
mg q4w 
tremelimumab (equivalent to mg/kg) are included in the current study.
Fixed dosing of durvalumab and tremelimumab will not be applied for patients who weigh 30 
kg or less; such patients will receive weight based dosing due to the regulatory limits for 
endotoxin exposure.  The durvalumab endotoxin specification (
 endotoxin unit 
[EU]/mg protein) supports the 
mg fixed durvalumab dose for a 1 hour infusion for a 
patient > 30 kg.  This ensures the USP criteria of no more than 5.0 EU/kg body weight/hour is 
met.  As the equivalent to the 
mg dose, patients weighing ≤ 30 kg will receive a 
mg/kg dose.
2.6.7
Rationale for study endpoints
The rationale for study endpoints is provided in Section 2.2.3 of the master protocol.
2.7 Benefit/risk and ethical assessment
The unmet need in refractory or resistant ED-SCLC is described in Sections 2.1 and 2.3 of the 
master protocol.  Additional information on the potential benefits of durvalumab and 
tremelimumab and an assessment of the potential and known risks can also be found in the 
respective IBs for each agent.  
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Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
103 (296)
2.7.1
Potential benefits
2.7.1.1
Durvalumab 
The majority of the safety and efficacy data currently available for durvalumab are based on 
the first-in-human, single-agent study (Study 1108) in patients with advanced solid tumors.  
Overall, as of 24 October 2016, 970 patients had been treated with durvalumab  10 mg/kg 
q2w.
 
 
 
 
 
 
 
 
 
Data from patients with SCLC in the durvalumab monotherapy Phase I Study 1108, although 
limited (n=21), 
 
 
 
2.7.1.2
Durvalumab + tremelimumab
Available data suggest that the combination of agents targeting PD-1/PD-L1 and CTLA-4 
may have profound and durable benefits in patients with melanoma (Wolchok et al 2013).  
Furthermore, preliminary efficacy data from Study D4190C00006 have demonstrated that this 
combination is clinically active and well-tolerated.  As of 28 February 2017,, 166 patients 
with at least 24 weeks of follow-up were evaluable for response across the following patient 
cohorts: dose escalation (advanced NSCLC); and dose-expansion Cohort A (treatment-naive 
NSCLC selected by PD-L1 status), Cohort B co-administration (immunotherapy-naïve, 1L or 
2L patients with NSCLC) and Cohort B sequential administration (2L patients with non-
squamous NSCLC).  
 
 
 
 
 
As of 20 October 2017,30 patients with ED-SCLC were treated on Study D4190C00010 with 
the combination of durvalumab  (20 mg/kg) and tremelimumab (1 mg/kg) administered q4w 
for 4 doses, followed by durvalumab alone at a dose of 10 mg/kg q2w for up to a total of 
12 months.  19 of these patients were platinum resistant/refractory.  Confirmed ORR was 
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Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
104 (296)
 
 
 
2.7.2
Identified and potential risks
mAbs directed against immune checkpoint proteins, such as PD-L1, as well as those directed 
against PD-1 or CTLA-4, aim to boost endogenous immune responses directed against tumor 
cells.  By stimulating the immune system, however, there is the potential for adverse effects 
on other tissues.
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, and are most commonly seen as gastrointestinal AEs such as colitis 
and diarrhoea, pneumonitis/interstitial lung disease (ILD), hepatic AEs such as hepatitis and 
liver enzyme elevations, skin events such as rash and dermatitis and endocrinopathies 
including hypo- and hyper-thyroidism.
2.7.2.1
Durvalumab 
Risks with durvalumab include, but are not limited to, diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, hypo- and 
hyper-thyroidism, type I diabetes mellitus and diabetes insipidus ) hepatitis/increases in 
transaminases, nephritis/increases in creatinine, rash/ dermatitis, myocarditis, 
myositis/polymyositis, infusion-related reactions, hypersensitivity reactions and serious 
infections, and other rare or less frequent inflammatory events including neuromuscular 
toxicities (e.g. Guillain Barre syndrome, myasthenia gravis).
For information on all identified and potential risks with durvalumab  please always refer to 
the current version of the durvalumab  IB.
In monotherapy clinical studies AEs at an incidence of > 20% include events such as fatigue, 
cough,decreased appetite, dyspnea, and nausea. Approximately 10% of patients discontinued 
the drug due to an AE. Please see the current version of the IB for a detailed summary of the 
monotherapy data including AEs, SAEs, and CTC Grade 3 to 5 events reported across the 
durvalumab program.
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see Section 7.5). 
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB.
CCI


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
105 (296)
2.7.2.2
Tremelimumab
Risks with tremelimumab monotherapy include, but are not limited to, GI effects (colitis, 
diarrhoea, enterocolitis and intestinal perforation), endocrine disorders (hypo and 
hyperthyroidism, hypophysitis and adrenal insufficiency), skin effects (rash, and pruritus), 
elevations in lipase and amylase and clinical manifestations of pancreatitis, hepatic events 
(including immune mediated hepatitis, and liver enzyme elevations); pneumonitis and ILD; 
neurotoxicity (including encephalitis, peripheral motor and sensory neuropathies, Guillain-
Barre syndrome),thrombocytopenia, anemia and neutropenia; infusion-related reactions, and 
allergic reactions; renal events (including nephritis, /autoimmune nephritis autoimmune 
arthritis, Sjogren's syndrome, giant cell temporal arteritis, and ulcerative colitis; 
hyperglycemia and diabetes mellitus. 
For information on all identified and potential risks with tremelimumab please always refer to 
the current version of the tremelimumab IB.
In monotherapy clinical studies AEs reported at an incidence of > 20% include events such as 
diarrhea, nausea, fatigue, pruritus, decreased appetite, rash,  vomiting, and dyspnoea. 
Approximately 16% of patients experienced an AE that resulted in permanent discontinuation 
of tremelimumab and approximately 45% of patients experienced an SAE.
Please see the current version of the IB for a detailed summary of monotherapy data, 
including AEs, SAEs, and CTC Grade 3 to 5 events reported across the tremelimumab 
program.
2.7.2.3
Durvalumab + tremelimumab
The safety of durvalumab + tremelimumab combination therapy was initially evaluated in the 
ongoing dose escalation and dose expansion Study D4190C00006, in patients with NSCLC, 
and is being studied in a number of other ongoing clinical trials in a number of different 
indications, and has to date shown a manageable safety and tolerability profile. 
The types of risks with the combination of durvalumab + tremelimumab (based on an 
equivalent durvalumab dose of 20m/kg and a tremelimumab dose of 1mg/kg) are similar to 
those for durvalumab  and tremelimumab monotherapy. Emerging data from study 
D4190C00006, other studies evaluating the combination, and from combinations of other 
agents in the same class indicate an increased frequency and/or severity of some of these 
immune-mediated toxicities. 
For information on all identified and potential risks with the durvalumab + tremelimumab 
combination please always refer to the current version of the durvalumab IB.
In durvalumab +tremelimumab combination studies at the dose of durvalumab 20mg/kg and 
tremelimumab 1mg/kg AEs reported at an incidence > 20% included events such as fatigue, 
diarrhoea, nausea, decreased appetite, pruritus, dyspnea, constipation, and anemia. 


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
106 (296)
Approximately 15% of patients experienced an AE that resulted in permanent discontinuation 
of study drug and approximately 15% of patients experienced an SAE that was considered to 
be related to durvalumab and tremelimumab by the study investigator.
Please see the current version of the durvalumab IB for a detailed summary of combination 
therapy data, including AEs, SAEs, and CTC Grade 3 to 5 events reported across the 
durvalumab program, including durvalumab in combination with tremelimumab.
2.7.3
Overall benefit risk
The prognosis of ED-SCLC remains very poor, a with median OS of about 10 months; 
patients who progress through first-line chemotherapy or within 90 days of completing 
chemotherapy have even worse prognosis; median OS is less than 6 months (von Pawel et al 
2014).  There is only 1 treatment approved for patients who are refractory or resistant to first-
line chemotherapy, which has shown very limited activity.  This has indicated a significant 
unmet medical need for improving treatment outcomes for patients with refractory or resistant 
ED-SCLC.  Treatment with durvalumab and/or tremelimumab has shown activity in several 
tumor types including SCLC.  The safety profile of durvalumab  in combination with 
tremelimumab is generally well tolerated; the safety monitoring and guidance are in place to 
manage potential toxicities.  Therefore, the benefit:risk ratio for this Phase II study supports 
the combined administration of durvalumab and tremelimumab to patients with documented 
refractory or resistant ED-SCLC.
2.8 Study design
Arm A will investigate the preliminary efficacy, safety and tolerability of durvalumab in 
combination with tremelimumab followed by durvalumab monotherapy given IV to patients 
who progress during first line chemotherapy or those who progress within 90 days of 
completing first line-chemotherapy.  


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
107 (296)
For Arm A, up to 40 eligible patients will be enrolled, and all patients will receive:
Durvalumab 1500 mg + tremelimumab 75 mg via IV infusion q4w, starting on Week 0, for up 
to a total of 4 doses/cycles followed by durvalumab monotherapy 1500 mg via IV infusion 
q4w, starting on Week 16 until confirmed PD and Investigator confirmation that the patient is 
no longer receiving clinical benefit from the treatment, or for other discontinuation criteria. If 
a patient’s weight falls to 30 kg or below, the patient should receive weight-based dosing after 
discussion between Investigator and Study Physician, until the weight improves to > 30 kg, at 
which point the patient should start receiving the fixed dosing of durvalumab  1500 mg and 
tremelimumab 75 mg q4w (during the combination phase of treatment). The equivalent weight 
based doses to the fixed doses are 20 mg/kg of durvalumab and 1mg/kg tremelimumab q4w.
Appendix A Figure 1
Arm A Study design
Durva  Durvalumab ; ED  Extensive stage disease small-cell lung cancer; ORR  Overall response rate; 
PFS  Progression-free survival; q4w  Every 4 weeks; Treme  Tremelimumab.
3.
STUDY OBJECTIVES
3.1 Primary objective
See Section 3.1 of the master protocol.
3.2 Secondary objectives
See Section 3.2 of the master protocol.  
3.3 Safety objectives
See Section 3.3 of the master protocol.
3.4 Exploratory objectives
See Section 3.4 of the master protocol.  


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
108 (296)
4.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
4.1 Inclusion criteria
1. Male or female ≥18 years at the time of screening.
2. Written informed consent and any locally required authorization (eg, Health Insurance 
Portability and Accountability Act in the US, EU Data Privacy Directive in the EU) 
obtained from the patient/legal representative prior to performing any protocol-related 
procedures, including screening evaluations.
3. Histologically or cytologically documented extensive disease American Joint Committee 
on Cancer Stage IV SCLC (T any, N any, M1 a/b) at initial diagnosis, also including 
patients with:

T3-4 due to multiple lung nodules that are too extensive or have 
tumor/nodal volume that is too large to be encompassed in a tolerable 
radiation plan.

Biopsy-proven mixed SCLC and NSCLC histology

Brain metastases; must be asymptomatic or treated and stable off steroids 
and anti-convulsants for at least 1 month prior to study treatment. Patients 
with suspected brain metastases at screening should have a computed 
tomography (CT)/magnetic resonance imaging (MRI) of the brain prior to 
study entry.
4. Patients must have demonstrated progressive disease (PD) either during first-line 
platinum-based chemotherapy (platinum refractory) or within 90 days of completing 
platinum-based chemotherapy (platinum resistant), and have not received further treatment 
apart from first-line platinum-based chemotherapy. Patients should be enrolled within 90 
days of progression in order to be accepted into the study.
5. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 0 to 1 at enrollment for the first 10 patients recruited to this arm 
(see Section 6.3.1 of master protocol for WHO/ECOG assessment parameters).  This can 
be extended to Performance Status 0 to 2 if the arm recruits an additional 10 patients.
6. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline 
as ≥10 mm in the longest diameter (except lymph nodes, which must have a short 
axis ≥15 mm) with CT or MRI and that is suitable for accurate repeated measurements as 
per RECIST 1.1 guidelines. 


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
109 (296)
7. No prior exposure to immune-mediated therapy including, but not limited to, other anti-
CTLA-4, anti-PD-1, anti-PD-L1, and anti programmed cell death ligand 2 (anti-PD-L2) 
antibodies, excluding therapeutic anticancer vaccines.
8. Body weight >30 kg. 
9. Mandatory provision of a fresh or archival (<1 year) tumour biopsy (or at least 15-20 × 5 
μm newly cut [within 3 months] unstained slides).
10. Willingness and ability to comply with study and follow-up procedures.
11. Life expectancy of at least 8 weeks.
12. Adequate organ and marrow function as defined below

Hemoglobin ≥9.0 g/dL

Absolute neutrophil count ≥1.0 × 109 /L (Use of granulocyte-colony 
stimulating factor is not permitted to raise neutrophils for screening.)

Platelet count ≥75 × 109/L

Serum bilirubin ≤1.5× upper limit of normal (ULN).  This will not apply to 
patients with confirmed Gilbert’s syndrome, who will be allowed in 
consultation with their physician.

In patients without hepatic metastasis: ALT and aspartate aminotransferase 
(AST) ≤2.5× ULN

In patients with hepatic metastases, ALT and AST ≤5× ULN

Calculated creatinine clearance (CL) >40 mL/min as determined by Cockcroft-
Gault (using actual body weight)
Males:
Creatinine CL = 
Weight (kg) × (140 - Age)
(mL/min)
72 × serum creatinine (mg/dL)
Females:
Creatinine CL = 
Weight (kg) × (140 - Age) 
× 0.85
(mL/min)
72 × serum creatinine (mg/dL)
13. Evidence of post-menopausal status or negative urinary or serum pregnancy test for 
female pre-menopausal patients.  Women will be considered post-menopausal if they have 
been amenorrheic for 12 months without an alternative medical cause.  The following age-
specific requirements apply:


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
110 (296)

Women <50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatments and if they have luteinizing hormone and follicle-
stimulating hormone levels in the post-menopausal range for the institution 
or underwent surgical sterilization (bilateral oophorectomy or 
hysterectomy).

Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all 
exogenous hormonal treatments, had radiation-induced oophorectomy with 
last menses >1 year ago, had chemotherapy-induced menopause with 
>1 year interval since last menses, or underwent surgical sterilization 
(bilateral oophorectomy or hysterectomy).
4.2 Exclusion criteria 
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site).
2. Previous enrollment in the present study.
3. Participation in another clinical study with an investigational product (IP) during the last 
4 weeks.
4. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical 
study regardless of treatment arm assignment. 
5. Concurrent enrollment in another clinical study unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study.
6. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of IP.  Note: Local surgery of isolated lesions for palliative intent is acceptable where 
this does not affect assessment of target lesions. 
7. Any condition that, in the opinion of the Investigator, would interfere with the evaluation 
of the IP or interpretation of patient safety or study results, including but not limited to 
ongoing or active infection, symptomatic congestive heart failure, uncontrolled 
hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious 
chronic gastrointestinal conditions associated with diarrhea or psychiatric illness/social 
situations that would limit compliance with study requirement, substantially increase risk 
of incurring AEs from the study medications, or compromise the ability of the patient to 
give written informed consent.
8. Active autoimmune disease, including a paraneoplastic syndrome of autoimmune nature, 
requiring systemic treatment other than chemotherapy for SCLC, within the past 3 months 


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
111 (296)
or a documented history of clinically severe autoimmune disease or a syndrome that 
requires or required systemic steroids or immunosuppressive agents.
9. Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn’s disease]), diverticulitis with the 
exception of (diverticulosis), celiac disease, systemic lupus erythematosus, Sarcoidosis 
syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Grave’s disease, 
rheumatoid arthritis, hypophysitis, uveitis, etc.  The following are exceptions to this 
criterion:

Patients with vitiligo or alopecia

Patients with hypothyroidism (eg, following Hashimoto syndrome) and stable 
on hormone replacement

Any chronic skin condition that does not require systemic therapy

Patients without active disease in the last 5 years may be included but only after 
consultation with the Study Physician

Patients with celiac disease controlled by diet alone
10. Active infection including tuberculosis (TB) [clinical evaluation that includes clinical 
history, physical examination and radiographic findings, and TB testing in line with local 
practice], hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] 
result), hepatitis C, or human immunodeficiency virus (HIV) [positive HIV 1/2 
antibodies].  Patients with a past or resolved HBV infection (defined as the presence of 
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible.  Patients 
positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain 
reaction is negative for HCV ribonucleic acid (RNA).
11. Persistent toxicities (>Common Terminology Criteria for Adverse Events [CTCAE] 
Grade 2) caused by previous cancer therapy.  Any unresolved toxicity (National Cancer 
Institute [NCI] CTCAE Grade >2) from previous anticancer therapy with the exception of 
alopecia, vitiligo, and the laboratory results defined in the inclusion criteria.  

Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab or tremelimumab may be included only after 
consultation with the Study Physician.

Patients with Grade >2 neuropathy will be evaluated on a case-by-case basis 
after consultation with the Study Physician
12. Any concurrent chemotherapy, immunotherapy (eg, a CTLA-4, PD-1, or PD-L1 inhibitor), 
or biologic or hormonal therapy for cancer treatment.  Concurrent use of hormones for 


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
112 (296)
non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) 
is acceptable.
13. Receipt of any live attenuated vaccination within 30 days prior to study entry, while 
receiving durvalumab + tremelimumab, and within 30 days of receiving 
durvalumab ± tremelimumab. 
14. Current or prior use of immunosuppressive medication within 14 days before the first dose 
of durvalumab or tremelimumab.  The following are exceptions to this criterion:

Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-
articular injection)

Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent

Steroids as pre-medication for hypersensitivity reactions (eg, computed 
tomography [CT] scan pre-medication)
15. Radiation therapy to the chest and whole-brain irradiation must be completed at least 
4 weeks prior to start of study treatment, and patients must have recovered from any acute 
adverse effects prior to start of study treatment.  An exception to this is palliative 
radiotherapy for bone lesions and must be completed before the first dose of study 
treatment.
16. Past medical history of interstitial lung disease, drug-induced pneumonitis, radiation 
pneumonitis that required steroid treatment, or any evidence of clinically active interstitial 
lung disease.
17. History of hypersensitivity to active or inactive excipients of any investigational drug in 
the study or drugs with a similar chemical structure or class to those investigated in the 
study.
18. History of another primary malignancy except for:

Malignancy treated with curative intent and with no known active disease 
≥5 years before the first dose of study drug and of low potential risk for 
recurrence

Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease

Adequately treated carcinoma in situ without evidence of disease (eg, 
cervical cancer in situ)
19. History of leptomeningeal carcinomatosis.


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
113 (296)
20. History of active primary immunodeficiency.
21. History of allogenic organ transplantation.
22. Spinal cord compression unless asymptomatic or treated and stable off steroids and anti-
convulsants for at least 1 month prior to study treatment.  
23. 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 durvalumab monotherapy or 180 days after the last dose of 
durvalumab tremelimumab combination therapy.
4.3 Patient enrollment and randomization
See Section 4.3 of the master protocol.
4.4 Procedures for handling incorrectly enrolled or randomized patients
See Section 4.4 of the master protocol.
4.5 Methods for assigning treatment groups
Not applicable.
4.6 Restrictions
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after (refer to Section 4.8 of the master protocol for restrictions 
applicable to all arms of study):
1. Female patient of child-bearing potential

Female patients of childbearing potential who are not abstinent and intend to 
be sexually active with a nonsterilized- male partner must use at least 1 
highly effective method of contraception (Appendix A Table 1) from the 
time of screening throughout the total duration of the drug treatment and the 
drug washout period (180 days after the last dose of durvalumab + 
tremelimumab combination therapy or 90 days after the last dose of 
durvalumab monotherapy). Non-sterilised male partners of a female patient 
of childbearing potential must use male condom plus spermicide 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 birth control. Female 
patients should also refrain from breastfeeding throughout this period.
2. Male patients with a female partner of childbearing potential


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
114 (296)

Non-sterilized male patients who are not abstinent and intend to be sexually 
active with a female partner of childbearing potential must use a male 
condom plus spermicide from the time of screening throughout the total 
duration of the drug treatment and the drug washout period (180 days after 
the last dose of durvalumab + tremelimumab combination therapy or 90 
days after the last dose of durvalumab monotherapy). However, 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.

Female partners (of childbearing potential) of male patients must also use a 
highly effective method of contraception throughout this period (Appendix 
A Table 1).  
N.B Females of childbearing potential are defined as those who are not surgically sterile (ie, 
bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-
menopausal. 
3. Women will be considered post-menopausal if they have been amenorrheic 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 amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatments 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 amenorrheic for 12 months or more following cessation of all 
exogenous hormonal treatments, had radiation-induced menopause with last 
menses >1 year ago, had chemotherapy-induced menopause with last 
menses >1 year ago .
4. 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 
Appendix A Table 1.  Note that some contraception methods are not considered highly 
effective (e.g. 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).
5. Patients should not donate blood or blood components while participating in this study 
and through 180 days after receipt of the final dose of durvalumab  + tremelimumab 
combination therapy or 90 days after receipt of the final dose of durvalumab  or 
alternative anti-cancer therapy is started.


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
115 (296)
6. Restrictions relating to concomitant medications are described in the accountability 
section of this appendix.
Appendix A Table 1 Highly effective methods of contraception (less than 1% failure 
rate per year)
Barrier/Intrauterine methods
Hormonal methods
Copper T intrauterine device
Implants
Levonorgestrel-releasing intrauterine system (eg, 
MIRENA®)a
Hormone shot or injection
Combined pill
Minipill
Intravaginal Devices
Patch
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices e.g. NuvaRing®
a
This is also considered a hormonal method.
4.7 Discontinuation of investigational product
Please also refer to Section 4.9 of the master protocol for discontinuation criteria applicable to 
all arms of the study.  Additional discontinuation criteria applicable to Arm A are listed 
below:

Grade ≥3 infusion reactions.

Clinical progression, i.e. Investigator determination that the patient is no longer 
benefiting from treatment with IP, with or without radiological progression by 
RECIST 1.1.
4.7.1
Assessments following discontinuation of investigational product
Please also refer to Section 4.9.2 of the master protocol for assessments following 
discontinuation of IP applicable to all arms of the study.  
Additional assessments following discontinuation of IP applicable to Arm A are listed below:
All SAEs occurring for up to 90 days after the last dose of study treatment must be recorded in 
the electronic case report form (eCRF).
4.8 Criteria for withdrawal 
See Section 4.10 of the master protocol.


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
116 (296)
4.9 Discontinuation of the study
See Section 4.11 of the master protocol.
5.
STUDY PLAN AND TIMING OF PROCEDURES
The procedures for the screening and the treatment periods in this study are presented in 
Appendix A Table 2.  The procedures for the follow-up period are presented in Appendix A 
Table 3.
Patients may delay dosing under certain circumstances.   

Dosing may be delayed per Toxicity Management Guidelines, due to either an 
immune or a non-immune-related AE.

If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible

Dosing intervals of subsequent cycles may be shortened as clinically feasible in 
order to gradually align treatment cycles with the schedule of tumor efficacy 
(RECIST) assessments.  Subsequent time between 2 consecutive doses cannot be 
less than 22 days, based on the half-lives of durvalumab and tremelimumab (see 
current Investigator Brochures for durvalumab and tremelimumab).  


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
117 (296)
Appendix A Table 2 Schedule of assessments for durvalumab  + tremelimumab combination therapy, and durvalumab  
monotherapy treatment period
Screening
C1
C2
C3
C4
C5
C6
C7
C8+ or PD
For details see
Week
-4to-1
0
4
8
12
16
20
24
28, 32, 36, 40+ or PD
Day
-28 to-1
1
29
57
85
113
141
169
197, 225, 253, 281, 309, 337, 
365, or PD
Window (days)
NA
±1
(±3 days, tumor assessment ±7 days)
Informed consent: study 
procedures including 
biomarker sample 
collectiona
X
Section 6 master 
protocol 
Study Procedures
Physical examination (full)
X
Section 6.2.2 master 
protocol
Targeted physical 
examination (based on 
symptoms)
X
X
X
X
X
X
X
X
Section 6.2.2 master 
protocol
Vital signsb
X
X
X
X
X
X
X
X
X
Section 6.2.4 master 
protocol and 
Section 6.2.2
Appendix A
ECGc
X
As clinically indicated
Section 6.2.3 master 
protocol
Concomitant medications
----------------------------------------------------------------------------------------------
Section 8.7 master 
protocol
Demography, including 
baseline characteristics and 
tobacco use
X
Section 6 master 
protocol


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
118 (296)
Appendix A Table 2 Schedule of assessments for durvalumab  + tremelimumab combination therapy, and durvalumab  
monotherapy treatment period
Screening
C1
C2
C3
C4
C5
C6
C7
C8+ or PD
For details see
Week
-4to-1
0
4
8
12
16
20
24
28, 32, 36, 40+ or PD
Day
-28 to-1
1
29
57
85
113
141
169
197, 225, 253, 281, 309, 337, 
365, or PD
Window (days)
NA
±1
(±3 days, tumor assessment ±7 days)
Eligibility criteria
X
Sections 4.1 and 4.2
master protocol and 
Appendix A sections 
4.1and 4.2
Laboratory assessments
Clinical chemistry
X
Xd
X
X
X
X
X
X
X
Table 4 Appendix A
Hematology
X
Xd
X
X
X
X
X
X
X
Table 5 Appendix A
TSH (reflex free T3, and 
free T4e)
Xq
X
X
X
X
X
X
X
X
Table 4 Appendix A
Coagulation (PT/INR/PTT) 
X
as clinically indicated
Table 5 Appendix A
Urinalysis
X
As clinically indicated
Table 6 Appendix A
Hepatitis B and C and HIV
X
Section 6.2.1 master 
protocol
Pregnancy testf
X
X
X
X
X
X
X
X
X
Section 6.2.1 master 
protocol
PKo
Durvalumab  PK sample  
(serum)o
Xg,o
Xh,o
Xh,o
Section 6.4 Appendix 
A
Tremelimumab PK sample 
(serum)o
Xg,o
Xh,o
Xh,o
Section 6.4 Appendix 
A


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
119 (296)
Appendix A Table 2 Schedule of assessments for durvalumab  + tremelimumab combination therapy, and durvalumab  
monotherapy treatment period
Screening
C1
C2
C3
C4
C5
C6
C7
C8+ or PD
For details see
Week
-4to-1
0
4
8
12
16
20
24
28, 32, 36, 40+ or PD
Day
-28 to-1
1
29
57
85
113
141
169
197, 225, 253, 281, 309, 337, 
365, or PD
Window (days)
NA
±1
(±3 days, tumor assessment ±7 days)
Tremelimumab PK sample 
(serum) for patients who 
complete 4 combo doses-
Follow up sample (12 weeks 
after last dose of 
tremelimumab)o
Xh,o
Section 6.4 Appendix 
A
Monitoring
WHO/ECOG performance 
status
X
X
X
X
X
X
X
X
X
Section 6.3.1 master 
protocol
AE/SAE assessmenti
----------------------------------------------------------------------------------------------
Section 7 master 
protocol
IP Administration
Durvalumab  (combination 
therapy)j, k
X
X
X
X
Section 8.1.1 master 
protocol
Tremelimumabj, k
X
X
X
X
Section 8.1.1 master 
protocol
Durvalumab 
(monotherapy)k
X
X
X
X
Section 8.1.1 master 
protocol
Study Laboratory 
Assessments
ADA sampling to identify 
ADA responses in patient 
circulationo
Xo
Xo
Xo
Section 6.3 Appendix 
A


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
120 (296)
Appendix A Table 2 Schedule of assessments for durvalumab  + tremelimumab combination therapy, and durvalumab  
monotherapy treatment period
Screening
C1
C2
C3
C4
C5
C6
C7
C8+ or PD
For details see
Week
-4to-1
0
4
8
12
16
20
24
28, 32, 36, 40+ or PD
Day
-28 to-1
1
29
57
85
113
141
169
197, 225, 253, 281, 309, 337, 
365, or PD
Window (days)
NA
±1
(±3 days, tumor assessment ±7 days)
mRNAo
Xo
Sections 6.6.1.2 and 
6.6.1.4 master 
protocol
Circulating tumour DNA
     X       
X
Section 6.3 Appendix 
A
Tumor biopsy (newly 
acquired or archival ≤1
years old)a,p
X
Section 6.6 master 
protocol
Tumor evaluation (CT or 
MRI) [RECIST 1.1]l, m
X
X
X
q8w ± 1week after 
week 12 until 
confirmed 
objective disease 
progression/death 
(whichever comes 
first).
Section 6.1 master 
protocol
a
If laboratory or imaging procedures were performed for other reasons prior to signing consent, these can be used for screening purposes with consent of the patient. 
However, all screening laboratory and imaging results must have been obtained within 28 days of enrollment.
b
Body weight is recorded at each visit along with vital signs.  Vital signs are recorded at every clinic visit. Vital signs should be measured separately for both drugs.
For details please check Section 6.2.2 Appendix A.
c
Any clinically significant detected require triplicate ECG results.
d
If screening laboratory assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be repeated at Day 1.  Serum or plasma chemistry, 
hematology, and/or LFT monitoring may be performed more frequently if clinically indicated.
e
Free T3 and free T4 will be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
f
For women of childbearing potential only.  A urine or serum pregnancy test is acceptable.  Women of childbearing potential are required to have a pregnancy test within 
7 days prior to the first dose of study drug and then every 4 weeks.  Pregnancy test may occur on Day 1, but results must be available and reviewed by the treating 
physician or Investigator prior to commencing an infusion. 
g
Within 10 minutes of the end of infusion.  


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
121 (296)
h
Up to 60 minutes pre-dose.
i
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed.
j
During the combination portion of treatment, tremelimumab will be administered first; the durvalumab infusion will start approximately 1 hour (maximum 2 hours) after 
the end of the tremelimumab infusion.  If there are no clinically significant infusion reactions with the first cycle, and at the discretion of the Investigator, then for all 
other cycles, the durvalumab can be given immediately after the tremelimumab infusion has finished. 
k
Results for serum or plasma chemistry and LFT monitoring must be available before commencing an infusion (within 3 days) and reviewed by the treating physician or 
Investigator prior to dosing.
l
RECIST 1.1 assessments will be performed on images from CT (preferred) or MRI, each preferably with IV contrast of the chest, abdomen (including liver and adrenal 
glands), and pelvis.  Pelvic imaging is recommended only when primary or metastatic disease in the pelvic region is likely.  Additional anatomy should be imaged based 
on signs and symptoms of individual patients at baseline and follow-up.  Baseline assessments should be performed no more than 28 days before the date of enrollment 
and, ideally, should be performed as close as possible to and prior to the start of the initial dose of IP.  The confirmatory scans should be performed preferably at the next 
scheduled imaging visit and no less than 4 weeks after the prior assessment of CR/PR or PD (in the absence of clinically significant deterioration).  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.  
m
Patients will have scans done at Week 8, 12, and then q8w thereafter (relative to the date of first dose) until confirmed objective disease progression.
o
Pharmacokinetic, ADA and mRNA samples will be collected from patients recruited into stage 1 and 2 only.  Collection of pharmacokinetic, ADA and mRNA samples 
are not required for patients recruited into the expansion cohorts.
p
If available, patient’s newly acquired or archival ≤1 year old tumor samples should be collected. For patients enrolled into the expansion cohort, provision of a tumour 
tissue sample is mandated prior to commencing study treatment. If sufficient archival tumour tissue is not available the patient will be invited to provide a fresh biopsy, 
following registration but prior to any protocol treatment. Adequate tissue is defined as availability of a tumour block or 15 to 20 unstained slides, each 4 to 5 microns 
thick and cut within 3 months of study treatment from an FFPE block from an archival sample ≤1 year old.
q
Samples can be collected within 3days prior to the visit.
r
Samples for 
 should be collected at baseline any time up to C1D1 as long as this is pre-dose. One further on-treatment sample is required at C3.
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated.
ADA  Anti-drug antibody; AE  Adverse event; C  Cycle; CR  Complete response; CT  Computed tomography; 
; DNA  Deoxyribonucleic acid; 
ECG  Electrocardiogram; ECOG  Eastern Cooperative Oncology Group; EOT  End of treatment; HIV  Human immunodeficiency virus; IP  Investigational product; 
IV  Intravenous; LFT  Liver function test; MRI  Magnetic resonance imaging; NA  Not applicable; PD  Progressive disease; PK  Pharmacokinetic; PR  Partial response; 
q8w  Every 8 weeks; RECIST 1.1  Response Evaluation Criteria in Solid Tumors, version 1.1; SAE  Serious adverse event; T3  Triiodothyronine; T4  Thyroxine; 
TSH  Thyroid-stimulating hormone; WHO  World health Organization.
CCI
CCI


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
122 (296)
Appendix A Table 3 Schedule of assessments: completed/discontinued treatment with durvalumab + tremelimumab 
combination therapy, and durvalumab  monotherapy
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
12 months and 
every 2 months 
(±2 weeks)
For details see
30
2
3
4
6
8
10
Physical examination (full)a
X
Section 6.2.2 master 
protocol
Vital signs (temperature, 
respiratory rate, blood 
pressure, and pulse)
X
Section 6.2.4 master 
protocol
Weight
X
Section 6.2.4 master 
protocol
Pregnancy testb
X
As clinically indicated
Section 6.2.1 master 
protocol
AE/SAE assessment
X
X
X
Section 7 master protocol
Concomitant medications
X
X
X
Section 8.7 master protocol
WHO/ECOG performance 
status
At timepoints consistent with tumor assessments; at 30, 60, and 90 days; and then at 
initiation of subsequent anticancer therapyc
Section 6.3.1 master 
protocol
Details of subsequent 
anticancer therapy to be 
recorded in eCRFd,e
<--------------------------------------------------------------------------------------------------------->
NA
Survival statusf
X
X
X
X
X
X
X
Section 6.1.1 master 
protocol
Hematology
X
X
X
Table 5 Appendix A
Clinical chemistry
X
X
X
Table 4 Appendix A
TSH (reflex free T3, and free 
T4g)
X
X
X
Table 4 Appendix A


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
123 (296)
Appendix A Table 3 Schedule of assessments: completed/discontinued treatment with durvalumab + tremelimumab 
combination therapy, and durvalumab  monotherapy
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
12 months and 
every 2 months 
(±2 weeks)
For details see
30
2
3
4
6
8
10
Durvalumab PK sample  
(serum)i
Xi
Section 6.4 master protocol
Tremelimumab PK sample 
(serum)i
(X) j,i
Section 6.4 master protocol
Immunogenicity assessment 
(ADA sampling) to identify 
ADA responsesi
Xi
Xi
Section 6.3 Appendix A
Tumor assessment (CT or 
MRI) (RECIST 1.1)h
Tumor assessments should be performed q8w ± 1week after week 12 until confirmed 
objective disease progression/death (whichever comes first).
Section 6.1 master protocol
a
Physical examinations are described in Section 6.2.2 of the master protocol.
b
For women of childbearing potential only.  A urine or serum pregnancy test is acceptable.  
c
WHO/ECOG performance status should also be collected at other site visits that the patient attends, if appropriate site staff are available to collect such information.  In 
addition, WHO/ECOG performance status should be provided when information on subsequent anticancer therapy is provided, where possible.
d
Details of any treatment for SCLC (including surgery) post the last dose of IP must be recorded in the eCRF.  At minimum, collect the start date and description of the 
subsequent anticancer therapy. 
e
For patients who discontinue their assigned IP following confirmed progression, available readings of CT/MRI from local practice will be collected from patients’ 
medical charts while information on subsequent anticancer treatment is collected.
f
Patients may be contacted in the week following data cutoffs to confirm survival status.  Details of any treatment for SCLC (including surgery) post the last dose of IP 
must be recorded in the eCRF.
g
Free T3 and free T4 will be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
h
Only for patients yet to progress.  RECIST 1.1 assessments will be performed on images from CT (preferred) or MRI, each preferably with IV contrast, of the chest, 
abdomen (including liver and adrenal glands), and pelvis.  Pelvic imaging is recommended only when primary or metastatic disease in the pelvic region is likely.  
Additional anatomy should be imaged based on signs and symptoms of individual patients.  The confirmatory scans should be performed preferably at the next scheduled 
imaging visit and no less than 4 weeks after the initial assessment of CR/PR or PD (in the absence of clinically significant deterioration).  If an unscheduled assessment 
was performed and the patient has not progressed, every attempt should be made to perform the subsequent assessments at their scheduled visits (relative to the date of  
first IP administration
i 
Pharmacokinetic, ADA and 
 samples will be collected from patients recruited into stage 1 and 2 only.  Collection of pharmacokinetic, ADA and 
 samples 
are not required for patients recruited into the expansion cohort.Details for processing, handling, and shipping are in the Laboratory Manual. 
j
To be collected only, if the patient has completed/discontinued treatment with durvalumab + tremelimumab combination therapy in stages 1 or 2 and no follow up 
tremelimumab PK sample was taken yet.
CCI
CCI


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
124 (296)
ADA  Anti-drug antibody; AE  Adverse event; CR  Complete response; CT  Computed tomography; ECOG  Eastern Cooperative Oncology Group; eCRF  Electronic case 
report form; IP  Investigational product; IV  Intravenous; MRI  Magnetic resonance imaging; NA  Not applicable; PD  Progressive disease; PR  Partial response; 
q8w  Every 8 weeks; RECIST 1.1  Response Evaluation Criteria in Solid Tumors, version 1.1; SAE  Serious adverse event; SCLC  Small-cell lung cancer; 
T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid-stimulating hormone; WHO  World health Organization.


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
125 (296)
5.1 Enrollment/screening period
All screening and enrollment procedures will be performed according to the assessment 
schedule in Appendix A Table 2.  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.
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.  If laboratory or imaging procedures were performed for other reasons prior to 
signing consent, these can be used for screening purposes with consent of the patient.  
However, all screening laboratory and imaging results must have been obtained within 
28 days of enrollment.  All patients will have the option to provide consent to supply a sample 
of their tumor (archived or newly acquired biopsy) for entry into this study.  This consent is 
included in the main patient informed consent form.  
Screening/baseline evaluations may be performed over more than 1 visit.
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 Appendix A Table 2.
5.2 Treatment period
All procedures to be conducted during the treatment period will be performed according to the 
assessment schedule (see Appendix A Table 2).
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 Appendix A Table 2.
5.3 Follow-up period
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment and will enter follow-up (see 
Appendix A Table 3).  
Patients who permanently discontinue IP for reasons other than objective RECIST disease 
progression should continue to have RECIST scans performed at Week 8 ± 1 week, Week 
12 ± 1 week, and then every 8 weeks ± 1 week (relative to the date of first dose) until 
confirmed objective disease progression/death (whichever comes first) as defined in 
Appendix A Table 3.
Following confirmed disease progression, patients should continue to be followed for survival. 
All procedures to be conducted during the follow-up period will be performed according to 
the assessment schedule (see Appendix A Table 3 ).


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
126 (296)
Whenever vital signs, 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 Appendix A Table 3.  All patients will be 
followed for survival until the end of the study.  
6.
STUDY ASSESSMENTS
Please also refer to Section 6 of the master protocol for study assessments applicable to all 
arms of the study.  Additional/specific study assessments applicable to Arm A are listed 
below.
6.1 Efficacy assessments
See Section 6.1 of the master protocol.
Efficacy in Arm A will be assessed on images collected at Week 8, Week 12, and then every 
8 weeks ± 1 week until confirmed objective disease progression or off study.  The Week 12 
scan must be acquired no earlier than 4 weeks from the prior Week 8 scan.  
It is important to follow the assessment schedule as closely as possible (Appendix A Table 2).  
If an unscheduled imaging assessment is performed and the patient has not progressed, every 
attempt should be made to perform the subsequent assessments at his or her next regularly 
scheduled imaging visit.
According to RECIST 1.1, objective tumor response (CR or PR) should be confirmed 
preferably at the next scheduled imaging visit and not less than 4 weeks after the visit when 
the response was last observed.
According to RECIST 1.1 modified for confirmation of progression, a confirmatory scan is 
required following an overall time point assessment of progression, preferably at the next 
scheduled imaging visit and no earlier than 4 weeks after the previous assessment of PD in the 
absence of clinically significant deterioration. Treatment will continue between the initial 
assessment of progression and confirmation for progression.
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) after the 
initial assessment of progression, then the patient should continue to be followed with 
scheduled imaging until confirmed objective disease progression.
Confirmation of progression guidelines are set for the following reasons: 

for patient management and treatment decisions

in the absence of significant clinical deterioration, to promote the collection of 
additional scans after the first radiologic RECIST 1.1 assessment of progressive 


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
127 (296)
disease (PD) in order to distinguish pseudoprogression from true radiologic 
progression, also known as RECIST 1.1 modified for confirmation of progression
Confirmed objective disease progression refers to either of the following scenarios: 1. clinical 
progression/deterioration followed by a radiologic verification scan (PD by RECIST 1.1); or 
2. in the absence of significant clinical deterioration, radiologic PD by RECIST 1.1 followed 
by a second radiologic confirmation scan with PD assessed according to the specific 
confirmation of progression criteria listed below. RECIST 1.1 modified for confirmation of 
progression refers to the second scenario above. The confirmatory scan should occur 
preferably at the next scheduled imaging visit and no earlier than 4 weeks following the date 
of the immediate prior assessment of RECIST 1.1 PD.
Immediate prior radiologic progression would be considered confirmed if any the following 
criteria are met in the confirmatory scan:

≥20% increase in the sum diameters of target lesions (TLs) compared with the nadir at 
2 consecutive visits, with an absolute increase of at least 5 mm in sum of diameters 
compared to nadir,

and/or significant progression (worsening) of non-target lesions (NTLs) and/or of pre-
existing new lesions at the confirmatory scan time-point compared with the immediate 
prior time-point (Note: Pre-existing new lesions are evaluated as NTLs at the 
confirmatory scan time-point),

and/or additional new unequivocal lesions at the confirmatory scan time-point.
NOTE: In order to have confirmed objective disease progression, there should be two 
consecutive PD’s, the first PD by RECIST 1.1 and the second PD using the confirmation of 
progression criteria (above). If the first PD by RECIST 1.1 is not confirmed, continue with 
assessments until the next PD by RECIST 1.1, which in turn will need its own immediate 
subsequent confirmation scan.
In the absence of significant clinical deterioration, treatment with study drug may continue 
between the initial assessment of progression and the scan to confirm progression.
If the confirmation scan confirms progression, then the date of the prior scan with PD should 
be declared as the date of progression.
If progression is not confirmed, in the absence of significant clinical deterioration, then the 
patient should continue study drug and on-treatment assessments until the next PD which will 
also require a follow-up confirmation scan. If the first PD is not confirmed by the 
immediate next scan, then the Investigator should not change the PD assessment of the 
first scan.


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
128 (296)
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to 
radiologic progression, then the patient should still continue to be followed until confirmed 
objective disease progression.
6.2 Safety assessments
6.2.1
Laboratory safety assessments
The laboratory variables to be measured are presented in Table 4 (clinical chemistry), Table 5
(hematology), and Table 6 (urinalysis).
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies, and human immunodeficiency virus antibodies.
The following laboratory variables will be measured:
Appendix A Table 4 Laboratory - clinical chemistry
Albumin
Lipaseb
Alkaline phosphatasea
Magnesiumc
ALTa
Potassium
Amylaseb
Sodium
ASTa
Total bilirubina
Bicarbonatec
Total protein
Calcium 
TSH
Chloridec
T3 freed (reflex)
Creatinine clearancec
T4 freed (reflex)
Creatinine 
Urea or blood urea nitrogen, depending on local 
practice
Gamma glutamyltransferasec
Glucose
Lactate dehydrogenase
a
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently.  
If total bilirubin is >2 × upper limit of normal (and evidence of Gilbert’s syndrome), then fractionate it into 
direct and indirect bilirubin.
b
It is preferable that both amylase and lipase parameters are assessed.  For sites where only 1 of these 
parameters is routinely measured, then either lipase or amylase is acceptable.
c
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, and magnesium 
testing are to be performed at screening, on Day 1 (unless screening laboratory assessments are performed 
within 3 days prior to Day 1), and if clinically indicated.
d
Free T3 and T4 will be measured in Arm A if TSH is abnormal or if there is a clinical suspicion of an AE 
related to the endocrine system.


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
129 (296)
AE  Adverse event; ALT  Alanine aminotransferase; AST  Aspartate aminotransferase; T3  Triiodothyronine; 
T4  Thyroxine; TSH  Thyroid-stimulating hormone.
Appendix A Table 5 Laboratory – hematology
Basophils
Monocytes
Eosinophils
Neutrophils
Hematocrit
Platelet count
Hemoglobin
Red blood cell count
Lymphocytes
Total while blood cell count
Mean corpuscular hemoglobin
Activated partial thromboplastin time
Mean corpuscular hemoglobin concentration
International Normalized Ratio
Mean corpuscular volume
Partial thromboplastin time 
Note: For coagulation parameters, activated partial thromboplastin time, partial thromboplastin time and 
international normalized ratio are to be assessed at baseline and as clinically indicated.
Note: absolute values of blood cells should be provided where possible rather than percentages (e.g. for white 
cell differential counts)
Appendix A Table 6 Laboratory – urinalysis
Bilirubin
Ketones
Blood
pH
Color and appearance
Protein
Glucose
Specific gravity
Note: Urinalysis must be done at baseline and then as clinically indicated.
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high power field for 
red blood cells.
6.2.2
Vital Signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules (see Appendix A Table 2 and Appendix A Table 3).  
Body weight is also recorded at each visit along with vital signs.
On the first infusion day, patients in the durvalumab + tremelimumab combination therapy 
group will be monitored, and vital signs will be collected/recorded in the eCRF prior to, 
during, and after infusion of IP as presented in the bulleted list below:

BP and pulse will be collected from patients in the I-O arms before, during, and 
after each infusion at the following times (based on a 60-minute infusion):


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
130 (296)

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)

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.  A 1-hour observation period is recommended after the first 
infusion of durvalumab and tremelimumab.  

Subsequent infusions

BP, pulse, and other vital signs should be measured and collected/recorded in the 
eCRF prior to the start of the infusion.  Patients should be carefully monitored, and 
BP and other vital signs should be measured during and post infusion as per
institution standard and as clinically indicated.  Any clinically significant changes 
in vital signs should be entered onto an unscheduled vital signs case report form 
(CRF) page. 
Situations in which vital signs results should be reported as AEs are described in Section 
7.3.7.  For any AEs of infusion reactions, please enter the vital signs values into the 
CRF.
6.2.3
Other Safety Assessments
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality 
suggestive of pneumonitis/interstitial lung disease is observed, a full investigation is required, 
as described in detail in the Dosing Modification and Toxicity Management Guidelines 
(Section 7.5). If this is a potential risk for the specific arm then specific safety management 
guidelines will be applied. The results of the full diagnostic workup (including high-resolution 
computed tomography (HRCT), blood and sputum culture, haematological 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 the Dosing Modification and Toxicity Management 
Guidelines should be followed. 
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


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
131 (296)

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
6.3 Biomarker analysis
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
CCI


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
132 (296)
6.4 Pharmacokinetic and Immunogenicity analysis
Durvalumab and tremelimumab PK concentration data and summary statistics will be 
tabulated by treatment, analyte and timepoint. Individual and mean blood concentration-time 
profiles will be generated. No PK parameters will be determined due to sparse sampling. 
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against durvalumab and tremelimumab.
The immunogenicity titer and presence of neutralizing ADAs will be reported for samples 
confirmed positive for the presence of ADAs. The effect of immunogenicity on PK, efficacy, 
and safety will be evaluated, if the data allow.
6.5 Storage and destruction of pharmacokinetic/ADA samples
PK and ADA samples will be disposed of a maximum of 10 years after the end of this study
PK and ADA samples may be disposed of or destroyed and anonymized by pooling.  
Additional analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method.  Results from such analyses may be reported 
separately from the Clinical Study Report (CSR).
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Validation Report.
Any residual back-up PK samples may be used for future exploratory biomarker research (in 
this case, residual back-up PK samples will be shipped to AstraZeneca Biobank; see details in 
the Laboratory Manual). 
7.
SAFETY REPORTING AND MEDICAL MANAGEMENT
Please refer to Section 7 of the master protocol for details of reporting of AEs, SAEs, AESIs, 
paternal exposure, and management of IP-related toxicities applicable to all arms in the study.  
Additional details for reporting of AEs, SAEs, AESIs, paternal exposure, and management of 
IP-related toxicities applicable to Arm A are described below.
7.1 Reporting of adverse events
New onset AEs and SAEs will be collected from the time of the patient signing signature of 
the informed consent form, throughout the treatment period, and including the follow-up 
period is completed (90 days after the last dose of durvalumab ±tremelimumbab).  If an event 
that starts post the defined safety follow up period noted above, is considered to be due to a 
late onset toxicity to study drug, then it should be reported as an AE or SAE as applicable.


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
133 (296)
7.2 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.
7.3 Pregnancy
7.3.1
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days 
after the last dose of durvalumab monotherapy, whichever is the longer time period.  
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 180 days after the 
last dose of durvalumab + tremelimumab combination therapy, or 90 days after the last dose 
of durvalumab monotherapy, whichever is the longer time period, should, if possible, be 
followed up and documented.
7.4 Overdose
Use of durvalumab or tremelimumab in doses in excess of that specified in the protocol is 
considered to be an overdose.  There is currently no specific treatment in the event of 
overdose of durvalumab or tremelimumab, and possible symptoms of overdose are not 
established.  See Section 7.6 of the master protocol. 
7.5 Management of investigational product-related toxicities
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 continued 
supportive care.  If medically appropriate, dose modifications are permitted

All dose modifications should be documented with clear reasoning and documentation 
of the approach taken

If new or worsening pulmonary symptoms (e.g. dyspnoea) or radiological 
abnormality suggestive of pneumonitis/interstitial lung disease is observed, toxicity 
management as described in detail in the Toxicity Management Guidelines will be 
applied. The results of the full diagnostic workup (including high-resolution 
computed tomography (HRCT), blood and sputum culture, haematological 
parameters etc) will be captured in the eCRF. It is strongly recommended to 
perform a full diagnostic workup, to exclude alternative causes such as 


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
134 (296)
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 the Toxicity Management Guidelines should be followed.
All toxicities will be graded according to NCI CTCAE, version 4.03.  
7.5.1
Durvalumab and durvalumab + tremelimumab
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 durvalumab and tremelimumab should be 
permanently discontinued (see Section 4.7 of the master protocol and the Toxicity 
Management Guidelines).
Following the first dose of IP, subsequent administration of durvalumab and tremelimumab 
can be modified based on toxicities observed as described in the Toxicity Management 
Guidelines.  These guidelines have been prepared by the Sponsor to assist the Investigator in 
the exercise of his or her clinical judgment in treating these types of toxicities.  These 
guidelines apply to AEs considered causally related to durvalumab monotherapy and the 
durvalumab + tremelimumab regimen by the reporting Investigator.
Dose reductions are not permitted.  In case of doubt, the Investigator should consult with 
the Study Physician.
7.5.2
Toxicity Management Guidelines
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 inhibitors durvalumab [MEDI4736] (PD-L1 inhibitor) and tremelimumab 
(CTLA-4 inhibitor). Given the similar underlying mechanisms of toxicities observed with 
these two compounds, these guidelines are applicable to the management of patients receiving 
either drug as monotherapy or in combination. Additionally, these guidelines are applicable 
when either drug is used alone or in combination and is administered concurrently or 
sequentially with other anti-cancer drugs (i.e. antineoplastic chemotherapy, targeted agents), 
as part of a protocol 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, 


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
135 (296)
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. In addition, a version of 
the current Dosing Modification and Toxicity Management Guidelines is available through 
the following link: https://tmg.azirae.com. Please contact the clinical study associate for 
information on how to gain access to this website.
7.6 Adverse events of special interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. 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.
AESIs for durvalumab ± tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent 
monitoring and/or interventions such as steroids, immunosuppressants, and/or hormone 
replacement therapy.  These AESIs are being closely monitored in clinical studies with 
durvalumab monotherapy and combination therapy.  An immune mediated adverse event 
(imAE) is defined as an AESI that is associated with drug exposure and is consistent with an 
immunemediated 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 imAE diagnosis.  Appropriate efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin, or other etiologic causes of the imAE.
If the Investigator has any questions in regard to an AE being an imAE, the Investigator 
should promptly contact the Study Physician.
AESI/imAEs observed with PD-L1/PD-1 agents such as durvalumab and durvalumab in 
combination with tremelimumab include:

Pneumonitis

Hepatitis 

Diarrhea/Colitis 

Intestinal perforations

Endocrinopathies (ie, events of hypo- and hyper-thyroidism, adrenal insufficiency, 
hypophysitis/hypopituitarism and type I diabetes mellitus)

Nephritis

Rash/Dermatitis


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
136 (296)

Myocarditis

Myositis / Polymyositis

Pancreatitis

Rare/less frequent imAEs including neuromuscular toxicities such as myasthenia 
gravis and Guillain-Barré syndrome.
Other inflammatory responses that are rare / less frequent with a potential immune-mediated 
aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and other events 
involving the eye, skin, haematological, rheumatological events, vasculitis, non-infectious 
meningitis and non-infectious encephalitis. It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all organs.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological aetiology are also considered AESIs.
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the durvalumab and tremelimumab IBs. More specific guidelines for their 
evaluation and treatment are described in detail in the Dosing Modification and Toxicity 
Management Guidelines (see Section 7.5). These guidelines have been prepared by the 
Sponsor to assist the Investigator in the exercise of his or her clinical judgment in treating 
these types of toxicities. These guidelines apply to AEs considered causally related to the 
study drug/study regimen by the reporting Investigator.
7.6.1
Immune-related adverse events
Based on the mechanism of action of durvalumab and tremelimumab leading to T-cell 
activation and proliferation, there is a possibility of observing irAEs during the conduct of this 
study.  Potential irAEs may be similar to those seen with the use of ipilimumab, BMS-936558 
(antiPD-1 mAb), and BMS-936559 (anti-PD-L1 mAb-) and may include immune-mediated 
enterocolitis, dermatitis, hepatitis (hepatotoxicity), pneumonitis, and endocrinopathies (Hodi
et al 2010, Brahmer et al 2012, Topalian et al 2012).  These AEs are inflammatory in nature 
and can affect any organ.  With anti-PD-L1 and anti-CTLA-4 combination therapy, the 
occurrence of overlapping or increasing cumulative toxicities that include irAEs could 
potentially occur at higher frequencies than with either durvalumab or tremelimumab 
monotherapy.  Patients should be monitored for signs and symptoms of irAEs.  In the absence 
of an alternate etiology (eg, infection or PD), an immune-related etiology should be 
considered for signs or symptoms of enterocolitis, dermatitis, pneumonitis, hepatitis, and 
endocrinopathy.  In addition to the dose modification guidelines provided in Appendix A 
Table 7, it is recommended that irAEs are managed according to the general treatment 
guidelines outlined for ipilimumab (Weber et al 2012).  These guidelines recommend the 
following:
1.
Patients should be evaluated to identify any alternative etiology.


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
137 (296)
2.
In the absence of a clear alternative etiology, all events of an inflammatory nature 
should be considered immune related.
3.
Symptomatic and topical therapy should be considered for low-grade events.
4.
Systemic corticosteroids should be considered for a persistent low-grade event or 
for a severe event.
5.
More potent immunosuppressives should be considered for events not responding to 
systemic steroids (eg, infliximab or mycophenolate; see Appendix A Table 7).
If the Investigator has any questions in regard to an AE being an irAE, the Investigator should 
immediately contact the Study Physician.  
8.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
8.1 Identity of investigational product(s)
Please see Section 8 of the master protocol for the general information on the IP.  Additional 
IP information applicable to Arm A is described in this section.  
Investigational product
Dosage form and strength
Durvalumab (MEDI4736)
50 mg/mL solution, IV
Tremelimumab
20 mg/mL solution, IV
8.1.1
Durvalumab
Durvalumab  will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL durvalumab (MEDI4736), 
 
 The nominal fill volume is 10 mL. IP 
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.
The dose of durvalumab (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 durvalumab (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. 
CCI


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
138 (296)
A dose of 1500mg (for patients >30kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 20 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm in-line filter. Add 30.0 mL of durvalumab (MEDI4736) (ie, 1500mg 
of durvalumab (MEDI4736)) to the IV bag. The IV bag size should be selected such that the 
final concentration is within 1 to 20 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag.
Weight-based dosing of 20 mg/kg (for patients ≤ 30 kg) will be a administered using an IV 
bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 20 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm in-line filter.
Standard infusion time 1 hour. In the event that there are interruptions during infusion, the 
total allowed infusion 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.
If either preparation time or infusion time exceeds the time limits a new dose must be 
prepared from new vials. Durvalumab (MEDI4736) does not contain preservatives, and any 
unused portion must be discarded.
Preparations are to be in accordance with the study-specific drug handling instructions.
8.1.2
Tremelimumab
Tremelimumab will be supplied by AstraZeneca as a 400-mg vial solution for infusion after 
dilution. The solution contains 20 mg/mL tremelimumab, 
 
 
 The nominal fill volume is 20.0 mL. IP 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 container until use to prevent excessive light exposure.
All preparation details can be found in the IP Handling Instructions.
The dose of tremelimumab 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 
tremelimumab vial to the start of administration should not exceed: 

24 hours at 2°C to 8°C (36°F to 46°F)
CCI


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
139 (296)

4 hours at room temperature
Infusion solution must be allowed to equilibrate to room temperature prior to commencement 
of administration.
A dose of 75 mg (for patients >30kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final tremelimumab concentration 
ranging from 0.10 to 10 mg/mL, and delivered through an IV administration set with a 0.2- or 
0.22-μm in-line filter.  Add 3.8 mL (ie,75 mg of tremelimumab, with the dose volume rounded 
to the nearest tenth mL) to the IV bag. The IV bag size should be selected such that the final 
concentration is within 0.10 to 10 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag. 
Weight-based dosing of 1 mg/kg (for patients ≤ 30 kg) will be a administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final tremelimumab concentration 
ranging from 0.10 to 10 mg/mL, and delivered through an IV administration set with a 0.2- or 
0.22-μm in-line filter. 
Standard infusion time is 60 minutes (± 5 minutes). Less than 55 minutes is considered a 
deviation. In the event that there are interruptions during infusion, the total allowed infusion 
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.
If either preparation time or infusion time exceeds the time limits a new dose must be 
prepared from new vials. Tremelimumab does not contain preservatives, and any unused 
portion must be discarded. 
Tremelimumab will be administered first; the durvalumab infusion will start approximately 
1 hour (maximum 2 hours) after the end of the tremelimumab infusion. Standard infusion time 
for each is 1 hour. In the event that there are interruptions during infusion, the total allowed 
time should not exceed 8 hours at room temperature per infusion. If there are no clinically 
significant concerns after the first cycle, then, at the discretion of the Investigator, all other
cycles of durvalumab can be given immediately after the tremelimumab infusion has finished.
8.2 Dose and treatment regimens
For Arm A, up to 20 eligible patients will be enrolled, and all patients will receive:
Durvalumab 1500 mg + tremelimumab 75 mg via IV infusion q4w, starting on Week 0, for up 
to a total of 4 cycles/doses followed by durvalumab  monotherapy 1500 mg via IV infusion 


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
140 (296)
q4w, starting after completion of the 4th cycle of combination treatment, until confirmed PD 
and Investigator confirmation that the patient is no longer receiving clinical benefit from the 
treatment, or for other discontinuation criteria.  If a patient’s weight falls to 30 kg or less the 
patient should receive weight-based after discussion between Investigator and Study 
Physician, until the weight improves to >30 kg, at which point the patient should start 
receiving the fixed dosing of durvalumab 1500mg and 75mg tremelimumab q4w (during the 
combination phase of treatment). The equivalent weight based doses to the fixed doses are 20 
mg/kg of durvalumab and 1mg/kg tremelimumab q4w. 
In the first cycle of durvalumab + tremelimumab treatment, tremelimumab will be 
administered first; the durvalumab infusion will start approximately 1 hour (maximum 
2 hours) after the end of the tremelimumab infusion.  If there are no clinically significant 
concerns after the first cycle, then, at the discretion of the Investigator, all other cycles of 
durvalumab can be given immediately after the tremelimumab infusion has finished.
Appendix A Figure 2
Durvalumab + tremelimumab combination therapy dosing 
schedule
IV  Intravenous; q4w  Every 4 weeks.
8.2.1
Duration of treatment and criteria for treatment through progression
All treatment will be administered beginning on Day 1 until confirmed PD unless there is 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.
Treatment through progression will only be considered for arms containing durvalumab +/-
tremelimumab.
Progression during treatment
During the treatment period patients may continue receiving therapy in the setting of 
unconfirmed radiologic progressive disease (PD) according to Response Evaluation Criteria in 
Solid Tumors version 1.1 (RECIST 1.1), at the Investigator’s discretion, until progression is 
confirmed.  A confirmatory scan is required following a RECIST 1.1 overall time point 
assessment of progression (PD), preferably at the next scheduled visit and no earlier than 4 


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
141 (296)
weeks after the previous assessment of PD.  Patients with PD by RECIST 1.1 (unconfirmed 
and confirmed) who, in the Investigator’s opinion, continue to receive benefit from their 
assigned treatment and who meet the criteria for treatment in the setting of PD may continue 
to receive their assigned treatment for as long as they are gaining clinical benefit.  However, 
patients will not be permitted to continue immunotherapy if progression occurs after 
confirmed response (CR or PR as defined by RECIST 1.1) to immunotherapy treatment in the 
target lesions (regardless of the appearance of new lesions) i.e the response and progression 
events both occurred in the target lesions while receiving immunotherapy during the same 
treatment period. 
Patients with rapid tumour progression or with symptomatic progression that requires urgent 
medical intervention (eg, central nervous system metastasis, respiratory failure due to tumor 
compression, spinal cord compression) will not be eligible for continuing durvalumab ± 
tremelimumab. 
Patients in the durvalumab  + tremelimumab combination therapy arm meeting the retreatment 
criteria below will follow the same treatment guidelines followed during the original treatment 
period, including the same dose and frequency of treatments and the same schedule of 
assessments (with the exception of the PK, ADA, tumor biopsies, biomarker samples and 
optional PGx assessments, which do not need to be collected a second time).  
Patients who meet the criteria for retreatment may only receive retreatment once.  
Patients receiving the durvalumab + tremelimumab combination therapy arm may undergo 
retreatment as described below:
Patients who complete the 4 dosing cycles of the combination of durvalumab and 
tremelimumab portion of the regimen (with clinical benefit per Investigator judgment), but 
subsequently have evidence of PD during the durvalumab monotherapy portion of the 
combination regimen, with or without confirmation according to RECIST 1.1, may restart 
treatment with the combination.
For all patients who are treated through progression and for patients who are restarting 
durvalumab + tremelimumab the Investigator should ensure that:

The patient does not have any significant, unacceptable, or irreversible toxicities that 
indicate continuing treatment will not further benefit the patient

There is absence of clinical symptoms or signs indicating clinically significant disease 
progression accompanied by a decline in WHO/ECOG performance status to >1

There is absence of rapid disease progression or threat to vital organs or critical 
anatomical sites (eg, central nervous system metastasis, respiratory failure due to 
tumor compression, or spinal cord compression) requiring urgent alternative medical 
intervention.


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
142 (296)

The patient still fulfills the eligibility criteria for this study with the exception of 
inclusion criteria numbers 4 and 7, and exclusion criteria number 19. 
During the retreatment period, patients in the durvalumab + tremelimumab combination 
therapy group will resume durvalumab dosing at 1500mg q4w with 75 mg of tremelimumab 
q4w for 4 doses/cycles each.  Patients will then continue with durvalumab monotherapy at 
1500mg q4w, beginning at Week 16, 4 weeks after the last dose of combination therapy until 
disease progression.  
Patients who AstraZeneca and the Investigator determine may not continue treatment after PD 
will be followed up for survival.  Patients who have discontinued treatment due to toxicity or 
symptomatic deterioration, or who have commenced subsequent anticancer therapy, will be 
followed up until confirmed disease progression and for survival.
8.3 Labeling
Please refer to Section 8.3 of the master protocol for details regarding labeling applicable to 
all arms. Additional details regarding labeling applicable to Arm A are described below.
Label text prepared for durvalumab  will show the product name as “MEDI4736” or 
“durvalumab (MEDI4736)” depending on the agreed product name used in the approved study 
master label document.  All naming conventions are correct during this transitional period. 
Label text prepared for tremelimumab will show the product name as “tremelimumab”.
8.4 Storage
Please see Section 8.4 of the master protocol.
8.5 Compliance
Please see Section 8.5 of the master protocol.
8.6 Accountability
Please see Section 8.6 of the master protocol.
8.7 Concomitant and other treatments 
Please refer to Section 8.7 of the master protocol for details regarding concomitant and other 
treatments applicable to all arms. Details regarding concomitant and other treatments 
applicable to Arm A are described below.
Refer also to the Dosing Modification and Toxicity Management Guidelines in Appendix A 
Table 7.  


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
143 (296)
Appendix A Table 7 Prohibited concomitant medications for Arm A
Prohibited medication/class of drug:
Usage
Any investigational anticancer therapy other 
than those under investigation in this study
Should not be given concomitantly
mAbs against CTLA-4, PD-1, or PD-L1 
Should not be given concomitantly
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those 
under investigation in this study
Should not be given during the study.  (Concurrent 
use of hormones for non-cancer-related conditions 
[eg, insulin for diabetes and hormone replacement 
therapy] is acceptable.  Local treatment of isolated 
lesions, excluding target lesions, for palliative 
intent is acceptable [eg, by local surgery or 
radiotherapy])
Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
TNF-α blockers
Should not be given concomitantly.  (Use of 
immunosuppressive medications for the 
management of IP-related AEs or in patients with 
contrast allergies is acceptable).  In addition, use of 
inhaled, topical, and intranasal corticosteroids is 
permitted.
Drugs with laxative properties and herbal or 
natural remedies for constipation
Should be used with caution through to 90 days 
after the last dose of tremelimumab during the 
study
Sunitinib
Should not be given concomitantly or through 90 
days after the last dose of tremelimumab (acute 
renal failure has been reported with combination 
therapy of tremelimumab and sunitinib)
EGFR TKIs 
Should not be given concomitantly 
Should be used with caution in the 90 days 
following the last dose of durvalumab 
Increased incidence of pneumonitis (with third 
generation EGFR TKIs) and increased incidence of 
transaminase increases (with first generation EGFR 
TKIs) have been reported when durvalumab  has 
been given concomitantly.
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP 
Herbal and natural remedies which may have 
immune-modulating effects
Should not be given concomitantly unless agreed 
by the sponsor
AE  Adverse event; CTLA-4  Cytotoxic T–lymphocyte-associated antigen 4; EGFR  Epidermal growth factor 
receptor; IP  Investigational product; mAb  Monoclonal antibody; PD-1  Programmed cell death 1; PD-
L1  Programmed cell death ligand 1; TKI  tyrosine kinase inhibitor; TNF  Tumor necrosis factor.


Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
144 (296)
Appendix A Table 8 Rescue/supportive medication for Arm A
Rescue/supportive medication
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
8.8 Post Study Access to Study Treatment
Please see Section 8.8 of the master protocol.
9.
STATISTICAL ANALYSES BY ASTRAZENECA
Please refer to Section 9 of the master protocol for details regarding statistical analyses 
applicable to all arms. Additional details regarding statistical analyses applicable to Arm A are 
described below.
 
 
 
  
 
9.2 Adverse events
AEs observed up to 90 days following discontinuation of study treatment or until the initiation 
of the first subsequent therapy following discontinuation of treatment (whichever occurs first) 
will be used for the reporting of AE summary tables.  This will more accurately depict AEs 
attributable to study treatment only, as a number of AEs up to 90 days following 
discontinuation of the study agents are likely to be attributable to subsequent therapy.  
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Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
145 (296)
9.3 Study and data management by AstraZeneca
Please refer to Section 10 of the master protocol for details of the management of the study 
and data.
10.
ETHICAL AND REGULATORY REQUIREMENTS
Please refer to Section 11 of the master protocol for details regarding ethical and regulatory 
requirements.


Clinical Study Protocol Appendix A1
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
146 (296)


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
147 (296)
APPENDIX B
ARM B: AZD1775 + CARBOPLATIN SUB-
PROTOCOL
1.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC
Area under the plasma drug concentration-time curve
AUC(0-∞)
Area under the plasma drug concentration-time curve time 0 to 
infinity
BCRP
Breast cancer resistance protein
BID
Twice daily
CBDP
Carboplatin
CIDP
Chronic inflammatory demyelinating polyneuropathy
Cmax,ss
Maximum plasma concentration at steady state
CrCl
Creatinine clearance
CRF
Case report form (electronic/paper)
CTCAE
Common Terminology Criteria for Adverse Event
CYP
Cytochrome P450
DHEA
Dehydroepiandrosterone
DNA
Deoxyribonucleic acid 
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
eCRF
Electronic case report form
ECOG
Eastern Cooperative Oncology Group
ED-SCLC
Extensive stage disease small-cell lung cancer


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
148 (296)
Abbreviation or 
special term
Explanation
5-FU
5-fluorouracil 
FDA
Food and Drug Administration
GFR
Glomerular filtration rate
IB
Investigator’s Brochure
IRB
Institutional Review Board
IP
Investigational product 
IV
Intravenous
MATE
Multi-antimicrobial extrusion protein
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
p53
Tumor protein 53
P-gp
P glycoprotein
PD
Progressive disease
PFS
Progression-free survival
PO
By mouth
PK
Pharmacokinetic(s)
PR
Partial response
q3w
Every 3 weeks
q4w
Every 4 weeks
q6w
Every 6 weeks
q12w
Every 12 weeks
RECIST 1.1
Response Evaluation Criteria in Solid Tumors
SAE
Serious adverse event 
SD
Stable disease
SCLC
small cell lung cancer
ULN
Upper limit of normal


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
149 (296)
Abbreviation or 
special term
Explanation
WEE1
A nuclear kinase belonging to the Ser/Thr family of protein kinases 
in the fission yeast Schizosaccharomyces pombe (S.◦pombe).
WoCBP
Women of childbearing potential


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
150 (296)
2.
INTRODUCTION
2.1 Background and rationale for conducting this study
Study D419QC00002 is an open-label, multicenter, multi-arm, Phase II study in patients with 
extensive-stage small cell lung cancer (ED-SCLC) who have refractory or resistant disease, 
defined as patients who progress during first-line platinum based chemotherapy or those who 
progress within 90 days after completing first-line platinum based chemotherapy.  Study 
D419QC00002 is modular in design, allowing evaluation of the safety, tolerability, 
pharmacokinetics (PK) and anti-tumor activity of different combinations of novel anti-cancer 
agents in patients with refractory or resistant ED-SCLC, and will consist of a number of study 
arms, each evaluating the safety and tolerability of a specific combination. 
Arm B in Study D419QC00002 investigates the efficacy, safety, and tolerability of treatment 
with oral AZD1775 (PO) in combination with intravenous (IV) carboplatin (CBDP) in 
ED-SCLC patients.
The rationale for conducting this study is in Section 2.2 of the master protocol.
2.2 AZD1775
AZD1775 is a highly selective, ATP competitive, small-molecule inhibitor of the WEE1
kinase that sensitises tumour cells to cytotoxic agents and is being developed for the treatment
of patients with advanced solid tumours with genetic deficiencies in DNA repair mechanisms.  
Inhibition of the DNA damage checkpoint kinase WEE1 potentiates genotoxic 
chemotherapies by abrogating cell-cycle arrest and eliminating the opportunity for proper 
DNA repair to occur.  From a therapeutic standpoint, inhibition of checkpoint kinases that 
mediate cell-cycle arrest may force tumor cells to continue cell division before chemically 
induced DNA damage is repaired, eventually causing apoptosis or mitotic catastrophe 
(Medema and Macurek 2012).
In in vitro studies, AZD1775 inhibits WEE1 activity and induces DNA damage as well as G2 
checkpoint escape in cell-based assays.  AZD1775 increases cytotoxicity when used in 
combination with other DNA damaging agents, such as gemcitabine (GEMZAR®), cisplatin 
(Platinol®), and topotecan (HYCAMTIN®) in tumor protein 53 (p53)-deficient cell lines.  In in 
vivo studies, AZD1775 was well tolerated and showed enhancement of anti-tumor efficacy by 
gemcitabine, CBDP, cisplatin, 5-fluorouracil (5-FU), and capecitabine (XELODA®) in nude 
rat xenograft tumor models.  Similarly, in nude mouse xenograft models, AZD1775 treatment 
resulted in significant tumor growth inhibition at tolerated doses, and also enhanced the 
anti-tumor growth effect of gemcitabine, CBDP, and radiation therapy (see most recent 
AZD1775 Investigator’s Brochure [IB]).
Small cell lung cancers (SCLCs) harbor multiple genomic alterations involved in cell cycle 
regulation, oncogenic signaling, and double-strand break repair.  The most common genetic 
alterations in SCLC occur in: pTP53 (90%), retinoblastoma 1 (RBI, 85%) [Byers et al 2012], 
MYC (cMYC, MYCN, and MYCL1 - ~5% each), RAS (2%), and BRCA1/2 (3%).  These 
alterations, and in particular, combinations of these alterations, force cancer cells to depend on 


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
151 (296)
the G2-M checkpoint for restoring cell cycle function and division.  It is estimated that 18% of 
SCLCs harbor mutations in cell cycle regulation (TP53) and in oncogenic signalling (MYC or 
RAS).  Likewise, 3% of SCLCs harbor mutations in both cell cycle regulation (TP53) and 
DSB repair (BRCA1/2).  
The high unmet medical need and prevalence of somatic alterations affecting cell cycle
control and DNA repair make SCLC an important cancer setting to investigate AZD1775.
2.3 Carboplatin
CBDP is a second-generation platinum containing chemotherapeutic compound, and an 
analog of cisplatin.  While cisplatin has two chloride groups, CBDP possesses a cyclobutane 
dicarboxylate (CBDCA) moiety.  This results in lower reactivity and DNA binding kinetics, 
though the same platinum-DNA adducts are formed as those induced by cisplatin.  CBDP 
however demonstrates less nephrotoxicity and neurotoxicity, and is less emetogenic than its 
parent compound cisplatin.
CBDP and etoposide (ETOPOPHOS®) or cisplatin and etoposide are the most commonly used 
chemotherapy regimen in the treatment of SCLC; CBDP is used more often than cisplatin in 
order to reduce the risk of emesis, neuropathy, and nephropathy (NCCN 2015).  
2.4 Rationale for study design, doses, and control groups
The rationale for the unmet medical need in refractory or resistant ED-SCLC is described in 
Section 2.2.1  of the master protocol.  The rationale for the specific study design aspects of 
Arm B is described below.
2.4.1
AZD1775 in combination with CBDP  
Tumor cells rely on cell cycle checkpoints for repair of DNA damage induced by cytotoxic 
agents.  As AZD1775 selectively inhibits WEE1, it effectively disrupts the regulation of cell 
cycle checkpoints, particularly the G2 checkpoint.  Because cell cycle checkpoints are critical 
in the DNA damage response, AZD1775 can potentiate the activity of cytotoxic agents and 
thus acts to sensitize the tumor cell to the cytotoxic agent.  Non-clinical studies have 
demonstrated that WEE1 effectively sensitizes tumor cells to cytotoxic effects of gemcitabine, 
cisplatin, or CBDP (refer to most recent AZD1775 IB).  This has also been demonstrated 
clinically in platinum refractory ovarian cancer with objective response rate (ORR) as high as 
41% (Leijen et al 2015).
2.4.2
Clinical experience with AZD1775
AZD1775 has been investigated in 12 AstraZeneca-sponsored or 
 clinical 
studies, 6 of which are ongoing.  As of 11 November 2015, a total of approximately 
443 patients have been exposed to AZD1775 in AstraZeneca-sponsored or 
 
clinical studies.  In addition, approximately 200 patients have also received AZD1775 as part 
of externally-sponsored scientific research.  These patients have received single doses per 
cycle as high as 1300 mg of AZD1775 as monotherapy, 325 mg of AZD1775 in a single-dose 
in combination with chemotherapy, and 325 mg twice daily (BID) in a multiple-dose regimen 
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Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
152 (296)
in combination with chemotherapy.  For details on those studies, and for complete summary 
of the clinical safety and efficacy profile of AZD1775, refer to the current IB.
The most common adverse events (AEs) observed in studies of AZD1775 combined with 
chemotherapy include blood and lymphatic disorders, (ie, thrombocytopenia, neutropenia, 
leukopenia, anemia, and febrile neutropenia), gastrointestinal disorders (ie, diarrhea, vomiting, 
nausea, abdominal pain, and constipation), and blood investigations (ie, hematology and 
serum chemistries).  Other reported safety concerns include electrocardiogram (ECG) QT 
prolongation, fatigue, influenza-like illness, malaise, mucosal inflammation, myalgia, 
palpitations, pruritus, pyrexia, rash, rash maculopapular, skin lesion, stomatitis, tachycardia, 
and loss of weight.
The single-dose maximum tolerated dose (MTD) for both the gemcitabine and cisplatin 
combination therapies was 200 mg of AZD1775 in this study (NCT00648648).  Dose-limiting 
toxicities (DLTs) tended to be hematological in nature in the gemcitabine group and 
constitutional in the cisplatin group.  The single-dose MTD for the combination with CBDP 
was 325 mg of AZD1775.  DLTs in this group were related to serum chemistry.
DLTs observed in the multiple-dose CBDP combination have been both hematological and 
constitutional in nature.  The multiple-dose MTD in combination with CBDP is 
AZD1775 225 mg BID × 5 for 2.5 days.  Hematologic DLTs were most commonly observed 
in the multiple-dose AZD1775 combination treatment groups with gemcitabine and cisplatin.  
A MTD of AZD1775 in combination with gemcitabine was established with an interim dose 
of 50 mg BID on Day 1, 25 mg BID on Day 2, and 25 mg on Day 3.  An attenuated once daily 
(QD) for 2-day schedule in combination with gemcitabine was invesitgated.  Two DLTs 
(Grade 3 febrile neutropenia and Grade 3 aspartate aminotransferase and alanine 
aminotransferase (AST/ALT) increase) were observed at 200 mg QD for 2 days with the 
regimen in combination with gemcitabine.  The dose was adjusted to 175 mg QD for 2 days 
and was determined to be the MTD.  The MTD for combination with cisplatin has been 
exceeded at the 250 mg dose level, and tolerability of the MTD at 200 mg BID × 5 for 
2.5 days has been confirmed.  
The MTD for AZD1775 in combination with 5-FU was not reached due to early study 
termination.  DLTs of encephalopathy and hyponatremia were observed in the 
AZD1775 20 mg BID in combination with 1000 mg/m2 5-FU treatment group.
Triplet-based therapy of AZD1775, CBDP, and paclitaxel was administered in study 
NCT01357161: a Phase II study evaluating AZD1775 combined with CBDP and paclitaxel 
(ABRAXANE®) in patients with platinum-sensitive p53-mutant ovarian cancer.  The starting 
dose of 225 mg AZD1775 (BID for 5 total doses) in Part 1 (an open-label dose escalation/
de-escalation study that employed a toxicity probability design to evaluate the
safety and tolerability of the triplet combination) was generally well-tolerated.  One patient 
experienced a DLT in the first 6 patients treated, and the dose remained at 225 mg BID for 
2.5 days.  A total of 15 patients were treated with 3 DLTs being reported (Grade 3 and 4 
febrile neutropenia and Grade 4 thrombocytopenia).  Other toxicities were generally blood and 
lymphatic system disorders and gastrointestinal disorders.  Of the 14 evaluable patients by 


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
153 (296)
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) in Part 1, there were 11 PRs (6 
confirmed and 5 unconfirmed), and 3 stable diseases (SDs); 7 patients were evaluable by CA-
125 with 3 CRs and 4 PRs.  All patients were treated at the 225 mg AZD1775 BID 2.5 day 
dose level in combination with paclitaxel and CBDP.  The dose established in Part 1 was 
determined to be the recommended Phase II dose.  Part 2 of the study compared the 
administration of AZD1775 at the recommended Phase II dose versus placebo in combination 
with CBDP AUC 5 and paclitaxel 175 mg/m2 in a double-blind fashion.  Part 2 of the study is 
completed and showed the below final safety and efficacy data summary.  As of 11 November 
2015, a total of 59 patients were treated in the AZD1775 combination with paclitaxel and 
CBDP arm, and the following grade ≥3 AEs were reported: 21 (35.6%) neutropenia, 12 
(20.3%) anemia, 12 (20.3%) thrombocytopenia, 6 (10.2%) diarrhea, 6 (10.2%) vomiting, and 
3 (5.1%) nausea; compared to placebo and CBDP arm (n=60) with the following grade ≥3 
AEs reported: 20 (33.3%) neutropenia, 7 (11.7%) thrombocytopenia, 4 (6.7%) anemia, 2 
(3.3%) diarrhea, 2 (3.3%) alopecia, 1 (1.7%) nausea, and 1 (1.7%) vomiting.
For enhanced RECIST, median progression-free survival (PFS) for patients receiving 
AZD1775 plus chemotherapy was 34.14 weeks compared to 31.86 weeks for those receiving 
chemotherapy alone (hazard ratio 0.63 80% CI [0.45,0.89], p=0.080) [Oza et al 2015].
The combination of AZD1775 with topotecan and cisplatin in adult patients with cervical 
cancer (study NCT01076400) was evaluated.  Toxicities were generally hematological and 
gastrointestinal in nature.  No unexpected toxicities were observed.
Available preliminary efficacy data are encouraging, with confirmed partial responses (PRs) 
in patients participating in the 2 ovarian cancer trials, as well as the first time in human 
(FTIM) Phase I trial in solid tumors.  Several studies are ongoing (AZD1775 IB).
2.4.3
Pharmacokinetic and pharmacodynamic data
The PK data of AZD1775 following a single oral administration showed a moderate rate of 
absorption with a maximum plasma drug concentration at steady state (Cmax) occurring at 3 to 
4 hours.  Post-peak plasma concentrations declined essentially in a mono-exponential manner 
with a half-life in the region of 10 hours.  Exposure as measured by Cmax and area under the 
curve AUC (0-∞) increased in a dose-proportional manner over the dose range of 325 to 1300 
mg.  Following single (100 to 325 mg) and multiple dose administrations of AZD1775 (25 to 
325 mg BID and 100 to 200 mg QD) with CBDP, cisplatin, and gemcitabine, plasma exposure 
of AZD1775 was consistent with predictions based on the single-dose regimen.  Preliminary 
investigation of drug-drug interactions (DDI) in the FTIM study (NCT00648648) suggests a 
40% to 60% increase in the exposure of AZD1775 in the presence of aprepitant (moderate 
CYP3A4 inhibitor), but no effect with the concomitant administration of steroids (moderate 
CYP3A4 inducers).  Preliminary studies also suggested that the Premarketed Oral 
Formulation (PMF) of AZD1775 was similar to that of the Fit-For-Purpose (FFP) formulation.
Based on the preliminary comparison of the results of AZD1775 PK parameters at the 225 mg 
dose, PK estimates in Asian patients were 30% to 45% higher than in Western patients.


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
154 (296)
Pharmacodynamic analyses have mainly focused on CDK-1.  By inhibiting WEE1, AZD1775 
reduces phosphorylated CDK-1 levels relative to total CDK-1 with 125 mg BID of AZD1775 
expected to be the threshold dose for target engagement.  
Further information on the PK, metabolism, and pharmacodynamics effects of AZD1775 is 
provided in the current version of the AZD1775 IB.
2.4.4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.4.5
Rationale for study endpoints
The rationale for study endpoints is provided in Section 2.2.3 of the master protocol.
2.5 Benefit/risk and ethical assessment
The unmet need in refractory or resistant ED-SCLC is described in Sections 2.1 and 2.3 of the 
master protocol.  Additional information on the potential benefits of each agent (AZD1775 
and CBDP) and an assessment of the potential and known risks can also be found in the 
current AZD1775 IB and in the manufacturer’s label for CBDP (Food and Drug 
Administration 2014).  Specific information relating to AZD1775 and CBDP is summarized 
below. 
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Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
155 (296)
2.5.1
Potential benefits
2.5.1.1
AZD1775
AZD1775 has shown some clinical activity as monotherapy.  Data is limited to 12 evaluable 
subjects from a Phase Ib study in advanced solid tumors (NCT02482311); 
 
 
 
 
  In Part 1 of this study, confirmed PRs were observed 
in 2 patients carrying BRCA mutations: 1 with head and neck cancer and 1 with ovarian 
cancer. (Do et al, JCO, 2015)
2.5.1.2
CBDP
CBDP is registered for the treatment of ovarian cancer as monotherapy or in combination 
therapy for recurrent disease.  CBDP is also used in the treatment of cancer of the lungs, testis, 
head and neck, and neuroblastoma.  Additionally, CBDP in combination with etoposide is the 
standard first-line chemotherapeutic treatment of ED-SCLC (NCCN 2015).
2.5.1.3
AZD1775 + CBDP 
AZD1775 in multiple-dose combination with CBDP: 44 out of 46 patients
(
%) were evaluable for response.  There was no confirmed PR observed in any
of the evaluable patients.  
 
  The most promising data comes from the 
recent Phase II study of AZD1775 + CBDP in patients with 
 
 
 
 
 
  The median PFS was 
 months (Leijen et al 2015).
2.5.2
Identified and potential risks
2.5.2.1
AZD1775
No AZD1775 monotherapy studies have been completed, and there are limited data available 
on the administration of AZD1775 as a monotherapy.  It has therefore not been possible to 
reliably estimate the frequency of occurrence of expected AEs and laboratory abnormalities 
for AZD1775 monotherapy.
Please refer to Section 5.4 ‘emerging safety profile’of the current AZD1775 IB for complete 
list of events considered as identified risks, and Section 6 of IB ‘summary of data and 
guidance to investigators’ for information on the potential risks and risk mitigation strategy. 
2.5.2.2
CBDP
Side effects of CBDP mainly consist of myelosuppression; especially thrombocytopenia, and 
leukopenia, nausea and vomiting, nephrotoxicity, liver toxicity (especially increased alkaline 
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Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
156 (296)
phosphatase), ototoxicity and tinnitus, allergic reactions, neurotoxicity, alopecia, taste 
alterations, fever, and conjunctivitis.
2.5.2.3
AZD1775 + CBDP
The most common 
 
 
 
 
 
Preliminary PK analyses revealed that co-administration of 
 
 
2.5.3
Summary benefit: risk statement
The safety profile of AZD1775 when combined with CBDP has been shown to be acceptable, 
and AZD1775 has shown activity in several tumor types in the clinical development program 
to date.  The potential benefit of this combination in ED-SCLC is unknown.  Overall risks and 
benefits support the investigation of oral AZD1775 and carboplatin in patients with platinum 
refractory ED-SCLC according to this clinical protocol.
2.6 Study design 
Arm B will investigate the preliminary efficacy, safety, and tolerability of AZD1775 (given 
PO) in combination with CBDP (given IV) to patients who progress during first-line 
chemotherapy (platinum refractory) or those who progress within 90 days after completing 
first-line chemotherapy (platinum resistant).
For Arm B, up to 20 eligible patients will be enrolled, and all patients will receive:

AZD1775 225 mg BID PO for 2.5 days from Day 1 + CBDP AUC 5 Day 1 IV; every 3 
weeks (q3w)
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Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
157 (296)
Appendix B Figure 1
Study design
BID  Twice daily; CBDP  Carboplatin; ED-SCLC  Extensive-stage disease small-cell lung cancer; ORR  Objective response rate; 
OS  Overall survival; PFS  Progression-free survival; PO  By mouth; q3w  Every 3 weeks.


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
158 (296)
3.
STUDY OBJECTIVES
3.1 Primary objective
See Section 3.1 of the master protocol.
3.2 Secondary objectives
See Section 3.2 of the master protocol.
3.3 Safety objectives
See Section 3.3 of the master protocol.
3.4 Exploratory objectives
See Section 3.4 of the master protocol.  
4.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
4.1 Inclusion criteria
1. Male or female ≥18 years at the time of screening.
2. Written informed consent and any locally required authorization (eg, Health Insurance 
Portability and Accountability Act in the US, EU Data Privacy Directive in the EU) 
obtained from the patient/legal representative prior to performing any protocol-related 
procedures, including screening evaluations.


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
159 (296)
3. Histologically or cytologically documented extensive disease American Joint Committee 
on Cancer Stage IV SCLC (T any, N any, M1 a/b) at initial diagnosis, also including 
patients with:

T3-4 due to multiple lung nodules that are too extensive or have 
tumor/nodal volume that is too large to be encompassed in a tolerable 
radiation plan.

Biopsy-proven mixed SCLC and NSCLC histology

Brain metastases; must be asymptomatic or treated and stable off steroids 
and anti-convulsants for at least 1 month prior to study treatment. Patients 
with suspected brain metastases at screening should have a computed 
tomography (CT)/magnetic resonance imaging (MRI) of the brain prior to 
study entry.
4. Patients must have demonstrated progressive disease (PD) either during first-line 
platinum-based chemotherapy (platinum refractory) or within 90 days of completing 
platinum-based chemotherapy (platinum resistant), and have not received further treatment 
apart from first-line platinum-based chemotherapy. Patients should be enrolled within 90 
days of progression in order to be accepted into the study.
5. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 01 at enrolment- (see Section 6.3.1 of master protocol for ECOG 
assessment parameters)
6. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline 
as ≥10 mm in the longest diameter (except lymph nodes, which must have a short 
axis ≥15 mm) with CT or MRI and that is suitable for accurate repeated measurements as 
per RECIST 1.1 guidelines. 
7. Able and willing to swallow oral medication 
8. Willingness and ability to comply with study and follow-up procedures.
9. Life expectancy of at least 8 weeks.
10. Adequate organ and marrow function as defined below;

Hemoglobin ≥9 g/dL

Absolute neutrophil count  ≥1500/μL (use of granulocyte-colony stimulating factor is 
permitted)

Platelets ≥100000/μL


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
160 (296)

ALT and AST ≤3 × upper limit of normal (ULN) or ≤5 × ULN if known hepatic 
metastases

Serum bilirubin within normal limits (WNL) or ≤1.5 × the ULN in patients with liver 
metastases; or total bilirubin ≤3.0 × ULN with direct bilirubin WNL in patients with 
well documented Gilbert’s syndrome

Serum creatinine ≤1.5 × the ULN, or a calculated creatinine clearance (CrCl) 
≥45 mL/min by the Cockcroft-Gault method:
CrCl (glomerular filtration rate [GFR]) = (140 - age) × (weight/kg) × Fa
(72 × serum creatinine mg/dL)
a where F= 0.85 for females and F=1 for males
11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for 
female pre-menopausal patients.  Women will be considered post-menopausal if they have 
been amenorrheic 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 amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatments and if they have luteinizing hormone and follicle-
stimulating hormone levels in the post-menopausal range for the institution 
or underwent surgical sterilization (bilateral oophorectomy or 
hysterectomy).

Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all 
exogenous hormonal treatments, had radiation-induced oophorectomy with 
last menses >1 year ago, had chemotherapy-induced menopause with 
>1 year interval since last menses, or underwent surgical sterilization 
(bilateral oophorectomy or hysterectomy).
Females of childbearing potential should agree to use adequate contraceptive measures 
from 2 weeks prior to the study and until 6 months after study treatment discontinuation.
12. Male patients who are willing to use barrier contraception (ie, condoms) for the duration 
of the study and for 3 months after study treatment discontinuation.


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
161 (296)
4.2 Exclusion criteria 
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site).
2. Previous enrollment in the present study.
3. Participation in another clinical study with an investigational product (IP) during the last 
4 weeks.  
4. Concurrent enrollment in another clinical study unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study.
5. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of IP.  Note: Local surgery of isolated lesions for palliative intent is acceptable where 
this does not affect assessment of target lesions. 
6. Any condition that, in the opinion of the Investigator, would interfere with the evaluation 
of the IP or interpretation of patient safety or study results, including but not limited to 
ongoing or active infection, symptomatic congestive heart failure, uncontrolled 
hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirement, substantially increase risk 
of incurring AEs from the study medications, or compromise the ability of the patient to 
give written informed consent.
7. Radiation therapy to the chest and whole-brain irradiation must be completed at least 
4 weeks prior to start of study treatment, and patients must have recovered from any acute 
adverse effects prior to start of study treatment.  An exception to this is palliative 
radiotherapy for bone lesions and must be completed before the first dose of study 
treatment.
8. Past medical history of interstitial lung disease, drug-induced pneumonitis, radiation 
pneumonitis that required steroid treatment, or any evidence of clinically active interstitial 
lung disease.
9. Patient has an inability to swallow oral medications.  Note: Patient may not have a 
percutaneous endoscopic gastrostomy tube or be receiving total parenteral nutrition.
10. Prior exposure to any WEE1 inhibitors.
11. Any known hypersensitivity or contraindication to the components of the study drugs, 
AZD1775 and CBDP, or drugs with a similar chemical structure or class to the study 
drugs.
12. History of hypersensitivity to active or inactive excipients of any investigational drug in 
the study those investigated in the study.


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
162 (296)
13. Patient has had prescription or non-prescription drugs or other products known to be 
sensitive to cytochrome P450 (CYP)3A4 substrates or CYP3A4 substrates with a narrow 
therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4 which 
cannot be discontinued 2 weeks prior to the first day of study drug dosing and withheld 
throughout the study until 2 weeks after the last dose of study drug.  Coadministration of 
aprepitant or fosaprepitant during this study is prohibited. The use of sensitive substrates 
of CYP3A4, such as atorvastatin, simvastatin and lovastatin, is also prohibited in this 
study. As grapefruit and Seville oranges are known to contain moderate inhibitors of 
CYP3A4, these fruits or their products (including marmalade, juice, etc.) should be 
avoided while taking AZD1775. (see Appendix I Disallowed Medications and 
Medications to ne Administered with Caution). Transporter studies (in vitro) have shown 
that AZD1775 is an inhibitor of breast cancer resistance protein (BRCP). The use of 
rosuvastatin in this study is prohibited.
14. Herbal preparations are not allowed throughout the study.  These herbal medications 
include but are not limited to:  St. John's wort, kava, ephedra (ma hung), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng.  Patients should 
stop using these herbal medications 7 days prior to first dose of study treatment.
15. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with AstraZeneca Study Physician.
16. Patient with mean resting corrected QT interval (specifically QTc calculated using the 
Fridericia formula) > 470 msec from 3 ECGs performed within 5 minutes apart at study 
entry or congenital long QT syndrome.
17. Any of the following cardiac diseases currently or within the last 6 months as defined by 
New York Heart Association ≥ Class 2 (Appendix B1
New York Heart Association 
Criteria
18. ).

Unstable angina pectoris

Congestive heart failure

Acute myocardial infarction

Conduction abnormality not controlled with pacemaker or medication

Significant ventricular or supraventricular arrhythmias (patients with chronic rate-
controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
18. AZD1775 should not be given to patients who have a history of Torsades de pointes 
unless all risk factors that contributed to Torsades have been corrected (see Section 


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
163 (296)
4.5.2AZD1775 has not been studied in patients with ventricular arrhythmias or recent 
myocardial infarction.
19. History of another primary malignancy except for:

Malignancy treated with curative intent and with no known active disease 
≥5 years before the first dose of study drug and of low potential risk for 
recurrence

Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease

Adequately treated carcinoma in situ without evidence of disease (eg, 
cervical cancer in situ)
20. History of leptomeningeal carcinomatosis.
21. Spinal cord compression unless asymptomatic or treated and stable off steroids and anti-
convulsants for at least 1 month prior to study treatment.  
22. Female patients who are pregnant or breastfeeding.
4.3Patient enrollment and randomization
See Section 4.3 of the master protocol.
4.3.1
Procedures for handling incorrectly enrolled or randomized patients
See Section 4.4 of the master protocol.
4.4 Methods for assigning treatment groups
Not Applicable.
4.5 Restrictions
Please refer to Section 4.6 of the master protocol for details of the restrictions that apply to all 
patients in the study.  Restrictions specific to Arm B include:
AZD1775 should be taken with 8 ounces of water approximately 2 hours before or 2 hours 
after food. 
If BID dosing and a patient misses one of the two daily doses according to schedule, the dose 
should be taken as soon as possible, but not more than 6 hours after the missed dose was 
scheduled.  If greater than 6 hours, the missed dose should be skipped and the patient should 
take the next dose when scheduled.


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
164 (296)
If vomiting occurs after a patient takes the AZD1775 dose, the patient should be instructed not 
to retake the dose, but to wait until the next scheduled dose of AZD1775.  If no dose is 
scheduled for the following day, the dose will not be ‘made up’.  If vomiting persists, the 
patient should contact the Investigator.
4.5.1
Women of childbearing potential 
Women of childbearing potential (WoCBP) may be included only if acceptable contraception 
is in place for 2 weeks before commencing study treatment, for the duration of the study, and 
for 6 months after the last dose of study drug.
WoCBP is defined as women between menarche and menopause who have not been 
permanently or surgically sterilized and are capable of procreation.
All WoCBP must have a negative pregnancy test during screening   and within 3 days prior to 
starting each treatment cycle.
Male patients who are involved in the study must agree to avoid procreative and unprotected 
sex (ie, using acceptable forms of contraception as described in Appendix G) and must not 
donate sperm during the study and for 6 months after the last dose of study drug.  Where the 
female partner is pregnant or not using effective birth control, men should be advised to 
abstain while in the study and for 6 months after the last dose of study drug. 
Female partners, who are of childbearing potential, of men participating in the study will also 
be required to use effective contraceptive measures (detailed in Appendix G) while their 
partner is on study drug and for 6 months thereafter.
Because of the possibility of irreversible infertility due to therapy with carboplatin, male 
patients will be advised to arrange for the freezing of sperm samples prior to the start of the 
study should they wish to father children at a future date. 
4.5.2
Patients with a history of Torsades de pointes  
AZD1775 should not be given to patients who have a history of  Torsades de pointes unless all 
risk factors that contributed to Torsades have been corrected.  AZD1775 has not been studied 
in patients with ventricular arrhythmias or recent myocardial infarction. See appendix I for a 
list of drugs that can cause Torsades de pointes.
4.6 Discontinuation of investigational product
See Section 4.9 of the master protocol.
4.7 Criteria for withdrawal 
See Section 4.10 of the master protocol.  
4.8 Discontinuation of the study
See Section 4.11 of the master protocol.  


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
165 (296)
5.
STUDY PLAN AND TIMING OF PROCEDURES 
The procedures for the screening and the treatment periods in this study are presented in 
Appendix B Table 1.  


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
166 (296)
Appendix B Table 1 Schedule of assessments for AZD1775 + Carboplatin combination therapy
AZD1775 and Carboplatin (cycle 21 days)
FOLLOW UP
For details 
see 
Screening
Cycle 1
Cycle 2
Cycle 3 and beyond
End of study 
treatment 
visit (30 days 
FU) ± 2 days
Every 
2 months 
(± 2 
weeks)
Assesment
Baseline 
(-28 to -1) 
Day 
1
Day 
3
Day
8
Day 
15
Day 1
(± 2 
days)
Day 8
(± 2 
days)
Day 1
(± 2 
days)
Day 
3
Day 8
(± 2 
days)
Informed consent: 
study procedures 
including 
biomarker sample 
collection a
X
Section 6 of 
the master 
protocol
Study 
Procedures
Physical 
examination (full)
X
X
X
X
X
Section 6.2.2
of master 
protocol
Vital signsb
X
X
X
X
X
Section 6.2.4
of master 
sprotocol
ECGc
X
X
X
X
Section 6.2.3
of master 
protocol
Concomitant 
medications
X
X
X
X
X
Section 8.7
of master 
protocol


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
167 (296)
Appendix B Table 1 Schedule of assessments for AZD1775 + Carboplatin combination therapy
AZD1775 and Carboplatin (cycle 21 days)
FOLLOW UP
For details 
see 
Screening
Cycle 1
Cycle 2
Cycle 3 and beyond
End of study 
treatment 
visit (30 days 
FU) ± 2 days
Every 
2 months 
(± 2 
weeks)
Assesment
Baseline 
(-28 to -1) 
Day 
1
Day 
3
Day
8
Day 
15
Day 1
(± 2 
days)
Day 8
(± 2 
days)
Day 1
(± 2 
days)
Day 
3
Day 8
(± 2 
days)
Demography, 
including baseline 
characteristics and 
tobacco use
X
Section 6 of 
master 
protocol
Eligibility criteria
X
Sections 4.1
and 4.2 of 
master 
protocol and 
Appendix B 
sections 5.1  
and 5.2
Laboratory 
assesments
  
Clinical chemistry
X
Xd
X
X
X
X
X
X
X
Table 2 
Appendix B
Hematology
X
Xd
X
X
Xe
X
Xe
X
X
Table 3 
Appendix B
Hepatitis B and C 
and HIV
X
Urinalysis
X
as clinically indicated
Table 4 
Appendix B


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
168 (296)
Appendix B Table 1 Schedule of assessments for AZD1775 + Carboplatin combination therapy
AZD1775 and Carboplatin (cycle 21 days)
FOLLOW UP
For details 
see 
Screening
Cycle 1
Cycle 2
Cycle 3 and beyond
End of study 
treatment 
visit (30 days 
FU) ± 2 days
Every 
2 months 
(± 2 
weeks)
Assesment
Baseline 
(-28 to -1) 
Day 
1
Day 
3
Day
8
Day 
15
Day 1
(± 2 
days)
Day 8
(± 2 
days)
Day 1
(± 2 
days)
Day 
3
Day 8
(± 2 
days)
Coagulation 
(PT/INR/PTT) 
X
as clinically indicated
Table 2 
appendix B
Pregnancy test
X
X
X
X
Section 6.2.1
of master 
protocol
Pharmacokinetics
  
AZD1775 PK 
sample (plasma)
Xg
Xg
Section 6.4
of master 
protocol and 
Appendix B 
Table
CBDP PK sample 
(plasma)
Xh
Xh
Section 6.4
of master 
protocol and 
Appendix B 
Table
Monitoring
WHO/ECOG 
performance 
status
X
X
X
X
X
Section 6.3.1
of master 
protocol


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
169 (296)
Appendix B Table 1 Schedule of assessments for AZD1775 + Carboplatin combination therapy
AZD1775 and Carboplatin (cycle 21 days)
FOLLOW UP
For details 
see 
Screening
Cycle 1
Cycle 2
Cycle 3 and beyond
End of study 
treatment 
visit (30 days 
FU) ± 2 days
Every 
2 months 
(± 2 
weeks)
Assesment
Baseline 
(-28 to -1) 
Day 
1
Day 
3
Day
8
Day 
15
Day 1
(± 2 
days)
Day 8
(± 2 
days)
Day 1
(± 2 
days)
Day 
3
Day 8
(± 2 
days)
AE/SAE 
assessment i
X
X
X
X
X
X
X
X
X
X
X
Xs
Section 7 of 
master 
protocol
IP 
Administration
CBDP,m, k
X
X
X
Section 8.1.2
of Appendix 
B
Dispense 
AZD1775 
Review/Collect 
Dosing Diary j,l, n
X
X
X
Section 8.1.1
of Appendix 
B
Study laboratory 
assessments
  
mRNA
X
Section 
6.6.1.4of 
master 
protocol
 
X
X
X
Section 
6.6.1.2 of 
CCI


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
170 (296)
Appendix B Table 1 Schedule of assessments for AZD1775 + Carboplatin combination therapy
AZD1775 and Carboplatin (cycle 21 days)
FOLLOW UP
For details 
see 
Screening
Cycle 1
Cycle 2
Cycle 3 and beyond
End of study 
treatment 
visit (30 days 
FU) ± 2 days
Every 
2 months 
(± 2 
weeks)
Assesment
Baseline 
(-28 to -1) 
Day 
1
Day 
3
Day
8
Day 
15
Day 1
(± 2 
days)
Day 8
(± 2 
days)
Day 1
(± 2 
days)
Day 
3
Day 8
(± 2 
days)
master 
protocol
Tumor biopsy 
(newly acquired 
or archival ≤3 
years old)ar
X
Section 
6.6.1.2  of 
master 
protocol
Tumor evaluation 
(CT or MRI) 
(RECIST 1.1)o, p
X
q6w ± 1week (relative to the date of first dose) until confirmed objective disease progression/death 
(whichever comes first).
Section 6.1
of master 
protocol
Subsequent 
anticancer therapy 
recording in 
eCRF
X
n/a
Survival status
Xs
Section 6.1.1
of master 
protocol
a
If laboratory or imaging procedures were performed for other reasons prior to signing consent, these can be used for screening purposes 
with consent of the patient.  However, all screening laboratory and imaging results must have been obtained within 28 days of enrollment.
b
Body weight is recorded along with vital signs.


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
171 (296)
c
ECG is mandatory on Day 1 of each Cycle and could be done at other visits if clinically indicated. Any clinically significant abnormalities 
detected require triplicate ECG results.
d
If screening laboratory assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be repeated at Day 
1.  Serum or plasma chemistry, coagulation, hematology, and/or LFT monitoring may be performed more frequently if clinically indicated.
e
Haematology results must be available prior to dosing of each cycle, and reviewed by the treating physician or Investigator according to
        the dose modification and safety management guidelines in Section 7.3  
f
For women of childbearing potential only.  A urine or serum pregnancy test is acceptable.  Women of childbearing potential are required to 
have a pregnancy test within 3 days prior to the first dose of study drug and then every 4 weeks.  Pregnancy test may occur on Day 1, but 
results must be available and reviewed by the treating physician or Investigator prior to commencing an infusion 
g
Predose and Cmax 2-4 hours post dose day 3 for alternate cycles starting from C1.
h
Up to 60 minutes pre-dose and end of infusion, for alternate cycles starting from C. Pre-dose PK sample should be taken prior to the 
dosing of any study drug .
i
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed.
j
Five doses of AZD1775 (225 mg PO BID) will be taken in approximate 12-hour intervals over 2.5 days (Days 1-3).  AZD1775 should be 
taken approximately 2 hours before or 2 hours after food.
k
Results for serum or plasma chemistry and LFT monitoring must be available before commencing administration (within 3 days) and 
reviewed by the treating physician or Investigator prior to dosing.
l
All patients must take a 5-HT3 antagonist prior to each dose of AZD1775, for example, ondansetron (ZOFRAN®) 8 mg PO BID or 
granisetron (KYTRIL®) 1 mg PO BID.  The 5-HT3 antagonist may be given by IV if necessary.
m
Carboplatin AUC 5 IV will be administered according to institutional standards on Day 1 of each 21-day cycle after AZD1775 dosing.
n
Review AZD1775 dosing compliance with the patient at the beginning of each new treatment cycle when study drug is dispensed. 
o
RECIST 1.1 assessments will be performed on images from CT (preferred) or MRI, each preferably with IV contrast of the chest, abdomen 
(including liver and adrenal glands), and pelvis every 6 weeks (+/- 1 week).  Pelvic imaging is recommended only when primary or 
metastatic disease in the pelvic region is likely.  Additional anatomy should be imaged based on signs and symptoms of individual patients 
at baseline and follow-up.  Baseline assessments should be performed no more than 28 days before the date of enrollment and, ideally, 
should be performed as close as possible to and prior to the start of the initial dose of IP.  
p
Patients will have scans done q6w for the first 48 weeks, and then q12w thereafter (relative to the date of first IP administration) until 
objective disease progression.
r
If available  patient’s newly acquired or archival ≤3 years old tumor samples should be collected. Should there be no sample available no 
new biopsy is needed to be obtained.
s
Following treatment discontinuation, assessments for survival and SAE/AE must be made monthly for the first 3 months and then every 
2 months thereafter.
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated.
AE  Adverse event; C  Cycle; CT  Computed tomography; ECG  Electrocardiogram; ECOG  Eastern Cooperative Oncology Group; 
HIV  Human immunodeficiency virus; IM  Intramuscular; INR  International normalized ratio; IP  Investigational Product; LFT  Liver function 


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
172 (296)
test; MRI  Magnetic resonance imaging; PD  Progressive disease; PK  Pharmacokinetic; PT  Prothrombin time; PTT Partial thromboplastin 
time; q6w  Every 6 weeks q8w  Every 8 weeks; q12w  Every 12 weeks; RECIST 1.1  Response Evaluation Criteria in Solid Tumors; 
SAE  Serious adverse event; T3 Triiodothyronine; T4 Thyroxine; TSH  Thyroidstimulating- hormone; WHO  World health Organization.


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
173 (296)
5.1 Enrollment/screening period
All screening and enrollment procedures will be performed according to the assessment 
schedule in Appendix B Table 1.  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.
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.  If laboratory or imaging procedures were performed for other reasons prior to 
signing consent, these can be used for screening purposes with consent of the patient.  
However, all screening laboratory and imaging results must have been obtained within 
28 days of enrollment.  All patients will have the option to provide consent to supply a sample 
of their tumor (archived or newly acquired biopsy) for entry into this study.  This consent is 
included in the main patient informed consent form.  
Screening/baseline evaluations may be performed over more than 1 visit.
The timing of vital sign assessments should be such that it allows the blood draw (eg, PK 
blood sample) to occur at the time points indicated in Appendix B Table 1.
5.2 Treatment period
All procedures to be conducted during the treatment period will be performed according to the 
assessment schedule (see Appendix B Table 1).
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 time points indicated in Appendix B Table 1).
5.3 Follow-up period
All procedures to be conducted during the follow-up period will be performed according to 
the assessment schedule Appendix B Table 1).
6.
STUDY ASSESSMENTS
Please also refer to Section 6 of the master protocol for the study assessments applicable to all 
arms in the study.  Additional study assessments applicable to Arm B are listed below.
6.1
Safety Assessments
6.1.1
Laboratory safety assessments
The laboratory variables to be measured are presented in Table 2 (clinical chemistry), Table 3 
(hematology), and Table 4 (urinalysis).


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
174 (296)
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies, and human immunodeficiency virus antibodies.
The following laboratory variables will be measured:
Appendix B Table 2 Laboratory - clinical chemistry
Albumin
Lipaseb
Alkaline phosphatasea
Magnesiumc
ALTa
Potassium
Amylaseb
Sodium
ASTa
Total bilirubina
Bicarbonatec
Total protein
Calcium 
TSH
Chloridec
T3 freed (reflex)
Creatinine clearancec
T4 freed (reflex)
Creatinine 
Urea or blood urea nitrogen, depending on local 
practice
Gamma glutamyltransferasec
Glucose
Lactate dehydrogenase
a
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently.  
If total bilirubin is >2 × upper limit of normal (and evidence of Gilbert’s syndrome), then fractionate it into 
direct and indirect bilirubin.
b
It is preferable that both amylase and lipase parameters are assessed.  For sites where only 1 of these 
parameters is routinely measured, then either lipase or amylase is acceptable.
c
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, and magnesium 
testing are to be performed at screening, on Day 1 (unless screening laboratory assessments are performed 
within 3 days prior to Day 1), and if clinically indicated.
d
Free T3 and T4 will only be measured in Arm A if TSH is abnormal or if there is a clinical suspicion of an 
AE related to the endocrine system.
AE  Adverse event; ALT  Alanine aminotransferase; AST  Aspartate aminotransferase; T3  Triiodothyronine; 
T4  Thyroxine; TSH  Thyroid-stimulating hormone.


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
175 (296)
Appendix B Table 3 Laboratory – hematology
Basophils
Monocytes
Eosinophils
Neutrophils
Hematocrit
Platelet count
Hemoglobin
Red blood cell count
Lymphocytes
Total while blood cell count
Mean corpuscular hemoglobin
Activated partial thromboplastin time
Mean corpuscular hemoglobin concentration
International Normalized Ratio
Mean corpuscular volume
Partial thromboplastin time 
Note: For coagulation parameters, activated partial thromboplastin time, partial thromboplastin time and 
international normalized ratio are to be assessed at baseline and as clinically indicated.
Note: absolute values of blood cells should be provided where possible rather than percentages (e.g. for white 
cell differential counts)
Appendix B Table 4 Laboratory – urinalysis
Bilirubin
Ketones
Blood
pH
Color and appearance
Protein
Glucose
Specific gravity
Note: Urinalysis must be done at baseline and then as clinically indicated.
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high power field for 
red blood cells.
6.1.2
ECG
A 12-lead safety ECG (paper ECG printout of 10 seconds for Investigator review) will be 
taken at screening and prior to dosing on day 1 of each study cycle. 
Triplicate ECG recordings should be taken within an approximate 5-minute period. Additional 
ECGs may be taken at any other time the Investigator deems necessary for safety during the 
administration period. The patients will rest for at least 10 minutes before the start of each 
recording and they must be in the same supine body position (maximum 30 degrees flexion in 
the hip and feet not in contact with the footboard) at the recording time point. 
The Investigator will judge the overall interpretation as normal or abnormal. If abnormal, it 
will be decided as to whether or not the abnormality is clinically significant or not clinically 
significant. The paper copy of each ECG reading will be retained with the patient’s completed 
source documents. Only overall evaluation (normal/abnormal) will be recorded in the eCRF. 
If there is a clinically significant abnormal unscheduled ECG finding during the treatment 


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
176 (296)
period, this should be recorded on the AE eCRF, according to standard AE collection and 
reporting processes (see Section 7). 
Attention should be paid to any detected increases in QTc interval. Patients who develop a 
single resting value of QTc interval of >450 msec/male and >470 msec/female or a shift from 
baseline of ≥60ms should stop taking AZD1775. Dosing can be resumed at a reduced dose 
after return of the resting QTc interval to pre-treatment status has been confirmed and 
correction of possible electrolyte imbalance has been made (see Appendix B Table ).
Monitoring of QTc, checking and correction of abnormal electrolyte levels and renal function 
are advised, especially in case of severe/prolonged diarrhoea.  If QTc increases markedly from 
baseline, but stays below the above limits, a cardiologist’s advice should be sought.
The concomitant use of ondansetron (known to prolong the QTc interval in rare cases, per 
labelling) should be taken into account when interpreting QTc changes.
6.2 Pharmacokinetics
6.2.1
Collection of blood pharmacokinetic samples 
Sparse PK samples will be collected for AZD1775 and CBDP during the study on Cycle 1 and 
at alternate cycles at the time points specified in Appendix B Table .   The date and actual 
time of the PK sample will be recorded.
Appendix B Table 5 PKs: Carboplatin and AZD1775 
Cycle 1, Cycle 3 and beyonda
Day 1
Day 3 a b
Timing
Predose 
End of infusion 
Pre-dose 
2-4 hr
PK sample for 
Carboplatin
X
X
PK samples for 
AZD1775
X
X
a
Alternate cycles (e.g Cycles, 3,5,7 etc.)
b
±15 minutes. 
PK  Pharmacokinetics
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual.
6.3 Efficacy Analysis
See Section 6.1 of the master protocol.
Efficacy in Arm B will be assessed using RECIST 1.1 criteria on images collected at baseline 
and then every 6 weeks ± 1 week until objective disease progression or off-study.  


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
177 (296)
It is important to follow the assessment schedule as closely as possible (see Appendix B 
Table 1).  If an unscheduled imaging assessment is performed and the patient has not 
progressed, every attempt should be made to perform the subsequent assessments at his or her 
next regularly scheduled imaging visit.
6.4 Biomarker analysis
Additional tumor based biomarkers that may be analyzed to investigate DNA damage/repair 
mechanisms related to AZD1775 include but are not limited to 
 
 
Whole blood samples will be collected for CTC analysis at predose on Cycle 1 Day 1, Cycle 2 
Day 1 and End of Treatment.  Details for processing, handling, and shipping are provided in 
the Laboratory Manual.
In addition, select samples taken for collection of 
 may be processed to generate 
circulating tumor DNA or blood samples may be collected in Streck DNA BCT tubes, and 
processed to isolate 
.  Additional samples may be taken to generate circulating mRNA 
for storage and subsequent analyses.  
 
 
7.
SAFETY REPORTING AND MEDICAL MANAGEMENT
Please refer to Section 7 of the master protocol for details of reporting AEs, SAEs, AEs of 
special interest, paternal exposure, and management of investigational product (IP) related 
toxicities applicable to all arms in the study.  Additional details for reporting AE, SAEs, AEs 
of special interest, paternal exposure, and management of IP-related toxicities applicable to 
Arm B are described below.
7.1 Reporting of adverse events
7.1.1
Time period for collection of adverse events
AEs and SAEs will be recorded from the time of informed consent, throughout the treatment 
period, and including the follow-up period (the follow-up period is 30 days after the last dose 
of study treatment of AZD1775 or CBDP).  SAEs occurring in the follow-up period should be 
reported in the usual manner. 
7.1.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last visit in the study are followed up 
by the Investigator for as long as medically indicated, but without further 
recording in the electronic case report form (eCRF).  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.
CCI
CCI
CCI
CCI


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
178 (296)
7.1.3
Reporting of serious adverse events
All SAEs must 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, Investigators or other site personnel must inform 
appropriate AstraZeneca representatives immediately or no later than 24 hours of when he or 
she becomes aware of it.
For fatal or life-threatening AEs for which important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel must 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).
In addition to standard SAE reporting process, the SCRI Innovations Safety Department will 
be notified about new SAE by sending automatic e-mail alert to SCRI Innovations SAE 
mailbox: CANN.SAE@SCRIInnovations.com.
Automatic e-mail alert about follow-up information for SAEs and information on non-serious 
AEs that become serious should also be sent to SCRI Innovations Safety Department as soon 
as it is available. 
The detailed SAE reporting process will be provided to the sites in the SAE reporting 
guidelines contained in the trial reference manual.
Investigators must report SAEs and follow-up information to their responsible Institutional 
Review Board (IRB) according to the policies of the responsible IRB.  For fatal or life 
threatening AEs where important or relevant information is missing, active follow up is 
undertaken immediately.
AstraZeneca or their representative will provide Regulatory Authorities, Ethics Committees, 
and Principal Investigators with clinical safety updates/reports according to local 
requirements.
7.1.4
Post study events
After the patient has been permanently withdrawn from the study, there is no obligation for 
the Investigator to actively report information on new AEs or SAEs occurring in former study 
patients after the armdesignated- number of days, or 30-day safety follow-up period.  
However, if an Investigator learns of any SAEs, including death, at any time after the patient 
has been permanently withdrawn from the study, and he/she considers there is a reasonable 
possibility that the event is related to the study treatment, the Investigator should notify 
AstraZeneca, Patient Safety, or its representative.


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
179 (296)
7.2 Pregnancy
7.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study treatment should be discontinued 
immediately.  Pregnancy itself is not regarded as an AE event unless there is a suspicion that 
the study treatment under investigation 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, the Investigator or other study center 
personnel must inform the appropriate AstraZeneca representatives within 1 calendar 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, and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
7.2.2
Paternal exposure
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) should be followed up and documented if possible.  To capture 
information about a pregnancy from the partner of a male patient, consent must be obtained 
from the male patient’s partner to collect information related to the pregnancy and outcome; 
the male patient should not be asked to provide this information. The outcome of any 
conception occurring should be followed up and documented.
7.3 Dose modifications and management of investigational product-related 
toxicities 
Guidelines for the management of hematological and non-hematological AEs for AZD1775 
and CBDP are described below.
Toxicity will be assessed utilizing the NCI Common Terminology Criteria for Adverse Event 
(CTCAE) version 4.03 unless otherwise specified.
Dose adjustments will be based on the organ system exhibiting the greatest degree of toxicity.  
Dose reductions or holds and initiation of supportive care are allowed as clinically indicated 
by the treating physician.  Any patient requiring a toxicityrelated- dose delay of more than 
28 days from the intended day of the next scheduled dose must be discontinued from the study 
unless there is approval from the Study Physician for the patient to continue.  If Day 1 
treatment with either AZD1775 or CBDP is interrupted, then both study medications will be 


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
180 (296)
delayed until the combination can be resumed.  See Appendix B Table and Appendix B 
Table for dose level reductions.
Appendix B Table 6 AZD1775 dose level reductions for toxicity
AZD1775 Starting Dosea
AZD1775
-1 level
AZD1775 
-2 level
225 mg BID
(5 doses over 2.5 days)
175 mg BID 
(5 doses over 2.5 days)
125 mg BID 
(5 doses over 2.5 days)
a
AZD1775 twice daily taken in 12 hour intervals over 2.5 days on Days 1-3
BID  twice daily
Appendix B Table 7 CBDP dose level reductions for toxicity
CBDP 
Starting Dosea
CBDP 
-1 level
CBDP 
-2 level
AUC 5
AUC 4
AUC 3
a
CBDP is administered on Day 1 of each 21-day cycle.
AUC  Area under the plasma drug concentration-time curve; CBDP  carboplatin
7.3.1
Dose modifications due to hematologic-related adverse events 
Hematologic panel (complete blood counts, 5-part differential [neutrophils, lymphocytes, 
monocytes, basophils and eosinophils], and platelets) will be obtained for all patients at the 
beginning of each treatment cycle (Day 1) and reviewed prior to dose administration.  If 
hematologic toxicity occurs (Appendix B Table 8), treatment should be held and ANC and 
platelets should be monitored at least weekly until recovery.  Patients should be managed as
medically indicated. Treatment should not be resumed until recovery to Grade 1 (ANC ≥1.5
x 109/L or 1,500/ μL; platelets ≥75,000/ μL).
Appendix B Table 8 Hematologic dose modifications and management
Neutrophil and Platelet Blood Counts and Study Drug Action 
Neutrophil 
count
Action 
AZD177
5
Action 
chemo 
2nd 
event
Action 
AZD177
5
Action 
chemo
3rd 
event
Action 
AZD177
5
Action 
chemo
Grade 2 
<1.5-1.0 
x109/L
Hold
Resume 
at same 
dose
Hold
Resume 
at same 
dose
Hold
Resume 
at DL-1
Hold
Resume at 
same dose
Hold
Resume 
at DL-2
Hold
Resume at 
DL-1
Grade 3
<1.0-0.5 
x109/L
Hold
Resume 
at DL-1
Hold
Resume 
at same 
dose
Hold
Resume 
at DL-2
Hold
Resume at 
DL-1
Hold
Resume 
at DL-2
Hold
Resume at 
DL-2


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
181 (296)
Neutrophil and Platelet Blood Counts and Study Drug Action 
Grade 3
<1.0-0.5 
x109/L with 
documente
d infection 
and/or 
fever
Hold
Resume 
at DL-1
Hold
Resume 
at DL-1
Hold
Resume 
at DL-2
Hold
Resume at 
DL-2
Hold
Contact 
Medical 
Monitor
Hold
Contact 
Medical 
Monitor
Grade 4
<0.5 x109/L
Hold
Resume 
at DL-1
Hold
Resume 
at DL-1
Hold
Resume 
at DL-2
Hold
Resume at 
DL-2
Discontin
ue and 
follow for 
disease 
progressi
on
Discontinue 
and follow 
for disease 
progression
Grade 4 
Febrile 
neutropenia 
or Grade 4  
Infection 
with 
neutropenia
Discontin
ue and 
follow for 
disease 
progressi
on
Discontin
ue and 
follow for 
disease 
progressi
on
Platelet
count
Action 
AZD177
5
Action 
chemo
2nd 
event
Action 
AZD177
5
Action 
chemo
3rd 
event
Action 
AZD177
5
Action 
chemo
Grade 2 
75,000-
50,000/ μL
Hold
Resume 
at same 
dose
Hold
Resume 
at same 
dose
Hold
Resume 
at DL-1
Hold
Resume at 
same dose
Hold
Resume 
at DL-1
Hold
Resume at 
DL-1
Grade 3
50,000-
25,000/ μL
Hold
Resume 
at DL-1
Hold
Resume 
at same 
dose
Hold
Resume 
at DL-2
Hold
Resume at 
DL-1
Hold
Resume 
at DL-2
Hold
Resume at 
DL-2
Grade 4
<25,000/ 
μL without 
any 
evidence of 
bleeding
Hold
Resume 
at DL-1
Hold
Resume 
at DL-1
Hold
Resume 
at DL-2
Hold
Resume at 
DL-2
Discontin
ue and 
follow for 
disease 
progressi
on
Discontinue 
and follow 
for disease 
progression
Thrombocy
topenic 
haemorrhag
e (gross 
occult 
bleeding) 
associated 
with 
platelet 
count 
<50,000/ 
μL
Discontin
ue
Discontin
ue


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
182 (296)
Neutrophil and Platelet Blood Counts and Study Drug Action 
a
If hematologic toxicity parameters do not recover within 28 days, the patient should be removed 
from the study treatment.
ANC  Absolute neutrophil count
Please consider using G-CSF in the event of severe neutropenia or febrile neutropenia 
according to institutional standards.
No more than two dose reductions will be allowed for any patient. Patients requiring further 
dose reduction due to toxicity must discontinue study treatment. Dose re-escalation is not
allowed. If the patient has concurrent neutropenia and thrombocytopenia, please follow the 
most conservative guidance in the table below and discuss with Medical Monitor AstraZeneca 
Study Physician as needed.
7.3.2
Dose modifications due to non-hematologic related adverse events 
Dose modifications for non-hematologic toxicities should be based on toxicities occurring 
during the previous cycle.  For toxicities that lead to a dose reduction, the dose will not be re-
escalated during subsequent cycles.  
Any patient who develops a Grade 3 or 4 non-hematologic toxicity that does not resolve to 
≤Grade 1 within 28 days should be discontinued from the study treatment.  However, if the 
Investigator determines that the non-hematologic toxicity was due to one study drug and not 
the other, treatment with the remaining study drug may continue as clinically appropriate.
Based upon the maximum non-hematologic toxicities experienced during the previous cycle, 
dose adjustments for subsequent cycles are to be made according to the criteria defined in 
Appendix B Table 9 (unless specified per unique toxicities as noted below).
Appendix B Table 9 Non-hematologic toxicity dose modification and management
Electrocardiogram QT corrected interval prolonged
QTc Value
CBDP
AZD1775
QTc 450-480 ms (males) or 
470-480 (females)
No dose modifications
Hold. Once QTc interval 
has returned to pretreatment 
status and correction of 
possible electrolyte 
imbalance has been made, 
resume at next lower dose 
level.
QTc 481-500 ms
No dose modifications
Hold. Seek cardiologist 
advice.


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
183 (296)
QTc ≥ 501 ms 
Discontinue treatment
Discontinue treatment
Shift from baseline of ≥
60ms
Discontinue treatment
Discontinue treatment
CTCAE version 4.03
CBDP
AZD1775 
Grade 0 - 2
No dose modification
No dose modification
Grade 3b,c,d
Holda
Holda
Grade 4b
Hold until toxicity resolves to 
Grade ≤1.  Resume with 1 dose 
level reduction
Hold until toxicity resolves to 
Grade ≤1.  Resume with 1 dose 
level reduction
Second repeat incidence 
of Grade 3 or 4 toxicity
(except nausea, 
vomiting, fatigue, 
malaise, lethargy, 
anorexia, alopecia)
Discontinue treatment
Discontinue treatment
Hepatic
CTCAE v4.03
CBDP
AZD1775 
Grade 1-2
No dose modification
No dose modification
Grade 3 or 4
(manifested as 
elevations in ALT, AST, 
ALP, or bilirubin)
Hold until resolves to Grade ≤1 or 
baseline, then resume CBDP with 
a 1 level dose reduction.  If not 
resolved within 28 days, 
discontinue CBDP.
Hold until resolves to Grade ≤1 or 
baseline, then resume study drug 
with a 1 level dose reduction.  If not 
resolved within 28 days, 
discontinue study drug.
Diarrhea or mucositis
CTCAE v4.03
CBDP
AZD1775 
Grade 1-2
No dose modification
No dose modification
Grade 3 or 4 (or 
requiring 
hospitalization)
Holda
Holda
Nephrotoxcity
CTCAE v4.03
CBDP
AZD1775 
Grade 0-1
No dose modification
No dose modification


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
184 (296)
a
Hold until toxicity resolves to ≤Grade 1 and then resume at the same dose with no 
modification. 
b
Dose reduction for nausea and vomiting should be made only if Grade 3 or Grade 4 toxicity 
occurs in spite of maximum anti-emetics.
c
For a Grade 3 pulmonary embolism, the dose should be held but the subsequent doses do not have 
to be reduced 1 dose level, at the Investigator’s discretion.   
d
Grade 3 electrolyte value(s) (ie, hypokalaemia) do not require a dose reduction once the 
electrolyte is ≤Grade 1. 
7.3.3
Non-hematologic toxicity management guidelines
7.3.3.1
Gastrointestinal system disorders
Gastrointestinal AEs including nausea, vomiting, and diarrhea have previously been 
associated with AZD1775 treatment.  These types of toxicities observed in AZD1775 studies 
are not unexpected for therapies that include full-dose chemotherapy.  Patients should 
therefore be closely monitored for signs of gastrointestinal AEs and, if necessary, they should 
be managed clinically with supportive treatment not limited to anti-emetics, IV hydration, and 
anti-diarrheal treatment as needed.  Weight should be carefully monitored with other vital 
signs and doses of AZD1775 adjusted accordingly.
Following the receipt of 3 SAEs of gastrointestinal haemorrhagic events from ongoing studies, 
this topic has been identified as a new important potential risk to be kept under close 
surveillance with immediate attention given to any case report received events.
7.3.3.2
Diarrhea
Due to frequent reports of diarrhea with AZD1775 administration, vigorous anti-diarrheal 
treatment loperamide (Imodium®) is required at the first onset of diarrhea, according to the 
American Society of Clinical Oncology guidelines.  Oral loperamide 4 mg should be 
administered every 2 hours until diarrhea-free for at least 12 hours.  The first dose of 
Grade ≥ 2
Hold until resolves to Grade ≤1 or 
baseline, then resume CBDP with 
a 1 level dose reduction.  If not 
resolved within 28 days, 
discontinue CBDP.
Holda
Neurotoxicity
CTCAE v4.03
CBDP
AZD1775 
Grade 1
No dose modification
No dose modification
Grade 2
Hold until toxicity resolves to 
Grade ≤1.  Resume with 1 dose 
level reduction.
No dose modification
Grade 3 or 4
Discontinue treatment
Discontinue treatment


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
185 (296)
loperamide could be lowered to 2mg if the diarrhoea is recurrent and if, in the opinion of the 
treating physician, the diarrhoea is not severe.
Patients should be instructed to notify the Investigator or research staff of the occurrence of 
bloody or black stools, symptoms of dehydration, fever, inability to take liquids by mouth, and 
inability to control diarrhea within 24 hours of using loperamide or other prescribed anti-
diarrhoeal medications.
If diarrhea is severe (ie, requiring IV rehydration) and/or associated with fever or severe 
neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed. Patients with 
severe diarrhea or any diarrhea associated with severe nausea or vomiting should be 
hospitalised for IV hydration and correction of electrolyte imbalances.
7.3.3.3
Nausea and vomiting
All patients must receive a 5-HT3 antagonist, ondansetron (ZOFRAN®) 8 mg PO BID or 
granisetron (KYTRIL®) 1 mg PO BID prior to each dose of AZD1775.  Additional doses of 5-
HT3 antagonist may be used if needed. In addition, dexamethasone 4 mg PO will be given 
with each AZD1775 dose, unless contraindicated or not well-tolerated.  Dexamethasone may 
be continued on further days of dosing, potentially at a lower dose. Dexamethasone or the 5-
HT3 antagonist may be given by IV.  Promethazine (PHENERGAN®), prochlorperazine 
(COMPAZINE®), and benzodiazepine may still be used as additional adjunctive treatments 
during AZD1775 therapy.  Please note: aprepitant [Emend] and fosaprepitant are not 
permitted due to known DDIs.
Patients should be strongly encouraged to maintain liberal oral fluid intake.
Suitable alternative medications may be used, with adequate justification, in those studies 
where the use of any of the above medications might interfere with other study procedures or 
are deemed insufficient. 
7.3.3.4
Motor neuropathy or muscle weakness
Any onset of Grade >2 motor neuropathy or Grade >2 muscle weakness should be evaluated 
by an electromyogram to rule out the possibility of chronic inflammatory demyelinating 
polyneuropathy (CIDP).  With a diagnosis of CIDP, the patient should be discontinued from 
study treatment.
7.3.3.5
Dose modifications for infusion reactions
Infusion reactions (eg, rash, urticaria, erythema, pruritus, bronchospasm, and hypotension) can 
occur with the agents used in this study.  There is increased risk of a reaction with CBDP.  
CBDP must be discontinued in patients experiencing a Grade 3 or 4 infusion reaction during 
treatment.
To identify the grade of a reaction, refer to the list below adapted from the General Disorders 
and Administration Site Conditions section of the NCI CTCAE version 4.03:


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
186 (296)
Grade 1: 
Mild transient reaction; infusion interruption not indicated; intervention not 
indicated
Grade 2: 
Therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (eg, antihistamines, nonsteroidal anti-inflammatory 
drugs, narcotics, IV fluids indicated for ≤24 hours)
Grade 3: 
Prolonged (eg, not rapidly responsive to symptomatic mediation and/or brief 
interruption of infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for other clinical sequelae.  Any 
infusion that is interrupted and not resumed within the visit will be considered 
a Grade 3 reaction.
Grade 4: 
Life-threatening consequences; urgent intervention indicated
7.3.3.6
QTc prolongation
The QTc interval will be measured in 12-lead ECGs at baseline and at the commencement of 
each treatment cycle; and an assessment made of the emergence, if any, of QTc prolongation.  
Serum electrolyte levels should be obtained at baseline and at commencement of each 
treatment cycle.
Checking and correction of abnormal electrolyte levels and renal function are advised, 
especially in case of diarrhoea.
The administration of AZD1775 with substances known to prolong the ECG QTc interval is 
not recommended.
Special note: The potential risk of concomitant use of AZD1775 with ondansetron (known to 
prolong the QTc interval) should be taken into account.
Dose modifications or discontinuations for patients experiencing QTc prolongations are 
summarized in Appendix B Table above.
8.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
8.1 Identity of investigational product(s)
Investigational product
Dosage form and strength
AZD1775
25 mg or 100 mg capsules
CBDP a
IV sourced locally
a
Under certain circumstances when local sourcing is not feasible, standard of care 
treatment may be supplied centrally through AstraZeneca


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
187 (296)
8.1.1
AZD1775
AstraZeneca will supply AZD1775 capsules for oral use.  The capsules will be supplied at 
2 strengths (100 and 25 mg) in high-density polyethylene bottles, which sufficiently protects 
the drug from light.  The different capsule strengths should not be combined in the same bottle 
at any time.  Additional information about the IP may be found in the IB.
AZD1775 225 mg is taken PO in approximately 12-hour intervals BID over 2.5 days on Days 
1 to 3 of each treatment cycle.  Treatment cycles are every 21 days.  AZD1775 should be 
taken with 8 ounces of water approximately 2 hours before or 2 hours after food.  All patients 
must take a 5-HT3 antagonist prior to each dose of AZD1775,  for example, ondansetron 8 mg 
PO BID or granisetron 1 mg PO BID.  The 5-HT3 antagonist may be given by IV if necessary.
If a patient misses 1 of the 2 daily doses according to schedule, the dose should be taken as 
soon as possible, but not more than 6 hours after the missed dose was scheduled.  If greater 
than 6 hours, the missed dose should be skipped, and the patient should take the next dose 
when scheduled.
If vomiting occurs after a patient takes the AZD1775 dose, the patient should be instructed  
not to retake the dose but to wait until the next scheduled dose of AZD1775.  If no dose is 
scheduled for the following day, the dose will not be ‘made up’.  If vomiting persists, the 
patient should contact the Investigator.  
8.1.2
Carboplatin
Area under the Curve (AUC) 5 IV Day 1 every 21 days
CBDP, at a dose calculated to produce an AUC of 5, will be administered by IV infusion 
according to institutional standards.  
The CBDP dose will be calculated using the Calvert formula based on the patient’s GFR, 
which is estimated by using the CrCl.  
Calvert formula: CBDP dose (mg) = target AUC × (GFR + 25)
The Food and Drug Administration (FDA) has recommended that physicians consider capping 
the dose of CBDP for the desired exposure (AUC) to avoid potential toxicity due to 
overdosing for all laboratories using the isotope dilution mass spectrometry derived serum
creatinine measurements.  Therefore, the maximum dose of CBDP should be based on a CrCl 
no greater than 125 mL/min for patients with normal renal function.  In these, CBDP can be 
safely dosed according to the instructions in the drug’s labelling.  Refer to the US FDA, 
Center for Drug Evaluation and Research website 
(http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/
ucm228974.htm) for more specific guidelines.


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
188 (296)
Cockcroft-Gault formula: 
CrCl (GFR) = [(140 – age) × (wt. in kg)] × (0.85 if female)
                       
(72 × serum creatinine [mg/dL])
Patients may receive prophylactic anti-emetic therapy for moderately emetogenic 
chemotherapy according to institutional standards, excluding aprepitant Emend.
Refer to the CBDP package insert for additional information.
8.2 Dose and treatment regimens
For Arm B, up to 20 eligible patients will be enrolled, and all patients will receive:
AZD1775 225 mg BID PO for 2.5 days from Day 1 + CBDP AUC 5 Day 1 IV; q3w until PD
Appendix B Figure 2
AZD1775 + carboplatin therapy dosing schedule
AZD1775 should be administered first, then followed by carboplatin infusion.
8.3 Labeling
Please refer to Section 8.3 of the master protocol for details regarding labelling applicable to 
all arms.  
8.4 Storage
Please see Section 8.4 of the master protocol.
8.5 Compliance
AZD1775 dosing compliance will be reviewed with the patient at the beginning of each new 
treatment cycle when AZD1775 is dispensed.  All patients will be required to complete a 
dosing diary, which must be returned to the clinic for review at each visit.  The patient should 
be instructed to record each date and time the dose(s) was taken in the dosing diary.  If a dose 


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
189 (296)
is missed, the reason must be noted in the diary.  A copy of the dosing diary is provided in the 
study reference materials.
Patients should be advised to return any unused AZD1775 in the original bottles, in addition 
to returning any empty bottles.
The administration of all study drugs (including IPs) should be recorded in the appropriate 
sections of the case report form (CRF).
8.6 Accountability
Please see Section 8.6 of the master protocol.
8.7 Concomitant and other treatments 
Please refer to Section 8.7 of the master protocol for details regarding concomitant and other 
treatments applicable to all arms.  Details regarding concomitant and other treatments 
applicable to Arm B are described below.
8.7.1
Prohibited concomitant medications

No formal clinical drug interaction studies have been performed with AZD1775.  An 
exploratory assessment of the effect of aprepitant on AZD1775 exposure in oncology 
patients suggests that there is a drug interaction between AZD1775 and aprepitant, as 
exposure to AZD1775 increased by ~60% when aprepitant was coadministered with 
AZD1775.  The observed increase in AZD1775 exposure is likely the result of 
CYP3A4 inhibition by aprepitant.  This increase in exposure is statistically significant.  
At the selected MTD, this increase may also be of clinical importance.  Therefore, 
concomitant treatment with aprepitant and fosaprepitant is not allowable per protocol 
until further evaluation.

Potent or moderate inhibitors or inducers of CYP3A4, sensitive CYP3A4 substrates, 
and CYP3A4 substrates with a narrow therapeutic window should be avoided until 
additional data on drug-drug interaction becomes available. The use of sensitive 
substrates of CYP3A4, such as atorvastatin, simvastatin and lovastatin, is prohibited in 
this study. As grapefruit and Seville oranges are known to contain moderate inhibitors 
of CYP3A4, these fruits or their products (including marmalade, juice, etc.) should be 
avoided while taking AZD1775.

In vitro data suggests that AZD1775 may also be a weak reversible inhibitor of 
CYP2C19.  Caution should be exercised with concomitant administration of AZD1775 
and agents that are sensitive substrates of CYP2C19, or substrates of this enzyme with 
narrow therapeutic range; refer to Appendix I for a list of sensitive substrates of 
CYP2C19, or substrates of this enzyme with narrow therapeutic range.


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
190 (296)

AZD1775 has been shown to be a weak inducer of CYP1A2 in vitro with a maximum 
measured response between donors of 39.9% to 93.1% (at 10 μM) and 18.6% to 32.5% 
(at 5 μM) of the positive control omeprazole (50 μM), respectively.  Given the nature 
of the AZD1775 dosing schedule, however, the risk of induction in the clinic is 
considered low.  No specific precautions are recommended at this time, except to be 
initially vigilant when using substrates of CYP1A2 with a narrow therapeutic range.

In vitro studies have shown that AZD1775 may be a substrate and inhibitor for human 
P glycoprotein (P-gp).  Caution should be exercised when agents that are inhibitors or 
substrates of P-gp are administered concomitantly with AZD1775 (see Appendix I).

Recent in vitro transporter studies have shown AZD1775 to be an inhibitor of breast 
cancer resistance protein (BCRP) [median inhibition concentration 5.1 µM].  This 
finding is particularly relevant for drugs administered PO where exposure is normally 
limited by BCRP-mediated efflux, in particular some statins.  Modeling has predicted a 
substantial increase in the exposure of atorvastatin when co-administered with 
AZD1775, and the use of atorvastatin is therefore prohibited in the current study.  
Other drugs where the disposition is mediated via BCRP should be administered with 
caution, dose modification considered, or substituted by an alternative drug.

Metformin should be used with caution.  AZD1775 has been shown to be an inhibitor 
of multi-antimicrobial extrusion protein (MATE) 1 and MATE2K transporters.  A drug 
interaction with substrates of either transporter cannot be ruled out, the most important 
substrate known to date being metformin.

Herbal preparations/medications are not allowed throughout the study.  These herbal 
medications include, but are not limited to: St. John’s wort, kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng.  Patients 
should stop using these herbal medications 7 days prior to first dose of AZD1775. 

Avoid concomitant use of strong CYP3A inhibitors and moderate CYP3A inhibitors: 
azole antifungals (ketoconazole itraconazole, fluconazole, and voriconazole), 
macrolide antibiotics (erythromycin and clarithromycin), cimetidine, HIV protease 
inhibitors, and nefazodone

Avoid concomitant use of strong CYP3A inducers and moderate CYP3A inducers: 
phenytoin, barbiturates, and rifampicin
8.7.2
Prohibited concomitant medications:  CBDP
CBDP has limited nephrotoxic potential, but concomitant treatment with aminoglycosides has 
resulted in increased renal and/or audiologic toxicity, and caution must be exercised when a 
patient receives both drugs.  Although peripheral neurotoxicity is infrequent, its incidence is 
increased in patients older than 65 years and in patients previously treated with cisplatin.  Pre-


Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
191 (296)
existing cisplatin-induced neurotoxicity does not worsen in about 70% of the patients 
receiving CBDP as secondary treatment.
8.7.3
Substances known to prolong the ECG QTc interval
The administration of AZD1775 with substances known to prolong the ECG QTc interval is 
not recommended. (See  Appendix I Disallowed Medications and Medications to be 
Administered with Caution).
Special note:    The potential risk of concomitant use of AZD1775 with ondansetron (known 
to prolong the QTc interval) should be taken into account.
8.7.4
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the CRF.
9.
STATISTICAL ANALYSES BY ASTRAZENECA
Please refer to Section 9 of the master protocol for details regarding statistical analyses 
applicable to all arms.  Additional details regarding statistical analyses applicable to Arm B 
are described below.
9.1Adverse events
AEs observed up to 30 days following discontinuation of study treatment or until the initiation 
of the first subsequent therapy following discontinuation of treatment (whichever occurs first) 
will be used for the reporting of AE summary tables.  This will more accurately depict AEs 
attributable to study treatment only, as a number of AEs up to 30 days following 
discontinuation of the study treatment are likely to be attributable to subsequent therapy.  
9.2 Study and data management by Astrazeneca
Please refer to Section 10 of the master protocol for details of study and data management.
10.
ETHICAL AND REGULATORY REQUIREMENTS
Please refer to Section 11 of the master protocol for details of ethical and regulatory 
requirements.


Clinical Study Protocol Appendix B1
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
192 (296)
APPENDIX B1 NEW YORK HEART ASSOCIATION CRITERIA
Stages of Heart Failure – New York Heart Association Classification
Class I (Mild) 
No Limitation of physical activity.  Ordinary physical activity does not cause undue fatigue,
palpitation, or dyspnea (shortness of breath).
Class II (Mild)
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, or dyspnea.
Class III (Moderate)
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary physical 
activity results in fatigue, palpitation, or dyspnea.
Class IV (Severe)
Unable to carry out any physical activity without discomfort.  Symptoms of cardiac 
insufficiency at rest. If any physical activity is undertaken, physical discomfort is increased.
Reference
The Criteria Committee of the New York Heart Association. Nomenclature and criteria for
diagnosis of diseases of the heart and great vessels. 9th ed. Boston (MA): Little Brown & 
Co;1994:253-256.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
193 (296)
APPENDIX  C ARM C: CERALASERTIB (AZD6738) + OLAPARIB 
SUB-PROTOCOL
1.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC
Area under the plasma drug concentration-time curve
AUC(0-∞)
Area under the plasma drug concentration-time curve time 0 to 
infinity
BCRP
Breast cancer resistance protein
BID
Twice daily
CBDP
Carboplatin
CIDP
Chronic inflammatory demyelinating polyneuropathy
Cmax,ss
Maximum plasma concentration at steady state
CrCl
Creatinine clearance
CRF
Case report form (electronic/paper)
CTCAE
Common Terminology Criteria for Adverse Event
CYP
Cytochrome P
DHEA
Dehydroepiandrosterone
DNA
Deoxyribonucleic acid 
DLT
Dose-limiting toxicity
DTIC
Dacarbazine chemotherapy
ECG
Electrocardiogram
eCRF
Electronic case report form
ECOG
Eastern Cooperative Oncology Group


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
194 (296)
Abbreviation or 
special term
Explanation
ED-SCLC
Extensive-stage small-cell lung cancer
5-FU
5-fluorouracil 
FDA
Food and Drug Administration
GFR
Glomerular filtration rate
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
IRB
Institutional Review Board
IP
Investigational product 
IR
Ionising radiation
IV
Intravenous
MATE
Multi-antimicrobial extrusion protein
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
p53
Tumor protein 53 (protein product of TP53 gene)
P-gp
P glycoprotein
PD
Progressive disease
PFS
Progression-free survival
PO
By mouth
PK
Pharmacokinetic(s)
PR
Partial response
q3w
Every 3 weeks
q4w
Every 4 weeks
q6w
Every 6 weeks
q12w
Every 12 weeks


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
195 (296)
Abbreviation or 
special term
Explanation
RECIST 1.1
Response Evaluation Criteria in Solid Tumors
SAE
Serious adverse event 
SD
Stable disease
SCLC
small cell lung cancer
TP53
Gene encoding tumour protein 53
ULN
Upper limit of normal
WoCBP
Women of childbearing potential


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
196 (296)
2.
INTRODUCTION
2.1 Background and rationale for conducting this study
Study D419QC00002 is an open-label, multicenter,  multiarm, Phase II study in patients with 
extensive-stage small cell lung cancer (ED SCLC) who have refractory or resistant disease, 
defined as patients who progress during first-line platinum based chemotherapy or those who 
progress within 90 days after completing first-line platinum based chemotherapy.  Study 
D419QC00002 is modular in design, allowing evaluation of the safety, tolerability, 
pharmacokinetics (PK) and anti tumor activity of different combinations of novel anti cancer 
agents in patients with refractory or resistant ED-SCLC, and will consist of a number of study 
arms, each evaluating the safety and tolerability of a specific combination. 
Arm C in Study D419QC00002 investigates the efficacy, safety, and tolerability of 
ceralasertib (PO), an inhibitor of the ataxia telangiectasia and RAD3-related kinase (ATR), in 
combination with olaparib (PO), trade name Lynparza, in ED SCLC patients. 
Small cell lung cancers (SCLCs) harbor multiple genomic alterations involved in cell cycle 
regulation, oncogenic signaling, and double-strand break repair.  The most common genetic 
alterations in SCLC occur in: TP53 (90%), retinoblastoma 1 (RBI, 85%) (Byers et al 2012), 
MYC (cMYC, MYCN, and MYCL1, ~5% each), RAS (2%), and BRCA1/2 (3%).  These 
alterations, and in particular, combinations of these alterations, force cancer cells to depend on 
the G2-M checkpoint for restoring cell cycle function and division.  It is estimated that 18% of 
SCLCs harbor mutations in cell cycle regulation (TP53) and in oncogenic signalling (MYC or 
RAS).  Likewise, 3% of SCLCs harbor mutations in both cell cycle regulation (TP53) and 
DSB repair (BRCA1/2).
ATR is an apical kinase in one of the DNA-damage induced checkpoint pathways that is 
crucial for the cell’s response to replication stress (RS) (reviewed in Marechal and Zou 2013). 
RS occurs when replication forks stall due to unrepaired DNA strand breaks or the presence of 
covalent adducts formed by reactive metabolites or xenobiotics, including chemotherapies, 
generating segments of single-stranded DNA that is coated by replication protein A (RPA). 
RPA recruits ATR to sites of replication stress, furthing stalling fork progression and firing of 
new replication origins, and allowing the damaged DNA to be repaired. Any treatment that 
causes RS, increases dependence on ATR, and inhibition of ATR under such circumstances is 
expected to lead to mitotic catastrophe and cell death. Synergy with ATR inhibition is 
expected with various treatments, including ionizing radiation, overtly DNA damaging 
chemotherapy and other targeted agents, especially those that impact DNA damage repair. 
ceralasertib is a potent inhibitor of ATR kinase with a significant margin over structurally 
related kinases.
Olaparib is an inhibitor of poly-ADP ribose polymerase, an enzyme that is crucial for the 
repair of single strand DNA breaks as part of base excision repair (BER) (reviewed in 
O’Connor 2015). Inhibition of the PARP enzymes leads to the accumulation of single-strand 
DNA breaks, which if not repaired are converted to double strand DNA breaks during DNA 


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
197 (296)
replication. The accumulation of double strand DNA breaks by treatment with olaparib 
activates the cell’s repair machinery and tumours that are defective in the detection and repair 
of double strand DNA breaks, such as those with BRCA1 or BRCA2 gene mutations, are 
exquisitively sensitive to olaparib. In contrast, non-tumour cells have normally functioning 
double strand DNA break repair and are much less sensitive to olaparib driving an anti-tumour 
effect while sparing toxicity in healthy tissues. Olaparib is now FDA approved in ovarian 
cancer in patients with BRCA1 or BRCA2 mutated disease and who have received prior 
platinum-based therapy.
The combination of ceralasertib,  an ATR inhibitor, and olaparib is attractive because olaparib 
generates RS, thereby creating dependency on the DNA damage response that is driven by 
ATR (Murai et al 2012, Pommier et al 2016). In patients with tumours that are aggressively 
dividing and may have underlying DNA repair defects, such as those with small cell lung 
cancer, the combination effect of ceralasertib and olaparib in generating anti-tumour activity is 
expected to be even greater, (McCabe et al 2006, Lord et al 2015, Lord et al 2008, Turner et al 
2008, Bajrami et al 2014). 
 
 
 
 
 
2.2
Ceralasertib
Ceralasertib is a potent, selective inhibitor of the serine/threonine-specific protein kinase, 
ataxia telangiectasia and Rad3-related protein (ATR), with good selectivity against other 
phosphatidylinositol 3-kinase-related kinase (PIKK) family members (Foote et al 2013). This 
compound is being developed as an oral anti-tumour agent in patients with disease that is 
dependent upon ATR function for DNA repair; an example being tumours that are deficient of 
the serine/threonine-specific protein kinase, ataxia telangiectasia mutated (ATM). The focus 
of this study is to combine ceralasertib with olaparib, where the combination synergy 
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Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
198 (296)
observed in human cancer models, can be tested in patients with small cell lung cancer who 
are resistant or refractory to 1st line platinum-based therapy.
Ceralasertib shows growth inhibition activity as monotherapy against multiple cancer cell 
lines in vitro, but showed strongest activity in haematological cell lines and those with 
deficiencies in the ATM signalling pathway, as determined by the inability to phosphorylate 
ATM on Ser1981 (autophosphorylation) or CHK2 on Thr68 (Foote et al 2015, Vendetti et al 
2015, Kwok et al 2016, Yap et al 2016).  For example, activity against ATM-pathway 
deficient LoVo (MRE11A mutant) cells is 0.44 µM compared to ATM-proficient HT-29 cells 
at 2.6 μM. The preferential cellular activity of ceralasertib against LoVo cells compared to 
HT-29 cells translated through to in vivo xenograft efficacy studies in nude mice. 
Ceralasertibwas active as a monotherapy in vivo with selective dose-dependent activity against 
LoVo xenografts with 81% TGI at 50 mg/kg PO once daily x14 days versus 10% growth 
inhibition against HT29 xenografts.  These data indicate ceralasertib has enhanced growth 
inhibition activity against ATM-deficient tumours compared to ATM-proficient tumours as a 
monotherapy.
In addition to monotherapy activity, ATR inhibitors are also predicted to potentiate the 
activity of cytotoxic DNA damaging agents (through inhibition of ATR-dependent DNA 
repair processes) when used in combination.  In in vitro combination studies against cancer 
cell lines, ceralasertibshowed good synergistic potentiation of the cytotoxic activities of DNA-
damaging agents cisplatin, gemcitabine, melphalan and ionising radiation (IR) (see 
Investigator’s Brochure).  Combination studies against in vivo xenograft models in nude mice 
confirmed the in vitro findings with ceralasertib showing a dose-dependent, synergistic 
potentiation of Carboplatin or IR activity leading to enhanced growth inhibition and tumour 
regressions respectively.   
2.3 Olaparib
Olaparib (AZD2281, KU-0059436, Lynparza) is a potent Polyadenosine 5’diphosphoribose 
[poly (ADP ribose)] polymerisation (PARP) inhibitor (PARP-1, -2 and -3) that is being 
developed as an oral therapy, both as a monotherapy (including maintenance) and for 
combination with chemotherapy and other anti-cancer agents.  Olaparib has been approved  
for the following indications (wording from US prescribing information): 

the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian 
tube or primary peritoneal cancer, who are in a complete or partial response to 
platinum-based chemotherapy.

the treatment of adult patients with deleterious or suspected deleterious germline 
BRCA-mutated advanced ovarian cancer who have been treated with three or more 
prior lines of chemotherapy. Select patients for therapy based on an FDA-approved 
companion diagnostic for Lynparza.
PARP inhibition is a novel approach to targeting tumours with deficiencies in DNA repair 
mechanisms.  PARP enzymes are essential for repairing DNA single strand breaks (SSBs).  


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
199 (296)
Inhibiting PARPs leads to the persistence of SSBs, which are then converted to the more 
serious DNA double strand breaks (DSBs) during the process of DNA replication.  During the 
process of cell division, DSBs can be efficiently repaired in normal cells by homologous 
recombination repair (HR).  
, such as ovarian cancers in 
patients with BRCA1/2 mutations, cannot accurately repair the DNA damage, which may 
become lethal to cells as it accumulates.  In such tumour types, olaparib may offer a 
potentially efficacious and less toxic cancer treatment compared with currently available 
chemotherapy regimens. 
BRCA1 and BRCA2 defective tumours are intrinsically sensitive to PARP inhibitors, both in 
tumour models in vivo (Rottenberg et al 2008, Hay et al 2009) and in the clinic (Fong et al 
2009). The mechanism of action for olaparib results from the trapping of inactive PARP onto 
the single-strand breaks preventing their repair (Helleday 2011; Murai et al 2012).  Persistence 
of SSBs during DNA replication results in their conversion into the more serious DNA DSBs 
that would normally be repaired by HR repair.  Olaparib has been shown to inhibit selected 
tumour cell lines in vitro and in xenograft and primary explant models as well as in genetic 
BRCA knock-out models, either as a stand-alone treatment or in combination with established 
chemotherapies.
2.4 Rationale for study design, doses, and control groups
The rationale for the unmet medical need in refractory or resistant ED SCLC is described in 
Section 2.2.1 of the master protocol.  The rationale for the specific study design aspects of 
Arm C is described below.
2.4.1
Ceralasertib in combination with olaparib  
Tumor cells rely on cell cycle checkpoints for repair of DNA damage induced by cytotoxic 
and other agents. Olaparib inhibits the repair of single strand DNA breaks by trapping inactive 
PARP onto the DNA. While these single strand DNA breaks are converted into double strand 
DNA breaks during replication, they also cause replication stress (RS) triggering activation 
and dependence on ATR. As ceralasertib selectively inhibits ATR, it prevents stalling of 
replication forks and firing of new replication forks begins, causing cells to continue through 
S phase with incompletely replicated DNA, ultimately resulting in cell death through 
apoptosis. Non-clinical studies have demonstrated the synergy of ceralasertib+olaparib in vitro
and in vivo, and early signs of the clinical benefit of the combination are becoming apparent in 
the ingoing clinical study (recenty presented at the joint EORTC-NCI-AACR conference) 
(Yap et al 2016).
2.4.2
Clinical experience with ceralasertib
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Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
200 (296)
•
 
 
 
 
 
 
 
 
 
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Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
201 (296)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.4.3
Ceralasertib pharmacokinetic and pharmacodynamic data
 
  
 
 
 
 
 
 
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Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
202 (296)
 
 
2.4.4
Clinical experience with olaparib
This section lists those ADRs that are currently regarded as expected for regulatory reporting 
purposes.  A description of selected adverse reactions associated with olaparib are provided 
below. For full information on the ‘Emerging safety profile’ of olaparib and ceralasertib, refer 
to sections 5 and 6 of the respective IBs.
Olaparib monotherapy has been associated with laboratory findings and/or clinical diagnoses, 
generally of mild or moderate severity (CTCAE Grade 1 or 2) and generally not requiring 
treatment discontinuation.  
The safety profile is based on pooled data from 1248 patients treated with olaparib 
monotherapy in clinical trials in the therapeutic indication at the recommended dose.
The following adverse reactions have been identified in completed clinical trials with patients 
receiving olaparib monotherapy where patient exposure is known.  
Adverse Drug Reactions are organised by Medical Dictionary for Regulatory Activities 
(MedDRA) SOC and then by MedDRA preferred term in Appendix C Table 2.  Within each 
SOC, preferred terms are arranged by decreasing frequency and then by decreasing 
seriousness.  Frequencies of occurrence of adverse reactions are defined as: very common 
(≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to 
<1/1000); and very rare (<1/10,000) including isolated reports.
CCI


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
203 (296)
Appendix C Table 2 Adverse Drug Reactions reported in Clinical Trials with 
Olaparib
MedDRA SOC
MedDRA Term
CIOMS descriptor/ 
Overall Frequency 
(All CTCAE 
grades)
Frequency of 
CTCAE 
Grade 3 and 
above
Blood and 
lymphatic system 
disorders
Anaemiaa
Very common
Very common
Neutropeniaa
Common
Common 
Thrombocytopeniaa
Common
Common 
Leukopeniaa
Common
Common
Lymphopeniaa
Uncommon
Uncommon 
Immune system 
disorders
Rasha
Common
-
Hypersensitivitya
Uncommon
-
Dermatitisa
Uncommon
-
Metabolism and 
nutrition disorders
Decreased appetite
Very common
Uncommon 
Nervous system 
disorders
Dizziness
Very common
Uncommon 
Headache
Very common
Uncommon
Dysgeusia
Very common
-
Gastrointestinal 
disorders
Vomiting
Very common 
Common 
Diarrhoea
Very common 
Common 
Nausea
Very common 
Common 
Dyspepsia
Very common
-
Stomatitis
Common
Uncommon
Upper abdominal pain
Common
Uncommon 
General disorders
Fatigue (including asthenia) 
Very common 
Common 
Investigations
Increase in creatinine
Common
Uncommon
Mean corpuscular volume 
elevation
Uncommon
-
a 
Anaemia includes PTs of anaemia, haemoglobin decreased, red blood cell count decreased, and haematocrit 
decreased; Neutropenia includes PTs of neutropenia, granulocytopenia, granulocyte count decreased and 
neutrophil count decreased, febrile neutropenia and neutropenic sepsis; Thrombocytopenia includes PTs of 
thrombocytopenia, platelet count decreased and plateletcrit decreased; Leukopenia includes PTs of 
leukopenia and white blood cell count decreased; Rash includes PTs of rash, rash erythematous, rash 
generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, exfoliative rash and generalised 
erythema; Hypersensitivity includes PTs of hypersensitivity and drug hypersensitivity; Dermatitis includes 
PTs of dermatitis, dermatitis allergic and dermatitis. CIOMS  Council for International Organizations of 
Medical Sciences; CTCAE  Common Terminology Criteria for Adverse Events v.3.0; MedDRA  Medical 
Dictionary for Regulatory Activities; SOC  System organ class.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
204 (296)
2.4.4.1
Description of selected adverse reactions associated with olaparib 
monotherapy 
Haematological toxicity
Anaemia and other haematological toxicities are generally low grade (CTCAE Grade 1 or 2), 
however, there are reports of CTCAE Grade 3 and higher events.  Anaemia was the most 
common CTCAE Grade ≥3 adverse reaction reported in clinical studies with first onset 
generally reported in the first 3 months of treatment.  An exposure-response relationship 
between olaparib and decreases in haemoglobin has been demonstrated.  In clinical studies 
with olaparib, the incidence of CTCAE Grade ≥2 shifts (decreases) from baseline in 
haemoglobin was 20%, absolute neutrophils 15%, platelets 5%, lymphocytes 30% and 
leucocytes 20% (all % approximate).
The incidence of elevations in MCV from low to normal at baseline to above the upper limit 
of normal was approximately 55%.  Levels appeared to return to normal after treatment 
discontinuation and did not appear to have any clinical consequences.
Baseline testing, followed by monthly monitoring of complete blood counts is recommended 
for the first 12 months of treatment with olaparib, and periodically after this time to monitor 
for clinically significant changes in any parameter during treatment which may require dose 
interruption or reduction and/or further treatment.
Other laboratory findings
In clinical studies with olaparib the incidence of CTCAE Grade ≥2 shifts (elevations) from 
baseline in blood creatinine was approximately 15%.  Data from a double-blind placebo 
controlled study showed median increase up to 23% from baseline remaining consistent over 
time and returning to baseline after treatment discontinuation, with no apparent clinical 
sequelae; 90% of patients had creatinine values of CTCAE Grade 0 at baseline and 10% were 
CTCAE Grade 1 at baseline.
Nausea and vomiting
Nausea was generally reported very early, with first onset within the first month of olaparib 
treatment in the majority of patients.  Vomiting was reported early, with first onset within the 
first two months of olaparib treatment in the majority of patients.  Both nausea and vomiting 
were reported to be intermittent for the majority of patients.
Combination studies
Safety data from studies in which olaparib has been administered in combination with other 
agents are discussed in Section 2.5. The degree of bone marrow suppression observed in some 
patients in the combination studies has however been greater than would be expected with the 
chemotherapy agent alone, as per label information.  Myelotoxicity has been observed in 
studies evaluating olaparib with the following combination therapies: DTIC; carboplatin; 


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
205 (296)
paclitaxel; carboplatin + paclitaxel; gemcitabine; topotecan; cisplatin; doxorubicin, cisplatin + 
gemcitabine; or irinotecan.
The principal haematological toxicities observed have been neutropenia, thrombocytopenia 
and anaemia.  These findings are consistent with pre-clinical findings (Delaney et al 2000, 
Evers et al 2008, Menear et al 2008, Miknyoczki et al 2003, and Rottenberg et al 2008).
2.4.4.2
Adverse events of special interest for olaparib
Myelodysplastic syndrome/acute myeloid leukaemia 
The incidence of MDS/AML in patients treated in clinical trials with olaparib monotherapy, 
including long-term survival follow-up, was <1.5% and the majority of events had a fatal 
outcome.  All patients had potential contributing factors for the development of MDS/AML, 
having received previous chemotherapy with platinum agents.  Many had also received other 
DNA damaging treatments.  The majority of reports were in germline BRCA mutation carriers 
and some of the patients had a history of previous cancer or of bone marrow dysplasia.  If 
MDS and/or AML are confirmed while on treatment with olaparib, it is recommended that 
olaparib should be discontinued and the patient be treated appropriately.
New Primary Malignancies other than MDS/AML
New primary malignancies have been reported in <1% of patients.  There were other 
contributing factors/potential alternative explanations for the development of the new primary 
malignancy in all cases, including documented BRCA mutation, treatment with radiotherapy 
and extensive previous chemotherapy including carboplatin, taxanes, anthracyclines and other 
alkylating and DNA damaging agents.
Pneumonitis 
Pneumonitis has been reported in <1.0% patients treated with olaparib monotherapy in clinical 
studies.  Reports of pneumonitis had no consistent clinical pattern and were confounded by a 
number of pre-disposing factors (cancer and/or metastases in lungs, underlying pulmonary 
disease, smoking history, and/or previous chemotherapy and radiotherapy).  When olaparib 
was used in clinical studies in combination with other therapies there have been events with a 
fatal outcome.  If patients present with new or worsening respiratory symptoms such as 
dyspnoea, cough and fever, or an abnormal chest radiologic finding is observed, olaparib 
treatment should be interrupted and prompt investigation initiated.  If pneumonitis is 
confirmed, olaparib treatment should be discontinued and the patient treated appropriately.
2.4.5
Ceralasertib + olaparib combination therapy dose rationale
The combination of olaparib and ceralasertib has been administered to 59 patients with 
advanced malignancy with the goal of establishing the dosing schedule. The recommended 
phase 2 dose was established as 160 mg QD ceralasertib days 1-7 in combination with 300 mg 
BID olaparib on a 28 day cycle. The dosing schedule of olaparib (300mg twice daily each 
day) is the same as the licensed dose.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
206 (296)
The dosing schedule of ceralasertib was supported by the PK-PD model of thrombocytopenia, 
predicting a period of 21 days free of drug to achieve a full platelet recovery. The 
recommended dose 160 mg QD was predicted to maintain ceralasertib mean steady state 
concentrations above the estimated IC90 threshold (based on ATR enzyme inhibition assay in 
LoVo cells) and the GI90 threshold (based on the cellular growth inhibition activity in LoVo 
cells) across the full dosing interval i.e 24 h. Please refer to ceralasertib IB for further 
information around the in-vitro threshold values. In addition, this daily dose level was 
associated with a decrease in peripheral monocytes in most of the patients and the preliminary 
blood cell count data from D5330C00004 and D5330C00002 studies suggested this decrease 
to be ceralasertib specific and dose dependent (monocyte decrease was not observed with 
either single agent olaparib or durvalumab. Monocytes have been characterized as being 
deficient in DNA base excision repair and PARP1 expression (Bauer et al 2011), suggesting 
an on-target synthetic lethal effect of ceralasertib mediated ATR inhibition in this cell type. 
Utilizing the monocyte decrease as a quantitative measure of ceralasertib pharmacological 
activity, the recommended Phase 2 dose of 160mg QD D1-7 was driven by maintaining 
maximally active exposure consistent with manageable safety. 
2.4.6
Rationale for study endpoints
The rationale for study endpoints is provided in Section 2.2.3 of the master protocol.
2.5
Benefit/risk and ethical assessment
The unmet need in refractory or resistant ED SCLC is described in Sections 2.1 and 2.3 of the 
master protocol.  Additional information on the potential benefits of each agent (ceralasertib
and olaparib) and an assessment of the potential and known risks can also be found in the 
current IBs. Specific information relating to ceralasertib and olaparib is summarized below. 
2.5.1
Potential benefits
2.5.1.1
Ceralasertib
 
 
 
 
 
 
 
 
 
 
 
CCI


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
207 (296)
2.5.1.2
Olaparib
Olaparib was first approved by the FDA as a capsule formulation (400 mg twice daily) for the 
treatment of women with BRCA-positive advanced ovarian cancer following treatment with 3 
or more prior lines of chemotherapy. The new drug application (NDA) for olaparib tablets was 
granted FDA priority review as a maintenance therapy in relapsed patients with platinum-
sensitive ovarian cancer. These are the current licensed indications for olaparib:

For the maintenance treatment of adult patients with recurrent epithelial ovarian, 
fallopian tube, or primary peritoneal cancer, who are in complete or partial response 
to platinum-based chemotherapy

For the treatment of adult patients with deleterious or suspected deleterious 
germline BRCA-mutated advanced ovarian cancer who have been treated with 3 or 
more prior lines of chemotherapy. Select patients for therapy based on an FDA-
approved companion diagnostic for LYNPARZA
2.5.1.3
Ceralasertib + olaparib 
Ceralasertib in combination with olaparib is considered to have a positive benefit-risk profile 
for all patients with advanced cancer. Pre-clinical data suggest that olaparib synergises with 
ceralasertib to drive tumour regressions in a range of human cancers, irrespective of BRCA 
mutation status. Where tumour cells are dependent upon ATR for DNA repair through defects 
in HR or other DNA repair pathways e.g. ATM mutations, ceralasertib will increase tumour 
sensitivity to olaparib therapy; however, an effect in tumour cells that are proficient in DNA 
repair may also occur and therefore this study has been designed to allow the potential for 
assessment of efficacy across allcomers with ED-SCLC. 
 
 
 
 
 
 
 
 
 
2.5.2
Identified and potential risks
2.5.2.1
Ceralasertib
As of 17th July 2017, no ceralasertib monotherapy studies have been completed, and 
ceralasertib has been administered to approximately 49 subjects as monotherapy in ongoing 
studies D5330C00001, D5330C00004 and D5330C00002. Thrombocytopenia and anemia are 
considered expected events when ceralasertib has been given as monotherapy and 
haematological toxicities (thromobocytopenia, neutropenia and anaemia) when ceralasertib
has been given in combination with other myelosuppressive agents. Anaemia and fatigue are 
CCI


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
208 (296)
very common across the programme. Overall, such events were predictable from pre-clinical 
data and from what is known about the mechanism of action of ceralasertib and the 
combination drug olaparib. The observed toxicities in the clinical setting have been 
manageable with standard practice. None of the events have been fatal. 
No reproductive toxicology nor teratogenic studies have been conducted with ceralasertib to 
date, and it is unknown whether the drug is excreted in human milk.  Therefore, women of 
childbearing potential and men should agree to use adequate contraception prior to
commencing study treatment and for the duration of study participation and women who are 
breast feeeding are excluded from the study.  Both women and men should be fully informed 
of the lack of reproductive toxicity testing, and women must have a negative pregnancy test 
prior to enrolment. 
Please refer to Section 5.4 ‘emerging safety profile’of the current ceralasertib IB for complete 
list of events considered as identified risks, and Section 6 of IB ‘summary of data and 
guidance to investigators’ for information on the potential risks and risk mitigation strategy. 
2.5.2.2
Olaparib
Adverse laboratory findings and/or clinical diagnoses considered to be associated with 
administration of olaparib monotherapy include haematological effects (anaemia, neutropenia, 
lymphopenia, thrombocytopenia, MCV elevation and increase in blood creatinine), nausea and 
vomiting, decreased appetite, diarrhoea, dyspepsia, stomatitis, upper abdominal pain, 
dysgeusia, fatigue (including asthenia), headache and dizziness.  Most of these events were 
generally mild or moderate in intensity. 
In a relatively small number of patients, pneumonitis, MDS/AML and new primary 
malignancies have been observed.  Evidence from across the development programme for 
olaparib does not support a conclusion that there is a causal relationship between olaparib and 
these events.  These are important potential risks for olaparib and are being kept under close 
surveillance.
See the latest version of the IB for further information.
2.5.2.3
Ceralasertib + olaparib
See Section 2.4 for clinical experience with ceralasertib and olaparib. A number of potential 
safety signals have been identified on the basis of general toxicology, safety pharmacology, 
genotoxicity and clinical studies, which were predictable from pre-clinical studies and the mode 
of action of ceralasertib. Most of these signals have not been confirmed to be causally related 
to ceralasertib; some are considered potential risks which are being monitored in ongoing 
clinical trials e.g. gastrointestinal toxicity, hepatic toxicity. The principal risk associated with 
the ceralasertib + olaparib combination is exacerbation of haematologic toxicity which is 
considered an Adverse Drug Reaction or identified risk for ceralasertib. In addition, some 
clinical toxicities from ceralasertib overlap with those seen with olaparib use in humans e.g. 
anaemia, neutropenia, leukopenia, thrombocytopenia of potential prolonged duration. A small 
number of patients have been exposed to the combination, and a tolerable dose and schedule 


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
209 (296)
has been reached. Risk minimisation and detailed toxicity management guidelines are 
incorporated in the current protocol and the sponsor will continued to monitor the clinical and
nonclinical data for emerging safety information. The risks are manageable within current 
clinical practice with the measures already in place and do not change the benefit / risk profile 
for ceralasertib in the ongoing and planned clinical studies.
2.5.2.4
Summary benefit:risk statement
The safety profile of ceralasertib when combined with olaparib has been shown to be 
acceptable, and ceralasertib has shown activity in several tumor types in the clinical 
development program to date.  Considering the measures taken to minimse risk to patients 
participating in the Phase I and II clinical studies, the identified and potential risks associated 
with ceralasertib in combination with olaparib are justified by the anticipated benefits that 
may be afforded to patients with relapsed SCLC. The overall benefit-risk evaluation supports 
the investigation of oral ceralasertib and olaparib in patients with platinum resistant and 
refractory ED-SCLC according to this clinical protocol.
3.
STUDY DESIGN 
Arm C will investigate the preliminary efficacy, safety, and tolerability of ceralasertib in 
combination with olaparib (both given PO) to patients who progress during first-line  
chemotherapy (platinum refractory) or those who progress within 90 days after completing 
first-line chemotherapy (platinum resistant) and have not received further treatment apart from 
first-line platinum-based chemotherapy. Patients should be enrolled within 90 days of 
progression in order to be accepted into the study.
For Arm C, up to 20 eligible patients will be treated, and all patients will receive:
•
ceralasertib 160 mg QD days 1-7 + olaparib 300 mg BID days 1-28; every 4 weeks 
(q4w)
Appendix C Figure 2
Study design
QD   once daily; ED-SCLC  Extensive-stage disease small-cell lung cancer; ORR  Objective response rate; OS  
Overall survival; PFS  Progression-free survival; PD Progression Disease  PO  By mouth; q4w  Every 4 weeks. 


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
210 (296)
4.
STUDY OBJECTIVES
4.1 Primary objective
See Section 3.1 of the master protocol.
4.2 Secondary objectives
See Section 3.2 of the master protocol.
4.3 Safety objectives
4.4 Exploratory objectives 
See Section 3.4 of the master protocol.  
5.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
5.1 Inclusion criteria
The complete set of inclusion criteria applicable to Arm C are described in this section. 
Patients should fulfil all inclusion criteria to to enter the study:
1.
Male or female ≥18 years at the time of screening.
2.
Ability to swallow and retain oral medication
3.
Written informed consent and any locally required authorization (eg, Health 
Insurance Portability and Accountability Act in the US, EU Data Privacy Directive 
in the EU) obtained from the patient/legal representative prior to performing any 
protocol-related procedures, including screening evaluations.
4.
Histologically or cytologically documented extensive disease American Joint 
Committee on Cancer Stage IV SCLC (T any, N any, M1 a/b) at initial diagnosis, 
also including patients with:


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
211 (296)

T3-4 due to multiple lung nodules that are too extensive or have tumor/nodal 
volume that is too large to be encompassed in a tolerable radiation plan.

Biopsy-proven mixed SCLC and NSCLC histology

Brain metastases; must be asymptomatic or treated and stable off steroids and 
anti-convulsants for at least 1 month prior to study treatment. Patients with 
suspected brain metastases at screening should have a computed tomography 
(CT)/magnetic resonance imaging (MRI) of the brain prior to study entry.
5.
Patients must have demonstrated progressive disease (PD) either during first-line 
platinum-based chemotherapy (platinum refractory) or within 90 days of 
completing platinum-based chemotherapy (platinum resistant), and have not 
received further treatment apart from first-line platinum-based chemotherapy. 
Patients should be enrolled within 90  days of progression in order to be accepted 
into the study.
6.
World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 0-1.
7.
At least 1 lesion, not previously irradiated, that can be accurately measured at 
baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have 
a short axis ≥15 mm) with CT or MRI and that is suitable for accurate repeated 
measurements as per RECIST 1.1 guidelines. 
8.
Willingness and ability to comply with study and follow up procedures.
9.
Life expectancy of at least 8 weeks.
10.
Patients must have adequate organ and bone marrow function measured within 28 
days prior to treatment as defined below:
Haemoglobin (Hb) ≥ 10.0 g/dL with no blood transfusions (packed red blood cells) 
in the past 28 days

Absolute neutrophil count (ANC) ≥1.5 x 109 / L without the use of G-CSF

Platelet count ≥ 100 x 109/L with no platelet transfusion in the past 28 
days

Total bilirubin ≤ 1.5 x institutional upper limit or normal (ULN) unless 
the patient has documented Gilbert’s Syndrome

Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 2.5 
x institutional ULN unless liver metastases are present in which case they 
must be ≤ 5 x ULN


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
212 (296)

Patients must have a creatinine clearance (CrCl) estimated using the 
Cockcroft-Gault equation of ≥ 51 mL/min:
Estimated CrCl = (140−	
[	])  
ℎ (
)  ()	
 	 (
/) 72
a where F=0.85 for females and F=1 for males
11.
Evidence of post-menopausal status or negative urinary or serum pregnancy test for 
female pre-menopausal patients.  Women will be considered post-menopausal if 
they have been amenorrheic 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 amenorrheic for 12 months or more following cessation of 
exogenous hormonal treatments and if they have luteinizing hormone and 
follicle-stimulating hormone levels in the post-menopausal range for the 
institution or underwent surgical sterilization (bilateral oophorectomy or 
hysterectomy).

Women ≥50 years of age would be considered post-menopausal if they 
have been amenorrheic for 12 months or more following cessation of all 
exogenous hormonal treatments, had radiation-induced oophorectomy 
with last menses >1 year ago, had chemotherapy-induced menopause 
with >1 year interval since last menses, or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).
12.
Women of childbearing potential and their partners, who are sexually active, must 
agree to the use of 2 highly effective forms of contraception in combination from 
the signing of the informed consent, through the period of taking study treatment
and for at least 1 month after last dose of study drug (s), or they must totally / truly 
abstrain from any form of sexual intercourse (as described in  Appendix G).
13.
Male patients must use a condom during treatment and for 6 months after the last 
dose of study drug(s) when having sexual intercourse with a pregnant woman or 
with a woman of childbearing potential. Female partners of male patients should 
also use a highly effective form of contraception (see Appendix G) for 6 months 
after the last dose of study drug(s) if they are of childbearing potential.
5.2 Exclusion criteria 
The complete set of exclusion criteria applicable to Arm C  are described in this section. 
Patients should not enter the study if any of the following exclusion criteria are fulfilled:


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
213 (296)
1.
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
2.
Previous enrollment in the present study.
3.
Participation in another clinical study with an investigational product (IP) during the last 
4 weeks.  
4.
Concurrent enrollment in another clinical study unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study.
5.
Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of IP.  Note: Local surgery of isolated lesions for palliative intent is acceptable 
where this does not affect assessment of target lesions. 
6.
Any condition that, in the opinion of the Investigator, would interfere with the evaluation 
of the IP or interpretation of patient safety or study results. This includes but is not limited 
to: ongoing or active infection, including any patient known to have hepatitis B, hepatitis 
C and human immunodeficiency virus (HIV), any evidence of severe or uncontrolled 
systemic diseases e.g. symptomatic congestive heart failure, uncontrolled hypertension, 
unstable angina pectoris, cardiac arrhythmia, severe COPD, severe Parkinson’s disease, 
active inflammatory bowel disease; active bleeding diatheses, renal transplant or 
psychiatric illness/social situations that would limit compliance with study requirement, 
substantially increase risk of incurring AEs from the study medications, or compromise 
the ability of the patient to give written informed consent. Screening for chronic 
conditions is not required.
7.
Past medical history of interstitial lung disease, drug-induced pneumonitis, radiation 
pneumonitis that required steroid treatment, or any evidence of clinically active interstitial 
lung disease.
8.
History of hypersensitivity to active or inactive excipients of any investigational drug in 
the study or drugs with a similar chemical structure or class to those investigated in the 
study.
9.
History of another primary malignancy except for:

Malignancy treated with curative intent and with no known active disease 
≥5 years before the first dose of study drug and of low potential risk for 
recurrence

Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease

Adequately treated carcinoma in situ without evidence of disease (eg, 
cervical cancer in situ)


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
214 (296)
10. History of leptomeningeal carcinomatosis.
11. A diagnosis of ataxia telangiectasia
12. Cytotoxic chemotherapy within 21 days of Cycle 1 Day 1 is not permitted (a shorter 
duration of five half times is allowed for patients treated with non-cytotoxic drugs). 
Exposure to a small molecule IP within 30 days or 5 half-lives (whichever is longer) prior 
to Cycle 1 Day 1. The minimum washout period for immunotherapy is 42 days.
13. Previous treatment with a PARP inhibitor (including olaparib) or ATR inhibitor.
14. With the exception of alopecia, any unresolved toxicities from prior therapy ≥ Common 
Terminology Criteria for Adverse Events (CTCAE) grade 2. Patients with Grade ≥2 
neuropathy will be evaluated on a case-by-case basis after consultation with AstraZeneca 
Study Physician
15. Spinal cord compression or brain metastases unless asymptomatic, stable and not 
requiring steroids for at least 4 weeks prior to start of study treatment
16. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. 
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). See Appendix I
Disallowed Medications and Medications to be Administered with Caution for list of 
CYP3A inhibitors. The required washout period prior to starting study treatment is 2 
weeks.
17. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or 
moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). See Appendix I
Disallowed Medications and Medications to be Administered with Caution for list of 
CYP3A inducers. The required washout period prior to starting study treatment is 5 
weeks for enzalutamide or phenobarbital and 3 weeks for other agents.  Patients should 
stop using herbal remedies 7 days prior to the first dose of study medication and for the 
duration ot the trial.
18. Persisting (> 4 weeks) severe pancytopenia due to previous therapy rather than disease 
(ANC < 0.5 x 109/L or platelets < 50 x 109/L)
19. Cardiac dysfunction as defined as: Myocardial infarction within six months of study 
entry, NYHA Class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias 
or known reduced LVEF < 55%
20. Any of the following cardiac criteria:


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
215 (296)

Mean resting corrected QT interval (QTc) >470 msec obtained from 3 
electrocardiograms (ECGs) in 24 hours using the Fredericia formula

Any clinically important abnormalities in rhythm, conduction or 
morphology of resting ECG (e.g., complete left bundle branch block, 
third degree heart block)

Any factors that increase the risk of QTc prolongation or risk of 
arrhythmic events such as heart failure, hypokalaemia, congenital long 
QT syndrome, immediate family history of long QT syndrome or 
unexplained sudden death under 40 years of age

Patients at risk of brain perfusion problems, e.g., carotid stenosis

Patients with relative hypotension (< 100/60 mm Hg) or clinically
relevant orthostatic hypotension, including a fall in blood pressure of 
>20mm Hg

Uncontrolled hypertension requiring clinical intervention
21. Refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant 
bowel resection, with clinically significant sequelae that would preclude adequate 
absorption of ceralasertib or olaparib.
22. Patients with uncontrolled seizures.
23. 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.
24. Radiation therapy to the chest and whole-brain irradiation must be completed at least 
4 weeks prior to start of study treatment, and patients must have recovered from any acute 
adverse effects prior to start of study treatment.  An exception to this is palliative 
radiotherapy with a limited field of radiation for palliation, which must be completed 
before the first dose of study treatment. In the case of palliative radiation to more than 
30% of the bone marrow or with a wide field of radiation this must also be completed at 
least 4 weeks prior to the first dose of study medication.
25. Intestinal obstruction or CTCAE grade 3 or grade 4 upper GI bleeding within 4 weeks 
before the dosing.
26. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features 
suggestive of MDS/AML.
27. Whole blood transfusions in the last 120 days prior to entry to the study (packed red 
blood cells and platelet transfusions are acceptable up to 28 days prior to commencing 
study drugs).


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
216 (296)
28. Pregnant females, female patients who are breast-feeding or male or female patients of 
reproductive potential who are not employing an effective method of birth control.
29. Persistent toxicities (> or = CTCAE grade 2) caused by previous cancer therapy, 
excluding alopecia and CTCAE grade 2 peripheral neuropathy.
5.3 Patient enrollment and randomization
See Section 4.3 of the master protocol.
5.3.1
Procedures for handling incorrectly enrolled or randomized patients
See Section 4.4 of the master protocol.
5.4 Methods for assigning treatment groups
Not Applicable.
5.5 Restrictions
5.5.1
Food Restrictions
It is not recommended to consume grapefruit juice while on olaparib therapy. When 
ceralasertib is administered in combination with olaparib, patients must fast as directed for at 
least 2 hours prior to the dosing and for at least 1 hour after the dose. When olaparib is given 
on its own, the olaparib tablet formulation can be given without regard to food.
5.5.2
Foetal risk
Olaparib is regarded as a compound with medium/high foetal risk. Women of childbearing 
potential (WoCBP) and their partners, who are sexually active, must agree to the use of TWO 
highly effective forms of contraception in combination throughout the period of taking study 
treatment and for at least 1 month after last dose of study drug(s), or they must totally/truly 
abstain from any form of sexual intercourse (see below).
Male patients and their partners, who are sexually active and of childbearing potential, must 
agree to the use of TWO highly effective forms of contraception in combination, throughout 
the period of taking study treatment and for 6 months after last dose of study drug(s) due to 
the unknown effects of the study drug on the sperm, or they must totally/truly abstain from 
any form of sexual intercourse (see below). Male patients should not donate sperm throughout 
the period of taking study treatment and for 6 months following the last dose of study drug(s). 
For definitions and lists of acceptable non-hormonal and hormonal birth control 
methods see Appendix G
Definition of Women of Childbearing Potential and Acceptable 
Contraceptive Methods.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
217 (296)
5.5.3
Concomitant treatments
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the Case Report Form.  In addition, any unplanned diagnostic, 
therapeutic or surgical procedure performed during the study period must be recorded in the 
CRF. Patients must comply with the concomitant treatment information described in the core 
study protocol and those described in the olaparib Investigators’ Brochure.
5.5.3.1
Women of childbearing potential 
Women of childbearing potential (WoCBP) may be included only if acceptable contraception 
is in place for 2 weeks before commencing study treatment for the duration of the study, and 
for 1month after the last dose of study drug.  Women of childbearing potential and their 
partners, who are sexually active, must agree to the use of TWO highly effective forms of 
contraception in combination (see Appendix G Definition of Childbearing Potential and 
Acceptable Contraceptive Methods), throughout the period of taking study treatment and for 
at least 1 month after last dose of study drug(s), or they must totally/truly abstain from any 
form of sexual intercourse.  Contraceptives that are prone to drug-drug interactions may not be 
effective due to a potential CYP3A4 interaction with ceralasertib. 
All WoCBP must have a negative pregnancy test during screening and within 3 days prior to 
starting each treatment cycle.
Male patients who are involved in the study must agree to avoid procreative and unprotected 
sex (ie, using acceptable forms of contraception as described in Appendix G) and must not 
donate sperm during the study and for 6 months after the last dose of study drug.  Where the 
female partner is pregnant or not using effective birth control, men should be advised to 
abstain while in the study and for 6 months after the last dose of study drug. 
Female partners, who are of childbearing potential, of men participating in the study will also 
be required to use effective contraceptive measures (detailed in Appendix G) while their 
partner is on study drug and for 6 months thereafter.
5.5.4
Photosensitivity
Patients are advised to take precautions when outside in the sun, e.g., limiting the duration of 
sun exposure, wearing protective clothing (hat and sunglasses) and sunscreen  
5.6 Discontinuation of investigational product
See Section 4.9 of the master protocol.
5.7 Criteria for withdrawal 
See Section 4.10 of the master protocol.  


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
218 (296)
5.8 Discontinuation of the study
See Section 4.11 of the master protocol.  
6.
STUDY PLAN AND TIMING OF PROCEDURES 
The procedures for the screening and the treatment periods in this study are presented 
in Appendix C Table 3
Schedule of assessment for olaparib + 
ceralasertib (AZD6738) combination therapy
.
  


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
219 (296)
Appendix C Table 3 Schedule of assessment for olaparib + ceralasertib (AZD6738) combination therapy
Screening
Cycle 1
Subsequent 
on 
treatment 
visits (every 
28 days)
Study 
treatment 
discontinued
30-day follow-
up after last 
dose of study 
medication
Follow up for 
progression 
and survival
Details in section
Visit Number
2
3
4
Visit No.5 
onwards
Day
-28 to -1
1
7
15
Cycle X, 
Day 1
Every 8 
weeksn
Visit Window
± 3d
up to 3 days 
prior to 
CXD1
up to 7 days 
after 
discontinuati
on
± 7d
± 7d
Informed consent
X
Appendix C section 
6.1
Optional Informed 
consent for Optional 
exploratory genetic 
sample
X
Appendix C section 
7.4.5
Optional Informed 
consent for Tumor 
Biopsy
X
Appendix C section 
6.1
Medical / surgical 
historya
X
Appendix C section 
6.1
Demographics
X
Appendix C section 
6.1
Smoking consumption
X
Appendix C section 
6.1
Inclusion/ Exclusion 
criteria
X
Appendix C 
sections 5.1  and 
5.2
Concomitant medications 
including blood 
transfusions
X
X
X
X
X
X
X
Section 8.7 of 
master protocol and 
Appendix C 
sections 5.5and 9.7


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
220 (296)
Screening
Cycle 1
Subsequent 
on 
treatment 
visits (every 
28 days)
Study 
treatment 
discontinued
30-day follow-
up after last 
dose of study 
medication
Follow up for 
progression 
and survival
Details in section
Visit Number
2
3
4
Visit No.5 
onwards
Day
-28 to -1
1
7
15
Cycle X, 
Day 1
Every 8 
weeksn
Visit Window
± 3d
up to 3 days 
prior to 
CXD1
up to 7 days 
after 
discontinuati
on
± 7d
± 7d
Adverse eventsb
X
X
X
X
X
X
X
Section 7 of master 
protocol and 
Appendix C section 
8
Vital signs (BP, pulse 
and temperature)
X
X
X
X
X
Section 6.2.4 of 
master protocol and 
Appendix C section 
7.1.2
Physical examination 
and weightc
X
X
X
X
X
Section 6.2.2 of 
master protocol and 
Appendix C section 
7.1.1
ECOG performance 
status
X
X
X
X
Section 6.3.1 of 
master protocol and 
Appendix C section 
7.1.1
Pregnancy testd
X
X
X
X
Section 6.2.1 of 
master protocol
Triplicate ECGe
X
X
X
X
X
Section 6.2.3 of 
master protocol and 
Appendix C section 
7.1.3
Haematology, 
coagulation, chemistry 
and urinalysisf
X
X
X
X
Xf
X
X
Section 7.1.4 of 
Appendix C


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
221 (296)
Screening
Cycle 1
Subsequent 
on 
treatment 
visits (every 
28 days)
Study 
treatment 
discontinued
30-day follow-
up after last 
dose of study 
medication
Follow up for 
progression 
and survival
Details in section
Visit Number
2
3
4
Visit No.5 
onwards
Day
-28 to -1
1
7
15
Cycle X, 
Day 1
Every 8 
weeksn
Visit Window
± 3d
up to 3 days 
prior to 
CXD1
up to 7 days 
after 
discontinuati
on
± 7d
± 7d
Hepatitis B, C and HIV
X
Section 6.3.2. of 
master protocol
Blood sample for 
Cytokines
X
X
X
X
Xm
Section 7.4.1 and 
7.4.2 of Appendix 
C
PK analysisg
X
X
Cycles 2 to 6 
only
Section 6.4 of 
master protocol and 
Appendix C section 
7.2
Blood samples for 
biomarker analysis:
plasma and PBMCs
isolated from whole 
blood
X
X
X
X
Xm
Section 6.6 of 
master protocol
Peripheral blood for 
X
X
Xm
Section 6.6.1.3of 
master protocol and 
Appendix C section 
7.4.1
Peripheral blood for 
X
X
Xm
Sections 6.6.1.2
and 6.6.1.3 of 
master protocol and 
Appendix C section 
7.4.2
mRNA
X
Appendix C section 
7.4.1
CCI
CCI


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
222 (296)
Screening
Cycle 1
Subsequent 
on 
treatment 
visits (every 
28 days)
Study 
treatment 
discontinued
30-day follow-
up after last 
dose of study 
medication
Follow up for 
progression 
and survival
Details in section
Visit Number
2
3
4
Visit No.5 
onwards
Day
-28 to -1
1
7
15
Cycle X, 
Day 1
Every 8 
weeksn
Visit Window
± 3d
up to 3 days 
prior to 
CXD1
up to 7 days 
after 
discontinuati
on
± 7d
± 7d
Tumour assessment 
(RECIST 1.1)h
X
First scan at 8 weeks, then 4 weeks later (i.e. at 12 weeks) and then every 8 weeks (all ± 1 
week), from the first day of investigational drug administration for the first 72 weeks, then 
every 12 weeks ± 1 week hereafter, until disease progression.
Section 6.1 of 
master protocol
Archival tissue (if 
availaible)i
X
Appendix C 
Section 7.4.3
Tumour biopsy with 
biomarker analyses 
(optional)j
X
X
Xm
Appendix C 
Section 7.4.4
Optional exploratory 
genetic sample (optional)
X
Appendix C 
Section 7.4.5
Ceralasertib and olaparib 
dispensing
X
X
Appendix C 
Section 9
Dispense/review/collect 
Dosing Diaryk
X
X
X
X
Appendix C 
Section 9
Dosing with ceralasertibl
Dosing once daily on Days 1-7 only
Appendix C 
sections 9.1.1. and 
9.2
Dosing with olaparibl
Continuous twice daily dosing
Appendix C 
sections 9.1.2 and 
9.2
Post discontinuation 
anticancer therapyo
X
NA


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
223 (296)
Screening
Cycle 1
Subsequent 
on 
treatment 
visits (every 
28 days)
Study 
treatment 
discontinued
30-day follow-
up after last 
dose of study 
medication
Follow up for 
progression 
and survival
Details in section
Visit Number
2
3
4
Visit No.5 
onwards
Day
-28 to -1
1
7
15
Cycle X, 
Day 1
Every 8 
weeksn
Visit Window
± 3d
up to 3 days 
prior to 
CXD1
up to 7 days 
after 
discontinuati
on
± 7d
± 7d
Survival status
X
Section 6.1.1 of 
master protocol
a    This should include any previous cancer therapies (including radiotherapy and respond to current chemotherapy regimen) as well as any history of blood transfusion  120 days prior to 
entry to the sudy, with reasons (e.g. bleeding or myelosuppression).
b    All ongoing AEs/ SAEs and any new AEs / SAEs identified during the 30 calendar day’s follow-up period after last dose of study medication must be followed up to resolution. 
c     Physical examination should be done as per schedule but does not need to be recorded in the eCRF after the baseline assessment (except for weight which should be collected at each 
visit). Any clinically significant changes not unequivocally related to disease progression should be recorded as AEs.Height will be measured at screening only.
d     Pregnancy tests using blood or urine samples will be performed for women of childbearing potential within 28 days prior to the start of study treatment, on Day 1 of the study prior to 
commencing treatment, on Day 1 of each subsequent cycle and at the follow-up visit 30 days after last dose of study medication. If results are positive, the patient must be discontinued from 
the study treatment immediately. Tests will be performed by the hospital’s local laboratory.
e    Triplicate ECG is required within 7 days prior to starting study treatment. All ECG assessments to be done in triplicate pre-dose on Cycle 1 Day 1 (additional baseline), within 1-2 hours 
of dosing on Day 7 of cycle 1, and Day 1 of every subsequent cycle, and on discontinuation of study treatment.
f      Lab tests include FBC, Coagulation, Clinical Chemistry, CRP, urinalysis (coagulation test and urinalysis should be performed at screening and only if clinically indicated thereafter).  
Safety blood samples should be assessed prior to starting a new cycle, ideally on the day dosing is planned, but within 3 days prior to dosing will be acceptable.
g     A common PK time window will be used for olaparib and ceralasertib in all patients: Cycle 1 Day 1: 1-3 hours, 3-6 hours and 6-12 hours post-dosing, Cycle 1 Day 7: pre-dose, 0.5-1 
hour, 1-3 hours, 3-6 hours and 6-12 hours post-dosing, and Cycle X Day 1: single sample at 1-6 hours post-dosing only
h     RECIST 1.1 assessments will be performed on images from CT (preferred) or MRI, each preferably with IV contrast of the chest, abdomen (including liver and adrenal glands), and 
pelvis.  Pelvic imaging is recommended only when primary or metastatic disease in the pelvic region is likely.  Additional anatomy should be imaged based on signs and symptoms of 
individual patients at baseline and follow-up.  Baseline assessments should be performed no more than 28 days before the date of enrollment and, ideally, should be performed as close as 
possible to and prior to the start of the initial dose of IP.  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.
i     Archival tissue collection if available, ideally 10 x 5 µm sections for sequencing
j     Optional biopsy can be taken in Cycle 1 between day 3 and day 8, up to 24 hours after the last dose of ceralasertib in that cycle. At study treatment discontinuation, the biopsy can be 
taken between 0 and 96 hrs post last dose.
k    Review ceralasertib and olaparib dosing compliance with the patient at the beginning of each new treatment cycle when study drug is dispensed.
l     Ceralasertib should be taken with approximately 8 ounces of water.  When ceralasertib is administered in combination with olaparib, patients must fast for at least 2 hours prior to the 
dosing and for at least 1 hour after the dose. When olaparib is given on its own, the olaparib tablet formulation can be given without regard to food.  Please note that the cycle length for 
ceralasertib + olaparib and olaparib monotherapy will be 28 days.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
224 (296)
m    Progression only
n
Following treatment discontinuation, assessments for survival must be made monthly for the first 3 months and then every 2 months thereafter.  
o
Details of any treatment for SCLC (including surgery) post the last dose of IP must be recorded in the eCRF.  At minimum, collect the start date and description of the subsequent 
anticancer therapy.
Note: All assessments on treatment days are to be performed prior to dosing, unless otherwise indicated.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
225 (296)
6.1 Enrollment/screening period
All screening and enrollment procedures will be performed according to the assessment 
schedule in Appendix C Table 3
Schedule of assessment for olaparib + ceralasertib 
(AZD6738) combination therapy
.  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.
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.  Optional informed consent for paired biopsies will also be 
obtained.  If laboratory or imaging procedures were performed for other reasons prior to 
signing consent, these can be used for screening purposes with consent of the patient.  
However, all screening laboratory and imaging results must have been obtained within 28 
days of enrollment.  All patients will have the option to provide consent to supply a sample of 
their tumor (archived or newly acquired biopsy) for entry into this study.  This consent is 
included in the main patient informed consent form.  
Screening/baseline evaluations may be performed over more than 1 visit.
The timing of vital sign assessments should be such that it allows the blood draw (eg, PK 
blood sample) to occur at the time points indicated in Appendix C Table 3 Schedule of 
assessment for olaparib + ceralasertib (AZD6738) combination therapy
.
6.2 Treatment period
All procedures to be conducted during the treatment period will be performed according to the 
assessment schedule (see Appendix C Table 3
Schedule of assessment for olaparib + 
ceralasertib (AZD6738) combination therapy
).
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 time points indicated in Appendix C Table 3
Schedule of 
assessment for olaparib + ceralasertib (AZD6738) combination therapy
.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
226 (296)
6.3 Follow-up period
All procedures to be conducted during the follow-up period will be performed according to 
the assessment schedule (see Appendix C Table 3
Schedule of assessment for olaparib + 
ceralasertib (AZD6738) combination therapy
).
A discontinuation assessment will be performed at the time investigational product is 
permanently discontinued.  In addition patients should be followed up for 30 days after the 
last dose of study treatment for any new reports of adverse events and other study 
assessments.  Patients should also be asked about concomitant medications at this follow-up. 
Patients will continue to be followed until disease progression.
7.
STUDY ASSESSMENTS
Please also refer to Section 6 of the master protocol for the study assessments applicable to all 
arms in the study.  Additional study assessments applicable to Arm C are listed below.
Prior to discharge from each in-patient and clinic visit, the Investigator or their deputy will be 
responsible for reviewing all available safety data, including vital signs and ECGs.
7.1.1
Physical examination
A complete physical examination with weight will be performed at the visits as indicated in 
the study plan and clinically indicated.  Height will be recorded at screening only. The 
following will be assessed: general appearance, respiratory, cardiovascular, abdomen, skin, 
head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, abdomen, 
musculo-skeletal (including spine and extremeities) and neurological systems. Clinically 
relevant worsening of physical examination findings will be recorded as AEs.
Performance status will be assessed at the visits as indicated in the study plan according to US 
ECOG criteria (see Section 6.3.1 of master protocol for ECOG assessment parameters).
7.1.2
Vital signs
Any changes in vital signs should be recorded as an AE if applicable.
7.1.2.1
Supine blood pressure and pulse rate 
Blood pressure and pulse rate will be assessed according to the study plan and as clinically 
indicated at any other time. 
Blood pressure and pulse rate will be measured preferable using a semi-automated BP 
recording device with an appropriate cuff size after 10 minutes rest.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
227 (296)
7.1.2.2
Body temperature
Body temperature will be measured in degrees Celsius at the visits indicated in the study plan.
7.1.3
ECG
Triplicate ECG recordings are required within 7 days prior to starting study treatment (i.e,
during screening), as well as at the times as shown in the study plan. 
Triplicate ECG recordings should be taken within an approximate 5-minute period.  
Additional ECGs may be taken at any other time the Investigator deems necessary for safety 
during the administration period. The patients will rest for at least 10 minutes before the start 
of each recording and they must be in the same supine body position (maximum 30 degrees 
flexion in the hip and feet not in contact with the footboard) at the recording time point. 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 and assess 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. For information on 
recording of AEs see Section 7.3. The original ECG traces must be stored in the patient 
medical record as source data.
A standardised ECG machine should be used and the patient should be examined using the 
same machine throughout the study, where feasible. ECGs will be recorded at 25 mm/sec. 
Attention should be paid to any detected increases in QTc interval. Patients who develop 
asingle resting value of QTc interval of >450 msec/male and >470 msec/female or a shift 
frombaseline of 60ms should stop taking the study treatment. Dosing can be resumed at a 
reduced dose after return of the resting QTc interval to pre-treatment status has been 
confirmed and correction of possible electrolyte imbalance has been made. Monitoring of 
QTc, checking and correction of abnormal electrolyte levels and renal function are advised, 
especially in case of severe/prolonged diarrhoea. If QTc increases markedly from baseline, but 
stays below the above limits, a cardiologist’s advice should be sought and Sponsor should be 
contacted for advice and notification. The concomitant use of ondansetron (known to prolong 
the QTc interval in rare cases, per labelling) should be taken into account when interpreting
QTc changes. 
7.1.4
Laboratory safety assessment
Blood and urine samples for safety assessments will be taken at the visits as indicated in the 
study plan. All laboratory assessments described will be performed at the local laboratories. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.
Laboratory tests do not need to be repeated at baseline if the baseline visit is within 3 days of 
the screening sample. The date, time of collection and results of each collection will be 
recorded in the appropriate CRF.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
228 (296)
Laboratory values that meet the criteria for CTCAE grade 3 or have changed significantly 
from baseline and are considered to be of clinical concern will be repeated/confirmed within 7 
days and followed up as appropriate.
The following laboratory variables will be measured:
Appendix C Table 4 Laboratory safety assessment
Clinical chemistry
Haematology
Serum (S)-Albumin
Blood (B)-Haemoglobin
B-Leukocyte
S-ALT
B-Absolute leukocyte differential count*
S/P-AST
Neutrophils
S-Alkaline phosphatase
Lymphocytes
S-Bilirubin, total
Monocytes
S-Calcium
B-Platelet count
S-Creatinine
B-Mean Cell Volume
S-Potassium
Coagulation**
S-Sodium
B-INR
S-Urea nitrogen or Urea
APTT
S– C-reactive protein
Urinalysis
S – total protein
Urine (U)-Protein/ Albumin
Pregnancy tests
U-Glucose
U-Blood/ Hb / Erythrocytes
*  If absolute differentials not available please provide % differentials
** Coagulation tests will be performed at screening and if clinically indicate. Each coagulation result will be 
recorded on the eCRF. Patients taking warfarin may participate in this study. 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.
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be retained at centre as source data for 
laboratory variables. For information on how AEs based on laboratory tests should be 
recorded and reported, see Section 7.3.7 in the master protocol. 
NB. In case a subject shows an AST or ALT ≥ 3xULN or total bilirubin ≥ 2xULN please refer 
to Appendix E ‘Actions required in cases of combined increase of aminotransferase and total 
bilirubin – Hy’s Law’ for further instructions.
Blood volumes can be found in the Laboratory Manual.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
229 (296)
7.1.5
Bone marrow or blood cytogenetic samples 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
haematological toxicities as defined in Section Management of prolonged haematological 
toxicities while on study treatment..
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.
7.2 Pharmacokinetics
7.2.1
Collection of pharmacokinetic samples
The following PK sampling will be performed on Cycle 1. 

Day 1; sampling times - 1-3 hours, 3-6 hours and 6-12 hours post-treatment

Day 7; sampling times - pre-dose and 0.5-1 hour, 1-3 hours, 3-6 hours and 6-12 
hours post-treatment.
The following PK samples will be performed on Day 1 of Cycles 2 to 6 only.

Cycle X, Day 1: Single sample 1-6 hours post treatment
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
The date and time of collection of each sample will be recorded in the medical notes and 
eCRF. All the post-dose samples collected within 10% of the scheduled time (e.g. ± 6 minutes 
for 60 minute sample) will be considered protocol compliant.
PK samples are to be taken as blood sample (4 mL) for determination of olaparib and 
ceralasertib concentrations in plasma. It is essential that PK blood sampling is conducted at 
the planned study timepoints. Patients should be instructed to fast and hold their morning dose 
of ceralasertib/olaparib on any day PK sampling is scheduled so it may have timed 
administration in the clinic. Any residual sample remaining after PK analysis has been 
performed may be used for exploratory biomarker research and characterisation of 
metabolites, if consent for this exploratory research has been obtained.
7.2.2
Determination of drug concentration in pharmacokinetic samples
Samples for determination of drug concentration will be analysed by Third party bioanalytical 
laboratory on behalf of AstraZeneca  Full details of the analytical methods used will be 
described in a separate bioanalytical report.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
230 (296)
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or six 
months after issuance of the draft Bioanalytical Report (whichever is earlier), unless requested
for future analyses.  Pharmacokinetic samples may be disposed of or destroyed and 
anonymised by pooling.  Additional analyses may be conducted on the anonymised, pooled 
PK samples to further evaluate and validate the analytical method. Any results from such 
analyses may be reported separately from the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Report.  Any residual back-up PK samples may be used for 
future exploratory biomarker research (in this case, residual back-up PK samples will be
shipped to the AZ biobank; see details in the Laboratory Manual).
7.3 Efficacy Analysis
See Section 6.1 of the master protocol.
Efficacy in Arm C will be assessed using RECIST 1.1 criteria on images collected at baseline 
and then at 8 weeks, then at 12 weeks and then every 8 weeks (all ± 1 week) for the first 72 
weeks and then every 12 weeks (± 1 week) thereafter, relative to the first day of 
investigational drug administration, up to objective disease progression by RECIST 1.1. After 
that, patients will then be followed for survival, regardless of whether study treatment is 
discontinued or delayed and/or protocol violations, unless they withdraw consent.
Categorisation of objective tumour response assessment will be based on the RECIST 1.1 
criteria of response: CR, PR, SD and PD. Target lesion (TL) progression will be calculated in 
comparison to when the tumour burden was at a minimum (ie, smallest sum of diameters 
previously recorded on study). In the absence of progression, tumour response (CR, PR, SD) 
will be calculated in comparison to the baseline tumour measurements obtained before starting 
treatment.
7.4
Biomarker analysis 
Biological samples (eg, archival tumour samples, tissue and/or blood) will be collected as 
detailed in the Laboratory Manual in order to carry out retrospective biomarker analysis to 
assess correlations with disease activity, effects of study drug, clinical outcomes and toxicity.  
7.4.1
 
 
  Such analysis may include, but is not restricted to:

 
 
CCI
CCI
CCI


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
231 (296)

 
 
 
Details of sample processing methods can be found in the study Laboratory Manual.
Results of these other exploratory analyses will not be reported in the CSR, but may be added 
in an appendix to the CSR.  No formal statistical analysis is planned.
7.4.2
Collection of peripheral blood for pharmacodynamic biomarker analysis
Peripheral blood samples will be collected and analyzed for downstream analysis of ATR 
pathway biomarkers that may include but are not limited to: 
 in purified 
peripheral blood mononuclear cells (PBMC) samples, possibly including 
 
.  Circulating soluble factors such as cytokines that may include but are not limited 
to GM-CSF, M-CSF and IFNγ may be assessed. Additional details of blood collection, shipping 
and storage of samples for biomarker assays can be found in the laboratory manual.
Peripheral blood samples will be collected for pharmacodynamic biomarker analysis at predose 
on Cycle 1 Day 1, 6 hours post dose on Cycle 1 Day 7, Cycle 1 Day 15,  Day 1 of each 
subsequent cycle and at End of Treatment.  Details for processing, handling, and shipping are 
provided in the Laboratory Manual.
In addition, blood samples will be collected in Streck DNA BCT tubes, and processed to isolate 
. Additional samples may also be taken to generate circulating mRNA for storage and 
subsequent analyses.  These samples will be used to assess the expression of genes and/or the 
presence of mutations in key driver genes and their association with response or resistance.
The timing of the pharmacodynamic biomarker samples may be adjusted during the study, 
dependent on emerging data, in order to ensure appropriate characterisation of biomarkers.
7.4.3
Collection of archival tumour samples
Formalin fixed tumour tissue embedded in paraffin blocks are optional for all dosed patients. 
If baseline biopsy samples can also be collected, retrieval of the archival diagnostic tumour 
material is still highly encouraged, to provide data on how the tumour has evolved since 
CCI
CCI
CCI
CCI


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
232 (296)
diagnosis. Archival samples from either primary or metastatic tumour will be accepted but 
tissue from the primary tumour is preferred. Tissue from the most recent biopsy would be 
preferred where a patient has archival tissue samples from multiple time points. 
Freshly prepared unstained slides (minimum 10, preferably 20), 4 micron sections from the 
archival tumour block are accepted if tumour blocks cannot be submitted, however tumour 
tissue blocks are preferred. Blocks will be repatriated to clinical sites upon request.
Details of sample collection, processing, shipping and storage will be described in the 
Laboratory Manual.
7.4.4
Collection of fresh biopsy samples
Collection of serial tumour biopsies will be encouraged during the study.  For patients with 
accessible tumours where patients’ consent has been obtained, a fresh tumour biopsy prior to 
first dose, following ceralasertib and olaparib treatment (on Cycle 1 Day 7), and following
progression will be analyzed for downstream effects on ATR pathway that may include but 
are not limited to biomarkers
, 
, 
  On-treatment biopsy timing may be 
refined with emerging pharmacokinetic and/or pharmacodynamic data during the course of the 
trial. Accessible lesions are defined as tumour lesions which are amenable to repeat biopsy, 
unless clinically contraindicated or the patient has withdrawn consent. Failure to obtain 
sufficient tumour sample after making best efforts to biopsy the tumour will not be considered 
a protocol deviation.
Details of sample collection, processing, shipping and storage are described in the Laboratory 
Manual.
7.4.5
 
 
 
 
 
Details on processes for collection and shipment and destruction of these samples can be 
found in 
 or in the Laboratory Manual.
CCI
CCI
CCI
CCI
C
CI CCI
CCI


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
233 (296)
7.5
Biological sampling procedures 
7.5.1
Volume of blood
The total volume of blood that will be drawn from each patient in this study during screening, 
treatment and follow-up is shown in the Laboratory Manual.
7.5.2
Handling, storage and destruction of biological samples
The samples will be used up, or disposed of after analyses or retained for further use as 
described below.
Any pharmacokinetic sample remaining after analysis for ceralasertib and its metabolites may 
be used for biomarker analyses.  These analyses are for AstraZeneca use only and will not be 
included in the Clinical Study Report.
Biological samples for future research will be retained at Sponsor or its designee for a 
maximum of 15 years following the finalisation of the Clinical Study Report. The results from 
future analysis will not be reported in the Clinical Study Report but separately in a Clinical 
Study Report Addendum, Scientific Report or Scientific Publication.
7.5.2.1
Pharmacokinetic samples
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples and reported in a separate bioanalytical report.
The results from the investigation will not be reported in the Clinical Study Report but 
separately in a bioanalytical report. 
7.5.2.2
Samples for exploratory research
Details of sample collection, processing, shipping and storage will be described in the 
Laboratory Manual.
Each sample for exploratory research will be identified with the study number and patient 
enrolment number.  In this way exploratory biomarker and genetic data may be correlated 
with clinical data, samples destroyed in the case of withdrawal of consent and regulatory audit 
enabled.
Where genetic analysis will be undertaken, no personal details identifying the individual will 
be available to any person (AstraZeneca employee or contract laboratory staff) working with 
the DNA.
7.5.3
Labelling and shipment of biohazard samples
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B (materials containing or 
suspected to contain infectious substances that do not meet Category A criteria), see Appendix 
D of this Clinical Study Protocol ‘IATA 6.2 Guidance Document’.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
234 (296)
Any samples identified as Infectious Category A materials are not shipped and no further 
samples taken from the patient unless agreed with AstraZeneca and appropriate labelling, 
shipment and containment provisions are approved.
All archival tumour samples should be shipped at ambient temperature as per the Laboratory 
Manual to the AstraZeneca designated central Contract Research Organisation. Please refer to 
section 6.6.5 of the master protocol for details about chain of custody of biological samples. 
7.5.4
Withdrawal of informed consent for donated biological samples
If a patient withdraws consent to the use of voluntarily donated biological samples, then the 
samples will be disposed of/destroyed, and the action documented.  If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research.
As collection of these biological samples is a voluntary part of the study then the patient may 
continue in the study.
The Principal Investigator:

Ensures AstraZeneca is notified immediately of the patient’s withdrawal of 
informed consent to the use of donated biological samples

Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action documented

Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the 
action documented and the signed document returned to the study site

Ensures that the patient and AstraZeneca are informed about the sample disposal
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the action 
documented and the document returned to the study site.
8.
SAFETY REPORTING AND MEDICAL MANAGEMENT
Please refer to Section 7 of the master protocol for details of reporting AEs, SAEs, AEs of 
special interest, paternal exposure, and management of investigational product (IP) related 
toxicities applicable to all arms in the study.  Additional details for reporting AE, SAEs, AEs 
of special interest, paternal exposure, and management of  IP related  toxicities applicable to 
Arm C are described below.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
235 (296)
8.1 Reporting of adverse events
8.1.1
Time period for collection of adverse events
AEs and SAEs will be recorded from the time of informed consent, throughout the treatment 
period, and including the follow-up period (the follow-up period is 30 days after the last dose 
of study treatment of ceralasertib and olaparib).  SAEs occurring in the follow-up period 
should be reported in the usual manner. 
8.1.2
Follow-up of unresolved adverse events
Please refer to Section 7.3.2 of the master protocol for details of follow-up of unresolved 
adverse events.
8.1.3
Reporting of serious adverse events
Please refer to Section 7.4 of the master protocol for details of reporting of serious adverse 
events.
8.1.4
Post study events
After the patient has been permanently withdrawn from the study, there is no obligation for 
the Investigator to actively report information on new AEs or SAEs occurring in former study 
patients after the arm designated  number of days, or 30 day safety follow-up period.  
However, if an Investigator learns of any SAEs, including death, at any time after the patient 
has been permanently withdrawn from the study, and he/she considers there is a reasonable
possibility that the event is related to the study treatment, the Investigator should notify 
AstraZeneca, Patient Safety, or its representative.
8.2 Pregnancy
8.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study treatment should be discontinued 
immediately.  Pregnancy itself is not regarded as an AE event unless there is a suspicion that 
the study treatment under investigation 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, the Investigator or other study center 
personnel must inform the appropriate AstraZeneca representatives within 1 calendar day (ie, 
immediately but no later than 24 hours of when he or she becomes aware of it).


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
236 (296)
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, and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
8.2.2
Paternal exposure
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) should be followed up and documented if possible.  To capture 
information about a pregnancy from the partner of a male patient, consent must be obtained 
from the male patient’s partner to collect information related to the pregnancy and outcome; 
the male patient should not be asked to provide this information.
8.3 Overdose of either olaparib or ceralasertib
There is no specific treatment in the event of olaparib or ceralasertib overdose, and no 
symptoms of overdose are established. In the event of overdose, physicians should follow 
general supportive measures and should treat symptomatically.
8.4 Dose modifications and management of investigational product related 
toxicities 
Guidelines for the management of hematological and non-hematological AEs for ceralasertib
and olaparib are described below.  Given the aggressive nature of relapsed or refractory SCLC 
and the lack of an effective standard of care in this clinical setting, doses of ceralasertib and 
olaparib will be modified by cycle (see Section 2.1 of the CSP).   Subsequent cycles will be 
further adjusted to patient tolerance and investigator judgement. 
Toxicity will be assessed utilizing the NCI Common Terminology Criteria for Adverse Event 
(CTCAE) version 4.03 unless otherwise specified. Every effort should be made to administer 
trial treatment at the planned dose and schedule. However, patients experiencing toxicities 
related to the trial treatment may have their dose modified as outlined in this section. 
Any toxicity observed during the course of the study could be managed by interruption of 
study treatment or dose reductions, and intiation of supportive care as deemed appropriate by 
the investigator. In the event that a patient has not recovered sufficiently to enable the next 
chemotherapy cycle to start, then the cycle should be delayed until the toxicity has recovered 
sufficiently to allow further dosage. The maximum cycle delay is permitted in 28 days. Repeat 
dose interruptions are allowed as required, for a maximum of 28 days on each occasion. Any 
patient requiring a toxicity related dose delay of more than 28 days from the intended day of 
the next scheduled dose must be discontinued from the study unless there is approval from the 
Study Physician for the patient to continue. 


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
237 (296)
If Day 1 treatment with either ceralasertib or olaparib is interrupted, then both study 
medications will be delayed until the combination can be resumed. Dose adjustments will be 
based on the organ system exhibiting the greatest degree of toxicity. 
8.4.1
Dose Reduction: Ceralasertib + Olaparib Combination
For ceralasertib, study treatment can be dose reduced according to the following dose 
modification table. A maximum of 2 dose reduction steps are permitted. If after the second 
dose reduction treatment is not tolerated, no further dose reduction is allowed, and study 
treatment should be discontinued. Dose re-escalation is not permitted. Further dose 
modifications are described in Appendix C Table 5 below.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
238 (296)
Appendix C Table 5 : Cohort C Guidance for dose reductions for ceralasertib and 
olaparib*
Dose Level
Ceralasertib
Olaparib
Initial dose level
160 mg QD Days 1-7
300 mg BID Days 1-28
1st dose reduction
Dose reduce either AZD6738 or Olaparib or Both
Haematological Toxicity
160mg QD Days 1-4
250 mg BID Days 1-28
Non-Haematological 
Toxicity
120mg QD Days 1-7
250 mg BID Days 1-28
2nd dose reduction
Dose reduce either Ceralasertib or Olaparib or Both
120 mg QDQ Days 1-4
200 mg BID Days 1-28
3rd dose reduction: No further reduction permitted, withdraw patient and treat as clinically indicated. 
Dose must not be re-escalated even if toxicities have resolved in subsequent cycles.
* Ceralasertib and olaparib may be reduced stepwise within each dose reduction level e.g., dose reduce olaparib 
first followed by ceralasertib if the AE recurs. Dose reductions for anaemia should occur for olaparib first (with 
consideration to a simultaneous dose reduction in ceralasertib depending on the severity, duration and recurrence 
of the anaemia). If a dose reduction is required for neutropenia, leukopenia and thrombocytopenia, olaparib and 
ceralasertib should be dose reduced simultaneously as there is a greater frequency associated with ceralasertib.
For a second dose-reduction, follow the guidance above on which of either, or both agents, to dose-reduce 
depending on the observed toxicity.
Appendix C Table 8 provides guidance for hematologic toxicity (neutropenia, leukopenia 
and thrombocytopenia) observed any time during the study treatment period. For Day 1 of 
each cycle please check the required blood counts to commence treatment in Appendix C 
Table 6.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
239 (296)
8.4.2
Management of Haematological Toxicities for Ceralasertib and Olaparib
Combination
Complete blood counts will be obtained for all patients at the beginning of each treatment 
cycle (Day 1) and should be checked by the Investigator prior to dosing the patient. If 
haematologic toxicity occurs treatment should be modified as below (Appendix C Table 6), 
and ANC and platelets should be monitored weekly (more often as clinically indicated until 
recovery). If haematologic parameters do not recover within 28 days, the patient should be 
removed from the study treatment.
Appendix C Table 6: Day 1 Haematologic dose modifications and management for 
ceralasertib plus olaparib combination
Treatment day blood counts and toxicity
ANC
Platelets
Action
≥1500/μL
And
≥100,000/μL 
No dose modification or 
interruption
<1500/μL
Or
<100,000/μL
Delay by 1week intervals 
until recovery
8.4.2.1
Management of Anemia
Common treatable causes of anaemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed. In some cases 
management of anaemia may require blood transfusions. For cases where patients develop 
prolonged haematological toxicity (≥2 week interruption/delay in study treatment due to CTC 
grade 3 or worse anaemia and/or development of blood transfusion dependence), refer to 
section below on Section 8.4.2.3 ‘Management of prolonged haematological toxicities while 
on study treatment’.
Appendix C Table 7: Management of anemia for ceralasertib plus olaparib combination
Haemoglobin
Action to be taken
Hb <10 but ≥8 g/dL (CTCAE Grade 2)
Give appropriate supportive treatment and 
investigate causality. 
Investigator judgement to continue study 
treatment with supportive treatment (eg 
transfusion) or interrupt dose for a maximum of 
4 weeks. 
If repeat Hb<10 but ≥8 g/dL, dose interrupt (for 
max of 4 weeks) until Hb ≥10 g/dL and upon 
recovery dose reduction to 250 mg BID as a first 
step and to 200 mg BID as a second step may be 
considered.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
240 (296)
Haemoglobin
Action to be taken
Hb <8 g/dL
(CTCAE Grade 3)
Give appropriate supportive treatment (eg, 
transfusion) and investigate causality. 
Interrupt study treatment for a maximum of 
4 weeks until improved to Hb ≥10 g/dL.
Upon recovery dose reduce to 250 mg BID as a 
first step and to 200 mg BID as a second step in 
the case of repeat Hb decrease.
Transfusion therapy may be required to maintain Hb levels >80g/L throughout the first three 
months of therapy to avoid dose reduction or interruption of olaparib. If a patient requires 
transfusions on a regular basis in the first 3 months, or cannot tolerate or be supported by 
transfusions, the dose of olaparib can be reduced.
8.4.2.2
Management of neutropenia, leukopenia and thrombocytopenia for 
ceralasertib plus olaparib combination
In the event of neutropenia, leukopenia or thrombocytopenia, ceralasertib and olaparib dosing 
should be halted until ANC and platelet count are restored to within the acceptable criteria:

ANC 1.5 × 109 /L

Platelets 100 × 109 /L
AEs 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.
Granulocyte colony-stimulating factor (G-CSF) should be used according to local prescribing 
guidance. Primary prophylaxis with 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 hospital guidelines.  Please note that G-
CSF should not be used within at least 24 hours (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.  List all interventions of these types into the 
appropriate CRF pages.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
241 (296)
Appendix C Table 8: Management of neutropenia, leukopenia and and 
thrombocytopenia 
Toxicity
Study treatment dose adjustment
CTCAE Grade 1-2
Investigator judgement 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 BID as a first step and 200 mg 
BID as a second step
8.4.2.3
Management of prolonged haematological toxicities while on study 
treatment.
If a patient develops prolonged haematological toxicity such as:

≥2 week interruption/delay in study treatment due to CTC grade 3 or worse anaemia 
and/or development of blood transfusion dependence

≥2 week interruption/delay in study treatment due to CTC grade 3 or worse 
neutropenia (ANC < 1 x 109/L)

≥2 week interruption/delay in study treatment due to CTC grade 3 or worse 
thrombocytopenia (Platelets < 50 x 109/L) and/or development of platelet 
transfusion dependence
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 haematologist for further investigations.  Bone marrow analysis 
and/or blood cytogenetic analysis should be considered at this stage according to standard 
haematological 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/acute myeloid leukemia 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.
Further details are provided in the Investigators Brochure. 


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
242 (296)
8.4.2.4
Management of non-haematological toxicity for ceralasertib and olaparib
Acute toxicities in the all treatment arms should be managed as medically indicated, with 
temporary suspension of IP and initiation of supportive care as clinically indicated by the 
treating physician. Treatment must be interrupted if any NCI-CTCAE Grade 3 or 4 non 
hematologic AE occurs which the Investigator considers to be related to the administration of 
the study treatment(s). Treatment should not be restarted until the toxicity has resolved to 
Grade ≤1. 
Repeat dose interruptions are permitted, for a maximum of 28 days. Any patient who develops 
a Grade 3 or 4 non-haematologic toxicity that does not resolve to ≤ Grade 1 within this period, 
should be removed from the study treatment. Once a dose is reduced, re escalation is not 
permitted. 
A summary of the dose reduction guidance for ceralasertib and olaparib is presented earlier.
At the first occurrence of CTCAE grade 3 and 4 non-haematological toxicity, ceralasertib and 
olaparib should be held until resolution of toxicity. At the resolution of the first occurrence of 
any of these toxicities, no change must be made to dose. At the second occurrence, upon 
resolution of toxicity, ceralasertib and/or olaparib should be reduced by the 1st dose reduction 
for non-haematological toxicity to 120 mg qd for 7 days and/or olaparib 250 mg BID q 12 
hours daily (Appendix C Table 5 and Appendix C Table 9) Despite this change, at the third 
occurrence, upon resolution of toxicity, ceralasertib and/or olaparib should be reduced by the 
2nd dose reduction to 120 mg qd for 4 days and 200 mg bid q 12 hours daily (Appendix C 
Table 5 and Appendix C Table 9). If despite these changes, there is a fourth occurrence of 
toxicity, the patient should permanently discontinue study drug. Please note that, for each dose 
reduction, the investigator may choose to reduce ceralasertib or olaparib or both drugs. If only 
one drug is dose reduced, the second drug may be reduced as an additional step. Refer to 
Appendix C Table 9 for specific dose modification guidance regarding non-haematological 
toxicity.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
243 (296)
Appendix C Table 9:  Summary of guidance on the management of non-haematologic 
toxicity for ceralasertib and olaparib
Toxicity
Ceralasertib and olaparib
Any non-haematologic 
toxicity (CTCAE grade ≥ 3)
1st occurrence
Withhold dose and monitor at least weekly for up to 28 
days until recovery to ≤CTCAE grade 1 then resume at 
original dose level. If a clinical CTCAE give supportive 
measures and rule out other causes; if a laboratory AE is 
not resolving within two weeks contact Sponsor for 
guidance
If symptoms do not recover to ≤CTCAE grade 1, 
contact Sponsor and consider discontinue ceralasertib
and olaparib .
2nd occurrence
Withhold dose for up to 28 days until recovery to 
≤CTCAE grade 1 then resume at 1st reduced dose level 
for non-haematological toxicity (see Appendix C, table
4).  The investigator may choose to reduce ceralasertib
or olaparib or both drugs. If only one drug is dose 
reduced, the second drug may be reduced as an 
additional step if the toxicity recurs.
If symptoms do not recover to ≤CTCAE grade 1, 
contact Sponsor and consider discontinue ceralasertib
and olaparib.
3rd occurrence
Withhold dose for up to 28 days until recovery to 
≤CTCAE grade 1 then resume at 2nd reduced dose level 
for non-haematological toxicity (see Appendix C, table 
4). The investigator may choose to reduce ceralasertib
or olaparib or both drugs. If only one drug is dose 
reduced, the second drug may be reduced as an 
additional step if the toxicity recurs.
If symptoms do not recover to ≤CTCAE grade 1, 
contact Sponsor and consider discontinue ceralasertib
and olaparib.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
244 (296)
Toxicity
Ceralasertib and olaparib
4th occurrence
Off-study drug
8.4.2.5
Management of new or worsening pulmonary symptoms
If new or worsening pulmonary symptoms (eg, dyspnoea) or radiological abnormality occurs, 
an interruption in study treatment dosing is recommended and a 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 
AstraZeneca Study Physician. 
8.4.2.6
Renal Impairment
If subsequent to study entry and while still on study therapy, a patient’s estimated CrCl 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 by Cockcroft-Gault equation of between 31 and 50 ml/min) 
for any reason during the course of the study: the dose of olaparib should be reduced to 200mg 
BID.  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 or a more 
formal test of creatinine clearance determination should be performed.
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.
8.4.2.7
Management of nausea and vomiting
Events of nausea and vomiting are known to be associated with olaparib treatment. They 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 with the 
incidence of nausea and vomiting not showing an increase over the treatment cycles.   
No routine prophylactic anti-emetic treatment is required at the start of study treatment, 
however, patients should receive appropriate anti-emetic treatment at the first onset of nausea 
or vomiting and as required thereafter, in accordance with local treatment practice guidelines.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
245 (296)
8.4.2.8
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 AZ 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 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.
9.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
9.1 Identity of investigational product(s)
Investigational product
Dosage form and strength
Ceralasertib
20 mg or 100 mg tablets
Olaparib
100 mg or 150 mg film-coated tablets
9.1.1
Ceralasertib
AstraZeneca will supply ceralasertib tablets for oral use.  The tablets will be supplied at 2 
strengths (20 mg and 100 mg) in high-density polyethylene bottles, which sufficiently protects 
the drug from light. Ceralasertib coated tablets contain a blend of ceralasertib, mannitol, 
microcrystalline cellulose, sodium starch glycolate, magnesium stearate and silicon dioxide.  
The coating is Opadry® II white.
The different tablet strengths should not be combined in the same bottle at any time.  
Additional information about the IP may be found in the IB.
Ceralasertib is taken PO daily on Days 1 to 7 of each treatment cycle at about the same time 
each day.  Treatment cycles are every 28 days. Ceralasertib should be taken with 
approximately 8 ounces of water.  When ceralasertib is administered in combination with 
olaparib, patients must fast as directed for at least 2 hours prior to the dosing and for at least 1 


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
246 (296)
hour after the dose. When olaparib is given on its own, the olaparib tablet formulation can be 
given without regard to food.
If a patient misses a daily dose, a double dose should not be taken on the next day. If vomiting 
occurs after a patient takes the ceralasertib dose, the patient should not take the dose again 
unless they can count all of the taken tablets.
9.1.2
Olaparib
Olaparib is presented for oral administration as a green, film-coated tablet containing 25 mg, 
100 mg, 150 mg or 200 mg of drug substance.  The 100 mg strength is also available as a 
yellow, film-coated tablet. 
Olaparib tablets are supplied in high-density polyethylene (HDPE) bottles containing 
desiccant.  Bottles are secured with a child-resistant closure; induction-sealed membranes 
provide tamper evidence.
The 25 mg, 100 mg, 150 mg and 200 mg strengths of olaparib tablets are composed of the 
same constituents.  The tablet cores comprise: olaparib, copovidone, colloidal silicon dioxide, 
mannitol and sodium stearyl fumarate.  The composition of the green tablet film coating is: 
hydroxypropyl methylcellulose (hypromellose), macrogol 400 (polyethylene glycol 400), 
titanium dioxide, iron oxide yellow and iron oxide black.  The yellow tablet film coating only 
differs from the green film coating with the omission of iron oxide black.
Olaparib tablets are taken PO, twice daily, approximately 12 hours apart. When ceralasertib is 
administered in combination with olaparib, patients must fast as directed for at least 2 hours 
prior to the dosing and for at least 1 hour after the dose. When olaparib is given on its own, 
the olaparib tablet formulation can be given without regard to food.
9.2 Dose and treatment regimens
For Arm C, up to 20 patients will be enrolled, and all patients will receive:
Ceralasertib 160 mg QD PO for 7 days from Day 1 + olaparib 300 mg BID PO from Day 1 for 
28 days; q4w until PD.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
247 (296)
Appendix C Figure 3
Ceralasertib + olaparib therapy dosing schedule
9.3 Labeling
Please refer to Section 8.3 of the master protocol for details regarding labelling applicable to 
all arms.  
9.4 Storage
Please see Section 8.4 of the master protocol.
9.5 Compliance
Dosing compliance will be reviewed with the patient at the beginning of each new treatment 
cycle when ceralasertib and olaparib is dispensed.  All patients will be required to complete a 
dosing diary, which must be returned to the clinic for review at each visit.  The patient should 
be instructed to record each date and time the dose(s) was taken in the dosing diary.  If a dose 
is missed, the reason must be noted in the diary.  A copy of the dosing diary is provided in the 
study reference materials.
Patients should be advised to return any unused ceralasertib and olaparib in the original 
bottles, in addition to returning any empty bottles.
The administration of all study drugs (including IPs) should be recorded in the appropriate 
sections of the case report form (CRF).
9.6 Accountability
Please see Section 8.6 of the master protocol.
9.7 Concomitant and other treatments 
Please refer to Section 8.7 of the master protocol for details regarding concomitant and other 
treatments applicable to all arms.  Details regarding concomitant and other treatments 
applicable to Arm C are described below.
Patients must comply with the concomitant treatment information described in the core study 
protocol and those described in the olaparib and ceralasertib Investigators’ Brochure.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
248 (296)
9.7.1
Medications that may NOT be administered

No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy 
(Hormone replacement therapy (HRT) and stable treatment of > 6 months with 
LHRH analogues are acceptable), radiotherapy (palliative radiotherapy is permitted, 
if study treatment has been withheld for at least 3 days, see Section 9.7.5), 
biological therapy or other novel agent) is to be permitted while the patient is 
receiving study medication.

Live virus and bacterial vaccines should not be administered whilst the patient is 
receiving study medication and during the 28 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 
medication are unknown.

Strong or Moderate CYP3A inhibitors (See Appendix I Disallowed Medications 
and Medications to be Administered with Caution

Known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, 
boosted protease inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) 
or moderate CYP3A inhibitors (ciprofloxacin, erythromycin, diltiazem, fluconazole, 
verapamil) should not be taken with study treatment.  

If there is no suitable alternative concomitant medication then the dose of study 
treatment should be reduced for the period of concomitant administration. 
Suggested dose reductions for olaparib are described below. The dose reduction of 
study treatment should be recorded in the CRF with the reason documented as 
concomitant CYP3A inhibitor use.

Strong CYP3A inhibitors - reduce the dose of olaparib to 100mg BID 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 150mg BID 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.

Strong or Moderate CYP3A inducers (See Appendix D International Airline 
Transportation Association 6.2 Guidance Document: 

Strong (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, 
carbamazepine, nevirapine, enzalutamide and St John’s Wort) and moderate 
CYP3A inducers (eg. bosentan, efavirenz, modafinil) of CYP3A should not be 
taken with study treatment. If the use of any strong or moderate CYP3A inducers 
are considered necessary for the patient’s safety and welfare this could diminish the 


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
249 (296)
clinical efficacy of study treatment.  If a patient requires use of a strong or moderate 
CYP3A inducer then they must be monitored carefully for any change in efficacy of 
study treatment.

P-gp inhibitors (See Appendix I
Disallowed Medications and Medications to be 
Administered with Caution):

It is possible that co-administration of P-gp inhibitors (eg amiodarone, 
azithromycin) may increase exposure to study treatment. Caution should therefore 
be observed.
9.7.2
Effect of olaparib on other drugs

Based on limited in vitro data, olaparib may increase the exposure to substrates of 
CYP3A4, , OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K.

Based on limited in vitro data, olaparib may reduce the exposure to substrates of
CYP2B6.

Caution should therefore be observed if substrates of these isoenzymes or 
transporter proteins are co-administered.
Examples of substrates include:

CYP3A4 – simvastatin, cisapride, cyclosporine, ergotalkaloids, fentanyl, pimozide, 
sirolimus, tacrolimus and quetiapine

CYP2B6 – bupropion, efavirenz

OATP1B1 - bosentan, glibenclamide, repaglinide, statins and valsartan

OCT1, MATE1, MATE2K – metformin

OCT2 - serum creatinine

OAT3 -furosemide, methotrexate
After commencement of IP if the use of any potent inducers or inhibitors of CYP3A4/5 are 
considered necessary for the patient’s safety and welfare, the investigator must contact the 
AstraZeneca Study Physician. A decision to allow the patient to continue study treatment will 
be made on a case-by-case basis.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
250 (296)
9.7.3
Anticoagulant Therapy
Patients who are taking warfarin may participate in this trial; however, it is recommended that 
prothrombin time (international normalised ratio (INR) and activated partial thromboplastin 
time (APTT)) be monitored carefully at least once per week for the first month, then monthly 
if the INR is stable. Subcutaneous heparin is permitted.
9.7.4
Anti-emetics/Anti-diarrhoeals
From the time the subject commences study medication, should the patient develop nausea, 
vomiting and / or diarrhoea, then these symptoms should be reported as AEs and appropriate 
treatment for the event given. All treatments should be recorded.
9.7.5
Palliative radiotherapy 
Palliative radiotherapy may be used for the treatment of pain at the site of bony metastases 
that were present at baseline.  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, 
provided the investigator does not feel that these pains are indicative of clinical disease 
progression during the study period.  
9.7.6
Administration of other anti-cancer agents
Patients must not receive any other concurrent anti-cancer 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. 
9.7.7
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.  Reasons for starting 
subsequent anti-cancer therapies including access to other PARP and ATR inhibitors or 
investigational drugs will be collected and included in the exploratory assessments of OS.
9.7.8
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the CRF.
10.
STATISTICAL ANALYSES BY ASTRAZENECA
Please refer to Section 9.1 of the master protocol for details regarding statistical analyses 
applicable to all arms.  Additional details regarding statistical analyses applicable to Arm C 
are described below.


Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
251 (296)
10.1
Adverse events
AEs observed up to 30 days following discontinuation of study treatment or until the initiation 
of the first subsequent therapy following discontinuation of treatment (whichever occurs first) 
will be used for the reporting of AE summary tables.  This will more accurately depict AEs 
attributable to study treatment only, as a number of AEs up to 30 days following 
discontinuation of the study treatment are likely to be attributable to subsequent therapy.  
10.2 Study and data management by AstraZeneca
Please refer to Section 10.4 of the master protocol for details of study and data management.
11.
ETHICAL AND REGULATORY REQUIREMENTS
Please refer to Section 11.3 of the master protocol for details of ethical and regulatory 
requirements.


Clinical Study Protocol Appendix D
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
252 (296)
APPENDIX D
INTERNATIONAL AIRLINE 
TRANSPORTATION ASSOCIATION 6.2 GUIDANCE DOCUMENT
Labeling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes, the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations in the 46th edition (2005).  
Infectious substances are now classified either as Category A, Category B, or Exempt.  There 
is no direct relationship between risk groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life threatening, or a fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are, eg, Ebola and Lassa fever 
virus.

are to be packed and shipped in accordance with IATA Instruction 602
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are, eg, hepatitis A, B, C, D, and E viruses; 
and human immunodeficiency virus types 1 and 2.  They are assigned the following UN 
number and proper shipping name:

 – Biological Substance, Category B

are to be packed in accordance with 
 and IATA 650
Exempt are all other materials with minimal risk of containing pathogens.

Clinical trial samples will fall into Category B or Exempt under IATA regulations.

Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650-compliant packaging. 

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content.

IATA-compliant courier and packaging materials should be used for packing and 
transportation, and packing should be done by an IATA-certified person, as applicable.

Samples routinely transported by road or rail are subject to local regulations, which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.
CCI
CCI


Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
253 (296)
APPENDIX E
ACTIONS REQUIRED IN CASES OF 
INCREASES IN LIVER BIOCHEMISTRY AND EVALUATION 
OF HY’S LAW
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law (HL).  It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries.  Specific guidance on the managing liver 
abnormalities can be found in Section 6.2.1 of the protocol.
During the course of the study, the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study, according to the definitions 
below.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met.  
HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug-induced liver injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting adverse events (AEs) and serious adverse events (SAEs) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3× upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥2× ULN at any point during the study 
following the start of study medication irrespective of an increase in alkaline phosphatase 
(ALP).
Hy’s Law
AST or ALT ≥3× ULN together with TBL ≥2× ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, or another drug.  
For PHL and HL, the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.


Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
254 (296)
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL, it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥3× ULN

AST ≥3× ULN

TBL ≥2× ULN
If a central laboratory is being used
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met.  Where this is the case, the Investigator will:

Request a repeat of the test (new blood draw) by the central laboratory

Complete the appropriate unscheduled laboratory case report form (CRF) arm(s) with 
the original local laboratory test result
When the identification criteria are met from central or local laboratory results, the 
Investigator will without delay:

Determine whether the patient meets PHL criteria (see Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results)
Follow-up
Potential Hy’s Law criteria not met
If the patient does not meet PHL criteria, the Investigator will:

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the clinical study protocol
Potential Hy’s Law criteria met
If the patient does meet PHL criteria, the Investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (see Actions Required When Potential Hy’s Law Criteria are Met Before and 
After Starting Study Treatment)

Notify the AstraZeneca representative who will then inform the central Study Team 


Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
255 (296)
The Study Physician contacts the Investigator to provide guidance, to discuss and agree on an 
approach for the study patients’ follow-up, and for the continuous review of data.  Subsequent 
to this contact, the Investigator will:

Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 

Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician.  This includes deciding which tests available in the Hy’s 
Law laboratory kit should be used.

Complete the three Liver CRF Arms as information becomes available 

If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other patient matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF.

If the alternative explanation is an AE/SAE, record the AE/SAE in the CRF 
accordingly and follow the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Report an SAE (report term “Hy’s Law”) according to AstraZeneca standard 
processes. 


Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
256 (296)
The “Medically Important” serious criterion should be used if no other serious criteria apply.
As there is no alternative explanation for the HL case, a causality assessment of “related” should 
be assigned.
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Report an SAE (report term “Potential Hy’s Law”) applying serious criteria and 
causality assessment as per above

Continue follow-up and review according to the agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review.
Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting 
Study Treatment 
This section is applicable to patientswith liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment.
At the first on-study treatment occurrence of PHL criteria being met, the Investigator will:

Determine if there has been a significant change in the patients’ condition compared 
with the last visit where PHL criteria were met.
If there is no significant change, no action is required.
If there is a significant change, notify the AstraZeneca representative, who will inform the central 
Study Team, then follow the subsequent process described in Potential Hy’s Law criteria met
of this appendix.
A “significant” change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or total bilirubin) in isolation or 
in combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on-study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of
PHL is based on the nature of the alternative cause identified for the previous occurrence.  


Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738)
Study Code D419QC00002
Version 05
Date 16Jan2020
257 (296)
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:

Was the alternative cause for the previous occurrence of PHL criteria being met found 
to be the disease under study, eg, chronic or progressing malignant disease or severe 
infection or liver disease, or did the patient meet PHL criteria prior to starting study 
treatment and at their first on-study treatment visit as described in Actions Required 
When Potential Hy’s Law Criteria are Met Before and After Starting Study Treatment?
If No: follow the process described in Potential Hy’s Law criteria met of this appendix.
If Yes:
Determine if there has been a significant change in the patient’s condition compared with 
when PHL criteria were previously met.

If there is no significant change, no action is required.

If there is a significant change, follow the process the subsequent process described in 
Potential Hy’s Law criteria met of this appendix.

A “significant” change in the patient’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST, or total 
bilirubin) in isolation or in combination, or a clinically relevant change in
associated symptoms.  The determination of whether there has been a significant 
change will be at the discretion of the Investigator; this may be in consultation with 
the Study Physician if there is any uncertainty.
References
FDA Guidance for Industry. Drug-induced liver injury: premarketing clinical evaluation. 
Issued July 2009. Available from: URL: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf.


Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
258 (296)
APPENDIX F
GUIDELINES FOR EVALUATION OF 
OBJECTIVE TUMOR RESPONSE USING RECIST 1.1 
CRITERIA (RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS)
1. INTRODUCTION
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors, 
version 1.1 (RECIST 1.1) guidelines (Eisenhauer et al 2009) for the D419QC00002 study with 
regard to Investigator assessment of tumor burden including protocol-specific requirements for 
this study.
2. DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET, 
AND NON-TARGET LESIONS
Patients with at least 1 target lesion (tumor) that can be accurately assessed at baseline on images 
from computed tomography (CT) or magnetic resonance imaging (MRI) should be included in 
this study.
2.1. Measurable
A lesion, not previously irradiated prior to first IP administration, that can be accurately 
measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have 
short axis1 ≥15 mm) with CT or MRI and that is suitable for accurate repeated measurements.
2.2. Non-measurable

All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 to <15 mm short axis at baseline2). 

Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by CT or 
MRI.
                                               
1 The short axis is defined as the longest axis perpendicular to the long axis of the tumor.
2 Lymph nodes with <10 mm short axis are considered non-pathological and should not be recorded or followed 
as non-target lesions (NTLs).


Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
259 (296)

Previously irradiated lesions3

Skin lesions assessed by clinical examination

Brain metastasis
2.3. Special cases

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.  Blastic lesions are considered non-measurable.

Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in 
the same patient, these should be selected as target lesions (TLs).
2.4. Target lesions
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline.  A bilateral organ, eg, adrenal glands, is considered as a single organ.  Lymph nodes, 
in any location, are collectively considered as a single organ, with a maximum of 2 lymph nodes 
as TLs.
2.5. Non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline.
3. METHODS OF ASSESSMENT
The same method of assessment (imaging modality), anatomical coverage, and imaging 
technique (eg, reconstruction interval: slice thickness, gap) should remain consistent 
across all imaging visits for any given patient.
A summary of the methods to be used for RECIST 1.1 assessment is provided in Appendix F
Table 1 below, and those excluded from tumor assessments for this study are highlighted with 
the rationale provided.
                                               
3 Localized post-radiation changes that affect lesion sizes may occur.  Therefore, lesions that have been previously 
irradiated will not be considered measurable and should be selected as NTL at baseline and followed up as part of 
the NTL assessment.


Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
260 (296)
Appendix F Table 1 Summary of methods of assessment
Target lesions 
Non-target lesions
New lesions
CT (preferred modality; 
preferably with IV contrast)
MRI (preferably with IV contrast)
CT (preferred modality; 
preferably with IV contrast)
MRI (preferably with IV 
contrast)
Clinical examination 
X-ray, chest X-ray
CT (preferred modality; 
preferably with IV contrast)
MRI (preferably with IV 
contrast)
Clinical examination 
X-ray, chest X-ray
Ultrasound
Bone scan
FDG-PET
Note: MRI with IV contrast is preferred modality over CT with IV contrast for brain imaging.
CT  Computed tomography; FDG-PET  fluorodeoxyglucose positron emission tomography; IV  Intravenous; 
MRI: Magnetic resonance imaging.
The following are scanning options in decreasing order of preference:
1. Chest-abdomen CT with intravenous (IV) contrast administration
2. Chest CT without IV contrast administration + abdomen MRI with gadolinium IV 
contrast, only if iodine contrast media are medically contraindicated at any time during 
the study
3. Chest-abdomen CT without IV contrast
3.1. CT and MRI 
CT and MRI, each preferably with IV contrast, are generally considered to be the best 
currently available and reproducible methods to measure TL selected for response assessment 
and to assess NTL and identification of any new lesions. 
In this study, it is recommended that IV contrast-enhanced CT examinations of the chest and 
abdomen (including liver and adrenal glands) will be used to assess tumor burden at baseline 
and follow-up visits.  In patients who are sensitive to IV CT contrast, a non-contrast CT 
examination of the chest and an MRI with IV contrast of the abdomen are appropriate.  For 
brain lesion assessment, MRI with IV contrast is the preferred method over contrast-enhanced 
CT.  It is strongly recommended to maintain use of the same imaging modality (CT or MRI), 
acquisition protocol, facility, and scanner across all imaging timepoints per patient.
3.2. Clinical examination 
In this study, clinical examination will not be used for assessment of TL.  Clinically detected 
lesions can be selected as TLs if they are assessed by CT or MRI scans.  Clinical examination 
can be used to assess NTLs in patients who also have other lesions assessable by CT, MRI, or 
plain X-ray and to identify the presence of new lesions.


Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
261 (296)
3.3. X-ray
Chest X-ray
In this study, chest X-ray assessment will not be used for assessment of TL as they will be 
assessed by CT or MRI examination.  Chest X-ray can, however, be used to assess NTL and 
to identify the presence of new lesions.
Plain X-ray 
In this study, plain X-ray may be used as a method of assessment for bone NTL and to 
identify the presence of new bone lesions. 
3.4. Ultrasound 
In this study, ultrasound examination will not be used for assessment of TL and NTL, as it is 
not a reproducible method, does not provide an accurate assessment of tumor size, and it is 
subjective and operator dependent.  Ultrasound examination can, however, be used to identify 
the presence of new lesions.  If new clinical symptoms occur and an ultrasound is performed, 
then new lesions should be confirmed by CT or MRI examination.
3.5. Endoscopy and laparoscopy 
In this study, endoscopy and laparoscopy will not be used for tumor assessments because they 
are not validated in the context of tumor assessment.
3.6. Tumor markers
In this study, tumor markers will not be used for tumor response assessments per RECIST 1.1. 
3.7. Cytology and histology 
In this study, histology will not be used as part of the tumor response assessment as per 
RECIST 1.1. 
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumor has met criteria for response or stable 
disease.  In such circumstances, the cytology is necessary for the Investigator to differentiate 
between response/stable disease (an effusion may be a side effect of the treatment) and 
progressive disease (if the neoplastic origin of the fluid is confirmed).  Where cytology 
findings are not available, any effusion that significantly worsens (from trace to large) or 
appearance of clinically significant effusion (requiring change in drug therapy) during the 
study treatment will be considered to be progression of NTL or disease progression due to 
new lesions. 
3.8. Isotopic bone scan
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
Xray- at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment.  


Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
262 (296)
In this study, isotopic bone scans may be used as a method of assessment to identify the 
presence of new bone lesions at follow-up visits.  New lesions will be recorded where a 
positive hot spot that was not present on the baseline bone scan assessment is identified on a 
bone scan performed at any time during the study.  The Investigator should consider the 
positive hot spot to be a significant new site of malignant disease and represent true disease 
progression in order to record the new lesion.  Confirmation by CT, MRI, and Xray- is 
recommended where bone scan findings are equivocal.
3.9. FDG-PET scan
18F-FDG-PET (fluorodeoxyglucose positron emission tomography) scans may be used as a 
method for identifying new lesions, according with the following algorithm: New lesions will 
be recorded where there is positive FDG uptake4 not present on baseline 18F-FDG-PET scan 
or in a location corresponding to a new lesion on CT/MRI at the same follow-up visit.  If there 
is no baseline 18F-FDG-PET scan available, and no evidence of new lesions on CT/MRI scans, 
then follow-up CT/MRI assessments should be continued, scheduled as per protocol or 
clinical indicated, in order to confirm new lesions.
4. TUMOR RESPONSE EVALUATION 
4.1. Schedule of evaluation
The methods of assessment of tumor burden used at baseline CT/MRI scans, preferably with 
IV contrast, of the chest and abdomen (including liver and adrenal glands) must be used at 
each subsequent follow-up assessment.  Additional imaging may be performed based on the 
signs and symptoms of the patient (eg, new lesions at follow-up).
Efficacy for all patients (all cohorts) will be assessed on images collected on visits as 
described in the corresponding appendix until confirmed objective disease progression or off 
study.  It is important to follow the assessment schedule as closely as possible (refer to the 
study plans in each arm [screening and treatment period, and follow-up]).  If an unscheduled 
imaging assessment is performed and the patient has not progressed, every attempt should be 
made to perform the subsequent assessments at his or her next regularly scheduled imaging 
visit.
A follow up scan should be collected for all patients following a prior timepoint with an 
overall assessment of complete response (CR), partial response (PR), or progressive disease 
(PD) by RECIST 1.1.  The follow up scan  should occur preferably at the next scheduled visit 
and no earlier than 4 weeks after the prior assessment of CR, PR, or PD, respectively.
                                               
4 A positive FDG-PET scan lesion should be reported only when uptake is greater than approximately twice that 
of the surrounding tissue or liver.


Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
263 (296)
4.2. Target lesions
4.2.1. Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ) and representative of all lesions 
involved, should be identified as TLs at baseline.  Target lesions should be selected on the 
basis of their size (longest diameter for non-nodal lesions or short axis for nodal lesions) but 
in addition should be those that lend themselves to reproducible repeated measurements.  It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion, which can be measured 
reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes).  All measurements should be recorded in 
millimeters.  At baseline, the sum of the diameters for all TLs will be calculated and reported 
as the baseline sum of diameters.  At follow-up visits, the sum of diameters for all TLs will be 
calculated and reported as the follow-up sum of diameters.  
4.2.2. Special cases

For TL measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short 
axis. 

If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable 
disease at baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the longest diameter should be recorded as 
0 mm.

If a TL splits into 2 or more parts, then record the sum of the diameters of those 
parts. 

If 2 or more TLs merge, then the sum of the diameters of the combined lesion 
should be recorded for one of the lesions and 0 mm recorded for the other lesion(s).  

If a TL is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned.  If an accurate measure can be given, this 
should be recorded, even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate 
of the size of the lesion. 

When a TL has had any intervention (eg, radiotherapy, embolization, or surgery) 
during the study, the size of the TL should still be provided where possible.


Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
264 (296)
4.2.3. Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL (see Appendix F Table 2 below).
Appendix F Table 2 Evaluation of TLs
Complete response
Disappearance of all TLs since baseline.  Any pathological lymph 
nodes selected as TLs must have a reduction in short axis to 
<10 mm.
Partial response
At least a 30% decrease in the sum of the diameters of TL, taking 
as reference the baseline sum of diameters
Stable disease
Neither sufficient shrinkage to qualify for partial response nor 
sufficient increase to qualify for progression of disease
Progression of disease
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition to the relative
increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.
Not evaluable
Only relevant if any of the TLs were not assessed or not evaluable 
or had a lesion intervention at this visit.  
Note: if the sum of diameters meets the progressive disease 
criteria, progressive disease overrides not evaluable as a TL 
response
TL  Target lesion.
4.3. Non-target lesions
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.  At each visit, an overall assessment of the NTL response should be 
recorded by the Investigator.  This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit (see 
Appendix F Table 3).


Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
265 (296)
Appendix F Table 3 Evaluation of non-target lesions
CR
Disappearance of all NTLs since baseline.  All lymph nodes must 
be non-pathological in size (<10 mm short axis).
Non-CR/Non-PD
Persistence of one or more NTL.
PD
Unequivocal progression of existing NTLs.  Unequivocal 
progression may be due to an important progression in 1 lesion 
only or in several lesions.  In all cases, the progression MUST be 
clinically significant for the physician to consider changing or 
stopping therapy.
NE
Only relevant when one or some of the NTLs were not assessed 
and, in the Investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit.
Note: for patients without TLs at baseline, this is relevant if any 
of the NTLs were not assessed at this visit and the progression 
criteria have not been met.
CR: complete response; NE: not evaluable; NTL: Non-target lesion; PD; progression; TL: Target lesion.
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of stable disease or PR 
in TLs, 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.
4.4. New lesions
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
1 or more new lesions is assessed as progression. 
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal, ie, not attributable to differences in 
scanning technique, change in imaging modality, or findings thought to represent something 
other than tumor.
If a new lesion is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
4.5. Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it may be a reason for 
stopping study therapy.


Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
266 (296)
Patients with “symptomatic deterioration” requiring discontinuation of treatment without 
objective radiographic evidence of disease progression at that time should continue to undergo 
regularly scheduled tumor assessments until objective disease progression is observed or death 
occurs (whichever comes first).
4.6. Evaluation of overall visit response and best overall response
The overall visit response will be derived using the algorithm shown in Appendix F Table 4.
Appendix F Table 4 Overall visit response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non-CR/Non-PD 
No
PR
CR
NE
No 
PR
PR
Non-PD or NE
No
PR
SD 
Non-PD or NE
No
SD
NA
Non-CR/Non-PD
No
SD (Non-CR/non-PD)
NE
Non-PD or NE
No
NE
NA
NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; NE: Not evaluable; 
NA: Not applicable (relevant when no TLs/NTLs at baseline); NTL: Non-target lesion; TL: Target lesion.
5. CONFIRMATION OF PROGRESSION
In this study, a confirmatory scan is required for all patients enrolled into arm A (durvalumab
+ tremelimumab) following the prior demonstration of PD.  The confirmatory scan should 
occur preferably at the next scheduled visit and no earlier than 4 weeks following the date the 
criteria for response were first met or after the prior assessment of PD.  
Confirmation of progression guidelines are set for the following reasons: 

for patient management and treatment decisions

in the absence of significant clinical deterioration, to promote the collection of 
additional scans after the first radiologic RECIST 1.1 assessment of progressive 


Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
267 (296)
disease (PD) in order to distinguish pseudoprogression from true radiologic 
progression, also known as RECIST 1.1 modified for confirmation of progression
Confirmed objective disease progression refers to either of the following scenarios: 1. clinical 
progression/deterioration confirmed by a radiologic scan if clinically feasible; or 2. in the 
absence of significant clinical deterioration, radiologic PD by RECIST 1.1 followed by a 
second radiologic confirmation scan with PD assessed according to the specific confirmation 
of progression criteria listed below. RECIST 1.1 modified for confirmation of progression 
refers to the second scenario above. The confirmatory scan should occur preferably at the next 
scheduled imaging visit and no earlier than 4 weeks following the date of the immediate prior 
assessment of RECIST 1.1 PD.
Immediate prior radiologic progression would be considered confirmed if any the following 
criteria are met in the confirmatory scan:

≥20% increase in the sum diameters of TLs compared with the nadir at 2 consecutive 
visits, with an absolute increase of at least 5 mm in sum of diameters compared to 
nadir,

and/or significant progression (worsening) of NTLs and/or of pre-existing new lesions 
at the confirmatory scan time-point compared with the immediate prior time-point 
(Note: Pre-existing new lesions are evaluated as NTLs at the confirmatory scan time-
point),

and/or additional new unequivocal lesions at the confirmatory scan time-point.
NOTE: In order to have confirmed objective disease progression, there should be two 
consecutive PD’s, the first PD by RECIST 1.1 and the second PD using the confirmation of 
progression criteria (above). If the first PD by RECIST 1.1 is not confirmed, continue with 
assessments until the next PD by RECIST 1.1, which in turn will need its own immediate 
subsequent confirmation scan.
In the absence of significant clinical deterioration, treatment with study drug may continue 
between the initial assessment of progression and the scan to confirm progression.
If the confirmation scan confirms progression, then the date of the prior scan with PD should 
be declared as the date of progression.
If progression is not confirmed, in the absence of significant clinical deterioration, then the 
patient should continue study drug and on-treatment assessments until the next PD which will 
also require a follow-up confirmation scan. If the first PD is not confirmed by the immediate 
next scan, then the Investigator should not change the PD assessment of the first scan.
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to 
radiologic progression, then the patient should still continue to be followed until confirmed 
objective disease progression.


Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
268 (296)
Patients will also be assessed every 6/8 weeks ± 1 week (please check applicable appendix for 
details) for a second progression defined according to local standard clinical practice and may 
involve any objective radiological, symptomatic progression, or death. 
6. SPECIFICATIONS FOR RADIOLOGICAL IMAGING
The use of standardized protocols for CT and MRI allows comparability both within and 
between different studies, irrespective of where the examination has been undertaken.  It is 
strongly recommended to maintain use of the same imaging modality (CT and/or MRI), 
acquisition protocol, facility, and scanner across all imaging timepoints per patient.
6.1. CT scan
CT scans should be contiguous throughout all the anatomical regions of interest.  In this study, 
it is recommended that CT examinations of the chest and abdomen (including liver and 
adrenal glands), preferably with IV contrast, will be used to assess tumor burden.
The most critical CT image acquisition parameters for optimal tumor evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval.
6.1.1. Anatomic coverage
Optimal anatomic coverage for most solid tumors is the chest, abdomen, and pelvis (chest and 
abdomen in this study).  Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual patients.  Because a lesion later 
identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, careful consideration should be given to the extent of 
imaging coverage at baseline and at subsequent follow-up timepoints.  This will enable better 
consistency not only of tumor measurements but also identification of new disease.
6.1.2. Intravenous contrast administration
Optimal visualization and measurement of metastases in solid tumors require consistent 
administration (dose and rate) of intravenous contrast as well as timing of scanning.  
Typically, most abdominal imaging is performed during the portal venous phase and 
(optimally) is about the same time frame after injection on each examination.  An adequate 
volume of a suitable contrast agent should be given so that the metastases are demonstrated to 
best effect and a consistent method is used on subsequent examinations for any given patient.  
It is very important that the same technique be used at baseline and on follow-up examinations 
for a given patient.  For patients who develop contraindications to contrast after baseline 
contrast CT is done, the decision as to whether non-contrast CT or MRI (enhanced or non-
enhanced) should be performed should also be based on the tumor type and anatomic location 
of the disease and should be optimized to allow for comparison to the prior studies if possible.  
Each case should be discussed with the radiologist to determine if substitution of these other 


Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
269 (296)
approaches is possible, and if not, the patient should be considered not evaluable from that 
point forward.  Care must be taken in measurement of TLs on a different modality and 
interpretation of non-target disease or new lesions since the same lesion may appear to have a 
different size using a new modality.  Oral contrast is recommended to help visualize and 
differentiate structures in the abdomen.
If iodine contrast media are medically contraindicated at baseline or at any time during the 
course of the study, then the recommended methods are CT thoracic examination without 
contrast and abdominal (and pelvic) MRI with contrast.  If MRI cannot be performed, then CT 
without intravenous contrast is an option for the thorax, abdomen, and pelvic examinations.  
For assessment of brain lesions, MRI is the preferred method.
6.1.3. Slice thickness and reconstruction material
It is recommended that CT scans be performed at 5-mm contiguous slice thickness, and this 
guideline presumes a minimum 5-mm thickness in recommendations for the measurable lesion 
definition.  Exceptionally, particular institutions may perform medically acceptable scans at 
slice thicknesses greater than 5 mm.  If this occurs, the minimum size of measurable lesions at 
baseline should be twice the slice thickness of the baseline scans.
All window settings should be included in the assessment, particularly in the thorax where 
lung and soft tissue windows should be considered.  When measuring lesions, the TLs should 
be measured on the same window setting for repeated examinations throughout the study.  All 
images from each examination should be included in the assessment and not “selected” 
images of the apparent lesion.
6.2. MRI scan
MRI has excellent contrast and spatial and temporal resolution; however, there are many 
image acquisition variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement.  Furthermore, the availability of MRI is variable globally.  The 
modality used at follow-up should be the same as was used at baseline, and the lesions should 
be measured/assessed on the same pulse sequence.  Generally, axial imaging of the abdomen 
and pelvis with T1 and T2 weighted imaging along with gadolinium-enhanced imaging should 
be performed.  The field of view, matrix, number of excitations, phase encode steps, use of fat 
suppression, and fast sequences should be optimized for the specific body part being imaged 
as well as the scanner used.  It is beyond the scope of this appendix to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the same type of 
scanner should be used, and the image acquisition protocol should be followed as closely as 
possible to prior scans.  Body scans should be performed with breath-hold scanning 
techniques if possible.  For these reasons, CT is the imaging modality of choice.
6.3. CT portion of PET/CT scans
At present, low dose or attenuation correction CT portions of a combined positron emission 
tomography (PET)/CT are of limited use in anatomically based efficacy assessments and it is 
therefore suggested that they should not substitute for dedicated diagnostic contrast-enhanced 


Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
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CT scans for tumor measurements by RECIST 1.1. In exceptional situations, if a site can 
document that the CT performed as part of a PET/CT is of identical diagnostic quality (with 
IV iodine-based CT contrast) to a dedicated diagnostic CT, then the CT portion of the PET/CT 
can be used for RECIST measurements. However, this is not recommended because the PET 
portion of the CT introduces additional (PET) data that may bias an Investigator if it is not 
routinely or serially performed.


Clinical Study Protocol Appendix G
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
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APPENDIX G DEFINITION OF WOMEN OF CHILDBEARING 
POTENTIAL AND ACCEPTABLE CONTRACEPTIVE 
METHODS 
1.
DEFINITION OF WOCBP AND WOMEN NOT OF 
CHILDBEARING POTENTIAL

Women of childbearing potential: 
Women between menarche and menopause who have not been permanently or surgically 
sterilized and are capable of procreation.

Women not of childbearing potential:
Women who are permanently or surgically sterilized or post-menopausal (definitions 
below):
Permanent sterilization includes hysterectomy and/or bilateral oophorectomy and/or 
bilateral salpingectomy but excludes bilateral tubal occlusion.  Tubal occlusion is 
considered a highly effective method of birth control but does not absolutely exclude 
possibility of pregnancy (the term occlusion refers to both occluding and ligating 
techniques that do not physically remove the oviducts).
Women who have undergone tubal occlusion should be managed on trials as if they are of 
WoCBP (eg, undergo pregnancy testing etc, as required by the study protocol).

Women will be considered post-menopausal if they are amenorrheic for 12 months 
without an alternative medical cause.  The following age-specific requirements apply:
Women under 50 years old will be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal treatments 
and with LH and FSH levels in the post-menopausal range.
Women over 50 years of age will be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments.
2.
ACCEPTABLE CONTRACEPTION METHODS
Highly effective method of birth control is defined in Note 3 in ICH Guidance M3 
(Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals) as 
one that results in a low failure rate (eg, ˂1% per year) when used consistently and correctly.
Note that women should have been stable on their chosen method of birth control for a 
minimum of 2 weeks before entering the trial.  Generic names and examples of trade names 
are given.  As trade names may vary, investigators should check the generic name of any 
contraception to ensure suitability.


Clinical Study Protocol Appendix G
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
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Acceptable Non-hormonal birth control methods include:

Vasectomised sexual partner PLUS male condom.  With participant assurance that 
partner received post-vasectomy confirmation of azoospermia.

Total sexual abstinence.  Abstinence must continue for the total duration of study 
treatment and for at least 1 month after the last dose for female study subjects, and for 
6 months after last dose for male study subjects. Periodic abstinence (eg, calendar 
ovulation, symptothermal post ovulation methods) and withdrawal are not acceptable 
methods of contraception.

Tubal occlusion PLUS male condom

Intra-uterine Device (IUD) - provided coils are copper-banded plus male condom
Acceptable hormonal methods:

Normal and low dose combined oral pills PLUS male condom 

Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the only highly 
efficacious progesterone based pill.

Hormonal shot or injection (eg., Depo-Provera) PLUS male condom

Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom 

Norelgestromin / ethinylestradiol transdermal system PLUS male condom 

Intrauterine system [IUS] device (eg., levonorgestrel releasing IUS -Mirena®) 
PLUS male condom 

Intravaginal device (e.g., ethinylestradiol and etonogestrel) PLUS male condom 

Cerazette (desogestrel) plus male condom.  Cerazette is currently the only highly 
efficacious progesterone based pill
The following methods are considered not to be highly effective and are therefore not 
acceptable contraceptive methods in AstraZeneca clinical trials:

Triphasic combined oral contraceptives (COCs)

All progesterone only pills except Cerazette

All barrier methods, if intended to be used alone

Non-copper containing Intra-Uterine Devices (IUDs)


Clinical Study Protocol Appendix G
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Study Code D419QC00002
Version 05
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
Fertility awareness methods

Coitus interruptus


Clinical Study Protocol Appendix H
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Version 05
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APPENDIX H ADDITIONAL SAFETY INFORMATION
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
“Life-threatening” means that the patient was at immediate risk of death from the adverse 
event (AE) as it occurred or it is suspected that use or continued use of the product would 
result in the patient’s death.  “Life-threatening” does not mean that had an AE occurred in a 
more severe form it might have caused death (eg, hepatitis that resolved without hepatic 
failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious adverse event (SAE), 
although the reasons for it may be (eg, bronchospasm, laryngeal edema).  Hospital admissions 
and/or surgical operations planned before or during a study are not considered AEs if the 
illness or disease existed before the patient was enrolled in the study, provided that it did not 
deteriorate in an unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the patient or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality, consider the following factors when deciding if 
there is a “reasonable possibility” that an AE may have been caused by the drug.


Clinical Study Protocol Appendix H
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Study Code D419QC00002
Version 05
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
Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another etiology 
such as the underlying disease, other drugs, other host, or environmental factors.

Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of “related” is made if, following a review of the relevant data, there is evidence for 
a “reasonable possibility” of a causal relationship for the individual case.  The expression 
“reasonable possibility” of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as “not related.”
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility


Clinical Study Protocol Appendix I
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
276 (296)
APPENDIX I
DISALLOWED MEDICATIONS AND 
MEDICATIONS TO BE ADMINISTERED WITH CAUTION 
In addition to any prohibited medications described in the individual arm sub protocol, any 
other drugs should be avoided at the Investigator’s discretion if, in their opinion, the co-
administration with study products may increase the risk of a clinically significant drug 
interaction.
A list of the main CYP3A4 substrates strong, moderate, and weak inhibitors, and strong and 
moderate and weak inducers, CYP2C19 substrates, P-gp substrates and inhibitors, BCRP 
substrates and drugs with a known risk of Torsades de pointes are shown below. This is not an 
exhaustive list and further details can be found at Expert Opin. Drug Metab. Toxicol. (2013) 
9(6):737-751
Appendix I CYP3A4 Inhibitors
Strong
Moderate
Weak
Boceprevir
ACT-178882
Almorexant
Isoniazid
Clarithromycin
Amprenavir
Alprazolam
Ivacaftor
Cobicistat (GS-9350)
Aprepitant
AMD070
Lacidipine
Conivaptan
Atazanavir
Amiodarone
I Linagliptin
Danoprevir
Casopitant
Amlodipine
Lomitapide
Elvitegravir
Ciprofloxacin
Atorvastatin
M100240
Fosamprenavir
Crizotinib
Azithromycin
Nilotinib
Grapefruit juice
Darunavir
Berberine
Oral contraceptives
Idelalisib
Dronedarone
Bicalutamide
Pazopanib
Indinavir
Diltiazem
Blueberry juice
Peppermint oil
Itraconazole
Erythromycin
Chlorzoxazone
Propiverine
Ketoconazole
FK1706
Cilostazol
Ranitidine
LCL161
Fluconazole
Cimetidine
Ranolazine
Lopinavir
Fosamprenavir
Clotrimazole
Resveratrol
Mibefradil
Imatinib
Cranberry juice
Roxithromycin
Nefazodone
Ledipasvir
Cyclosporine
Seville orange juice
Nelfinavir
Lomitapide
Daclatasvir
Simeprevir
Posaconazole
Netupitant
Delavirdine
Sitaxentan


Clinical Study Protocol Appendix I
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
277 (296)
Appendix I CYP3A4 Inhibitors
Strong
Moderate
Weak
Ritonavir
Schisandra 
sphenanthera
Everolimus
Suvorexant
Saquinavir
Tofisopam
Faldaprevir
Tabimorelin
Telaprevir
Verapamil
Fluvoxamine
Tacrolimus
Telithromycin
Fosaprepitant (IV)
Teriflunomide
Tipranavir
Ginkgo
Ticagrelor
Troleandomycin
Goldenseal
Tipranavir/ritonavir
Voriconazole
GSK1292263
Tolvaptan
GSK2248761
Zileuton
Appendix I CYP3A4 Inducers
Strong and Moderate
Weak
Avasimibe
Amprenavir
PA-824
Bosentan
Aprepitant
Pleconaril
Carbamazepine
Armodafinil
Prednisone
Efavirenz
AZD 7325
Quercetin
Enzalutamide
Bexarotene
Raltegravir
Etravirine
Boceprevir
Ritonavir
Genistein
Brivaracetam
Rufinamide
Lersivirine
Clobazam
Sorafenib
Lopinavir
Danshen
Stribild
Mitotane
Dexamethasone
Telaprevir
Modafinil
Echinacea
Terbinafine
Nafcillin
Eslicarbazepine
Ticagrelor
Phenobarbital
Garlic
Ticlopidine
Phenytoin
Gingko
Topiramate
Rifabutin
Ginseng
Troglitazone
Rifampin
Glycyrrhizin
Vemurafenib
Ritonavir
LCL161
Vicriviroc and ritonavir
Semagacestat
Methylprednisolone
Vinblastine
St John's Wort
Nevirapine
Thioridazine
Oritavancin


Clinical Study Protocol Appendix I
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
278 (296)
Appendix I CYP3A4 Inducers
Strong and Moderate
Weak
Tipranavir
Oxcarbazepine
Appendix I CYP3A and CYP3A4 Sensitive Substrates or Substrates with a Narrow 
Therapeutic Range
ABT-384
osphamide
Ifosfamide
Quetiapine
Alfentanil
Cyclosporine
Imatinib
Quinidine
Aprepitant
Danoprevir
Indinavir
Ranolazine
Alfuzosin
Darifenacin
Ironotecan
Ridaforolimus
Almorexant
Darunavir
Ivacaftor
Romidepsin
Alpha-
Dihydroergocryptine
Dasatinib
Ixabepilone
Saquinavir
Amiodarone
Dihydroergotamine
L-771,688
Sildenafil
Aplaviroc
Disopyramide
Lapatinib
Simeprevir
Aprepitant
Dronedarone
Levomethadyl 
(LAAm)
Simvastatin
Astemizole
Docetaxol
Lomitapide
Sirolimus
Atazanavir
Dofetilide
Lopinavir
Tacrolimus
Atorvastatin
Doxorubicin
Lovastatin
Temsirolimus
Avanafil
Ebastine
Lurasidone
Terfenadine
Bexarotine
Eletriptan
Maraviroc,
Ticagrelor
BIRL 355
Elvitegravir
Midazolam
Theoophylline
Bortezomib
Eplerenone
Midostaurin
Thioridazine
Bosutinib
Ergotamine
Mosapride
Thiotepa
Brecanavir
Erlotinib
Neratinib
Tilidine
Brotizolam
Etoposide
Nilotinib
Tipranavir
Budesonide
Everolimus
Nisoldipine
Tolvaptan
Buspirone
Felodipine
Paclitaxel
Triazolam
Capravirine
Fentanyl
Pazopanib
Tretinoin
Carbamazepine
Fluticasone
Perospirone
Ulipristal
Casopitant
Gefitinib
Pimozide
Vardenafil
Cisapride
Halofantrine
Propafenone
Vicriviroc
Conivaptan
Ibrutinib
Propofol
Voclosporin


Clinical Study Protocol Appendix I
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
279 (296)
Appendix I CYP2C19 Sensitive Substrates or Substrates with a Narrow Therapeutic 
Range
Diazepam
Gliclazide
Lansoprazole
(R)-Lansoprazole
(S)-Lansoprazole
(S)-Mephenytoin
(R)-Mephobarbital
Omeprazole
(R)-Omeprazole
Pantoprazole
(+)-Pantoprazole
Rabeprazole
Tilidine
Appendix I CYP1A2 Sensitive Substrates or Substrates with a Narrow Therapeutic 
Range
Alosetron
Caffeine
Duloxetine
Melatonin
Ramelteon
Tacrine
Theophylline
Tizanidine
Appendix I P-gp Substrates
Colchicine
Digoxin
Fexofenadine
Indinavir
Paclitaxel
Toptecan
Vincristine
If a patient requires initiation of digoxin during the study, or is already receiving treatment with digoxin, 
monitoring of digoxin levels is recommended according to local practice (as the levels of digoxin may 
increase). Monitoring of digoxin levels is also recommended when the patient has completed dosing with 
study treatment (as the levels of digoxin may then decrease).
Appendix I P-gp Inhibitors (Strong)
Cyclosporine
Elacridar
Erythromycin
Itraconazole
Ketocoanzole
LY335979Quinidine
Ritonavir
Valspodar
Verapamil
Appendix I BCRP Substrates
Daunorubicin
Doxorubicin
Rosuvastatin
Sulfasalazine
Topotecan
Appendix I Medicines with a known risk of Torsades de pointes
Amiodarone
Disopyramide
Ibogaine
Probucol


Clinical Study Protocol Appendix I
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
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Anagrelide
Dofetilide
Ibutilide
Procainamide
Arsenic trioxide
Domperidone
Levofloxacin
Propofol
Astemizole
Donepezil
Levomepromazine 
Quinidine
Azithromycin
Dronedarone
Levomethadyl acetate 
Roxithromycin
Bepridil
Droperidol
Levosulpiride
Sevoflurane
Chloroquine
Erythromycin
Mesoridazine
Sotalol
Chlorpromazine
Escitalopram
Methadone
Sparfloxacin
Cilostazol
Flecainide
Moxifloxacin
Sulpiride
Ciprofloxacin
Fluconazole
Ondansetron
Sultopride
Cisapride
Gatifloxacin
Oxaliplatin
Terfenadine
Citalopram
Grepafloxacin
Papaverine HCl
Thioridazine
Clarithromycin
Halofantrine
Pentamidine
Vandetanib
Cocaine
Haloperidol
Pimozide
Note: Medicines on this list are reviewed on an ongoing basis to assure that the available 
evidence supports their continued placement on this list. The list changes regularly and we 
recommend checking the website at crediblemeds.org for the most up-to-date information. 
There may be many additional brand names that are not listed on this form. Disclaimer and 
Waiver: The information presented is intended solely for the purpose of providing general 
information about health-related matters. It is not intended for any other purpose, including 
but not limited to medical advice and/or treatment, nor is it intended to substitute for the users’ 
relationships with their own health care providers. To that extent, by use of this website and 
the information it contains, the user affirms the understanding of the purpose and releases 
AZCERT, Inc. from any claims arising out of his/her use of the website and its lists. The 
absence of drugs from these lists should not be considered an indication that they are free of 
risk of QT prolongation or Torsades de pointes. Many medicines have not been tested for this 
risk in patients, especially those with congenital long QT syndrome.


Clinical Study Protocol Appendix K
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Study Code D419QC00002
Version 05
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Genetic research plan and procedures
Selection of genetic research population
Study selection record
All subjects will be asked to participate in this genetic research.  Participation is voluntary and 
if a subject declines to participate there will be no penalty or loss of benefit.  The subject will 
not be excluded from any aspect of the main study.
CCI
CCI


Clinical Study Protocol Appendix K
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
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Inclusion criteria

For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and: Provide informed 
consent for the genetic sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection
Withdrawal of consent for genetic research:  
Subjects may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study.  Voluntary withdrawal will not 
prejudice further treatment.  Procedures for withdrawal are outlined in Section 6.6.6of the 
main Clinical Study Protocol.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the subjects at Screening Visit.
Although DNA is stable, early sample collection is preferred to avoid introducing bias through 
excluding subjects who may withdraw due to an adverse event (AE), such subjects would be 
important to include in any genetic analysis.  If for any reason the sample is not drawn at 
Screening Visit, it may be taken at any visit until the last study visit.  Only one sample should 
be collected per subject for genetics during the study.  Samples will be collected, labelled, 
stored, and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality.  Samples will be stored for a maximum of 15
years, from the date of last subject last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable only by the second, unique number.  This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organisation.  No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA).
The link between the subject enrolment/randomisation code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations.  The link will be used to identify the relevant DNA samples for 


Clinical Study Protocol Appendix K
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Study Code D419QC00002
Version 05
Date 16Jan2020
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analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 11.
Informed consent
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study the subject must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the subject and the original filed at the study centre.  The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
subject understands that they may freely withdrawal from the genetic aspect of the study at 
any time.
Patient data protection
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an investigator might know a subject’s 
identity and also have access to his or her genetic data.  In addition, Regulatory authorities 
may require access to the relevant files, though the subject’s medical information and the 
genetic files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples.
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organisations or health insurance companies.  This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease.  The researchers can 
only use this information for health related research purposes.  Researchers may see summary 
results but they will not be able to see individual subject data or any personal identifiers.  
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.


Clinical Study Protocol Appendix K
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
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284 (296)
Statistical methods and determination of sample size
The number of subjects that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A Statistical 
Analysis Plan may be prepared where appropriate.


Clinical Study Protocol Appendix K
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
285 (296)
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Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
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Clinical Study Protocol Appendix K
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
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Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
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Clinical Study Protocol Appendix K
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
293 (296)
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Clinical Study Protocol Appendix K
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
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Clinical Study Protocol Appendix K
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
295 (296)
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 
Apr;44(4):1108-18. doi: 10.1002/eji.201343781. Epub 2014 Feb 16.
Tapia and DiazPadilla- 2013
Tapia G, Diaz-Padilla I. Molecular mechanisms of platinum resistance in ovarian cancer, 
ovarian cancer - a clinical and translational update. Dr. Ivan Diaz-Padilla, editor; 2013. ISBN: 
978-953-51-1030-9, InTech, DOI: 10.5772/55562. 
Tarhini and Kirkwood 2008
Tarhini AA, Kirkwood JM. Tremelimumab (CP-675,206): a fully human anticytotoxic 
T lymphocyte-associated antigen 4 monoclonal antibody for treatment of patients with 
advanced cancers. Expert Opin Biol Ther 2008;8:1583-93.
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, 
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and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin 
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Clinical Study Protocol Appendix K
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
296 (296)
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Phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-
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expressions in pancreatic carcinoma. World J Surg 2010;34(5):1059-65.
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of monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009;49(9):1012-24.
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Wang E, Kang D, Bae KS, Marshall MA, Pavlov D, Parivar K. Population pharmacokinetic 
and pharmacodynamics analysis of tremelimumab in patients with metastatic melanoma. 
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kinetics of response with ipilimumab. J Clin Oncol 2012;30(21):2691-7.
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Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122-33.
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Yap T, Krebs MG, Postel-Vinay S, Bang YJ, El-Khoueiry A, Abida W, et al. Phase I modular 
study of AZD6738, a novel oral, potent and selective ataxia telangiectasia Rad3-related (ATR) 
inhibitor in combination (combo) with carboplatin, olaparib or durvalumab in patients (pts) 
with advanced cancers. Presented at 28th EORTC-NCI-AACR Symposium on Moelcular 
Targets and Cancer Therapeutics; 29 November to 02 December 2016; Munich, Germany; 
Abstract published in European Journal of Cancer 2016;(69 Supp1):S2


Clinical Study Protocol Appendix K
Drug Substance Durvalumab (MEDI4736), tremelimumab, AZD1775, carboplatin, olaparib, ceralasertib (AZD6738) 
Study Code D419QC00002
Version 05
Date 16Jan2020
297 (297)
Zhang et al 2012
Zhang S, Shi R, Li C, Parivar K, Wang 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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SAP_001.pdf: 
Protocol number: D419QC00002 
Document title: A Phase II, Open-Label, Multi-Arm Study to   
Determine the Preliminary Efficacy of Novel Combinations of 
Treatment in Patients with Platinum Refractory Extensive-Stage 
Small-Cell Lung Cancer (BALTIC) 
NCT number: NCT02937818 
Version number: 4.0 
Date of the document: 12 April 2019 


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Statistical Analysis Plan  
Study Code D419QC00002 
Edition Number 4.0  
Date 12 Apr 2019 
2 
TABLE OF CONTENTS 
                                          PAGE 
 
TITLE PAGE ........................................................................................................... 1 
 
 
 
TABLE OF CONTENTS ......................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................. 6 
AMENDMENT HISTORY ..................................................................................... 9 
1. 
STUDY DETAILS ................................................................................................. 10 
1.1 
Study objectives ..................................................................................................... 10 
1.1.1 
Primary objective ................................................................................................... 10 
1.1.2 
Secondary objectives ............................................................................................. 10 
1.1.3 
Safety objectives .................................................................................................... 10 
1.1.4 
Exploratory objectives ........................................................................................... 10 
1.2 
Study design ........................................................................................................... 12 
1.3 
Number of patients ................................................................................................. 15 
2. 
ANALYSIS SETS ................................................................................................. 15 
2.1 
Definition of analysis sets ...................................................................................... 15 
2.1.1 
Full analysis set ...................................................................................................... 15 
2.1.2 
PK analysis set ....................................................................................................... 15 
2.2 
Protocol deviations ................................................................................................. 16 
3. 
PRIMARY AND SECONDARY VARIABLES ................................................... 17 
3.1 
Efficacy .................................................................................................................. 17 
3.1.1 
Derivation of RECIST visit responses ................................................................... 17 
3.1.1.1 
Target lesions ......................................................................................................... 19 
3.1.1.2 
Non-target lesions and new lesions ........................................................................ 24 
3.1.1.3 
Overall visit response ............................................................................................. 26 
3.2 
Efficacy variables ................................................................................................... 26 
3.2.1 
Primary endpoint .................................................................................................... 26 
3.2.1.1 
Objective response rate .......................................................................................... 26 
3.2.2 
Secondary endpoints .............................................................................................. 27 
3.2.2.1 
Duration of response .............................................................................................. 27 
3.2.2.2 
Disease control rate ................................................................................................ 28 


Statistical Analysis Plan  
Study Code D419QC00002 
Edition Number 4.0  
Date 12 Apr 2019 
3 
3.2.2.3 
Time to response .................................................................................................... 28 
3.2.2.4 
Progression-free survival ....................................................................................... 28 
3.2.2.5 
Overall survival ...................................................................................................... 30 
3.3 
Safety variables ...................................................................................................... 30 
3.3.1 
Adverse events ....................................................................................................... 30 
3.3.2 
Adverse events of special interest .......................................................................... 31 
3.3.3 
Duration of exposure .............................................................................................. 31 
3.3.4 
Dose intensity ......................................................................................................... 32 
3.3.5 
ECG ........................................................................................................................ 33 
3.3.6 
Vital signs .............................................................................................................. 33 
3.3.7 
General considerations for safety assessments ...................................................... 34 
3.4 
Biomarker variables ............................................................................................... 36 
3.5 
Pharmacokinetics and immunogenicity variables .................................................. 36 
3.5.1 
Pharmacokinetic analysis ....................................................................................... 36 
3.5.2 
Immunogenicity analysis ....................................................................................... 37 
4. 
ANALYSIS METHODS ....................................................................................... 37 
4.1 
General principles .................................................................................................. 37 
4.2 
Analysis methods ................................................................................................... 38 
4.2.1 
Patient disposition .................................................................................................. 38 
4.2.2 
Protocol deviations ................................................................................................. 38 
4.2.3 
Demographics and other baseline characteristics .................................................. 38 
4.2.4 
Medical history ...................................................................................................... 39 
4.2.5 
Disease history ....................................................................................................... 39 
4.2.6 
Concomitant medication ........................................................................................ 39 
4.2.7 
Exposure ................................................................................................................ 40 
4.2.8 
Efficacy .................................................................................................................. 40 
4.2.8.1 
Objective response rate .......................................................................................... 40 
4.2.8.2 
Duration of response .............................................................................................. 40 
4.2.8.3 
Disease control rate ................................................................................................ 40 
4.2.8.4 
Time to response .................................................................................................... 41 
4.2.8.5 
Progression-free survival ....................................................................................... 41 
4.2.8.6 
Overall survival ...................................................................................................... 41 
4.2.9 
Sensitivity analyses ................................................................................................ 41 
4.2.10 
Safety ..................................................................................................................... 42 
4.2.10.1 Adverse events ....................................................................................................... 42 
4.2.10.2 Laboratory evaluations ........................................................................................... 44 
4.2.10.3 ECG assessments ................................................................................................... 45 
4.2.10.4 Vital signs and weight ............................................................................................ 46 
4.2.10.5 ECOG performance status ..................................................................................... 46 
 
 
4.2.12 
Pharmacokinetics and immunogenicity ................................................................. 46 
4.2.12.1 Pharmacokinetic data ............................................................................................. 46 
4.2.12.2 Immunogenicity data ............................................................................................. 47 
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Study Code D419QC00002 
Edition Number 4.0  
Date 12 Apr 2019 
4 
5. 
INTERIM ANALYSES ......................................................................................... 47 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL (NOT APPLICABLE) .......... 48 
7. 
REFERENCES (NOT APPLICABLE) ................................................................. 48 
8. 
APPENDIX – PROTOCOL DEVIATION INSTRUCTIONS .............................. 48 
 
 
 
 
 


Statistical Analysis Plan  
Study Code D419QC00002 
Edition Number 4.0  
Date 12 Apr 2019 
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LIST OF TABLES 
Table 1 
Summary of outcome variables and analysis populations ........................ 15 
Table 2 
  TL visit responses ................................................................................... 20 
Table 3 
  NTL visit responses ................................................................................ 24 
Table 4 
 Overall visit response .............................................................................. 26 
Table 5 
  
 
 
 
 
LIST OF FIGURES 
Figure 1  
Overall study design ................................................................................. 13 
 
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Statistical Analysis Plan  
Study Code D419QC00002 
Edition Number 4.0  
Date 12 Apr 2019 
6 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
ADAs 
Antidrug antibodies 
AE(s) 
Adverse event(s) 
AESI(s) 
Adverse event(s) of special interest 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve  
BID 
Twice daily 
BMI 
Body mass index 
BoR 
Best objective response 
BP 
Blood pressure 
CBDP 
Carboplatin 
CI(s) 
Confidence interval(s) 
CR 
Complete response 
CrCl 
Creatinine clearance 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CT 
Computed tomography 
 
 
CTC 
Common toxicity criteria 
 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLL3 
Delta-Like 3 (Drosophila) 
DNA 
Deoxyribonucleic acid 
DCO 
Data cut-off 
DCR 
Disease control rate 
DoR 
Duration of response 
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Edition Number 4.0  
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Abbreviation or 
special term 
Explanation 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ED-SCLC 
Extensive-stage small cell lung cancer 
FAS 
Full Analysis Set 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase/gamma-glutamyl transpeptidase 
 
 
IFN 
Interferon 
IPDs 
Important protocol deviations 
IV 
Intravenous 
KM 
Kaplan-Meier 
LD 
Longest diameter 
MDS/AML 
Myelodysplastic syndrome/acute myeloid leukaemia 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NA 
Not applicable 
NE 
Not evaluable 
NED 
No evidence of disease 
NTL(s) 
Non-target lesion(s) 
ORR 
Objective response rate 
OS 
Overall survival 
p53 
Tumour protein 53 
PD 
Progressive disease 
PD-L1 
Programmed cell death ligand 1 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PO 
By mouth 
PR 
Partial response 
PS 
Performance status 
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Study Code D419QC00002 
Edition Number 4.0  
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8 
Abbreviation or 
special term 
Explanation 
PT 
Preferred term 
q3w 
Every three weeks 
q4w 
Every four weeks 
QD 
Once a day 
QTcF 
Fridericia QTc correction 
RDI 
Relative dose intensity 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumours, version 1.1 
RR 
Interval between the R spikes of 2 consecutive complexes on an ECG 
SAE(s) 
Serious adverse event(s) 
SD 
Stable disease 
SOC 
System organ class 
T3 
Triiodothyronine 
T4 
Thyroxine 
TL(s) 
Target lesion(s) 
 
 
TSH 
Thyroid-stimulating hormone 
TTR 
Time to response 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
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Statistical Analysis Plan  
Study Code D419QC00002 
Edition Number 4.0  
Date 12 Apr 2019 
9 
AMENDMENT HISTORY 
Date 
Brief description of change 
30 November 2016 N/A 
16 January      
2017      
Updated after the CRM 
18 January      
2017 
Updated after medics’ comments 
15 February 2017 
Additional sensitivity analysis was added 
22 May 2017 
Amended as per protocol amendment 1 (protocol version 2.0 dated 30 March 
2017) 
30 June 2017 
Updated after medic’s comments 
25 August 2018 
Amended as per protocol amendment (protocol version 4.0 dated 25 June 
2018) due to addition of Arm C and Arm A expansion  
18 February 2019  
Revise the definition of important protocol deviations and the visit window for 
safety assessments. 
12 April 2019  
Revise the definition of important protocol deviation: Baseline RECIST 
1.1 scan more than 42 days before start date of study treatment 
(Deviation 3) 
 
 
 


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Study Code D419QC00002 
Edition Number 4.0  
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1. 
STUDY DETAILS 
1.1 
Study objectives 
1.1.1 
Primary objective 
Primary Objective: 
Outcome Measure: 
To assess the preliminary efficacy of each 
treatment arm in terms of objective response 
rate (ORR) 
ORR using Investigator assessments 
according to Response Evaluation Criteria in 
Solid Tumours, version 1.1 (RECIST 1.1) 
 
1.1.2 
Secondary objectives 
Secondary Objective: 
Outcome Measure: 
To further assess the preliminary efficacy of 
each treatment arm in terms of duration of 
response (DoR), disease control rate (DCR), 
time to response (TTR), progression-free 
survival (PFS), and overall survival (OS) 
DoR, DCR, TTR, and PFS using Investigator 
assessments according to RECIST 1.1 
OS 
To assess the pharmacokinetics (PK) of novel 
combination treatments (Arm A stage 1 and 2 
only, Arms B and C only) 
Concentration of novel combination 
treatments in blood 
 
1.1.3 
Safety objectives 
Safety Objective: 
Outcome Measure: 
To assess the safety and tolerability profile of 
each treatment arm 
Adverse events (AEs); physical examinations; 
vital signs, including blood pressure (BP) and 
pulse; electrocardiograms (ECGs); and 
laboratory findings, including clinical 
chemistry, haematology, and urinalysis 
 
1.1.4 
Exploratory objectives 
Exploratory Objective: 
Outcome Measure: 
 
 
 
 
 
 
 
 
 
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Exploratory Objective: 
Outcome Measure: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Exploratory Objective: 
Outcome Measure: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2 
Study design 
This is a Phase II, open-label, multi-drug, multi-center, multi-arm study to determine the 
preliminary efficacy of novel combinations of treatment in patients with Extensive-stage 
disease small-cell lung cancer (ED-SCLC) who have refractory or resistant disease, defined as 
patients who progress during first-line platinum-based chemotherapy or those who progress 
within 90 days after completing first-line platinum-based chemotherapy. 
This multi-arm study initially opened with 2 arms (Arms A and B), and an additional arm 
(Arm C) was added in version 3; additional arms may be opened provided there is compelling 
rationale for the combination and a safe and tolerable dose and schedule have been determined 
from ongoing Phase I studies.The 3 experimental arms are: 
 
 Arm A: Durvalumab 1500 mg + tremelimumab 75 mg via intravenous (IV) infusion 
every 4 weeks (q4w), starting on Week 0, for up to a total of 4 doses/cycles) followed 
by durvalumab monotherapy 1500 mg via IV infusion q4w, starting after completion 
of the 4th cycle of combination treatment until confirmed progressive disease (PD) and 
Investigator confirmation that the patient is no longer receiving clinical benefit from 
the treatment, or for other discontinuation criteria. If a patient’s weight falls to 30 kg or 
less, the patient should receive weight-based dosing after discussion between 
Investigator and Study Physician, until the weight improves to > 30 kg, at which point 
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the patient should start receiving the fixed dosing of durvalumab 1500mg and 75mg 
tremelimumab q4w (during the combination phase of treatment). The equivalent 
weight based doses to the fixed doses are 20 mg/kg of durvalumab and 1 mg/kg 
tremelimumab q4w.    
 Arm B: AZD1775 225 mg twice daily (BID) by mouth (PO) for 2.5 days from Day 1 + 
Carboplatin (CBDP) area under the curve (AUC) 5 Day 1 IV; every 3 weeks (q3w) 
until PD.  
The CBDP dose will be calculated using the Calvert formula based on the patient’s 
Glomerular filtration rate (GFR), which is estimated by using the Creatinine Clearance 
(CrCl). 
 
Calvert formula: CBDP dose (mg) = target AUC × (GFR + 25) 
 
where CrCl (GFR) = [(140 – age) × (wt. in kg)] × F / (72 × serum creatinine [mg/dL]),   
 where F = 0.85 for females and F =1 for males.  
 Arm C: AZD6738 160 mg once daily (QD) days 1-7 + olaparib 300 mg BID days 1-
28; every 4 weeks (q4w) until PD. 
 
The schematic diagram of the study design of each treatment arm is shown in  
Figure 1 below. 
 
Figure 1  
Overall study design 
 
 


Statistical Analysis Plan  
Study Code D419QC00002 
Edition Number 4.0  
Date 12 Apr 2019 
14 
Note: Arm A = durvalumab + tremelimumab followed by durvalumab monotherapy; Arm B = AZD1775 + 
carboplatin [CBDP]; Arm C = AZD6738 + olaparib; ED-SCLC: Extensive-stage disease small-cell lung cancer; 
ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival 
This study will enroll up to 40 eligible patients in each treatment arm. Stage 1 will initially 
enroll a minimum of 10 patients; after a minimum of 12 weeks an interim analysis will be 
performed, which will determine whether recruitment should expand to the second stage (an 
additional 10 patients for a total of 20 eligible patients) or stop. If the results of the primary 
ORR from the completed 2nd stage are encouraging the Review Committee could recommend 
expansion to add up to an additional 20 eligible subjects (for a total of 40 eligible patients), to 
further explore the findings. 
There is no randomization in the study. 
 
 
All patients in the study will be followed for preliminary efficacy, safety and tolerability of 
each treatment arm as per the study plan. 
All patients should be assessed as described in the study plan until PD and Investigator 
confirmation that the patient is no longer receiving clinical benefit from the treatment, or for 
other discontinuation criteria. Then all patients should be followed up for overall survival. 


Statistical Analysis Plan  
Study Code D419QC00002 
Edition Number 4.0  
Date 12 Apr 2019 
15 
1.3 
Number of patients 
This study will enroll up to 40 eligible patients in each treatment arm. 
The table below shows the 2-sided exact 95% confidence intervals (CI) for the ORR of a 
treatment arm at each stage of the study, assuming the observed ORR is 
% or 
%: 
ORR 
% 
% 
Stage 1 (10 patients) 
(
%, 
%) 
(
%, 
%) 
Stage 2 (20 patients in total)) 
(
%, 
%) 
(
%, 
3%) 
Expansion (40 patients in total) 
(
%, 
%) 
(
%, 
%) 
 
2. 
ANALYSIS SETS 
2.1 
Definition of analysis sets 
Definitions of the analysis sets for each outcome variable are provided in Table 1. 
Table 1 
Summary of outcome variables and analysis populations 
Outcome variable 
Population 
Efficacy data 
 
ORR, DoR, DCR, TTR, PFS, and OS 
Full analysis set 
Demography 
Full analysis set 
    PK data 
PK analysis set 
Safety data 
 
Exposure 
Full analysis set 
    AEs including AESI 
Full analysis set 
Laboratory measurements 
Full analysis set 
Vital signs 
Full analysis set 
     ECGs 
Full analysis set 
 
2.1.1 
Full analysis set 
The Full Analysis Set (FAS) will include all treated patients. Patients who were enrolled but 
did not subsequently go on to receive investigational product are not included in the FAS. 
There is no separate Safety Analysis Set because all treated patients are included in the Full 
Analysis set and analysed for safety. 
2.1.2 
PK analysis set 
All patients who received at least one dose of study treatment per the protocol for whom any 
post-dose data are available and who do not violate or deviate from the protocol in ways that 
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would significantly affect the PK analyses will be included in the PK Analysis Set. The 
population will be defined by the Study Physician, Pharmacokineticist, and Statistician prior 
to any analyses being performed.  
2.2 
Protocol deviations 
Eligibility criteria deviations are deviations from the protocol inclusion and exclusion criteria. 
Post-entry deviations are deviations from the protocol that occurred after the patient was 
assigned to study treatment. Protocol deviations are classified as major and minor during the 
study and will be reviewed by the study statistician and study physician to determine 
importance (i.e. whether the deviation could impact the study results for that patient). 
Important protocol deviations (IPDs) are defined as a subset of protocol deviations that may 
significantly affect the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect safety. 
The following general categories will be considered important deviations which may be listed 
and discussed in the clinical study report (CSR) as appropriate for the study: 
 Study medication is not administered according to the CSP, i.e, overdose,  wrong dose, 
wrong drug (Deviation 1). 
 Patients who deviate from key entry criteria per the Clinical Study Protocol (CSP) 
(Deviation 2) 
 Baseline RECIST 1.1 scan more than 42 days before start date of study treatment 
(Deviation 3) 
 No baseline RECIST 1.1 assessment on or before start of study treatment (Deviation 4) 
 Prohibited medication deviation (including other anticancer agents) (Deviation 5). 
Please refer to protocol sections 18.7 and 28.7 for those medications that are detailed 
as being ‘excluded’ from permitted use during the study for each arm. These will be 
used as guiding principle for the physician review of all medications prior to database 
lock.  
 Tumor assessment is not done according to Protocol or RECIST 1.1 
Criteria (Deviation 6). 
 
If any patients have any other protocol deviations, which are considered important by the 
study team, these will also be described.  
Patients who violate or deviate from the protocol in ways that would significantly affect the 
PK analysis such as out sampling window or vomiting after taking oral drug will be excluded 
from the PK Analysis Set according to PK scientist opinion after reviewing PK data.  
Determination of the important deviations above will be based on monitoring notes and where 
feasible programmatic determination from the clinical database. 


Statistical Analysis Plan  
Study Code D419QC00002 
Edition Number 4.0  
Date 12 Apr 2019 
17 
 
The final classification of important protocol deviations will be made by the study physician 
in collaboration with the study statistician prior to database lock or data cut-off.   
 
Important protocol deviations will be listed and summarised separately by treatment arm.   
For a detailed description of Protocol Deviation (PD) collection process and classification 
please see Annex 1 – Protocol Deviation Instructions. 
3. 
PRIMARY AND SECONDARY VARIABLES 
3.1 Efficacy 
3.1.1 
Derivation of RECIST visit responses 
From the investigators review of the imaging scans, the RECIST tumour response data will be 
used to determine each patient’s visit response according to RECIST 1.1.  It will also be used 
to determine if and when a patient has progressed in accordance with RECIST 1.1.   
Baseline radiological tumour assessments should be performed no more than 28 days before 
the start of study treatment, and ideally as close as possible to the start of study treatment.  
The RECIST 1.1 assessments of baseline images identify target (defined measurable) and non-
target lesions, and each lesion (and any new lesion) is evaluated in subsequent on-treatment 
follow-up images. This allows determination of follow-up target lesion response, non-target 
lesion response, and overall time point tumour responses (complete response [CR], partial 
response [PR], stable disease [SD], progressive disease [PD], or not evaluable [NE]).    
Efficacy for all patients (both treatment arms) will be assessed on images collected either 
every 6 or 8 weeks ± 1 week (dependent on treatment arm) until confirmed objective disease 
progression or when the patient has been taken off-study. Tumour assessments specific to 
each treatment arm are performed at the following time points:  
 Arm A: at baseline and at Week 8, Week 12 and then every 8 weeks ± 1 week until 
confirmed objective disease progression or off-study. For patients treated beyond 
progression RECIST 1.1 assessments will continue every 8 weeks until the patient no 
longer experiences clinical benefit. 
 Arm B: at baseline and then every 6 weeks ± 1 week until objective disease 
progression or off-study.  
 Arm C: at baseline and at Week 8, Week 12 and then every 8 weeks ± 1 week, from 
the first day of investigational drug administration for the first 72 weeks, then every 12 
weeks ± 1 week thereafter, until disease progression. 


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In the absence of significant clinical deterioration, or in the case of any doubt, treatment with 
study drug may continue between the initial assessment of progression and a subsequent scan 
to confirm progression. 
If an unscheduled assessment is performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits.  This 
schedule is to be followed in order to minimize any unintentional bias caused by some patients 
being assessed at a different frequency than other patients. 
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to 
radiologic progression, then the patient should continue to be followed with scheduled 
imaging until confirmed objective disease progression. 
According to RECIST 1.1, objective tumour response (CR or PR) should be confirmed 
preferably at the next scheduled imaging visit and not less than 4 weeks after the visit when 
the response was last observed.   
At each visit, patients will be programmatically assigned an overall visit response of CR, PR, 
SD or PD using the information from TLs, NTLs and new lesions and depending on the status 
of their disease compared with baseline and previous assessments.  If a patient has had a 
tumour assessment which cannot be evaluated, then the patient will be assigned a visit 
response of NE (unless there is evidence of progression, in which case the response will be 
assigned as PD). 
All RECIST 1.1 assessments, scheduled or unscheduled, will be included in the calculations.  
This is also regardless of whether a patient discontinues study treatment or receives another 
anti-cancer therapy. 
Arm A only 
For the immunotherapy arm only (Arm A: durvalumab + tremelimumab followed by 
durvalumab monotherapy), a confirmatory scan is required following the prior demonstration 
of PD. The confirmatory scan should occur preferably at the next scheduled visit and no 
earlier than 4 weeks following the date the criteria for response were first met or after the prior 
assessment of PD. Confirmation of progression guidelines are set for the following reasons: 
 for patient management and treatment decisions 
 in the absence of significant clinical deterioration, to promote the collection of 
additional scans after the first radiologic RECIST 1.1 assessment of progressive 
disease (PD) in order to distinguish pseudo-progression from true radiologic 
progression, also known as RECIST 1.1 modified for confirmation of progression. 
Confirmed objective disease progression refers to either of the following scenarios: 1. Clinical 
progression/deterioration followed by a radiologic verification scan (PD by RECIST 1.1) or 2. 
In the absence of significant clinical deterioration, radiologic PD by RECIST 1.1 followed by 
a second radiologic confirmation scan with PD assessed according to specific confirmation of 


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progression criteria listed below. RECIST 1.1 modified for confirmation of progression refers 
to the second scenario above. The confirmation scan should occur preferably at the next 
scheduled imaging visit and no earlier than 4 weeks following the date of the immediate prior 
assessment of RECIST 1.1 PD.   
Immediate prior radiologic progression in the confirmatory scan would be considered 
confirmed if the following criteria are met with the confirmatory scan: 
 ≥20% increase in the sum diameters of target lesions (TLs) compared with the nadir at 
two consecutive visits, with an absolute increase of at least 5mm in sum of diameters 
compared to nadir,  
 and/or significant progression (worsening) of non-target lesions (NTLs) and/or of pre-
existing new lesions at the confirmatory scan time point compared with the immediate 
prior time point (Note: Pre-existing new lesions are evaluated as NTLs at the 
confirmatory scan time-point),  
 and/or additional new unequivocal lesions at the confirmatory scan time point. 
Note: In order to have confirmed objective disease progression, there should be two 
consecutive PD’s, the first PD by RECIST 1.1 and the second PD using the confirmation of 
progression criteria (above). If the first PD by RECIST 1.1 is not confirmed, continue with 
assessments until the next PD by RECIST 1.1, which in turn will need its own immediate 
subsequent confirmation scan.  
In the absence of significant clinical deterioration, treatment with study drug may continue 
between the initial assessment of progression and the scan to confirm progression.  
If the confirmation scan confirms progression, then the date of the prior scan with PD should 
be declared as the date of progression. 
If progression is not confirmed, in the absence of significant clinical deterioration, then the 
patient should continue study drug and on-treatment assessments until the next PD which will 
also require a follow-up confirmation scan. If the first PD is not confirmed by the immediate 
next scan, then the Investigator should not change the PD assessment of the first scan. 
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to 
radiologic progression, then the patient should still continue to be followed until confirmed 
objective disease progression. 
3.1.1.1 
Target lesions 
Measurable disease is defined as having at least one measurable (by RECIST 1.1) lesion, that 
has not been previously irradiated, which is ≥10 mm in the longest diameter (except lymph 
nodes, which must have short axis ≥15 mm) with computed tomography (CT) or magnetic 
resonance imaging (MRI) and which is suitable for accurate repeated measurements.  


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A patient can have a maximum of five measurable lesions, with a maximum of two lesions per 
organ (representative of all lesions involved suitable for accurate repeated measurements) and 
these are referred to as TLs at baseline.  If more than one baseline scan is recorded then 
measurements from the one that is closest and prior to start of study treatment will be used to 
define the baseline sum of TLs.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion, 
which can be measured reproducibly, should be selected. 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits. 
Table 2 provides the definitions of the criteria used to determine objective tumour visit 
response for TL. 
Table 2  
 TL visit responses 
Visit Responses 
Description 
CR 
Disappearance of all TLs since baseline.  Any pathological lymph nodes 
selected as TLs must have a reduction in short axis to <10 mm. 
PR 
At least a 30% decrease in the sum of the diameters of TLs, taking as 
reference the baseline sum of diameters as long as criteria for PD are not 
met. 
SD 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD. 
PD 
At least a 20% increase in the sum of the diameters of TLs, taking as 
reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on the study). In addition to the relative increase of at least 
20%, the sum must also demonstrate an absolute increase of at least 5 
mm.  
NE 
Only relevant if any of the TLs were not assessed or not evaluable or had 
a lesion intervention at this visit.   
Note:  If the sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a TL response. 
NA 
No TLs are recorded at baseline. 
CR: Complete response, NA: Not applicable, NE: Not evaluable, PD: Progressive disease, PR: Partial 
response, SD: Stable disease, TL: Target lesion. 
Rounding of TL data 
For calculation of PD and PR for TLs, percentage changes from baseline and previous 
minimum should be rounded to 1 decimal place before assigning a TL response.  For example, 
19.95% should be rounded to 20.0% but 19.94% should be rounded to 19.9%.   
Missing TL data  


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For a visit to be evaluable, all TL measurements should be recorded.  However, a visit 
response of PD should still be assigned if any of the following occurred: 
 A new lesion is recorded 
 A NTL visit response of PD is recorded 
 The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute 
increase of ≥5 mm, from nadir even assuming the non-recorded TLs have disappeared. 
The nadir (i.e., smallest measurement) can only be taken from assessments where all the TLs 
had a longest diameter (LD) recorded. 
Lymph nodes 
For lymph nodes, if the size reduces to <10 mm, these are considered non-pathological.  
However, a size will still be measured and this size should still be used to determine the TL 
visit response as normal.  In the special case where all lymph nodes are <10 mm and all other 
TLs are 0 mm, then although the sum may be >0 mm, the calculation of TL response should 
be over-written as a CR.  
TL visit responses subsequent to CR 
A CR response can only be followed by CR, PD or NE.  If a CR has occurred then the 
following rules at the subsequent visits must be applied: 
 Step 1:  If all lesions meet the CR criteria (i.e., 0 mm or <10 mm for lymph nodes), the 
response will be set to CR irrespective of whether the criteria for PD of TL is also met 
for lymph node (i.e., if a lymph node LD increases by 20% but remains <10 mm). 
 Step 2:  If some lesion measurements are missing but all other lesions meet the CR 
criteria (i.e., 0 mm or <10 mm for lymph nodes), the response will be set to NE 
irrespective of whether the criteria for PD is also met when referencing the sum of TL 
diameters. 
 Step 3:  If not all lesions meet the CR criteria, and the sum of lesions meets the criteria 
for PD, the response will be set to PD. 
 Step 4:  If, after steps 1 through 3, a response can still not be determined, the response 
will be set to remain as CR. 
TL too big to measure 
If a TL becomes too big to measure, this should be indicated in the database and an estimated 
size (‘x’) above which it cannot be accurately measured should be recorded.  If using a value 
of x in the calculation of TL response would not give an overall visit response of PD, then this 


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will be flagged and reviewed by the study team.  It is expected that a visit response of PD will 
remain in the vast majority of cases. 
TL too small to measure 
If a TL becomes too small to measure, a value of 5 mm will be entered into the database and 
used in TL calculations, unless the radiologist has indicated and entered a smaller value that 
can be reliably measured.  If a TL response of PD results then this will be reviewed by the 
study team.  
Irradiated lesions/lesion intervention 
Previously irradiated lesions (i.e., lesion irradiated prior to entry into the study) should be 
recorded as NTLs and should not form part of the TL assessment. 
Any TL (including lymph nodes) which has had intervention during the study (for example, 
irradiation/palliative surgery/embolization) should be handled in the following way and once a 
lesion has had intervention then it should be treated as having intervention for the remainder 
of the study, noting that an intervention will most likely shrink the size of tumours: 
 Step 1: the diameters of the TLs (including the lesions that have had intervention) will 
be summed and the calculation will be performed in the usual manner.  If the visit 
response is PD this will remain as a valid response category.  
 Step 2: If there was no evidence of progression after step 1, treat the lesion diameter 
(for those lesions with intervention) as missing and, if ≤1/3 of the TLs have missing 
measurements, scale up as described in the scaling section below.  If the scaling results 
in a visit response of PD then the patient would be assigned a TL response of PD.   
 Step 3: If after both steps PD has not been assigned, then, if appropriate (ie, if ≤1/3 of 
the TLs have missing measurements), the scaled sum of diameters as calculated in 
Step 2 should be used, and PR or SD then assigned as the visit response.  Patients with 
intervention are evaluable for CR as long as all non-intervened lesions are 0 (or 
<10 mm for lymph nodes) and the lesions that have been subject to intervention also 
has a value of 0 recorded.  If scaling up is not appropriate due to too few non-missing 
measurements then the visit response will be set to NE. 
At subsequent visits the above steps will be repeated to determine the TL and overall visit 
response.  When calculating the previous minimum, lesions with intervention should be 
treated as missing and scaled up (as per step 2 above). 
Scaling (applicable only for irradiated lesions/lesion intervention) 
If >1/3 of TL measurements are missing (because of intervention) then the TL response will 
be NE, unless the sum of diameters of non-missing TL would result in PD (ie, if using a value 


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of 0 for missing lesions, the sum of diameters has still increased by 20% or more compared to 
nadir and the sum of TLs has increased by ≥5 mm from nadir). 
If ≤1/3 of the TL measurements are missing (because of intervention) then the results will be 
scaled up (based on the sizes at the nadir visit to give an estimated sum of diameters) and this 
will be used in calculations; this is equivalent to comparing the visit sum of diameters of the 
non-missing lesions to the nadir sum of diameters excluding the lesions with missing 
measurements. 
Example of scaling 
Lesion 
Longest diameter at nadir visit 
Longest diameter at follow-up visit 
1 
7.2 
7.1 
2 
6.7 
6.4 
3 
4.3 
4.0 
4 
8.6 
8.5 
5 
2.5 
intervention 
Sum 
29.3 
26 
 
Lesion 5 is missing at the follow-up visit.  
The sum of lesions 1 to 4 at the follow-up visit is 26 cm.  The sum of the corresponding 
lesions at the nadir visit is 26.8 cm. 
Scale up as follows to give an estimated TL sum of 28.4 cm: 
 
26
26.8 × 29.3 = 28.4 cm 
CR will not be allowed as a TL response for visits where there is missing data.  Only PR, SD 
or PD (or NE) could be assigned as the TL visit response in these cases.  However, for visits 
with  1/3 lesion assessments not recorded, the scaled up sum of TLs diameters will be 
included when defining the nadir value for the assessment of progression. 
Lesions that split 
If a TL splits into two or more parts, then the LDs of the split lesions should be summed and 
reported as the LD for the lesion that split. 
Lesions that merge 
If two or more TLs merge, then the LD of the merged lesion should be recorded for one of the 
TL sizes and the other TL size(s) should be recorded as 0 mm. 
Change in method of assessment of TLs 


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CT, MRI and clinical examination are the only methods of assessment that can be used within 
a trial, with CT and MRI being the preferred methods and clinical examination only used in 
special cases.  If a change in method of assessment occurs between CT and MRI this will be 
considered acceptable and no adjustment within the programming is needed.   
If a change in method involves clinical examination (eg, CT changes to clinical examination 
or vice versa), any affected lesions should be treated as missing.  The TL visit response may 
still be evaluable if the number of missing TL measurements at a visit is ≤1/3 of the total 
number of TLs. 
3.1.1.2 
Non-target lesions and new lesions 
At each visit, an overall assessment of the NTL response should be recorded by the 
Investigator. Table 3 provides the definitions of the criteria used to determine and record 
overall response for NTLs at the investigational site at each visit. 
NTL response will be derived based on the investigator’s overall assessment of NTLs as 
follows: 
Table 3  
 NTL visit responses 
Visit Responses 
Description 
CR 
Disappearance of all NTLs since baseline.  All lymph nodes must be 
non-pathological in size (<10 mm short axis). 
Non CR/Non PD 
Persistence of one or more NTLs (with no evidence of progression). 
PD 
Unequivocal progression of existing NTLs.  Unequivocal progression 
may be due to an important progression in one lesion only or in 
several lesions.  In all cases, the progression MUST be clinically 
significant for the physician to consider changing (or stopping) 
therapy.  
NE 
Only relevant when one or some of the NTLs were not assessed and, 
in the Investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit. 
Note:  For patients without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression criteria 
have not been met. 
NA 
Only relevant if there are no NTLs at baseline. 
CR Complete response, NA Not applicable, NE Not evaluable, PD Progressive disease, NTL Non-target 
lesion 
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumour burden has increased sufficiently to merit a determination of progression.  
A modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for 
unequivocal progression status. 


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Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression. 
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered as a new lesion and will indicate disease progression. 
The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality, or findings thought to represent something 
other than tumour. 
New lesions will be identified via a Yes/No tick box.  The absence and presence of new 
lesions at each visit should be listed alongside the TL and NTL visit responses. 
A new lesion indicates progression so the overall visit response will be PD irrespective of the 
TL and NTL response. 
If the question ‘Any new lesions since baseline’ has not been answered with Yes or No and 
the new lesion details are blank, this is not evidence that no new lesions are present and 
should be treated as NE in the derivation of overall visit response. 
Symptomatic progression is not a descriptor for progression of NTLs: it is a reason for 
stopping study therapy and will not be included in any assessment of NTLs. 
Patients with ‘symptomatic progression’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumour 
assessments, where possible, until objective disease progression is observed. 
 


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3.1.1.3 
Overall visit response 
Table 4 defines how the previously defined TL and NTL visit responses will be combined 
with new lesion information to give an overall visit response. 
Table 4  
Overall visit response 
Target lesions 
Non-target lesions 
New lesions 
Overall visit 
response 
CR 
CR (or NA) 
No 
CR 
CR 
Non CR/Non PD or NE 
No (or NE) 
PR 
PR 
Non PD or NE 
No (or NE) 
PR 
SD 
Non PD or NE 
No (or NE) 
SD 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Yes 
PD 
NE 
Non PD 
No 
NE 
NA 
CR 
No 
CR 
NA 
Non CR/Non PD  
No 
SD 
NA 
NE 
No (or NE) 
NE 
NA 
NA 
No (or NE) 
NED 
CR Complete response, NA Not applicable (only relevant if there were no NTLs at baseline), NE Not 
evaluable, NED No evidence of disease, PD Progressive disease, PR Partial response, SD Stable disease. 
3.2 Efficacy variables 
3.2.1 
Primary endpoint 
3.2.1.1 
Objective response rate  
ORR is defined as the number (%) of patients with a confirmed investigator-assessed 
objective response of CR or PR and will based on patients in the FAS.   
A confirmed response of CR/PR means that a response of CR/PR is recorded at one visit and 
confirmed by repeat imaging, preferably at the next regularly scheduled imaging visit, and not 
less than four weeks after the visit when the response was first observed, with no evidence of 
progression between the initial and CR/PR confirmation visit.  Therefore, data obtained up to 
first progression (including unconfirmed), or the last evaluable assessment in the absence of 
progression, will be included in the assessment of ORR.  Any patient who discontinues 
treatment without progression, receives a subsequent therapy, and then responds will not be 
included as a responder for the ORR (ie, both visits contributing to a response must be prior to 
subsequent therapy for the patient to be considered as a responder). 
The denominator for ORR will be all patients in the FAS for the primary analysis. 


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A sensitivity analysis will be performed by assessing the ORR using the RECIST 1.1 – with 
data obtained up until progression, or the last evaluable assessment in the absence of 
progression, as for primary analysis - within a subgroup of FAS with baseline and at least one 
post-baseline RECIST 1.1 assessment. In this analysis, the denominator for the calculation of 
ORR will include those patients in the FAS who have baseline and at least one post-baseline 
RECIST 1.1 assessment. 
3.2.2 
Secondary endpoints 
3.2.2.1 
Duration of response 
DoR (per RECIST 1.1 according to the Investigator’s assessment) is defined as the time from 
the date of first documented response (which is subsequently confirmed) until the date of 
documented progression, or death in the absence of disease progression, in months and is 
calculated as follows:  
𝐷𝑜𝑅= 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑃𝐹𝑆 𝑒𝑣𝑒𝑛𝑡 𝑜𝑟 𝑐𝑒𝑛𝑠𝑜𝑟𝑖𝑛𝑔−𝑑𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑟𝑒𝑠𝑝𝑜𝑛𝑠𝑒+ 1
30.4375
 
 
The time of the initial response will be defined as the latest of the dates contributing toward 
the first visit response of CR or PR. 
If a patient does not progress following a response, then their DoR will use the PFS censoring 
time (see section 3.2.2.4).  DoR will not be defined for those patients who do not have 
documented response (which is subsequently confirmed). 
Sensitivity analyses of DoR may be performed based on Investigator assessment according to 
RECIST 1.1 modified for confirmation of progression, as described for ORR in section 
3.2.1.1. 
 


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3.2.2.2 
Disease control rate 
DCR at 12 weeks is defined as the percentage of patients who have a best objective response 
of CR or PR in the first 13 weeks (to allow for a late assessment within the assessment 
window) or who have demonstrated SD for a minimum interval of 11 weeks (to allow for an 
early assessment within the assessment window) following the start of study treatment.  
DCR will be determined programmatically based on RECIST 1.1 using site Investigator data 
and all data up until the first progression event. 
Sensitivity analyses of DCR may be performed based on Investigator assessment according to 
RECIST 1.1 modified for confirmation of progression, as described in section 3.2.1.1. 
3.2.2.3 
Time to response 
TTR (per RECIST 1.1 as assessed by the Investigator) is defined as the time from the date of 
first dose until the first date of documented response (which is subsequently confirmed), in 
months and is calculated as follows:  
𝑇𝑇𝑅= date of DoR event –  date of first dose + 1
30.4375
 
The date of first documented response should coincide with that used for the RECIST 1.1 
DoR endpoint (see section 3.2.2.1).  
TTR will not be defined for those patients who do not have documented response (which is 
subsequently confirmed). 
3.2.2.4 
Progression-free survival 
PFS (per RECIST 1.1 according to the Investigator’s assessment) is defined as the time from 
the date of the first dose of study treatment until the date of objective disease progression or 
death (by any cause in the absence of progression) regardless of whether the patient withdraws 
from allocated therapy or receives another anti-cancer therapy prior to progression, in months 
and is calculated as follows:   
𝑃𝐹𝑆= 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑜𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒 𝑑𝑖𝑠𝑒𝑎𝑠𝑒 𝑝𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛 𝑜𝑟 𝑐𝑒𝑛𝑠𝑜𝑟𝑖𝑛𝑔−𝑑𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒+ 1
30.4375
 
Patients who have not progressed or died at the date of data cut-off (DCO) will be censored at 
the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment. 
However, if the patient progresses or dies after two or more missed visits, the patient will be 
censored at the time of the latest evaluable RECIST 1.1 assessment.   


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Given that the scheduled tumour assessment scheme differs by treatment arm (see Section 
3.1), the definition of two missed visits will change. 
Arm A 
 Up to and including Week 12, two missing visits will equate to 14 weeks (12 weeks +2 
x1 weeks for visit window)). 
 From Week 12 onwards (when the scheduling is every eight-weekly assessments), two 
missing visits will equate to 18 weeks (i.e. 2 × 8 weeks + 2 x 1 week for visit window 
= 18 weeks). 
Arm B 
 From Day 1 onwards (when the scheduling is every six-weekly assessments), two 
missing visits will equate to 14 weeks (i.e. 2 × 6 weeks + 2 x 1 week for visit window 
= 14 weeks).  
Arm C 
 Up to and including Week 12, two missing visits will equate to 14 weeks (12 weeks + 
2 x 1 week for visit window). 
 From Week 12 to Week 72 (inclusive) (when the scheduling is every eight-weekly 
assessments), two missing visits will equate to 18 weeks (i.e. 2 × 8 weeks + 2 x 1 week 
for visit window = 18 weeks). 
 From Week 72 onwards (when the scheduling is every twelve-weekly assessments), 
two missing visits will equate to 26 weeks (i.e. 2 × 12 weeks + 2 x 1 week for visit 
window = 26 weeks). 
If the patient has no evaluable visits or does not have baseline data, they will be censored at 
Study Day 1 unless they die within two visits of baseline (12 weeks + 2 weeks allowing for a 
late assessment within the visit window, for Arm A, Arm B and Arm C). 
The PFS time will always be derived based on scan/assessment dates not visit dates. 
RECIST 1.1 assessments/scans contributing towards a particular visit may be performed on 
different dates.  The following rules will be applied: 
 Date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression on the first set of scans that indicate 
progression. 
 When censoring a patient for PFS, the patient will be censored at the latest of the dates 
contributing to a particular overall visit assessment. 
In the absence of clinically significant deterioration, the investigational site is advised to 
continue the patients on their respective treatments until progression has been confirmed. 


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Sensitivity analyses of PFS may be performed based on Investigator assessment according to 
RECIST 1.1 modified for confirmation of progression, as described in section 3.2.1.1. 
3.2.2.5 
Overall survival 
OS is defined as the time from the date of the first dose of study treatment until death due to 
any cause, in months and is calculated as follows:  
𝑂𝑆= 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑑𝑒𝑎𝑡ℎ 𝑜𝑟 𝑐𝑒𝑛𝑠𝑜𝑟𝑖𝑛𝑔−𝑑𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒+ 1
30.4375
 
 
Any patient not known to have died before the date of DCO for the analysis will be censored 
at the date last known alive, or DCO. 
Note: Survival calls will be made in the week following the date of data cut-off for the 
analysis, and if patients are confirmed to be alive or if the death date is post the data cut-off 
date, these patients will be censored at the date of data cut-off. Death dates may be found by 
checking publicly available death registries. 
3.3 
Safety variables 
Safety and tolerability will be assessed in terms of AEs (including serious adverse events 
[SAEs]), deaths, laboratory data (including clinical chemistry, hematology and urinalysis), 
vital signs, ECGs and exposure.  These will be collected for all patients.  
Data from all cycles of treatment will be combined and the safety data will be presented by 
treatment arm.  
The FAS will be used for reporting of safety data. 
3.3.1 
Adverse events 
AEs and SAEs will be collected from the time the informed consent is signed throughout the 
treatment period, and up to the follow-up period, ie 90 days after the last dose of durvalumab 
or tremelimumab for patients in Arm A; 30 days after the last dose of AZD1775 or CBDP for 
patients in Arm B;  30 days after the last dose of AZD6738 or olaparib for patients in Arm C.   
On treatment, or treatment-emergent, AEs are defined as any AEs that started after the first 
dose of study treatment or started prior to treatment dosing that worsen following exposure to 
treatment, through 90 days after the last dose of durvalumab or tremelimumab for Arm A, up 
to 30 days after the last dose of AZD1775 or CBDP for Arm B, and up to 30 days after the last 
dose of AZD6738 or olaparib for Arm C. 
The latest version of Medical Dictionary for Regulatory Activities (MedDRA) will be used to 
code the AEs. AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for AEs ([CTCAE] Version 4.03).   


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3.3.2 
Adverse events of special interest 
AESIs for durvalumab ± tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent 
monitoring and/or interventions such as steroids, immunosuppressants, and/or hormone 
replacement therapy. These AESIs are being closely monitored in clinical studies with 
durvalumab monotherapy and combination therapy. 
AESIs for olaparib include but are not limited to events with myelodysplastic syndrome/acute 
myeloid leukaemia (MDS/AML), new primary malignancies other than MDS/AML, and 
pneumonitis. Astrazeneca medical team will review the AE data, flag the AESIs and send the 
listed preferred terms to PAREXEL programmer to merge to back to AE dataset.   
3.3.3 
Duration of exposure 
Exposure will be reported separately for each treatment arm. The duration of exposure will be 
calculated by date of the last dose – date of the first dose + # of days in the drug cycle - # of 
dosing days per each study drug as below. . 
Intended exposure time (days) of durvalumab will be calculated as follows: 
 the total treatment period from the date of first dose of durvalumab to the earliest of 
(last dose date of durvalumab + 27 days, death date, DCO) 
Intended exposure time (days) of tremelimumab will be calculated as follows: 
 the total treatment period from the date of first dose of tremelimumab to the earliest of 
(last dose date of tremelimumab + 27 days, death date, DCO) 
Intended exposure time (days) of AZD1775 will be calculated as follows: 
 the total treatment period from the date of first dose of AZD1775 to the earliest of (last 
dose date of AZD1775 + 18 days, death date)  
Intended exposure time (days) of CBDP will be calculated as follows: 
 the total treatment period from the date of first dose of CBDP to the earliest of (last 
dose date of CBDP + 20 days, death date) 
Intended exposure time (days) of AZD6738 will be calculated as follows: 
 the total treatment period from the date of first dose of AZD6738 to the earliest of (last 
dose date of AZD6738 + 21 days, death date, DCO)  
Intended exposure time (days) of olaparib will be calculated as follows: 
 the total treatment period from the date of first dose of olaparib to the earliest of (last 
dose date of olaparib, death date, DCO) 


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Exposure will also be measured by the number of cycles initiated.  A cycle of durvalumab and 
tremelimumab corresponds to a period of 28 days (ie, four weeks); for AZD1775 and CBDP, a 
cycle corresponds to a period of 21 days (ie, three weeks); for AZD6738 and olaparib, a cycle 
corresponds to a period of 28 days (ie, four weeks).  If a cycle is prolonged for any reason, 
this should still be counted as one cycle.  A cycle will be counted if treatment is started even if 
the full dose is not delivered. 
3.3.4 
Dose intensity 
Dose intensity will be derived separately for each treatment arm for the initial treatment 
period and the re-treatment period for the immunotherapy agents (durvalumab/tremelimumab) 
as well as for AZD1775, CBDP, AZD6738 and olaparib.  Relative dose intensity (RDI) is the 
percentage of the actual total dose delivered relative to the intended total dose through to a 
treatment duration.  RDI will be defined as follows: 
𝑅𝐷𝐼 (%) = 100 × 𝑑
𝐷 
where d is the actual cumulative dose delivered up to the actual last day of dosing and will be 
calculated by summing doses for each drug and each patient; and D is the intended cumulative 
dose up to the actual last day of dosing. D is the total dose that would be delivered and will be 
calculated for each drug and each patient by planned dose * planned number of doses in the 
corresponding duration of each study drug. Laboratory variables  
Laboratory data will be collected throughout the study, from screening to the follow-up visits 
as per study plan for each treatment arm described in the protocol.  These include blood and 
urine samples for determination of clinical chemistry, haematology, and urinalysis (see 
Appendix A, Appendix B and Appendix C of the protocol).  For the definition of baseline and 
the derivation of post baseline visit values considering visit window and how to handle 
multiple records, derivation rules as described in Section 3.3.7 will be used. 
Original ranges and units from local labs will be recorded and presented in data listings. The 
low (below range), normal (within range or on limits of range) and high (above range) will be 
derived based on the original ranges. 
All lab values and ranges will be converted to values in SI units at database (e.g., SDTM). All 
the lab data summaries will be based on the SI values.  
Change from baseline in clinical chemistry (including liver function tests, serum 
amylase/lipase, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), 
Triiodothyronine (T3), Thyroxine (T4), Thyroid-stimulating hormone (TSH)) and hematology 
variables will be calculated for each post-dose visit on treatment.  Common toxicity criteria 
(CTC) grades will be derived according to the CTCAE document (version 4.03).The 


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following parameters have CTC grades defined for both high and low values, so high and low 
CTC grades will be calculated: bicarbonate,  haemoglobin, leucocytes, platelets, neutrophils, 
lymphocytes, TSH, T3, T4, potassium, sodium, magnesium, glucose and corrected calcium. 
Corrected calcium (mmol/L) will be derived using the following formula (where total calcium 
is measured in mmol/L and albumin is measured in G/L): 
𝐶𝑜𝑟𝑟𝑒𝑐𝑡𝑒𝑑 𝑐𝑎𝑙𝑐𝑖𝑢𝑚= 𝑇𝑜𝑡𝑎𝑙 𝑐𝑎𝑙𝑐𝑖𝑢𝑚+ (40 −𝑎𝑙𝑏𝑢𝑚𝑖𝑛) × 0.02 
The maximum (or minimum) on-treatment value (depending on the direction of an adverse 
effect) will be defined for each laboratory parameter as the maximum (or minimum) post-dose 
value at any time. 
3.3.5 
ECG 
Arm A 
Only baseline ECG will be performed routinely, and ECGs will only be collected if clinically 
indicated throughout the study. Therefore no formal reporting of ECG data will be performed 
for Arm A. 
Arms B and C 
ECG data obtained up until the 30 days from date of last dose of study treatments will be used 
for reporting.  For the derivation of post-baseline visit values, considering visit windows, and 
to handle multiple records present in any visit window, derivation rules as described in 
Section 3.3.7 will be used.  
The Fridericia QTc correction (QTcF) will be used by Investigators to enter the corrected QT 
and it will be calculated as follows (where RR is in seconds):  
𝑄𝑇𝑐𝐹= 𝑄𝑇
√𝑅𝑅
3
 
3.3.6 
Vital signs 
Vital signs data (blood pressure, pulse, temperature, and respiration rate) obtained up until the 
30 days from the date of last dose of study treatments will be used for reporting.  Change from 
baseline in vital signs variables will be calculated for each post-dose visit on treatment.  For 
derivation of post-baseline visit values, considering visit window, and to handle multiple 
records, derivation rules as described in Section 3.3.7 will be used.  
The denominator in vital signs summaries should include only those patients with recorded 
data. 


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3.3.7 
General considerations for safety assessments 
Time windows will need defining for any presentations that summarise values by visit.  The 
following conventions should also apply: 
 The time windows should be exhaustive so that data recorded at any time point has the 
potential to be summarised.  Inclusion within the time window should be based on the 
actual date and not the intended date of the visit.   
 All unscheduled visit data should have the potential to be included in the summaries.   
 The window for the visits following baseline will be constructed in such a way that the 
upper limit of the interval falls half way between the two visits (the lower limit of the 
first post-baseline visit will be Day 2).  If an even number of days exists between two 
consecutive visits then the upper limit will be taken as the midpoint value minus one 
day. 
 For summaries showing the maximum or minimum values, the maximum/minimum 
value recorded on treatment will be used (regardless of where it falls in an interval). 
 Listings should display all values contributing to a time point for a patient. 
 For visit-based summaries, if there is more than one value per patient within a time 
window then the value closest to the planned study day should be summarised, or the 
earlier in the event the values are equidistant from the planned study day.  The listings 
should highlight the value for that patient that went into the summary table, wherever 
feasible. 
For summaries at a patient level, all values should be included, regardless of whether they 
appear in a corresponding visit based summary, when deriving a patient level statistic such as 
a maximum.  
The visit windows of safety assessments for ARM A, ARM B and ARM C per protocol 
scheduled visit: 
ARM A:  
Avisit 
Avisitn 
Target Day 
Window 
SCREENING 
1 
 
Day -28 to  -1 
CYCLE 1 
2 
1 
Day 1* 
CYCLE 2 
3 
29 
Day 2  to  14 +28 
CYCLE 3 
4 
57 
Day 15 +28   to  14 +28 +28 
CYCLE 4 
5 
85 
Day 15 +28 +28  to  14 +28 +28 +28 
….. 
 
 
 
Last visit: 
CYCLEx 
x 
xxxxx 
(target date-cycle days/2) to (target date+ 
LDD+30-15). 


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Follow-up 
98 
Date of  last 
dose +30 
Date of  last dose +15 to Date of  last dose +30 
+28 
*If the CYCLE 1 value is missing use the value in the SCREENING. 
ARM B:  
Avisit 
Avisitn 
Target Day 
Window 
SCREENING 
1 
 
Day -28 to  -1 
C1D1 
2 
1 
Day 1   
C1D3 
3 
3 
Day 2  to  5 
C1D8 
4 
8 
Day 6  to 11 
C1D15 
5 
15 
Day 12  to 18 
C2D1 
6 
22 
Day 19  to  25 
C2D8 
7 
29 
Day 26  to  35 
C3D1 
8 
43 
Day 36  to 44 
C3D3 
9 
45 
Day 45  to 47 
C3D8 
10 
50 
Day 48  to 56 
C4D1 
11 
43 +21 
Day 36 +21  to 44 +21   
C4D3 
12 
45+21 
Day 45 +21  to 47 +21   
C4D8 
13 
50+21 
Day 48  +21   to 56 +21   
….. 
 
 
 
Last visit: CxDy 
x 
xxxxx 
(target date-cycle days/2) to 
(target date+ LDD+30-15). 
Follow-up 
98 
Date of  last 
dose +30 
Date of  last dose +15 to 
Date of  last dose +30 +28 
CxDy: Cycle x Day y, i.e., C1D1=Cycle 1 Day 1 
ARM C:  
Avisit 
Avisitn 
Target Day 
Window 
SCREENING 
1 
 
Day -28 to  -1 
C1D1 
2 
1 
Day 1   
C1D7 
3 
7 
Day 2  to  11 
C1D15 
4 
15 
Day 12  to 22 
C2D1 
5 
29 
Day 23  to 43 
C3D1 
6 
29 + 28 
Day 44  to  71 
C4D1 
7 
29 + 28 +28 
Day 44+28  to  71+28 
….. 
 
 
 
Last visit: CxDy 
x 
xxxxx 
(target date-cycle days/2) to 
(target date+ LDD+30-15). 
Follow-up 
98 
Date of  last 
dose +30 
Date of  last dose +15 to 
Date of  last dose +30 +28 
CxDy: Cycle x Day y, i.e., C1D1=Cycle 1 Day 1 


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Not all the safety assessments follow the protocol scheduled visits. For a particular assessment 
for an example, ECG, following algorism will be applied for deriving the visit window: 
Lower border for X assessment: Min_X = Max_(X-1) +1 
Diff_X = Day (Assessment_(X+1) – Day (Assessment_X) 
Higher border for X assessment: Max_X = Day (Assessment_X) + 
                            (Diff_X/2) -1 if Diff_X is an even number, 
Or Integer part of (Diff_X/2) if Diff_X is an odd number 
Baseline will be defined as the last non-missing measurement prior to dosing with study 
treatment.  For laboratory data, any assessments made on Study Day 1, when time is not 
captured, will be considered pre-dose.  Alternatively, if two visits are equally eligible to assess 
patient status at baseline (eg, screening and baseline assessments both on the same date prior 
to first dose with no washout or other intervention in the screening period), the average can be 
taken as a baseline value.  Where safety data are summarised over time, study day will be 
calculated in relation to date of first study treatment. 
Missing safety data, other than for partial dates, will generally not be imputed.  However, 
safety assessment values of the form of “<x” (i.e., below the lower limit of quantification) or 
>x (i.e., above the upper limit of quantification) will be imputed as “x” in the calculation of 
summary statistics but displayed as “<x” or “>x” in the listings. 
3.4 
Biomarker variables 
Summaries and analyses for exploratory biomarkers will be documented in a separate analysis 
plan and will be reported in a separate report outside the clinical study report (CSR).  The 
results of this biomarker research may be pooled with biomarker data from other studies to 
generate hypotheses to be tested in future research. 
3.5 
Pharmacokinetics and immunogenicity variables 
3.5.1 
Pharmacokinetic analysis 
Concentration data and summary statistics will be tabulated by nominal visit/timepoint for 
both treatment arms.  Samples below the lower limit of quantification will be treated as 
missing in the analyses. 
A population PK analysis is not planned for this study given the sparse PK sampling.  
However the PK, pharmacodynamics, safety and efficacy data collected in this study may be 
combined with similar data from other studies and explored using population PK and/or 
PK-pharmacodynamic analysis approach.  


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3.5.2 
Immunogenicity analysis 
For Arm A only, immunogenicity samples will be measured for the presence of ADAs and 
ADA-neutralizing antibodies for durvalumab and tremelimumab using validated assays. ADA 
assessments will be conducted utilizing a tiered approach (screen, confirm, titer). 
4. 
ANALYSIS METHODS 
4.1 
General principles 
The following general principles will be followed throughout the study: 
 All analyses will be descriptive, and no inferential analysis will be performed based on 
statistical tests.  All evaluations will be exploratory in nature. 
 All summaries will be presented by treatment arm.   
 Continuous variables will be summarised by the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Categorical variables will be 
summarised 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. 
 The minimum and maximum will be reported to the same number of decimal places as 
the raw data recorded in the database.  The mean and median will be reported to one 
more decimal place, and the standard deviation will be reported to two more decimal 
places, than the raw data recorded in the database.  
 Percentages will be presented to one decimal place. 
 SAS® version 9.3 will be used for all analyses. 
 For time interval analyses in months, duration in months will be calculated as total 
duration in days/30.4375. 
Study Day 1 is defined as the date of first dose of study treatment.  For visits (or events) that 
occur on or after first dose, study day is defined as (date of visit [event] - date of first dose of 
study treatment + 1).  For visits (or events) that occur prior to first dose, study day is defined 
as (date of visit [event] - date of first dose of study treatment).  There is no Study Day 0. 
Baseline is defined as the last assessment of the variable under consideration prior to the 
intake of the first dose of study treatment, except for efficacy variables. For efficacy variables, 
baseline is defined as the last visit prior to first dose of study treatment. 


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All data collected will be listed.  Efficacy and safety data will be summarised and analysed 
based on the FAS. PK data will be summarised and analysed based on the PK Analysis Set. 
The primary analysis of ORR will occur approximately 12 weeks after the last patient has 
initiated treatment. All study endpoints will be analysed at this time with the exception of OS. 
A final analysis of OS will take place when approximately 75% maturity for OS events is 
achieved or as determined by the Sponsor. 
4.2 
Analysis methods 
4.2.1 
Patient disposition 
The total number of patients screened, including screening failures, enrolled (i.e. patients with 
informed consent) consisting of patients assigned to treatment and patients not assigned to 
treatment, patients who received any study treatment and patients who did not receive any 
study treatment, patients who completed treatment and patients who discontinued treatment 
will be summarised. In addition, the number of patients in the FAS will also be provided. 
The number and percentage of patients who discontinued treatment and the main reason for 
discontinuation as well as the number of patients included in the analysis populations and the 
number of patients recruited by country and center will be also presented. 
4.2.2 
Protocol deviations 
All identified important protocol deviations will be listed and summarised for the FAS. All 
protocol deviations will be defined by the study team and identified and classified as 
important or not important before database lock. 
4.2.3 
Demographics and other baseline characteristics 
Demographic and baseline patient characteristics (age, gender, race, ethnicity, height, 
weight[kg], weight group [<70, ≥70 – ≤90, >90], body mass index [BMI], Eastern 
Cooperative Oncology Group (ECOG) performance status (PS), previous cancer therapy, 
smoking history) will be summarised for the FAS. 
Descriptive statistics will be presented for the continuous variables and total counts and 
percentages of patients will be presented for the categorical variables. 
Additionally, the following variables will be summarised: 
 Age as a continuous variable  
 Age by  
o class (<50; ≥50 - <65; ≥65 - <75; ≥75 - <80, ≥80) and  
o class (<65; ≥65) 
 


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4.2.4 
Medical history 
Relevant medical history (past and current) and relevant surgical history will be coded using 
the latest version of MedDRA. 
All medical history will be summarised (number and percentage of patients) for the FAS by 
system organ class (SOC) and preferred term (PT). 
All relevant surgical history will be summarised similarly. 
4.2.5 
Disease history 
The following disease characteristics will be summarised for all patients in the FAS (unless 
specified otherwise): 
 Disease characteristics at baseline (time from diagnosis to first dose of study 
treatment [months], American Joint Committee on Cancer [AJCC] stage, 
primary tumour location, histology type, best response to previous therapy 
[CR, PR, SD, PD, NE, NA]) 
 Extent of disease upon entry to study [site of metastatic disease] 
 Previous disease-related treatment modalities  
 Number of regimens of previous chemotherapy 
4.2.6 
Concomitant medication 
Prior and concomitant medications are defined as follows: 
 Prior medications are medications taken prior to or during screening with a stop date 
prior to the first dose of study treatment 
 Concomitant medications are medications with a stop date on or after the date of first 
dose of study treatment (and could have started prior to or during treatment). 
The medication with missing or partial medication stop date will be considered as concomitant 
medication. Concomitant medication will be summarised using frequency tables by 
Anatomical therapeutic chemical (ATC) classification code (based on World Health 
Organization [WHO] classification). 
Concomitant medication data will be reviewed by Astrazeneca clinical team and prohibited 
concomitant medications will be identified and flagged.  
Moreover, the following concomitant medications or therapies will be listeded: 
 Disallowed concomitant medications (other anti-cancer therapies, investigational 
agents, and radiotherapy should not be given while the patient is on study drug) 
 Post-treatment anti-cancer therapies (post-treatment medications are those with a start 
date after the last dose date of study treatment) 


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4.2.7 
Exposure  
The following summaries will be produced for the FAS: 
 Total (or intended) duration of exposure to study treatments, by each treatment  
 Actual duration of exposure to study treatments, by each treatment  
 Number of cycles of study treatments initiated, by each treatment  
 Number of and reasons for dose delays, interruptions, by each treatment  
 Reductions of study treatments (AZD1775, CBDP, AZD6738 and olaparib), by each 
treatment 
 RDI of each treatment arm, for each AZ investigational product 
 
4.2.8 
Efficacy 
All efficacy analyses are exploratory, and will be performed on the FAS. 
4.2.8.1 
Objective response rate  
ORR will be estimated for each treatment arm with corresponding two-sided exact 95% 
confidence intervals (CIs).  The analysis will be based on the programmatically derived ORR 
based on site Investigator assessments, and using all scans; regardless of whether they were 
scheduled or not. Two sensitivity analyses will be performed –on programmatically derived 
ORR RECIST 1.1 modified for confirmation of progression, and on ORR RECIST 1.1 for a 
subset of FAS patients without important protocol deviations (Section 4.2.9). The primary 
analysis population for ORR will be the FAS. The analysis population for the former 
sensitivity analysis - according to modified RECIST 1.1 - will also be the FAS. The analysis 
population for the second sensitivity analysis will be the FAS without important protocol 
deviations.  
The summary will include all patients in the FAS for the primary and the RECIST modified 
sensitivity analysis while all patients in the FAS without important protocol deviations will be 
included in the protocol deviations related sensitivity analysis.  Summaries will be produced 
that present the number and percentage of patients with a tumour response (CR/PR).  The 
number (%) of patients with a confirmed response and the number (%) of patients with a 
single visit response (ie, an unconfirmed response) will also be presented. 
4.2.8.2 
Duration of response  
A Kaplan-Meier (KM) plot of DoR will be presented by treatment arm, if appropriate.  The 
median (calculated from the KM plot, with 95% CIs), lower quartile and upper quartile will be 
presented for DoR, for patients with a response.  Only patients who have a confirmed response 
will be included in this summary table.   
4.2.8.3 
Disease control rate 
The number and percentage of patients with each best objective response (BoR) category (CR, 
PR, SD, PD and NE) will be summarised for each treatment arm.   


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The DCR at 12 weeks will be summarised for each treatment arm.   
4.2.8.4 
Time to response 
TTR will be presented by treatment arm. The number and percentage of patients with TTR 
based on the site Investigator assessment of RECIST 1.1 will be summarised for each 
treatment arm by the scheduled assessment time point that the response was first observed. 
The median, minimum, maximum, lower quartile and upper quartile will also be presented for 
TTR, for patients with a response. Only patients who have a confirmed response will be 
included in this summary table. 
4.2.8.5 
Progression-free survival 
A KM plot of PFS will be presented by treatment arm.  The total number of patients 
experiencing a PFS event and the type of event (RECIST progression or death), along with 
median PFS (calculated from the KM plot, with 95% CIs) will be presented. Moreover, the 
PFS rate at 6 and 12 months will be calculated along with the 95% CIs by using the Kaplan-
Meier technique. 
The total number of patients censored and the reasons for censoring (censored RECIST 
progression, censored death, progression-free at time of analysis, lots to follow-up, withdrawn 
consent) will also be summarised.  
4.2.8.6 
Overall survival 
A KM plot of OS will be presented by treatment arm.  The total number of deaths, the number 
of patients still in survival follow-up, the number of patients who have withdrawn consent, 
and median OS (calculated from the KM plot, with 95% CIs) will be summarised for each 
treatment arm. Moreover, the OS rate at 6 and 12 months will be calculated along with the 
95% CIs using Kaplan-Meier techniques. 
The total number of patients censored and the reasons for censoring (still in survival follow-
up, terminated prior to death, lost to follow-up, withdrawn consent) will also be summarised.  
4.2.9 
Sensitivity analyses 
Two sensitivity analyses will be performed: a) a sensitivity analysis on RECIST 1.1 modified 
for confirmation of progression on all patients in the FAS and b) a sensitivity analysis where, 
efficacy data on RECIST 1.1 will be summarised/analysed in a subgroup of FAS for patients 
without important protocol deviations. Protocol deviations will be reviewed by the clinical 
team before database lock to determine the patients who have important protocol divisions and 
will be excluded from the analysis population for this sensitivity analysis. 
The above mentioned sensitivity analyses will be performed for ORR, DoR and DCR, to 
determine whether there is any difference in ORR, DoR and DCR when using a) progression 
confirmation rules and b) when only patients without important protocol deviations are 
included.  


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In particular, ORR, DoR and DCR will be assessed using the RECIST 1.1 site Investigator 
tumour data following a modification where any objective progression requires confirmation. 
Therefore, data obtained up until confirmed progression, or the last evaluable assessment in 
the absence of a confirmed progression, will be included in the assessment of ORR, DoR and 
DCR. Note that the response may be after an unconfirmed progression. 
In addition, the following figures will be generated for each arm if needed. 
 Waterfall plot of best change from baseline in target lesion size (%) 
 Spider plot of change in sum of target lesion diameter from baseline (%) 
 Swimmer plot of patient profiles indicating time to first response, treatment duration, 
off treatment, first PD, death or alive or censored.   
4.2.10 
Safety 
Safety data will be summarised for each treatment arm. No formal statistical analyses will be 
performed on the safety data. All safety and tolerability data will be presented separately for 
each treatment arm.  Data from all cycles of treatment will be combined in the presentation of 
safety data.  All safety summaries will use the FAS. 
The following sections describe the planned safety summaries for AEs, vital signs, laboratory 
parameters, ECG and ECOG PS.   
4.2.10.1 Adverse events 
The summary tables will include all AEs that first occurred or worsened after the start of 
treatment up until 90 days after discontinuation of study treatment for Arm A or 30 days after 
discontinuation of study treatment for Arm B or 30 days after discontinuation of study 
treatment for Arm C, or the initiation of the first subsequent cancer therapy following the 
discontinuation of treatment (whichever is first).  This will more accurately depict AEs 
attributable to study treatment only, as a number of AEs up to 90 days following 
discontinuation of the immunotherapy agents/30 days after CBDP/AZD1775 or 
AZD6738/olaparib are likely to be attributable to subsequent therapy.  Multiple events per 
patient will be counted once within that SOC and PT. 
However, to assess the longer term toxicity profile, AE summaries will also be produced 
containing AEs observed up until 90 days following discontinuation of the immunotherapy 
agents (durvalumab and tremelimumab) or 30 days following discontinuation of AZD1775 
and CBDP or 30 days following discontinuation of AZD6738 and olaparib (i.e., without 
taking subsequent therapy into account).  
All reported AEs will be listed along with the date of onset (including study day), date of 
resolution (if AE is resolved), investigator’s assessment of CTCAE grade and relationship to 
study drug.  Any events that occur after a patient has received further therapy for cancer 
(following discontinuation of study treatment) will be flagged. 


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Summaries of AEs and SAEs will be presented by SOC and PT. AEs leading to death and 
AEs leading to treatment discontinuation will also be summarised by SOC and PT. 
AEs will be assigned CTCAE grades and summaries of the number and percentage of patients 
will be provided by maximum (most severe) reported CTCAE grade, SOC, PT and treatment 
arm.   
Summaries of the rates of AEs per person-years at risk may be produced. 
A separate data listing of AEs occurring more than until the time period specified in each 
specific study arm after discontinuation of IP will be produced. These events will not be 
included in AE summaries. 
Adverse events of special interest  
Adverse events of special interest for Arm A are the following: 
 Diarrhea / Colitis 
 Pneumonitis / ILD 
 Alanine aminotransferase (ALT)/ Aspartate aminotransferase (AST) increases / 
hepatitis / hepatotoxicity 
 Neuropathy / neuromuscular toxicity (i.e., events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis)  
 Endocrinopathies (ie, events of hypophysitis, hypopituitarism, adrenal insufficiency, 
diabetes insipidus, hyper- and hypothyroidism and type I diabetes mellitus) 
 Rash / Dermatitis 
 Nephritis / Blood creatinine increases 
 Pancreatitis (or laboratory results suggestive of pancreatitis - increased serum lipase or 
increased serum amylase) 
 Other inflammatory responses that are rare with a potential immune-mediated 
aetiology include, but are not limited to, myocarditis, pericarditis, and uveitis. 
Adverse events of special interest for Arm C are the following: 
 MDS/AML 
 New primary malignancies other than MDS/AML 
 Pneumonitis.  
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological aetiology are also considered AESIs.  
Summaries of the above mentioned AESIs will include number (%) of patients who have: 
 At least one AESI 
 At least one AESI causally related to any study treatment 


Statistical Analysis Plan  
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 At least one AESI leading to discontinuation of a study treatment 
A summary of total duration (days) of selected AESI will be provided for events which have 
an end date, and this may be supported by summaries of ongoing AESIs at death and, 
separately, at data cut-off. Duration will be calculated as duration of the longest event if 
presented twice for the same patient. 
Additionally, summaries of AESIs requiring immunosuppressive agents, steroids and/or 
hormone replacement therapy, with separate summary of AESIs requiring immunosuppressive 
agents at high doses will be presented. 
Deaths 
As a summary of deaths will be provided with the OS, a corresponding listing will also be 
produced. Deaths outside the period covered by the OS will be listed. 
4.2.10.2 Laboratory evaluations 
Data obtained up until the 90 days following discontinuation of immunotherapy agents (i.e., 
the last dose of durvalumab + tremelimumab followed by durvalumab monotherapy) or 30 
days following discontinuation of AZD1775 + CBDP or 30 days following discontinuation of 
AZD6738 + olaparib, or until the initiation of the first subsequent anti-cancer therapy 
following discontinuation of  sub-study treatment (whichever occurs first) will be used for 
reporting.  This will more accurately depict laboratory toxicities attributable to study treatment 
only as a number of toxicities up to 90 days following discontinuation of Arm A (durvalumab 
+ tremelimumab followed by durvalumab monotherapy) or 30 days following discontinuation 
of Arm B (AZD1775 + CBDP) or 30 days following discontinuation of Arm C (AZD6738 + 
olaparib) are likely to be attributable to subsequent therapy.  
Data summaries will be provided after conversion of lab results to corresponding project-wide 
preferred units. 
Absolute values and change from baseline for all continuous haematology, clinical chemistry 
and urinalysis laboratory parameters will be summarised by treatment arm and visit. 
Shift tables for laboratory values by worst CTC grade will be produced, and for specific 
parameters separate shift tables indicating hyper- and hypo- directionality of change will be 
produced.  The laboratory parameters for which CTC grade shift outputs will be produced are: 
 
Haematology: haemoglobin (hypo- and hyper-), lymphocytes (absolute count) 
(hypo- and hyper-), neutrophils (absolute count) (hypo- and hyper-), platelets 
(hypo- and hyper-), activated partial thromboplastin time, and international 
normalized ratio 
 
Clinical chemistry: ALT, AST, alkaline phosphatase, amylase, lipase, leucocytes 
(hypo- and hyper-), total bilirubin, albumin, bicarbonate (hypo- and hyper-), 
magnesium (hypo- and hyper-), sodium (hypo- and hyper-), potassium (hypo- and 


Statistical Analysis Plan  
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hyper-), corrected calcium (hypo- and hyper-), glucose (hypo- and hyper-), gamma-
glutamyl transferase or gamma-glutamyl transpeptidase (GGT), creatinine 
 
Thyroid function tests (hypo- and hyper-) 
 
Liver function tests 
For categorical urinalysis parameters (bilirubin, blood, glucose, ketones, and protein), a shift 
table may be produced comparing baseline value to the maximum on-treatment value.   
For the parameters with no CTC grading available that are listed as being recorded in the 
protocol, shift tables from baseline to worst value on-treatment will be provided. 
Hy's law 
The following summaries will include the number (%) of patients who have: 
 Elevated ALT, AST, and total bilirubin during the study 
o ALT ≥3x – ≤5x, >5x – ≤8x, >8x – ≤10x, >10x – ≤20x, and >20x upper limit of 
normal (ULN) during the study 
o AST ≥3x – ≤5x, >5x – ≤8x, >8x – ≤10x, >10x – ≤20x, and >20x ULN during 
the study 
o Total bilirubin ≥2x – ≤3x, >3x – ≤5x, >5x ULN during the study 
o ALT or AST ≥3x – ≤5x, >5x – ≤8x, >8x – ≤10x, >10x – ≤20x, >20x ULN 
during the study 
o ALT or AST ≥3x ULN and total bilirubin ≥2x ULN during the study (potential 
Hy’s law): the onset date of ALT or AST elevation should be prior to or on the 
date of total bilirubin elevation  
Liver biochemistry test results over time for patients with elevated ALT or AST (i.e., 
≥ 3 × ULN) and elevated total bilirubin (i.e., ≥ 2 × ULN) at any time will be plotted.   
Individual patient data where ALT or AST plus total bilirubin are elevated at any time will be 
listed (i.e., ALT and/or AST ≥3 × ULN and total bilirubin ≥2 × ULN, at any time). 
Plots of maximum post-baseline ALT and AST versus maximum post-baseline total bilirubin, 
expressed as multiples of ULN, will also be produced with reference lines at 3 × ULN for 
ALT and AST, and 2 × ULN for total bilirubin.  In each plot, total bilirubin will be presented 
on the vertical axis. 
4.2.10.3 ECG assessments 
Arm A 


Statistical Analysis Plan  
Study Code D419QC00002 
Edition Number 4.0  
Date 12 Apr 2019 
46 
No outputs for ECG will be summarised. 
Arms B and C 
ECG data obtained up until the 30 day safety follow-up visit will be included in the summary 
tables. 
Absolute values and change from baseline for QTcF will be summarised by treatment arm and 
visit. 
The number and percentage of patients with normal, abnormal, not clinically significant and 
abnormal, clinically significant ECG results will be presented as a shift table from baseline to 
worst evaluation during the study. 
4.2.10.4 Vital signs and weight 
Vital sign data obtained up until the 30 day safety follow-up visit will be included in the 
summary tables. 
Absolute values and change from baseline for BP, pulse, temperature, respiration rate and 
weight will be summarised by treatment arm and visit. 
4.2.10.5 ECOG performance status 
Absolute values and change from baseline for ECOG PS will be summarised by treatment arm 
and visit. 
A shift table will present ECOG PS changes from baseline to the maximum value on 
treatment.   
4.2.11 
 
 
 
 
 
   
4.2.12 
Pharmacokinetics and immunogenicity  
4.2.12.1 Pharmacokinetic data 
PK concentration data will be listed for each patient at each visit, for the PK analysis set.  
A summary of PK concentration-time profiles by visit and treatment arm will be provided for 
the PK analysis set. 
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Statistical Analysis Plan  
Study Code D419QC00002 
Edition Number 4.0  
Date 12 Apr 2019 
47 
4.2.12.2 Immunogenicity data 
All immunogenicity data will be listed for each patient at each visit, including titer value for 
samples confirmed to be ADA positive, for the FAS.  
The number and percentage of patients included in the following immunogenicity categories 
will be summarised for Arm A only:  
 ADA positive at any visit 
 ADA positive at both baseline and post-baseline 
 ADA positive only at post-baseline 
 ADA positive only at baseline 
 ADA persistently positive 
 ADA transiently positive 
 ADA positive at post-baseline with positive nAb 
The effect of immunogenicity on PK, pharmacodynamics, efficacy, and safety will be 
evaluated, if the data allow.  
5. 
INTERIM ANALYSES 
An interim analysis will be conducted on each arm. This will assess ORR in all evaluable 
patients in that arm, to determine whether to progress to stage 2 of the arm. The DCO for the 
interim analysis will take place approximately 12 weeks after the 10th patient has initiated 
treatment. The decision to stop or expand the treatment in each arm will depend on the 
outcome of the ORR, whose rationale is outlined below.  
If there are 
 responders, then there is a low posterior probability of achieving ORR of at 
least 
% in 20 patients and no further patients will be recruited to the arm. If there are 
 or 
 responders out of 10, then an additional 10 patients will be recruited and the final estimate 
of ORR will be based on 20 patients. If there are 
 responders out of 10 patients, 
then it will be regarded as strong efficacy and the Review Committee may decide to stop 
recruitment into the particular arm. 
The posterior probability of having at leas
 responders in 20 patients for 
 
responders in 10 patients is shown in below. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan  
Study Code D419QC00002 
Edition Number 4.0  
Date 12 Apr 2019 
48 
If the Review Committee decides to recommend expansion of any given arm (for a maximum 
total of 40 eligible patients), no further interim analysis will be conducted and the entire 
expansion cohort (additional 20 patients) will be recruited with no break. Primary analysis 
will be ORR of all subjects recruited to the individual arm (i.e. 1st and 2nd stage cohorts plus 
the expansion cohort) after 12 weeks follow up of the last patient dosed in that arm. However, 
a sensitivity analysis may be performed to analyze the cohorts separately due to potential 
changes in population (e.g. due to differences in the 1st line therapy) between recruitment of 
the initial 2 cohorts and the expansion cohort of that arm. 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL (NOT 
APPLICABLE) 
7. 
REFERENCES (NOT APPLICABLE) 
8. 
  
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