A Phase 1b/2, Open-Label, Multicentre Study Assessing the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-tumor Activity of MEDI4736 in Combination With AZD9150 or AZD5069 in Patients With Advanced Solid Malignancies and Subsequently Comparing AZD9150 and AZD5069 Both as Monotherapy and in Combination With MEDI4736 as Second Line Treatment in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck.
Phase: PHASE1
Conditions: Advanced Solid Tumors & Metastatic Squamous Cell Carcinoma of the Head and Neck
Sponsor: AstraZeneca

Clinical Study Protocol 
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Clinical Study Protocol 
Drug Substance
AZD9150, AZD5069, MEDI4736, 
tremelimumab
Study Code
D5660C00004
Version
Amendment 11 v 12.0
Date
20 Nov 2019
A Phase 1b/2, Open-Label, Multicentre Study Assessing the Safety, 
Tolerability, Pharmacokinetics, and Preliminary Anti-tumor 
Activity of MEDI4736 in Combination With AZD9150 or AZD5069 
in Patients With Advanced Solid Malignancies and Subsequently 
Comparing AZD9150 and AZD5069 Both as Monotherapy and in 
Combination With MEDI4736 as Second Line Treatment in 
Patients With Recurrent and/or Metastatic Squamous Cell 
Carcinoma of the Head and Neck
Sponsor: AstraZeneca AB, 151 85, Södertälje, Sweden
AstraZeneca Research and 
Development site representative
AstraZeneca
One MedImmune Way
Gaithersburg, MD 20878 USA
Date
This submission/document contains trade secrets and confidential commercial information, disclosure of which is 
prohibited without providing advance notice to AstraZeneca and opportunity to object.
The following Amendment(s) and Administrative Changes are included in this revised protocol: 
Amendment No.
Date of Amendment
Local Amendment No.
Date of local Amendment
1
18 August 2015
2
14 December 2015
3
22 March 2016
4
31 July 2016
5.1 (Version 6.0)
5.2 (Version 6.0)
17 February 2017 (UK)
10 May 2017 (UK)
5
10 May 2017
6
12 February 2018
7
31 July 2018
8
12 August 2018
9
24 August 2018
9.1 (Version 10.1)
26 May 2019 (Germany)
10
18 June 2019
11 (Version 12)
20 November 2019
11.1 (Version 12.1)
13 November 2019 (Germany)
Redacted

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VERSION HISTORY
Amendment 11 Version 12, 20 Nov 2019
This protocol amendment has been prepared globally for all patients currently enrolled in this 
study, with the exception of patients enrolled in Germany (Germany must use the Germany-
specific protocol amendment 11.1, version 12.1, 13 Nov 2019).
The key protocol amendment changes are as follows:
!
Amendment number and version number updated on the cover page and header.
!
Addition of pemphigoid as a potential risk for durvalumab in Section 1.3.2.
!
Revisions to Section 6.12 to provide additional guidance on continuation of patient’s
treatment after last subject last visit for the primary endpoint. In addition, the actual
study start date and the data cut-off date for primary endpoint were updated.
!
Revisions to Appendix I to align with the updated Toxicity Management Guidelines
for durvalumab (MEDI4736) and tremelimumab issued based on CTCAE version 4.03
dated 17 October 2019. Please note: Appendix I has been replaced with an Annex to
the protocol.
!
Minor formatting changes were made, and the table of contents were updated
accordingly.
Amendment 10 Version 11.0, 18 June 2019
This protocol amendment has been prepared globally for all patients currently enrolled in this 
study, except for patients enrolled in Germany (Germany must continue to use the Germany-
specific protocol amendment 9.1, version 10.1, 26 May 2019 until a future protocol 
amendment is generated for Germany).
The key protocol amendment changes are as follows:
•
Revision of sponsor signatory on cover page.
•
Amendment number and version number updated on the cover page and header.
•
Administrative amendment to correct inconsistencies/formatting in the text.
•
Revisions throughout to reflect the current status (closed) of enrolment across all cohorts.
•
Revision to delete the secondary objective with the outcome measure of tumor PD-L1
expression as this was added in error in a previous amendment. PD-L1 expression in
prostate cancer is not yet validated.
•
Revision to clarify the exploratory objective with the outcome measure of tumor-derived
DNA mutations at baseline, and changes upon treatment that may correlate with treatment
or response.
•
Revision to Sections 1.1.1, 1.3.1, 1.3.2, 6.7.1, 6.7.2, and 6.9.1, to align with the AZD9150

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Investigator’s Brochure (IB) edition 9.0, dated 14 June 2019. 
•
Addition of Section 6.4.8 (Serious bleeding events with combination drug MEDI4736
(durvalumab) in squamous cell carcinoma of the head and neck patients) to align with the
AZD9150 IB edition 9.0, dated 14 June 2019.
•
For Arm B8, global revisions to clarify that the urine PK sampling is mandatory for up to
12 patients and then optional consent thereafter. Additionally, noted that this collection
applies to the US enrolled patients only and that instructions will be provided to patients
to collect samples, as applicable, at home. Further, the testing requirement for “Cycle 1,
Day 1: 6 to 24 hours after start time of AZD9150 infusion” has been removed as a
requirement for Arm B8.
•
Global revisions to clarify that weight obtained on Day 1 of each cycle will be used to
calculate the weigh-related doses for each cycle.
•
Global revisions to clarify for Arm B8 the relationship between 1 and 2 hours post
AZD9150 infusion ECG measurements.
•
Global revisions to clarify that for Arm B8 vital signs will not be required for Day 8 and
Day 22 (all cycles) as there are no dosing visits scheduled for these patients on these days.
•
Global revisions to clarify a few inconsistencies in text around the PBMC sample
collection days. It was clarified that the collection of PBMC samples will be collected on
Day −7 of the lead-in period; Days 1, 8, and 15 of Cycle 1; on Day 1 of Cycles 3, 6, and
9; and at the EOT visit.
•
Global revisions (see bold text) to clarify the screening biopsy sample timing as follows:
“if patient has a biopsy report and sample from fewer than 45 days prior to start of
treatment (Day -7), it would be considered acceptable.
•
Revision to Section 5.8.1.3 (see bold text) to clarify the number of archival tumor
samples as follows: “Freshly prepared unstained slides (minimum of 3, but preferably 10
to 20) from the archival tumor block will be accepted if tumor blocks cannot be
submitted.”Revisions to Table 10 (Volume of blood to be drawn from each patient during
screening, lead-in period, and Cycle 1 of Part 1 and Part B) to reflect the blood volumes
listed in the Laboratory Manual for this study.
•
Revision to the study team contacts for emergencies in Section 6.10.
•
Revisions to Appendix G (Actions Required in Cases of Increases in Liver Biochemistry
and Evaluation of Hy’s Law) to align with Hy’s Law version 2.0 (dated 10 January 2019)
as described in the SOP Detection and Handling of Potential Hy’s Law Cases in Clinical
Studies.
Amendment 9 Version 10.0, 24 Aug 2018 
Key Protocol Amendment Changes:
•
Administrative amendment to correct inconsistencies in the text
•
Version history updated to include the initial version and wording changed from
Version to Amendment
•
For B8, corrected the anti-AZD9150 antibody immunogenicity sample collection in
the study plan for pharmacokinetic, pharmacodynamic, immunogenicity, and
pharmacogenetic assessments in Part B (B8) (Table 8 in Section 5.2) from Cycle 2

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Day 15 to Cycle 2 Day 1 to match text in Section 5.7
•
For B8, corrected time points for circulating-free deoxyribonucleic acid (cfDNA)
samples in Table 8 in Section 5.2 and Section 5.8.1.1 to be aligned, and to ensure that
these samples are taken on Day −7 of the lead-in period, Day 1 of all even-numbered
cycles, Day 1 of Cycle 3, and at the End-of-Treatment (EOT) visit
•
For B8, corrected time points for serum, plasma and peripheral blood mononuclear
cell (PBMC) sample collection in Section 5.8.1.1 to match the updated the footnotes
in Table 8 in Section 5.2.
Amendment 8 Version 9.0, 12 Aug 2018 –Not submitted
Key Protocol Amendment Changes:
•
Updated AZD9150 PK collection & ECG time point for B8 from Day -1 to Day -7
(Table 8 in Section 5.2, Section 5.4.3 & Section 5.5.1)
•
Added Day -7 anti-AZD9150 antibody immunogenicity sampling for B8 (Table 8 in
Section 5.2 & 5.7)
•
Corrected typographical error in Figure 6 from ≤30mg to ≤30kg (Section 7.7.1)
•
Removed reference to personnel remaining blinded as this is not a blinded study
(Section 8.1)
Amendment 7 Version 8.0, 31 Jul 2018 – Not submitted
Throughout Document
Transferred to a new template with updates of protocol structure and protocol language
Updated Version Number and Date throughout 
Updated paging and internal references
Added treatment arm B8
Further minor clarifications
Key Protocol Amendment Changes
•
Update of protocol structure/organization according to the new template with a Doc ID of
LDMS_001_00026737 and the authoring instructions presented in the new template.
•
A removal of treatment arms of A5 and A7 from Part A as decided by AstraZeneca to not
open the cohort for enrolment based on data analysed for combination of AZD5069 and
MEDI4736
•
An additional treatment arm of B8 to enroll 48 patients who are efficacy evaluable
first-line squamous cell carcinoma of the head and neck (SCCHN) (no prior systemic
treatment for recurrent or metastatic SCCHN [RM SCCHN]) to test the flat dosing of
AZD9150 in combination with MEDI4736 as dosed every 2 weeks (Q2W)
Resulting updates to the following sections:

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Section 1 Introduction
•
Minimized the information according to the new template instruction and the IB is
referenced in order to avoid amending the protocol following to the annual update of the
IB.
Section 2 Study objectives
•
Established the additional primary objective based on the details provided in the
respective IBs, for dose-expansion Part B to evaluate response rate (ORR) of AZD9150 as
a fixed dosed Q2W in patients with no prior exposure to anti-PD−(L)1 therapies and who
have not received prior systemic treatment for RM SCCHN (1L RM SCCHN).
Section 3 Subject selection, enrolment, randomisation, restrictions, discontinuation and 
withdrawal
•
Added the criteria applicable to B8.
•
Provided minor clarifications.
Section 4.1 Dose-escalation and safety cohorts Part A
•
Removed a section for the food effect study for AZD5069.
•
Removed text for Arm A5 and Arm A7.
Section 4.2 Dose-expansion Part B
•
Added treatment arm B8 to Table 4 for assessment schedule.
•
Added text for B8.
•
Removed text for B7.
Section 5 Study assessments
•
Added treatment arm B8 to Table 5 and modified the footnote accordingly.
•
Removed treatment arms A5 and A7 from Table 6.
•
Added B2, B4, and B8 to the footnote of Table 6.
•
Clarified that Table 7 indicated the assessment scheduled for treatment arms B1
through B7.
•
Provided a new Table 8 for treatment arm B8 (pharmacokinetic, pharmacodynamic,
immunogenicity, and pharmacogenetic assessments in Part B).
Section 5.4.1 Laboratory safety assessments
•
Added text to clarify that the central laboratory will analyse all the blood samples.
Section 5.4.4 Vital signs
•
Added text regarding treatment arm B8.
Section 5.5 Pharmacokinetics
•
Added text regarding treatment arm B8.
•
Removed text regarding the food effect evaluation
•
Removed treatment arm A5
•
Added text for treatment arm B8 regarding a requirement of consent for urine
samples for PK assessments.
•
Added the time points in detail for the PK samples.
Section 5.8.1 Exploratory biomarker research
•
Added text for biological samples.
Section 6.4.12 Disease under study (DUS)
•
Added new text regarding DUS.
Section 6.6 Overdose
•
Changed the definition of overdose of AZD9150: >10% above the recommended

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dose and added advice to Investigators who are required to closely monitor any 
patient who receives a higher dose than that intended.
Section 6.9.1 Dose modifications
•
Clarified the dose for AZD9150 and MEDI4736.
Section 6.10 Study team contacts for emergencies
•
Replaced Minal Mehta to Gail Doughton.
Section 6.11 Duration of treatment
•
Added text for details of the MEDI4736 monotherapy treatment.
Section 6.12 Expected start and end of study
•
Added new text for post-analysis and reporting access to study treatment.
Section 7.2 Dose and treatment regimens
•
Section 7.2.1: Added text for administration of AZD9150 in treatment arms, A1, A4,
A6, B1, B3, B5, B7, and B8.
•
Section 7.2.2: Added text for administration of AZD5069 in treatment arms A5, A7,
B2, B4, and B6 and removed text for A3 in regard to recommended Phase 2 dose
(RP2D).
•
Section 7.2.3: Added text for administration of MEDI4736 in treatment arms A1, A7,
B1, B4, B7, and B8.
Section 7.7.1 Starting dose and dose-escalation scheme
•
Clarified the dose-reduction levels for treatment arm B8
Section 7.7.7 Confirmation of the presumed recommended dose
•
Removed text for A3 in regard to RP2D.
Section 7.8 Concomitant and other treatments
•
Changed the time point to correct information on any treatment to 30 days before
starting study treatment from 28 days.
Section 8.2.1 Dose-escalation Part A
•
Removed text for Arms A5 and A7.
Section 8.2.2 Dose-expansion Part B
•
Updated the number of the patients to be enrolled.
•
Added text regarding treatment arm B8.
Section 8.10 Methods of statistical analysis
•
Added treatment arm B8.
Section 9.2.1 Source data
•
Added new text regarding source data.
•
Added new information for the case report form that serves as the source.
Section 9.4 Data management by AstraZeneca
•
Added new text for data management of genotype data.
•
Added new text for data associated with human biological samples.
Amendment 6 Version 7.0, 12 February 2018
As documented in Clinical Study Protocol Amendment 6

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Amendment 5 Version 6.0, 10 May 2017
As documented in Clinical Study Protocol Amendment 5
Amendment 4 Version 5.0, 31 July 2016
As documented in Clinical Study Protocol Amendment 4
Amendment 3 Version 4.0, 22 March 2016
As documented in Clinical Study Protocol Amendment 3
Amendment 2 Version 3.0, 14 December 2015
As documented in Clinical Study Protocol Amendment 2
Amendment 1 Version 2.0, 18 August 2015
As documented in Clinical Study Protocol Amendment 1
Version 1.0
Initial creation

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This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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CLINICAL STUDY PROTOCOL SYNOPSIS
A Phase 1b/2, Open-Label, Multicentre Study Assessing the Safety, 
Tolerability, Pharmacokinetics, and Preliminary Anti-tumor 
Activity of MEDI4736 in Combination With AZD9150 or 
AZD5069 in Patients With Advanced Solid Malignancies and 
Subsequently Comparing AZD9150 and AZD5069 Both as 
Monotherapy and in Combination With MEDI4736 as Second 
Line Treatment in Patients With Recurrent and/or Metastatic 
Squamous Cell Carcinoma of the Head and Neck
Principal Investigator:
Study design
This multicentre, open-label, Phase 1b/2 study is designed as a 2-part study consisting of 
dose-escalation and safety run-in cohorts in Part A and a dose-expansion in Part B at the 
recommended Phase 2 dose (RP2D)/maximum tolerated dose (MTD). 
The dose-escalation and safety run-in cohorts in Part A of this study initially involves patients 
with advanced solid malignancies refractory to standard therapy or for which no standard of 
care regimen currently exists. Subsequently, there is further confirmation of dose, safety, and 
tolerability assessments done in specific solid tumor types that are refractory to standard 
therapy or for which no standard of care regimen currently exists. Further, there is also a 
tolerability safety run-in with the RP2D/MTD for AZD9150 and AZD5069 in combination 
with fixed dose of MEDI4736 (durvalumab)/tremelimumab. Up to 30 evaluable patients per 
treatment arm are planned to be enrolled in dose-escalation cohorts; approximately 18 patients 
are planned to be enrolled in each of the safety run-in cohorts (in combination with 
MEDI4736/tremelimumab), and approximately 20 patients per tumor type are planned to be
enrolled in the solid malignancy safety cohorts. For the dose-escalation cohorts, considering 
the patient’s history of taking any drugs, herbal supplements, and/or foods prohibited with 
concurrent administration of AZD5069 or within 14 days of the first dose of AZD5069 as well 
as the patient’s anticipated need or likelihood to consume such products at any time 
throughout the study, patients are allocated sequentially to treatment arm A1 
(AZD9150/MEDI4736) or treatment arm A2 (AZD5069/MEDI4736). A continual 
Redacted

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reassessment method based approach is used to identify the set of AZD9150/MEDI4736 and 
AZD5069/MEDI4736 dose combinations where the incidence of dose-limiting toxicity (DLT) 
is no larger than 33%.
At the time of protocol amendment 5 dated 10 May 2017, the MTDs/ RP2D for each of the 2 
agents in combination with MEDI4736 (durvalumab) were identified from the dose-escalation 
Arm A1 and Arm A2 [AstraZeneca 2016 (a), AstraZeneca 2016 (b)]. The RP2D for AZD5069 
was established at 40 mg twice daily (BID). Also, based on clinical review of maturing data 
from patients treated with AZD5069 in combination with MEDI4736 in Arm A2, it was 
determined that the DLTs of neutropenia occurring in patients treated with AZD5069 were 
due to mechanism of AZD5069 (myelokathexis, which was inhibition of mature neutrophil 
release from the bone marrow) and were likely to confer much lower risk of infection than 
neutropenia associated with cytoreductive therapies (reduced numbers of early through late 
stage developing myeloid cells). Therefore, the Safety Review Committee (SRC) decided to 
enroll an additional cohort of at least 6 to 12 evaluable patients under an alternative dose 
schedule of AZD5069 (80 mg BID with scheduled dose holds and titration) designed to enable 
optimal efficacy and safety for individual patients. This cohort was labelled as Arm A3. At the 
time of amendment 5, the SRC reviewed the outcome of 6 evaluable patients from Arm A3 
and determined that 80 mg BID (using the alternate dosing schedule for managing neutropenic 
toxicity) was safe, tolerable, and thus declared as RP2D.
For the safety run-in cohorts (Arm A4 and Arm A5) that include tremelimumab, patients with 
solid tumor were planned to be allocated to AZD9150/MEDI4736/tremelimumab or 
AZD5069/MEDI4736/tremelimumab with consideration of the patient’s history of taking any 
drugs, herbal supplements, and/or foods prohibited with concurrent administration of 
AZD5069, or within 14 days of the first dose of AZD5069.
For the dose and safety confirmation cohorts (Arm A6 and Arm A7) in solid tumor indications, 
patients were planned to be allocated sequentially to AZD9150/MEDI4736 or 
AZD5069/MEDI4736 with considerations of other medication usage identical to that for the 
safety run-in cohorts described above. Based on preliminary data from Arms A1 and A2, 
metastatic prostate tumor and breast cancer patients were planned to be treated. 
In addition, it was initially planned to demonstrate the absence of a food effect on AZD5069 
absorption enrolling approximately 10 patients either in a fasted or following a high fat meal. 
Sponsor decision is to not open the cohort for enrolment based on data analysed for 
combination of AZD5069 and MEDI4736.

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In summary, the status of all Part A arms conducted at study sites in the United States at the 
time of protocol amendment 7 were as follows:
!
Treatment arm A1: enrolled 2 cohorts of AZD9150 (2 mg/kg and 3 mg/kg) every week
(QW) respectively in combination with MEDI4736 (20 mg/kg every 4 weeks [Q4W]).
Cohort is closed to enrolment.
!
Treatment arm A2: enrolled 2 cohorts of AZD5069 (40 mg BID capsules/tablet and
80 mg tablet BID) respectively in combination with MEDI4736 (20 mg/kg Q4W). Cohort
is closed to enrolment.
!
Treatment arm A3: AZD5069 (80 mg BID tablet) in combination with MEDI4736
(20 mg/kg Q4W) Cohort is closed to enrolment.
!
Treatment arm A4: enrolled into 3 cohorts AZD9150 3 mg/kg QW +tremelimumab
1 mg/kg Q4W +MEDI4736 20 mg/kg Q4W, AZD9150 2 mg/kg QW +tremelimumab
1 mg/kg Q4W+MEDI4736 20 mg/kg Q4W and AZD9150 3 mg/kg every 2 weeks
(Q2W)+tremelimumab 1mg/kg Q4W +MEDI4736 20 mg/kg Q4W. The latter 2 cohorts
were opened based on observed DLT in the cohort that dosed with AZD9150 at 3 mg/kg
QW. These Cohorts are closed to enrolment
!
Treatment arm A5: AZD5069+MEDI4736+tremelimumab was originally planned.
Sponsor portfolio decision was to not open the cohort for enrolment based on data
analysed for combination of AZD5069 and MEDI4736.
!
Treatment arm A6: AZD9150 3 mg/kg QW + MEDI4736 20 mg/kg Q4W was originally
planned to enroll prostate and breast cancer patients. Enrolment occurred in patients with
prostate cancer. Cohort is closed to enrolment.
!
Treatment arm A7: AZD5069+MEDI4736 was originally planned for patients with breast
and prostate cancer. Sponsor portfolio decision to not open the cohort for enrolment was
based on data analysed for combination of AZD5069 and MEDI4736.
When the maximum or recommended doses for dose-expansion was established in Part A 
from Arms A1 and A2, in parallel with the other arms of Part A, Part B of the study 
commenced in patients with recurrent and/or metastatic (RM) SCCHN. The primary objective 
of the dose-expansion phase is to evaluate the objective response rate (ORR) of AZD9150 and 
AZD5069 both as monotherapy and in combination with MEDI4736 for treatment of patients 
with RM SCCHN. In the dose-expansion across Part B (B1-B6), 10 to 55 eligible and efficacy 
evaluable second line+ patients with RM SCCHN patients were planned to be enrolled and 
randomized depending on the treatment arms. In addition, non-randomized Arms B7 and B8 
have been planned, for a total of approximately 48 efficacy evaluable first-line SCCHN 
patients (no prior systemic treatment for RM SCCHN).
In summary, for Arms B1-B6, 2 patient types were planned to be studied, those pretreated 
with prior programmed cell death-ligand 1 (PD-L1) treatment and those naïve to PD-L1 
treatment. Patients were randomized in a 1:1 ratio on the pretreated arms and 2:2:1:1 ratio on 

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the naïve combination arms (combination: combination: monotherapy: monotherapy). The 
enrolment in Part B of the study is closed.
!
Treatment arm B1: 10-52 2L+ RM SCCHN patients were planned to be enrolled in this
Arm where patients were dosed with AZD9150 3 mg/kg QW in combination with
MEDI4736 20 mg/kg Q4W in patients with prior exposure to anti-PD-(L)1 antibodies.
Cohort is closed to enrolment.
!
Treatment arm B2: 10-52 2L+ RM SCCHN patients were planned to be enrolled in this
Arm where patients were dosed with AZD5069 80 mg BID in combination with
MEDI4736 20 mg/kg Q4W in patients with prior exposure to anti-PD-(L)1 antibodies.
Cohort is closed to enrolment.
!
Treatment arm B3: 12-35 2L+ RM SCCHN patients were planned to be enrolled in this
Arm where patients were dosed with AZD9150 3 mg/kg QW in combination with
MEDI4736 20 mg/kg Q4W in patients with no prior exposure to anti-PD-(L)1 antibodies.
Interim analysis for this cohort was planned at 20 patients. There were patients who were
1L RM SCCHN enrolled in this Arm which were replaced. Cohort is closed to enrolment.
!
Treatment arm B4: 12-35 2L+ RM SCCHN patients were planned to be enrolled in this
Arm where patients were dosed with AZD5069 40 mg BID in combination with
MEDI4736 20 mg/kg in patients with no prior exposure to anti-PD-(L)1 antibodies.
Interim analysis for this cohort was planned at 20 patients Provision was made to extend
enrolment in this Arm to 55 patients if at Interim analysis the dose of AZD5069 was
changed from 40 mg BID to 80 mg BID. Cohort is closed to enrolment.
!
Treatment arm B5: 12 2L+ RM SCCHN patients were planned to be enrolled in this Arm
where patients were dosed with AZD9150 3 mg /kg QW alone in patients with no prior
exposure to anti-PD-(L)1 antibodies. Cohort is closed to enrolment.
!
Treatment arm B6: 12 2L+ RM SCCHN patients were planned to be enrolled in this Arm
where patients were dosed with AZD5069 40 mg BID alone in patients with no prior
exposure to anti-PD-(L)1 antibodies. Cohort is closed to enrolment.
In addition, the following non-randomized Arms were planned to enroll patients with no prior 
exposure to anti-PD-(L)1 therapies and patients who have not received prior systemic 
treatment for RM disease.
!
Treatment arm B7: 48 1L RM SCCHN patients were planned to be enrolled in this Arm
where patients were planned to be dosed with AZD9150 3 mg/kg QW in combination
with MEDI4736 20 mg/kg Q4W. Cohort is closed to enrolment.
!
Treatment arm B8: 48 1L RM SCCHN patients were planned to be enrolled in this Arm
where patients were planned to dosed with an alternate-week dosing schedule and with
flat dose of both combination drugs. AZD9150 400 mg Q2W (200 mg in lead-in period)
in combination with MEDI4736 1.5 g Q4W. Cohort is closed to enrolment.

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Study flow chart
Part A: Dose-escalation & Safety Cohorts
Patients with advanced solid malignancies refractory to standard therapy or for which no standard of care 
regimen currently exists.
Abbreviations: MTD=maximum tolerated dose; PK=pharmacokinetics; PD=pharmacodynamics; treme=tremelimumab.
Note: Treatment arms A1, A2, A3, A4, and A6 are closed to enrolment. Treatment arms A5 and A7 will not open. 

Clinical Study Protocol 
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Part B: Dose-Expansion
Abbreviations: CRM=continual reassessment method; DCR=disease control rate; DOR=duration of response; IA=interim 
analysis; MTD=maximum tolerated dose; OS=overall survival; PD-(L)1=programmed cell death 1 (CD279) and/or 
programmed cell death-ligand 1 (also known as B7 homolog 1, CD274); PFS=progression-free survival; 
PK/PD=pharmacokinetics/pharmacodynamics; SRC=Safety Review Committee; SCCHN=squamous cell carcinoma of the 
head and neck; treme=tremelimumab.
Note: Treatment arms B1, B2, B3, B4, B5, B6, B7, and B8 are closed to enrolment.

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Objectives
Primary Objective:
Outcome Measure:
Dose-escalation and safety cohorts Part A
To determine the MTDs or recommended doses for 
dose-expansion and to determine the safety profiles 
of either AZD9150 or AZD5069 in combination 
with MEDI4736 and/or MEDI4736/tremelimumab 
in patients with advanced solid malignancies 
refractory to standard therapy or for which no 
standard of care regimen currently exists. 
MTD based on patients who completed the DLT 
Evaluation
AEs, SAEs, laboratory evaluations, vital signs, and 
physical examinations
Treatment-emergent AEs (TEAEs), SAEs and death(s), 
graded in accordance with NCI CTCAE v4.03
Dose-expansion Part B
To evaluate the ORR of AZD9150 and AZD5069 
both as monotherapy and in combination with 
MEDI4736 in the second-line treatment of patients 
with RM SCCHN and in patients with no prior 
exposure to anti-PD-(L)1 therapies and also in 
patients who have not received prior systemic 
treatment for recurrent or metastatic SCCHN (1L 
RM SCCHN). To evaluate ORR of AZD9150 as a 
fixed dosed Q2W in patients with no prior exposure 
to anti-PD-(L)1 therapies and who have not 
received prior systemic treatment for recurrent or 
metastatic SCCHN (1L RM SCCHN).
Objective response −defined as a complete response (CR) 
or partial response (PR) according to RECIST version 1.1
Secondary Objective:
Outcome Measure:
Dose-escalation and safety cohorts Part A
To assess the PK of AZD9150, AZD5069, and 
MEDI4736 and/or MEDI4736/tremelimumab in the 
selected dose combinations.
PK parameters as outlined in Section 8.5
To determine the IM of MEDI4736 and/or 
MEDI4736/tremelimumab in combination with 
AZD9150 or AZD5069 and the IM of AZD9150 in 
combination with MEDI4736 and/or 
MEDI4736/tremelimumab
ADAs
To assess pharmacodynamic response in blood for 
AZD9150.
STAT3 knockdown (signal transducer and activator of 
transcription 3 [STAT3] knockdown)

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Dose-expansion Part B
To assess secondary measures of efficacy (DCR at 
12 weeks; duration of overall response [DOR], 
PFS, OS; and proportion of patients alive at 12 
months).
Disease control defined as a CR, PR, or stable disease 
(SD), according to RECIST version 1.1 criteria, at 12 
weeks
DOR according to RECIST version 1.1 criteria (measured 
from the time measurement criteria are first met for CR or 
PR, whichever is first recorded, until the first date that 
recurrent or progressive disease (PD) is objectively 
documented (taking as reference for PD the smallest 
measurements recorded on study)
PFS - defined as the time from randomisation to the first 
documentation of PD as determined by the Investigator or 
death from any cause, whichever occurs first
OS - defined as the time from randomisation to death from 
any cause
Best overall response (including CR, PR, SD, and PD, 
according to RECIST version 1.1 criteria), ordered from 
best to worst
Survival at 12 months
To assess the PK of AZD9150 and AZD5069 both 
as monotherapy and in combination with 
MEDI4736.
PK parameters as outlined in Section 8.5
To assess the urinary PK of AZD9150 and 
MEDI4736 in combination with AZD9150 or 
AZD5069.
PK parameters as outlined in Section 8.5
To determine the IM of AZD9150 alone or in 
combination with MEDI4736 and the IM of 
MEDI4736 in combination with AZD9150 or 
AZD5069.
ADAs
To assess pharmacodynamic response in blood for 
AZD9150 and MEDI4736 (sPD-L1 will not be 
evaluated for Arm B1, B2, and B4 post the first 
20 patients and for Arm B7 and B8).
(STAT3 knockdown) and sPD-L1 in blood
Pharmacodynamics of MEDI4736 (sPD-L1) and 
tremelimumab (will not be evaluated for Arm B1, B2, and 
B4 post the first 20 patients and for Arm B7 and B8)
To assess tumor cell pharmacodynamics (STAT3 
knockdown).
Pharmacodynamics of AZD9150 (STAT3 knockdown) in 
tumor tissue
To assess baseline circulating MDSCs and effect of 
treatment on circulating MDSCs (will not be 
evaluated for Arm B1, B2, and B4 post the first 
20 patients and for Arm B7 and B8).
Circulating MDSCs
To evaluate baseline tumor PD-L1 expression for 
potential correlation with drug activity or the ability 
to prospectively identify patients likely to respond 
to treatment.
Tumor PD-L1 expression

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Safety Objective:
Outcome Measure:
Dose-expansion Part B
To evaluate the safety and tolerability of AZD9150 
and AZD5069 both as monotherapy and in 
combination with MEDI4736.
AEs, SAEs, laboratory evaluations, vital signs, and 
physical examinations
TEAEs, SAEs, and death, graded in accordance with 
National Cancer Institute (NCI) CTCAE version 4.03
Exploratory Objectives
Outcome Measures
Dose-escalation (Part A) and Dose-expansion (Part B)
To evaluate baseline levels of and changes in 
blood-borne biomarkers that may correlate with 
treatment or clinical response.
Include, but are not limited to, gene expression, 
immunogenomics (genetics associated with immune 
responses such as homozygosity/ heterozygosity of 
MHC-I genes), T cell activation or proliferation 
markers, T cell repertoire, and cytokines and other 
soluble factors
To assess serum samples for pharmacodynamic 
response to AZD5069.
Transient increase in CXCR2 ligands interleukin-8 and 
GRO-α
To evaluate tumor-based biomarkers in 
archival/baseline tumor samples that may correlate 
with treatment or prospectively identify patients 
likely to respond to treatment with AZD9150 or 
AZD5069 in combination with MEDI4736 and/or 
MEDI4736/tremelimumab.
These may include but are not limited to PD-L1 
expression, phospho- or total STAT3 expression, tumor 
genetics, immunogenomics (genetics associated with 
immune responses such as 
homozygosity/heterozygosity of MHC-I genes), 
characterisation of immune infiltrates, gene expression 
or other stratification markers
To evaluate circulating-free deoxyribonucleic acid
(cfDNA; including circulating tumor 
deoxyribonucleic acid [DNA] as well as non-tumor 
cell free DNA) measures at baseline or on-
treatment or changes upon treatment or changes 
upon treatment that may correlate with treatment or 
response. (Note: only cfDNA required to be 
obtained for new patients consented under protocol 
amendment 5, dated 10 May 2017 and onwards 
[B3, B7, B8, and Part A]). 
For tumor-derived DNA mutations at baseline, and 
changes upon treatment that may correlate with 
treatment or response.
To collect and store tumor, blood, plasma, and 
serum samples or analyse surplus blood or tissue 
including patient-specific archival tumor tissue, if 
available.
For potential future exploratory research into factors 
that may influence development of the tumor or 
response to treatment (where response is defined 
broadly to include efficacy, tolerability, or safety). In 
the event that additional tumor molecular profiling is 
required to understand further any response to 

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treatment, AstraZeneca may request a sample of the 
most recent tumor biopsy for additional research. Any 
sample collection can be discontinued or suspended at 
the discretion of the Sponsor, without the need for a 
protocol amendment
To explore the relationship between PK and 
selected endpoints 
Which may include pharmacodynamics, efficacy, 
and/or safety, where deemed appropriate
To collect and store DNA 
Carry out future exploratory research into genes/genetic 
variation that may influence response (i.e., distribution, 
safety, tolerability, and efficacy) to treatment with 
AZD9150 and AZD5069 both as monotherapy and in 
combination with MEDI4736 (and/or 
MEDI4736/tremelimumab) and/or development of 
cancer
Part B Only 
To evaluate changes in tumor-based biomarkers 
that may correlate to treatment or response 
Changes including but not limited to immune cell 
infiltrate, gene expression changes, cell activation or 
proliferation markers, and cytokines
Target subject population
The dose-escalation Part A targets patients with histologically confirmed solid malignancies 
(other than hepatocellular carcinoma) that are refractory to standard therapy or for which no 
standard of care regimen currently exists.
The dose-expansion Part B (B1 to B8) is targeting patients with histologically and/or 
cytologically confirmed SCCHN that is RM and not amenable to curative therapy by surgery 
or radiation. Patients may have failed 0 to 3 previous cytoreductive chemotherapeutic (B1 to 
B6) or patients who have not received any prior systemic treatment for RM SCCHN (B7 and 
B8) as described in more detail in Section 3. Patients must have at least 1 tumor lesion 
amenable to biopsy and must be medically fit and willing to undergo a biopsy during 
screening and, unless clinically contraindicated, at the end of Cycle 1. (In the event of disease 
progression, biopsies at the EOT are optional but encouraged.)
Section 3 provides the full and detailed eligibility criteria; key inclusion requirements for 
patients in both parts of the study are:
!
Able and willing to give written informed consent including consent for collection
of formalin fixed paraffin-embedded blocks or slides from archival diagnostic
histology samples, where available. For inclusion in the optional genetic research,
patients must provide a separate informed consent.

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!
Male and female patients, at least 18 years of age
!
Eastern Cooperative Oncology Group performance status score of 0 or 1
!
Measurable disease
!
Number of prior lines of treatment by Arm:
∀
Arms A1 to A4 and A6: Has undergone ≤3 previous regimens of cytoreductive
chemo-therapies including, but not limited to, platinum-based compounds,
taxanes, or 5-fluorouracil
∀
Arms B1 to B6: Has undergone 1-3 previous regimens of cytoreductive chemo-
therapies including, but not limited to, platinum-based compounds, taxanes, or
5-fluorouracil
∀
Arm B3: Has undergone at least 1 previous regimen of systemic chemotherapy
and received up to 3 previous regimens of cytoreductive treatments in the
recurrent metastatic disease setting. If a patient has received systemic
chemotherapy for local disease only, they would not be considered eligible for
Arm B3.
∀
Arms B7 and B8: Has not received any previous systemic therapies for
recurrent metastatic disease, nor had any prior exposure to anti-PD-(L)1
therapies. Patients who have received chemotherapy for local disease may be
considered for eligibility to Arms B7 and B8.
!
Adequate organ and marrow function
!
Women of childbearing potential and men who are sexually active with a female
partner of childbearing potential must prevent pregnancy and women may not be
breast feeding
Section 3 provides the full and detailed eligibility criteria; key exclusion requirements for 
patients in both parts of the study are:
!
Symptomatic spinal cord compression
!
Second malignancy
!
Concurrent chemotherapy, radiotherapy, immunotherapy, or biologic or hormonal
therapy for cancer
!
Ongoing toxicity related to prior treatment and assessed as grade >1

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!
Immune-related AEs while receiving prior immunotherapy (including anticytotoxic
T-lymphocyte-associated protein 4 treatment) and assessed as grade ≥3
!
Has active or prior documented autoimmune disease within the past 2 years with the
exception of vitiligo, Grave’s disease, and/or psoriasis not requiring systemic
treatment
!
Active or prior documented inflammatory bowel disease
!
History of primary immunodeficiency
!
Prior organ transplant that requires use of immunosuppressive treatment
!
Cardiac conditions that render the patient unsuitable for participation in the study
!
Inability to take oral medications and/or has a clinical or radiological diagnosis of
bowel obstruction
!
History of allergic reactions attributed to the study treatments (AZD9150,
AZD5069, tremelimumab [for Part A, Arm A4 only] or MEDI4736), their
compounds, or agents of similar chemical or biologic composition
!
Suffers from a comorbidity that in the opinion of the Investigator renders the patient
unsuitable for participation in the study
!
As judged by the Investigator, any evidence of severe or uncontrolled diseases such
as active bleeding diatheses, or has an active viral infection of human
immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus
(HCV)
!
History of tuberculosis
!
Condition that, in the opinion of the Investigator, would interfere with the
evaluation of the study drugs or the interpretation of patient safety or study results
!
Live attenuated vaccine within 30 days before the first dose of study drug
!
Judgement 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
!
Patients with brain metastases considered stable may be enrolled into Part A of the
study; they are excluded from Part B of the study
!
Patients must not be included in the optional genetic research if they have
previously received an allogeneic bone marrow transplant or have received

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nonleukocyte depleted whole blood transfusion(s) within 120 days before the date 
of the genetic sample collection
Duration of treatment
Patients participating in either part of the study will be administered study drug(s) following a 
7-day lead-in period in 4-week treatment cycles. This may continue for as long as they are
continuing to show clinical benefit, as judged by the Investigator, unless a patient has
confirmed progression of disease (PD) with either clinical deterioration and/or no further
benefit from treatment, experiences unacceptable toxicity, or discontinues for any other
reason. If a patient on either monotherapy arm (treatment arms B5 or B6) has confirmed PD,
they may, at Investigator’s discretion and with notification to the Medical Monitor, add
MEDI4736 to their treatment regimen. These patients, post addition of MEDI4736 to the
monotherapy treatment will continue to be part of the safety analysis but will be censored
from the efficacy analysis. After discontinuation of treatment, all patients will continue to be
followed for safety, subsequent anticancer therapy, and survival. During this time, all patients
will be followed for safety (including concomitant medication) for 28 days (+7 days) after the
last dose of study drug or until the initiation of a subsequent anticancer therapy. In addition,
patients who received MEDI4736 as part of their combination treatment will be followed for
immunogenicity for 90 days (±7 days) after the last dose of MEDI4736 or until the initiation
of alternative anticancer therapy. Patients who discontinued treatment for reasons other than
PD will continue to undergo tumor assessments every 2 months (±7 days) until PD is noted.
All patients will be followed for subsequent anticancer therapy every 2 months (±7 days) and
will also be followed for overall survival every 2 months (±7 days) from the date of
randomisation to the date of death due to any cause, assessed for approximately 40 months.
The patients will be censored on the date of last follow-up visit.
Investigational product, dosage and mode of administration
AZD9150: Arms A1, A4, A6, B1, B3, B5, B7, and B8: Patients will receive a loading dose of 
AZD9150 (Days −7, −5, and −3) at the defined dose in each treatment arm as described in the 
study design. Following loading dose, patients will receive QW dosing of AZD9150 (except 
in Cohort 2 of Arm A4 and Arm B8 where the schedule of AZD9150 is Q2W). AZD9150 will 
be administered as a 1-hour (± 10 minutes) infusion. In all cases, infusion of AZD9150 is 
planned to be completed at least 1 hour (Cycle 1) or at least 30 minutes (in subsequent cycles 
if no infusion reaction in first cycle) before the start of the MEDI4736 infusion on days that 
both drugs are administered. For Arm A4 specifically the sequence of dosing for the first 4 
cycles would be AZD9150 infused over 1 hour (± 10 minutes) followed by tremelimumab 
infused over 1 hour (± 10 minutes) followed by MEDI4736 infused over 1 hour (± 10 
minutes). Ideal body weight (IBW) will be used to calculate the administered dose in all arms 
where AZD9150 is to be infused except Arm B8 where fixed dosed AZD9150 is to be 
administered, i.e., 200 mg as lead-in doses on Days −7, −5, and −3 and 400 mg Q2W 
thereafter in a 28-day cycle. 

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Ideal body weight will be determined using the Devine formula (Pai and Paloucek 2000; see 
Section 7.2.1). If the actual weight is less than the IBW or the patient is less than 5 feet tall, 
the actual weight will be used to determine the dose. During the 7-day lead-in period, 
AZD9150 will be administered as a loading dose on Days -7, -5, and -3. Starting with Cycle 1, 
AZD9150 will be administered QW on Days 1, 8, 15, and 22 of each treatment cycle.
AZD5069: Arms A2, A3, A5, A7, B2, B4, and B6: Patients will receive AZD5069 as 40 mg 
BID starting with Day −7 of a 7-day lead-in period at the defined dose in each treatment arm 
as described in the study design. Following the lead-in period, patients will receive BID 
dosing of AZD5069 daily for a 28-day cycle. On days when both AZD5069 and MEDI4736 
are given, the morning dose of AZD5069 is administered at least 30 minutes before starting 
infusion of MEDI4736. For Arm A5 specifically, the sequence of dosing for the first 4 cycles 
was planned to be AZD5069 followed 30 minutes later by tremelimumab infused over 1 hour 
(± 10 minutes) followed by MEDI4736 infused over 1 hour (±10 minutes). As discussed in the 
study design Arm A5, Arm A7, and the food effect substudy will not open for enrolment. In 
all cases, AZD5069 should be administered either 2 hours before or 2 hours after (with 
± 2 hours) food consumption at approximately the same time each day.
MEDI4736: Arms A1-A7, B1-B4, B7, and B8: Patients will receive MEDI4736 starting on 
Day 1 of Cycle 1 and will be administered as 20 mg/kg infusion administered over 1 hour 
Q4W in a 28-day cycle. In addition to the above arms, patients in monotherapy Arms (B5 and 
B6) who develop confirmed disease progression may have MEDI4736 added, at the discretion 
of the Investigator and after notifying the Medical Monitor. MEDI4736 will be added to the 
dosing schedule beginning on Day 1 of the following treatment cycle. Thereafter, all study 
treatment will follow the same schedule as for a patient on a combination therapy arm. For 
Arm B8, a flat dose of 1.5 g will be administered. In Arms B5 and B6, MEDI4736 could be 
added to treatment after progression on AZD9150 or AZD5069 monotherapy agents,
respectively.
Tremelimumab: Arms A4 and A5: Patients will receive tremelimumab starting Day 1 of 
Cycle 1 and will be administered as 1 mg/kg infusion administered over 1 hour Q4W in a 
28-day cycle. Tremelimumab will be infused for a maximum of 4 cycles.
Statistical methods
The dose-escalation Part A used a continual reassessment method-based approach to identify 
the set of AZD9150/MEDI4736 and AZD5069/MEDI4736 dose combinations where the 
incidence of DLT is no larger than 33%. Once the MTDs for each of the 2 agents in 
combination with MEDI4736 were identified or the maximum doses of each of the 2 agents in 
combination with MEDI4736 were reached, the SRC decided (based on emerging and 
maturing data) to enroll an additional 6-12 patients to Arm A3 to test alternative dosing 
schedule of AZD5069. Also, Arms A4, A5, A6 and A7 are designed with a small number of 

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patients (6 to 18) to gather and confirm safety information and will start/continue to enroll for 
A5 and A7, based on emerging safety and efficacy data from Part B. The dose-expansion Part 
B for Arms B1-B6 will use an adaptive approach to sample size based on Bayesian statistical 
methodology, so the number of actively enrolling treatment arms may decrease as the study 
continues. The maximum number of evaluable patients to be included in naïve combination 
arms is N=35. The maximum number of patients to be included in pretreated combination 
arms is N=52.
For the 2 combination arms in the anti-PD-(L)1 naïve patients (Arms B3 and B4), once 
12 efficacy outcomes have been observed in the first 12 efficacy evaluable patients in each 
arm, a predictive power calculation will be used to assess the chance of observing at least 8 of 
35 responses (either PR or CR) in each arm. The method of calculating predictive power is 
based on a parameter free approach to predictive power as it applies to variables that follow a 
binomial distribution (Jennison and Turnbull 2000). Predictive power (chance to observe at 
least 8 of 35 responses) will be recalculated following the observation of the efficacy outcome 
in each efficacy evaluable patient as they were dosed in the trial. If, following the observation 
of any patient’s outcome, predictive power falls below 20%, the arm in which this happens 
will be stopped. If predictive power remains above 20% following the 19th efficacy evaluable 
patient, then an interim analysis will be conducted following the 20th efficacy evaluable 
patient. Each of the combination arms will continue to enroll patients up to a maximum of 35 
efficacy evaluable patients following the interim analysis if at least 5 of 20 patients have 
responded with at least a PR. 
Predictive power monitoring will not be performed for the 2 monotherapy groups (B5 and B6) 
in dose-expansion Part B and the 1L RM SCCHN patients in Arm B7. The 2 monotherapy 
arms will continue recruiting until 12 efficacy evaluable patients have been enrolled in each 
arm.
For the 2 combination arms in the anti-PD-(L)1 pretreated patients (B1 and B2), once efficacy 
outcomes have been observed in the first 10 efficacy evaluable patients in each arm, a 
predictive power calculation will be used to assess the chance of observing at least 3 of 20 
responses (either PR or CR) in each arm. Predictive power (chance to observe at least 3 of 20 
responses) will be recalculated following the observation of the efficacy outcome in each 
efficacy evaluable patient as they were dosed in the trial. If, following the observation of any 
patient’s outcome, predictive power falls below 20%, the arm in which this happens will be 
stopped. However, no formal interim analysis will be conducted for the combination arms in 
the anti-PD-(L)1 pretreated patients.
In addition, Arms B7 and B8 will enroll patients who have not received prior systemic 
treatment for RM SCCHN and will receive combination treatment of AZD9150 in 
combination with MEDI4736. With approximately 48 patients in each arm, the chance that 

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fewer than 12 patients with CR or PR (responding) will be observed, given the true fraction of 
patients responding is 35%, is 9%. The chance that at least 15 patients responding is observed, 
given the true fraction of patients responding is 25%, is 20%. In addition, B8 will incorporate 
predictive power monitoring for futility beginning with the 15th patient. If at any time from 
the 15th patient through the 48th patient, the chance to observe 13 responses in 48 patients 
falls below 20%, then the arm will be stopped.
Recruitment will continue while predictive power is measured. If an arm is to be stopped, no 
new patients will be recruited to that arm, but patients who are already on study in that arm 
will continue in accordance with study guidelines outlined in Section 4. 

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY........................................................................................................... 2
CLINICAL STUDY PROTOCOL SYNOPSIS ..................................................................... 9
TABLE OF CONTENTS.................................................................................................... 25
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.......................................... 32
1
INTRODUCTION............................................................................................ 38
1.1
Background and rationale for conducting this study .......................................... 38
1.1.1
AZD9150.......................................................................................................... 38
1.1.2
AZD5069.......................................................................................................... 38
1.1.3
MEDI4736........................................................................................................ 39
1.1.4
Tremelimumab ................................................................................................. 39
1.1.5
Disease background .......................................................................................... 39
1.2
Rationale for study design, doses and control groups ........................................ 40
1.3
Benefit/risk and ethical assessment ................................................................... 46
1.3.1
Potential benefits .............................................................................................. 46
1.3.2
Potential risks ................................................................................................... 48
1.3.3
Overall benefit-risk and ethical assessment ....................................................... 51
1.4
Study Design .................................................................................................... 52
2
STUDY OBJECTIVES..................................................................................... 56
2.1
Primary objective.............................................................................................. 56
2.2
Secondary objectives ........................................................................................ 56
2.3
Safety objectives............................................................................................... 58
2.4
Exploratory objectives ...................................................................................... 58
3
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ................... 59
3.1
Inclusion criteria............................................................................................... 59
3.1.1
All patients ....................................................................................................... 59
3.1.2
Additional inclusion criteria Dose-escalation and safety cohorts Part A ............ 61
3.1.3
Additional inclusion criteria Arm A6 of Part A................................................. 61
3.1.4
Additional inclusion criteria-Dose-expansion Part B......................................... 61
3.1.5
Additional inclusion criteria - Dose-expansion Part B: treatment arms B1 and 
B2..................................................................................................................... 62
3.2
Exclusion criteria.............................................................................................. 62
3.2.1
All patients ....................................................................................................... 62
3.2.2
Additional exclusion criteria: Dose-escalation and safety cohorts Part A........... 64
3.2.3
Additional exclusion criteria: Dose-expansion Part B........................................ 64
3.2.4
Additional exclusion criteria: Dose-expansion Part B: treatment arms B3, B4, 
B5, B6, B7, and B8........................................................................................... 65
3.2.5
Additional exclusion criteria: Optional genetic research.................................... 65

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3.3
Subject enrolment and screening....................................................................... 65
3.4
Procedures for handling incorrectly enrolled or randomized subjects ................ 66
3.5
Methods for assigning treatment groups............................................................ 66
3.6
Methods for ensuring blinding .......................................................................... 66
3.7
Methods for unblinding..................................................................................... 67
3.8
Restrictions....................................................................................................... 67
3.8.1
Birth control ..................................................................................................... 67
3.8.2
Eligibility of patients for treatment with AZD5069 ........................................... 68
3.9
Discontinuation of investigational product........................................................ 70
3.9.1
Procedures for discontinuation of a subject from investigational product .......... 71
3.10
Criteria for withdrawal...................................................................................... 71
3.10.1
Screen failures .................................................................................................. 71
3.10.2
Withdrawal of the informed consent ................................................................. 71
3.11
Discontinuation of the study ............................................................................. 71
4
STUDY PLAN AND TIMING OF PROCEDURES ......................................... 72
4.1
Dose-escalation and safety cohorts Part A......................................................... 72
4.1.1
Screening/Enrolment period.............................................................................. 75
4.1.2
Treatment period............................................................................................... 75
4.2
Dose-expansion Part B...................................................................................... 79
4.2.1
Screening/Enrolment period.............................................................................. 82
4.2.2
Treatment period............................................................................................... 82
4.2.3
End-of-treatment evaluations and follow-up...................................................... 86
5
STUDY ASSESSMENTS................................................................................. 86
5.1
Recording of data.............................................................................................. 86
5.2
Study plan and event overview.......................................................................... 87
5.3
Efficacy assessments....................................................................................... 105
5.3.1
Tumor assessments ......................................................................................... 105
5.3.1.1
Response assessment ...................................................................................... 105
5.4
Safety assessments.......................................................................................... 106
5.4.1
Laboratory safety assessments ........................................................................ 106
5.4.2
Physical examination ...................................................................................... 108
5.4.3
ECG ............................................................................................................... 109
5.4.3.1
Resting 12-lead ECG ...................................................................................... 109
5.4.4
Vital signs....................................................................................................... 110
5.4.5
Eastern Cooperative Oncology Group performance status (Other safety 
assessments) ................................................................................................... 110
5.5
Pharmacokinetics............................................................................................ 111
5.5.1
Collection of samples...................................................................................... 111
5.5.2
Determination of drug concentration............................................................... 115
5.5.3
Storage and destruction of pharmacokinetic samples....................................... 115
5.6
Pharmacodynamics and patient selection biomarkers ...................................... 116
5.6.1
Collection of blood samples for pharmacodynamics assessments.................... 116

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5.6.2
Collection of blood for myeloid-derived suppressor cells................................ 116
5.6.3
Collection of tumor biopsies for evaluation of STAT3 and PD-L1 expression. 117
5.6.4
Storage, re-use and destruction of pharmacodynamic samples......................... 117
5.7
Immunogenicity.............................................................................................. 118
5.8
Exploratory research....................................................................................... 118
5.8.1
Exploratory biomarker research ...................................................................... 118
5.8.1.1
Collection of exploratory blood-borne biomarkers .......................................... 119
5.8.1.2
Collection of exploratory tumor biomarkers.................................................... 120
5.8.1.3
Collection of archival tumor samples .............................................................. 120
5.8.2
Pharmacogenetics ........................................................................................... 120
5.8.3
Volume of blood............................................................................................. 121
5.8.4
Handling, storage, and destruction of biological samples ................................ 123
5.8.4.1
Pharmacokinetic samples................................................................................ 123
5.8.4.2
Samples for exploratory research .................................................................... 124
5.8.5
Labelling and shipment of biological samples................................................. 124
5.8.6
Chain of custody of biological samples........................................................... 124
5.8.7
Withdrawal of Informed Consent for donated biological samples.................... 124
5.9
Patient reported outcomes............................................................................... 125
6
SAFETY REPORTING AND MEDICAL MANAGEMENT.......................... 125
6.1
Definition of adverse events............................................................................ 125
6.2
Definitions of serious adverse event................................................................ 125
6.3
Definitions of adverse events of special interest .............................................. 126
6.4
Recording of adverse events ........................................................................... 126
6.4.1
Time period for collection of adverse events................................................... 126
6.4.2
Follow-up of unresolved adverse events.......................................................... 127
6.4.3
Variables ........................................................................................................ 127
6.4.4
Causality collection......................................................................................... 128
6.4.5
Adverse events based on signs and symptoms................................................. 128
6.4.6
Adverse events based on examinations and tests ............................................. 128
6.4.7
Hy’s Law........................................................................................................ 129
6.4.8
Serious bleeding events with combination drug MEDI4736 (durvalumab) in 
squamous cell carcinoma of the head and neck patients................................... 129
6.4.9
Investigators should carefully assess the risk in relation to benefit of using 
anticoagulation or other medications that might exacerbate bleeding during 
study participation. Investigators should consider discontinuation of these 
agents if the clinical scenario permits it unless discontinuation would be 
clinically contraindicated.Disease progression ................................................ 129
6.4.10
New cancers ................................................................................................... 130
6.4.11
Handling of deaths.......................................................................................... 130
6.4.12
Disease under Study (DUS) ............................................................................ 130
6.5
Reporting of serious adverse events ................................................................ 130
6.6
Overdose ........................................................................................................ 131
6.6.1
AZD9150........................................................................................................ 132
6.6.2
AZD5069........................................................................................................ 132

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6.6.3
MEDI4736...................................................................................................... 133
6.6.4
Tremelimumab ............................................................................................... 133
6.7
Pregnancy....................................................................................................... 133
6.7.1
Maternal exposure .......................................................................................... 133
6.7.2
Paternal exposure............................................................................................ 134
6.8
Medication Error............................................................................................. 134
6.9
Management of IP related toxicities................................................................ 135
6.9.1
Dose modifications ......................................................................................... 136
6.9.2
Infusion reactions ........................................................................................... 138
6.9.3
Hypersensitivity reactions............................................................................... 138
6.9.4
Differential diagnosis: Infusion-related reaction versus anaphylaxis................ 138
6.9.5
Liver chemistry tests....................................................................................... 140
6.9.6
Potential immune-related adverse events......................................................... 140
6.10
Study team contacts for emergencies............................................................... 143
6.11
Duration of treatment...................................................................................... 144
6.12
Expected start and end of study....................................................................... 145
6.13
Study suspension or early termination............................................................. 145
7
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS................ 146
7.1
Identity of investigational product(s)............................................................... 146
7.2
Dose and treatment regimens .......................................................................... 147
7.2.1
Administration of AZD9150 ........................................................................... 147
7.2.2
Administration of AZD5069 ........................................................................... 148
7.2.3
Administration of MEDI4736 ......................................................................... 149
7.2.4
Administration of tremelimumab .................................................................... 150
7.3
Labelling ........................................................................................................ 150
7.4
Storage ........................................................................................................... 150
7.5
Distribution of AZD5069 to the patient........................................................... 151
7.6
Treatment compliance and accountability ....................................................... 151
7.7
Dose-escalation and safety cohorts: Part A and Part B .................................... 152
7.7.1
Starting dose and dose-escalation scheme ....................................................... 152
7.7.2
Management of causally related infusion events.............................................. 156
7.7.3
Definition of dose-limiting toxicity................................................................. 158
7.7.4
Definition of maximum tolerated dose ............................................................ 159
7.7.5
Definition of dose-limiting toxicity evaluable patient...................................... 159
7.7.6
Safety Review Committee............................................................................... 159
7.7.7
Confirmation of the presumed recommended dose.......................................... 160
7.7.8
Definition of efficacy evaluable patient........................................................... 161
7.8
Concomitant and other treatments................................................................... 161
7.8.1
Other concomitant treatment........................................................................... 163
8
STATISTICAL ANALYSES BY ASTRAZENECA....................................... 164
8.1
Statistical considerations................................................................................. 164
8.2
Sample size estimate....................................................................................... 164

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8.2.1
Dose-escalation Part A.................................................................................... 164
8.2.2
Dose-expansion Part B.................................................................................... 165
8.3
Definitions of analysis sets.............................................................................. 169
8.3.1
Efficacy analysis set........................................................................................ 170
8.3.2
Safety analysis set........................................................................................... 170
8.3.3
PK analysis set................................................................................................ 170
8.3.4
PD analysis sets.............................................................................................. 170
8.4
Calculation or derivation of safety variables.................................................... 170
8.5
Calculation or derivation of pharmacokinetic variables................................... 171
8.6
Calculation or derivation of pharmacodynamic variables ................................ 172
8.7
Pharmacokinetics/Pharmacodynamic analysis................................................. 172
8.8
Calculation or derivation of exploratory research variables ............................. 172
8.9
Calculation or derivation of tumor response variables..................................... 173
8.10
Methods of statistical analysis......................................................................... 175
9
STUDY AND DATA MANAGEMENT BY ASTRAZENECA...................... 183
9.1
Training of study site staff .............................................................................. 183
9.2
Monitoring of the study................................................................................... 183
9.2.1
Source data..................................................................................................... 183
9.2.2
Study agreements............................................................................................ 184
9.2.3
Archiving of study documents ........................................................................ 184
9.3
Study timetable and end of study .................................................................... 184
9.4
Data management by AstraZeneca .................................................................. 184
10
ETHICAL AND REGULATORY REQUIREMENTS.................................... 186
10.1
Ethical conduct of the study............................................................................ 186
10.2
Subject data protection.................................................................................... 186
10.3
Ethics and regulatory review........................................................................... 186
10.4
Informed consent ............................................................................................ 187
10.5
Changes to the Clinical Study Protocol and Informed Consent Form............... 187
10.6
Audits and inspections .................................................................................... 188
11
LIST OF REFERENCES................................................................................ 189
ANNEX 1......................................................................................................................... 228
LIST OF TABLES
Table 1
Highly effective methods of contraception............................................... 67
Table 2
Prohibited medications and foods for patients administered AZD5069..... 69
Table 3
Treatment schedule, dose-escalation Part A ............................................. 73
Table 4
Treatment schedule, dose-expansion Part B ............................................. 80

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Table 5
Study plan for study entry, treatment, safety, and tumor assessments ....... 88
Table 6
Study plan for pharmacokinetic, pharmacodynamic, immunogenicity, 
and pharmacogenetic assessments in Part A............................................. 93
Table 7
Study plan for pharmacokinetic, pharmacodynamic, immunogenicity, 
and pharmacogenetic assessments in Part B (Arms B1-B7)...................... 97
Table 8
Study plan for pharmacokinetic, pharmacodynamic, immunogenicity, 
and pharmacogenetic assessments in Part B (B8)................................... 102
Table 9
Laboratory Safety Variables................................................................... 108
Table 10
Volume of blood to be drawn from each patient during screening, lead-in 
period, and Cycle 1 of Part A and Part B................................................ 122
Table 11
Dose modifications for toxicity (excluding liver function tests and in 
case of neutropenia for AZD5069 alternate dosing schedule arms)......... 136
Table 12
Dose modifications for elevations in liver function tests......................... 137
Table 13
Dosage form and strength of the investigational products....................... 146
Table 14
Expected sample sizes for a series of true objective response rates for 
combination therapy in anti-PD-(L)1 naïve and anti-PD-(L)1 pretreated 
patients .................................................................................................. 167
Table 15
Analysis sets.......................................................................................... 170
Table 16
Expected probability of DLT in treatment arm A1 of Part A 
(AZD9150/MEDI4736) ......................................................................... 176
Table 17
Expected probability of DLT in treatment arm A2 of Part A 
(AZD5069/MEDI4736) ......................................................................... 176
LIST OF FIGURES
Figure 1
Generation and regulation of anti-tumor immunity................................... 41
Figure 2
Study flow chart ...................................................................................... 53
Figure 3
Study Scheme: Part A and Part B............................................................. 55
Figure 4
Dose-escalation and de-escalation Arms A1, A4, A6 and dose-reduction 
levels for Part B (B1, B3, B5, and B7) ................................................... 155
Figure 5
Dose-escalation and de-escalation Arm A2 and dose-reductions levels 
for Part B (B2, B4, and B6).................................................................... 155
Figure 6
Dose-reduction levels for treatment Arm B8 .......................................... 156
Figure 7
Alternative dose schedule, titration and dose-reduction for Arms A3 and 
B4 (post-interim analysis)...................................................................... 157

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Figure 8
Alternative dose schedule, dose titration and dose-reduction for Arms A3 
and B4 (post-interim analysis) ............................................................... 157
Figure 9
Adaptive approach to sample size Part B (B1-B6).................................. 168
LIST OF APPENDICES
Appendix A
Additional Safety Information................................................................ 196
Appendix B
Further Guidance On The Definition Of A Serious Adverse Event (SAE)198
Appendix C
International Airline Transportation Association (IATA) 6.2 Guidance 
Document .............................................................................................. 200
Appendix D
Ethical and Regulatory Requirements .................................................... 201
Appendix E
Data and Study Management ................................................................. 204
Appendix F
Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors).................. 208
Appendix G
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 219
Appendix H
MEDI4736 Adverse Events of Special Interest ...................................... 226

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this Clinical Study Protocol (CSP).
Abbreviation or 
special term
Explanation
2′-MOE
2′-methoxyethyl
Ab(s)
Antibody(ies)
ADA(s)
Antidrug antibody(ies)
ADCC
Antibody-dependent cell-mediated cytotoxicity
AE(s)
Adverse event(s) (see definition in Section 6.1)
AESI(s)
Adverse event(s) of special interest (see definition in Section 6.3)
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ApcMin/+
Adenomatous polyposis coli/multiple intestinal neoplasia
aPTT
Activated partial thromboplastin time
ASO
Antisense oligonucleotide
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC(ss)
Area under the plasma concentration-time curve at steady state
AUC(0-12)
Area under the plasma concentration-time curve from zero to 12 hours
AUC(0-48)
Area under the plasma concentration-time curve from zero to 48 hours
AUC(0-t)
Area under the plasma concentration-time curve from zero to the time of 
the last measurable concentration
AUC(0-∞)
Area under the plasma concentration-time curve from zero to infinity
β-hCG
Beta human chorionic gonadotropin
BCRP
Breast cancer resistance protein
BID
Bis in die (i.e., twice daily)
BP
Blood pressure
CD
Cluster of differentiation
cEt
Constrained ethyl
cfDNA
Circulating-free deoxyribonucleic acid
CI
Confidence interval
CL
Clearance
CL/F
Apparent plasma clearance

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Abbreviation or 
special term
Explanation
CLp
Plasma clearance
CLss/F
Apparent plasma clearance at steady state 
Cmax
Maximum plasma concentration
CR
Complete response
CRF
Case report form (electronic/paper)
CRM
Continual reassessment method
CSP
Clinical Study Protocol
CSR
Clinical Study Report
Css max
Maximum plasma concentration at steady state
Css min
Minimum plasma concentration at steady state
CT
Computerised tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA4
Cytoxic T-lymphocyte-associated protein 4
Ctrough
Concentration at the end of a dosing interval
CXCR2
CXC chemokine receptor-2
CYP
Cytochrome P450
D
Day
DCR
Disease control rate
DILI
Drug-induced liver injury
DLBCL
Diffuse large B-cell lymphoma
DLT(s)
Dose-limiting toxicity(ies)
DNA
Deoxyribonucleic acid
DOR
Duration of response
ECG
Electrocardiogram
ECL
Electrochemiluminescence
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EOT
End-of-Treatment
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transpeptidase

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Abbreviation or 
special term
Explanation
gmean
Geometric mean
GRO-α
Growth regulated oncogene-alpha
h
Hour(s)
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HCC
Hepatocellular carcinoma
HIV
Human immunodeficiency virus
HPF
High-power field
HL
Hy’s Law
IATA
International Air Transport Association
IB
Investigator’s Brochure
IBW
Ideal body weight
ICF
Informed Consent Form
ICH
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IEC(s)
Independent Ethics Committee(s)
Ig
Immunoglobulin
IgG1κ
Immunoglobulin G1 kappa
ILD
interstitial lung disease
IM
Immunogenicity
imAE
Immune-mediated adverse events
IP
Investigational product
irAE
Immune-related adverse events
IRB(s)
Institutional Review Board(s)
IV
Intravenous(ly)
IWRS
Interactive web-based randomisation system
kg
Kilogram(s)
KM
Kaplan-Meier
L
Litre(s)
LDH
Lactate dehydrogenase
mAb(s)
Monoclonal antibody(ies)
MDSC(s)
Myeloid-derived suppressor cell(s)

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Abbreviation or 
special term
Explanation
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute(s)
mL
Millilitre
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
MRTlast
Mean residence time
MTD(s)
Maximum tolerated dose(s)
NC
Not calculated
NCI
National Cancer Institute
NE
Not evaluable
NTL
Nontarget lesion
OAE(s)
Other significant adverse event(s)
ORR
Objective response rate
OS
Overall survival
P-gp
P-glycoprotein 1 (also known as multidrug resistance protein 1)
PD
Progression of disease
PD-1
Programmed cell death 1 (CD279)
PD-L1
Programmed cell death-ligand 1 (also known as B7 homolog 1, CD274)
PD-(L)1
Programmed cell death 1 (CD279) and/or programmed cell death-
ligand 1 (also known as B7 homolog 1, CD274)
PDRNA
Pharmacodynamic RNA
PFS
Progression-free survival
PHL
Potential Hy’s Law
PK
Pharmacokinetic(s)
PO
Per os (i.e., by mouth)
PR
Partial response
PS
Performance status
Q2W
Every 2 weeks
Q3W
Every 3 weeks
Q4W
Every 4 weeks

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Abbreviation or 
special term
Explanation
QT
ECG interval measured from the onset of the QRS complex to the end of 
the T wave
QTc
Corrected QT interval
QTcF
Calculated QTc using Fridericia’s formula
QW
Every week
Rac
Extent of accumulation on multiple dosing
RBC
Red blood cell(s)
RECIST
Response Evaluation Criteria in Solid Tumors
RM
Recurrent and/or metastatic
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 dose
SAE(s)
Serious adverse event(s) (see definition in Section 6.2)
SC
Subcutaneous
SCCHN
Squamous cell carcinoma of the head and neck
SD
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
sPD-L1
Soluble programmed cell death-ligand 1
SRC
Safety Review Committee
STAT3
Signal Transducer and Activator of Transcription 3
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Concentration half-life
t1/2λz
Terminal (elimination) half-life 
T3
Triiodothyronine
T4
Thyroxine
TBD
To be determined
TBL
Total bilirubin
TEAE(s)
Treatment-emergent adverse event(s)
TGI
Tumor growth inhibition
TL
Tumor lesion
Tmax
Time to reach Cmax
TMG
Toxicity Management Guidelines

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Abbreviation or 
special term
Explanation
TSH
Thyroid-stimulating hormone
Tss max
Time to reach Cmax at steady state
Tx
Treatment
ULN
Upper limit of normal
V1
Central volume of distribution
Vd/F
Apparent volume of distribution
Vss
Apparent volume of distribution after intravenous distribution
Vss/F
Apparent volume of distribution after oral administration
Vz/F
Apparent volume of distribution
WBC
White blood cell(s)
WBDC
Web-based data capture

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1
INTRODUCTION
1.1
Background and rationale for conducting this study
Below are brief summaries introducing the properties of the investigational agents used in this 
CSP and their mechanism of action. Further details are provided in the respective 
Investigator’s Brochures (IBs). This CSP was written based on the following IBs: 1) For 
AZD9150, the AZD9150 IB by AstraZeneca Pharmaceuticals, 2) for AZD5069, the AZD5069 
IB by AstraZeneca “CXCR2 inhibition in oncology indications,” and 3) for MEDI4736 and 
tremelimumab, the MEDI4736 and the tremelimumab IBs by MedImmune, LLC, a wholly 
owned subsidiary of AstraZeneca. When relevant, updates with data cut off dates more recent 
than those presented in the 4 IBs are provided and referenced.
1.1.1
AZD9150
AZD9150 (ISIS 481464) is a 16-nucleotide antisense oligonucleotide (16-mer ASO) designed 
to target down-regulate expression of human Signal Transducer and Activator of Transcription 
3 (STAT3) messenger ribonucleic acid (mRNA).AZD9150 is a phosphorothioate-modified 
chimeric ASO, with a 10-base oligonucleotide centre that is flanked by 3 constrained ethyl 
(cEt)-modified nucleosides on both the 5′ and 3′ ends [Generation 2.5 ASO] (Seth et al 2009). 
STAT3 belongs to the STAT family of transcription factors. STAT3 is considered to be a 
promising cancer drug target because of its pleiotropic involvement in tumorigenesis. STAT3 
not only regulates the expression of many genes directly important to the survival of tumor 
cells (Alvarez et al 2005), but it is also an important factor in non-tumor cells of the tumor 
microenvironment involved in immune evasion of tumor cells, angiogenesis, and metastasis 
(Kortylewski et al 2009).
1.1.2
AZD5069
AZD5069 is a highly selective and potent small-molecule CXC chemokine receptor-2 
(CXCR2) antagonist. CXCR2 is a G-protein coupled receptor expressed on a number of 
inflammatory cells (monocytes, macrophages, neutrophils) as well as epithelium that are 
believed to be critical in the pathogenesis of inflammation related disorders. CXCR2 can also 
be expressed on endothelium.
CXC chemokine receptor-2 was recently identified as a novel target for modulating tumor 
immunity (Di Mitri et al 2014Highfill et al 2014). Tumor signalling of programmed cell death 
1 (PD-1; CD279) on T cells and expansion of myeloid-derived suppressor cells (MDSCs) are 
major mechanisms of tumor immune escape. CXC chemokine receptor 2 regulates the 
trafficking of MDSCs to the tumor (Highfill et al 2014), and CXCR2 inhibition was found to 
retard tumor progression both alone and in combination with docetaxel (Di Mitri et al 2014). 
Further, when tumor trafficking of MDSCs was inhibited by CXCR2 deficiency anti-PD-1 
treatment induced significant anti-tumor effects in established tumors (Highfill et al 2014).

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1.1.3
MEDI4736
MEDI4736 (durvalumab) is a human monoclonal antibody (mAb) of the immunoglobulin G1 
kappa (IgG1κ) subclass that inhibits binding of programmed cell death-ligand 1 (PD-L1) to 
PD-1 and cluster of differentiation (CD) 80 (B7-1). PD-L1 is part of a complex system of 
receptors and ligands that are involved in controlling T cell activation through delivery of 
inhibitory signals (Fife and Bluestone 2008) and is one of the immunosuppressive 
mechanisms keeping the immune system from identifying and eliminating cancerous cells. In 
vivo studies show that MEDI4736 inhibits tumor growth in a xenograft model via a T cell 
dependent mechanism. Moreover, an anti-mouse (m)PD-L1 antibody demonstrated improved 
survival in a syngeneic tumor model when given as monotherapy and resulted in complete 
tumor regression in >50% of treated mice when given in combination with chemotherapy. 
Combination therapy (dual targeting of PD-L1 and cytotoxic T lymphocyte associated protein 
4 [CTLA4]) resulted in tumor regression in a mouse model of colorectal cancer.
1.1.4
Tremelimumab
Tremelimumab (formerly CP-675,206) is a human IgG2 mAb being investigated as a cancer 
immunotherapeutic agent. Tremelimumab is expressed in NS0 (murine myeloma) cells and 
has an overall molecular weight of approximately 149 kDa. Tremelimumab is specific for 
human CTLA-4, with no cross-reactivity to related human proteins. Tremelimumab blocks the 
inhibitory effect of CTLA-4 and therefore enhances T cell activation. Tremelimumab shows 
minimal specific binding to Fc receptors, does not induce natural killer (NK) antibody-
dependent cell-mediated cytotoxicity (ADCC), and does not deliver inhibitory signals 
following platelet-bound aggregation.
1.1.5
Disease background
Squamous cell carcinoma is the most frequent malignant tumor of the head and neck region 
and develops from the mucosal linings of the upper aerodigestive tract, comprising 1) the 
nasal cavity and paranasal sinuses; 2) the nasopharynx; 3) the hypopharynx, larynx, and 
trachea; and 4) the oral cavity and oropharynx. The American Cancer Society estimated 
55,000 new cases of head and neck cancer would be diagnosed in the United States in 2014, 
with 12,000 patients dying from the disease (American Cancer Society 2014). Although the 
majority of patients present with loco regional disease, more than 50% will succumb to 
recurrent and/or metastatic (RM) disease despite aggressive therapy with surgery, radiation, 
and/or chemotherapy; 14% of patients present with distant disease at the time of diagnosis 
(Jemal et al 2010).
Despite progress in the therapeutic management of patients with squamous cell carcinoma of 
the head and neck (SCCHN), the mortality rate of patients presenting with advanced disease 
remains high. Recurrent or metastatic SCCHN is an incurable disease with a poor prognosis. 
Platinum-based combination chemotherapy has been the standard first-line treatment for RM-

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SCCHN, providing a median overall survival (OS) of 6 to 9 months (Forastiere et al 1992, 
Gibson et al 2005, Hussain et al 1999, Molin and Fayette 2011, Vermorken et al 2008). Since 
the EXTREME Phase 3 trial has shown the addition of the epidermal growth factor receptor 
inhibitor cetuximab (Erbitux) to a platinum doublet to be superior to chemotherapy alone 
(Vermorken et al 2008), cetuximab has become a key drug for first-line treatment of RM 
patients. The addition of cetuximab to cisplatin and 5-fluorouracil was associated with 
statistically significant improvements in all cancer control outcomes: response rate (36% 
versus 20%), progression-free survival (PFS) (5.6 months versus 3.3 months), and OS 
(10.1 months versus 7.4 months). However, the benefit is modest and comes at the expense of 
increased toxicity and cost. Further, virtually all patients who have a meaningful tumor 
regression on a cetuximab treatment regimen ultimately develop acquired tumor resistance 
after a few months of treatment.
In patients who have progressive disease (PD) while they are receiving platinum-based 
regimens, the projected median survival falls to approximately 3.5 months (León et al 2005). 
Active treatment options for patients with platinum-refractory RM-SCCHN include taxanes 
alone (Fayette et al 2010, Guardiola et al 2004), taxane- and vinorelbine-based regimens (Iop 
et al 1998, Moroni et al 2003, Numico and Merlano 2002), taxanes in combination with 
cetuximab (Hitt et al 2012, Péron et al 2012a), capecitabine (Martinez-Trufero et al 2010, 
Péron et al 2012b), or methotrexate (Forastiere et al 1992). Second-line treatments are often 
reserved for patients who have a good performance status (PS); many patients will receive 
only best supportive care. Because current treatment options are so limited, there is a clear 
need for new therapies for patients with RM-SCCHN.
1.2
Rationale for study design, doses and control groups
Activating the immune system for therapeutic benefit in cancer has long been a goal in 
immunology and oncology. Based on our current understanding of the immune response, one 
can identify 3 distinct steps that must be achieved, either spontaneously or therapeutically, in 
order to mount effective anti-tumor immunity (see Figure 1, Mellman et al 2011) to initiate 
immunity, dendritic cells must sample antigens derived from the tumor, mature and 
differentiate, and ultimately process and present tumor antigens; 2) next, in lymphoid organs, 
tumor antigen-loaded dendritic cells must generate protective T cell responses; and 3) finally, 
cancer specific T cells must enter the tumor bed to perform their function. To do so, they have 
to overcome the challenge of stromal immune suppression. Targeting immunosuppression in 
the tumor bed provides novel opportunities for cancer therapy, in general and for tumors of 
the head and neck in particular. Myeloid-derived suppressor cells play a key 
immunosuppressive role in various types of cancer (Filipazzi et al 2007, Gabrilovich and 
Nagaraj 2009, Hoechst et al 2009) and are abundant in SCCHN (Chikamatsu et al 2012, Pak 
et al 1995, Vasquez-Dunddel et al 2013).

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Figure 1
Generation and regulation of anti-tumor immunity
After Mellman et al 2011 and Luke et al 2015
It follows that combining a PD-L1 antagonist, MEDI4736, with an agent targeting 
immunosuppression in the tumor bed (either AZD9150 or AZD5069) is a complementary 
anti-tumor strategy, as the 2 immunotherapeutics attempt to restore effective anti-tumor 
immunity at 2 distinct stages: promoting the effector function of T cell responses (MEDI4736) 
while hindering immune escape in the tumor bed (AZD9150, AZD5069).
In addition to the PD-1 pathway described above, the CTLA-4 receptor for CD 80 and CD86 
also plays a key role in the early activation of naïve and memory T cells. Because the PD-1 
and CTLA-4 pathways are nonredundant modulators of immunocyte selection and survival 
that have individually shown to be important therapeutic targets, combination therapy with 
antibodies directed toward both is now being explored in a variety of tumor types. 
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The rationale for simultaneously combining anti-PD-L1 and anti-CTLA-4 treatment with 
either an inhibitor of STAT3 or of CXCR2 (“triplet” therapy) is identical to that described 
above for therapy with durvalumab alone in combination with either AZD9150 or AZD5069. 
Specific data considering the potential risks and benefits of triplet therapy are discussed below 
as well.
In the second part of this study, the recommended Phase 2 dose (RP2D) from the first phase 
will evaluate the objective response rate (ORR) of AZD9150 and AZD5069 both as 
monotherapy and in combination with MEDI4736 in the second-line treatment of patients 
with RM-SCCHN, a patient population with a currently unmet medical need. Both parts of 
this study will also evaluate PK, immunogenicity (IM), and pharmacodynamic parameters as 
well as biomarkers that may correlate with activity or prospectively identify patients likely to 
respond to the various treatments. The results from this study will form the basis for decisions 
for future studies.
The combination of MEDI4736 (or any other prior anti PD-(L)1 therapy) with either 
AZD9150 or AZD5069 has not been tested in humans; therefore, this study has been designed 
to evaluate the safety and tolerability of the combination in patients with advanced solid 
malignancies (other than hepatocellular carcinoma [HCC]) refractory to standard therapy or 
for which no standard of care regimen currently exists.
Approximately 25% of RM-SCCHN patients treated with an anti-PD-1 antibody 
(pembrolizumab) alone exhibit complete response (CR) or partial response (PR) (Seiwert et al 
2015). This rate is at least comparable to the results of treatment with platinum- or taxane-
based regimens, with significantly less toxicity than that observed with cytoreductive 
therapies. Furthermore, because 75% of patients treated with an anti-PD-1 antibody alone still 
exhibit disease progression, these patients will likely constitute a group with significant unmet 
medical need. 
Since host anti-tumor immune responses depend upon a number of steps in addition to those 
directly controlled by T cell checkpoint molecules such as PD-1, agents that enhance antigen 
presenting cell function (AZD9150, by inhibiting STAT3) or prevent MDSCs from entering 
tumor tissue (AZD5069, by inhibiting CXCR2) may reasonably be expected to relieve a block 
to the generation and function of anti-tumor T cells. 
Because release of this block may sensitise previously resistant tumors to CTL-mediated 
killing, 2 cohorts of patients whose disease previously progressed in the face of prior PD-1 
pathway directed therapeutics alone will be included in this study. These patients will be 
treated with combinations of either MEDI4736 and AZD9150 or MEDI4736 and AZD5069.
Additionally, preliminary data from the KEYNOTE-012 trial (Seiwert et al 2015) showed that 
patients with RM-SCCHN sequentially failing different lines of therapy could respond to 

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PD-1 pathway blockade. Because 37.9% of the responding patients in that trial had previously 
been treated with 3 or more different lines of therapy, this trial will allow enrolment of 
patients who have failed 0 to 3 previous lines of therapy based on platinum compounds or 
other agents.
Further, because initial overall response rates to PD-1 pathway directed therapy are substantial, 
patients initially receiving either AZD5069 or AZD9150 (anti-CXCR2 or anti-STAT3 
treatments, respectively) alone and who progress will be deemed eligible for the addition of 
MEDI4736 to their original therapeutic agent. 
Rationale for adding first-line recurrent/metastatic SCCHN patients
Emerging response data from the AZD9150 and MEDI4736 combination of the 
D5660C00004 trial conducted to date suggests that treatment of first-line RM-SCCHN 
patients may benefit this population at a rate exceeding that observed to date for PD-1 
pathway blockade alone.
!
Response rates for patients treated to date in the D5660C00004 trial exceed those 
currently published for second line treatment of RM-SCCHN with anti-PD-1 pathway 
monotherapies with antibodies these include durvalumab (11%; Segal et al 2016), 
nivolumab (13.3%; NEJM 2016), and pembrolizumab (16%; Bauml et al 2017). By 
comparison, our currently observed confirmed response rate to date in the SCORES trial 
is 20% (4/20 subjects), plus one unconfirmed PR in a population of patients most directly 
comparable to those reported by Segal et al 2016.
!
At the time of protocol amendment 5, activity in a limited number of first-line 
RM-SCCHN patients has been observed in the study. Because the CSP currently allows 
enrollment of first-line patients who refuse or are ineligible for platinum-based therapies. 
To date 6 such patients have been treated with MEDI4736+AZD9150: of note, 2 
exhibited PR. This initial data, although limited, suggests this combination may impact 
disease in this population and clearly warrants further investigation.
!
At the time of protocol amendment 5, the clinical course of a fifth RM-SCCHN patient on 
Study D5660C00004, Arm B3, receiving durvalumab+AZD9150 strongly suggests this 
patient responded to the combination as well. Sequential Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1 target lesion reductions of 24% and 48% 6 weeks after 
beginning AZD9150 (six doses in total) and durvalumab (1 dose in total) were observed 
and persisted up to six months after initiation of treatment. Unfortunately, pneumonitis 
initially identified after 6 weeks of treatment required discontinuation of dosing and the 
patient subsequently developed additional non-target disease lesions, preventing formal 
confirmation by RECIST. These lesions were observed 16 weeks after last combination 
treatment with AZD9150 and MEDI4736.
!
Further updated efficacy data for the combination of AZD9150 and MEDI4736 are 
presented in the latest IB.
In summary, appreciating the preliminary nature of findings from a group of 20 patients (14 in 
2L and 6 in 1L RM setting) treated with MEDI4736+AZD9150 it is considered that the 

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observed data warrant vigorous further exploration in the first-line population, and this study 
amendment enables further study of the combination in these 2 populations.
Rationale for study design
A 2-part study design was initially chosen to allow for rapid transition from an initial dose-
escalation in patients with advanced solid malignancies (Part A) determining the dose for 
further clinical exploration to a dose-expansion (Part B) investigating the anti-tumor activity 
of AZD9150 and AZD5069 alone or in combination with MEDI4736 as second-line treatment 
for patients with RM SCCHN. To minimise patient exposure during the dose-escalation phase, 
a continual reassessment method-based approach was used to devise the set of 
AZD9150/MEDI4736 and AZD5069/MEDI4736 dose combinations where the incidence of 
dose-limiting toxicity (DLT) is no larger than 33%. This approach tends to incur fewer toxic 
events and more accurately estimates the maximum tolerated dose (MTD) as compared to 
standard Phase 1 dose-escalation designs (Cheung 2011).
The starting doses and additional dose levels chosen for each agent in this study were based 
on the clinical experience with each agent as monotherapy in previous trials. Considering 
practical aspects for the combination of AZD9150 and MEDI4736, the infusion time for 
AZD9150 was shortened from 3 hours in previous studies to a 1-hour infusion. The change 
seemed appropriate as this study specifically evaluates safety and tolerability of AZD9150 in 
combination. The Safety Review Committee (SRC) will continue to monitor patients dosed 
with AZD9150 for any toxicities possibly associated with the shortened infusion time and may 
recommend to modify the length of infusion if any toxicities associated with maximum 
plasma concentration (Cmax) are observed. The rationale for the starting dose of MEDI4736 in 
this study is described in detail in Section 1.1.3.
Additional combinations of MEDI4736 plus tremelimumab with either AZD9150 or with 
AZD5069 will similarly be investigated during Part A of the study. Because previous clinical 
trials have established recommended doses of tremelimumab and durvalumab in combination, 
a safety run-in initiated at that dose level with addition of either AZD9150 or AZD5069 will 
be carried out. The starting doses of AZD9150 or AZD5069 will be the RP2Ds established 
from dose escalations of each in combination with MEDI4736 alone in oncology patients. 
AZD5069, AZD9150, and durvalumab may be reduced by 1 or 2 levels during Part A of the 
trial, as shown in Figure 4, Figure 7, and Figure 8.
Because of the possibly greater complexity of interpreting safety data from Part A for triplet 
therapy, these triplets (AZD9150/durvalumab/tremelimumab or 
AZD5069/durvalumab/tremelimumab) will be explored only in Part A of the trial.
A Bayesian adaptive design approach for the dose-expansion Part B of the study has been 
employed to limit the exposure of patients to treatment arms that provide little clinical benefit.

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As part of the clinical drug development program for AZD9150/AZD5069, AstraZeneca plans 
to include investigations into differences in pharmacodynamic and exploratory biomarker 
profiles and their relationship to drug effect. These biomarkers may be derived from 
deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, and/or metabolites. There are 
many potential benefits of this exploratory research, including the possibility to identify 
patients most likely to benefit from treatment, explain outliers or nonresponders, or explain 
adverse reactions related to drug exposure. This research may result in an understanding of the 
impact of variation between individuals and how it can be utilised to bring better drugs to the 
clinic. The ability to acquire appropriate consent to collect biological samples is important to 
establish an archive and allow future meta-analysis of data derived across studies with these 
agents.
Rationale for an AZD9150 flat dose (Arm B8)
A population pharmacokinetic (PK) model was developed for AZD9150 using PK data from 3 
completed or ongoing Phase I/II studies (481464-CS1, D5660C00001 [NCT01839604], 
D5660C00004 [NCT02499328]) in patients with diffuse large B-cell lymphoma (DLBCL), 
HCC, and SCCHN, respectively. A total of 123 patients received AZD9150 doses ranging 
from 1 to 4 mg/kg from both monotherapy or in combination with durvalumab data, with most 
of them on 3 mg/kg (n=70). A 2-compartment model with linear absorption and linear 
elimination well described the data. Population PK analysis revealed ideal body weight (IBW) 
is not a significant covariate on the PK of AZD9150. The impact of an IBW-based dose at the 
R2PD AZD9150 dose of 3 mg/kg versus a flat dose of 200 mg was evaluated by comparing 
simulated steady state area under the curve (AUC) and Cmax using the population PK model. A 
total of 1000 patients for each dosing regimen were simulated using body weight distribution 
of 30 to 100 kg. Simulation results demonstrate that IBW-based and flat dosing regimens (3 
mg/kg versus 200 mg) yield similar median steady state AUC and Cmax with slightly less 
overall between-subject variability with the flat dosing regimen. Since a flat dosing approach 
is preferred by the prescribing community and there is lack of influence of body weight on PK, 
a flat dose of 200 mg will be used instead of 3 mg/kg.
Rationale for an AZD9150 alternate-week dosing schedule (Arm B8)
An alternate-week (every 2 weeks [Q2W]) dosing schedule for an intravenously delivered 
drug is expected to yield better patient adherence when compared to a weekly-dosing schedule.
In order to investigate the impact of AZD9150 dosing schedule on platelet response, a 
population PK-pharmacodynamic model was developed for AZD9150 using PK and platelet 
data from 2 completed or ongoing Phase I/II studies (481464-CS1, D5660C00004 
[NCT02499328]) in patients with DLBCL and SCCHN, respectively. Study D5660C00001 
[NCT01839604] in HCC was not included in the analysis due to very different platelet profile 
(e.g., lower baseline platelet count) in this patient population compared to DLBCL and 

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SCCHN. A total of 87 patients received AZD9150 doses ranging from 1 to 4 mg/kg with 981 
platelet data points were used in the modeling. 
A 2-compartment model with linear absorption and linear elimination and an indirect response 
model well described the PK and platelet data. AZD9150 concentration from the effective 
compartment linked the PK and platelet response. 
The PK-pharmacodynamic model revealed that none of the covariates (study, sex, baseline 
platelet count, age, IBW, and creatinine clearance) significantly impacted platelet response. 
The impact of dosing frequency was evaluated by comparing simulated incidence rate of 
grade 3 or higher of thrombocytopenia for 200 mg every week (QW) versus 400 mg every 
other week for 6 months after the same loading dose (200 mg on Days 1, 3, and 5 in Week 1). 
A total of 100 trials, each with 87 patients (reflecting characteristics of patients in Study 
D5660C00004) were simulated for each dosing schedule. Simulation results demonstrate that 
200 mg QW resulted in a similar percentage of grade 3 or above thrombocytopenia at 400 mg 
every other week dosing.
Since a less frequent dosing schedule (every other week) is preferred by the prescribing 
community and the thrombocytopenia (Grade 3 or above) incidence rate is similar, an
AZD9150 dose of 400 mg every other week was tested for safety/tolerability and PK in Part A 
Arm A 1 of study D5660C00016. Preliminary safety data from study D5660C0016 examining 
alternate weekly dosing of AZD9150 has revealed no DLTs and only mild thrombocytopenia 
occurring at approximately Week 5 of therapy. Based on this clinical safety and preliminary 
PK data, Arm B8 will evaluate 400 mg at an every other week schedule in first-line RM-
SCCHN patients.
1.3
Benefit/risk and ethical assessment
1.3.1
Potential benefits
Patients with advanced solid tumors refractory to standard treatment or for which no standard 
therapy exists represent a patient population with unmet medical needs. In the case of patients 
with RM-SCCHN, an incurable disease with a poor prognosis, second-line treatments are 
often reserved for patients who have a good PS, and many patients will receive only best 
supportive care. Because current treatment options are so limited, there is a clear need for new 
therapies for patients with RM-SCCHN.
MEDI4736, a human mAb directed against human PD-L1, may offer benefit to this patient 
population. MEDI4736 has a high affinity for human PD-L1 and is able to completely block 
the interaction of recombinant human PD-L1 with both recombinant human PD-1 and 
recombinant human CD80 in a biochemical assay. In vitro, MEDI4736 enhances the 
proliferation and activation of primary human T cells cultured in the presence of recombinant 
PD-L1. Non-clinical studies demonstrate that MEDI4736 inhibits tumor growth in mouse 

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xenograft models. This activity is shown to be dependent upon the presence of human T cells, 
supporting the hypothesis that PD-L1 blockade can enhance anti-tumor immune response. An 
early clinical efficacy signal observed in the SCCHN dose-expansion cohort in Study CD ON 
MEDI4736-1108 strongly suggests that further exploration of the clinical activity of 
MEDI4736 in SCCHN is warranted.
AZD9150 has also shown signs of clinical activity in early clinical studies. The clinical 
activity of AZD9150 in patients with third-line DLBCL as evidenced by an overall response 
rate of 9% was remarkable although deemed insufficient for further clinical development as a 
monotherapy in this disease.
AZD5069 has not been tested in an oncology indication. However, MDSCs have been 
hypothesised to play an important role in the tumor microenvironment, potentially down 
regulating host immune responses to malignancies as well as affecting tumor cell senescence. 
Because CXCR2 signalling has been shown to affect myeloid cell traffic from the marrow and 
transit from the circulation into tissues, strong antagonism to this chemokine receptor may 
favourably affect host cell immune responses to tumors of different histological types. Modest 
reductions in the numbers of peripheral blood neutrophils are to be expected and may actually 
prove to reflect dosing of AZD5069 at levels adequate to reduce intratumoral MDSCs and 
tumor-associated neutrophils.
During the review of data with data cut-off date of 10 January 2019, a total of 428 patients 
have been exposed to AZD9150 in AstraZeneca-sponsored studies. The safety profile and 
benefit risk was acceptable and warrants the continuation of studies. No new risks have been 
identified during the review of data with data cut-off date of 10 January 2019. The safety 
profile of AZD9150 is maintained even when administered in combination with MEDI4736 
(durvalumab) in the clinical trials of patients with advanced solid malignancies, recurrent 
and/or metastatic SCCHN, relapsed or refractory DLBCL.
Combining a PD-L1 antagonist, MEDI4736, with an agent targeting immunosuppression in 
the tumor bed (either AZD9150 or AZD5069) is a complementary anti-tumor strategy, as the 
2 immunotherapeutics attempt to restore effective anti-tumor immunity at 2 distinct stages: 
promoting the effector function of T cell responses (MEDI4736) while hindering immune 
combination therapy with antibodies directed toward both the PD-1 and CTLA-4 pathways is 
now being explored in a variety of tumor types. For example, in melanoma, (Larkin et al 
2015) have recently demonstrated overall response rates to a combination of nivolumab (anti-
PD-1) plus ipilimumab (anti-CTLA-4) that significantly exceed (57.6%) the response rates 
observed in comparable patients treated with nivolumab (43.7%) or ipilimumab (19.0%) as 
monotherapies. Similar trials with other agents have been proposed or are underway in 
SCCHN (Swanson et al 2015). 

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The combination of MEDI4736 (or any other prior anti-PD-(L)1 therapy) with either 
AZD5069 has not been tested in humans, nor have the combinations of 
AZD5069/durvalumab/tremelimumab or AZD9150/durvalumab/tremelimumab. Therefore, 
this study has been designed to evaluate the safety and tolerability of each combination. The 
starting doses and additional dose levels chosen for each agent in this study are based on the 
clinical experience with each agent as monotherapy or in combination during previous trials; 
the selected starting doses for this study are within the range that is predicted to provide 
biological activity based upon prior clinical experience.
1.3.2
Potential risks
Risks with durvalumab include, but are not limited to, diarrhoea, colitis and intestinal 
perforation/large intestine perforation, pneumonitis/interstitial lung disease (ILD), 
endocrinopathies (hypo- and hyper-thyroidism, blood thyroid stimulating hormone (TSH) 
increased, blood TSH decreased, type I diabetes mellitus, diabetes insipidus, 
hypophysitis/hypopituitarism, and adrenal insufficiency), hepatitis/hepatotoxicity/increases in 
transaminases, amylase and lipase increases, neurotoxicities, nephritis/increases in creatinine, 
pancreatitis/increases in amylase and lipase, rash/pruritus/dermatitis, myocarditis, 
myositis/polymyositis, other rare or less frequent inflammatory events including 
neurotoxicities, infusion-related reactions, anaphylaxis, hypersensitivity or allergic reactions, 
pemphigoid, and infections/immune complex disease and serious infections. 
For information on all the identified and potential risks with durvalumab always refer to the 
current edition of the durvalumab IB.
In monotherapy clinical studies, AEs (all grades) very commonly (≥ 10% of patients) reported 
are fatigue, nausea, decreased appetite, dyspnoea, cough, constipation, diarrhoea, vomiting, 
back pain, pyrexia, abdominal pain, asthenia, anaemia, arthralgia, peripheral oedema, 
headache, rash, and pruritus. Approximately 98% of patients experienced an AE that resulted 
in permanent discontinuation of durvalumab and approximately 6% of patients experienced a 
serious AE (SAE) that was considered to be related to durvalumab by the study Investigator.
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 with the Dosing Modification and Toxicity 
Management Guidelines in Annex 1.
A detailed summary of durvalumab monotherapy AE data can be found in the current edition 
of the durvalumab IB. 
For AZD9150, liver enzyme elevation (aspartate aminotransferase [AST]/alanine 
aminotransferase [ALT]) is an important identified risk, especially in the liver compromised 
HCC patient population, which has been excluded from this study. Thrombocytopenia is also 

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an important identified risk. Reduced haemoglobin/anaemia and reduced absolute neutrophil 
count/neutropenia are important potential risks. When AZD9150 is given in combination with 
durvalumab, there is a potential for increased frequency and/or magnitude of liver enzymes 
(since AST/ALT increase is an identified overlapping adverse drug reaction for both drugs; 
referred to as increased frequency of immune reactions in combination with durvalumab). 
Risks associated with other combination drugs in recently initiated studies, or studies in 
course of being initiated (including for example acalabrutinib, or different chemotherapy 
agents) are yet unknown. For a complete characterisation of each risk, see Section 6 of the IB 
for AZD9150, Summary of data and guidance for the Investigators.
Effects on blood neutrophils, including reduction in their number (neutropenia) is an identified 
risk with AZD5069. These effects have been observed at mild levels in healthy volunteers’
studies. Across all respiratory studies, now completed, events suggestive of this risk occurred 
at both mild, moderate, but also 1 severe occurrence (event that was considered serious by the 
Investigator). In the ongoing D5660C00004 oncology trial so far, although reductions in 
peripheral blood neutrophil counts have been observed, these have been reversible, not 
associated with significant clinical symptoms, and not considered serious by the Investigators. 
Therefore, for regulatory reporting purposes that consider seriousness, events suggestive of 
this risk are considered expected in patients treated in respiratory indications only, and not yet 
in the oncology population. Host defence (infections) is a potential risk for AZD5069. 
However, while reduction of neutrophils in peripheral blood or sputum could have an impact 
on host defense with regard to infections, previous studies with AZD5069 in healthy subjects 
and in patients with chronic obstructive pulmonary disease, bronchiectasis, and asthma did not 
show an increased rate of overall infections compared with placebo. For a complete list of 
potential risks and their characterisation, see Section 6 of the IB for AZD5069, Summary of 
data and guidance for the Investigators.
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, other 
gastrointestinal events (e.g., ulcerative colitis, dehydration, nausea, and vomiting); hepatic 
events including hepatitis, and liver enzyme elevations; pneumonitis and ILD; clinical
manifestations of pancreatitis; nervous system events including encephalitis, peripheral motor 
and sensory neuropathies, Guillain-Barre and proximal muscle weakness; cytopenias 
including thrombocytopenia, anaemia and neutropenia; infusion-related reactions, 
anaphylaxis, and allergic reactions; renal events including renal failure, acute kidney injury, 
nephritis, nephrotic syndrome, autoimmune nephritis and electrolyte abnormalities such as 
hypokalaemia; autoimmune diseases including autoimmune arthritis, Sjögren’s syndrome and 
giant cell temporal arteritis; hyperglycaemia and diabetes mellitus; and pyrexia.

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For information on all the identified and potential risks with tremelimumab always refer to the 
current edition of the tremelimumab IB.
Using pooled data from monotherapy clinical studies AEs (all grades) reported very 
commonly (≥10% of patients) were diarrhoea, nausea, fatigue, pruritus, decreased appetite, 
rash, vomiting, dyspnoea, constipation, cough, pyrexia, abdominal pain, decreased weight, 
headache, asthenia, and anaemia. Approximately 16% of patients experienced an AE that 
resulted in permanent discontinuation of tremelimumab and approximately 45% of patients 
experienced an SAE.
A detailed summary of tremelimumab monotherapy AE data can also be found in the current 
edition of the tremelimumab IB. The safety of durvalumab+tremelimumab combination 
therapy was initially evaluated in the ongoing dose-escalation and dose-expansion Study 006, 
in patients with non-small cell lung cancer. It is being studied in a number of other ongoing 
clinical trials as well as, in a number of different indications, and has to date shown a 
manageable safety and tolerability profile. 
The types of potential risks with the combination of durvalumab+tremelimumab (based on an 
equivalent durvalumab dose of 20mg/kg and a tremelimumab dose of 1mg/kg) are similar to 
those for durvalumab and tremelimumab monotherapy. Emerging data from study 006, 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 potential immune-mediated 
toxicities.
For information on all identified and potential risks with the durvalumab+tremelimumab 
combination always refer to the current edition of the durvalumab IB.
In durvalumab+tremelimumab combination studies at the dose of durvalumab 20mg/kg and 
tremelimumab 1mg/kg AEs (all grades) reported very commonly (≥10% of patients) are 
fatigue, diarrhoea, nausea, dyspnea, decreased appetite, pruritus, vomiting, anaemia, 
constipation, cough, abdominal pain, pyrexia, back pain, arthralgia, hypothyroidism, asthenia, 
oedema peripheral, weight, decreased hyponatraemia, and rash. 
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.
A detailed summary of durvalumab + tremelimumab combination AE data can be found in the 
current edition of the durvalumab IB. There is a potential for increase in severity and 
frequency of AST and ALT increase when MEDI4736/tremelimumab is given in combination 
with AZD9150. There is no additional risk of increase in myelosuppressive adverse 
events (AEs) observed with either AZD9150 or AZD5069 when given in combination with 

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MEDI4736 in dose escalation. Hence, patients will be closely monitored for all irAEs, liver 
toxicities, and myelosuppression in the current study.
In summary, the risks of combined CTLA-4 and PD-(L)1 inhibition have been partly 
characterized and deemed tolerable in patients with several tumor types (Larkin et al 2015, 
Antonia et al 2014). While the rates of AEs leading to discontinuation of study drugs in 
combination are significant (e.g., 7.7% for nivolumab alone, 14.8% for ipilimumab alone, or 
36.4% for the combination for patients with previously untreated advanced melanoma; Larkin 
et al 2015), the nature of the adverse effects are consistent with the profiles for individual 
agents and are reversible at rates of 85-100% for most organ systems excepting the endocrine.
Bleeding has been reported in up to 10% or greater in patients with head and neck cancer. 
Reports of bleeding, including fatal reports, have been received from head and neck cancer 
patients enrolled in AstraZeneca clinical trials with durvalumab as monotherapy or in 
combination. While it is not yet conclusively known whether the risk of bleeding would be 
higher or lower with the experimental treatment than with standard chemotherapy, an interim 
internal safety analysis conducted by the Sponsor concluded that a reasonable possibility of a 
causal relationship between bleeding complications in SCCHN patients and treatment with 
durvalumab, either alone or in combination with tremelimumab, could not be established. 
Given the minimal toxicity profiles of PD-1/CTLA-4 inhibition and either STAT3 blockade or 
CXCR2 blockade, the potential benefit of combining 2 T cell checkpoint inhibitors 
(durvalumab, anti-PD-L1 and tremelimumab, anti CTLA-4) with either AZD5069 or 
AZD9150 can reasonably be regarded as offering the possibility of enhanced anti-tumor 
effects with a manageable rate of AEs in very difficult- to-treat patients who have failed 
previous lines of therapy in a variety of tumors.
1.3.3
Overall benefit-risk and ethical assessment
The combination of MEDI4736 and/or MEDI4736/ tremelimumab (or any other prior anti-
PD-(L)1 therapy) with either AZD9150 or AZD5069 has not been tested in humans; therefore, 
this study has been designed to evaluate the safety and tolerability in patients treated with this 
combination. The study design aims to minimise potential risks and, although the potential 
benefits in patients are unknown at this time, prior early clinical signs, and non-clinical data 
provide a sound basis supporting the hypothesis that combining a PD-L1 antagonist, 
MEDI4736 (and/or CTL4 inhibitor, tremelimumab), with an agent targeting 
immunosuppression in the tumor bed (either AZD9150 or AZD5069) is a complementary 
anti-tumor strategy. Thus, the benefit/risk assessment for this Phase 1b/2 study is anticipated 
to be favourable based on the lack of effective alternative treatments, the limited life 
expectancy due to malignant disease, and the strength of the scientific hypothesis under 
evaluation.

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1.4
Study Design 
This multicentre, open-label, Phase 1b/2 study is designed as a 2 part study consisting of 
dose-escalation and safety cohorts in Part A and a dose-expansion in Part B. A study flow 
chart for both phases is presented in Figure 2, and a study scheme for both phases is shown in
Figure 3.
Patients will be allocated to treatment in both parts of the study after first considering their 
history, and any anticipated need to use herbal supplements and/or foods prohibited with 
concurrent administration of AZD5069. During Part B only, the patient’s history of exposure 
to anti-PD-(L)1 antibodies and prior treatment received for recurrent metastatic disease will 
also determine their eligibility to be enrolled in specific treatment arms.

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Figure 2
Study flow chart
Part A: Dose-escalation & Safety Cohorts
Patients with advanced solid malignancies refractory to standard therapy or for which no standard of care 
regimen currently exists.
Abbreviations: MTD=maximum tolerated dose; PK=pharmacokinetics; PD=pharmacodynamics; treme=tremelimumab.
Note: Treatment arms A1, A2, A3, A4, and A6 are close to enrolment. Treatment arms A5 and A7 will not open.

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Part B: Dose-Expansion
Abbreviations: CRM=continual reassessment method; DCR=disease control rate; DOR=duration of response; IA=interim 
analysis; MTD=maximum tolerated dose; OS=overall survival; PD-(L)1=Programmed cell death 1 (CD279) and/or 
programmed cell death-ligand 1 (also known as B7 homolog 1, CD274); PFS=progression-free survival;
PK/PD=pharmacokinetics/pharmacodynamics; SRC=Safety Review Committee; SCCHN=squamous cell carcinoma of the 
head and neck.
Note: Treatment arms B1, B2, B3, B4, B5, B6, B7, and B8 are closed to enrolment.

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Figure 3
Study Scheme: Part A and Part B
a
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease.

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2
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
Dose-escalation and safety cohorts Part A
To determine the MTDs or recommended doses for 
dose-expansion and to determine the safety profiles 
of either AZD9150 or AZD5069 in combination 
with MEDI4736 and/or MEDI4736/tremelimumab 
in patients with advanced solid malignancies 
refractory to standard therapy or for which no 
standard of care regimen currently exists. 
MTD based on patients who completed the DLT 
Evaluation
AEs, SAEs, laboratory evaluations, vital signs, and 
physical examinations
Treatment-emergent AEs (TEAEs), SAEs and death(s), 
graded in accordance with National Cancer Institute (NCI) 
CTCAE version 4.03
Dose-expansion Part B
To evaluate the ORR of AZD9150 and AZD5069 
both as monotherapy and in combination with 
MEDI4736 in the second-line treatment of patients 
with RM SCCHN and in patients with no prior 
exposure to anti-PD-(L)1 therapies and also in 
patients who have not received prior systemic 
treatment for recurrent or metastatic SCCHN (1L 
RM SCCHN). To evaluate ORR of AZD9150 as 
fixed dosed Q2W in patients with no prior exposure 
to anti-PD-(L)1 therapies and who have not 
received prior systemic treatment for recurrent or 
metastatic SCCHN (1L RM SCCHN).
Objective response - defined as a CR or PR according to 
RECIST version 1.1
2.2
Secondary objectives
Secondary Objective:
Outcome Measure:
Dose-escalation and safety cohorts Part A
To assess the PK of AZD9150, AZD5069, and 
MEDI4736 and/or MEDI4736/tremelimumab in the 
selected dose combinations.
PK parameters as outlined in Section 8.5
To determine the IM of MEDI4736 and/or 
MEDI4736/tremelimumab in combination with 
AZD9150 or AZD5069 and the IM of AZD9150 in 
combination with MEDI4736 and/or 
MEDI4736/tremelimumab.
ADAs
To assess pharmacodynamic response in blood for 
AZD9150.
STAT3 knockdown (signal transducer and activator of 
transcription 3 [STAT3] knockdown)

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Dose-expansion Part B
To assess secondary measures of efficacy (DCR at 
12 weeks; duration of overall response [DOR], 
PFS, OS; and proportion of patients alive at 12 
months)
Disease control defined as a CR, PR, or stable disease 
(SD), according to RECIST version 1.1 criteria, at 12 
weeks
DOR according to RECIST version 1.1 criteria (measured 
from the time measurement criteria are first met for CR or 
PR, whichever is first recorded, until the first date that 
recurrent or PD is objectively documented (taking as 
reference for PD the smallest measurements recorded on 
study)
PFS - defined as the time from randomisation to the first 
documentation of PD as determined by the Investigator or 
death from any cause, whichever occurs first
OS - defined as the time from randomisation to death from 
any cause
Best overall response (including CR, PR, SD, and PD, 
according to RECIST version 1.1 criteria), ordered from 
best to worst
Survival at 12 months
To assess the PK of AZD9150 and AZD5069 both 
as monotherapy and in combination with 
MEDI4736
PK parameters as outlined in Section 8.5
To assess the urinary PK of AZD9150 and 
MEDI4736 in combination with AZD9150 or 
AZD5069
PK parameters as outlined in Section 8.5
To determine the IM of AZD9150 alone or in 
combination with MEDI4736 and the IM of 
MEDI4736 in combination with AZD9150 or 
AZD5069
ADAs
To assess pharmacodynamic response in blood for 
AZD9150 and MEDI4736 (sPD-L1 will not be 
evaluated for Arms B1, B2, and B4 post the first 20 
patients and for Arms B7 and B8)
(STAT3 knockdown) and sPD-L1 in blood
Pharmacodynamics of MEDI4736 (sPD-L1) and 
tremelimumab (will not be evaluated for Arm B1, B2, and 
B4 post the first 20 patients and for Arm B7 and B8)
To assess tumor cell pharmacodynamics (STAT3 
knockdown)
Pharmacodynamics of AZD9150 (STAT3 knockdown) in 
tumor tissue
To assess baseline circulating MDSCs and effect of 
treatment on circulating MDSCs (will not be 
evaluated for Arms B1, B2, and B4 post the first 
20 patients and for Arms B7 and B8)
Circulating MDSCs 
To evaluate baseline tumor PD-L1 expression for 
potential correlation with drug activity or the ability 
to prospectively identify patients likely to respond 
to treatment
Tumor PD-L1 expression

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2.3
Safety objectives
Safety Objective:
Outcome Measure:
Dose-expansion Part B
To evaluate the safety and tolerability of AZD9150 
and AZD5069 both as monotherapy and in 
combination with MEDI4736.
AEs, SAEs, laboratory evaluations, vital signs, and 
physical examinations
TEAEs, SAEs, and death, graded in accordance with NCI 
CTCAE version 4.03
2.4
Exploratory objectives
Exploratory Objective:
Outcome Measure :
Dose-escalation (Part A) and Dose-expansion (Part B)
To evaluate baseline levels of and changes in 
blood-borne biomarkers that may correlate with 
treatment or clinical response.
Include, but are not limited to, gene expression, 
immunogenomics (genetics associated with immune 
responses such as homozygosity/heterozygosity of MHC-I 
genes), T cell activation or proliferation markers, T cell 
repertoire, and cytokines and other soluble factors
To assess serum samples for pharmacodynamic 
response to AZD5069.
Transient increase in CXCR2 ligands interleukin-8 and 
GRO-α
To evaluate tumor-based biomarkers in 
archival/baseline tumor samples that may correlate 
with treatment or prospectively identify patients 
likely to respond to treatment with AZD9150 or 
AZD5069 in combination with MEDI4736 and/or 
MEDI4736/tremelimumab. 
These may include but are not limited to PD-L1 
expression, phospho- or total STAT3 expression, tumor 
genetics, immunogenomics (genetics associated with 
immune responses such as homozygosity/heterozygosity of 
MHC-I genes), characterisation of immune infiltrates, gene 
expression, or other stratification markers
To evaluate circulating-free DNA (cfDNA; 
including circulating tumor DNA as well as non-
tumor cell free DNA) measures at baseline or on-
treatment or changes upon treatment or changes 
upon treatment that may correlate with treatment or 
response. (Note: only cfDNA required to be 
obtained for new patients consented under protocol 
amendment 5, dated 10 May 2017 and onwards 
[B3, B7, B8, and Part A]).
For tumor-derived DNA mutations at baseline, and 
changes upon treatment that may correlate with treatment 
or response
To collect and store tumor, blood, plasma, and 
serum samples or analyse surplus blood or tissue 
including patient-specific archival tumor tissue, if 
available.
For potential future exploratory research into factors that 
may influence development of the tumor or response to 
treatment (where response is defined broadly to include 
efficacy, tolerability, or safety). In the event that additional 
tumor molecular profiling is required to understand further 
any response to treatment, AstraZeneca may request a 
sample of the most recent tumor biopsy for additional 
research. Any sample collection can be discontinued or 
suspended at the discretion of the Sponsor, without the 
need for a protocol amendment.

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To explore the relationship between PK and 
selected endpoints.
Which may include pharmacodynamics, efficacy, and/or 
safety), where deemed appropriate
To collect and store DNA.
Carry out future exploratory research into genes/genetic 
variation that may influence response (i.e., distribution, 
safety, tolerability, and efficacy) to treatment with 
AZD9150 and AZD5069, both as monotherapy and in 
combination with MEDI4736 (and/or 
MEDI4736/tremelimumab) and/or development of cancer
Part B Only
To evaluate changes in tumor based biomarkers that 
may correlate to treatment or response 
Changes including but not limited to immune cell infiltrate, 
gene expression changes, cell activation or proliferation 
markers, and cytokines
3
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study. Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
3.1.1
All patients
For inclusion in the study subjects should fulfil the following criteria:
1.
The patient or legal representative (legal representative not permitted to consent in 
Germany) must be able to read and understand the Informed Consent Form (ICF) and 
must have been willing to give written informed consent and any locally required 
authorisation (e.g., Health Insurance Portability and Accountability Act in the United 
States; European Union Data Privacy Directive in the European Union) before any study-
specific procedures, including screening evaluations, sampling, and analyses.
2.
For inclusion in the optional genetic research, patients must provide a separate ICF for 
genetic research.
3.
Male and female patients must be at least 18 years of age
4.
Has an Eastern Cooperative Oncology Group (ECOG) PS score of 0 or 1.
5.
Has measurable disease, defined as at least 1 lesion that can be accurately measured in at 
least 1 dimension (longest diameter to be recorded) with a minimum size of 10 mm by 
computerised tomography (CT) scan, except lymph nodes, which must have minimum 
short axis size of 15 mm (CT scan slice thickness no greater than 5 mm in both cases). 
Indicator lesions must not have been previously treated with surgery, radiation therapy, or 
radiofrequency ablation unless there is documented progression after therapy.
6.
Number of prior lines of treatment by Arm:

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Arms A1 to A4 and A6: Has undergone ≤3 previous regimens of cytoreductive chemo-
therapies including, but not limited to, platinum-based compounds, taxanes, or 5-
fluorouracil.
Arms B1 to B6: Has undergone 1-3 previous regimens of cytoreductive chemo-therapies 
including, but not limited to, platinum-based compounds, taxanes, or 5-fluorouracil
Arm B3: Has undergone at least 1 previous regimen of systemic chemotherapy and 
received up to 3 previous regimens of cytoreductive treatments in the recurrent metastatic 
disease setting. If a patient has received systemic chemotherapy for local disease only, 
they would not be considered eligible for Arm B3.
Arms B7 and B8: Has not received any previous systemic therapies for recurrent 
metastatic disease, nor had prior exposure to anti-PD-(L)1 therapies. Patients who have 
received chemotherapy for local disease may be considered for eligibility to Arms B7 and 
B8.
7.
Has adequate organ and marrow function as defined below. Transfusions intended to
elevate any parameters below solely for the intent of meeting study eligibility are not
permitted.
-
Leukocytes ≥3000 mcL
-
Absolute neutrophil count ≥1500 mcL
-
Platelets ≥100 000 mcL
-
Haemoglobin ≥9 g/dL
-
Total bilirubin (TBL) ≤1.5 x upper limit of normal (ULN); TBL ≤3 × ULN
in patients with documented Gilbert’s Syndrome (unconjugated
hyperbilirubinaemia) or in the presence of liver metastases
-
ALT and AST ≤2.5 × ULN if no demonstrable liver metastases or
≤5 × ULN in the presence of liver metastases
-
Creatinine within normal limits
OR, for patients with levels above institutional normal:
-
Creatinine clearance measured by 24-hour urine collection
≥60 mL/min,
OR
-
Calculated corrected creatinine clearance ≥60 mL/min/1.73 m2 using
the Cockcroft-Gault formula (Cockcroft and Gault 1976) (see
Section 8.4).
8.
Women of childbearing potential and men who are sexually active with a female partner
of childbearing potential must be surgically sterilised, practicing abstinence, or agree to

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use 2 birth control methods before study entry, for the duration of study participation, and 
for 20 weeks after the final dose of study drug (180 days after final dose if patients 
enrolled in Arm A4); cessation of birth control after this point should be discussed with a 
responsible physician.
Women of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as 12 months with no menses without an alternative medical 
cause). Section 3.8.1 and Table 1 lists the methods of contraception considered adequate; 
note that 2 methods must be combined. Periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of birth control.
Should a woman become pregnant or suspect she is pregnant while participating in this 
study, she should inform her treating physician immediately.
9.
Women of childbearing potential also may not be breast feeding and must have a negative 
serum or urine pregnancy test within 72 hours before the start of study treatment.
10. The patient or legal representative (legal representative not permitted to consent in 
Germany) must be willing to provide written consent for collection of formalin fixed 
paraffin-embedded blocks or slides from archival diagnostic histology samples, where 
available.
3.1.2
Additional inclusion criteria Dose-escalation and safety cohorts Part A
1.
Has a histological confirmation of a solid malignancy (other than HCC) that is refractory 
to standard therapy or for which no standard of care regimen currently exists.
3.1.3
Additional inclusion criteria Arm A6 of Part A
1.
Has a histological confirmation of castrate-resistant prostate cancer.
3.1.4
Additional inclusion criteria-Dose-expansion Part B
For inclusion into the dose-expansion Part B of the study, each patient must fulfil all of the 
criteria listed in Section 3.1.1 as well as the following conditions:
1.
Has histologically and/or cytologically confirmed SCCHN that is RM and not amenable 
to curative therapy by surgery or radiation. Squamous cell carcinoma of the head and 
neck originating from the following sites is eligible: oral cavity, oropharynx, larynx, or 
hypopharynx.
Not eligible are:
∀
Patients with squamous cell carcinoma of any other primary anatomic location 
in the head and neck (e.g., paranasal cavity)
∀
Patients with squamous cell carcinoma of unknown primary
∀
Patients with nonsquamous histologies of head and neck tumors

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2.
Has at least 1 SCCHN tumor lesion (TL) amenable to biopsy and must be medically fit
and willing to undergo a biopsy during screening and, unless clinically contraindicated, at
the end of Cycle 1. (In the event of PD, biopsies at the End-of-Treatment [EOT] are
optional but encouraged.) Tumor lesions used for biopsy should not be lesions used as
RECIST TLs, unless there are no other lesions suitable for biopsy. If a RECIST TL is
used for biopsy, the lesion must be ≥2 cm in longest diameter.
3.
For patients in Arm B1-B6, patients must have failed 1 prior platinum-based
chemotherapy for RM-SCCHN.
4.
Patients in Arms B7 and B8 should have received no prior anti-PD-(L)1 therapies nor
systemic treatment for RM SCCHN.
3.1.5
Additional inclusion criteria - Dose-expansion Part B: treatment arms 
B1 and B2
1.
Has had prior exposure to any anti-PD-(L)1 antibody.
3.2
Exclusion criteria
3.2.1
All patients
A patient must not enter either part of the study if any of the following exclusion criteria are 
fulfilled:
1.
Has a spinal cord compression unless asymptomatic and not requiring steroids for at least
4 weeks before the start of study treatment.
2.
Presently has a second malignancy other than SCCHN, or history of treatment for
invasive cancer other than SCCHN in the past 3 years. Exceptions are:
∀
Previously treated in-situ carcinoma (i.e., noninvasive)
∀
Cervical carcinoma stage 1B or less
∀
Noninvasive basal cell and squamous cell skin carcinoma
∀
Radically treated prostate cancer (prostatectomy or radiotherapy) with normal
prostate-specific antigen, and not requiring ongoing antiandrogen hormonal therapy
3.
Patients must have completed any previous cancer-related treatments before enrolment.
Any concurrent chemotherapy, radiotherapy, immunotherapy, or biologic or hormonal
therapy for cancer excludes the patient (concurrent use of hormones for noncancer-related
conditions [e.g., insulin for diabetes and hormone replacement therapy] is acceptable).
The following intervals between the end of the prior treatment and first dose of study drug
must be observed:
∀
Port-a-cath placement: No waiting is required.

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∀
Minor surgical procedures (as defined by the Investigator): #7 postoperative days
∀
Major surgery (as defined by the Investigator): ≥4 weeks
∀
Ongoing therapy at a stable dose greater than 2 months duration prior to enrolment 
and directed to maintaining a stable hormonal milieu (e.g., Lupron in prostate cancer 
patients) is allowed.
∀
Radiotherapy: ≥4 weeks (patients who receive palliative radiation for non-target 
tumor lesions need not be subjected to this washout period and can be enrolled 
immediately)
∀
Chemotherapy: within 21 days or 5 half-lives (whichever is shorter) from enrolment
∀
Immunotherapy and/or investigational anticancer therapy with agents including 
mAbs: ≥4 weeks (with the exceptions of intranasal and inhaled corticosteroids or 
systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or equivalent)
4.
Is still experiencing toxicity related to prior treatment and assessed as CTCAE grade >1. 
Exceptions are alopecia and/or anorexia. The eligibility of patients who are still 
experiencing irreversible toxicity that is not reasonably expected to be exacerbated by the 
study drugs in this study (e.g., hearing loss) must be reviewed and approved by both the 
Principal Investigator and Medical Monitor.
5.
Has experienced immune-related AEs (irAEs) while receiving prior immunotherapy 
(including anti-CTLA4 treatment) and assessed as CTCAE grade ≥3
6.
Has active or prior documented autoimmune disease within the past 2 years with the 
exceptions of vitiligo, Grave’s disease, and/or psoriasis not requiring systemic treatment
7.
Has active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, 
ulcerative colitis)
8.
Has a history of primary immunodeficiency
9.
Has undergone an organ transplant that requires use of immunosuppressive treatment
10. Has any of the following cardiac criteria:
∀
Any abnormalities in rhythm, conduction or morphology of resting 12-lead ECG that 
in the opinion of the Investigator render the patient unsuitable for participation in the 
study
∀
Mean resting corrected QT interval (QTc) calculated using Fridericia’s formula 
(QTcF) >450 msec for males and >470 msec for females according to local 
assessment and obtained from 3 ECGs within 5 minutes (exception: patients stable 
on pacemaker with higher QTc).

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∀
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalaemia, congenital long QT syndrome, any concomitant 
medication known to prolong the QT interval, or family history of long QT 
syndrome, or unexplained sudden death under 40 years of age
11. Is unable to take oral medications and/or has a clinical or radiological diagnosis of bowel 
obstruction. Patient may not have a percutaneous endoscopic gastrostomy tube and may 
not be receiving total parenteral nutrition. (only applicable for patients enrolled on the
oral pill arms)
12. Has a history of allergic reactions attributed to the study treatments (AZD9150, 
AZD5069, tremelimumab [for Part A, Arm A4 only] or MEDI4736), their compounds, or 
agents of similar chemical or biologic composition (e.g., antibody therapeutics)
13. Suffers from a comorbidity that in the opinion of the Investigator renders the patient 
unsuitable for participation in the study. Such comorbidity may include, but is not limited 
to, uncontrolled intercurrent illness such as active infection, severe active peptic ulcer 
disease or gastritis, myocardial infarction within 6 months before entry, congestive heart 
failure, symptomatic congestive heart failure, active cardiomyopathy, unstable angina 
pectoris, cardiac arrhythmia, uncontrolled hypertension, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
14. As judged by the Investigator, has any evidence of severe or uncontrolled diseases such as 
active bleeding diatheses, or has an active viral infection for human immunodeficiency 
virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV)
15. Has a known history of tuberculosis
16. Has a condition that, in the opinion of the Investigator, would interfere with the 
evaluation of the study drugs or the interpretation of patient safety or study results
17. Has received a live attenuated vaccine within 30 days before the first dose of study drug
18. Judgement 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
3.2.2
Additional exclusion criteria: Dose-escalation and safety cohorts Part A
1.
Patients with clinically active brain metastases (known or suspected) are excluded unless 
the brain metastases have been previously treated and are considered stable. Stable brain 
metastases are defined as no change on CT scan or magnetic resonance imaging (MRI) 
scan for a minimum of 2 months AND no change in steroid dose for a minimum of 4 
weeks, unless change due to intercurrent infection or other acute event.
2.
Has had prior exposure to AZD9150, AZD5069, tremelimumab (only Arm A4), 
MEDI4736, or any other anti PD (L)1 antibody.
3.2.3
Additional exclusion criteria: Dose-expansion Part B
1.
Patients with brain metastases (known or suspected) are excluded.

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3.2.4
Additional exclusion criteria: Dose-expansion Part B: treatment arms 
B3, B4, B5, B6, B7, and B8
1.
Has had prior exposure to AZD9150, AZD5069, MEDI4736, or any other anti 
PD (L)1 antibody.
3.2.5
Additional exclusion criteria: Optional genetic research
A patient must not be included in the optional genetic research if any of the following 
exclusion criteria are fulfilled.
1.
Patients who have previously received an allogeneic bone marrow transplant are excluded 
from the optional genetic research.
2.
Patients who have received nonleukocyte depleted whole blood transfusion(s) within 
120 days before the date of the genetic sample collection are excluded from the optional 
genetic research.
3.3
Subject enrolment and screening
Each potential patient must provide informed consent before starting any study-specific 
procedures (see Appendix D of this CSP “Ethical and Regulatory Requirements”). All patients 
must sign the main ICF for this study. In addition, there are 2 separate optional ICFs:
!
One optional ICF for:
o
Additional optional PK blood samples for first 10 patients in Part B of the 
study randomised to AZD5069 in combination with MEDI4736 (i.e., treatment 
arms B2 and B4) (on the first day of the Lead-in, Day -7 at 10 hours after the 
first morning dose of AZD5069 and on Day 1 of Cycle 2 at 10 hours after the 
first morning dose of AZD5069) (see Section 5.5.1)
o
Additional optional PK urine samples the first 12 patients in Arm B7, the first 
12 patients in Arm B7, and mandatory consent for up to 12 patients (USA only) 
in Arm B8 (optional consent thereafter) (see Section 5.5.1)
o
Additonal optional consent for blood samples for cfDNA for patients enrolled 
prior to 10 May 2017
o
Additional optional consent for patients in Part B for an additional tumor 
biopsy for additional tumor molecular profiling research for patients who 
discontinue study treatment
!
One optional ICF for:
o
Optional pharmacogenetic testing for all patients in Part A and Part B (see 
Section 5.8.2)
Investigator(s) should keep a record on the subject screening log of subjects who entered 
prestudy screening. Each patient must meet all of the inclusion criteria and none of the 

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exclusion criteria for this study at the time of allocation in Part A and randomisation in Part B 
of the study. Under no circumstances can there be exceptions to this rule.
The Investigator(s) will:
1.
Obtain signed informed consent from the potential subject or legal representative before 
any study-specific procedures are performed.
2.
Assign potential subject a unique enrolment number, beginning with ‘E#’.
3.
Determine subject eligibility. See Section 3.1 and 3.2.
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused.
3.4
Procedures for handling incorrectly enrolled or randomized 
subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Subjects who are 
enrolled, but subsequently found not to meet all the eligibility criteria must not be randomized 
or initiated on treatment, and must be withdrawn from the study.
Where a subject does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the Investigator regarding whether to continue or discontinue the subject from 
treatment. The AstraZeneca study physician must ensure all decisions are appropriately 
documented.
3.5
Methods for assigning treatment groups
For Part A, eligible patients are to be allocated to treatment arms in parallel. The details of the 
enrolment in the arms are provided in Sections 4.1.1 and 4.1.2.
For Part B, eligible/evaluable patients are to be randomized to treatment arms via an 
interactive web-based randomisation system (IWRS) in a ratio specified to each arm, while 
the treatment Arms B7 and B8 are non-randomized arms. The details are provided in 
Sections 4.2.1 and 4.2.2.
3.6
Methods for ensuring blinding
Not applicable as this is an open-label study.

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3.7
Methods for unblinding 
Not applicable as this is an open-label study.
3.8
Restrictions
3.8.1
Birth control
The following restrictions apply to all patients while the patient is receiving study treatment 
and for the specified times before and after:
!
Female patients who are of childbearing potential (as defined in Section 4.1 above) 
must use highly effective methods of contraception from the time of screening until 20 
weeks after the final dose of study drug (180 days after final dose if patients enrolled 
in Arm A4); cessation of birth control after this point should be discussed with a 
responsible physician. 
!
Acceptable highly effective methods of contraception include total sexual abstinence 
in line with the preferred and usual lifestyle choice of the patient, tubal ligation, 
vasectomised partner, and methods listed in Table 1.
!
All highly effective methods of contraception (with the exception of total abstinence) 
must be used in combination with the use of a condom by their male sexual partner for 
intercourse. Periodic abstinence, the rhythm method, triphasic combined oral 
contraceptives, all progesterone only pills except, Cerazette™, all barrier methods, if 
intended to be used alone, non-copper containing intrauterine devices s, fertility 
awareness methods, and the withdrawal method (coitus interruptus) are not acceptable 
highly effective methods of birth control. 
!
Should a woman become pregnant or suspect she is pregnant while participating in this 
study, she should inform her treating physician immediately.
Table 1
Highly effective methods of contraception
Intrauterine Device Methods
Hormonal Methods
!
Copper T
!
Levonorgestrel-releasing 
intrauterine system (e.g., Mirena®)a
Any registered and marketed contraceptive agent that 
contains an oestrogen and/or a progestational agent 
(including oral, subcutaneous, intrauterine, or 
intramuscular agents) such as
!
Medroxyprogesterone injections 
(Depo-Provera®)
!
Etonogestrel implants (e.g., Implanon, 
Norplant)
!
Hormone shot or injection
!
Normal and low dose combined oral pills
!
Norelgestromin ethinyl estradiol transdermal 
system

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a
This is also considered a hormonal method.
!
Male patients must be asked to avoid unprotected sex with all sexual partners but use 
condoms during the study, and for 20 weeks after the last dose of study drug (180 days 
after last study drug for patients in Arm A4). 
!
Where a sexual partner of a male participant is a woman of childbearing potential, 
patients must avoid procreation for 20 weeks after completion of study drug treatment. 
!
Patients must refrain from donating sperm from the start of dosing until 20 weeks after 
discontinuing study treatment. If male patients wish to father children, they must be 
advised to arrange for freezing of sperm samples before the start of study treatment.
3.8.2
Eligibility of patients for treatment with AZD5069
As described in Section 1.1.2 and detailed in the IB for AZD5069, in patients treated with 
AZD5069, coadministration of drugs that are known potent or moderate CYP3A4 inhibitors, 
potent or moderate CYP3A4 inducers, P-glycoprotein 1 (P-gp) substrates with narrow 
therapeutic index, sensitive CYP2B6 substrates, warfarin or any other coumarin derivatives, 
breast cancer resistance protein (BCRP)-substrates that reduce blood neutrophils, Seville 
orange or grapefruit products, and any herbal medications should be avoided.
For each patient enrolled in this study (Part A or Part B), the Investigator has to assess both 
the patient’s medication history for any such products as well as the patient’s anticipated need 
or likelihood to consume such products at any time throughout the study.
Restrictions apply starting 14 days prior to the first dose of AZD5069 and last for as long as 
the patient is treated with AZD5069 and until 24 hours after the last dose of AZD5069.
A list of the main potent or moderate CYP3A4 inhibitors, potent or moderate CYP3A4 
inducers, P-gp substrates with narrow therapeutic index, sensitive CYP2B6 substrates, 
warfarin or any other coumarin derivatives, and BCRP-substrates that reduce blood 
neutrophils is shown in Table 2. This is not an exhaustive list and further details can be found 
in Bloomer et al 2013. In addition, Investigators should look at a frequently updated drug 
reference such as Lexicomp to see if any medicine they want to prescribe is on a list of drugs 
to avoid.
Any further questions regarding concomitant treatments in patients treated with AZD5069 
should be referred to study personnel listed in Section 6.10.

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Table 2
Prohibited medications and foods for patients administered AZD5069
Class
Examples (including and not limited to)
Potent/moderate CYP 3A4 
inhibitors
amprenavir
aprepitant
atazanavir
atazanavir/ritonavir
boceprevir
casopitant
cimetidine
ciprofloxacin
clarithromycin
cobicistat (GS-9350)
conivaptan
crizotinib
cyclosporine
danoprevir/ritonavir
darunavir
darunavir/ritonavir
diltiazem
dronedarone
elvitegravir/ritonavir
erythromycin
fluconazole
fosamprenavir
grapefruit juice
idelalisib
imatinib
indinavir
indinavir/ritonavir
itraconazole
ketoconazole
ledipasvir
lomitapide
lopinavir/ritonavir
mibefradil
nefazodone
nelfinavir
netupitant
posaconazole
ritonavir
saquinavir
saquinavir/ritonavir
schisandra sphenanthera
telaprevir
telithromycin
tipranavir/ritonavir
tofisopam
troleandomycin
verapamil
voriconazole
Potent/moderate CYP 3A4 
inducers
avasimibe
bosentan
carbamazepine
efavirenz
etravirine
modafinil
nafcillin
phenytoin 
rifampin
St. John’s wort
Sensitive CYP 2B6 substrates
bupropion
efavirenz
P-gp substrates with narrow 
therapeutic index
digoxin
dabigatran
Coumarin derivatives
acenocoumarol
phenprocoumon
warfarin
Breast cancer resistance
protein (BCRP) substrates 
that reduce blood neutrophils
topotecan
Any herbal medications

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Class
Examples (including and not limited to)
Seville orange or grapefruit 
products
Seville orange marmalade
Seville orange juice
grapefruit
grapefruit juice
grapefruit marmalade
Abbreviations: CYP=cytochrome P450; P-gp=P-glycoprotein 1.
3.9
Discontinuation of investigational product
Subjects may be discontinued from investigational product (IP) in the following situations:
!
Subject decision. The subject is at any time free to discontinue treatment, without 
prejudice to further treatment
!
AE
!
Severe noncompliance with the CSP as judged by the Investigator and/or AstraZeneca.
!
Confirmed PD with either clinical deterioration and/or no further benefit from treatment
!
Patients incorrectly initiated on IP (see Section 5.10)
!
If a female patient becomes pregnant during the course of the study
!
Investigator discretion 
!
Sponsor decision (Section 6.13)
EOT evaluations, including safety assessments, shall be performed as soon as possible 
following the decision to discontinue treatment in all patients. Any patient who is 
discontinued from IP will be followed up for safety. In addition, patients who discontinued 
treatment for reasons other than PD will continue to undergo tumor assessments every 2 
months (± 7 days) until PD is noted. All patients will be followed for subsequent anticancer 
therapy every 2 months (± 7 days) and will also be followed for OS every 2 months (± 7 days) 
from the date of randomisation to the date of death due to any cause, assessed for 
approximately 40 months. The patients will be censored on the date of last follow-up visit. See 
Section 4.2.3 for details of the Follow-up period.
Patients may withdraw from any aspects of the voluntary exploratory research at any time, 
without prejudice to further treatment and independent of any decision concerning 
participation in other aspects of the main study. Procedures for withdrawal from the 
exploratory research are outlined in Section 5.8.7.
Patients who decide to withdraw from the main study will not receive any further study 
treatment, but will be encouraged to undergo all EOT evaluations, safety assessments, and 
follow-up assessments detailed in Section 4.2.3. Patients who decide to withdraw from the 
study may elect to undergo some but not all evaluations (e.g., they may elect to be followed 
for safety as well as subsequent anticancer therapy and survival every 2 months but not 

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undergo tumor assessments). As a minimum, patients will be strongly encouraged to allow 
evaluation of AEs as outlined in Section 6.3.
Unused study drug should be returned by the patient.
3.9.1
Procedures for discontinuation of a subject from investigational 
product 
At any time, subjects are free to discontinue IP or withdraw from the study (i.e., IP and 
assessments – see Section 3.10), without prejudice to further treatment. A subject that decides 
to discontinue IP will always be asked about the reason(s) and the presence of any AEs. If 
possible, they will be seen and assessed by an Investigator(s). AEs will be followed up (See 
Section 6); and all study drugs should be returned by the subject.
If a subject is withdrawn from study, see Section 3.10.
3.10
Criteria for withdrawal 
3.10.1
Screen failures 
Screening failures are subjects who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomized. These subjects should have the reason for study withdrawal 
recorded as ‘Screen failure’ (the potential subject who does not meet one or more criteria 
required for participation in a trial, this reason for study withdrawal is only valid for not 
randomized subjects). ‘Failure to meet randomization criteria’ should be selected for an 
indication that the subject has been unable to fulfil/satisfy the criteria required for assignment 
into a randomized group (it is only applicable for randomized studies and should be used for 
subject withdrawal postscreening).
3.10.2
Withdrawal of the informed consent
Subjects are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment.
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs. The Investigator will follow-up AEs outside of the clinical study.
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn subjects will not be replaced. 
3.11
Discontinuation of the study
The study may be stopped if, in the judgement of AstraZeneca, trial subjects are placed at 
undue risk because of clinically significant findings that:
!
meet individual stopping criteria or are otherwise considered significant 

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!
are assessed as causally related to study drug, 
!
are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the case report form (CRF). All reasons for 
discontinuation of treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests.
4
STUDY PLAN AND TIMING OF PROCEDURES 
4.1
Dose-escalation and safety cohorts Part A
Treatment schedule for dose-escalation Part A is provided in Table 3.

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Table 3
Treatment schedule, dose-escalation Part A
Treatment arm A1, A4, and A6: AZD9150 in combination with MEDI4736 with and without tremelimumab 
(AZD9150/MEDI4736/tremelimumab; AZD9150/MEDI4736)
7-day Lead-in
Treatment Cycle 1 (and beyond)
C1 Week 1
C1 Week 2
C1 Week 3
C1 Week 4
D
-7
D
-6
D
-5
D
-4
D
-3
D
-2
D
-1
D
1
D
8
D
15
D
22
AZD9150
(2mg/kg or 3 
mg/kg IBW 
IV)
x
x
x
x
x
x
x
MEDI4736
(20 mg/kg IV)
x
a
Tremelimum
ab (1 mg/kg) 
IV
x
Treatment arm A2 and A3: AZD5069 in combination with MEDI4736 with and without tremelimumab 
(AZD5069/MEDI4736/tremelimumab; AZD5069/MEDI4736)
7-day Lead-in
Treatment Cycle 1 (and beyond)
C1 Week 1
C1 Week 2
C1 Week 3
C1 Week 4
D
-7
D
-6
D
-5
D
-4
D
-3
D
-2
D
-1
D
1
D
8
D
15
D
22
AZD5069
(40 mg BID/ 
80 mg BID, 
PO)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x

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MEDI4736
(20 mg/kg IV)
x
Abbreviations: BID=twice daily; C=cycle; D=day; IBW=ideal body weight; IV=intravenous; PO=by mouth.
Only applicable to Arm A4 (AZD9150/MEDI4736/tremelimumab) and tremelimumab will be infused only for first 4 cycles.

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4.1.1
Screening/Enrolment period
Patients not previously treated with any anti-PD-(L)1 antibodies were assigned to 1 of 2 
treatment arms (Arm A1:AZD9150/MEDI4736 or Arm A2:AZD5069/MEDI4736). Currently, 
patients not previously treated with anti-PD-(L)1 antibodies will now be enrolled in Arm A3 
(AZD5069 in alternative dosing schedule in combination with MEDI4736), Arm A4 
(AZD9150 in combination with MEDI4736/tremelimumab), and in Arm A6 (safety and dose 
confirmation cohorts with AZD9150 with MEDI4736 in prostate cancer). 
4.1.2
Treatment period
Description of Part A Study Arms
For Arms A1 and A2: DLT evaluable patients were enrolled in the dose-escalation Part A of 
this study. At the time of protocol amendment 5, the MTDs/RP2D for each of the 2 agents in 
combination with MEDI4736 (durvalumab) had been identified [AstraZeneca 2016 (a), 
AstraZeneca 2016 (b)]. In addition, the Arm A3 dose of AZD5069 80 mg twice daily (BID)
with alternate dosing schedule was determined to be safe and tolerable. All additional cohorts 
of Part A enrolled (Arms A4 and A6) patients with advanced solid malignancies refractory to 
standard therapy or for which no standard of care regimen currently exists. Patients were
allocated to treatment in both parts of the study after first considering their history, and any 
anticipated need to use herbal supplements and/or foods prohibited with concurrent 
administration of AZD5069. A 14 day washout period will be required for patients who have 
previously been receiving preparations not compatible with AZD5069. Based on the criteria 
detailed in Section 3.8.2 the Investigator will then assess whether the patient may be allocated 
to treatment with AZD5069.
Patients thus excluded by the Investigator from treatment with AZD5069 are allocated to:
!
Treatment arm, A4 or A6: AZD9150 in combination with MEDI4736 or 
MEDI4736/tremelimumab.
Patients thus included by the Investigator for treatment with AZD5069 will be allocated to one
of the following treatment arms:
!
Treatment arm A4 or A6: AZD9150 in combination with MEDI4736 or 
MEDI4736/tremelimumab, or
!
Treatment arm A3: AZD5069 in combination with MEDI4736.
The starting doses and additional dose levels chosen for each agent in this study are based on 
the clinical experience with each agent as monotherapy in previous trials and from Arms A1 
and A2 of the dose-escalation phase of this trial. Following a 7−day lead-in period, each 
treatment cycle will span 28 days.

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Dosing details of Part A study arms
AZD9150 Arms
For all AZD9150 arms, 3 doses of oligonucleotide are initially administered every other day 
during a 1-week lead-in period (Day −7 to Day −1). Subsequent cycles of dosing with the 
addition of antibody drugs (MEDI4736 or tremelimumab) in combination with AZD9150 will 
begin on Day 1 after the lead-in as described below: 
Arm A1: On Day 1 after the lead-in, AZD9150 was administered at a starting dose of 2 mg/kg 
(IBW) Q1W via a 1-hour IV infusion, followed at least 30 minutes later on the same day by 
MEDI4736 20 mg/kg IV. AZD9150 was subsequently dosed Q1W, while MEDI4736 was 
administered every 4 weeks (Q4W). An additional dose level of AZD9150 (3 mg/kg of IBW 
IV Q1W) was evaluated and determined as RP2D.
Arm A4: For the AZD9150 with MEDI4736 and tremelimumab combination, beginning on 
Day 1 after the lead-in, AZD9150 will be administered first at 3 mg/kg IV over 1 hour (±10 
minutes). The tremelimumab infusion at 1 mg/kg IV will start approximately 1 hour after the 
end of infusion for AZD9150 and will be administered over approximately 1 hour. One hour 
after the end of infusion of tremelimumab, MEDI4736 will be infused at 20 mg/kg over a 
period of 1 hour (±10 minutes). Tremelimumab will be given Q4W for a total of 4 months (up 
to 4 doses). MEDI4736 and AZD9150 dosing will continue Q4W throughout patient 
participation in the study. Therefore, the first dose of AZD9150/MEDI4736 (without 
tremelimumab) will be given 4 weeks after the last dose of tremelimumab.
Arm A6: Upon completion of the lead-in period, AZD9150 will be administered at 3 mg/kg 
of IBW IV Q1W, in combination with MEDI4736 20 mg/kg IV Q4W as described for Arm 
A1 above. Again, the infusion of AZD9150 should be completed 30 minutes prior to start of 
MEDI4736 infusion. 
Ideal body weight (IBW) will be determined using the Devine formula (Pai and Paloucek 
2000; see Section 7.2.1). If the actual weight is less than the IBW or the patient is less than 
5 feet tall, the actual weight will be used to determine the dose. During the 7-day lead-in 
period, AZD9150 will be administered as a loading dose on Days −7, −5, and −3. Starting 
with Cycle 1, AZD9150 will be administered QW on Days 1, 8, 15, and 22 of each treatment 
cycle.

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AZD5069 Arms
For all AZD5069 arms, BID doses of appropriately sized tablets are initially administered 
during a 1 week lead-in period (Day −7 to Day 0). Subsequent dosing of additional antibody 
drugs (MEDI4736 or tremelimumab) in combination with AZD5069 will begin on Day 1 after 
completion of the lead-in as described below:
Arm A2: Beginning on Day 1 after the lead-in, oral/per os (PO) dosing of AZD5069
continued as before (40 mg PO BID). At least 30 minutes after the morning dose of AZD5069, 
MEDI4736 was administered at 20 mg/kg IV over 1 hour. Subsequent to this, AZD5069 
dosing continued BID while MEDI4736 dosing was repeated Q4W. An additional dose level 
of AZD5069 (80 mg BID) was also evaluated in combination with MEDI4736 under the same 
schedule.
Arm A3: AZD5069 will be initially dosed at 80 mg BID with scheduled dose holds and 
titrations to manage treatment-related reductions in peripheral blood neutrophil counts, as 
described in Section 5.5. MEDI4736 dosing at 20 mg/kg will begin on Day 1 after the lead-in 
period as described for Arm A2. At the time of amendment 5, the SRC evaluated the outcome 
of 6 evaluable patients from Arm A3 and determined that 80 mg BID using the alternate 
dosing schedule for managing neutropenic toxicity was safe and tolerable to be considered as 
RP2D. In all arms with patients receiving AZD5069, tablets should be administered either 
2 hours before or 2 hours after food, with a 2 hour window. Dose should be taken on an empty 
stomach at approximately the same time each day. Additional dose levels may be tested if 
deemed necessary to characterise combination tolerability. 
Conduct of Part A Study Arms (A3, A4, and A6)
Arm A3: 6 patients were initially assessed. Since these patients progressed through the DLT 
period with one DLT event of Grade 3 immune hepatitis deemed related to MEDI4736, an 
additional 6 patients will be added to confirm the dose schedule. The algorithm as determined 
in Figure 7 and Figure 8 will be followed. Non-evaluable patients may be replaced. In addition 
to determining DLT in the DLT evaluation period (see Section 5.3.4), the SRC (see 
Section 5.3.5) will critically review all available data pertaining to safety, tolerability, and IM 
as well as PK, pharmacodynamic, and anti-tumor activity before deciding on the viability of 
explored dose and schedule. 
For Arm A4: the aim is to conduct a safety run-in of the established dose of AZD9150 and 
AZD5069 (from Arms A1, A2/A3) in combination with fixed dose of MEDI4736/ 
tremelimumab in all solid tumor patients. There is no dose-escalation planned for Arm A4. If 
the dose is not tolerated (≥2 DLT) in this combination of 3 drugs then dose-reductions will be 
conducted as described in Figure 4, Figure 7, and Figure 8. 

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For Arm A6: the dose and safety confirmation cohort AZD9150 will be given in combination 
with MEDI4736 at established doses of AZD9150 (from Arms A1, A2/A3) in combination 
with a fixed dose of MEDI4736. This will be done in patients with prostate cancer and there 
will be no intra-patient dose escalation. If the dose is not tolerated in this combination of 2 
drugs, then dose-reduction will be conducted as shown in Figure 4, Figure 7, and Figure 8.
Potential subjects who provide written informed consent will be screened; those who are 
identified as eligible will be enrolled, assessed by the Investigator for treatment with 
AZD5069, and assigned accordingly to a treatment arm. Following a 7-day lead-in period 
during which only AZD9150 or AZD5069 will be administered, combination treatment with 
MEDI4736 and/or tremelimumab starts on Day 1 of Cycle 1. A cycle of study treatment is 
defined as 28 days. 
Each patient will undergo assessments for safety (DLTs, AEs, vital sign measurements, 
clinical laboratory tests, PS, ECGs, and physical examinations) and other assessments 
according to the study plan (see Section 5.2).
The DLT evaluation period will be defined as the time from the first dose of AZD9150 or 
AZD5069 to the end of Cycle 1 (i.e., 35 days total), or until a patient experiences a DLT, 
whichever occurs first. For patients in treatment arm A4
(AZD9150/MEDI4736/tremelimumab), to be deemed evaluable, a patient must have received 
all 3 loading doses of AZD9150 during the 7-day lead-in period, and at least 3 additional 
doses during Cycle 1, as well as the MEDI4736 and tremelimumab infusion during the DLT 
evaluation period. Patients who have suffered a DLT during or before Day 35 will also be 
deemed evaluable. For patients in treatment arm A3 (AZD5069/MEDI4736) to be deemed 
evaluable, they must have received all doses during the 7-day lead-in period (i.e., 14 doses) 
and at least 50% of the planned doses of AZD5069. 
For Arm A6, the aim is to establish, collect, and confirm safety, tolerability, and 
PK/pharmacodynamic relations of the RP2D/MT2D for the 2 combinations (i.e., 
AZD9150/MEDI4736 and AZD5069/MEDI4736) in specific tumor types of prostate cancer at 
established doses from Arms A1, A2, and A3. Hence, Arm A6 will not be followed for DLTs. 
Treatments in Arms A3, A4, and A6 will be administered in 4-week treatment cycles until a 
patient: has confirmed PD with either clinical deterioration and/or no further benefit from 
treatment, experiences unacceptable toxicity, or discontinues for any other reason. All patients 
will be evaluated regularly for response to treatment according to the study plan (see 
Section 5.2, Table 5). Study treatment will continue between the initial assessment of 
progression and the confirmation of progression. Patients may continue to receive study 
treatment beyond confirmed PD in the absence of clinical deterioration and if the Investigator 
is of the opinion that the patient continues to receive benefit from treatment. 

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After discontinuation of treatment, patients will continue to be followed for safety, subsequent 
anticancer therapy, and survival. EOT evaluations, including safety assessments, shall be 
performed as soon as possible following the decision to discontinue treatment. Safety follow-
up for IM will continue for all patients for 90 days (± 7 days) after the last dose of MEDI4736 
or until the initiation of subsequent anticancer therapy. Patients who discontinue treatment for 
reasons other than PD will continue to undergo tumor assessments every 2 months (± 7 days) 
until PD is noted. All patients will be followed for subsequent anticancer therapy every 2 
months (± 7 days) and for OS every 2 months (± 7 days) from the date of randomisation to the 
date of death due to any cause, assessed for approximately 40 months. The patients will be 
censored on the date of last follow-up visit. Figure 3 depicts the study scheme.
4.2
Dose-expansion Part B
Treatment schedule for dose-expansion Part B is provided in Table 4.

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Table 4
Treatment schedule, dose-expansion Part B
7-day Lead-in
Treatment Cycle 1 (and beyond)
C1 Week 1
C1 Week 2
C1 Week 3
C1 Week 4
D
-7
D
-6
D
-5
D
-4
D
-3
D
-2
D
-1
D
1
D
8
D
15
D
22
Treatment arm B5: AZD9150 alone
*AZD9150
(3 mg/kg IBW
IV)
x
x
x
x
x
x
x
Treatment arm B6: AZD5069 alone
*AZD5069
(40 mg BID, PO)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Treatment arm B1, B3 and B7: AZD9150 in combination with MEDI4736 (AZD9150/MEDI4736)
AZD9150
(3 mg/kg IBW 
IV)
x
x
x
x
x
x
x
MEDI4736
(20 mg/kg IV)
x
Treatment arm B2 and B4: AZD5069 in combination with MEDI4736 (AZD5069/MEDI4736)
**AZD5069
(40 mg BID/80 
mg BID, PO)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
MEDI4736
(20 mg/kg IV)
x

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Treatment arm B8 AZD9150 in combination with MEDI4736 (AZD9150/MEDI4736 both flat doses)
AZD9150
(200 mg during 
lead-in and 400 
mg Q2W
starting 
fromC1D1)
x
x
x
x
x
MEDI4736
(1.5 g IV)
x
Abbreviations: BID=twice daily; C=cycle; D=day; IBW=ideal body weight; IV=intravenous; PO=by mouth; Q2W=every 2 weeks.
*Arms B1- B6: In the event of disease progression and after proper approval for the addition of MEDI4736, MEDI4736 will be added to the dosing schedule 
beginning on Day 1 of the following treatment cycle (i.e., study treatment will follow the same schedule as a patient on a combination therapy arm). 
**In the case of the Arm B4 post-interim analysis, the dose of AZD5069 will be 80 mg BID alternate dosing schedule.

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4.2.1
Screening/Enrolment period
In Part B of the study, 2L patients will be either allocated or randomly assigned to 1 of the 
first 6 treatment arms (AZD9150 alone, AZD5069 alone, AZD9150/MEDI4736 with or 
without prior exposure to an anti PD (L)1 antibody, or AZD5069/MEDI4736 with or without 
prior exposure to an anti PD (L)1 antibody). Additionally, 2 non-randomized Arms B7 and B8, 
will enroll patients who have no prior exposure to anti-PD-(L)1 antibody, and who are 1L (no 
prior systemic treatment for RM SCCHN). Treatments will be administered with a 7-day 
lead-in period, followed by 4-week treatment cycles for as long as the patient is (considered to 
be) achieving clinical benefit. Patients will be discontinued from treatment if they have 
confirmed PD with either clinical deterioration and/or no further benefit derived from 
treatment, experience unacceptable toxicity, or discontinue for any other reason as per
Section 3.9. Patients in the monotherapy arms of Part B with confirmed PD may continue on 
their current study drug and add MEDI4736 at the discretion of the Investigator with 
notification to the Medical Monitor (and so long as there is ongoing active enrolment in the 
treatment combination arms for PD (L)1 naïve patients). In these patients, MEDI4736 will be 
dosed without a lead-in period. After addition of MEDI4736, these patients will be followed 
for safety.
4.2.2
Treatment period
Part B of the study will commence once the doses for the combination treatments 
(AZD9150/MEDI4736 and AZD5069/MEDI4736) have been established in Part A of the 
study from Arms A1 and A2/A3. In the case of the Arm B4 post-interim analysis, the dose of 
AZD5069 will be 80 mg BID alternate dosing schedule. If the RP2D combination is 
established earlier in one arm of Part A than the other, the Sponsor may manually assign 
patients to a pretreated arm (treatment arm B1/B2 as discussed below) of the determined 
RP2D combination to obtain safety data (for US sites ONLY). One such patient was manually 
randomized to Arm B1; this patient will not be included for any efficacy analysis and could be 
replaced with an actual randomised patient. 
The doses for the monotherapy treatments will be determined by the SRC based on the 
experience with the 2 agents gained in other trials and available at that time. The primary 
objective of the dose-expansion phase is to evaluate the ORR of AZD9150 and AZD5069 
alone or in combination with MEDI4736 in the second-line treatment of patients with RM 
SCCHN and in patients who are 1L RM SCCHN with no prior systemic treatment. 
In the dose-expansion Part B (B1-B6), 155 eligible and efficacy evaluable patients have been 
enrolled. Based on the patient’s history of treatment with an anti-PD-(L)1 antibody, the patient 
will be assigned to either treatment arms B1 or B2 or treatment arms B3, B4, B5, or B6. 
Additionally, Arms B7 and B8 will each enroll at least 48 evaluable patients who have not 
received prior systemic treatment for RM SCCHN. Additionally, based on the patient’s 
history of taking any drugs, herbal supplements, and/or foods prohibited with concurrent 

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administration of AZD5069 or within 14 days of the first dose of AZD5069 and detailed in 
Section 7.2.2 as well as the patient’s anticipated need or likelihood to consume such products 
at any time throughout the study, the Investigator will assess whether the patient may be 
treated with AZD5069. 
ANTI-PD-(L)1 pretreated population
Patients with prior anti-PD-(L)1 antibody exposure that have also been excluded by the 
Investigator for treatment with AZD5069 will be assigned to the following treatment arm:
!
Treatment arm B1: AZD9150 in combination with MEDI4736 (anti-PD-(L)1 pretreated 
population)
Patients with prior anti-PD-(L)1 antibody exposure who have not been excluded by the 
Investigator for treatment with AZD5069 will be assigned via an interactive web-based 
randomisation system (IWRS) in a 1:1 ratio to 1 of the following 2 treatment arms:
!
Treatment arm B1: AZD9150 in combination with MEDI4736 (anti-PD-(L)1 pretreated 
population)
!
Treatment arm B2: AZD5069 in combination with MEDI4736 (anti-PD-(L)1 pretreated 
population)
ANTI-PD-(L)1 NAÏVE POPULATION
Patients with no prior anti-PD-(L)1 antibody exposure who have been excluded by the 
Investigator for treatment with AZD5069 will be assigned via an IWRS in a 2:1 ratio to 1 of 
the following 2 treatment arms:
!
Treatment arm B3: AZD9150 in combination with MEDI4736 (anti-PD-(L)1 naïve 
population)
!
Treatment arm B5: AZD9150 alone (anti-PD-(L)1 naïve population)
Patients with no prior anti-PD-(L)1 antibody exposure who have not been excluded by the 
Investigator for treatment with AZD5069 will be assigned via an IWRS in a 2:2:1:1 ratio to 1 
of the following 4 treatment arms:
!
Treatment arm B3: AZD9150 in combination with MEDI4736 (anti-PD-(L)1 naïve 
population)
!
Treatment arm B4: AZD5069 in combination with MEDI4736 (anti-PD-(L)1 naïve 
population)
!
Treatment arm B5: AZD9150 alone (anti-PD-(L)1 naïve population)
!
Treatment arm B6: AZD5069 alone (anti-PD-(L)1 naïve population)

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!
Non-randomized treatment arms B7 and B8: AZD9150 in combination with MEDI4736 
(anti-PD-(L)1 [flat dose for B8] naïve population) for patients who have not received 
prior systemic treatment for RM SCCHN. 
The dose-expansion Part B will use an adaptive approach to sample size based on Bayesian 
statistical methodology, so the number of actively enrolling treatment arms may decrease as 
the study continues. See Section 8.2.2 for details on sample size, conditions for stopping an 
arm, and the conduct of an interim analysis.
The dose-expansion Part B is based on efficacy evaluable patients (Section 7.7.8 and 
Section 8.2.2). Patients identified as not efficacy evaluable will be replaced.
The doses for the combination treatments (AZD9150/MEDI4736 and AZD5069/MEDI4736) 
will have been established in Part A of the study. In the case of the Arm B4 post-interim 
analysis, the dose of AZD5069 will be 80 mg BID alternate dosing schedule.
AZD9150 will be administered at the dose determined in Part A of the study via a 1-hour IV 
infusion (± 10 minutes). During the 7-day lead-in period, AZD9150 will be administered as a 
loading dose on Days −7, −5, and −3. Starting with Cycle 1, AZD9150 will be administered 
QW on Days 1, 8, 15, and 22 of each treatment cycle.
The patients allocated to Arm B8 will receive a flat dose of AZD9150 at 400 mg Q2W 
(200 mg lead-in dose) in combination with MEDI4736 at a 1.5 g flat dose Q4W.
For those patients randomly assigned to treatment arm B1 or B3, AZD9150 will be 
administered before the infusion of MEDI4736 and should end at least 30 minutes before 
MEDI4736 infusion starts.
AZD5069 will be administered at the dose determined in Part A of the study PO BID (i.e., in 
the morning [at least 30 minutes before MEDI4736 infusion starts] and the evening of each 
day) starting with Day -7 of the 7-day lead-in period for treatment arms B2 and B4. 
MEDI4736 will be administered Q4W via a 1 hour IV infusion (± 10 minutes). Patients will 
receive MEDI4736 on Day 1 of each treatment cycle, starting with Cycle 1. MEDI4736 will 
be infused after the administration of AZD9150 or the morning dose of AZD5069. There 
should be an interval of at least 30 minutes between the end of the AZD9150 infusion or the 
taking of the morning dose of AZD5069 and the start of the MEDI4736 infusion.
Each patient will undergo assessments for efficacy and safety as well as other assessments 
according to the study plan (see Section 5.2, Table 5).
Of the patients randomly assigned to treatment arm B5 and B8, 12 evaluable patients will be 
asked to provide urine samples for PK assessments in urine. Patients’ consent to this 
evaluation will be mandatory for B8 and voluntary for B5.

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Patients participating in Part B of the study will be administered study drug(s) following the 
7-day lead-in period in 4-week treatment cycles for as long as they are continuing to show
clinical benefit, as judged by the Investigator, unless a patient has confirmed PD with either
clinical deterioration and/or no further benefit from treatment, experiences unacceptable
toxicity, or discontinues for any other reason.
Patients in the monotherapy arms of Part B (i.e., Arm B5 or B6) with confirmed PD may 
continue on their current study drug and add MEDI4736 at the discretion of the Investigator 
with notification to the Medical Monitor (and so long as there is active enrolment ongoing in 
the treatment combination arms for PD-(L)1 naïve patients). In these patients, MEDI4736 will 
be added to the schedule beginning on Day 1 of the following treatment cycle with AZD9150 
and MEDI4736 (i.e., study treatment will be dosed on the same schedule as a patient on a 
combination therapy arm starting on Day 1 of the following Cycle; see Table 4 for dosing 
schedule). After addition of MEDI4736, these patients will be followed for safety but 
censored from the efficacy analysis. When the addition of MEDI4736 (durvalumab) occurs, 
the first safety reassessment for the combination of treatment in these patients is to take place 
45 days after the first administration (of combination treatment) and every 8 weeks thereafter. 
All patients will be evaluated according to the study plan (see Section 5.2, Table 5) and their 
clinical status classified according to the RECIST guidelines version 1.1 (Eisenhauer et al 
2009) with modifications to account for the unique response kinetics, which have been 
observed in some patients where responses to immunotherapy may occur after PD is assessed 
(Wolchok et al 2009). Specifically, RECIST criteria will be modified so that PD in the 
absence of clinical deterioration must be confirmed at least 4 weeks after the initial 
assessment of PD. Study treatment will continue between the initial assessment of progression 
and the confirmation for progression. Patients may continue to receive study treatment beyond 
confirmed PD in the absence of clinical deterioration and if the Investigator is of the opinion 
that the patient continues to receive benefit from treatment.
Following a 7-day lead-in period, each treatment cycle will span 28 days. Table 4 provides an 
overview of the treatment schedule in the dose-expansion Part B of the study.
After discontinuation of treatment, patients will continue to be followed for safety, subsequent 
anticancer therapy, and survival. During this time, all patients will be followed for safety 
(including concomitant medication) for 28 days (± 7 days) after the last dose of study drug or 
until the initiation of a subsequent anticancer therapy. In addition, patients who received 
MEDI4736 as part of their combination treatment will be followed for IM for 90 days 
(±7 days) after the last dose of MEDI4736 or until the initiation of alternative anticancer 
therapy. Patients who discontinued treatment for reasons other than PD will continue to 
undergo tumor assessments every 2 months (± 7 days) until PD is noted. All patients will be 
followed for subsequent anticancer therapy every 2 months (± 7 days) and will also be 

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followed for OS every 2 months (± 7 days) from the date of randomisation to the date of death 
due to any cause, assessed for approximately 40 months. The patients will be censored on the 
date of last follow-up visit. Figure 3 depicts the Part B study scheme.
4.2.3
End-of-treatment evaluations and follow-up
EOT evaluations, including safety and tumor assessments, shall be performed as soon as 
possible following the decision to discontinue treatment (see the study event overview, Table 
5).
In addition, patients should be followed up for at least 28 days (+7 days) after the last dose of 
study treatment for any new reports of AEs, SAEs, and concomitant medications.
Safety follow-up for IM will continue for all patients treated with MEDI4736 for 90 days 
(±7 days) after the last dose of MEDI4736 or until the initiation of subsequent anticancer 
therapy.
Patients who discontinued treatment for reasons other than PD will continue to undergo tumor 
assessments every 2 months (± 7 days) until PD is noted. All patients will be followed for 
subsequent anticancer therapy every 2 months (± 7 days) and will also be followed for OS 
every 2 months (± 7 days) from the date of randomisation to the date of death due to any 
cause, assessed for approximately 40 months. The patients will be censored on the date of last 
follow-up visit.
The status of “ongoing,” “withdrawn from the study,” and “lost to follow-up” for patients at 
the time of an OS analysis should be obtained by the site personnel through checking the 
patient notes, hospital records, contacting the patient’s general practitioner, and checking 
publicly available death registries. If the patient has actively withdrawn consent to the 
processing of their personal data, the vital status of the patient can be obtained by site 
personnel from publicly available resources where it is possible to do so under applicable 
local laws.
5
STUDY ASSESSMENTS
5.1
Recording of data
Web-based data capture (WBDC) will be used for data collection and query handling. The 
Investigator will ensure that data are recorded in the electronic CRFs (eCRFs) as specified in 
the CSP 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. An electronic copy of the completed eCRFs will 
be archived at the study site.

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For details of data and study management see Appendix E, “Data and Study Management” of 
this CSP.
5.2
Study plan and event overview
Procedures and assessments during study entry, as well as subsequent safety and tumor 
assessments are similar in Part A and Part B of the study; an overview of these study events is 
provided in the Study Plan in Table 5.
Pharmacokinetic, pharmacodynamic, and IM assessments, however, differ between Part A and 
Part B; Table 6 provides an overview of these assessments for Part A, Table 7 for Arms B1 to 
B7, and Table 8 for B8.
Details of the various procedures and assessments are provided in the footnotes to the figures 
and in the subsequent CSP sections.

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Table 5
Study plan for study entry, treatment, safety, and tumor assessments
Assessments
Day:
Screening
Lead-in
(-7 to -1)
Cycle 1 and all subsequent cycles, unless noted
Even 
cycles 
only
End-of-
Treatmenta Follow-
upb
Week 1
Week 2
Week 3
Week 4
-21 to -8
-7
-5
-3
1
2-7
8
9-14
15
16-21
22
23-28
Informed consent
x
Demography, baseline 
characteristics, medical, and 
surgical history
x
Previous tumor-related tx
x
Selection criteria
x
x
Complete physical examc
x
x
x
x
Targeted physical examc
x
ECOG performance status
x
x
x
x
Vital signsq
x
x
x
x
x
x
x
Height
x
Weightc,d
x
x
x
x
12-Lead ECG in triplicatee
x
xe
x
Laboratory safety tests 
(haematology, serum 
chemistry)c,f
x
x
x
xf
x
xf
x
Laboratory safety tests 
(coagulation)c,g
x
x
x
xg
x
Urinalysisc,h
x
x
x
xh
x
Thyroid function testsc,i
x
x
x
x
HIV, HBV, HCV serology
x

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Assessments
Day:
Screening
Lead-in
(-7 to -1)
Cycle 1 and all subsequent cycles, unless noted
Even 
cycles 
only
End-of-
Treatmenta Follow-
upb
Week 1
Week 2
Week 3
Week 4
-21 to -8
-7
-5
-3
1
2-7
8
9-14
15
16-21
22
23-28
HPV status
x
Pregnancy testj
x
x
x
x
Tumor assessmentsk
xk
xk
x
xk
Concomitant medicationsl
x
x
x
AEl
x
x
x
AZD9150m
x
x
x
x
x
x
x
AZD9150m (Arm B8 only)
x
x
x
x
x
AZD5069 (combination 
therapy or monotheapy) 
(BID)n 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
tremelimumab p
x
MEDI4736o
x
MEDI4736o (1.5g flat dose 
for Arm B8 only)
x
a
An EOT visit shall occur as soon as possible following the decision to discontinue treatment.
b
Patients are to be followed up for 28 (+7) days after the last dose of study treatment for any new reports of AEs, SAEs, and concomitant medications. Safety 
follow-up for IM will continue for all patients treated with MEDI4736 for 90 days (± 7 days) after the last dose of MEDI4736 or until the initiation of 
subsequent anticancer therapy. Patients who discontinued treatment for reasons other than PD will continue to undergo tumor assessments every 2 months 
(± 7 days) until PD is noted. All patients will be followed for subsequent anticancer therapy every 2 months (± 7 days) and will also be followed for overall 
survival every 2 months (± 7 days) from the date of randomisation to the date of death due to any cause, assessed for approximately 40 months. The patients 
will be censored on the date of last follow-up visit. 
c
To facilitate scheduling of predose assessments, a window of −2 days is allowed to obtain the following procedures prior to dosing a patient: complete and 
targeted physical exam, weight, laboratory safety tests (haematology, serum chemistry, and coagulation), urinalysis, and thyroid function tests.
d
Weight (in kilograms) will be obtained at screening, before dosing on Day −7 of the lead-in, before dosing on Day 1 of each cycle, and at the EOT visit. 
Weight obtained on Day −7 of the lead-in will be used to calculate the weight-related doses of AZD9150 for the lead-in. Weight obtained on Day 1 of each
cycle will be used to calculate the weight-related doses of AZD9150 and MEDI4736 for each cycle..

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e
For patients treated with AZD5069, 12-lead resting ECGs in triplicate will be obtained at screening, throughout the treatment, and at the EOT visit. On 
Day 1 of Cycle 1, 12-lead ECGs should be recorded at 2 hours after the morning dose of AZD5069, and for patients treated with MEDI4736, again 2 hours 
after end of the MEDI4736 infusion. On Day 1 of Cycle 2 and of all subsequent odd-numbered cycles (to match PK assessments), 12-lead ECGs should be
recorded at the end of infusion and 2 hours after the morning dose of AZD5069. The timing and number of ECGs may be adjusted by the SRC in response 
to the emerging PK and safety profile. For patients not treated with AZD5069, 12-lead resting ECGs in triplicate will be obtained at screening, on Day 1 of 
Cycle 1 (2 hours after the end of the AZD9150 infusion, and for patients treated with MEDI4736, again 2 hours after end of the MEDI4736 infusion), and at 
the EOT visit. For B8, digital triplicate ECGs should be taken at predose, 1 hour after the start of the AZD9150 infusion (end of AZD9150 infusion) and 2 
hours after the start of infusion on lead-in Day -7, Day 1 of Cycle 1, 2, and at subsequent PK time points. Refer to Section 5.4.3 for additional details. 
f
Blood samples for routine haematology and serum chemistry safety assessments will be obtained at screening; before dosing on Day −7 of the lead-in; 
before dosing on Days 1, 8, 15, and 22 of Cycle 1; before dosing on Days 1 and 15 of all subsequent cycles; and at the EOT visit. To shorten the time 
between the blood draw and the decision if dosing may proceed, blood samples for routine haematology and serum chemistry safety assessments are to be 
drawn and split into 2 samples. One portion of the sample is to be analysed locally to determine toxicity prior to dosing and the second portion of the sample 
is to be sent to the designated central laboratory. Samples are not to be split on days where no study drug administration is scheduled. Haematology 
parameters include haemoglobin, haematocrit, RBC count, mean corpuscular volume, mean corpuscular haemoglobin concentration, WBC count with 
differential (absolute and %), and platelet count. Serum chemistry parameters include sodium, potassium, chloride, bicarbonate, magnesium, calcium, 
phosphate, blood urea nitrogen, uric acid, creatinine, glucose (random), TBL, indirect bilirubin, LDH, total protein, albumin, ALP, ALT, AST, GGT, 
creatine phosphokinase, C-reactive protein, cholesterol, and triglycerides. Refer to Section 5.4.1, for details.
g
Blood samples for routine coagulation assessments will be obtained at screening; before dosing on Day −7 of the lead-in; before dosing on Days 1 and 15 of 
Cycle 1; before dosing on Day 1 of all subsequent cycles; and at the EOT visit. Tests include prothrombin time, partial thromboplastin time, fibrinogen, 
haptoglobin, and international normalised ratio. Refer to Section 5.4.1, for details.
h
Urine samples for routine urinalysis will be obtained at screening; before dosing on Day −7 of the lead-in; before dosing on Days 1 and 15 of Cycle 1; 
before dosing on Day 1 of all subsequent cycles, and at the EOT visit. Urinalysis parameters include colour, appearance, specific gravity, pH, protein, 
glucose, ketones, blood, bilirubin, and microscopic evaluation of WBC/HPF, and RBC/HPF. Refer to Section 5.4.1, for details.
i
Thyroid function tests are required at screening, before dosing on Day −7 of the lead-in, before dosing on Day 1 of each cycle, and at the EOT visit. Thyroid 
function tests include TSH, and free T3 and T4.
j
For women of childbearing potential, defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete 
hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause): A blood sample to determine serum β hCG 
is required at screening; this sample will be analysed at the central laboratory for the study. Additionally, urine samples for a urine-based pregnancy test will 
be collected before dosing on Day −7 of the lead-in, before dosing on Day 1 of each cycle, and at the EOT visit. Urine-based pregnancy tests will be 
performed at the study centres.
k
Tumor assessments to be performed at screening, on Day 15 of Cycle 2 (i.e., at the beginning of Week 7), at the beginning of each subsequent even-
numbered cycle, and at the EOT visit. Patients who are on study treatment for more than 24 months may have the frequency of tumor assessment reduced to 
every 12 to 16 weeks at the discretion of the Investigator. Patients who discontinue treatment for reasons other than PD will continue to undergo tumor 
assessments every 2 months (± 7 days) until PD is noted. To facilitate scheduling of tumor assessments, a window of ±7 days is allowed. For the additional 
48 patients to be enrolled in first-line in Arms B7 and B8, a central imaging read will be done in addition to the local site RECIST evaluation. See 
Section 5.3.1 for additional details.

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The reporting period for AEs and concomitant medication starts immediately following the time that written informed consent is obtained and ends 28 (+7)
days after the last dose of study drug or until the initiation of subsequent anticancer therapy. For patients dose-reduced to levels −1 or −2 of AZD9150 in
Arms B1, B3, or B7 who are experiencing treatment-related AEs of Grade 2 or lower, visits on Day 8 and Day 22 of each cycle (no AZD9150 dosing) may
be considered optional, unless, in the Investigator's estimation, more frequent individual evaluations are appropriate.
m
During the 7-day lead-in period, AZD9150 will be infused on Days −7, −5, and −3. A window of +1 day per loading dose is allowed. Doses should not be
given on back-to-back days. Starting with Cycle 1, AZD9150 will be administered every week on Days 1, 8, 15, and 22 of each treatment cycle; doses have
a ±2 day dosing window. When given in combination with MEDI4736, AZD9150 will be administered before the infusion of MEDI4736 and must be
completed at least 30 minutes before the start of MEDI4736 infusion. When given in combination with tremelimumab, AZD9150 will be administered
before the infusion of MEDI4736 and must be completed at least 1 hour before the start of MEDI4736 infusion. For treatment Arm B8, AZD9150 will be
administered at 200 mg on lead-in Days −7, −5, and −3 and 400 mg every 2 weeks starting in Cycle 1.
n
In combination therapy arms, patients will receive AZD5069 BID (i.e., in the morning at least 30 minutes before MEDI4736 infusion or tremelimumab
infusion [as applicable] and in the evening) starting with Day −7 of the lead-in cycle. The morning dose of AZD5069 on Day −7 of the lead-in period and
on any subsequent day when blood samples before the morning dose are required must be administered at the study centre and the precise time noted. All
other doses may be self-administered by the patient; self-administration of AZD5069 will be recorded in the Patient Diary. Subsequently, AZD5069 will be
administered BID (i.e., in the morning and in the evening) starting with Day 1 of Cycle 1. The morning dose of AZD5069 in the lead-in period and on any
subsequent day when blood samples before the morning dose are required must be administered at the study centre and the precise time noted. All other
doses may be self-administered by the patient; self-administration of AZD5069 will be recorded in the Patient Diary.
o
For MEDI4736, a window of ±2 days is allowed for dosing days. Patients will receive MEDI4738 Q4W on Day 1 of each cycle. When given in
combination with tremelimumab, the infusion of MEDI4736 will be 1 hour after the end of the tremelimumab infusion. Patients should be observed after
administration of MEDI4736 for a minimum of 2 hours for the appearance of any acute drug reactions. In the event of an acute reaction, in order to help
understand the potential drug relatedness of such a reaction, a blood sample should be drawn during the event for possible additional ADA testing. Serum
tryptase or other blood or urine testing relevant to the diagnosis of anaphylaxis may be obtained at the discretion of the Investigator. For patients on
monotherapy in Arms B5 and B6: In the event of disease progression and after proper approval for the addition of MEDI4736— MEDI4736 will be added
to the dosing schedule beginning on Day 1 of the following treatment cycle (i.e., study treatment will follow the same schedule as a patient on a
combination therapy arm, [see Table 4 for dosing schedule]). After addition of MEDI4736, these patients will be followed for safety; the first safety
reassessment for the combination of treatment in these patients is to take place 45 days after the first administration (of combination treatment) and every 8
weeks thereafter. See Section 5.4 for details on safety assessments. MEDI4736 will be administered as a 1.5g flat dose Q4W for treatment Arm B8. If body
weight decreases to less than 30 kg, weight-based dosing (20 mg/kg Q4W) will be implemented.
p
(Applicable only for Arm A4) Tremelimumab will be given only for 4 cycles (once a month on Day 1 of every cycle for up to 4 months), and will be
infused after AZD9150 and AZD5069, and prior to MEDI4736 infusions in Arm A4 (AZD9150/MEDI4736/tremelimumab).
q
Vital signs for patients on AZD5069 will not be required for Day 8 and Day 22 visits beyond Cycle 2 as there are no dosing visits scheduled for these
patients on these days. Vital signs for patients in Arm B8 will not be required for Day 8 and Day 22 (all cycles) as there are no dosing visits scheduled for
these patients on these days.

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Abbreviations: ADA=antidrug antibody; AE=adverse event; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; β 
hCG=beta human chorionic gonadotropin; BID=twice daily; CT=computerised tomography; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology
Group; EOT=End-of-Treatment; GGT=gamma-glutamyl transpeptidase; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
HPF=high-power field; IM=immunogenicity; kg=kilogram; LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; PD=progression of disease; 
PK=pharmacokinetic(s); PS=performance status; Q4W=every 4 weeks; RBC=red blood cell(s); SRC= Safety Review Committee; T3=triiodothyronine; 
T4=thyroxine; TBL=total bilirubin; TSH=thyroid-stimulating hormone; tx=treatment; WBC=white blood cells

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Table 6
Study plan for pharmacokinetic, pharmacodynamic, immunogenicity, and pharmacogenetic assessments in 
Part A
Assessments         
Day:
Screening Lead-in
(-7 to -1)
Cycles
EOT
a
FU
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 C11 *C12
-21 to -8
-7
-5 -4 -3
1
8
15
1
15
1
1
1
1
1
1
1
1
1
1
Blood samples for pharmacokinetic assessments
AZD9150b
x
x
x
x
x
x
x
x
x
AZD5069c
x
x
x
x
x
x
x
x
x
MEDI4736d
x
x
x
x
xd
x
x
x
Tremelimumabl
x
x
x
Blood samples for pharmacodynamic assessments
PDRNAe
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
sPD-L1f
x
x
x
x
x
x
x
x
MDSCsg
x
x
x
x
x
x
x
Blood samples for IM assessments
ADAh
x
x
x
x
x
x
x
x
Anti-AZD9150 Abi
x
x
x
x
x
x
x
Blood samples for exploratory blood-borne biomarkersj
Serum samplej
x
x
x
x
x
x
x
x
x
x
x
x
x
Plasma samplej
x
x
x
x
x
x
x
x
x
x
x
x
PBMCj
x
x
x
x
x
x
x
x
x
sPSA m
x
x
x
x
x
x
x
x
cfDNA blood 
sampleo
x
x
x
x
x
x
x
x
x
x

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Other
Collection of archival 
tumor samplesn
x
Optional
Pharmacogeneticsj
x
Tumor biopsyk
x
* In order to ensure all samples required for sample point collection are accurately collected, the cycles beyond Cycle 12 should mimic Cycle 9, 10, 11, and 12 in 
a repeated pattern through to Cycle 40, except where noted in the footnotes below (eg, PBMC collection). 
An EOT visit shall occur as soon as possible following the decision to discontinue treatment.
a
For patients treated with AZD9150 (Arm A1, A4 and A6), PK blood samples for AZD9150 (2 mL) will be collected relative to the AZD9150 infusion as 
follows; a window of 10% of the nominal time point is acceptable:
Lead in, Day −7: Predose and at 0.5 hour (±3 min), 1 hour (end of infusion; ±6 min), 2 hours (±12 min), 4 hours (±24 min), and 6 hours (±36 min) after the 
start of the infusion
Lead in, Day −5: At 48 (±4) hours after the start of the first infusion (on Day −7) and before the second infusion (on Day −5)
Cycle 1, Day 1: Predose
Cycle 2, Day 1: Predose and at 0.5 hour (±3 min), 1 hour (end of infusion; ±6 min), 2 hours (±12 min), 4 hours (±24 min), and 6 hours (±36 min) after the 
start of the infusion
Cycle 3 and all subsequent odd-numbered cycles, Day 1: Predose
b
For patients treated with AZD5069 (PRIOR TO DETERMINATION OF RP2D, Arms A2 and A3), PK blood samples for AZD5069 and its metabolite 
AZ13587715 (2 mL total) will be collected as follows; a window of 10% of the nominal time point is acceptable:
Lead-in, Day −7: Before the first morning dose and at 0.5 hour (±3 min), 1 hour (±6 min), 2 hours (±12 min), 4 hours (±24 min), 6 (±36 min), 8 (±48 min), 
and 10 hours (±60 min) (when possible) after the first morning dose
Cycle 1, Day 1: Before the morning dose and at 2 hours (±12 min) after the morning dose
Cycle 2, Day 1: Before the morning dose and at 0.5 hour (±3 min), 1 hour (±6 min), 2 hours (±12 min), 4 hours (±24 min), 6 (±36 min), 8 (±48 min), and 10 
hours (±60 min) (when possible) after the morning dose 
Cycle 3 and all subsequent odd-numbered cycles, Day 1: Before the morning dose and at 2 hours (±12 min) after the morning dose
The morning dose of AZD5069 on Day −7 of the lead-in period and on any subsequent day where blood samples before the morning dose are required must 
be administered at the study centre and the precise time noted. Failure to obtain the 10-hour samples will not be considered a protocol deviation.
c
For all patients, PK blood samples for MEDI4736 (3.5 mL) will be collected relative to the MEDI4736 infusion as follows; a window of 10% of the 
nominal time point is acceptable:
Cycle 1, Day 1: Predose and 1 hour (±6 min) after the start of the infusion (end of infusion)

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Cycle 2, Day 15:
Any time
Cycle 4 and all subsequent even-numbered cycles, Day 1: Predose
Cycle 8, Day 1: In addition to the predose sample, a sample at 1 hour (±6 min) after the start of the infusion (end of infusion)
Follow-up: For patients who discontinue MEDI4736, a sample will be drawn 90 days after their last dose of MEDI4736 (coinciding with an IM [ADA] 
sample)
d
For all patients, 2 blood samples (2.5 mL each) for pharmacodynamic RNA (PDRNA) will be collected predose at each specified time point to assess 
pharmacodynamic response in blood for AZD9150 (STAT3 knockdown) and exploratory blood-borne biomarkers that may correlate to treatment or 
response (gene expression changes or modification of genomic DNA): At screening; on Day −7 of the lead-in period; on Day 1 and Day 8 of Cycle 1; on 
Day 1 of subsequent; and at the EOT visit. The revised sample collection for PDRNA samples is applicable to newly enrolled patients only (under protocol 
amendment 5, dated 10 May 2017, and onwards), existing patients will have samples collected up to Cycle 5, Day 1. New patients will be required to have 
samples collected beyond Cycle 5.
e
For all patients (except for patients in Arms A3, A4, and A6), a single blood sample (3.5 mL) will be collected predose at each specified time point to assess 
the pharmacodynamic response in blood for MEDI4736 (sPD-L1): Day 1 of Cycle 1, Day 15 of Cycle 2, and Day 1 of all subsequent even-numbered cycles.
On Day 1 of Cycle 1 and on Day 1 of Cycle 8, in addition to the predose sample, a sample will also be obtained at the end of the MEDI4736 infusion.
For patients who discontinue MEDI4736, a sample will be drawn 90 days after their last dose of MEDI4736 coinciding with an IM (ADA) sample.
f
For all patients, blood samples for MDSC (5 mL), will be collected predose at the specified time points to assess the treatment effect on circulating MDSCs: 
At screening; on Day −7 of the lead-in period; on Day 1 of Cycles 1, 2, 3, 5; and at the EOT visit.
g
For all patients, blood samples for IM (5 mL) will be collected predose on Day 1 of Cycle 1, on Day 15 of Cycle 2, and on Day 1 of each subsequent even-
numbered cycle. For patients who discontinue MEDI4736, a blood sample will also be collected during follow-up at 90 days after the last dose of 
MEDI4736.
h
For patients treated with AZD9150, blood samples for IM (2 mL) will be collected relative to AZD9150 infusion as follows: Cycle 1, Day 1: Predose; Cycle 
2, Day 1: Predose; and Cycle 4 and all subsequent even-numbered cycles, Day 1: Predose.
i
For all patients, at the time points specified, a single 2 mL blood sample for serum, a single 10 mL blood sample for plasma, and two 6 mL blood samples 
for PBMC will be collected predose for the assessment of exploratory biomarkers.
The 2 mL blood sample for serum will be obtained at screening; on Days −7 and −3 of the lead-in period; on Days 1, 8, and 15 of Cycle 1; on Day 1 of 
Cycle 2; on Day 1 of all subsequent odd-numbered cycles; and at the EOT visit.
The 10 mL blood sample for plasma will be obtained at screening; on Day −7 of the lead-in period; on Days 1, 8, and 15 of Cycle 1; on Day 1 of Cycle 2; 
on Day 1 of all subsequent odd-numbered cycles; and at the EOT visit.
The two 6 mL blood samples for PBMC will be obtained at screening; on Day −7 of the lead-in period; on Days 1, 8, and 15 of Cycle 1; on Day 1 of cycles 
3, 6, and 9; and at the EOT visit.
j
If a patient agrees to participate in the host pharmacogenetics research component of the study and signs a separate informed consent for genetic research, a 
saliva sample will be collected. The saliva sample for genetic research will ideally be obtained from the patients immediately prior to dosing on Day 1. If 
for any reason, the sample is not obtained prior to dosing, it may be taken at any visit until the last study visit. Only 1 sample should be collected per patient 
for genetics during the study. See Section 6.8.2 for details. 
k
If a patient in treatment Arm A6 agrees to provide a screening tumor biopsy, this will be documented via an optional ICF.

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For all patients in treatment Arms A4 and A5, PK blood samples for tremelimumab (3.5 mL) will be collected relative to the tremelimumab infusion as 
follows: a window of 10% of the nominal time point is acceptable:
Cycle 1, Day 1: Predose and 1 hour (±6 min) after the start of the infusion (end of infusion)
Cycle 2, Day 15: any time
Cycle 4, Day 1: Predose
m
For all prostate cancer patients in treatment Arm A6, 2.5 mL of blood will be collected at screening, Cycle 1 Day 1, at all response assessment visits and 
EOT.
n
Archival tumor biopsy is mandatory if available. If the archival tumor sample is not available it will not impact the patient’s right to participate in the trial.
o
The collection of cfDNA samples is only required to be obtained for newly enrolled patients consented (under protocol amendment 5, dated 10 May 2017 
and onwards). It is not a requirement to collect cfDNA samples for patients enrolled prior to the implementation of protocol amendment 5, dated 10 May 
2017.
Abbreviations: Ab=antibody; ADA=antidrug antibody; cfDNA=circulating-free DNA; EOT=End-of-Treatment; FU=follow-up; ICF=informed consent form; 
IM=immunogenicity; MDSC1=myeloid-derived suppressor cells; PBMC=peripheral blood mononuclear cell(s); PK=pharmacokinetic; 
PDRNA=pharmacodynamic RNA (samples for STAT3 RNA and other exploratory analyses); sPD-L1=soluble programmed death-ligand 1; sPSA=serum 
prostate-specific antigen.

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Table 7
Study plan for pharmacokinetic, pharmacodynamic, immunogenicity, and pharmacogenetic assessments in 
Part B (Arms B1-B7)
Assessments         
Day:
Screening Lead-in
(-7 to -1)
Cycles
EOT
a
FU
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 C11 *C12
-21 to -8
-7
-5
-3
1
8
15
1
15
1
1
1
1
1
1
1
1
1
1
Blood samples for pharmacokinetic assessments
AZD9150b
First 10 ptsb
x
x
x
x
x
x
x
x
x
Subsequent pts & 
B7b
x
x
x
x
x
x
AZD5069 
(monotherapy arm)c
x
x
x
x
x
x
AZD5069 (combination therapy arms)d
First 10 ptsd
x
x
x
x
x
x
x
x
Subsequent ptsd
x
x
x
x
x
x
MEDI4736e
x
x
x
x
xe
x
x
x
Urine samples for pharmacokinetic assessments (optional consent)
AZD9150f
x
x
x
Blood samples for pharmacodynamic assessments
PDRNAg
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
sPD-L1h
x
x
x
x
x
x
x
x
MDSCsi
x
x
x
x
x
x
x
Blood samples for immunogenicity assessments
ADAj
x
x
x
x
x
x
x
x

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Assessments         
Day:
Screening Lead-in
(-7 to -1)
Cycles
EOT
a
FU
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 C11 *C12
-21 to -8
-7
-5
-3
1
8
15
1
15
1
1
1
1
1
1
1
1
1
1
Anti-AZD9150 Abk
x
x
x
x
x
x
x
Blood samples for exploratory blood-borne biomarkersl
Serum samplel
x
x
x
x
x
x
x
x
x
x
x
x
x
Plasma samplel
x
x
x
x
x
x
x
x
x
x
x
x
PBMCl
x
x
x
x
x
x
x
x
x
cfDNA blood 
sampleo
x
x
x
x
x
x
x
x
x
Other
Collection of 
archival tumor 
samples
x
Tumor biopsym
x
x
xm
Optional
Pharmacogeneticsn
x
a
*In order to ensure all samples required for sample point collection are accurately collected, the cycles beyond Cycle 12 should mimic Cycle 9, 10, 11 and 
12 in a repeated pattern through to Cycle 40, except where noted in the footnotes below (e.g., PBMC collection). An EOT visit shall occur as soon as 
possible following the decision to discontinue treatment.
b
In the first 10 patients randomized to treatment with AZD9150 alone or in combination with MEDI4736 (i.e., treatment arm B1, B3, or B5), PK blood 
samples for AZD9150 (2 mL) will be taken as follows; a window of 10% of the nominal time point is acceptable:
Lead-in, Day −7: Predose and at 0.5 hour (±3 min), 1 (end of infusion; ±6 min), 2 (±12 min), 4 (±24 min), and 6 hours (±36 min) after the start of the 
infusion
Lead-in, Day −5: At 48 (±4) hours after the start of the first infusion (on Day −7) and before the second infusion (on Day −5)
Cycle 1, Day 1: Predose
Cycle 2, Day 1: Predose and at 0.5 hour (±3 min), 1 (end of infusion; ±6 min), 2 (±12 min), 4 (±24 min), and 6 hours (±36 min) after the start of the 
infusion

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Cycle 3 and all subsequent odd-numbered cycles, Day 1: Predose
In patients following the first 10 patients randomised to treatment with AZD9150 alone or in combination with MEDI4736 (i.e., treatment arm B1, B3, or 
B5) and Arm B7, a predose and a 2-hour (±12 min) sample will be collected on Day 1 of Cycle 2 and subsequent odd-numbered cycles.
c
In patients randomized to treatment with AZD5069 monotherapy (arm B6), PK blood samples for AZD5069 and its metabolite AZ13587715 (2 mL total) 
will be collected as follows; a window of 10% of the nominal time point is acceptable:
Cycle 2, Day 1: Before the morning dose 
Cycle 3 and all subsequent odd-numbered cycles, Day 1: Before the morning dose
The morning dose of AZD5069 on any day where blood samples before the morning dose are required must be administered at the study centre and the 
precise time noted. 
d
In the first 10 patients randomised to treatment with AZD5069 combination therapy (i.e., treatment arm B2 or B4), PK blood samples for AZD5069 and its 
metabolite AZ13587715 (2 mL total) will be collected as follows; a window of 10% of the nominal time point is acceptable:
Lead-in, Day −7: Before the morning dose and at 0.5 hour (±3 min), 1 hour (±6 min), 2 hours (±12 min), 4 hours (±24 min), 6 hours (±36 min), and 
8 hours (±48 min), and 10 hours (±60 min) (when possible) after the first morning dose
Cycle 1, Day 1: Before the morning dose and at 2 hours (±12 min) after the morning dose
Cycle 2, Day 1: Before the morning dose and at 0.5 hour (±3 min), 1 hours (±6 min), 2 hours (±12 min), 4 hours (±24 min), 6 hours (±36 min), and 
8 hours (±48 min), and 10 hours (±60 min) (when possible) after the morning dose 
Cycle 3 and all subsequent odd-numbered cycles, Day 1: Before the morning dose and 2 hours (±12 min) after the morning dose
Failure to obtain the 10-hour samples will not be considered a protocol deviation.
In patients following the first 10 patients randomised to treatment with AZD5069 in combination with MEDI4736 (i.e., treatment arm B2 or B4), a 
predose and a 2 hour (±12 min) sample will be collected on Day 1 of Cycle 2 and subsequent odd-numbered cycles. The morning dose of AZD5069 on 
Day −7 of the lead-in period and on any subsequent day where blood samples before the morning dose are required must be administered at the study 
centre and the precise time noted. Failure to obtain 10 and 12 hour samples will not be considered as protocol deviation.
e
In patients randomized to receive MEDI4736 (i.e., treatment arm B1, B2, B3, B4, or B7), PK blood samples for MEDI4736 (3.5 mL) will be collected 
relative to the MEDI4736 infusion as follows; a window of 10% of the nominal time point is acceptable:
Cycle 1, Day 1: Predose and 1 hour (±6 min) after the start of the infusion (end of infusion)
Cycle 2, Day 15: Predose
Cycle 4 and all subsequent even-numbered cycles, Day 1: Predose
Cycle 8, Day 1: In addition to the predose sample, a sample at 1 hour (±6 min) after the start of the infusion (end of infusion)
Follow-up: For patients who discontinue MEDI4736, a sample will be drawn 90 days after their last dose of MEDI4736 (coinciding with an IM (ADA) 
sample

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f
In patients randomized to AZD9150 alone (treatment arm B5) and first 12 patients for the Arm B7, who optionally consented to urine PK sampling, urine 
PK samples (20 to 40 mL) will be collected from the total urine samples provided during each of the following collection intervals; a window of 10% of the 
nominal time point is acceptable:
Lead-in, Day −7: 0 to 1, 1 to 6, and 6 to 24 hours after start time of AZD9150 infusion
Lead-in, Day −6 to −5: 24 to 48 hours after the start time of the first AZD9150 infusion
Cycle 1, Day 1: 0 to 1, 1 to 6, and 6 to 24 hours after start time of AZD9150 infusion
g
Note: Instructions will be provided to patients to collect these samples, as applicable, at home.For all patients, 2 blood samples (2.5 mL each) for PDRNA 
will be collected predose at each specified time point to assess pharmacodynamic response in blood for AZD9150 (STAT3 knockdown) and exploratory 
blood-borne biomarkers that may correlate to treatment or response (gene expression changes or modification of genomic DNA): At screening, Day −7 of 
the lead-in period, Day 1 and Day 8 of Cycle 1, Day 1of subsequent Cycles and at the EOT visit. The revised sample collection for PDRNA samples is 
applicable to newly enrolled patients only under protocol amendment 5, dated 10 May 2017 and onwards; existing patients will have samples collected up 
to Cycle 5, Day 1. New patients will be required to have samples collected beyond Cycle 5.
h
In patients randomized to receive MEDI4736 (i.e., treatment arms B1, B2, B3 and B4), a single blood sample (3.5 mL) will be collected predose at each 
specified time point to assess the pharmacodynamic response in blood for MEDI4736 (sPD-L1): Day 1 of Cycle 1, Day 15 of Cycle 2, Day 1 of all 
subsequent even-numbered cycles.
On Day 1 of Cycle 1 and on Day 1 of Cycle 8, in addition to the predose sample, a sample will also be obtained at the end of the MEDI4736 infusion.
For patients who discontinue MEDI4736, a sample will be drawn 90 days after their last dose of MEDI4736 coinciding with an IM (ADA) sample. sPDL 
samples will NOT be collected for the following patients: patients in B1, B2 and B4 post first 20 patients and patients in Arm B7
i
For all patients, blood samples for MDSC (5 mL), will be collected predose at the specified time points to assess the treatment effect on circulating MDSCs: 
At screening, Day −7 of the lead-in period, Day 1 of Cycles 1, 2, 3, 5, and at the EOT visit. MDSC samples will NOT be collected for the following 
patients: patients in B1, B2 and B4 post first 20 patients and patients in Arm B7.
j
In patients randomised to receive MEDI4736 (i.e., treatment arms B1, B2, B3, B4, and B7), blood samples for IM (5 mL) will be collected predose on 
Day 1 of Cycle 1, on Day 15 of Cycle 2, and on Day 1 of each subsequent even-numbered cycle. For patients who discontinue MEDI4736, a blood sample 
will also be collected during follow-up at 90 days after the last dose of MEDI4736.
k
For patients treated with AZD9150, blood samples for IM (2 mL) will be collected relative to AZD9150 infusion as follows: Cycle 1, Day 1: Predose; Cycle 
2, Day 1: Predose; and Cycle 4 and all subsequent even-numbered cycles, Day 1: Predose.
l
For all patients, at the time points specified, a single 2 mL blood sample for serum, a single 10 mL blood sample for plasma, and two 6 mL blood samples 
for PBMC will be collected predose for the assessment of exploratory biomarkers.
The 2 mL blood sample for serum will be obtained at screening, on Days −7 and −3 of the lead-in period, Days 1, 8, and 15 of Cycle 1, on Day 1 of 
Cycle 2, on Day 1 of all subsequent odd-numbered cycles, and at the EOT visit.
The 10 mL blood sample for plasma will be obtained at screening, on Day −7 of the lead-in period, Days 1, 8, and 15 of Cycle 1, on Day 1 of Cycle 2, 
on Day 1 of all subsequent odd-numbered cycles, and at the EOT visit.
The two 6 mL blood samples for PBMC will be obtained at screening, on Day −7 of the lead-in period, on Days 1, 8, and 15 of Cycle 1, on Day 1 of 
cycles 3, 6, and 9, and at the EOT visit.

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m
To be eligible, patients must have at least 1 SCCHN lesion amenable to biopsy and must be medically fit and willing to undergo a mandatory biopsy during 
screening and, unless clinically contraindicated, again at the end of Cycle 1 (designated as Cycle 2 Day 1 in the table above). Lesions used for biopsy should 
not be those used as RECIST lesions, unless there are no other lesions suitable for biopsy (in which case, the lesion must be ≥2 cm in longest diameter). In 
the event of disease progression, biopsies at the EOT are optional but encouraged. On-treatment biopsy timing may be refined with emerging PK and/or 
pharmacodynamic data during the course of the trial, and the collection of on-treatment tumor samples may be stopped at the Sponsor’s discretion. 
Screening biopsy sample: if patient has a biopsy report and sample from fewer than 45 days prior to start of treatment (Day -7), it would be considered 
acceptable. On-treatment biopsy: there is a ± 1 week window for collection of this biopsy sample. 
n
If a patient agrees to participate in the host pharmacogenetics research component of the study and signs a separate ICF for genetic research, a saliva sample 
will be collected. The saliva sample for genetic research will ideally be obtained from the patients immediately prior to dosing on Day 1. If for any reason, 
the sample is not obtained prior to dosing, it may be taken at any visit until the last study visit. Only 1 sample should be collected per patient for genetics 
during the study. See Section 5.8.2 for details.
o
The collection of cfDNA samples is only required to be obtained for newly enrolled patients consented under protocol amendment 5, dated 10 May 2017 
and onwards. It is not a requirement to collect cfDNA samples for patients enrolled prior the implementation of protocol amendment 5, dated 10 May 2017.
Abbreviations: ADA=antidrug antibody; cfDNA=circulating-free DNA; EOT=End-of-Treatment; FU=follow-up; IM=immunogenicity; MDSC=myeloid-derived 
suppressor cells; PBMC=peripheral blood mononuclear cell(s); PK=pharmacokinetic; PDRNA=pharmacodynamic RNA (samples for STAT3 RNA and other 
exploratory analyses); pts=patients; RECIST=Response and Evaluation Criteria for the Evaluation of Solid Tumors; SCCHN=squamous cell carcinoma of the 
head and neck; sPD-L1=soluble programmed death-ligand 1.

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Table 8
Study plan for pharmacokinetic, pharmacodynamic, immunogenicity, and pharmacogenetic assessments in 
Part B (B8)
Assessments         
Day:
Screening Lead-in
(-7 to -1)
Cycles
EOT
a
FU
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 C11 *C12
-21 to -8
-7
-5
-3
1
8
15
1
15
1
1
1
1
1
1
1
1
1
1
Blood samples for pharmacokinetic assessments
AZD9150b
x
x
x
x
x
x
x
x
MEDI4736c
x
x
x
x
x
x
x
xd
Urine samples for pharmacokinetic assessments (mandatory for up to 12 patients and then optional consent thereafter – USA only)
AZD9150e
x
x
x
Blood samples for pharmacodynamic assessments
PDRNA
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Blood samples for immunogenicity assessments
ADAf
x
x
x
x
x
x
x
x
Anti-AZD9150 Abg
x
x
x
x
x
x
x
x
x
Blood samples for exploratory blood-borne biomarkersh
Serum sampleh
x
x
x
x
x
x
x
x
x
x
x
x
Plasma sampleh
x
x
x
x
x
x
x
x
x
x
x
PBMCh
x
x
x
x
x
x
x
x
cfDNA blood 
sample
x
x
x
x
x
x
x
x
x
x
Other
Collection of 
archival tumor 
samples
x

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Assessments         
Day:
Screening Lead-in
(-7 to -1)
Cycles
EOT
a
FU
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 C11 *C12
-21 to -8
-7
-5
-3
1
8
15
1
15
1
1
1
1
1
1
1
1
1
1
Tumor biopsyi
x
x
x
Optional
Pharmacogeneticsj
x
a
*In order to ensure all samples required for sample point collection are accurately collected, the cycles beyond Cycle 12 should mimic Cycle 9, 10, 11 and 
12 in a repeated pattern through to Cycle 40, except where noted in the footnotes below (eg, PBMC collection). An EOT visit shall occur as soon as 
possible following the decision to discontinue treatment.
b
AZD9150 PK samples are required at predose, 1 hour (end of infusion) and 2 hours (±12 min) on lead-in Day −7, Day 1 of Cycle 1, Cycle 2, Cycle 3, Cycle 
5, Cycle 7, Cycle 9, and Cycle 11 in the first year and then every 6 cycles.
c
PK blood samples for MEDI4736 (3.5 mL) will be collected relative to the MEDI4736 infusion as follows; a window of 10% of the nominal time point is 
acceptable:
Cycle 1, Day 1: Predose and 1 hour (±6 min) after the start of the infusion (end of infusion)
Cycle 2, Day 15: Predose
Cycle 4 and all subsequent even-numbered cycles, Day 1: Predose
Cycle 8, Day 1: In addition to the predose sample, a sample at 1 hour (±6 min) after the start of the infusion (end of infusion)
d
Follow-up: For patients who discontinue MEDI4736, a sample will be drawn 90 days after their last dose of MEDI4736 (coinciding with an IM (ADA) 
sample or prior to the initiation of a subsequent anticancer therapy.
e
USA only: For up to 12 patients enrolled into this cohort, it will be mandatory to obtain urine PK sampling; for subsequent patients in B8, these samples 
will be optional. Urine PK samples (20 to 40 mL) will be collected from the total urine samples provided during each of the following collection intervals; a 
window of 10% of the nominal time point is acceptable:
Lead-in, Day −7: 0 to 1, 1 to 6, and 6 to 24 hours after start time of AZD9150 infusion
Lead-in, Day −6 to −5: 24 to 48 hours after the start time of the first AZD9150 infusionCycle 1, Day 1: 0 to 1 and 1 to 6 hours after start time of 
AZD9150 infusion.
Note: Instructions will be provided to patients to collect these samples, as applicable, at home.
f
MEDI4736 blood samples for IM (5 mL) will be collected predose on Day 1 of Cycle 1, on Day 15 of Cycle 2, and on Day 1 of each subsequent even-
numbered cycle. For patients who discontinue MEDI4736, a blood sample will also be collected during follow-up at 90 days after the last dose of 
MEDI4736.

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g
AZD9150 blood samples for IM (2 mL) will be collected relative to AZD9150 infusion as follows: Day -7, Day 1 of Cycle 1, on Day 1 of Cycle 2, and on 
Day 1 of each subsequent even-numbered cycle. For patients who discontinue AZD9150, a blood sample will also be collected during follow-up at 90 days 
after the last dose of AZD9150.
h
For all patients, at the time points specified, a single 2 mL blood sample for serum, a single 10 mL blood sample for plasma, and two 6 mL blood samples 
for PBMC will be collected predose for the assessment of exploratory biomarkers.
The 2 mL blood sample for serum will be obtained at screening, on Days −7 and −3 of the lead-in period, Days 1 and 15 of Cycle 1, on Day 1 of Cycle 
2, on Day 1 of all subsequent odd-numbered cycles, and at the EOT visit.
The 10 mL blood sample for plasma will be obtained at screening, on Day −7 of the lead-in period, Days 1 and 15 of Cycle 1, on Day 1 of Cycle 2, on 
Day 1 of all subsequent odd-numbered cycles, and at the EOT visit.
The two 6 mL blood samples for PBMC will be obtained at screening, on Day −7 of the lead-in period, Days 1 and 15 of Cycle 1, on Day 1 of Cycles 
3, 6, and 9, and at the EOT visit.
i
To be eligible, patients must have at least 1 SCCHN lesion amenable to biopsy and must be medically fit and willing to undergo a mandatory biopsy during 
screening and, unless clinically contraindicated, again at the end of Cycle 1 (designated as Cycle 2 Day 1 in the table above). Lesions used for biopsy should 
not be those used as RECIST lesions, unless there are no other lesions suitable for biopsy (in which case, the lesion must be ≥2 cm in longest diameter). In 
the event of disease progression, biopsies at the EOT are optional but encouraged. On-treatment biopsy timing may be refined with emerging PK and/or 
pharmacodynamic data during the course of the trial, and the collection of on-treatment tumor samples may be stopped at the Sponsor’s discretion. 
Screening biopsy sample: if patient has a biopsy report and sample from fewer than 45 days prior to start of treatment (Day -7), it would be considered 
acceptable. On-treatment biopsy: there is a ± 1 week window for collection of this biopsy sample. 
j
If a patient agrees to participate in the host pharmacogenetics research component of the study and signs a separate ICF for genetic research, a saliva sample 
will be collected. The saliva sample for genetic research will ideally be obtained from the patients immediately prior to dosing on Day 1. If for any reason, 
the sample is not obtained prior to dosing, it may be taken at any visit until the last study visit. Only 1 sample should be collected per patient for genetics 
during the study. See Section 5.8.2 for details.
Abbreviations: ADA=antidrug antibody; cfDNA=circulating-free DNA; EOT=End-of-Treatment; FU=follow-up; IM=immunogenicity; MDSC=myeloid-derived 
suppressor cells; PBMC=peripheral blood mononuclear cell(s); PK=pharmacokinetic; PDRNA=pharmacodynamic RNA (samples for STAT3 RNA and other 
exploratory analyses); pts=patients; RECIST=Response and Evaluation Criteria for the Evaluation of Solid Tumors; SCCHN=squamous cell carcinoma of the 
head and neck; sPD-L1=soluble programmed death-ligand 1.

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5.3
Efficacy assessments
5.3.1
Tumor assessments
Tumor assessments will be performed at screening, on Day 15 of Cycle 2, at the beginning of 
Week 7, at the beginning of each subsequent even-numbered cycle, and at the EOT visit. 
Patients who are on study treatment for more than 24 months may have the frequency of 
tumor assessment reduced to every 12 to 16 weeks at the discretion of the Investigator. 
Patients who discontinue treatment for reasons other than PD will continue to undergo tumor 
assessments every 2 months (±7 days) until PD is noted.
It is important to follow the assessment schedule as closely as possible. To facilitate 
scheduling of tumor assessments, a window of ±7 days is allowed.
Baseline tumor assessments should encompass all areas of known predilection for metastases 
in the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual patients. Baseline assessments should be 
performed no more than 21 days before the start of study treatment and ideally should be 
performed as close as possible to the start of study treatment. Tumor assessments obtained as 
standard of care before consent may be used for the study provided the assessments fall within 
the protocol-specified period before the first dose of study treatment.
Tumor assessments may include the following evaluations: Physical examination (with 
photograph and measurement of skin lesions as applicable); CT or MRI scan of the chest, 
abdomen, and pelvis; and CT or MRI scan of the brain. CT or MRI scan of the brain will be 
performed only at screening or if the patient is neurologically symptomatic. The preferred 
method of disease assessment is CT with contrast. If CT with contrast is contraindicated, CT 
without contrast is preferred over MRI. The methods of assessment used at baseline should be 
used at each subsequent follow-up assessment. Any other sites at which new disease is 
suspected should also be appropriately imaged. If an unscheduled assessment is performed 
and the patient has not progressed, every attempt should be made to perform subsequent 
assessments at the scheduled visits while the patient remains on study treatment.
Sites will be required to store electronic copies of all scans, and the study Sponsor may 
arrange for possible centralized storage of all imaging data. The centralized storage of 
imaging data would be for possible independent centralized review of disease assessments.
5.3.1.1
Response assessment
All patients will be evaluated according to the study plan (see Section 5.2, Table 5) and their 
clinical status classified according to the revised RECIST guidelines version 1.1 (Eisenhauer 
et al 2009) with modifications to account for the unique response kinetics that have been 

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observed in some patients where responses to immunotherapy may occur after PD is assessed 
(Wolchok et al 2009). Specifically, RECIST version 1.1 has been modified so that PD in the 
absence of clinical deterioration must be confirmed at least 4 weeks after the initial 
assessment of PD. The modified RECIST guidelines version 1.1 for measurable, 
non-measurable, TLs, and nontarget lesions (NTLs) and the objective tumor response criteria 
are presented in Appendix F “Guidelines for Evaluation of Objective Tumor Response Using 
RECIST 1.1 (Response Evaluation Criteria in Solid Tumors)” of this CSP.
If the Investigator is in doubt as to whether progression has occurred, particularly with 
response to NTLs or the appearance of a new lesion, it is advisable to continue treatment and 
reassess the patient’s status at the next scheduled assessment or sooner if clinically indicated.
To achieve ”unequivocal progression” on the basis of nontarget disease, there must be an 
overall level of substantial worsening in nontarget disease such that, even in the presence of 
stable disease (SD) or PR in target disease, the overall tumor burden has increased sufficiently 
to merit discontinuation of therapy. A modest increase in the size of 1 or more NTLs is 
usually not sufficient to qualify for unequivocal disease progression status. 
5.4
Safety assessments
At each clinic visit, the Investigator will be responsible for reviewing all available safety data, 
including vital sign measurements and ECG recordings, and assessing the patient for signs of 
tumor progression. To facilitate scheduling of predose assessments, a window of -2 days is 
allowed to obtain the following procedures prior to dosing a patient: Complete and targeted 
physical exam, weight, laboratory safety tests (haematology, serum chemistry, and
coagulation), urinalysis, and thyroid function tests.
5.4.1
Laboratory safety assessments
All blood samples will be analyzed at the central laboratory for the study on behalf of 
AstraZeneca. On days of study drug administration, to shorten the time between the blood 
draw and the decision if dosing may proceed, blood samples for routine haematology and 
serum chemistry safety assessments are to be drawn and split into 2 samples: one portion of 
the sample is to be analysed locally to determine toxicity prior to dosing, and the second 
portion of the sample is to be sent to the designated central laboratory. 
Samples are not to be split on days where no study drug administration is scheduled. See 
Study Plan (Section 5.2, Table 5) for details. 
Blood samples for routine haematology and serum chemistry safety assessments will be 
obtained at screening; before dosing on Day −7 of the lead-in; before dosing on Days 1, 8, 15, 
and 22 of Cycle 1; before dosing on Days 1 and 15 of all subsequent cycles; and at the EOT 
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Blood samples for routine coagulation assessments will be obtained at screening; before 
dosing on Day −7 of the lead-in; before dosing on Days 1 and 15 of Cycle 1; before dosing on 
Day 1 of all subsequent cycles; and at the EOT visit.
Urine samples for routine urinalysis will be obtained at screening; before dosing on Day −7 of 
the lead-in; before dosing on Days 1 and 15 of Cycle 1; before dosing on Day 1 of all 
subsequent cycles; and at the EOT visit.
The study plan shown in Table 9 lists the variables that will be measured for routine 
haematology, serum chemistry, coagulation, and urinalysis.
In addition, thyroid function tests are required at screening, before dosing on Day −7 of the 
lead-in, before dosing on Day 1 of each cycle, and at the EOT visit. Thyroid function tests 
include thyroid-stimulating hormone and free T3 and T4.
Blood samples for HIV, HBV, and HCV serology are required at screening. The eligibility of 
patients who have active infection for HIV, HBV, and/or HCV is at the discretion of the 
Investigator. HIV screening will be based on an FDA-approved antigen/antibody combination 
immunoassay; HBV screening will include HBsAg, anti-HBc, and anti-HBs, and HCV 
screening will be based on anti-HCV. HPV status will be collected at screening visit.
For women of childbearing potential (see Section 3.8.1), negative pregnancy tests are required 
before entering the study and while on study. A blood sample to determine serum β-human 
chorionic gonadotropin (β hCG) is required at screening; this sample will be analysed at the 
central laboratory for the study. Additionally, urine samples for a urine-based pregnancy test 
will be collected before dosing on Day −7 of the lead-in, before dosing on Day 1 of each cycle, 
and at the EOT visit. Urine-based pregnancy tests will be performed at the study centres.
On Day −7 of the lead-in, laboratory safety assessments do not need to be repeated if the 
screening assessments were performed no more than 3 days before. The date of each 
collection will be recorded in the appropriate eCRF.
The timing of blood samples may be altered depending on the emerging PK and safety profile. 
Additional sampling times may be added if indicated by the emerging data.
Laboratory values that meet the criteria for CTCAE grade 3 or have changed significantly 
from baseline and are considered to be of clinical concern should be repeated/confirmed 
within 7 days and followed up as appropriate.
Importantly, in case a patient’s AST, ALT, or TBL test results show an AST or ALT 
≥3 × ULN or TBL ≥2 × ULN, please refer to Appendix G of this CSP “Actions Required in 
Cases of Increases of Liver Biochemistry and Evaluation of Hy’s Law” for further instructions.

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For blood volume, see Section 5.8.3.
The following laboratory variables will be measured:
Table 9
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haematocrit (HCT)
S/P-Albumin
B-Haemoglobin (Hb)
S/P-Alkaline phosphatase
B-Platelet count
S/P-ALT
B-Red blood cell count
S/P-AST
B-White blood cells
S/P-Bilirubin, total
B-WBC differential (%)
S/P-Bilirubin, direct
B-Absolute neutrophil count
S/P-Bilirubin, indirect
B-Absolute lymphocyte count
S/P-GGT
B-Mean corpuscular volume
S/P-Calcium, total
B-Mean corpuscular haemoglobin concentration
S/P-Creatinine
S/P-Glucose
S/P-LDH
Urinalysis (dipstick)
S/P-Magnesium
U-Specific gravity
S/P-Phosphate
U-pH
S/P-Potassium
U-Bilirubin
S/P-Sodium
U-Blood
S/P-Total protein
U-Glucose
S/P-Urea nitrogen
U-Ketones
S/P-Chloride
U-Protein
S/P-Bicarbonate
U-Color
S/P-Uric acid
U-WBC/HPF and RBC/HPF (macroscopic)
S/P-Creatine phosphokinase
U-Appearance
S/P-Cholesterol
S/P-Triglycerides
Coagulation
S/P-C-reactive protein
PT (sec)
aPTT (sec)
INR
Fibrinogen
Haptoglobin
Abbreviations: ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate 
aminotransferase; B=blood; GGT=gamma-glutamyl transpeptidase; INR=international normalised ratio; 
HPF=high power field; LDH=lactate dehydrogenase; P=plasma; PT=prothrombin time; RBC=red blood cell 
count; RBC/HPF=red blood cells per high power field; S=serum; WBC/HPF=white blood cells per high power 
field.
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables. For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.3.
5.4.2
Physical examination
A complete physical examination will be performed at screening, before dosing on Day −7 of 
the lead-in, before dosing on Day 1 of each cycle, and at the EOT visit. A targeted physical 

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examination as directed by disease, signs and symptoms is required before dosing on Day 15 
of each cycle.
5.4.3
ECG
Electrocardiograms will be obtained at screening, throughout the treatment, and at the EOT 
visit. On days when ECGs and PK samples are drawn, ECG must always be taken prior to the 
PK blood draw.
!
For patients treated with AZD5069: On Day 1 of Cycle 1, 12-lead ECGs should be 
recorded 2 hours after the morning dose of AZD5069 and for patients treated with 
MEDI4736, again 2 hours after end of the MEDI4736 infusion. On Day 1 of Cycle 2 and 
of all subsequent odd-numbered cycles (to match PK assessments), 12 lead ECGs should 
be recorded 2 hours after the morning dose of AZD5069. The timing and number of 
ECGs may be adjusted by the SRC in response to the emerging PK and safety profile.
!
For patients not treated with AZD5069, 12-lead ECGs will be obtained at screening, on 
Day 1 of Cycle 1 (2 hours after the end of the AZD9150 infusion, and for patients treated 
with MEDI4736, again 2 hours after end of the MEDI4736 infusion), and at the EOT visit.
!
For B8, 12-lead ECGs will be obtained at screening, Day −7, Day 1 of Cycles 1, 2, and 3,
and subsequent odd-numbered cycles for first year: pre-dose and 1 hour after the start of 
AZD9150 infusion (end of AZD9150 infusion) and 2 hours after the start of infusion, 
every 6 cycles after 1 year, and at the EOT visit.
5.4.3.1
Resting 12-lead ECG
Twelve-lead ECGs will be obtained after the patient has been resting semi-supine for at least 
10 minutes. All ECGs should be recorded with the patient in the same physical position. A 
standardised ECG machine should be used and the patient should be examined using the same 
machine throughout the study, where feasible. For Arm B8, central digital ECGs will be used.
For each time point, 3 ECG recordings should be taken within a 5 minute interval, but a 
window of up to -30 minutes is acceptable (as all the ECGs are triplicate). The mean QTcF 
interval from all 3 ECGs at any given time point should be considered for evaluation of 
eligibility and toxicity.
After paper ECGs have been recorded, the Investigator or designated physician will review 
each of the ECGs and may refer to a local cardiologist if appropriate. A paper copy should be 
filed in the patient’s medical records. If an abnormal ECG finding at screening or baseline is 
considered to be clinically significant by the Investigator, it should be reported as a concurrent 
condition. For all ECGs, details of rhythm, PR, R-R, QRS, and QTc intervals and an overall 
evaluation will be recorded.

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5.4.4
Vital signs
Vital signs including resting pulse, supine blood pressure (BP), respiratory rate, and body 
temperature measured in degrees Celsius, should be assessed at screening; before dosing on 
Day −7 of the lead-in; before dosing on Days 1, 8, 15, and 22 of each cycle; and at the EOT 
visit. Measurements should be taken in a supine position following at least 10 minutes of rest.
Vital signs for patients on AZD5069 will not be required for Day 8 and Day 22 visits beyond 
Cycle 2 as there are no dosing visits scheduled for patients on these days. Vital signs for 
patients in Arm B8 will not be required for Day 8 and Day 22 (all cycles) as there are no 
dosing visits scheduled for these patients on these days.
Height (in centimetres) will be obtained at screening.
Weight (in kilograms) will be obtained at screening, before dosing on Day −7 of the lead-in, 
before dosing on Day 1 of each cycle, and at the EOT visit. Weight obtained on Day −7 of the 
lead-in will be used to calculate the weight-related doses of AZD9150 (with the exception of 
Arm B8) for the lead-in. Weight obtained on Day 1 of each cycle will be used to calculate the 
weight-related dose of AZD9150 for each cycle.. In Arm B8, a flat dose for AZD9150 and 
MEDI4736 will be administered. MEDI4736 will be administered as 1.5g flat dose Q4W. If 
body weight decreases to less than 30 kg, weight-based dosing (20 mg/kg Q4W) will be 
implemented from that cycle onwards.
The Investigator should assess any abnormal changes (i.e., changes that are out of range) in 
vital sign measurements for their clinical significance and determine if they require to be 
recorded as an AE.
5.4.5
Eastern Cooperative Oncology Group performance status (Other safety 
assessments)
Eastern Cooperative Oncology Group PS will be assessed at screening, before dosing on 
Day -7 of the lead-in, before dosing on Day 1 of each cycle, and at the EOT visit. The ECOG 
PS will be used to assess how a patient’s disease is progressing, assess how the disease affects 
the patient’s daily activities, and help the Investigator determine the appropriate treatment and 
progress. The ECOG scales and criteria are defined as follows:
0 = 
Fully active, able to carry out all predisease activities without restrictions
1 = 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light housework, office work)
2 = 
Ambulatory and capable of self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours

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3 = 
Capable of only limited self-care confined to bed or chair more than 50% of 
waking hours
4 = 
Completely disabled; cannot carry on self-care; totally confined to bed or 
chair
5 = 
Death
5.5
Pharmacokinetics
5.5.1
Collection of samples
Venous blood samples for analysis of AZD9150, AZD5069 and its metabolite AZ13587715, 
tremelimumab, and MEDI4736 will be obtained to determine the plasma concentrations of 
each of the various agents under investigation (see Table 6 for the dose-escalation Part A and 
Table 7 for the dose-expansion Part B of the study). The date and time of collection of each 
sample will be recorded. A window of 10% of the nominal time point is acceptable (e.g., ±3 
minutes for a 30-minute timepoint, ±6 minutes for a 60-minute time point, etc.).
!
For patients treated with AZD9150 in Part A, PK blood samples for AZD9150 (Arms A1, 
A4 and A6) (2 mL) will be collected relative to the AZD9150 infusion as follows:
-
Lead-in, Day −7: Predose and at 0.5 hour (±3 min), 1 (end of infusion; ±6 
min), 2 hours (±12 min), 4 hours (±24 min), and 6 hours (±36 min) after the 
start of the infusion
-
Lead-in, Day −5: At 48 (±4) hours after the start of the first infusion (on 
Day −7) and before the second infusion (on Day −5)
-
Cycle 1, Day 1: Predose
-
Cycle 2, Day 1: Predose and at 0.5 hour (±3 min), 1 (end of infusion; ±6 
min), 2 hours (±12 min), 4 hours (±24 min), and 6 hours (±36 min) after the 
start of the infusion
-
Cycle 3 and all subsequent odd-numbered cycles, Day 1: Predose
-
In Part B, only the first 10 patients randomised to treatment with AZD9150 
alone or in combination with MEDI4736 (i.e., treatment arm B1, B3 or B5), 
will follow the schedule as in Part A. In patients following the first 10 
patients randomised to treatment with AZD9150 alone or in combination 
with MEDI4736 (i.e., treatment arm B1 or B3) and in Arms B7 and B8, a 
predose and a 2 hour (±12 min) sample will be collected on Day 1 of Cycle 
2 and subsequent odd-numbered cycles.

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!
For patients treated with AZD5069 (Arms A2 and A3) in Part A (PRIOR TO 
DETERMINATION OF RP2D), PK blood samples for AZD5069 and its metabolite 
AZ13587715 (2 mL total) will be collected as follows:
-
Lead-in, Day −7: Before the first morning dose and at 0.5 hour (±3 min), 
1 hour (±6 min), 2 hours (±12 min), 4 hours (±24 min), 6 hours (±36 min), 
8 hours (±48 min), and 10 hours (±60 min) (when possible, if optional 
consent is provided) after the first morning dose
-
Cycle 1, Day 1: Before the morning dose and at 2 hours (±12 min) after the 
morning dose
-
Cycle 2, Day 1: Before the morning dose and at 0.5 hour (±3 min), 1 hour 
(±6 min), 2 hours (±12 min), 4 hours (±24 min), 6 hours (±36 min), 8 hours 
(±48 min), and 10 hours (±60 min) (when possible, if optional consent is 
provided) after the morning dose 
-
Cycle 3 and all subsequent odd-numbered cycles, Day 1: Before the 
morning dose and at 2 hours (±12 min) after the morning dose
-
Failure to obtain the 10 hour (±60 min) samples will not be considered a 
protocol deviation
The morning dose of AZD5069 on Day −7 of the lead-in period and on any 
subsequent day where blood samples before the morning dose are required 
must be administered at the study centre and the precise time noted.
!
In Part B, only the first 10 patients randomised to treatment AZD5069 in combination 
with MEDI4736 (i.e., treatment arm B2 or B4), will follow the schedule as in Part A. In 
patients following the first 10 patients randomised to treatment with AZD5069 in 
combination with MEDI4736 (i.e., treatment arm B2 or B4), a predose and a 2 hour 
(±12 min) sample will be collected on Day 1 of Cycle 2, and subsequent odd-numbered 
cycles.
-
Failure to obtain the 10-hour samples will not be considered a protocol 
deviation
-
The morning dose of AZD5069 on any day where blood samples before the 
morning dose are required must be administered at the study centre and the 
precise time noted.
!
For patients treated with AZD5069 monotherapy in Part B (i.e., treatment arm B6) PK 
blood samples for AZD5069 and its metabolite AZ13587715 (2 mL total) will be 
collected as follows:
-
Cycle 2, Day 1: Before the morning dose 

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-
Cycle 3 and all subsequent odd-numbered cycles, Day 1: Before the 
morning dose
-
The morning dose of AZD5069 on any day where blood samples before the 
morning dose are required must be administered at the study centre and the 
precise time noted.
!
For all patients in Part A and for patients randomised to receive MEDI4736 in Part B 
(i.e., treatment arm B1, B2, B3, B4, or B7), PK blood samples for MEDI4736 (3.5 mL) 
will be collected relative to the MEDI4736 infusion as follows:
-
Cycle 1, Day 1: Predose and 1 hour (±6 min) after the start of the infusion 
(end of infusion)
-
Cycle 2, Day 15: Any time
-
Cycle 4 and all subsequent even-numbered cycles, Day 1: Predose
-
Cycle 8, Day 1: In addition to the predose sample, a sample at 1 hour (±6 
min) after the start of the infusion (end of infusion)
-
Follow-up: For patients who discontinue MEDI4736, a sample will be 
drawn 90 days after their last dose of MEDI4736 (coinciding with an IM 
[antidrug antibody (ADA)] sample)
!
For all patients in treatment arm A4 in Part A, PK blood samples for tremelimumab (3.5 
mL) will be collected relative to the tremelimumab infusion as follows:
-
Cycle 1, Day 1: Predose and 1 hour (±6 min) after the start of the infusion 
(end of infusion)
-
Cycle 2, Day 15: Any time
-
Cycle 4, Day 1: Predose
Of the patients randomly assigned to treatment with AZD9150 alone in the dose-expansion 
Part B (treatment arm B5) and the first 12 patients for arm B7 will be asked to provide urine 
samples for AZD9150 PK assessments in urine (see Table 7). For Arm B8, up to 12 patients 
enrolled will be required to provide consent for urine samples for PK assessments (mandatory, 
USA only). For the subsequent patients enrolled in this arm, consent will be optional (see 
Table 8). Patients’ consent to this evaluation will be documented on a separate ICF for urine
sample collection. The date and time of collection and the weight of each urine collection will 
be recorded.

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!
For patients randomised to AZD9150 alone (treatment arm B5) and first 12 patients for 
the Arm B7 who optionally consented to urine PK sampling and up to 12 patients of Arm 
B8 (mandatory, USA only)(or if optional consent was provided), urine PK samples (20 to 
40 mL) will be collected from the total urine samples provided during each of the 
following collection intervals:
-
Lead-in, Day −7: 0 to 1, 1 to 6, and 6 to 24 hours after start time of 
AZD9150 infusion
-
Lead-in, Day −6 to −5: 24 to 48 hours after the start time of the first 
AZD9150 infusion
-
Cycle 1, Day 1: 0 to 1, 1 to 6, and 6 to 24 hours after start time of 
AZD9150 infusion. Note: The Cycle 1, Day 1, 6 to 24 hour time point is 
not required for treatment arm B8.
Note: Instructions will be provided to patients to collect these samples, as applicable, 
at home.
!
For patients enrolled in treatment arm B8 to receive AZD9150 400 mg Q2W (200 mg in 
lead-in period) in combination with MEDI4736 1.5 g, PK blood samples for AZD9150 
will be collected relative to the AZD9150 infusion as follows:
-
Predose, 1 hour and 2 hours (±12 min) on: Lead-in Day −7, and Day 1 of 
Cycle 1, Cycle 2, Cycle 3, Cycle 5, Cycle 7, Cycle 9, and Cycle 11 and 
then every 6 cycles
!
For patients enrolled in treatment arm B8 to receive AZD9150 400 mg Q2W (200 mg in 
lead-in period) in combination with MEDI4736 1.5 g, PK blood samples for MEDI4736 
(3.5 mL) will be collected relative to the MEDI4736 infusion as follows:
-
Cycle 1, Day 1: Predose and 1 hour (±6 min) after the start of the infusion 
(end of infusion)
-
Cycle 2, Day 15: Predose
-
Cycle 4 and all subsequent even-numbered cycles, Day 1: Predose
-
Cycle 8, Day 1: In addition to the predose sample, a sample at 1 hour (±6 
min) after the start of the infusion (end of infusion)
-
Follow-up: For patients who discontinue MEDI4736, a sample will be 
drawn 90 days after their last dose of MEDI4736 (coinciding with an IM 
[ADA] sample or prior to the initiation of a subsequent anticancer therapy).
The timing of the PK samples may be adjusted during the study, dependent on emerging data, 
in order to ensure appropriate characterisation of the plasma concentration-time profiles. The 

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total number of samples and the total volume of blood taken from each patient will not exceed 
those presented in Table 10, Section 5.8.3.
If a patient misses any doses of AZD9150 or AZD5069 within 3 days of PK sampling, please 
contact the AstraZeneca PK representative via the Medical Monitor 
 (see 
Section 6.10 for contact information) to inquire if changes in the timing of the PK assessments 
are required. (Note: All other assessments, including laboratory safety assessments, vital 
signs, and RECIST should continue to be performed as per study plan, relative to baseline 
assessments.)
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
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. 
5.5.2
Determination of drug concentration
Samples for determination of AZD9150, AZD5069 and its metabolite AZ13587715, 
tremelimumab, and MEDI4736 will be analysed, using appropriate bioanalytical methods. 
Full details of the analytical method used will be described in a separate bioanalytical report.
All samples still within the known stability of the analytes of interest at the time of receipt by 
the bioanalytical laboratory will be analysed by a central laboratory on behalf of AstraZeneca.
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalisation or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
requested for future analyses.
5.5.3
Storage and destruction of pharmacokinetic samples
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or six 
months after issuance of the draft Bioanalytical Report (whichever is earlier), unless requested 
for future analyses. 
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling. 
Additional analyses may be conducted on the anonymised, pooled pharmacokinetic samples to 
further evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the Clinical Study Report (CSR).
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Report.
Redacted

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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).
5.6
Pharmacodynamics and patient selection biomarkers
Any sample collections listed in this Section may be discontinued at any time during the study 
at the Sponsor’s discretion. See Table 6 for the dose-escalation Part A and Table 7 for the 
dose-expansion Part B of the study.
5.6.1
Collection of blood samples for pharmacodynamics assessments
In both the dose-escalation and safety cohorts Part A and dose-expansion Part B of the study, 
blood samples (2.5 mL) for evaluation of STAT3 RNA knockdown (secondary objective) and 
associated gene expression changes (exploratory objective)/pharmacodynamic RNA 
(AZD9150) will be collected from patients at screening; on Day −7 of the lead-in period; on 
Day 1 and Day 8 of Cycle 1; on Day 1 of all subsequent cycles; and at the EOT visit. The 
revised sample collection for pharmacodynamic RNA samples is applicable to newly enrolled 
patients only under protocol amendment 5, dated 10 May 2017 and onwards, existing patients 
will have samples collected up to Cycle 5, Day 1. New patients will be required to have 
samples collected beyond Cycle 5.
In both the dose-escalation (except safety cohorts A3, A4, and A6) Part A and dose-expansion 
Part B (B1-B6) of the study, blood samples (3.5 mL) for evaluation of circulating sPD-L1 
protein (MEDI4736) will be collected from patients on Day 1 of Cycle 1; on Day 15 of Cycle 
2; and on Day 1 of all subsequent even-numbered cycles. On Day 1 of Cycle 1 and on Day 1 
of Cycle 8, in addition to the predose sample, a sample will also be obtained at the end of the 
MEDI4736 infusion. For patients who discontinue MEDI4736, a sample will be drawn 90 
days after their last dose of MEDI4736 coinciding with an IM (ADA) sample. For patients in 
Arm B1, B2, and B4 sPD-L1 samples will not be collected after the first 20 patients. The sPD-
L1 samples will also not be collected for Arms B7 and B8. 
Details of pharmacodynamic blood sample collection, processing, shipping, and storage will 
be described in the Laboratory Manual.
5.6.2
Collection of blood for myeloid-derived suppressor cells
In both the dose-escalation Part A and dose-expansion Part B of the study, blood sample 
(5 mL for MDSC) will be collected: At screening, Day −7 of the lead-in period, Day 1 of 
Cycles 1, 2, 3, 5, and at the EOT visit. Samples will be used for quantification of MDSCs by 
flow cytometry using a multicolour panel of cell surface markers. Myeloid-derived suppressor 
cell levels at baseline and/or effect of treatment on MDSCs may predict clinical responses. For 
patients in Arm B1, B2, and B4 MDSC samples will not be collected after the first 20 patients. 
MDSC samples will also not be collected for Arms B7 and B8.

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Details of sample collection, processing, shipping, and storage will be described in the 
Laboratory Manual.
5.6.3
Collection of tumor biopsies for evaluation of STAT3 and PD-L1 
expression
In Part B of the study, eligibility criteria require a patient to have at least 1 SCCHN lesion 
(TL) amenable for a biopsy and to be medically fit and willing to undergo a biopsy during 
screening and, unless clinically contraindicated, at the end of Cycle 1. Lesions used for biopsy 
should not be those used as RECIST lesions, unless there are no other lesions suitable for 
biopsy. If a RECIST TL is used for biopsy, the lesion must be ≥2 cm in the longest diameter.
A baseline biopsy is mandatory, and an on-treatment biopsy at the end of Cycle 1 is 
mandatory and will be performed when clinically feasible (i.e., unless clinically 
contraindicated or the patient has withdrawn consent); a biopsy collection upon disease 
progression is optional but encouraged when feasible. Failure to obtain sufficient on treatment 
tumor samples after making best efforts to biopsy the tumor will not be considered a protocol 
deviation. Also biopsy reports and samples of biopsy done fewer than 45 days prior to start of 
treatment (Day -7) on the trial would be an acceptable substitute to baseline biopsy. 
On-treatment biopsy timing may be refined with emerging PK and/or pharmacodynamic data 
during the course of the trial, and the collection of on-treatment tumor samples may be 
stopped at the Sponsor’s discretion. There is a ± 1 week window for on treatment biopsy 
collection.
Baseline and on-treatment biopsies will be used to assess tumor STAT3 pharmacodynamics in 
tumor and immune infiltrating cells by immunohistochemistry and/or gene expression analysis.
Baseline biopsies will be used to assess PD-L1 as a potential patient selection biomarker by 
examining its expression level and localisation on tumor and immune infiltrating cells by 
immunohistochemistry.
Details of sample collection, processing, shipping, and storage will be described in the 
Laboratory Manual.
5.6.4
Storage, re-use and destruction of pharmacodynamic samples
Samples will be stored for a maximum of 15 years from the date of the Last Subject’s Last 
Visit, after which they will be destroyed. The results of any investigation will be reported 
either in the CSR itself or as an addendum, or separately in a scientific report or publication.
Details of sample collection, processing, shipping, and storage will be described in the 
Laboratory Manual.

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5.7
Immunogenicity
In all patients treated with MEDI4736, venous blood samples for IM assessments will be 
obtained. This applies to all patients in the dose-escalation Part A and patients randomised to 
receive MEDI4736 in the dose-expansion Part B (i.e., treatment arms B1, B2, B3, B4, B7, and 
B8). The date and time of collection of each sample will be recorded.
Blood samples for IM (5 mL) will be collected predose on Day 1 of Cycle 1, on Day 15 of 
Cycle 2, and on Day 1 of each subsequent even-numbered cycle. For patients who discontinue 
MEDI4736, a blood sample will also be collected during follow-up at 90 days after the last 
dose of MEDI4736.
Blood samples for IM determination of a potential anti-AZD9150 antibody (2 mL) will be 
collected predose from all patients treated with AZD9150 on Day -7 (B8 only), Day 1 of 
Cycle 1, Day 1 of Cycle 2, and Day 1 of each subsequent even-numbered cycle.
Samples will be measured for the presence of ADA using a validated bridging immunoassay. 
Tiered analysis will be performed to include screening, confirmatory, and titre assay 
components and positive-negative cut points will be employed that were statistically 
determined from drug naïve validation samples.
Samples will be stored for assessing the neutralisation capacity in the future.
5.8
Exploratory research
5.8.1
Exploratory biomarker research
Participation in the exploratory biomarker research component of the study is mandatory. 
Biological samples (e.g., plasma, serum, PBMCs, PDRNA, archival tumor samples, and tumor 
biopsy sections remaining after secondary biomarker assessments) will be collected and 
analysed for exploratory biomarkers to assess correlations with disease activity, effects of 
study drug and clinical outcomes.
These samples serve as a source of protein, DNA, RNA, or other products of biological 
processes that can be used to analyse, e.g., immunogenomics (gene sequences associated with 
patients’ immune responses), gene expression immune cell abundance by 
immunohistochemistry or based on gene expression, genetic alterations, alternative pathway 
activation, or other emerging biomarkers.
Additional biomarker-related information (for example, gene mutations, cytogenetic 
abnormalities, etc.) may be collected directly from the clinical sites for exploratory analyses 
based on emerging science and available data.

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Exploratory biomarker analysis will be as described in a biomarker plan separate from the 
CSP.
The results of this exploratory biomarker research will be reported separately and will not 
form part of the CSR.
The results of this exploratory biomarker research may be pooled with biomarker data from 
other studies with the study drugs to generate hypotheses to be tested in future studies.
5.8.1.1
Collection of exploratory blood-borne biomarkers
In both the dose-escalation Part A and dose-expansion Part B of the study, blood samples for 
exploratory biomarkers will be taken pretreatment and at multiple time points on-treatment:
!
The 2 mL blood sample for serum will be obtained at screening; on Days −7 and −3 of the 
lead-in period; on Days 1, 8 (not B8), and 15 of Cycle 1; on Day 1 of Cycle 2; on Day 1 
of all subsequent odd-numbered cycles; and at the EOT visit.
!
The 10 mL blood sample for plasma will be obtained at screening; on Day −7 of the 
lead-in period; on Days 1, 8 (not B8), and 15 of Cycle 1; on Day 1 of Cycle 2; on Day 1 
of all subsequent odd-numbered cycles; and at the EOT visit.
!
The 10 mL blood sample for double-spun plasma (cfDNA sample) will be obtained at 
screening; on Day -7 of the lead-in period, and on Day 1 of all even-numbered cycles; 
Day 1 of Cycle 3 (B8 only) and at the EOT visit. The collection of cfDNA samples are 
only required to be obtained for new patients consented under protocol amendment 5, 
dated 10 May 2017 and onwards (B3, B7, and B8 as well as Part A). It is not a 
requirement to collect cfDNA samples for all other existing patients.
!
The 6 mL blood samples for PBMC will be obtained at screening; on Day −7 of the lead-
in period; on Days 1, 8 (not B8), and 15 of Cycle 1; on Day 1 of Cycles 3, 6, and 9; and at 
the EOT visit. 
Serum and/or plasma samples may be analysed for changes in factors associated with drug 
treatment. These include but are not limited to cytokines (e.g., IL-8, GRO-α, interferon 
gamma, IL 6, IL 8, TIMP1, CXCL9, CXCL10, tumor necrosis factor α) or other soluble 
factors (e.g., CRP, ARG1) or metabolites/small molecules (e.g., arginine). Plasma samples 
may also be used to evaluate circulating tumor or free DNA (cfDNA), or exosomes, or cell-
free RNA for correlation with treatment effects or clinical responses. Double-spun plasma 
samples (“cfDNA” samples) will be prioritized for evaluation of circulating tumor DNA but 
may also be used for other analyses. Peripheral blood mononuclear cell samples may be 
analysed for changes in activated or proliferating T cells or changes in diversity of T cell 
receptor expression that correlate with treatment or clinical responses, or as a source of protein, 
DNA, RNA or other cellular product to analyze emerging biomarkers associated with 
response to treatment or clinical response.
Additional details on exploratory research blood sample processing, handling, shipment, and 
storage will be provided in the Laboratory Manual.

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5.8.1.2
Collection of exploratory tumor biomarkers
In addition to secondary biomarkers outlined in Section 5.6.3, mandatory (archival tissue and 
baseline and on-treatment tumor biopsies, and optional disease progression tumor biopsies 
will be used for exploratory research as indicated in Section 5.8.1.1 above and used for 
investigating potential mechanisms and markers of response or resistance by evaluating 
immunogenomics (gene sequences associated with patients’ immune responses), gene 
expression, immune cell infiltrate, genetic alterations, or alternative pathway activation. Other 
analyses may be conducted based on emerging data in the scientific literature.
Details of sample collection, processing, shipping, and storage will be described in the 
Laboratory Manual.
5.8.1.3
Collection of archival tumor samples
Formalin fixed tumor tissue embedded in paraffin blocks will be retrieved for all patients if 
available. The archival samples will be preferably from the primary tumor and/or metastatic 
site. Freshly prepared unstained slides (minimum of 3, but preferably 10 to 20) from the 
archival tumor block will be accepted if tumor blocks cannot be submitted. Because 
uncontrolled oxidation processes affect tumor sections, tumor tissue blocks are preferred. 
From submitted archival tumor blocks, 2 cores may be removed in order to construct tissue 
microarrays for later biomarker analysis. The remaining part of the tumor block will be 
returned to the institution.
Details of archival tumor sample collection, processing, shipping, and storage will be 
described in the Laboratory Manual.
5.8.2
Pharmacogenetics
If a patient agrees to participate in the host pharmacogenetics research component of the study 
and signs a separate ICF for genetic research, a saliva sample will be collected. The results of 
this pharmacogenetic research will be reported separately and will not form part of the CSR.
The saliva sample for genetic research will ideally be obtained from the patients immediately 
prior to dosing on Day 1. Although genotype is a stable parameter, early sample collection is 
preferred to avoid introducing bias through excluding patients who may withdraw due to an 
AE. Such patients would be important to include in any genetic analysis. If for any reason, the 
sample is not obtained prior to dosing it may be taken at any visit until the last study visit. 
Only 1 sample should be collected per patient for genetics during the study.
Samples will be collected, labelled, stored, and shipped as detailed 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 

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with clinical data. Samples will be destroyed in the case of withdrawal of consent and 
regulatory audit enabled.
Where genetic analysis will be undertaken, the processes adopted for the coding and storage 
of samples will be more stringent in order to maintain patient confidentiality. As an added 
precaution, irrespective of the type of sample, the DNA sample will be assigned a unique 
number replacing the information on the sample tube. Thereafter, the DNA sample will be 
identifiable by the unique DNA number only. The DNA number will be used to identify the 
sample and corresponding data at the AstraZeneca genetics laboratories or at the designated 
contract laboratory. No personal details identifying the individual will be available to any 
person (AstraZeneca employee or contract laboratory staff) working with the DNA.
The samples and data for genetic analysis in this study will be single coded. The link between 
the patient enrolment code and the DNA number will be maintained and stored in a secure 
environment, with restricted access within the Clinical Genotyping Group Laboratory 
Information Management System at AstraZeneca. The link will be used to identify the 
relevant DNA samples for analysis, to facilitate correlation of genotypic results with clinical 
data, to allow regulatory audit, and to trace samples for destruction in the case of withdrawal 
of consent when the patient has requested disposal/destruction of collected samples not yet 
analysed.
5.8.3
Volume of blood
The volume of blood that will be drawn from each patient in this study during the lead-in 
period and during the first cycle of treatment for Parts A and B is shown in Table 10.

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Table 10
Volume of blood to be drawn from each patient during screening, 
lead-in period, and Cycle 1 of Part A and Part B
Test Type
Name
Sample volume
(mL)
Number 
of 
samples
Total 
volume
(mL)
Safety 
Clinical 
chemistry/pregnancy 
test
5 (Screening only) 
2.5
1
5
17.5
Haematology
2
6
12
Coagulation
1.8
4
7.2
Thyroid panel
3.5
3
10.5
Hepatitis B and C
3.5
1
3.5
HIV
2.5
1
2.5
Pharmacokinetics 
AZD9150
2
9
18
OR
AZD5069 and its 
metabolite AZ13587715 
(combination therapy, 
Part A)
2
10
20
OR
AZD5069 and its 
metabolite AZ13587715 
(combination therapy, 
Part B)
2
9
18
OR
AZD5069 and its 
metabolite AZ13587715 
(food effect, Part A)
2
18
36
MEDI4736 
(combination therapy 
arms only)
3.5
2
7
Tremelimumab (part A 
Arms A4 and A5)
3.5
4
14
Immunogenicity
Anti-drug antibody
5
1
5
Anti-AZD9150 antibody 
(AZD9150-treated arms 
only)
2
2 (required for Arm B8)
1
2
2
4
Pharmacodynamics
PDRNA
5
4
20
sPD-L1
3.5
2
7
MDSCs
2
2
4

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Test Type
Name
Sample volume
(mL)
Number 
of 
samples
Total 
volume
(mL)
sPSA
2.5 (Part A only)
3
7.5
Exploratory 
biomarker research
Serum
2
6
12
Plasma
10
5
50
PBMC
12
5
60
cfDNA
10
2
20
MAXIMUM 
TOTALa
357.7
a
Note that for pharmacokinetic sampling in the Part B combination therapy arms a reduced sampling 
schedule will only occur after the first 10 patients. In addition, sPDL and MDSC samples will not be 
collected for the following patients: patients in B1, B2 and B4 post first 20 patients and patients in Arms B7
and B8.
Abbreviations: cfDNA=circulating-free DNA; HIV=human immunodeficiency virus; MDSCs=myeloid-derived 
suppressor cells; PBMC=peripheral blood mononuclear cells; PDRNA=pharmacodynamic RNA (samples for 
STAT3 RNA and other exploratory analyses); sPD-L1=soluble programmed death-ligand 1; sPSA=serum 
prostate-specific antigen.
In all subsequent cycles past Cycle 1, a maximum total of 76.5 mL of blood will be taken per 
cycle. The number and timing of samples taken, as well as the volume required for each 
analysis, may be changed during the study as emerging PK, pharmacodynamic, or safety data 
on the study drugs become available.
5.8.4
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 PK sample remaining after analysis for AZD9150, AZD5069 (and AZ13587715, the 
metabolite of AZD5069), tremelimumab, or MEDI4736 may be used for biomarker analyses. 
These analyses are for AstraZeneca use only, and results will not be included in the CSR. 
Biological samples for future research can be retained on behalf of AstraZeneca for a 
maximum of 15 years following the last patient’s last visit in the study. The results from 
future analysis will not be reported in the CSR but separately in a CSR addendum/scientific 
report or scientific publication. No personal details identifying the individual will be available 
to AstraZeneca or designated organizations working with the DNA
5.8.4.1
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.

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5.8.4.2
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 data may be correlated with clinical 
data, samples destroyed in the case of withdrawal of consent and regulatory audit enabled.
5.8.5
Labelling and shipment of biological samples
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix C ‘IATA 6.2 Guidance Document.’
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the subject unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved.
All archival tumor samples should be shipped at ambient temperature as per the Laboratory 
Manual to the AstraZeneca designated central Contract Research Organisation.
5.8.6
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator, at each centre, keeps full traceability of collected biological 
samples from the subjects while in storage at the centre until shipment or disposal (where 
appropriate) and keeps documentation of receipt of arrival.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca biobank system during the 
entire life cycle.
5.8.7
Withdrawal of Informed Consent for donated biological samples 
If a subject withdraws consent to the use of voluntarily donated biological samples, the 
samples will be disposed of/destroyed, and the action documented. If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research.

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If collection of the biological samples is an integral part of the study, then the subject is 
withdrawn from further study participation.
The Principal Investigator:
!
Ensures that AstraZeneca is notified immediately of the subjects’ withdrawal of informed 
consent to the use of donated samples
!
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented
!
Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site
!
Ensures that the subject and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
5.9
Patient reported outcomes
There will be no patient reported outcomes assessed in this study.
6
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.
6.1
Definition of adverse events
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (e.g., an abnormal laboratory finding), symptom (for example nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
The term AE is used to include both serious and nonserious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
6.2
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria:

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!
Results in death
!
Is immediately life-threatening
!
Requires in-subject hospitalisation or prolongation of existing hospitalisation 
!
Results in persistent or significant disability or incapacity. 
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above.
For further guidance on the definition of an SAE, see Appendix A to the CSP.
6.3
Definitions of adverse events of special interest
AEs of special interest (AESIs) are events of scientific and medical interest for the further 
understanding of the AZD9150, AZD5069, tremelimumab, and MEDI4736 safety profiles and 
require close monitoring and rapid communication by the Investigator to AstraZeneca. Such 
AESIs may be serious or non-serious. The rapid reporting of these AESIs allows ongoing 
analysis of these events in order to characterise and understand them in association with the 
use of these IPs.
MEDI4736, an anti-PD-L1 antibody, binds with high affinity and specificity to PD-L1 and 
blocks its binding to PD-1 (CD279) and B7-1 (CD80) molecules, thus promoting anti-tumor 
immunity and tumor cell killing. Potential risks based on these mechanisms of action include 
immune-mediated reactions such as enterocolitis, dermatitis, hepatotoxicity or hepatitis, 
endocrinopathy, neuropathy or neurologic events, pancreatitis, and pneumonitis. More specific 
guidelines for their evaluation, reporting, and treatment are described in detail for MEDI4736 
in Annex 1. Further information on these risks (e.g., presenting symptoms) can also be found 
in the current edition of the MEDI4736 (durvalumab) IB. 
AZD5069, an inhibitor of CXCR2, acts by modulating neutrophil migration and has been 
shown to weakly bind the hERG receptor. Therefore, effects on neutrophil count, including 
reduction in their number (neutropenia), infections (especially requiring the administration of 
outpatient oral or IV antibiotics) are deemed of special interest, as are ECG abnormalities 
arising after the beginning of treatment with this agent.
At present, there are no AESIs for AZD9150.
6.4
Recording of adverse events
6.4.1
Time period for collection of adverse events
AEs and concomitant medications will be collected and reported throughout the study. The 
reporting period for AEs and concomitant medication starts immediately following the time 
that written informed consent is obtained and ends 28 days (+7 days) after the last dose of 

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study drug or until the initiation of subsequent anticancer therapy. SAEs occurring in the 
follow-up period should be reported to AstraZeneca in the usual manner (see Section 6.5).
Safety follow-up for IM continues for all patients for 90 days (±2 days) after the last dose of 
MEDI4736 or until the initiation of subsequent anticancer therapy.
SAEs will be recorded from the time of informed consent.
6.4.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the CRF. 
AstraZeneca retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
If an Investigator learns of any SAEs, including death, at any time after a patient has 
completed the study and he/she considers there is a reasonable possibility that the event is 
related to study treatment the Investigator should notify AstraZeneca.
6.4.3
Variables 
The following variables will be collect for each AE;
!
AE diagnosis/description (verbatim)
!
The date when the AE started and stopped
!
CTCAE grade
!
Whether the AE is serious or not
!
Investigator causality rating against the IP (yes or no)
!
Action taken with regard to IP
!
Outcome.
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date Investigator became aware of SAE
!
AE is serious due to
!
Date of hospitalisation
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)
!
Causality assessment to other medication

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!
Description of AE.
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Section 6.2.
The grading scales found in the current CTCAE version 4.03 (14 June 2010) will be utilised 
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 current CTCAE version can be 
downloaded from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
6.4.4
Causality collection
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the IP?’
For SAEs causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B “Additional 
Safety Information” of this CSP.
6.4.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: “Have you/the child had any health problems since the previous 
visit/you were last asked?”, or revealed by observation will be collected and recorded in the 
CRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms; However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.
6.4.6
Adverse events based on examinations and tests
The results from the CSP mandated laboratory tests and vital signs, ECGs, and other safety 
assessments will be summarised in the CSR. Deterioration as compared to baseline in 
protocol-mandated parameters should therefore only be reported as AEs if they fulfil any of 
the SAE criteria or are the reason for discontinuation of treatment with the IP.

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If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin 
value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
nonmandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
6.4.7
Hy’s Law
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN may need to be 
reported as SAEs. Please refer to Appendix G for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law.
6.4.8
Serious bleeding events with combination drug MEDI4736 (durvalumab) 
in squamous cell carcinoma of the head and neck patients
Reports of bleeding, including fatal reports, have been received from patients with RM 
SCCHN (Arms B1 to B8) enrolled in AstraZeneca clinical trials with MEDI4736 
(durvalumab) as monotherapy or in combination (with any of the other study drugs). While it 
is not yet conclusively known whether the risk of bleeding would be higher or lower with the 
experimental treatment than with standard chemotherapy, an interim internal safety analysis 
conducted by the Sponsor concluded that a reasonable possibility of a causal relationship 
between bleeding complications in SCCHN patients and treatment with durvalumab, either 
alone or in combination with tremelimumab, could not be established.
6.4.9
Investigators should carefully assess the risk in relation to benefit of 
using anticoagulation or other medications that might exacerbate 
bleeding during study participation. Investigators should consider 
discontinuation of these agents if the clinical scenario permits it unless 
discontinuation would be clinically contraindicated. Disease 
progression
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the IP is being studied. It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease. The development of new 
or progression of existing metastasis to the primary cancer under study should be considered 

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as disease progression and not an AE. Events, which are unequivocally due to disease 
progression, should not be reported as an AE during the study.
6.4.10
New cancers
The development of a new cancer should be regarded as an AE and will generally meet at 
least 1 of the serious criteria. New cancers are those that are not the primary reason for the 
administration of the study treatment and have been identified after the patient’s inclusion in 
this study. They do not include metastases of the original cancer.
6.4.11
Handling of deaths
All deaths that occur during the study, or within the follow-up period after the administration 
of the last dose of IP, should be reported as follows:
!
Death that is unequivocally due to disease progression should be communicated to the 
study monitor at the next monitoring visit and should be documented in the eCRF module 
but should not be reported as an SAE during the study.
!
Where death is not clearly due to disease progression of the disease under study the AE 
causing the death should be reported as an SAE within 24 hours. The report should 
contain a comment regarding the coinvolvement of PD, if appropriate, and should assign 
a single primary cause of death with any contributory causes.
!
Deaths with an unknown cause should always be reported as an SAE but every effort 
should be made to establish a cause of death. A postmortem may be helpful in the 
assessment of the cause of death, and, if performed, a copy of the postmortem results 
(with translation of important parts into English) should be reported in an expedited 
fashion within the usual timeframes.
6.4.12
Disease under Study (DUS)
Symptoms of DUS are those which might be expected to occur as a direct result of solid 
tumors (Arms A1 to A4), prostate cancer (Arm A6), and RM SCCHN (Arms B1 to B8). 
Events that are unequivocally due to disease under study should not be reported as AEs during 
the study unless they meet SAE criteria or lead to discontinuation of the IP.
6.5
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.

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The designated AstraZeneca representative works with the Investigator to ensure that all the
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within one 
calendar day i.e., immediately but no later than 24 hours of when he or she becomes aware 
of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site staff reports an 
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.
The reference document for definition of expectedness/listedness is the IBs for each of the 3 
study drugs.
6.6
Overdose
Use of AZD5069, MEDI4736, or tremelimumab in doses in excess of those specified in the 
CSP is considered to be an overdose. For AZD9150, administration in doses significantly 
exceeding those specified in the CSP (>10% above the recommended dose) may be 
considered to be an overdose. In all cases, Investigators should be advised that any patient 
who receives a higher dose than that intended should be monitored closely, managed with 
appropriate supportive care, and followed up expectantly. There is currently no specific 
treatment in the event of overdose of MEDI4736 or tremelimumab, and possible symptoms of 
overdose are not established. See Section 6.6.3 for details. Exception: Overdose in an amount 
of ≤10% of the specified dose does not need to be reported for AZD9150 if there are no 
associated AEs.
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.
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!
An overdose without associated symptoms is only reported on the Overdose CRF module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. For each 
case of overdose, study sites are required to record the overdose as a protocol deviation within 
the clinical database.
For overdoses associated with an SAE, the standard reporting timelines apply (see 
Section 6.5). For other overdoses, reporting must occur within 30 days.
6.6.1
AZD9150
Overdose with an injectable drug can take 2 forms. The first is the acute type where either a 
dose contains more drug than intended or the appropriate dose was IV infused in a 
substantially shorter time (e.g., 1000 mg infused in 30 minutes instead of 3 hours). Depending 
on the extent of the overdose, both of these events will lead to higher plasma concentrations 
(both Cmax and AUC) than planned for an ASO. Greater prolongation of aPTT and 
prothrombin time and increased international normalised ratio is a likely outcome. 
Complement pathway activation is a possible outcome. Clinical signs and symptoms for both 
should be monitored and appropriate supportive care and necessary countermeasures should 
be undertaken if clinical evidence suggests either has occurred. Since the distribution 
concentration half-life (t1/2)of ASO in plasma is 1 to 2 hours, the 2 side effects are expected to 
be transient.
The second type of overdose is repeated administration of a substantially higher dose (e.g., 
repeated administration of 1000 mg by 3-hour IV infusion instead of 600 mg). In addition to 
the potential acute effects described above, this type of overdose will also result in the 
accumulation of higher tissue levels of ASO than planned. Patients should be monitored 
closely for target organ toxicity (kidney and liver). If effects are suspected, appropriate 
supportive care and necessary countermeasures should be instituted. Based on measurements 
in monkey, the tissue t1/2 of AZD9150 is approximately 3 to 4 weeks.
There are no known occurrences of adverse outcomes related to AZD9150 overdose in man.
6.6.2
AZD5069
The maximum single dose so far given to human subjects is 200 mg. This dose was well 
tolerated. A single overdose higher than this is expected to cause a drop in blood neutrophil 

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counts but it is not known what other signs or symptoms may occur. Neutrophil counts should 
be monitored until they return to normal.
There is no experience of overdose and no known antidote to AZD5069. In cases of known or 
suspected overdose, symptomatic treatment and monitoring of vital functions should be 
performed according to routine clinical practice. If there is a prolonged, profound reduction in 
blood neutrophil counts administration of G-CSF may be considered as this has been shown in 
a healthy volunteer study (D3550C00017) to produce a sustained increase in blood neutrophil 
count during treatment with AZD5069 at a relatively high dose (100 mg BID).
6.6.3
MEDI4736
There has been no experience with overdose in the ongoing clinical studies of MEDI4736. 
There are no recommended specific treatments for an overdose with MEDI4736, and the 
Investigator is advised to use clinical judgement to treat such an event.
6.6.4
Tremelimumab
There has been no experience with overdose in the ongoing clinical studies of tremelimumab. 
There are no recommended specific treatments for an overdose with tremelimumab, and the 
Investigator is advised to use clinical judgement to treat such an event.
6.7
Pregnancy
All pregnancies and their subsequent outcomes (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) of pregnancy should 
be reported to AstraZeneca using the appropriate forms except for:
!
If the pregnancy is discovered before the study subject has received any study drug.
6.7.1
Maternal exposure
If a subject becomes pregnant during the course of the study, IP must be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. 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 subject 
was discontinued from the study.

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If any pregnancy occurs during exposure to IP or in the 28 days after discontinuing IP, then 
the Investigator or other site personnel informs the appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 6.5) and within 28 days for all other pregnancies.
The same timelines apply when outcome information is available.
6.7.2
Paternal exposure 
Pregnancy of a patient’s partner should not be considered an AE. However, the outcome of all 
pregnancies occurring from the date of dosing until 16 weeks after the last dose of study drug 
should, if possible, be followed up, documented, and reported to AstraZeneca and documented 
in the Pregnancy report Form. Consent from the partner must be obtained before the 
Pregnancy Report Form is completed.
6.8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the subject or 
has the potential to cause harm to the subject. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or subject.
Medication error includes situations where an error. 
!
occurred
!
was identified and intercepted before the subject received the drug
!
did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error, e.g., medication prepared incorrectly, even if it was not actually given 
to the subject
!
Drug not administered as indicated, e.g., wrong route or wrong site of administration
!
Drug not taken as indicated, e.g., tablet dissolved in water when it should be taken as a 
solid tablet 
!
Drug not stored as instructed, e.g., kept in the fridge when it should be at room 
temperature 

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!
Wrong subject received the medication (excluding IVRS/IWRS errors)
!
Wrong drug administered to subject (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error 
!
Subject accidentally missed drug dose(s), e.g., forgot to take medication
!
Accidental overdose (will be captured as an overdose)
!
Subject failed to return unused medication or empty packaging
!
Errors related to background and rescue medication, or standard of care medication in 
open-label studies, even if an AstraZenca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.5) and within 30 days for all other medication errors.
6.9
Management of IP related toxicities 
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for durvalumab and tremelimumab are provided in the 
durvalumab/tremelimumab Toxicity Management Guidelines (TMGs).  Please see Annex 1. 
The most current version of the TMGs is also available through the following link: 
https://tmg.azirae.com. In addition a version of the current TMGs is maintained within the Site 
Master File. Please contact your clinical trial associate for information on how to gain access 
to this website.
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the immune-mediated AEs 
(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 tremelimumab should be permanently 
discontinued (see Section 3.9 of this CSP and the Toxicity Management Guidelines).

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Following the first dose of IP, subsequent administration of tremelimumab can be modified 
based on toxicities observed as described in the TMGs. These guidelines have been prepared 
by the Sponsor to assist the Investigator in the exercise of his/her clinical judgement in 
treating these types of toxicities. These guidelines apply to AEs considered causally related to 
tremelimumab by the reporting Investigator.
6.9.1
Dose modifications
If a patient experiences a clinically significant and/or unacceptable toxicity with the IP, dosing 
will be interrupted or the dose reduced and supportive therapy administered as required. 
Because of the long tissue t1/2 of AZD9150 and MEDI4736, a 21-day (unless otherwise 
specified) recovery period has been allowed. If the toxicity resolves or reverts to a lower 
CTCAE grade within 21 days of onset and the patient is showing clinical benefit, study 
treatment may be restarted using the rules below for dose modifications (see Table 11 and 
Table 12).
If the toxicity does not resolve to CTCAE grade 2 (grade 1 for liver function tests) after 
21 days, study treatment should be permanently discontinued (unless otherwise specified) and 
the patient should be followed up for safety (see Section 4.2.3 for details).
A maximum of 2 dose-reductions (Figure 4, Figure 5, Figure 7, and Figure 8) will be allowed 
for an individual patient. If the second dose-reduction is not tolerated, study treatment should 
be permanently discontinued and the patient should be followed up for safety (see 
Section 4.2.3 for details). The lowest doses that may be administered are:
!
AZD9150: 2 mg/kg IBW Q2W (200 mg Q2W for Arm B8) 
!
AZD5069: 20 mg BID
!
MEDI4736: flat dose administration of 10 mg/kg Q4W (MEDI4736 dose-reductions are
not permitted for Arm B8)
!
Tremelimumab: 1 mg/kg
If a patient experiences a clinically significant and/or unacceptable toxicity at these dose 
levels, study treatment should be permanently discontinued and the patient should be followed 
up for safety (see Section 5.9 for details).
Table 11
Dose modifications for toxicity (excluding liver function tests and in case 
of neutropenia for AZD5069 alternate dosing schedule arms)
Toxicity
Recovery
Re-dosing
Notes
Grade 3
G2a ≤21 days
Restart at dose level -1
If second dose interruption, 
decrease to dose level -2

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G2a >21 days
Discontinue study drug 
treatment
Grade 4
G2a ≤21 days
Restart at dose level -2 
If second grade 4 toxicity, 
discontinue study drug 
treatment
G2a >21 days
Discontinue study drug 
treatment
a
Patients starting with an abnormal baseline may restart when the lab/AE returns to pretreatment status. If 
thrombocytopenia is accompanied by bleeding, discontinue study drug treatment. Neutropenia when on 
AZD5069 alternate dosing schedule should be managed as in Figure 7 and Figure 8
Abbreviation: G=grade.
If in the Investigator’s clinical judgement, the thrombocytopenia events with patients on 
AZD9150 monotherapy or in combination with MEDI4736 (durvalumab) needs to be 
managed in a way different from the one proposed above in the Table 11, it will warrant 
discussion with the Sponsor Study Team Physician  and the Study Investigator and the 
Sponsor Study Team Physician approval/waiver on the alternate management.
Table 12
Dose modifications for elevations in liver function tests
Toxicity
Recovery
Re-dosing
Notes
Grade 3
G1a ≤21 days
Restart at dose level -1
If second dose interruption, 
decrease to dose level -2
G1a >21 days
Discontinue study 
drug treatment
Grade 4 – and assessed 
by the Investigator as 
related to study 
treatment
Discontinue study 
drug treatment
a
Patients starting with an abnormal baseline may restart when the lab/AE returns to pretreatment status. If 
thrombocytopenia is accompanied by bleeding, discontinue study drug treatment.
Abbreviation: G=grade.
All dose-reductions must be discussed case-by-case by the Investigator and the Sponsor Study 
Team Physician (see Section 6.10 for contact information). Until this discussion occurs, 
dosing of study treatment must be interrupted temporarily. Dose-reductions are defined as 
doses below the dose at which the toxicity occurred and they may only include dose levels 
tested during the dose escalation. In combination treatments, a dose-reduction may involve 1 
or both of the 2 agents. All decisions regarding dose-reductions will be presented to the SRC 
at the next scheduled meeting.

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6.9.2
Infusion reactions
In order to help understand the potential drug relatedness of any acute reaction, a blood 
sample should be drawn during the event for possible additional ADA testing. Serum tryptase 
or other blood or urine testing relevant to the diagnosis of anaphylaxis may be obtained at the 
discretion of the Investigator.
In the event of a grade 2 infusion related reaction as determined by the Investigator, the 
infusion should be interrupted and restarted at the same rate as the original infusion after 
symptomatic treatment (e.g., antihistamines, nonsteroidal anti-inflammatory drugs, narcotics, 
and IV fluids) and resolution of the reaction.
In the event of a grade 3 infusion related reaction, the infusion should be interrupted and 
restarted at half the rate after symptomatic treatment and resolution of the reaction. If the 
infusion reaction returns to grade 3 or greater, the patient should discontinue the study 
treatment permanently.
In the event of a grade 4 infusion-related reaction, the patient should discontinue the study 
treatment permanently.
6.9.3
Hypersensitivity reactions
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti 
PD-(L)1 therapy (Brahmer et al 2012). Although MEDI4736 is a human anti-PD-L1 mAb, as 
with any antibody, allergic reactions following the infusion are possible and can be caused by 
various mechanisms, including acute anaphylactic (IgE-mediated) and anaphylactoid reactions 
against the mAb, and serum sickness.
Severe hypersensitivity reactions should be managed according to standard clinical practice. 
At all sites, appropriate drugs and medical equipment to treat acute anaphylactic reactions 
must be immediately available, and study personnel must be trained to recognise and treat 
anaphylaxis. The study site must have immediate access to emergency resuscitation teams and 
equipment in addition to the ability to admit patients to an intensive care unit if necessary.
In order to help understand the potential drug relatedness of any acute reaction, a blood 
sample should be drawn during the event for possible additional ADA testing. Serum tryptase 
or other blood or urine testing relevant to the diagnosis of anaphylaxis may be obtained at the 
discretion of the Investigator.
6.9.4
Differential diagnosis: Infusion-related reaction versus anaphylaxis
Anaphylaxis and infusion-related reactions have some common manifestations and may be 
difficult to distinguish from each other. The Investigator is advised to carefully examine 
symptoms of adverse reactions observed during or shortly after exposure to study drug, 

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especially MEDI4736, and to consider the following guidance prior to making a final 
diagnosis.
Infusion-related reactions are commonly observed during or shortly after the first exposure to 
therapeutic mAbs delivered through IV infusion. These reactions are less common following 
subsequent exposures. Unlike infusion-related reactions, anaphylaxis is a rare event, usually 
occurring after subsequent exposure to an antigen, and it is most commonly accompanied by 
severe systemic skin and or mucosal reactions.
Reactions occurring at the time of or shortly after subsequent infusions of IP(s) are to be 
judged by the Investigator at his/her own discretion. The following guidance for anaphylaxis 
diagnosis, based on the 2006 National Institute of Allergy and Infectious Diseases and Food 
Allergy and Anaphylaxis Network symposium (Sampson et al 2006), is provided guidance for 
is provided for the Investigator’s convenience and in order to facilitate consistency in 
judgements.
National Institute of Allergy and Infectious Diseases and Food Allergy and Anaphylaxis 
Network define anaphylaxis as a serious allergic reaction that is rapid in onset and may cause 
death. They recognise 3 categories of anaphylaxis, with criteria designated to capture from 
80% of cases (category 1) to >95% of all cases of anaphylaxis (for all 3 categories).
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (e.g., generalised hives, pruritus or flushing, swollen lips-tongue-uvula),
AND AT LEAST 1 OF THE FOLLOWING:
∀
Respiratory compromise (e.g., dyspnoea, wheeze-bronchospasm, stridor, reduced 
peak expiratory function, hypoxemia), and/or
∀
Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia 
[collapse], syncope, incontinence).
2.
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):
∀
Involvement of the skin-mucosal tissue (e.g., generalised hives, itch-flush, swollen 
lips-tongue-uvula),
∀
Respiratory compromise (e.g., dyspnoea, wheeze-bronchospasm, stridor, reduced 
peak expiratory function, hypoxemia),
∀
Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence), and/or
∀
Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting).

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3.
Reduced BP after exposure to known allergen for that patient (minutes to several hours):
∀
Infants and children: low systolic BP (age specific) or greater than 30% decrease in
systolic BP,
∀
Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that
person’s baseline.
6.9.5
Liver chemistry tests
If the conditions for dose interruption or dose discontinuation (see above) are fulfilled, retest 
of liver chemistries (ALT, AST, alkaline phosphatase [ALP], international normalised ratio, 
and indirect and TBL) should occur at least once weekly until levels stabilise or begin to 
recover. Further investigation may include the following:
!
Obtain a more detailed history of symptoms and prior and concurrent diseases
!
Obtain further history for concomitant drug use (including nonprescription medication,
herbal, and dietary supplement preparations), alcohol use, recreational drug use, and
special diets
!
Obtain a history for exposure to environmental chemical agents and travel
!
Scan for liver metastasis as appropriate
!
Serology for viral hepatitis (hepatitis A virus IgM, hepatitis B surface antigen, HCV
antibody, cytomegalovirus IgM, and Epstein Barr virus antibody panel)
!
Serology for autoimmune hepatitis (e.g., antinuclear antibody)
For any combined increases of aminotransferases and bilirubin, please refer to Appendix G 
“Actions Required in Cases of Increases of Liver Biochemistry and Evaluation of Hy’s Law” 
of this CSP.
6.9.6
Potential immune-related adverse events
Based on the mechanism of action of MEDI4736 leading to T cell activation and proliferation, 
there is the possibility of observing irAEs during the conduct of this study. Potential irAEs 
may be similar to those seen with the use of ipilimumab (YERVOY®) and nivolumab 
(OPDIVO®) and may include irAE such as enterocolitis, dermatitis, hepatotoxicity, 
endocrinopathy, pneumonitis, neuropathy, and the development of serious infection (Hodi et 
al 2010, Brahmer et al 2012). For tremelimumab, identified risks include: diarrhoea, rash, and 
pruritus, and important potential risks are immune-mediated gastrointestinal events including 
colitis, intestinal perforation, abdominal pain, dehydration, nausea and vomiting, and 
decreased appetite (anorexia); immune-mediated dermatitis including urticaria, skin 
exfoliation, and dry skin; immune-mediated endocrinopathies including hypophysitis, adrenal 
insufficiency, and hyper- and hypothyroidism; immune-mediated hepatitis including 
autoimmune hepatitis, and increased serum ALT and AST; immune-mediated pancreatitis 

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including autoimmune pancreatitis, and lipase and amylase elevation; immune-mediated 
respiratory tract events including pneumonitis and interstitial lung disease; immune-mediated 
nervous system events including encephalitis, peripheral motor and sensory neuropathies, and 
Guillain-Barre syndrome; immune-mediated cytopenias including thrombocytopenia, anemia 
and neutropenia; infusion-related reactions, anaphylaxis, and serious allergic reactions; and 
headache, fatigue, and pyrexia. 
Potential risks are associated with MEDI4736 and tremelimumab given their mechanism of 
action, which involves immune system activation, as well as data from studies of relevant or 
similar therapies. The occurrence of irAEs that are either overlapping or greater than when 
each of these drugs is/are used as monotherapy is possible. For information on all identified 
and potential risks with MEDI4736 and tremelimumab, always refer to the current editions of 
the respective IBs.
AEs 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. 
An immune-mediated AE (imAE) is defined as an AESI that is associated with drug exposure 
and is consistent with an immune-mediated mechanism of action and where there is no clear 
alternate aetiology. 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 regards to an event being an imAE, the Investigator 
should promptly contact the Study Physician.
AESIs observed with durvalumab ± tremelimumab include:
!
Diarrhoea / Colitis and intestinal perforation
!
Pneumonitis / ILD
!
ALT/AST increases / hepatitis / transaminase increases / hepatotoxicity
!
Neuropathy / neuromuscular toxicity (e.g., Guillain-Barré and myasthenia gravis)
!
Endocrinopathies (i.e., events of hypophysitis/ hypopituitarism, adrenal insufficiency,
diabetes insipidus, hyperthyroidism, hypothyroidism, and type I diabetes mellitus)
!
Rash / Dermatitis
!
Nephritis / Blood creatinine increases
!
Pancreatitis / serum (or labs suggestive of pancreatitis - increased serum lipase and ,
increased serum amylase increases)

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!
Myocarditis
!
Myositis / Polymyositis
!
Neuropathy / neuromuscular toxicity (e.g., Guillain-Barré, and myasthenia gravis)
!
Other inflammatory responses that are rare/less frequent with a potential immune-
mediated aetiology include, but are not limited to, myocarditis, pericarditis, sarcoidosis,
and uveitis and other events involving the eye, skin, haematological and rheumatological
events.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological aetiology are also considered AESIs.
Further information on these risks (e.g., presenting symptoms) can be found in the current 
edition(s) 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 Annex 1). These guidelines have been prepared by the Sponsor 
to assist the Investigator in the exercise of his/her clinical judgement in treating these types of 
toxicities. These guidelines apply to AEs considered causally related to the study drug/study 
regimen by the reporting Investigator.
Patients should be monitored for signs and symptoms of irAEs. In the absence of an alternate 
etiology (e.g., infection or PD), an immune-related aetiology should be considered for signs or 
symptoms of enterocolitis, dermatitis, hepatotoxicity, endocrinopathy, pneumonitis, or 
neuropathy. In addition to the dose-reductions described in Section 5.5.1 above, management 
of irAEs should generally be consistent with the guidelines previously outlined for ipilimumab 
(Weber et al 2012), which recommend the following:
1.
Patients should be evaluated to identify any alternative aetiology.
2.
In the absence of clear alternative aetiology, all events of an inflammatory nature should
be considered to be 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 (e.g., infliximab, mycophenolate).
More specific recommendations concerning the diagnosis and management of irAEs related to 
MEDI4736 are provided in Annex 1 (MEDI4736 Adverse Events of Special Interest) and 
Annex 1 (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]). Because the 
side effects of AZD9150 and MEDI4736 are to some degree overlapping (possible ALT/AST 
elevations, thrombocytopenia, and neutropenia), ascertaining the cause of any toxicity to 

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involved organ systems will require careful consideration in patients receiving both drugs 
simultaneously. If the Investigator has any questions in regards to an AE being an AE, the 
Investigator should immediately contact the Medical Monitor 
(see 
Section 6.10 for contact information).
6.10
Study team contacts for emergencies
The Principal Investigator(s) 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 (see Section 6.5).
In the case of a medical emergency, the Investigator may contact the Medical Monitor  
. If the Medical Monitor 
is not available, contact the Sponsor 
Study Team Physician.
In case of nonmedical emergencies, please contact either the Operational Lead 
 
 or the Operational Lead at AstraZeneca. If neither is available, contact the Medical 
Monitor 
.
 
 
 
 
 
 
 
 
 
 
 
 
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6.11
Duration of treatment
Patients participating in either part of the study will be administered study drug(s) following a 
7-day lead-in period in 4-week treatment cycles. This may continue for as long as they are
continuing to show clinical benefit, as judged by the Investigator, unless a patient has
confirmed PD with either clinical deterioration and/or no further benefit from treatment,
experiences unacceptable toxicity, or discontinues for any other reason.
If a patient on either monotherapy arm (treatment arms B5 or B6) has confirmed PD, they may, 
at Investigators’ discretion and with notification to the Medical Monitor, add MEDI4736 to 
their treatment regimen. These patients, after the addition of MEDI4736 to the monotherapy
treatment, will continue to be part of the safety analysis but will be censored from the efficacy 
analysis. 
After discontinuation of treatment, all patients will continue to be followed for safety, 
subsequent anticancer therapy, and survival. During this time, all patients will be followed for 
safety (including concomitant medication) for 28 days (+7 days) after the last dose of study 
drug or until the initiation of a subsequent anticancer therapy. In addition, patients who 
received MEDI4736 as part of their combination treatment will be followed for IM for 
90 days (±7 days) after the last dose of MEDI4736 or until the initiation of alternative 
anticancer therapy. Patients who discontinued treatment for reasons other than PD will 
continue to undergo tumor assessments every 2 months (±7 days) until PD is noted. All 
patients will be followed for subsequent anticancer therapy every 2 months (±7 days) and will 
also be followed for OS every 2 months (±7 days) from the date of randomisation to the date 
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of death due to any cause, assessed for approximately 40 months. The patients will be 
censored on the date of last follow-up visit.
6.12
Expected start and end of study
The study started on 05 Aug 2015 (first patient screening visit). The data cut-off for the 
primary endpoint will be the 28 Feb 2020 (6 months + 90 days follow up after the last patient 
recruited and started IP). Data analysis will be performed, and a CSR will be written based on 
this data cut-off.
Any patients still receiving IP at the time of this data cut-off will be able to continue to receive 
IPs within the current study, through a continued treatment period, while they are in the 
Investigator’s opinion, deriving clinical benefit and not fulfilling discontinuation criteria. 
During this continued treatment period, assessments will revert to the standard of care for each 
individual site. Data will not be entered into the clinical study database after the data cut-off 
date. During this continued treatment period, patients will continue to be monitored for all 
SAEs up to 28 days after the last dose of IP. Paper based SAE reporting will be used for any 
SAEs identified after the data cut-off. SAE data will be entered in to the AstraZeneca’s global 
safety database. All SAEs, overdoses and pregnancies will be reported until 28 days after last 
dose. The IVRS system will be closed following the data cut-off, and sites will manually order 
IP. The IP dispensation and reconciliation will be handled by the study site at each patient’s 
visit. The IP accountability information must still be collected until all patients have 
completed treatment. After the data cut-off for the CSR, individual study sites will be closed 
once their final patient completes the 28-day follow-up visit. The continued treatment period 
will remain available to patients until the last patient completes treatment and has his or her
28-day safety follow-up visit. The Last Subject Last Visit is defined as the date of the last
patient’s 28-day safety follow-up visit.
6.13
Study suspension or early termination
The Sponsor reserves the right to temporarily suspend or terminate this study at any time. The 
reasons for temporarily suspending or terminating the study early may include, but are not 
limited to, the following:
1.
The incidence or severity of AEs in this or other studies indicates a potential health
hazard to patients
2.
Patient enrolment is unsatisfactory
3.
Noncompliance that might significantly jeopardise the validity or integrity of the study
4.
Sponsor decision to terminate development
5.
Sponsor decision to terminate the study based on a planned futility analysis
If the Sponsor determines that temporary suspension or early termination of the study is
required, the Sponsor will discuss the reasons for taking such action with all participating

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Investigators. When feasible, the Sponsor will provide advance notice to all participating 
Investigators of the impending action.
If the study is suspended or terminated early for safety reasons, the Sponsor will promptly 
inform all Investigators. The Sponsor will also promptly inform the relevant regulatory 
authorities of the suspension/early termination along with the reasons for such action. Where 
required by applicable regulations, the Investigator must inform the site’s Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) promptly and in writing of the 
suspension/early termination along with the reasons for such action and send a copy of the 
notification to the Sponsor.
If the study is suspended for safety reasons and it is deemed appropriate by the Sponsor to 
resume the study, approval from the relevant regulatory authorities (and IRBs/IECs when 
applicable) will be obtained prior to resuming the study.
7
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
AstraZeneca’s Pharmaceutical Development, R&D Supply Chain will supply the IPs shown in
Table 13.
Table 13
Dosage form and strength of the investigational products
Investigational product
Dosage form and strength
AZD9150
2 mL vial, 50 mg/mL concentrate for solution for 
infusion 
AZD5069 capsulesa
20 mg hard gelatine brown capsules for oral use
AZD5069 tablets
10 mg beige tablets for oral use
AZD5069 tablets
40 mg beige tablets for oral use
MEDI4736
10 mL vial, 50 mg/mL concentrate for solution for 
infusion 
tremelimumab
Formulated at a nominal concentration of 20 mg/mL in 
20 mM histidine/histidine HCl, 222 mM trehalose 
dihydrate, 0.02% (w/v) polysorbate 80, and 0.27 mM 
EDTA, pH 5.5.
a
Capsule formulation was used in Part A in the dose-escalation Arm A2 for first cohort.

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7.2
Dose and treatment regimens
7.2.1
Administration of AZD9150
AZD9150: Arms A1, A4, A6, B1, B3, B5, B7, and B8: Patients will receive loading dose of 
AZD9150 (Days −7, −5, and −3) at the defined dose in each treatment arm as described in the 
study design. Following loading dose, patients will receive QW dosing of AZD9150 (except 
in Cohort 2 of Arm A4, and Arm B8 where the schedule of AZD9150 is Q2W). AZD9150 
will be administered as a 1-hour (± 10 minutes) infusion. In all cases, infusion of AZD9150 is 
planned to be completed at least 30 minutes (in subsequent cycles if no infusion reaction in 
first cycle) before the start of the MEDI4736 infusion on days that both drugs are administered. 
For Arm A4 specifically, the sequence of dosing for first 4 cycles would be AZD9150 infused 
over 1 hour (± 10 minutes), followed by tremelimumab infused over 1 hour (± 10 minutes) 
followed by MEDI4736 infused over 1 hour (± 10 minutes). Ideal body weight will be used to 
calculate the administered dose in all arms where AZD9150 is to be infused except Arm B8 
where flat dose AZD9150 is to be administered, i.e. 200 mg as lead-in doses on Days −7, −5,
and −1 and 400 mg Q2W thereafter in a 28-day cycle.
AZD9150 will be administered on an mg/kg IBW basis via a 1-hour IV infusion (a window of 
±10 minutes will be allowed). However, the patients allocated in B8 will be administered on a 
flat dosing regimen. As described in Section 1, the infusion time for AZD9150 has been 
shortened from 3 hours in previous studies to a 1 hour infusion. The SRC will continue to 
monitor patients dosed with AZD9150 for any toxicities possibly associated with the 
shortened infusion time and may recommend modifying the length of infusion if any toxicities 
associated with Cmax are observed.
Ideal body weight is used for the administration of AZD9150 as the apparent volume of 
distribution for oligonucleotides does not increase proportionately to body weight in obese 
patients or patients who weigh substantially less than their IBW (Dorr et al 1999). Ideal body 
weight will be determined using the Devine formula (Pai and Paloucek 2000):
Men (kg)
= 50+2.3kg*inch over 5 feet
= 50+2.3kg*((actual height (cm)–152.4) * 0.4)
Women (kg)
= 45.5+2.3kg*inch over 5 feet
= 45.5+2.3kg*((actual height (cm)–152.4) * 0.4)
If the actual weight is less than the IBW or the patient is less than 5 feet tall, the actual weight 
will be used to determine dose.

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Weight obtained on Day −7 of the lead-in will be used to calculate the weight-related doses of 
AZD9150 for the lead-in. Weight obtained on Day 1 of each cycle will be used to calculate 
the weight-related dose of AZD9150 for each cycle.
During the 7-day lead-in period, AZD9150 will be administered as a loading dose on Days −7, 
−5, and −3. A window of +1 day per loading dose is allowed. Doses should not be given on
back-to-back days. Starting with Cycle 1, AZD9150 will be administered QW on Days 1, 8,
15, and 22 of each treatment cycle; doses have a ±2 day dosing window.
7.2.2
Administration of AZD5069
When given in combination with MEDI4736 (Arms A2, A3, A7, B2, B4, and B6): AZD5069 
will be administered as 40 mg BID starting with Day −7 of the 7-day lead-in period at the 
defined dose in each treatment Arm as described in the study design. Following the lead-in 
period, patients will receive BID dosing of AZD5069 daily for a 28-day cycle. On days when 
both AZD5069 and MEDI4736 are given, the morning dose of AZD5069 is administered at 
least 30 minutes before starting infusion of MEDI4736. For Arm A5 specifically, the sequence 
of dosing for first 4 cycles would be AZD5069 followed 30 minutes later by tremelimumab 
infused over 1 hour (± 10 minutes) followed by MEDI4736 infused over 1 hour 
(+/−10 minutes). As discussed in the study design, Arms A5, A7, and food effect substudy 
will not open for enrolment. In all cases, AZD5069 should be administered either 2 hours 
before or 2 hours after (with ± 2 hours window) food consumption at approximately the same 
time each day.
Tremelimumab will be administered at 1mg/kg (once Q4W), and the infusion duration will be 
approximately 1 hour. The MEDI4736 infusion at 20 mg/kg (once Q4W), will start 
approximately 1 hour after the end of infusion of tremelimumab, and the infusion will be 
administered over approximately 1 hour (a window of ±10 minutes will be allowed). The dose 
of AZD5069 will be 80 mg BID alternate dosing schedule. Tremelimumab will be infused for 
a total of 4 months (up to 4 doses). After completion of the initial 4 doses of tremelimumab, 
patients will continue to receive AZD5069/MEDI4736 as in Arm A2. The first 
AZD5069/MEDI4736 dose will be given 1 day after the last received dose of AZD5069 of a 
cycle (Week 4 dose) with MEDI4736 and tremelimumab combination therapy. In the case of 
the Arm B4 post-interim analysis, the dose of AZD5069 will be 80 mg BID alternate dosing 
schedule.
When given alone (treatment arm B6 in Part B): AZD5069 will be administered as a fixed PO 
at flat doses PO BID starting with Day −7 of the 7-day lead-in period. AZD5069 should be 
administered either 2 hours before, or 2 hours after food (± 2 hours). Dose should be taken on 
an empty stomach (unless specified for a particular visit for monotherapy arm patients) at 
approximately the same time each day. 

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In the fasted condition, patients will be fasted for ≥10 hours before AZD5069 dosing, until 
4 hours postdose. Patients may have glucose (sugar tablets) and/or juice (except for grapefruit 
juices or juices containing grapefruit or Seville oranges) if they have signs or symptoms of 
hypoglycaemia after they have received AZD5069 in the fasted state. Water will be restricted 
from 1 hour predose until 1 hour postdose, except for the water administered with AZD5069. 
After review of the PK data, if it is agreed that the data support no clinically relevant impact 
of food on the PK of AZD5069 and so recommended by the SRC and AstraZeneca, the 
AZD5069 fasting/administration instructions may be removed.
The morning dose of AZD5069 taken during the lead-in period and on any subsequent day 
when blood samples before the morning dose are required must be administered at the study 
centre and the precise time noted. All other doses may be self-administered by the patient; 
self-administration of AZD5069 will be recorded in the Patient Diary.
As part of the pharmaceutical development of the AZD5069 formulation, a new tablet 
formulation has been developed to meet manufacturability concerns and the strengths for 
oncology studies and will be used in Part A enrolment in Arms A3, A5, and A7 and in Part B 
of the trial. 
7.2.3
Administration of MEDI4736
MEDI4736 will be administered on an mg/kg (with the exception of Arm B8) basis Q4W via 
a 1-hour IV infusion. 
MEDI4736: Arms (A1 to A7, B1 to B4, B7): Patients will receive MEDI4736 starting Day 1 
of Cycle 1 administered as a 20 mg/kg infusion over 1 hour Q4W in a 28-day cycle. In 
addition to the above arms, patients in monotherapy arms (B5 and B6) who develop confirmed 
disease progression may have MEDI4736 added, at the discretion of the Investigator and after 
notifying the Medical Monitor. MEDI4736 will be added to the dosing schedule beginning on 
Day 1 of the following treatment cycle. Thereafter, all study treatment will follow the same 
schedule as for a patient on a combination therapy arm. 
For patients in B8, a 1.5 g flat dose will be administered via infusion starting Day 1 of Cycle 1 
over 1 hour Q4W in a 28-day cycle. If body weight decreases to less than 30 kg, weight-based 
dosing (20 mg/kg Q4W) will be implemented. 
Patients will receive MEDI4736 on Day 1 of each treatment cycle, starting with Cycle 1; 
doses have a ±2 day dosing window. Weight obtained on Day 1 of each cycle will be used to 
calculate the weight-related dose of MEDI4736 for each cycle.
Patients should be observed after administration of MEDI4736 for a minimum of 2 hours for 
the appearance of any acute drug reactions. In the event of an acute reaction, in order to help 
understand the potential drug relatedness of such a reaction, a blood sample should be drawn 

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during the event for possible additional ADA testing. Serum tryptase or other blood or urine 
testing relevant to the diagnosis of anaphylaxis may be obtained at the discretion of the 
Investigator.
7.2.4
Administration of tremelimumab
Tremelimumab will be administered in Arm A4 as 1 mg/kg IV infusion over 1 hour Q4W in a 
28-day cycle, starting on Day 1 of Cycle 1 with a ± 2 days window and given Q4W for a total
of 4 cycles (up to 4 doses). Weight obtained on Day 1 of each cycle will be used to calculate
the dose of tremelimumab for each cycle.
The dose will be calculated using the following formula:
Dose (mL) = [patient weight (kg) × tremelimumab dose level (mg/kg)]
20 mg/mL
where 20 mg/mL is tremelimumab concentration.
The corresponding volume of tremelimumab should be rounded to the nearest 0.1 mL. If no 
institutional standard on dose calculations exists, then dose adjustments for each cycle are 
only needed for a greater than 10% change in weight.
Tremelimumab will be infused after AZD9150 and AZD5069 and prior to MEDI4736 
infusions in Arm A4.
7.3
Labelling
Labelling of the IP will be carried out by AstraZeneca or designee in accordance with Annex 
13 and current Good Manufacturing Practice 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.
The patient’s emergency contact details and patient’s dosing instructions will not be on the 
labels but can be found in the ICF and the Patient Information Card. For emergency purposes, 
the patient must be in possession of the emergency contact details at all times.
Additional information about the 4 IPs may be found in the respective IBs.
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions. The IP 
label on the vial/bottle specifies the appropriate storage.
AZD9150 and MEDI4736 are to be stored at the study centre in a secured facility with limited 
access and controlled temperature (2ºC to 8ºC). The temperature should be monitored on daily 

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basis and documented in the temperature monitoring log according to the study drug handling 
instructions.
AZD5069 (capsules and tablets) is to be stored at the study centre in ambient temperature in a 
secured facility with limited access. The temperature should be monitored on a daily basis and 
documented in the temperature monitoring log according to the study drug handling 
instructions.
Tremelimumab is to be stored with investigational site pharmacy at 2°C to 8°C (36°F to 
46°F). Do not freeze.
The IPs must be kept in the original outer container and under conditions specified on the 
labels.
In the following cases, the centre staff should not use affected study drug and should 
immediately contact AstraZeneca representative for further guidance:
!
Temperature excursion upon receipt or during storage at the study
!
Damaged kit upon receipt
!
Damaged vial/bottle
Damaged study drug should be documented according to the instructions provided by 
AstraZeneca representative.
7.5
Distribution of AZD5069 to the patient
A description of how AZD5069 will be packaged for distribution to the patient and detailed 
instructions how to dispense AZD5069 to the patient will be provided in writing to the study 
centres before or at the time of site initiation.
7.6
Treatment compliance and accountability
The study drug provided for this study will be used only as directed in the CSP.
The study site staff will account for all study drugs received at the centre, for unused study 
drugs, and for appropriate destruction (according to local procedures). Certificates of delivery, 
destruction, and/or return should be signed.
The administration of all medications (including study drug) and details of treatment with IP 
should be recorded in the appropriate sections of the eCRF.
AZD9150, tremelimumab, and MEDI4736 will be administered IV at the study centre on 
treatment visits and within visit windows as specified in Section 5.2, Table 5.

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AZD5069 will be administered orally by patients at times at the study centre but more often at 
home as specified in Section 5.2, Table 5. Self-administration of AZD5069 will be recorded in 
the Patient Diary, which will be used as a measure of compliance. Patients will be asked to 
return all unused medication and empty containers to the study centre on each treatment visit. 
The patient’s compliance will be assessed by the Investigator and recorded in the eCRF. A 
capsule/tablet count should be performed at the patient level and recorded in the eCRF as well 
as in a dispensing log by the study centre personnel.
7.7
Dose-escalation and safety cohorts: Part A and Part B
In the dose-escalation part of the study, 31 evaluable patients were enrolled. At the time of 
protocol amendment 5, the MTDs/RP2D for each of the 2 agents in combination with 
MEDI4736 (durvalumab) had been identified [AstraZeneca 2016 (a), AstraZeneca 2016 (b)]. 
Based upon the safety data gathered from 6 evaluable patients enrolled in Arm A3, the SRC 
determined on 29 March 2017, that the 80 mg BID alternate dosing schedule for AZD5069 
was also a safe and tolerable dose. 
All cohorts of Part A will enroll patients with advanced solid malignancies refractory to 
standard therapy or for which no standard of care regimen currently exists. Following 
enrolment, based on the patient’s history of taking any drugs, herbal supplements, and/or 
foods prohibited with concurrent administration of AZD5069 or within 14 days of the first 
dose of AZD5069 and detailed in Section 3.8.2, as well as the patient’s anticipated need or 
likelihood to consume such products at any time throughout the study, the Investigator will 
then assess whether the patient may be allocated to treatment with AZD5069.
Patients thus excluded by the Investigator from treatment with AZD5069 will be allocated to:
!
Treatment arm A4 or A6: AZD9150 in combination with MEDI4736 
(AZD9150/MEDI4736/tremelimumab or AZD9150/MEDI4736).
Patients thus included by the Investigator for treatment with AZD5069 will be allocated 
sequentially to 1 of the following 2 treatment arms:
!
Treatment arm A4 or A6: AZD9150 in combination with MEDI4736 
(AZD9150/MEDI4736/tremelimumab or AZD9150/MEDI4736), or
!
Treatment arm A3: AZD5069 in combination with MEDI4736.
7.7.1
Starting dose and dose-escalation scheme 
The starting doses and additional dose levels chosen for each agent in this study were based 
on the clinical experience with each agent as monotherapy in previous trials.
In Arm A1, AZD9150 was administered at a starting dose of 2 mg/kg IBW. Additional dose 
level up to 3 mg/kg IBW was evaluated and determined as RP2D. Lower dose selection is 

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based on PD (STAT3 protein expression) analysis of peripheral blood and tumor biopsy 
specimens from patients with DLBCL treated in a ISIS Phase 1/2 clinical trial (Clinical study 
ISIS 481464-CS1, see Section 1.2). The upper limit of 3 mg/kg IBW is based on MTD 
determination for patients in the same study.
In Arm 2, AZD5069 was administered at a starting dose of 40 mg PO BID (i.e., daily dose of 
80 mg). Additional dose level up to 80 mg BID (for a maximum total daily dose of 160 mg) 
was evaluated. The 40 mg BID dose was considered as the MTD based on initial safety 
assessment, but based on maturing safety data it was better understood that the DLTs of 
neutropenia occurring in patients treated with AZD5069 are due to mechanism of AZD5069 
(myelokathexis) and are hence functional. The SRC determined to enroll an additional cohort 
at 80 mg BID dose of AZD5069 with a different dose schedule involving drug holds to 
manage treatment-related functional toxicities (Arm A3 as described below). The outcome of 
this cohort has been determined and it concludes 80 mg BID alternate dosing schedule as a 
viable RP2D. The lowest dose is based on PD (CD11b expression) analysis of peripheral 
blood cells from healthy volunteers treated in a single ascending dose Phase 1 study 
(D3550C00001). Arm A3: 6 patients will be initially dosed. If tolerating the dosing schedule 
well, an additional 6 patients will be added to confirm the dose schedule. If ≥2 patients do not 
tolerate the dose (i.e., meet DLT criteria), the dose will be reduced back to 40 mg BID of 
AZD5069 (Figure 7 and Figure 8). Non-evaluable patients may be replaced.
For Arm A4, the aim is to conduct a safety run-in of the established dose of AZD9150 (from 
Arms A1, A2/A3) in combination with a fixed dose of MEDI4736/ tremelimumab in all solid 
tumor patients. No dose-escalation is planned for Arm A4. If the dose is not tolerated (i.e., 
patient meets DLT criteria) in this combination of 3 drugs, then dose-reductions will be 
conducted as described in Figure 4, Figure 7, and Figure 8.
For Arm A6, the dose and safety confirmation cohort, AZD9150 will be given at the 
established dose of AZD9150 (from Arms A1, A2/A3) in combination with fixed dose of 
MEDI4736. This will be done in patients with prostate cancer, and there is no intent to do any 
intra-patient dose escalation. If the dose is not tolerated in this combination of 2 drugs, then 
dose-reduction will be conducted as in Figure 4, Figure 7, and Figure 8.
MEDI4736 was administered at a dose of 20 mg/kg Q4W.
Tremelimumab was administered at a dose of 1 mg/kg Q4W.
For the definition of DLT, see Section 7.7.3.
In Arms A1 and A2, dose-escalation for the 2 combination treatments (i.e., 
AZD9150/MEDI4736 and AZD5069/MEDI4736) advanced independent of each other. In 
addition to determining DLT in the DLT Evaluation period, the SRC critically reviewed all 

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available data pertaining to safety, tolerability, and IM as well as PK, pharmacodynamic, and 
anti-tumor activity before deciding on the next dose levels/schedules to be explored. Dose-
escalation in each arm was considered completed once 1 of the following criteria was met:
!
The MTD (for definition of MTD see Section 7.7.4) for the 2 agents in combination have
been identified
!
The SRC has recommended doses for the 2 agents in combination to be further explored
in the dose-expansion Part B
!
The maximum doses of the 2 agents in combination have been reached (i.e., AZD9150 3
mg/kg IBW, AZD5069 120 mg BID [for a maximum total daily dose of 240 mg], and
MEDI4736 20 mg/kg)
See Figure 4 for the for the possible dose combinations for study Arms A1, A4, A6 and dose-
reduction levels for Part B, and Figure 5 for the possible dose combinations for study Arm A2 
and dose-reduction levels for Part B. All potential dose-escalation and de-escalation levels 
after the starting doses will be determined by the SRC in light of emerging safety, tolerability, 
and/or PK data (see Section 7.7.6).
There will be no intra-patient dose escalations.

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Figure 4
Dose-escalation and de-escalation Arms A1, A4, A6 and dose-reduction 
levels for Part B (B1, B3, B5, and B7)
Additional dose combinations not listed in the table may be explored based on emerging safety, tolerability, 
and/or PK data. All dose combinations will be determined by the SRC. For Part B, AZD9150 will be 
administered at 3 mg/kg QW.
Figure 5
Dose-escalation and de-escalation Arm A2 and dose-reductions levels 
for Part B (B2, B4, and B6)
Additional dose combinations not listed in the table may be explored based on emerging safety, tolerability, 
and/or pharmacokinetic data. All dose combinations will be determined by the SRC. Figure 7, and Figure 8
provide dosing guidelines for Arms A in Part A and for Arm B2 (post first 20 patients) and Arm B4 (post-interim 
analysis) in Part B. For Part B, AZD5069 will be administered at 40 mg BID.

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Figure 6
Dose-reduction levels for treatment Arm B8
If body weight decreases to less than 30 kg, weight-based MEDI4736 dosing (20 mg/kg Q4W) 
will be implemented. No other dose-reductions will be permitted for MEDI4736 for B8.
!
AZD9150 Dose level -1: 300 mg Q2W
!
AZD9150 Dose level -2: 200 mg Q2W
7.7.2
Management of causally related infusion events
For events deemed causally related to infusion of MEDI4736 or tremelimumab refer to 
Annex 1.
AZD9150 400mg Q2W
MEDI4736 1.5g Q4W
Body weight reduces to
< 30kg
Weight-based 
MEDI4736 dosing 
20mg/kg Q4W to 
be implemented
AZD9150 Dose level -1
300mg Q2W
MEDI4736 1.5g Q4W
AZD9150 Dose level -2
200mg Q2W
MEDI4736 1.5g Q4W
Dose-reduction

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Figure 7
Alternative dose schedule, titration and dose-reduction for Arms A3
and B4 (post-interim analysis)
One round of granulocyte-colony stimulating factor will be permitted when dose-reductions 
are done in the manner prescribed above. If granulocyte-colony stimulating factor  is required 
for second time, the alternative dose schedule and titration as described in Figure 8 will be 
followed.
Figure 8
Alternative dose schedule, dose titration and dose-reduction for Arms 
A3 and B4 (post-interim analysis)

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7.7.3
Definition of dose-limiting toxicity
The DLT evaluation period will be defined in Part A of the study as the time from the first 
dose of AZD9150 or AZD5069 to the end of Cycle 1 (i.e., 35 days total) or until a patient 
experiences a DLT, whichever occurs first.
A DLT is defined as any AE that occurs from the first dose of study treatment up to the end 
the DLT evaluation period, that is judged by the Investigator to be drug-related (i.e., unrelated 
to PD, intercurrent illness, or concomitant medications), and that is assessed as grade 3 or 
worse according to the NCI CTCAE, with the following exceptions:
!
Increases in transaminase levels (serum glutamic oxaloacetic transaminase [SGOT]/AST 
and serum glutamic-pyruvic transaminase [SGPT]/ALT) are DLT if:
∀
SGOT/AST and/or SGPT/ALT increase to >15 × ULN at any time, and/or
∀
SGOT/AST and/or SGPT/ALT increase to >10× to 15 × ULN over a span of 
14 consecutive days, and/or
∀
SGOT/AST and/or SGPT/ALT increase to >ULN, and 1 or more of the following 
conditions is met and not explained by other causes:
(a) TBL increased to >2 × ULN
(b) New appearance of eosinophilia (>5%)
(c) Clinical signs of functional liver impairment
!
Nausea, vomiting, and diarrhoea will be considered a DLT only if assessed as grade 3 or 
worse after optimal prophylactic or treatment measures have been prescribed.
!
Fatigue will not be considered a DLT.
!
Neutropenia will be considered a DLT only:
∀
If in the context of grade 3 febrile neutropenia (i.e., absolute neutrophil count [ANC] 
<1,000 mm3 with a single temperature of more than 38.3ºC (101ºF) or a sustained 
temperature of at least 38ºC (100.4ºF) for more than 1 hour;
∀
If in the context of grade 4 febrile neutropenia (i.e., ANC <1,000 mm3 with 
life-threatening consequences that indicate urgent intervention);
∀
If assessed as grade 3 or worse (i.e., ANC <1,000 mm3) and associated with an 
infection that is clinically severe, associated with sepsis or requiring hospitalization. 
Grade 3 non febrile neutropenia with clinically minor (as judged by the Investigator) 
infection need not be regarded as DLT; or
∀
If assessed as grade 4 (i.e., ANC <500 mm3) for more than 5 days.

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!
Thrombocytopenia will be considered a DLT only:
∀
If assessed as grade 3 or worse (i.e., platelet count <50,000 mm3) and associated with 
bleeding, or
∀
If assessed as grade 4 i.e., platelet count <25,000 mm3).
Any other grade 3 or grade 4 laboratory evaluations that are asymptomatic will be considered 
a DLT only if assessed by the Investigator as clinically significant.
Any toxicity judged by the Investigator to be drug-related (i.e., causality rated as possible or 
greater) that requires study treatment to be discontinued for more than 10 consecutive days 
will be considered a DLT.
7.7.4
Definition of maximum tolerated dose
A dose will be considered non-tolerated and dose-escalation will cease if ≥33% of patients on 
that dose experience a DLT. Once the non-tolerated dose is defined, the MTD will be 
confirmed at a dose level below the non-tolerated dose or a dose between the non-tolerated 
dose and the last tolerated dose may be investigated. At least 6 evaluable patients are required 
to determine the MTD.
7.7.5
Definition of dose-limiting toxicity evaluable patient
For patients in treatment arms A1 and A4 (AZD9150/MEDI4736 or 
AZD9150/MEDI4736/tremelimumab), to be deemed evaluable for dose-escalation purposes, a 
patient must have received all 3 loading doses of AZD9150 during the 7-day lead-in period 
and at least 3 additional doses during Cycle 1 as well as the MEDI4736 and tremelimumab 
infusion during the DLT Evaluation period or have suffered a DLT within the first 35 days of 
treatment.
For patients in treatment arm A2 or A3 (AZD5069/MEDI4736 or 
AZD5069/MEDI4736/tremelimumab), to be deemed evaluable for dose-escalation purposes, a 
patient must have received all doses during the 7-day lead-in period (i.e., 14 doses) and at 
least 42 additional doses of AZD5069 or 50% of planned doses during the DLT Evaluation 
period) as well as the MEDI4736 infusion and remained active on trial at the end of Day 35 of 
the study.
7.7.6
Safety Review Committee
The SRC will be chaired by the Sponsor Study Team Physician (or delegate) and include the 
Investigator (or delegate) from each of the investigational sites. In addition, other physicians 
such as the Global Safety Physician (or delegate) or a senior physician from the same or 
another project, as well as the Clinical Pharmacology Scientist, Study Statistician, Patient 
Safety Scientist, Associate Director Study Management, and others may be invited as 

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appropriate. Further internal or external experts may be consulted by the SRC as necessary. 
The Global Safety Physician or delegate should always be present at the SRC if there are 
safety issues for discussion. The SRC Remit document for this study will define the exact 
membership and who should be present for decisions to be made.
The SRC will review and assess all available safety data from the cohort, with available PK 
and pharmacodynamics data to determine the dose for the next cohort of patients. Any dose 
interruptions and reductions (see Section 5.5 for dose modifications) will be taken into 
account.
Once a DLT has been observed, SRC may decide to:
1.
Expand the cohort to include additional patients
2.
De-escalate the dose either to a previous lower dose level (up to a maximum of 
6 evaluable patients) or to an intermediate lower dose level
3.
Stop the arm enrolment
When there are other patients ongoing at the time of this review, the SRC may decide to defer 
their decision until these further patients become evaluable.
Any patient started on treatment in error (e.g., he/she failed to comply with all of the selection 
criteria) who meets the criteria of a DLT evaluable patient will be reviewed on a case-by-case 
basis by the SRC to determine if the patient’s data should be included or excluded in the 
decision for dose escalation.
The decisions and decision-making of the SRC on the next dose level will be documented and 
provided to the Investigators before dosing any new patients.
7.7.7
Confirmation of the presumed recommended dose
Once the MTDs for each of the 2 agents in combination with MEDI4736 and/or 
MEDI4736/tremelimumab have been identified or the maximum doses of each of the 2 agents 
in combination with MEDI4736 and/or MEDI4736/tremelimumab have been reached, the 
SRC may decide to enroll an additional cohort of at least 6 evaluable patients per treatment 
arm to confirm the presumed recommended dose for each of the 2 agents in combination with 
MEDI4736 to be further explored in the dose-expansion Part B.
Dose-expansion Part B
Once the doses for AZD9150 and AZD5069 in combination with MEDI4736 have been 
established in Part A of the study as detailed in Section 5.3, the dose-expansion Part B will 
begin. If the RP2D combination is established earlier in one arm of Part A than the other, the 
Sponsor may manually assign patients to a pretreated arm (treatment arm B1/B2 as discussed 
below) of the determined RP2D combination to get safety data (for US sites ONLY). One 

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such patient was manually randomized to Arm B1; this patient will not be included for any 
efficacy analysis and could be replaced with an actual randomized patient. The doses for the 
monotherapy treatments will be determined by the SRC based on the experience with the 2 
agents gained in other trials and available at that time.
In the dose-expansion Part B, based on the patient’s history of treatment with any 
anti-PD-(L) 1 antibody, the Investigator will assess whether the patient will be assigned 
treatment in 1 of the anti-PD-(L)1 pretreated arms or naïve treatment arms. Additionally, 
Arms B7 and B8 will enroll patients who are PD-(L)-1 treatment naïve and have not received 
any prior systemic treatment for recurrent metastatic SCCHN. Also additionally, based on the 
patient’s history of taking any drugs, herbal supplements, and/or foods prohibited with 
concurrent administration of AZD5069 or within 14 days of the first dose of AZD5069 and 
detailed in Section 5.1.2 as well as the patient’s anticipated need or likelihood to consume 
such products at any time throughout the study, the Investigator will further assess each 
patient enrolled in the study to determine if the patient may be treated with AZD5069. Details 
regarding study arms for Part B can be found in Section 4.2. 
The dose-expansion Part B will use an adaptive approach to sample size based on Bayesian 
statistical methodology and so the number of actively enrolling treatment arms may decrease 
as the study continues. See Section 8.2.2 for details on sample size, conditions for stopping an 
arm, and the conduct of an interim analysis.
7.7.8
Definition of efficacy evaluable patient
As described in Section 8.2.2, the dose-expansion Part B is based on efficacy evaluable 
patients. Patients identified as not efficacy evaluable will be replaced.
An efficacy evaluable patient is defined as a patient with unidimensional measurable disease 
at baseline as per the RECIST v1.1 criteria, meeting all eligibility criteria, and who received at 
least 1 dose of study treatment. For combination arm patients this population will hence 
include all patients who have received at least one dose of combination.
7.8
Concomitant and other treatments 
Information on any treatment in the 30 days before starting study treatment and all 
concomitant treatments given during the study, including start and stop dates as well as the 
reasons for the treatment, will be recorded in the eCRF. If medically feasible, patients taking 
regular medication, with the exception of medications restricted during the course of the study 
(see Table 2 above) or herbal supplements, should be maintained on these medications 
throughout the study period.

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Other anticancer agents, investigational agents, and radiotherapy should not be given while 
the patient receiving study treatment, although radiation for palliation at focal sites is 
permitted.
Blood and blood product transfusions, including platelet infusions are allowed at any time 
during the study.
Patients already receiving erythropoietin at the time of screening for the study may continue 
the erythropoietin providing they have been receiving it for more than 1 month at the time 
study treatment is started. Prophylactic erythropoietin should not be started during the 7-day 
lead-in period and Cycle 1 in Part A (i.e., the DLT Evaluation period) but may be started 
during Cycle 2 or after at the discretion of the Investigator. There are no restrictions on the use 
of erythropoietin in Part B of the study.
Antiemetic premedication for nausea and granulocyte colony stimulating factors are permitted 
for use at the discretion of the Investigator. The use of either prophylactic antiemetic 
premedication for nausea or granulocyte colony stimulating factors is not permitted during the 
7-day lead-in period and Cycle 1 in Part A (i.e., the DLT Evaluation period); it may be started 
during Cycle 2 or after at the discretion of the Investigator. There are no restrictions on the use 
of antiemetic premedication for nausea and granulocyte colony stimulating factors in Part B of 
the study.
Patients may receive treatment with megestrol acetate when prescribed for appetite 
stimulation.
Patients may receive treatment with corticosteroids and/or bisphosphonates for the treatment 
of bone metastases.
Patients may take low molecular weight dextran. The use of Coumadin (warfarin) is not 
permitted in patients treated with AZD5069 but allowed for all other patients. It is 
recommended that patients treated with an anticoagulant should have their anticoagulation 
monitored carefully and dose adjusted accordingly.
Patients allocated to treatment with MEDI4736 may not receive live attenuated vaccines 
during the study and for 30 days after the last dose of MEDI4736. Non-clinical studies have 
demonstrated that MEDI4736 partially suppressed the primary antibody response to a T cell 
dependent antigen (keyhole limpet haemocyanin). Secondary antibody responses to this 
antigen were normal. The relevance of this finding with respect to a human immune response 
is theoretical; a reduction in humoral immunity may result in a reduced response to 
vaccination and increased risk of infection.

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As described in the previous section, patients treated with AZD5069, coadministration of 
drugs that are known potent or moderate CYP3A4 inhibitors, potent or moderate CYP3A4 
inducers, P-gp substrates with narrow therapeutic index, sensitive CYP2B6 substrates, 
warfarin or any other coumarin derivatives, BCRP-substrates that reduce blood neutrophils, 
and any herbal medications should be avoided. See Section 3.8.2 for details and Table 2 for a 
list of prohibited medications for patients administered AZD5069. Any questions regarding 
concomitant treatments in these patients should be referred to the Medical Monitor 
 
 (see Section 6.10 for contact information).
With the exceptions noted above, other medication that is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the Investigator and will be 
recorded in the appropriate sections of the eCRF.
Patients should abstain from donating blood and plasma during the study.
Investigators should carefully assess the risk in relation to benefit of using anticoagulation or 
other medications that might exacerbate bleeding during study participation. Investigators 
should consider discontinuation of these agents if the clinical scenario permits it unless 
discontinuation would be clinically contraindicated. For example, if the clinical condition for 
which anticoagulation/nonsteroidal anti-inflammatory drugs/aspirin is/are being used may be 
managed with an alternate agent/s that has a lower risk of bleeding, a substitution should be 
considered.
7.8.1
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
subject’s safety and well-being, may be given at the discretion of the Investigator and 
recorded in the appropriate sections of the CRF.
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ed
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8
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
!
Analyses will be performed by AstraZeneca or its representatives.
!
Refer to Statistical Analysis Plan (SAP) for further details.
!
For open-label studies, and if there is a regulatory requirement to submit SAP to 
regulatory agencies with the CSP, the SAP should be signed off before enrolment of the 
first subject. For all other studies, the SAP will be signed off before review of any 
potential treatment-revealing data is undertaken (this includes blinded delivery reviews 
and data monitoring committee reviews). For all situations, a full draft of the SAP should 
be available to ensure sufficient time to prepare for any blinded or unblinded data review.
8.2
Sample size estimate
8.2.1
Dose-escalation Part A
A CRM–based approach will be used to identify the set of AZD9150/MEDI4736 and 
AZD5069/MEDI4736 dose combinations where the incidence of DLT is no larger than 33%. 
In each cohort, up to 3 patients will be initially assessed. Dose-escalation to the next higher 
dose level for the next cohort group of 3 patients will occur if all 3 patients in the initial cohort 
complete Cycle 1 without DLT. Following the first DLT, the CRM model will be run and the 
output made available to the SRC to guide further dosing decisions.
The CRM model will use a stopping criterion based on posterior variance (posterior variance 
<0.03). When this criterion is met, the model will recommend that the trial be stopped. The 
dose with expected DLT incidence closest and below 0.33 at this point will be “model 
estimated” MTD. During trial execution, the SRC will determine the MTD. For the purposes 
of describing the operating characteristics of the model, the stopping criterion based on the
posterior variance will be the only criterion considered. Model performance is measured using 
simulation methods. In each case, the trial is simulated 10,000 times, and trials that select each 
MTD among the doses explored are counted. A logistic dose-toxicity model of the following 
form will be used:
p = {1 + exp(-a – (exp(beta)*dose)}^{-1},
where p is the probability of occurrence of a DLT; the intercept, a, is assigned a fixed value 
equal to 3; and the prior distribution of the slope parameter, beta, is assumed to be normal 
with mean=0 and variance=1.34.
In the case of AZD9150/MEDI4736, 4 dose levels are included. The start dose is the second 
highest dose level among the 4 dose levels. This is also the true MTD. The prior model 
assumes that the second dose is also the MTD. Using the posterior variance criterion above, 
the model selects the correct dose combination in 60.1% of simulated trials. The model selects 
the dose below the true MTD in 18.1% of simulated trials, and the dose above MTD in 21.8% 

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of simulated trials. On average, the number of patients treated at each of the 4 dose levels is 
5.7, 4.8, 3.0, and 1.3. The average number of DLTs at each of the 4 doses is 0.7, 1.5, 1.7, and 
1.0.
In the case of AZD5069/MEDI4736, 6 dose levels are included. The start dose is the third 
highest dose among the 6 dose levels. This true MTD is the fourth highest dose among the 
6 dose levels. The prior model assumes that the fourth dose is the MTD. Using the posterior 
variance criterion above, the model selects the correct dose combination in 50.9% of 
simulated trials. The model selects the dose below the true MTD in 22.2% of simulated trials, 
and the dose above MTD in 26.9% of simulated trials. On average, the number of patients 
treated at each of the 6 dose levels is 0.2, 1.2, 5.5, 4.5, 0.8, and 2.9. The average number of 
DLTs at each of the 6 dose levels is 0.0, 0.0, 0.6, 1.4, 0.45, and 2.3.
In Arm A3; 6-12 patients will be enrolled.
Approximately 18 patients will be enrolled in the safety run-in cohorts of AZD9150 or
AZD5069 in combination with MEDI4736 and tremelimumab (Arm A4).
Approximately 40 patients (approximately 20 patients with breast cancer and 20 patients with 
prostate cancer) will be enrolled in Arm A6.
These sample sizes are selected based on the need to gather and confirm safety, MTD/RP2D, 
PK/pharmacodynamic information in solid relapsed/refractory patient population for further 
exploration in next trials.
8.2.2
Dose-expansion Part B
The dose-expansion Part B will use an adaptive approach to sample size based on Bayesian 
statistical methodology (Figure 9). 
Anti-PD-(L)1 naïve patients 
For the 2 combination arms in the anti-PD-(L)1 naïve patients (B3 and B4), once 12 efficacy 
outcomes have been observed in the first 12 efficacy evaluable patients in each arm, a 
predictive power calculation will be used to assess the chance of observing at least 8 of 
35 responses (either PR or CR) in each arm. The method of calculating predictive power is 
based on a parameter free approach to predictive power as it applies to variables that follow a 
binomial distribution (Jennison and Turnbull 2000). Predictive power (chance to observe at 
least 8 of 35 responses) will be recalculated following the observation of the efficacy outcome 
in each efficacy evaluable patient as they were dosed in the trial. If, following the observation 
of any patient’s outcome, predictive power falls below 20%, the arm in which this happens 
will be stopped. If predictive power remains at or above 20% following the 19th efficacy 
evaluable patient then an interim analysis will be conducted following the 20th efficacy 

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evaluable patient. Each of the combination arms will continue to enroll patients up to a 
maximum of 35 efficacy evaluable patients following the interim analysis if at least 
5 of 20 patients have responded with at least a PR. 
Predictive power monitoring will not be performed for the 2 monotherapy groups (B5 and B6) 
in dose-expansion Part B and the 1L RM SCCHN patients in Arm B7. The 2 monotherapy 
arms will continue recruiting until 12 efficacy evaluable patients have been enrolled in each 
arm.
Anti-PD-(L)1 pretreated patients
For the 2 combination arms in the anti-PD-(L)1 pretreated patients (B1 and B2), once efficacy 
outcomes have been observed in the first 10 efficacy evaluable patients in each arm, a 
predictive power calculation will be used to assess the chance of observing at least 3 of 20 of 
responses (either partial or complete) in each arm. Predictive power (chance to observe at least 
3 of 20 responses) will be recalculated following the observation of the efficacy outcome in 
each efficacy evaluable patient as they were dosed in the trial. If, following the observation of 
any patient’s outcome, predictive power falls below 20%, the arm in which this happens will 
be stopped. However, no formal interim analysis will be conducted for the combination arms 
in the anti-PD-(L)1 pretreated patients.
Recruitment will continue while predictive power is measured. If an arm is to be stopped, no 
new patients will be recruited but patients who are already on study will continue in 
accordance with study guidelines outlined in Section 4.
If at least 2 CRs or PRs are observed in the first 20 patients in either of the 2 pretreated 
expansion arms, an additional 25 to 32 patients may be enrolled to that particular pretreated 
combination arm.
An efficacy evaluable patient is defined as a patient with unidimensional measurable disease 
at baseline as per the RECIST 1.1 criteria who received at least 1 dose of study treatment.
Simulation methods (10,000 simulated trials) were used to estimate the operating 
characteristics of the dose-expansion studies. The expected sample size for a series of true 
ORR values for the combination therapy arms are presented in Table 14 below. These 
simulation data show that between 207 and approximately 255 patients are expected to be 
treated in all 8 randomized arms of the dose-expansion Part B (B1 to B8).
The sample size is based on the operating characteristics of a decision procedure using a beta 
binomial posterior distribution based on observed data assuming a non-informative prior.

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Table 14
Expected sample sizes for a series of true objective response rates for 
combination therapy in anti-PD-(L)1 naïve and anti-PD-(L)1 pretreated 
patients
True objective response rate of combination therapy
Expected sample sizea
Naïve
Pretreated
0.25
0.15
121.3
0.25
0.05
121.5
0.25
0.025
121.3
0.15
0.15
114.9
0.15
0.05
115
0.15
0.025
115
0.05
0.15
103.9
0.05
0.05
103.8
0.05
0.025
103.7
a
The results are averaged over the corresponding set of naïve and pretreated values. The expected sample 
size includes 12 patients in each of the 2 monotherapy arms.
Thus, with the study design and interim assessments as described above, the chance to stop a 
combination arm in anti-PD-(L)1 naïve patients given an optimistic true ORR value (0.45 for 
naïve and 0.31 for pretreated patients) is approximately 19.3%. The chance to stop a 
combination arm in anti-PD-(L)1 pretreated patients is approximately 11.7%. If the true ORR 
performance of the combination arms is low (i.e., approximately 10% for naïve, 5% for 
pretreated), the chance that any combination will stop before fully recruiting is >98% for 
naïve and >94% for pretreated.

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Figure 9
Adaptive approach to sample size Part B (B1-B6)

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If at least 2 CR or PR are observed in the first 20 patients in either of the 2 pretreated 
expansion arms (Arm B1 or B2), then an additional 25-32 patients may be enrolled.
In addition, Arms B7 and B8 will enroll patients who have not received prior systemic 
treatment for RM SCCHN and will receive combination treatment of AZD9150 in 
combination with MEDI4736. With approximately 48 patients in each arm, the chance that 
fewer than 12 patients with CR or PR (responding) will be observed, given the true fraction of 
patients responding is 35%, is 9%. The chance that at least 15 patients responding is observed,
given the true fraction of patients responding is 25%, is 20%. In addition, B8 will incorporate 
predictive power monitoring for futility beginning with the 15th patient. If at any time from 
the 15th patient through the 48th patient, the chance to observe 13 responses in 48 patients 
falls below 20%, then the arm will be stopped.
In anti-PD-(L)1 pretreated patients, approximately 10 to 52 patients will be treated in each of 
the 2 combination therapy arms (B1, B2). In anti-PD-(L)1 naïve patients, approximately 12 to 
35 patients will be treated in each of the 2 combination therapy arms (B3 or B4). If in Arm B4, 
the arm is stopped due to lack of efficacy at the IA (following N=20) a higher dose may be 
tested under the original sample size requirements (N=35) so the total number of patients in 
Arm B4 would then be N=55 (N=20 from the original IA and N=35 under the original design 
for Arm B4). In anti-PD-(L)1 naïve patients, 12 patients will be treated in each of the 
2 monotherapy arms (B5, B6). In addition, Arms B7 and B8 each will enroll up to 48 patients 
who have not received any PD-L1 therapies and have received no prior systemic treatment for 
RM SCCHN. As a result, the total number of patients in Part B will be between 207 and 
approximately 255.
8.3
Definitions of analysis sets
The analysis of data will be based on different subsets according to the purpose of the analysis. 
Throughout the safety results sections, erroneously treated patients (e.g., those assigned to 
receive dose A, who actually received dose B, those who failed to meet the selection criteria) 
will be accounted for in the actual dose group received.

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Table 15
Analysis sets
Analysis Set
Definition
Safety
All patients who received at least 1 dose of AZD9150, AZD5069, 
or MEDI4736
Pharmacokinetics
All dosed patients with reportable AZD9150, AZD5069, or 
MEDI4736 plasma concentrations and no important AEs or 
protocol deviations that may impact PK
Pharmacodynamics
All patients who provided biological samples for 
pharmacodynamic research
Efficacy
All patients with unidimensional measurable disease at baseline as 
per the RECIST 1.1 criteria who received at least 1 dose of study 
treatment
8.3.1
Efficacy analysis set
All patients with unidimensional measurable disease at baseline as per the RECIST 1.1 criteria 
who received at least 1 dose of study treatment.
8.3.2
Safety analysis set
All patients who received at least 1 dose of AZD9150, AZD5069, or MEDI4736
tremelimumab (for patients in Arm A4).
8.3.3
PK analysis set
All patients who provided biological samples for pharmacodynamic research.
8.3.4
PD analysis sets
All patients who provided biological samples for pharmacodynamic research.
8.4
Calculation or derivation of safety variables
Safety and tolerability will be assessed in terms of AEs, SAEs, laboratory data, vital signs, 
ECG changes, and physical examinations. These will be collected for all patients. Appropriate 
summaries of these data will be presented.
ECG changes
Immediate clinical management of patients will be according to local assessment of the QT 
interval. For the CSR, QTc will be calculated using Fridericia’s formula:
QTcF=QT/(3√RR).

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Creatinine clearance
Creatinine clearance may be measured by 24-hour urine collection or calculated by using the 
Cockcroft and Gault equation (Cockcroft and Gault 1976).
For creatinine values in μmol/L:
Men: [(140-age) × weight (kg)×1.23)]/serum creatinine (μmol/L)]
Females: [(140-age) × weight (kg)×1.04)]/serum creatinine (μmol/L)]
For creatinine values in mg/dL:
Men: [(140-age) × weight (kg)/[72×serum creatinine (mg/dL)]
Females: 0.85 × [(140-age)×weight (kg)/[72×serum creatinine (mg/dL)]
Other significant adverse events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs. Based on the expert’s judgement, AEs of particular clinical importance may, 
after consultation with the Global Safety Physician, be considered other significant AEs 
(OAEs) and reported as such in the CSR. A similar review of laboratory values, vital signs, 
ECGs, and other safety assessments will be performed for identification of OAEs.
8.5
Calculation or derivation of pharmacokinetic variables
Pharmacokinetic analysis of plasma (for all compounds) and urine (for AZD9150 only) 
concentration data for AZD9150, AZD5069, and MEDI4736 will be performed by a central 
laboratory on behalf of AstraZeneca. The actual sampling times will be used in the parameter 
calculations and PK parameters will be derived using standard non-compartmental methods.
Where possible, the following PK parameters will be determined for AZD9150, AZD5069, 
and MEDI4736.
Pharmacokinetic parameters for AZD9150:
!
Single dose: Cmax, Tmax, AUC(0-∞), AUC(0-t), AUC(0-48), CL, Vz/F, MRT, t1/2, as data permit
!
Multiple dose: Css max, Css min, Tss max, Ctrough, AUC(0-24), Vss, extent of accumulation on 
multiple dosing (Rac), Ae, and %Fe
Pharmacokinetic parameters for AZD5069:
!
Single dose: Cmax, Tmax, AUC(0-∞), AUC(0-t), AUC(0-24), apparent plasma clearance (CL/F), 
apparent volume of distribution (Vd/F), MRT, and t1/2, as data permit

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!
Multiple dose: Css max, Tss max, Ctrough, AUC(0-24), Vss/F, apparent plasma clearance at 
steady state (CLss/F), Rac
Pharmacokinetic parameters for MEDI4736:
!
Cmax, Tmax, Ctrough
The Cmax, the Css max, Tmax, and the Tss max will be determined by inspection of the 
concentration-time profiles. Where possible the terminal elimination rate constant (λz) will be 
calculated by log-linear regression of the terminal portion of the concentration-time profiles 
where there are sufficient data and the terminal (elimination) half-life (t1/2λz) will be calculated 
as ln 2/λz. The AUC(0-t) and the AUC(0-24/48) will be calculated using the linear up, log down 
trapezoidal rule. Where appropriate, the AUC(0-t) will be extrapolated to infinity using λz to 
obtain AUC. The area under the concentration-time curve across the dosing interval, AUC(ss)
will be calculated using the linear up, log down trapezoidal rule. The CL/F following the 
single dose and CLss/F following multiple dosing) will be determined from the ratio of 
dose/AUC or dose/AUC(ss). The volume of distribution (Vss, Vss/F, or Vz/F) will be determined 
from the MRT×CL/F and/or the accumulation ratio (RAC) will be calculated as the ratio of the 
AUC(0-24) on Cycle 2 Day 1. The time dependency of the PK on multiple dosing will be 
assessed by the calculation of the ratio of AUC(ss)/AUC(single dose).
8.6
Calculation or derivation of pharmacodynamic variables
Change from baseline and percent change from baseline for pharmacodynamic variables will 
be calculated for all patients.
8.7
Pharmacokinetics/Pharmacodynamic analysis
The plasma concentration data for AZD9150, MEDI4736, tremelimumab, and AZD5069 may 
be analysed using a population PK approach, which may include exploring the influence of 
covariates on PK, if the data allows. A population pharmacodynamic approach will be used to 
investigate the relationship between PK and selected primary, secondary, and/or exploratory 
endpoints, where deemed appropriate. Results may be reported separately from the CSR for 
the main study. The PK, pharmacodynamic, demographic, safety, and tumor response 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. The results of any such analyses 
will be reported separately from the CSR.
8.8
Calculation or derivation of exploratory research variables
Results from the exploratory biomarker research and/or pharmacogenetic research will be 
reported separately from the CSR for the main study.

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8.9
Calculation or derivation of tumor response variables
At each visit, patients will be programmatically assigned a RECIST version 1.1 overall visit 
response of CR, PR, SD, or PD, not evaluable (NE) depending on the status of their disease 
compared with baseline and previous visit assessments.
Progression of TLs will be calculated in comparison to when the tumor burden was at a 
minimum (i.e., smallest sum of diameters previously recorded on study, including baseline). 
In the absence of progression, tumor response (CR, PR, and SD) will be calculated in 
comparison to the baseline tumor measurements obtained before starting treatment.
If a patient has had a tumor assessment that cannot be evaluated (either because the scan was 
unreadable or taken before Day 15 of Cycle 2), the patient will be assigned an overall visit 
response of NE unless there is evidence of progression, in which case the response will be 
assigned as PD.
For TL measurements, if one-third of the TL sizes are missing then a scaling up rule will be 
applied as follows:
!
If ≤ one-third of all lesions recorded at baseline are missing, the results will be scaled up 
(based on the nadir sizes, including baseline) to give an estimated sum of diameters and 
this will be used in calculations. (This is equivalent to comparing the visit sum of 
diameters of the non-missing lesions to the nadir sum of diameters excluding the lesions 
that are missing and determining at what rate the lesions are changing.)
!
If > one-third of all lesions recorded at baseline are missing, the TL response will be NE. 
However, if the sum of non-missing TL diameters would result in PD (i.e., if using a 
value of 0 for missing lesions the sum of diameters has still increased by >20% or more 
compared with the smallest sum of diameters on study); PD takes precedence over NE.
!
Only responses of PR, SD, PD, or NE will be permitted if any of the TL data are missing.
An overall visit response of CR is defined when all TL and NTL lesions present at baseline 
have disappeared (with the exception of lymph nodes, which must be less than 10 mm to be 
considered non-pathological) and no new lesions have developed since baseline. An overall 
visit response of PR is defined when the sum of diameters of the TLs has decreased by 30% or 
more compared with baseline (with no evidence of progression) and the NTLs are at least 
stable with no evidence of new lesions. To be assigned a status of PR or CR, changes in tumor 
measurements must be confirmed by repeat assessments that should be performed no less than 
4 weeks after the criteria for response are first met.
SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD. In the case of SD, follow-up measurements must have met the SD criteria at 
least once after study entry at a minimum interval of not less than 35 days.

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When the Investigator is in doubt as to whether PD has occurred and therefore reassesses the 
patient at a later date, the date of the initial scan should be declared as the date of progression 
if the repeat scans confirm progression.
Best overall response
A best overall response (CR, PR, SD, PD, or NE ordered from best to worst here) will be 
determined for each patient based on the best overall visit response recorded from start of 
study treatment to the EOT, including any assessments for confirmation after the EOT. 
Confirmation (values of CR or PR in the case of PR and CR for CR is required for best overall 
response values of CR or PR).
Objective response
A patient is said to have an objective response if he/she has had at least 1 response of 
confirmed CR or PR before any evidence of progression (as defined by RECIST version 1.1) 
that is confirmed at least 4 weeks later.
Disease control
A patient is said to have achieved disease control at a given visit if they have a tumor response 
of SD, PR, or CR at that visit. Disease control will be assessed at 12 weeks after the start of 
study drug and is defined as the proportion of all patients dosed that have an overall visit 
response of SD, PR, or CR at Week 12. Therefore, earlier overall visit responses of CR or PR 
that become PD at Week 12 or NE responses at Week 12 do not constitute disease control at 
12 weeks. A time window of 1 week around the Week 12 visit will be applied, and it is 
recommended that any visits occurring 11 weeks or more after dosing are acceptable; 
however, if an earlier visit is defined as PD, the overall visit response at Week 12 would also 
be defined as PD. If the Week 12 overall response is missing or NE but the next evaluable 
response is SD or better, the patient will be defined as having an overall visit response of SD, 
PR, or CR at 12 weeks.
Duration of response
Duration of response will be defined as the time from the date of first documented confirmed 
response until date of documented progression or death in the absence of disease progression. 
The end of response should coincide with the date of progression or death from any cause 
used for the PFS endpoint. The time of the initial response will be defined as the latest of the 
dates contributing towards the first overall visit response of PR or CR.
If a patient does not progress following a response, then his/her DOR will use the PFS 
censoring time.

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Durable response
A patient is said to have a durable response of 3 months if they have either a confirmed CR or 
PR that lasts 3 months following the initial confirmation of the response.
Progression-free survival
Progression-free survival is defined as the time from start of treatment (Cycle 1, Day 1) 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 before 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 
version 1.1 assessment. However, if the patient progresses or dies after 2 or more missed 
visits, the patient will be censored at the time of the latest evaluable RECIST version 1.1 
assessment. If the patient has no evaluable visits or does not have baseline data, he/she will be 
censored at 0 days unless he or she dies within 2 visits of baseline.
The PFS time will always be derived based on scan/assessment dates not visit dates.
RECIST version 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
!
When censoring a patient for PFS the patient will be censored at the latest of the dates
contributing to a particular overall visit assessment
Overall survival
Overall survival is defined as the time from the date of Cycle 1, Day 1 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.
Survival at 12 months
Patients who are alive 1 year following the beginning of treatment are said to have survived 
12 months. Patients whose vital status is unknown at 12 months will be censored at the last 
date that the patient was known to be alive.
8.10
Methods of statistical analysis
The statistical analyses will be performed 
, under the direction of the Early 
Clinical Biometrics Group, AstraZeneca.
The methods outlined below apply to Parts A and B unless specified otherwise.
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Patients who have a dose modification during the trial will be presented according to the dose 
group to which they were initially assigned.
Data will be presented separately for each combination group (cohort) within Part A and by 
anti-PD-(L)1 status and treatment arm in Part B. Further, within arms A6 and A7, data will be 
presented by primary indication (metastatic breast [ER+ve for Arm A6, 50% ER+ve and 50% 
HER2+ve metastatic breast cancer patients for Arm A7] or castrate-resistant prostate cancer).
Data for the combination cohorts in Part A will be presented in order of increasing order of 
expected probability of DLT as illustrated in Table 16 and Table 17.
Table 16
Expected probability of DLT in treatment arm A1 of Part A 
(AZD9150/MEDI4736)
Ranked in 
Increasing Order of 
Expected 
Probability of DLT
Dose of AZD9150 
(mg/kg)
Dose of MEDI4736 
(mg/kg)
Note
1
2
10
2
2
20
Planned starting combination
3
3
10
4
3
20
Abbreviation: DLT=dose-limiting toxicity.
Table 17
Expected probability of DLT in treatment arm A2 of Part A 
(AZD5069/MEDI4736)
Ranked in 
Increasing Order of 
Expected 
Probability of DLT
Dose of AZD5069 
(mg) BID
Dose of MEDI4736 
(mg/kg)
Note
1
20
3
2
20
10
3
40
10
Planned starting combination
4
80
10
5
80
3
6
120
10
Abbreviations: BID=twice daily; DLT=dose-limiting toxicity.
Data for the 8 randomised treatment arms in dose-expansion Part B will be presented in the 
following order:

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1.
Anti-PD-(L)1 naïve patients – AZD9150 monotherapy
2.
Anti-PD-(L)1 naïve patients – AZD5069 monotherapy
3.
Anti-PD-(L)1 naïve patients – AZD9150 + MEDI4736
4.
Anti-PD-(L)1 naïve patients – AZD5069 + MEDI4736
5.
Anti-PD-(L)1 pretreated patients – AZD9150 + MEDI4736
6.
Anti-PD-(L)1 pretreated patients – AZD5069 + MEDI4736
7.
Anti-PD-(L)1 naïve patients – AZD9150+MEDI4736-1L
8.
Anti-PD-(L)1 naïve patients – AZD9150 (flat dose) + MEDI4736 (flat dose)-1L
Demographic data
Characteristics of the patients, including medical history and disease characteristics at 
baseline, will be listed for each patient and summarised by cohort.
Reasons for discontinuation of IP will be listed, including the study day of treatment 
discontinuation, and will be summarised by cohort.
Exposure
Exposure to IP (i.e., total amount of study drug received) will be listed for all patients by 
cohort.
Total exposure (date of last dose minus date of first dose + 1) and total time on study (date of 
discontinuation minus date of first dose + 1) will be summarised by the following: Mean, 
standard deviation, minimum, maximum, median, and number of observations. In addition, 
the number and percentage of patients with at least 1 dose interruption/dose delay and at least 
1 dose-reduction will be presented separately for the initial period of evaluability defined as 
28 days and for any time following this initial period of the study.
Relative dose intensity and percentage intended dose for AZD9150, AZD5069, and 
MEDI4736 will be derived and summarised by the following: Median, minimum, maximum, 
75th percentile, 25th percentile, and number of observations. Relative dose intensity is the 
percentage of actual dose intensity delivered relative to the intended dose intensity through 
treatment discontinuation. The entire intended treatment period will be used in the derivation 
of relative dose intensity.
Safety
No inferential testing will be performed on safety data. Safety data will be summarised using 
descriptive statistics. At the end of the study, appropriate summaries of all safety data will be 
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AEs will be listed individually by patient and treatment group. For patients who have a dose 
modification, all AEs (due to drug or otherwise) will be assigned to the associated initial dose 
combination/treatment dose.
AESIs will also be summarised and listed separately for each compound.
The number of patients experiencing each AE will be summarised by the Medical Dictionary 
for Regulatory Activities (MedDRA) system organ class, MedDRA preferred term and 
CTCAE grade. The number and percentage of patients with AEs in different categories (e.g., 
causally related, CTCAE ≥3) will be summarised by dose group, and events in each category 
will be further summarised by MedDRA system organ class and preferred term, by cohort (as 
appropriate). SAEs and other significant AEs will be summarised separately if a sufficient 
number occur.
Any AE occurring before the first dose of IP will be included in the data listings but will not 
be included in the summary tables of AEs. Summary tables will include only AEs observed 
following the beginning of combination dosing up to and including 28 days after last dose. 
One table summarising the incidence of AE occurring from the beginning of monotherapy up 
to the beginning of combination therapy will be generated. 
Any AE occurring within the defined 28-day follow-up period after discontinuation of IP will 
be included in the AE summaries. AEs occurring after the 28-day follow-up period after 
discontinuation of IP will be listed separately but not included in the summaries.
Haematology, clinical chemistry, vital signs, and ECG data will be listed individually by 
patient and suitably summarised. For all laboratory variables, which are included in the 
current version of CTCAE, the CTCAE grade will be calculated. Summary statistics of mean, 
median, standard deviation, minimum, maximum, and number of observations will be used.
Details of any deaths will be listed for all patients.
For urinalysis parameters, any qualitative assessments will be summarised for all patients 
using the number of patients with results of negative, trace, or positive.
Graphical presentations of safety data will be presented as is deemed appropriate. This may 
include, but is not restricted to, presentation of parameters against time, concentration or shift 
plots. Appropriate scatter plots will also be considered to investigate trends in parameters 
compared with baseline.

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Pharmacokinetics
Plasma concentrations for each of the drug substances AZD9150, AZD5069, tremelimumab,
and MEDI4736 measured within each of the combination groups with any associated 
metabolites will be summarised by nominal sample time.
The following summary statistics will be presented for plasma concentrations at each time 
point and for the following PK parameters including, AUC, AUC(0-24), AUC(0-48), AUC(0-t), 
AUC(ss), Cmax, Css max, Ctrough, and Css min:
!
The geometric mean (calculated as exp [μ], where μ is the sample mean of the data on a
logarithmic scale)
!
Coefficient of variation (calculated as 100 √ [exp(s2)-1], where s is the standard deviation
of the data on a log-scale)
!
Gmean ± standard deviation (calculated as exp[μ±s])
!
Arithmetic mean calculated using untransformed data
!
Standard deviation calculated using untransformed data
!
Minimum
!
Maximum
!
Number of observations
The following summary statistics will be presented for CL, CL/F, CLss/F, volume of
distribution, t1/2λz, Rac, Ae, and % dose excreted:
!
Arithmetic mean
!
Standard deviation
!
Minimum
!
Maximum
!
Number of observation
The following summary statistics will be presented for Tmax and Tmax ss:
!
Median
!
Minimum
!
Maximum
!
Number of observations
The PK data for AZD9150, MEDI4736, tremelimumab, and AZD5069 will also be displayed
graphically as appropriate. Displays will include plasma concentration patient profiles (on the
linear and log-scale) versus time and gmean concentration (± standard deviation) versus time,
stratified by cohort and others as necessary.

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Pharmacodynamics
Pharmacodynamic variables will be summarised using descriptive statistics (n, mean, standard 
deviation, median, minimum, maximum) by visit and cohort.
Summaries of change from baseline and percent change from baseline will also be presented 
for pharmacodynamic variables by visit and cohort.
Immunohistochemistry scores will be plotted as a function of dose combination. 
Histograms for each of the pharmacodynamic variables will also be presented by visit and 
dose.
Pharmacokinetics/pharmacodynamics
Scatterplots of each pharmacodynamic variable as a function of plasma concentrations of 
MEDI4736, AZD5069, tremelimumab, or AZD9150 may be presented. 
Population analysis of pharmacokinetic/pharmacodynamic variables
The plasma concentration data for AZD9150, MEDI4736, tremelimumab, and AZD5069 may 
be analysed using a population PK approach, which may include exploring the influence of 
covariates on PK, if the data allow. A population pharmacodynamic approach will be used to 
investigate the relationship between PK and selected primary, secondary, and/or exploratory 
endpoints, where deemed appropriate. Results may be reported separately from the CSR for 
the main study. The PK, pharmacodynamic, demographic, safety, and tumor response 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. The results of any such analyses 
will be reported separately from the CSR.
Exploratory biomarker research and pharmacogenetics
Results will be reported separately and will not be part of the CSR.
Tumor response
Tumor response data will be summarised for dosed patients with measurable disease at 
baseline and separately for dosed patients who only had non-measurable disease at baseline.
Tumor response data will be listed and summarised by cohort using the following response 
categories: CR, PR, SD, PD, and NE.
The number (%) of patients with a response of CR, PR, or SD at the beginning of each even-
numbered cycle and at the EOT visit will be summarised.

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Waterfall plots (bar charts) indicating the percentage change from baseline at Week 12, and 
best percentage change from baseline in sum of the diameters of TLs will be produced by 
cohort.
The number (%) of patients who have a confirmed response (complete or partial) who have a 
durable response will be summarised.
For Part B, duration of overall response will be analysed using Kaplan-Meier (KM) methods, 
where patients who do not progress before dying will be censored at time of death or at the 
administrative end of the trial.
Best overall response
For patients with baseline measurable disease, best overall response will be summarised for 
the number (%) of patients in each category of response (CR, PR, SD, PD, or NE, ordered 
from best to worst here). Confirmation of CR and PR responses is required.
For Part B, an exact 2-sided 80% CI will be computed using the method of Clopper and 
Pearson (Clopper and Pearson 1934). Summaries only will be provided as appropriate for 
Part A.
Objective response rate
Objective response rate is defined as the proportion of patients who have an objective 
response (confirmed CR or PR) at a given visit. The ORR will be summarised by treatment 
group. For the primary endpoint in Part B, an exact 2 sided 80% CI for the ORR will be 
computed using the method of Clopper and Pearson (Clopper and Pearson 1934).
If there is a sufficient distribution of overall response observed in the study, the relationship 
between biomarkers and ORR may be explored using logistic regression.
Disease control rate
Disease control rate is defined as the proportion of patients who have achieved disease control 
at a given visit. Disease control rate will be summarised by treatment and visit. For Part B, an 
exact 2-sided 80% CI will be computed using the method of Clopper and Pearson (Clopper 
and Pearson 1934) at 12 weeks. Summaries only will be provided as appropriate for Part A.
Duration of response
Duration of response will be summarised using KM based methods and will include minimum, 
25th percentile, median, 75th percentile, and maximum. Kaplan-Meier plots will also be 
presented. Only patients who achieve an overall response will be included in this analysis.

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Durable response rate
Durable response rate is defined as the percentage of patients who have a durable response. 
The denominator for the durable response rate will be the efficacy analysis set (see
Section 8.3).
Progression-free survival
Progression-free survival will be analysed using KM methods in an exploratory manner. 
Summaries of PFS (number of events, medians, quartiles, and proportion progression free at 1, 
2, 3, and 4 months after the first dose of IP) will be presented.
If there is a sufficient number of PFS events observed in the study, the relationship between 
biomarkers and PFS may be explored using Cox regression.
Overall survival
Summaries of OS (n, deaths, medians, quartiles), and KM plots will be provided as 
appropriate.
If there is a sufficient number of OS events observed in the study, the relationship between 
biomarkers and OS may be explored using Cox regression.
Proportion of patients surviving at 12 months
The proportion of patients surviving at 12 months will be presented. An exact 2-sided 80% CI
will be computed using the method of Clopper and Pearson (Clopper and Pearson 1934). In 
addition, OS at 12 months will be estimated using the survival probability at 12 months from 
the KM analyses.

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9
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site staff
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the CSP and related documents with the investigational staff 
and also train them in any study-specific procedures and web-based system(s) utilised.
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).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:
!
Provide information and support to the Investigator(s)
!
Confirm that facilities remain acceptable
!
Confirm that the investigational team is adhering to the CSP, 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 subject’s
medical records at the hospital or practice, and other records relevant to the study)
including verification of informed consent of participating subjects. This will require
direct access to all original records for each subject (e.g., clinic charts)
!
Ensure withdrawal of informed consent to the use of the subject’s biological samples is
reported and biological samples are identified and disposed of/destroyed accordingly, and
the action is documented, and reported to the subject.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.2.1
Source data
Source documents provide evidence for the existence of the patient and substantiate the
integrity of the data collected. Source documents are filed at the Investigator’s site. Data
reported on the CRF that are transcribed from source documents must be consistent with the
source documents or the discrepancies must be explained. The Investigator may need to
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.

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9.2.2
Study agreements
The Principal Investigator at each/the centre 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 CSP shall 
prevail with respect to the conduct of the study and the treatment of subjects and in all other 
respects, not relating to study conduct or treatment of subjects, the terms of the Clinical Study 
Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or subjects are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement.
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last subject undergoing the study’.
The study may be terminated at individual centres if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow. AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with AZD5069, AZD9150, MEDI4736, and tremelimumab.
9.4
Data management by AstraZeneca 
Data management will be performed 
, according to the Data Management 
Plan.
The data collected through third party sources will be obtained and reconciled against study 
data.
AEs and medical/surgical history will be classified according to the terminology of the latest 
version the Medical Dictionary for Regulatory Activities (MedDRA). Medications will be 
classified according to the WHO Drug Dictionary. All coding will be performed by the 
Medical Coding Team 
.
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 
Redacted
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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, clean file will be declared. Any 
treatment-revealing data may thereafter be added and the final database will be locked.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data Management of genotype data
Any genotype data generated in this study will be stored at a secure system at AstraZeneca
and/or designated organizations to analyse the samples.
AstraZeneca and its designated organizations 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 organizations, 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 patient 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.
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratories internal or 
external to AstraZeneca. Any genotype data generated in this study will be stored in the
AstraZeneca genotyping LIMS database or other appropriate secure system within
AstraZeneca and/or third party contracted to work with AstraZeneca to analyse samples. The
results from this genetic research will be reported separately from the clinical study report for
the main study. Some or all of the clinical datasets from the main study may be merged with
the genetic data in a suitable secure environment separate from the clinical database.
Management of external data
The data collected through third party sources will be obtained and reconciled against study 
data.
Data from external providers (e.g., central laboratories) will be validated as appropriate to 
ensure it is consistent with the clinical data and included in the final database. In the case of 
biomarker (tumor tissue or blood for exploratory analyses) data, the results of any analyses 

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will not be recorded in the database, but information relating to the processing of the sample, 
including the original date of biopsy (historical tumor tissue sample and the actual date the 
sample[s] were collected) will be recorded in the eCRF and database.
10
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH)/GCP, applicable regulatory requirements and the AstraZeneca policy on Bioethics and 
Human Biological Samples.
10.2
Subject data protection
The Informed Consent Form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
10.3
Ethics and regulatory review
An Ethics Committee should approve the final CSP, including the final version of the ICF and 
any other written information and/or materials to be provided to the subjects. The Investigator 
will ensure the distribution of these documents to the applicable Ethics Committee, and to the 
study site staff.
The opinion of the Ethics Committee should be given in writing. The Investigator should 
submit the written approval to AstraZeneca before enrolment of any subject into the study. 
The Ethics Committee should approve all advertising used to recruit subjects for the study.
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the CSP should be re-approved by the Ethics Committee 
annually.
Before enrolment of any subject into the study, the final CSP, including the final version of 
the ICF, is approved by the national regulatory authority or a notification to the national 
regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.

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AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements.
Each Principal Investigator is responsible for providing the Ethics Committees/IRBs 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/she can meet these reporting requirements.
10.4
Informed consent
The Principal Investigator(s) at each centre will:
!
Ensure each subject is given full and adequate oral and written information about the
nature, purpose, possible risk and benefit of the study
!
Ensure each subject is notified that they are free to discontinue from the study at any time
!
Ensure that each subject is given the opportunity to ask questions and allowed time to
consider the information provided
!
Ensure each subject provides signed and dated ICF 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 subject
!
Ensure that any incentives for subjects who participate in the study as well as any
provisions for subjects harmed as a consequence of study participation are described in
the ICF that is approved by an Ethics Committee.
10.5
Changes to the Clinical Study Protocol and Informed Consent 
Form
Study procedures will not be changed without the mutual agreement of, National Co-
ordinating Investigator, and the Principal Investigator and AstraZeneca.
If there are any substantial changes to the CSP, then these changes will be documented in a 
new version of the study protocol.
The new version of the CSP is to be approved by the relevant Ethics Committee and if 
applicable, also the national regulatory authority approval, before implementation. Local 
requirements are to be followed for new versions of CSPs.
AstraZeneca will distribute any new versions of the CSP to each Principal Investigator(s). For 
distribution to Ethics Committee see Section 10.3.
If a change to a CSP requires a change to a centre’s ICF, AstraZeneca and the centre’s Ethics 
Committee are to approve the revised ICF before the revised form is used.

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10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification. The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the CSP, GCP, guidelines 
of the ICH, and any applicable regulatory requirements. The Investigator will contact 
AstraZeneca immediately if contacted by a regulatory agency about an inspection at the 
centre.

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11
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Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life-threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (e.g., hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it
may be (e.g., bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or
convulsions that do not result in hospitalisation
Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality, consider the following factors when deciding if 
there is a ‘reasonable possibility’ that an AE may have been caused by the drug.

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!
Time Course. Exposure to suspect drug. Has the subject actually received the suspect
drug? Did the AE occur in a reasonable temporal relationship to the administration of the
suspect drug?
!
Consistency with known drug profile. Was the AE consistent with the previous
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same
pharmacological class? Or could the AE be anticipated from its pharmacological
properties?
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose
of the suspect drug?
!
No alternative cause. The AE cannot be reasonably explained by another aetiology such
as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a
‘reasonable possibility’ of a causal relationship for the individual case. The expression
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgement. With limited or insufficient information in the 
case, it is probably 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 B
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Appendix B
Further Guidance On The Definition Of A Serious Adverse 
Event (SAE)
Life-threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (e.g., hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (e.g., bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
! Angioedema not severe enough to require intubation but requiring iv hydrocortisone
treatment
! Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with
N-acetylcysteine
! Intensive treatment in an emergency room or at home for allergic bronchospasm
! Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc) or
convulsions that do not result in hospitalisation
Development of drug dependency or drug abuse

Clinical Study Protocol Appendix B
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A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.
! Time Course. Exposure to suspect drug. Has the subject actually received the suspect drug?
Did the AE occur in a reasonable temporal relationship to the administration of the suspect
drug?
! Consistency with known drug profile. Was the AE consistent with the previous knowledge
of the suspect drug (pharmacology and toxicology) or drugs of the same pharmacological
class? Or could the AE be anticipated from its pharmacological properties?
! De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose
of the suspect drug?
! No alternative cause. The AE cannot be reasonably explained by another aetiology such as
the underlying disease, other drugs, other host or environmental factors.
! Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.
! Laboratory tests. A specific laboratory investigation (if performed) has confirmed the
relationship.
In difficult cases, other factors could be considered such as:
! Is this a recognized feature of overdose of the drug?
! Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgement. With limited or insufficient information in the 
case, it is probable 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 C
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Appendix C
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm). 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 fatal disease in 
otherwise healthy humans or animals. Category A pathogens are e.g., Ebola, Lassa fever 
virus:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for
inclusion in Category A. Category B pathogens are e.g., Hepatitis A, B, C, D, and E viruses,
Human immunodeficiency virus (HIV) types 1 and 2. They are assigned the following UN
number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations
!
Clinical trial samples will routinely be packed and transported at ambient temperature in
IATA 650 compliant packaging
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm)
!
Biological samples transported in dry ice require additional dangerous goods
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and
transportation and packing should be done by an IATA certified person, as applicable
!
Samples routinely transported by road or rail are subject to local regulations which
require that they are also packed and transported in a safe and appropriate way to contain
any risk of infection or contamination by using approved couriers and packaging /
containment materials at all times. The IATA 650 biological sample containment
standards are encouraged wherever possible when road or rail transport is used.

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Appendix D
Ethical and Regulatory Requirements
1.
ETHICAL AND REGULATORY REQUIREMENTS
1.1 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 the ICH/ GCP guidelines, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
1.2 Ethics and regulatory review
An Ethics Committee should approve the final CSP, including the final version of the ICF and 
any other written information and/or materials to be provided to the patients. This will include 
approval of the exploratory biomarker and pharmacogenetic research and associated 
consent(s) forms. The Investigator will ensure the distribution of these documents to the 
applicable Ethics Committee, and to the study site staff. 
The opinion of the Ethics Committee should be given in writing. The Investigator should 
submit the written approval to AstraZeneca before enrolment of any patient into the study. If 
applicable this approval should clearly state that the exploratory biomarker and 
pharmacogenetic research is approved. 
The Ethics Committee 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 CSP should be re-approved by the Ethics Committee
annually.
Before enrolment of any patient into the study, the final CSP, including the final version of the 
ICF, is approved by the national regulatory authority or a notification to the national 
regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements, including SUSARs 
(Suspected Unexpected Serious Adverse Reactions), where relevant.

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Each Principal Investigator is responsible for providing the Ethics Committees/Institutional 
Review Board (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/she can meet these reporting requirements.
1.3 Informed consent
Any incentives for patients who participate in the study as well as any provisions for patients 
harmed as a consequence of study participation should be described in the ICF that is 
approved by an Ethics Committee.
The Principal Investigator at each centre will:
!
Ensure that each patient is given full and adequate oral and written information about the
nature, purpose, possible risk and benefit of the study and the optional exploratory
biomarker and genetic research component(s)
!
Ensure that each patient is notified that they are free to withdraw from the study or the
research components 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 each original, signed ICF is stored in the Investigator’s Study File
!
Ensure a copy of each signed ICF is given to the patient
The exploratory biomarker and genetic research component(s) of this study are voluntary and 
the patient may participate in the main study without participating in the exploratory 
biomarker and/or genetic research part(s) of the study. To participate in the exploratory 
biomarker and/or genetic component of the study the patient should sign and date the consent 
form for the main study and as applicable separate consent forms for the exploratory 
biomarker and/or the genetic components of the study.
1.4 Changes to the Clinical Study 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 CSP, then these changes will be documented in a 
CSP Amendment and where required in a new version of the CSP (Revised Protocol).
The amendment should be approved by each Ethics Committee and if applicable, also the 
national regulatory authority, before implementation. Local requirements should be followed 
for Revised Protocols.

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AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator. For distribution to Ethics Committee see Section 1.2.
If a protocol amendment requires a change to a centre’s ICF, AstraZeneca and the centre’s 
Ethics Committee should approve the revised ICF before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
1.5 Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification. The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the CSP, GCP, guidelines 
of the ICH, and any applicable regulatory requirements. The Investigator will contact 
AstraZeneca immediately if contacted by a regulatory agency about an inspection at the centre.

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Appendix E
Data and Study Management
1.
DATA AND STUDY MANAGEMENT
1.1 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. 
Due to the exploratory nature of the biomarker and genetic research, there will be no routine 
communication of these results to patients. AstraZeneca will not provide individual results to 
patients, any insurance company, any employer, their family members, general physician or 
any other third party, unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca physician or an Investigator might know a patient’s 
identity and also have access to his/her genetic data. Also regulatory authorities may require 
access to the relevant files, though the patient’s medical information and the genetic files 
would remain physically separate.
1.2 Pre-study activities
Before the first patient is entered into the study, it is necessary for a representative of 
AstraZeneca to visit the investigational study site to:
!
Determine the adequacy of the facilities
!
Determine availability of appropriate patients for the study
!
Discuss with the Investigator(s) (and other personnel involved with the study) their
responsibilities with regard to CSP adherence, and the responsibilities of AstraZeneca or
its representatives. This will be documented in a Clinical Study Agreement between
AstraZeneca and the Investigator
1.3 Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca representative will visit the 
study site to review and discuss the requirements of the CSP and related documents with the 
investigational staff and also to train them in any study-specific procedures including 
collection of samples and the WBDC system utilised. The additional requirements for the 
collection of the patients’ samples for the exploratory biomarker and genetic research will also 
be clarified.

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The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of the 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 staff members involved in the study 
(medical, nursing and other staff).
1.4 Source data
Refer to the Clinical Study Agreement for location of source data.
1.5 Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study sites, 
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 CSP including the specific
requirements of the biomarker and genetic research, that data are being accurately and
timely recorded in the CRFs, and that IP 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 the ICF(s)of participating patients. This will require direct access
to all original records for each patient (e.g., clinic charts)
!
If applicable, 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 centre needs information and advice about the study conduct.
1.6 Data management
Data management will be performed 
 on behalf of AstraZeneca.
Data entered in the WBDC system or data captured electronically will be immediately saved 
to the applicable database and changes tracked to provide an audit trail.
The data collected through third party sources will be obtained and reconciled against study 
data.
AEs and medical/surgical history will be classified according to the terminology of the latest 
version the Medical Dictionary for Regulatory Activities (MedDRA). Medications will be 
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classified according to the AstraZeneca Drug Dictionary. All coding will be performed 
 
 on behalf of AstraZeneca.
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.
When all data have been coded, validated, signed and locked, clean file will be declared. Any 
treatment-revealing data may thereafter be added and the final database will be locked.
Genotype data generated in this study will be stored in the AstraZeneca genotyping 
Laboratory Information Management System (LIMS) database, or other appropriate secure 
system, separate from the database used for the main study.
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database. The results from this 
genetic research will be reported separately from the Clinical Study Report for the main study.
1.7 Study agreements
The Principal Investigator at each centre 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 CSP shall prevail with 
respect to the conduct of the study and the treatment of patients and in all other respects, the 
terms of the Clinical study Agreement shall prevail.
Specific reference to requirements relating to this optional biomarker and genetic 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 patients be enrolled.
1.7.1
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement.
1.8 End of study
The end of the study is defined as the last visit of the last patient undergoing the study.
R
ed
Redacted

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The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow. AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with AZD9150.

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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 RECIST 1.1 Guidelines (Eisenhauer et al 2009) 
for the study with regards to Investigator assessment of tumor burden including CSP-specific 
requirements for this study.
2.
DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET AND NON-
TARGET LESIONS
Only patients with measurable disease at baseline should be included in the study. Measurable 
disease is defined by the presence of at least one measurable lesion which has not been 
previously irradiated. 
Measurable:
A lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in 
the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with CT or 
magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.
Non-measurable:
!
All other lesions, including small lesions (longest diameter <10 mm or pathological
lymph nodes with ≥10 to <15mm short axis at baseline).
!
Truly non-measurable lesions include the following: bone lesions, leptomeningeal disease,
ascites, pleural / pericardial effusion, inflammatory breast disease, lymphangitic
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by
physical examination that is not measurable by CT or MRI.
!
Previously irradiated lesions
!
Skin lesions assessed by clinical examination
!
Brain metastasis
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.
Target lesions:

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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 
target lesions (TL) at baseline.
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 and the same technique should be used to characterize 
each identified and recorded lesion at baseline and during follow-up visits.
A summary of the methods to be used for RECIST assessment is provided below and those 
excluded from tumor assessments for this study are highlighted, with the rationale provided.
Table 1: Summary of Methods of Assessment
Target Lesions 
Non-Target Lesions
New Lesions
CT (preferred)
MRI
CT (preferred)
MRI
Clinical examination 
Plain X-ray (includes Chest X-
ray)
CT (preferred)
MRI
Clinical examination 
Plain X-ray (includes Chest 
X-ray)
Ultrasound
Bone Scan
FDG-PET
3.1 CT and MRI 
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TL selected for response assessment and to assess NTL and identification 
of any new lesions. 
In this study it is recommended that CT examinations will be used to assess tumor burden at 
baseline and follow-up visits. CT examination with intravenous (i.v.) contrast media 
administration is the preferred method. MRI should be used where CT is not feasible or it is 
medically contraindicated. For brain lesion assessment, MRI is the preferred method.
3.2 Clinical examination

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In this study, clinical examination will not be used for assessment of TL. Clinically detected 
lesions can be selected as target lesions 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.
3.3 X-ray
3.3.1
Chest X-ray
Chest X-ray assessment will not be used for assessment of TL as they will be assessed by CT 
examination or MRI examination. Chest X-ray can, however, be used to assess NTL and to 
identify the presence of new lesions.
3.3.2
Plain X-ray 
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
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
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated 
in the context of tumor assessment.
3.6 Tumor markers
Tumor markers will not be used for tumor response assessments as per RECIST 1.1.
In this study CA-125 will be collected for patients with ovarian cancer for separate analysis 
However, the results will not contribute to tumor response based on RECIST 1.1 assessment.
3.7 Cytology and histology 
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 SD. 

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In such circumstances, the cytology is necessary to differentiate between response/SD (an 
effusion may be a side effect of the treatment) and PD (if the neoplastic origin of the fluid is 
confirmed). Where cytology findings are not available, any effusion that significantly worsens 
(from trace to large) or appearance of clinically significant effusion (requiring change in drug 
therapy) during the study treatment will be considered to be progression of NTL, or disease 
progression due to new lesions. 
3.8 Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI or 
X-ray at baseline should be recorded as NTL and followed by the same method as per baseline
assessment.
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. New lesions will be recorded where a positive hot-spot that 
was not present on the baseline bone scan assessment is identified on a bone scan performed 
at any time during the study. The Investigator should consider the positive hot-spot to be a 
significant new site of malignant disease and represent true disease progression in order to 
record the new lesion. Confirmation by CT, MRI and X-ray is recommended where bone scan 
findings are equivocal.
3.9 FDG-PET scan 
FDG-PET scans may be used as a method for identifying new lesions, according with the 
following algorithm: New lesions will be recorded where there is positive FDG uptake not 
present on baseline FDG-PET scan or in a location corresponding to a new lesion on CT/MRI 
at the same follow-up visit. If there is no baseline FDG-PET scan available, and no evidence 
of new lesions on CT/MRI scans then follow-up CT/MRI assessments should be continued, 
scheduled as per CSP or clinical indicated, in order to confirm new lesions.
4.
TUMOR RESPONSE EVALUATION
4.1 Schedule of evaluation
Baseline assessments should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based 
on signs and symptoms of individual patients and should be performed no more than 30 days 
before the start of study treatment. Follow-up assessments will be performed every 6 weeks (± 
1 week) until objective disease progression as defined by RECIST 1.1 or withdrawal of 
consent. In addition to the above, for Japanese sites only, an additional assessment is 
performed at Day 1 of Cycle 2 (± 3 days). Any other sites at which new disease is suspected 
should also be adequately imaged at follow-up.

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4.2 Target lesions (TL)
4.2.1
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved should be identified as TL at baseline. 
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions), but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest lesion, 
which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimeters. At baseline the sum of the diameters for all TL will be calculated and reported as 
the baseline sum of diameters. At follow-up visits the sum of diameters for all TL will be 
calculated and reported as the follow-up sum of diameters.
Special cases:
For TL measurable in 2 or 3 dimensions, always report the longest diameter. For pathological 
lymph nodes measurable in 2 or 3 dimensions, always report the short axis. 
!
If the CT/MRI slice thickness used is > 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 TL merge then the sum of the diameters of the combined lesion should be
recorded for one of the lesions and 0 mm recorded for the other lesion(s).
!
If a TL is believed to be present and is faintly seen but too small to measure, a default
value of 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, e.g., radiotherapy, embolisation, surgery etc., during
the study, the size of the TL should still be provided where possible.

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4.2.2
Evaluation of target lesions
This Section provides the definitions of the criteria used to determine objective tumor visit 
response for TL.
Table 2: Evaluation of target lesions
Complete Response (CR)
Disappearance of all target lesions since baseline. Any 
pathological lymph nodes selected as target lesions must have a 
reduction in short axis to < 10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking 
as reference the baseline sum of diameters
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD
Progressive Disease (PD)
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5mm.
Not Evaluable (NE)
Only relevant if any of the target lesions were not assessed or not 
evaluable or had a lesion intervention at this visit. Note: If the sum 
of diameters meets the PD criteria, PD overrides not evaluable as 
a target lesion response
4.3 Non-Target lesions (NTL)
4.3.1
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.

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Table 3: Evaluation of Non-Target Lesions
Complete Response (CR)
Disappearance of all non-target lesions since baseline. All lymph 
nodes must be non-pathological in size (< 10 mm short axis).
Non CR/Non PD
Persistence of one or more NTL 
Progression (PD)
Unequivocal progression of existing non-target lesions. 
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.
Not Evaluable (NE)
Only relevant when one or some of the non-target lesions were not 
assessed and, in the Investigator's opinion, they are not able to
provide an evaluable overall non-target lesion assessment at this 
visit.
Note: For patients without target lesions at baseline, this is 
relevant if any of the non-target lesions were not assessed at this 
visit and the progression criteria have not been met.
To achieve ‘unequivocal progression’ on the basis of non-target lesions, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target lesions 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 
one or more new lesions is assessed as progression. 
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: i.e., not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumor.
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 is a reason for 
stopping study therapy.

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Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumor 
assessments where possible until objective disease progression is observed.
4.6 Evaluation of Overall Visit Response
The overall visit response will be derived using the algorithm shown in Table 4.
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 TL/NTLs at baseline).
5.
SPECIFICATIONS FOR RADIOLOGICAL IMAGING
These notes are recommendations for use in clinical studies. The use of standardized protocols 
for CT and MRI allows comparability both within and between different studies, irrespective 
of where the examination has been undertaken.
5.1 CT Scan
CT scans of the chest, abdomen, and pelvis should be contiguous throughout all the anatomic 
region of interest.
The most critical CT image acquisition parameters for optimal tumor evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval.

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a. Anatomic coverage: Optimal anatomic coverage for most solid tumors is the chest, 
abdomen and pelvis. 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 time points. This will enable better 
consistency not only of tumor measurements but also identification of new disease.
b. IV contrast administration: Optimal visualisation and measurement of metastases in solid 
tumors requires consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. Typically, most abdominal imaging is performed during the portal venous phase and 
(optimally) about the same time frame after injection on each examination. An adequate 
volume of a suitable contrast agent should be given so that the metastases are demonstrated to 
best effect and a consistent method is used on subsequent examinations for any given patient. 
It is very important that the same technique be used at baseline and on follow- up 
examinations for a given patient. For patients who develop contraindications to contrast after 
baseline contrast CT is done, the decision as to whether non-contrast CT or MRI (enhanced or 
non-enhanced) should be performed should also be based on the tumor type, anatomic 
location of the disease and should be optimised to allow for comparison to the prior studies if 
possible. Each case should be discussed with the radiologist to determine if substitution of 
these other approaches is possible and, if not, the patient should be considered not evaluable 
from that point forward. Care must be taken in measurement of target lesions on a different 
modality and interpretation of non-target disease or new lesions, since the same lesion may 
appear to have a different size using a new modality. Oral contrast is recommended to help 
visualise and differentiate structures in the abdomen. 
If iodine contrast media is medically contraindicated at baseline or at any time during the 
course of the study then the recommended methods are: CT thoracic examination without 
contrast and abdominal and pelvis MRI with contrast. If MRI cannot be performed then CT 
without i.v. contrast is an option for the thorax, abdomen and pelvis examination. For brain 
lesions assessment, MRI is the preferred method. 
c. Slice thickness and reconstruction interval: It is recommended that CT scans be 
performed at 5mm contiguous slice thickness and this guideline presumes a minimum 5 mm 
thickness in recommendations for measurable lesion definition. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses greater than 5 mm. If 
this occurs, the minimum size of measurable lesions at baseline should be twice the slice 
thickness of the baseline scans.

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All window settings should be included in the assessment, particularly in the thorax where 
lung and soft tissue windows should be considered. When measuring lesions, the TL should 
be measured on the same window setting for repeated examinations throughout the study. All 
images from each examination should be included in the assessment and not “selected” 
images of the apparent lesion.
5.2 MRI Scan
MRI has excellent contrast, spatial and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity 
and measurement. Furthermore, the availability of MRI is variable globally. The modality 
used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. Generally, axial imaging of the abdomen and 
pelvis with T1 and T2 weighted imaging along with gadolinium-enhanced imaging should be 
performed. The field of view, matrix, number of excitations, phase encode steps, use of fat 
suppression and fast sequences should be optimised for the specific body part being imaged as 
well as the scanner utilised. It is beyond the scope appendix to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts and diseases. Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans. Body scans should be performed with breath-hold scanning techniques 
if possible.
For these reasons, CT is the imaging modality of choice.
5.3 FDG-PET scans 
FDG-PET has gained acceptance as a valuable tool for detecting, staging and restaging several 
malignancies. If FDG-PET scans are included in a protocol, an FDG uptake period of 60 
minutes prior to imaging has been decided as the most appropriate for imaging of patients 
with malignancy. Whole-body acquisition is important since this allows for sampling of all 
areas of interest and can assess if new lesions have appeared thus determining the possibility 
of interval progression of disease. Images from the base of the skull to the level of the mid-
thigh should be obtained 60 minutes post-injection. PET camera specifications are variable 
and manufacturer specific, so every attempt should be made to use the same scanner, or the 
same model scanner, for serial scans on the same patient. Whole-body acquisitions can be 
performed in either 2- or 3-dimensional mode with attenuation correction, but the method 
chosen should be consistent across all patients and serial scans in the clinical trial.

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5.3.1
PET/CT scans
At present, low dose or attenuation correction CT portions of a combined PET–CT are of 
limited use in anatomically based efficacy assessments and it is therefore suggested that they 
should not be substituted for dedicated diagnostic contrast enhanced CT scans for 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 to a diagnostic CT (with IV 
and oral contrast) 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 
data that may bias an Investigator if it is not routinely or serially performed.
6.
REFERENCES
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R. New response 
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer 45 
(2009) 228-247

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Appendix G
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
1.
INTRODUCTION
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. 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 6.9.1 of the CSP.
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 PHL 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory.
The Investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The Investigator participates 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 IP. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
2.
DEFINITIONS
Potential Hy’s Law (PHL)
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in ALP. 

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Hy’s Law (HL)
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than 
the IP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e., on 
the same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
3.
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 subject who meets any of the following identification criteria in 
isolation or in combination:
!
ALT ≥ 3 × ULN
!
AST ≥ 3 × ULN
!
TBL ≥ 2 × ULN
Central laboratories being used:
When a subject meets any of the PHL 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 without delay
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original local
laboratory test result
When the identification criteria are met from central or local laboratory results, the 
Investigator will without delay:
!
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix for
definition) by reviewing laboratory reports from all previous visits (including both central
and local laboratory results)

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Local laboratories being used:
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Determine whether the patient meets PHL criteria (see Section 2 Definitions within this
Appendix for definition) by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory CRF
4.
FOLLOW-UP
4.1 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 CSP.
4.2 Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
!
Determine whether PHL criteria were met at any study visit prior to starting study
treatment (see Section 6 of this Appendix)
!
Notify the AstraZeneca representative who will then inform the central Study Team
!
Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of
PHL; serious criteria ‘important medical event’ and causality assessment ‘yes/related’
according to CSP process for SAE reporting
!
For subjects that met PHL criteria prior to starting IP, the Investigator is not required to
submit a PHL SAE unless there is a significant change# in the patient’condition
!
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an
approach for the study patients’ follow-up and the continuous review of data.
!
Subsequent to this contact the Investigator will:
!
Monitor the patient until liver biochemistry parameters and appropriate clinical
symptoms and signs return to normal or baseline levels, or as long as medically
indicated. Complete the follow-up SAE Form as required
!
Investigate the aetiology of the event and perform diagnostic investigations as
discussed with the Study Physician. This includes deciding which the tests
available in the HL lab kit should be used
!
Complete the 3 Liver CRF Modules as information becomes available

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5.
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.
As soon as possible 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 IP, 
to ensure timely analysis and reporting to health authorities within 15 calendar days from date 
PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and Global Safety 
Physician will also be involved in this review with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where 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 an 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: update the previously submitted
PHL AE/SAE CRFs accordingly with the new information (reassessing event
term; causality and seriousness criteria) following the AstraZenca standard
processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP:
!
Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard
processes.
∀
The ‘medically important’ serious criterion should be used if no other
serious criteria apply
∀
As there is no alternative explanation for the HL case, a causality assessment
of ‘related’ should be assigned
If, there is an unavoidable delay, of over 15 calendar days 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:
!
Provides any further update to the previously submitted SAE of PHL, (report
term now ‘Hy’s Law case’) ensuring causality assessment is related to IP and
seriousness criteria is medically important, according to CSP process for SAE
reporting

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!
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are still met. Update the previously submitted 
PHL SAE report following CSP process for SAE reporting, according to the 
outcome of the review and amending the reported term if an alternative 
explanation for the liver biochemistry elevations is determined
6.
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW CRITERIA ARE MET 
BEFORE AND AFTER STARTING STUDY TREATMENT 
This Section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment.
At the first on-study treatment occurrence of PHL criteria being met the Investigator will
determine if there has been a significant change in the patients’ condition# compared with the 
last visit where PHL criteria were met#
!
If there is no significant change, no action is required
!
If there is a significant change, notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Section 4.2 of this Appendix
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBL) 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.
7.
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW
This Section is applicable when a  patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found to 
be the disease under study, e.g., chronic or progressing malignant disease, severe 
infection or liver disease, or did the patient meet PHL criteria prior to starting study 

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treatment and at their first on study treatment visit (as described in Section 6 of this 
Appendix)?
If No: Follow the process described in Section 4.2 of this Appendix for reporting PHL as an 
SAE.
If Yes: Determine if there has been a significant change in the subject’s condition# compared 
with when PHL criteria were previously met.
!
If there is no significant change no action is required
!
If there is a significant change follow the process described in Section 4.2 of this
Appendix for reporting PHL as an SAE
# 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 TBL) 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.
8.
LABORATORY TESTS
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory when using a central laboratory. For studies using a local 
laboratory, the list may be modified based on clinical judgement. If required, additional 
assistance on which tests could be used to evaluate other potential causes of liver dysfunction 
consult with the Hepatic Safety Knowledge Group. Any test results need to be recorded.
Law lab kit for central laboratories (18 December 2018)
Additional standard chemistry and 
coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgG anti-HCV
HCV RNA* 
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
CD-transferrin**

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Autoimmune hepatitis
ANA
Anti-LKM Ab
ASMA
Metabolic diseases
Alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
* HCV RNA is only tested when IgG anti-HCV is positive or inconclusive
** CD-transferrin is not available in China. Study teams should amend this list accordingly
Abbreviations: Ab=antibody; ANA=antinuclear antibody; ASMA=anti-smooth muscle Ab; CD=carbohydrate
deficient; CMV=cytomegalovirus; DNA=deoxyribonucleic acid; EBV=Epstein-Barr virus; GGT=gamma-
glutamyl transferase; HAV=Hepatitis A virus; HBc=Hepatitis B core; HBsAg=Hepatitis B surface antigen;
HBV=Hepatitis B virus; HCV=Hepatitis C virus; HEV= Hepatitis E virus; HSV=Herpse simplex virus;
IgG=Immunoglobulin G; IgM=Immunoglobulin M; INR=international normalized ratio; LDH=lactate
dehydrogenase; LKM=liver/kidney microsomal; RNA=ribonucleic acid.
REFERENCES
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case 
definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther 
2011;89(6):806-15.
FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury –
Premarketing Clinical Evaluation. 
Revision History
Version
Description of Change
1.0
The previous version of the Hy’s Law Appendix E was not numbered. Version 
numbering introduced with version 2.0 of the SOP Detection and Handling of Potential 
Hy’s Law Cases And Hy’s Law Cases In Clinical Studies AZDoc0007120 
Document revised with updated SOP.
2.0
Section 8 Laboratory Tests revised to clarify tests are recommended.
Table of tests updated to include footnotes.

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Appendix H
MEDI4736 Adverse Events of Special Interest
1.
MEDI4736 ADVERSE EVENTS OF SPECIAL INTEREST
1.1 Immune-related adverse events (general)
An immune-related AE (irAE) is defined as a clinically significant AE of unknown etiology of 
any organ that is associated with drug exposure and is consistent with an immune-mediated 
mechanism. Serologic, immunologic, and histologic (biopsy) data should be used to support 
an irAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the irAE.
If the Investigator has any questions in regards to an AE being an irAE, the Investigator 
should immediately contact the Study Physician.
1.2 Pneumonitis
If new or worsening pulmonary symptoms (e.g., dyspnoea or cough) or radiological 
abnormalities occur in the absence of a clear diagnosis, an interruption in study treatment 
dosing is recommended and further diagnostic work-up should be performed to exclude 
pneumonitis. The differential diagnosis should include the possibility of both immune-related 
and non-immune related processes. AEs of pneumonitis are of interest for AstraZeneca as 
pneumonitis has been observed with use of anti-PD-1 monoclonal antibodies (mAbs), 
(although not with anti-PD-L1 mAbs), and instances of pneumonitis have been reported in 
patients undergoing olaparib treatment.
Initial work-up should consider the inclusion of a clinical evaluation, high-resolution CT scan, 
ruling out infection, pulse oximetry, and other appropriate laboratory work-up. Pulmonary 
consultation is highly recommended. Guidelines for the management of patients with irAEs 
including pneumonitis are provided in MEDI4736 Annex 1.
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then study treatment can be restarted, if deemed appropriate by the 
Investigator. If significant pulmonary abnormalities are identified, these need to be discussed 
with the Study Physician.
1.3 Infusion reactions
AEs of infusion reactions (also termed infusion-related reactions) are of special interest to 
AstraZeneca and are defined, for the purpose of this CSP, as all AEs occurring from the start 
of study drug infusion up to 48 hours after the infusion start time. For all infusion reactions, 
the eCRF should be completed as instructed in Section 7.1.4, and all SAEs should be reported 
to AstraZeneca Patient safety as described in Section 7.1.5.

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1.4 Hypersensitivity reactions
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-
PD-L1 and anti-PD-1 therapy. As with the administration of any foreign protein and/or other 
biologic agents, reactions following the infusion of mAbs can be caused by various 
mechanisms, including acute anaphylactic (immunoglobulin E-mediated) and anaphylactoid 
reactions against the mAbs and serum sickness. Acute allergic reactions may occur, may be 
severe, and may result in death. Acute allergic reactions may include hypotension, dyspnoea, 
cyanosis, respiratory failure, urticaria, pruritis, angioedema, hypotonia, arthralgia, 
bronchospasm, wheeze, cough, dizziness, fatigue, headache, hypertension, myalgia, vomiting, 
and unresponsiveness. Guidelines for the management of patients with hypersensitivity 
(including anaphylactic reaction) and infusion-related reactions are provided in MEDI4736 
Annex 1.
1.5 Hepatic function abnormalities (hepatotoxicity)
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 
3 × ULN and concurrent increase in TBL to be greater than 2 × ULN. Concurrent findings are 
those that derive from a single blood draw or from separate blood draws taken within 8 days 
of each other. Follow-up investigations and inquiries will be initiated promptly by the 
investigational site to determine whether the findings are reproducible and/or whether there is 
objective evidence that clearly supports causation by a disease (e.g., cholelithiasis and bile 
duct obstruction with distended gallbladder) or an agent other than the study medication. 
Guidelines for management of patients with hepatic function abnormality are provided in 
MEDI4736 Annex 1.
1.6 Endocrine disorders
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and 
hyper- and hypothyroidism. Guidelines for the management of patients with immune-
mediated endocrine events are provided in MEDI4736 Annex 1.
1.7 Neurotoxicity
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis. Guidelines for the management of 
patients with immune-mediated neurotoxic events are provided in MEDI4736 Appendix J.

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Annex 1 Toxicity Management Guidelines for Durvalumab (MEDI4736)
The most current version of these guidelines is maintained within the Site Master File. In 
addition, a version of the current Dosing Modifications and Toxicity Management Guidelines 
is available through the following link: https://tmg.azirae.com. Please contact the clinical 
research associate for information on how to gain access to this website.