Conditions: Metastatic Pancreatic Ductal Adenocarcinoma
Keywords: Pancreatic Ductal Adenocarcinoma, PDAC, immunotherapy, PDL1, AZD5069, MEDI4736
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

Brief summary:
A Phase Ib and II Open-Label, Multi-Center Study of MEDI4736 Evaluated in Different Combinations (with chemotherapy or AZD5069) in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

Detailed description:
This is a Phase Ib and II open-label, multi-center study to evaluate the safety, tolerability, pharmacodynamics, and antitumor activity of MEDI4736 in combination with chemotherapy or AZD5069 in patients with pancreatic ductal adenocarcinoma (PDAC). This study will consist of 2 independent cohorts.

Arms:
arm 1: MEDI4736 in combination with nab-paclitaxel + gemcitabine chemotherapy regimen via IV infusion arm 2: MEDI4736 via IV infusion and oral AZD5069

Interventions: intervention 1: MEDI4736 in combination with nab-paclitaxel and gemcitabine intervention 2: MEDI4736 in combination with AZD5069
Intervention descriptions: intervention 1: MEDI4736 in combination with nab-paclitaxel + gemcitabine chemotherapy regimen via IV infusion intervention 2: MEDI4736 via IV infusion and oral AZD5069

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol (CSP), ANGEL
Version 17.0
Template Form Doc ID: LDMS_001_00026737
Parent Doc ID: SOP AZDoc0018580
Clinical Study Protocol 
Drug Substance
MEDI4736 and AZD5069
Study Code
D4198C00003
Edition Number
5.0
Date
08 February 2018
A Phase Ib and II Open-Label, Multi-Center Study of MEDI4736 Evaluated 
in Different Combinations in Patients with Metastatic Pancreatic Ductal 
Adenocarcinoma
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
2(176)
VERSION HISTORY
Version 5.0, 08 February 2017
Main changes to the protocol are summarised below,
Substantial changes:
1. Synopsis, Section 2.2 (Secondary objectives of Cohort 1 and Cohort 2), Section 
8.4.3.2 (Pharmacokinetic analysis)
−
Rationale for change: Serum and plasma are used as matrices for PK 
analysis. Standard noncompartment methods will not be used due to low 
volume of data
2.
Section 1.3.2.1 (Potential risks MEDI4736), Section 6.7.1.1 and Appendix E 
−
Rationale for update: updated to reflect MEDI4736 (Durvalumab) 
Investigational Brochure Edition 12 
3. Section 1.3.2.2 (Potential risks AZD5069) 
−
Rationale for change: Neutropenia/Neutrophil count decreased is 
considered expected for regulatory purposes in the respiratory indication 
only, and not yet in the oncology population (change arising from alignment 
with the CTFG Guidelines).
4. Section 8.4.2.3 (Safety assessments) and Section 8.5.1 (Efficacy data)
−
Rational for change: Additional sensitivity analysis for Overall Response 
Rate was removed as it will not be conducted due to lack of meaningful 
contribution to the interpretation of the data
In addition, there are non-substantial changes made in the protocol amendment that are 
listed below. These are inclusive of administrative changes made to the amendment, 
clarifying existing protocol text and correcting existing discrepancies between different 
sections of protocol.
Please note: Minor clerical corrections are not detailed in this Summary of Changes 
document.
Non substantial changes:
1. Section 8.4.2.4 (Secondary endpoints): Corrected errors in disease control rate
Version 4.0, 17 July 2017
Main changes to the protocol are summarised below,
Substantial changes:
1. Synopsis, Section 1.2, Section 6.7.: Language was updated to reflect the initial 
dosing of AZD5069 at 80 mg po bid, with provision for dose reductions described in 
Section 6.7.3. Text throughout protocol has been updated for consistency. 
−
Rationale for update: updated to reflect that the adopted current RP2D for 
AZD5069 from the D5660C00004 (SCORES) study.  The revised dosing 
scheme (previously included as Appendix F in the previous version of this 


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
3(176)
protocol) is now presented in the toxicity management section of our study 
(section 6.7.3).
2. Synopsis, Section 2 & Section 8: Primary objective was clarified to be inclusive of 
safety and tolerability of MEDI4736 + AZD5069 in combination, thus separate 
safety objective was removed.
−
Rationale for clarification: the protocol had originally separated out safety 
as a separate safety objective. This has now been clarified that safety is 
primary objective which now aligns with the statistical analysis plan for the 
study. 
3. Section 1.1.2: Section has been updated to include the most current clinical data 
available for MEDI4736.
−
Rationale for change: to update background data based on updated IB 
4. Synopsis & Section 3.1:  Inclusion criteria #3 text was simplified and Cohort 2 
progression timeline for prior therapy was removed.
−
Rationale for change: Significant simplification and clarification of entry 
criterion #3 has been taken in response to investigator feedback and queries 
about eligibility.  Limiting the patient population to PDAC patients with 
metastatic disease and a single prior line of therapy is intended to make the 
patient population more homogeneous.  This will enhance our ability to 
understand the meaning of responses without compromising the primary 
endpoint in this initially small study.  
5. Section 3.1, section 3.3, Section 4, Section 5.1: Added inclusion criteria #9 (cohort 
2) for taking mandatory tumor biopsy in screening period (or <45 days prior to first 
dosing if adequate tissue samples are available). Text throughout protocol has been 
updated for consistency. 
−
Rationale for change: this has been the intent of the original protocol but 
discrepancy between protocol sections has been addressed and the intent is 
reflected more clearly via addition of the requirement in eligibility criteria 
and in schedule of procedures. 
In addition, there are non-substantial changes made in the protocol amendment that are 
listed below. These are inclusive of administrative changes made to the amendment, 
clarifying existing protocol text and correcting existing discrepancies between different 
sections of protocol. 
Please note: Minor clerical corrections are not detailed in this Summary of Changes 
document.
Non substantial changes:
1. Synopsis: Statistical methods for Cohort 1 narratives will be replaced with 
programmed listings.
2. Section 1.1.3: Section formatting was corrected.
3. Section 3.1 & Section 7.2:  Inclusion criteria #7 SI units were added.
4. Section 4, Section 5.1: Clarification for archival tumor sample at screening, that they 
are mandatory to be collected, if available.
5. Section 4: Clarification regarding sample requirements.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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6. Section 5.5: Clarification that there will be no exploratory biomarker research on 
samples from cohort 1 patients.
7. Section 5.5.1.2: Clarification on sample handling.
8. Section 5.5.1.1: Clarification that there will be no exploratory biomarker research on 
samples from cohort 1 patients.
9. Section 5.5.3: AZD5069 data will also be pooled with biomarker data from other 
studies.
10. Appendix F deleted since text was incorporated in Section 6.7.3.
Version 3.0, 14 December 2016
Main changes to the protocol are summarised below,
All Sections:  Language has been updated to reflect the current enrolment status of Cohort 1 
as recruitment has been permanently stopped in this Cohort.
All Sections:  Language has been updated to reflect the how analysis of Cohort 1 will 
change as recruitment was stopped after only 3 patients had been enrolled.
Synopsis:  Added an additional International Coordinating Investigator for Cohort 2.
Synopsis, Objectives Cohort 1:  Objectives have been updated as only 3 patients will be 
available for analysis.
Synopsis, Objectives Cohort 2:  Objectives have been updated to reflect the new 
exploratory objectives for the Cohort 2 population.
Synopsis, Investigational product, dosage and mode of administration:  Section has been 
updated to include language on how dosing will be managed in Cohort 2, including details 
regarding a dosing regimen currently being established in study D4660C00004.
Section 1.1.2:  Language has been added to clarify that MEDI4736 may also be referred to 
as durvalumab throughout the protocol and other study documents.  AstraZeneca has 
recently agreed upon this non-proprietary name.
Section 1.1.3:  Section has been updated to include the most current clinical data available 
for AZD5069.
Section 1.1.4:  Section has been updated to include the most current clinical data available 
for AZD5069.
Section 1.2.1:  Section has been updated to include the most current clinical data available 
for MEDI4736.
Section 1.2.3:  Language has been edited to clarify the rationale for combination dosing 
with MEDI4736 and AZD5069.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Section 1.2.4: Section has been updated to include the most current clinical data available 
for AZD5069.
Section 1.3.1.2:  Section has been updated to include the most current clinical data available 
for AZD5069.
Section 1.4:  Pharmacokinetics has been added to the list of evaluable data to remain 
consistent with the study objectives.
Section 1.4.1:  Section has been updated to reflect the current status of Cohort 1.
Figure 1:  Figure has been updated to reflect the fact that recruitment into Cohort 1 was 
permanently stopped after 3 patients had been enrolled.
Objectives, Cohort 1:  Objectives have been updated as only 3 patients will be available for 
analysis.
Objectives, Cohort 2: Objectives have been updated to reflect the new exploratory 
objectives for the Cohort 2 population.
Section 3.1:  Inclusion criteria #3 Cohort 2 progression timeline for prior therapy was 
updated to ≤ 6 months.
Section 3.2:  Exclusion criteria #11 was update to include chemotherapy induced nausea 
and vomiting.
Section 3.2:  Exclusion criteria #14 was updated to remove “psoriasis not requiring 
systemic treatment”.
Section 3.2:  Exclusion #16 was updated to include prostate cancer.
Section 3.2:  Exclusion #19 was updated to match the most current PSSR language for 
MEDI4736.
Section 3.9:  Discontinuation criteria #9 was updated to remove “and Investigator 
determination that the patient is no longer benefiting from treatment with IP”.
Table 2: Updated to remove all PK and biomarker collection requirements as these are no 
longer required for the objectives of the Cohort 1 population.
Table 3: Updated to include the collection of circulating soluble factors (serum and plasma), 
Pharmacogenetic sample, ctDNA and updated collection times of MDSC and PBMCs.
Table 4: Updated to remove all PK, immunogenicity and biomarker collection requirements 
as these are no longer required for the objectives of the Cohort 1 population.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Table 5: Updated to include the collection of ctDNA.
Section 5.2.3: Updated to specify that 12-Lead ECGs will be recorded in triplicate for 
Cohort 2 at specified times.
Section 5.4.5:  Updated to reflect current AstraZeneca standard sample storage language.
Section 5.4.7:  Updated to reflect current AstraZeneca standard sample storage language.
Section 5.5:  Updated to reflect which samples will be analysed for each Cohort.
Section 5.5.1.1: Updated to specify tumor biopsy requirements for the Cohort 2 population, 
including mandatory and optional samples and the types of potential analyses to be 
conducted on the collected tissue.
Section 5.5.1.2:  Updated to further define the exploratory biomarker plan for the Cohort 2 
population.
Section 5.6:  Pharmacogentics section was added as this is now a requirement for the 
Cohort 2 population.
Section 6.7.1.1:  Added a header to separate “Adverse events of special interest” from the 
previous paragraph.
Section 6.7.3: Added toxicity management for AZD5069 40 mg starting dose.
Section 7.1:  Updated the dosage table to reflect an additional AZD5069 tablet strength.
Section 7.1.3:  Updated to reflect that an additional AZD5069 tablet strength is available.
Section 7.2.1.2:  Updated to reflect that a 20mg dose of AZD5069 may be used in the study.
Section 7.2.3: Removed all DLT evaluation language.  As the Cohort has been closed for 
enrollment, no further consideration of DLT is required.
Section 7.2.5: Section added to include DLT information for Cohort 2.
Section 8.2.1:  Updated to reflect the currently enrollment status of Cohort 1.
Table 10:  Updated the probability table data.
Section 8.2.2:  Updated the wording surrounding DLT criteria and patient numbers.
Table 11:  Updated the probability table data.
Table 12:  Added table of Posterior Probabilities of True DLT Incidence > 33% with 
Various priors as well as explanatory text.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Section 8.3, Table 13:  Updated to reflect that the Full analysis set will be used in some 
outcome variables.
Section 8.4.1.3:  The disease control rate will be evaluated at 6 and 12 months, instead of 3 
months.
Section 8.4.3.3:  Section was updated to clarify how immunogenicity results will be 
analysed.
Section 8.5:  Clarified that data from Cohort 1 will only be listed.
Section 11:  The list of references was update where required.
Appendix E:  Updated to include the most current version of “MEDI4736 Dosing 
Modification and Toxicity Management Guidelines”.
Appendix F:  Added information regarding the dose toxicity management and alternative 
dosing regimen for AZD5069 80 mg BID currently under exploration.
Version 2.0, 29 Mar 2016
Main changes to the protocol are summarised below,

Version history and appendices are added due to template update (toxicity 
management guidelines to stay as Appendix E).

Clarification of section 1.2.4 and 7.2.1.2 regarding dose of AZD5069 used in this 
study.

Updating of section 1.3.2.1 regarding reference to IB for latest risk profile of 
MEDI4736.

Updating of section 1.3.2.2 to be consistent with the recent AZD 5069 IB v8.0 
changes (addendum dated 13 December, 2015). 

Clarification of section 3.1 and protocol synopsis regarding inclusion criteria #3, 9.

Clarification of section 3.2 regarding exclusion criteria #14, 15, 20.

Clarification of criteria to replace withdrawn patients in cohort 1/2 in section 3.3 and 
definition of 'evaluable patient' for Cohort 2 clarified. 

Clarification of section 3.8 regarding use, type and period of contraceptions before, 
during and after the trial. 

ECG frequency for Cohort 2 modified on Table 3.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
8(176)

Clarification of footnote b, d, j of Table 2 & 3.

Removal of section regarding the tumor assessment in patients who omit day 15 
dose administrationsection 5.1. 

Removal of the requirements for central reading of scans in section 5.1.1. 

ECG frequency for Cohort 2 updated to screening and day 1 of each cycle to match 
the evaluation on Study D5660C00004.

Clarification of vital signs collection time point pre-dose, during and post-dose in 
section 5.2.4.

Amending sections 5.4.5, 5.4.7, 5.5.5 regarding the Biobank used in the study. 

Clarification that the recording of adverse events in section 6.3 also refers to the 
AESIs. 

Clarification of AESIs associated with MEDI4736 in section 6.7.1.

Removal of dose reduction or modification guidance of AZD5069 in section 6.7.3 as 
this document does not exist. 

Clarification of MEDI4736 dosage and strength in section 7.1.

Removal of table 9 from section 7.1.1

Removal of the omission of day 15 treatment in case of patient toxicity in section 
7.2.1.1. 

Figure 3 updated to correct week schedule of MEDI4736 dose 7.

Added clarification in section 7.7 that the use of cannabinoids must be avoided in 
patients administered with AZD5069 alone and in combination with MEDI4736.

Removal of the overall survival text from section 8.4.1.2, as it is the duplicate of the 
paragraph in section 8.4.1.3.

Corrected errors in disease control rate and progression free survival calculation in 
section 8.4.1.3.

Removal of “lesions <2 cm biopsied within the screening period (fresh tumor 
biopsy)” as a non-measurable lesion in Appendix D as it does not pertain to 
imaging/RECIST. 

Clarification of section 9.3 regarding the start date of the study.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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
Removal of sPD-L1 tests thoughout the protocol as sPD-L1 will no longer be 
analyzed in the study. 

Updated toxicity management guidelines in Appendix E to current version (dated 02 
Oct 2015). 

Minor administrative changes and inconsistency errors throughout the protocol. 
Version 1.0, 24 Aug 2015
Changes to the protocol are summarised below,
Initial creation


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
10(176)
PROTOCOL SYNOPSIS
A Phase Ib and II Open-Label, Multi-Center Study of MEDI4736 Evaluated 
in Different Combinations in Patients with Metastatic Pancreatic Ductal 
Adenocarcinoma
International Coordinating Investigators
Cohort 1
 
Cohort 2
 
UK 
Number of patients planned
This study will consist of 2 cohorts.  Cohort 1 has enrolled 3 patients who received 
MEDI4736 in combination with nab-paclitaxel + gemcitabine. Cohort 2 will enroll 
approximately 16 evaluable patients to receive MEDI4736 in combination with AZD5069, a 
CXC chemokine receptor-2 inhibitor.
Study period
Phase of development
Estimated date of first patient enrolled
Q4 2015
Ib and II
Estimated date of last patient completed
Q4 2018
Ib and II
Study design
This study will evaluate the safety, tolerability, pharmacodynamics, and antitumor activity of 
MEDI4736 in combination with chemotherapy and novel anticancer agents in patients with 
pancreatic ductal adenocarcinoma (PDAC).
This study will consist of 2 independent cohorts, each of which will run at separate times.
Cohort 1 is a Phase Ib, open-label, dose exploration assessment of the safety, tolerability, 
antitumor activity, and pharmacokinetics (PK) of MEDI4736 in combination with the 
nab-paclitaxel + gemcitabine chemotherapy regimen in patients with metastatic PDAC who 
are treatment-naïve.  Initially, 3 patients have been enrolled into a safety run-in period and 
will also be evaluated for anti-tumor efficacy of this combination.  At present, no further 
expansion of this cohort is planned.  
PPD
PPD
PPD


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Cohort 2 is a Phase II, open-label, multicenter assessment of the safety and preliminary 
antitumor activity of MEDI4736 in combination with AZD5069 in patients with metastatic 
PDAC whose disease has progressed on 5-fluoropyrimidine (5-FU)-containing or 
gemcitabine-containing first-line chemotherapy.  Initially, 6 evaluable patients will be 
enrolled into a safety run-in period.  The dosing regimen employed will be that established by 
the D5660C00004 trial currently in progress.  This regimen involves initial dosing of 
AZD5069 at 80 mg po bid, with provision for dose reductions described in Section 6.7.3 of 
the protocol.  After this, approximately 10 additional evaluable patients will be enrolled 
providing defined safety criteria are met.
Tumor assessments will be performed every 8 weeks ±7 days (Cohort 1) or every 6 weeks ±7
days (Cohort 2) for the first 48 weeks relative to the date of first infusion and then every 12
weeks ±7 days thereafter for both cohorts until confirmed progressive disease (PD), with 
categorization of objective tumor response by Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST 1.1).
Objectives
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine chemotherapy
Primary objective:
Outcome measure:
To assess the safety and tolerability of 
MEDI4736 in combination with nab-paclitaxel 
+ gemcitabine
Occurrence of dose-limiting toxicities
AEs, physical examinations, laboratory findings 
(including clinical chemistry, hematology, and 
urinalysis), vital signs (including blood pressure and 
pulse), electrocardiograms (ECGs)
Secondary objectives:
Outcome measures:
To assess the efficacy of MEDI4736 in 
combination with nab-paclitaxel + gemcitabine 
in terms of ORR, DoR, DCR, PFS, and OS 
ORR, DoR, DCR, and PFS using Investigator 
assessments according to RECIST 1.1, and OS.
To assess the PK of MEDI4736 and the 
combination of MEDI4736 and nab-paclitaxel 
+ gemcitabine 
Concentration of MEDI4736/nab-paclitaxel + 
gemcitabine in serum or plasma and PK parameters 
(such as peak concentration and trough, as data allow; 
sparse sampling only)


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069
Primary objective:
Outcome measure:
To assess the safety, tolerability and ORR of 
MEDI4736 + AZD5069 in combination. 
Occurrence of dose-limiting toxicities AEs, physical 
examinations, laboratory findings (including clinical 
chemistry, hematology, and urinalysis), vital signs 
(including blood pressure and pulse), 
electrocardiograms (ECGs), and ORR using 
Investigator assessments according to RECIST 1.1
Secondary objectives:
Outcome measures:
To further assess the efficacy of MEDI4736 
+AZD5069 in terms of DoR, DCR, PFS, 
PFS3, PFS6, OS, OS6, and OS12
DoR, DCR, PFS, PFS3, and PFS6 in all patients using 
Investigator assessments according to RECIST 1.1
OS, OS6, and OS12
To investigate the relationship between PD-L1 
expression by IHC and efficacy parameters
ORR, DoR, DCR, and PFS across PD-L1 expression 
using Investigator assessments according to 
RECIST 1.1
OS
To investigate the immunogenicity of 
MEDI4736 in combination with AZD5069
Presence of ADAs for MEDI4736 (confirmatory 
results: positive or negative; titers)
To assess the PK of MEDI4736 and the 
combination of MEDI4736 and AZD5069 
Concentration of MEDI4736/AZD5069 in serum or 
plasma and PK parameters (such as peak 
concentration and trough, as data allow; sparse 
sampling only)
Exploratory objectives:
Outcome measures:
Evaluate changes in blood-borne biomarkers 
that may correlate with treatment or clinical 
response
Assessments may include, but are not limited to, 
measurement of gene expression, immune cell types, 
soluble factors such as cytokines and chemokines, T-
cell receptor repertoire, circulating tumor DNA and 
activation and proliferation markers at baseline and 
with treatment.
Evaluate tumor-based biomarkers in archival 
tumor samples that may correlate with 
treatment or prospectively identify patients 
likely to respond to treatment 
Assessments may include tumor genetics, 
characterisation of immune infiltrates, gene expression 
signatures, T cell repertoire, or other stratification 
markers.
To collect and store deoxyribonucleic acid 
(DNA) for future exploratory research 
Future exploratory research may include but is not 
limited to exploration of genes/genetic variation that 
may influence response (i.e. distribution, safety, 
tolerability and efficacy) to treatment.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Exploratory objectives:
Outcome measures:
Collect and store tumor, blood, plasma, and 
serum samples or analyse surplus blood or 
tissue including patient-specific archival tumor 
tissue, if available
Samples may be used 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 need for a 
protocol amendment.
Target subject population
Cohort 1: Patients (aged ≥18 years) with histologically or cytologically confirmed metastatic 
PDAC who have received no previous systemic chemotherapy, targeted therapy, 
immunotherapy, or investigational agents (except adjuvant or neoadjuvant therapy if 
progression occurred >6 months from last treatment for adjuvant or surgery for neoadjuvant).
Cohort 2: Patients (aged ≥18 years) with histologically or cytologically confirmed metastatic 
PDAC who have received no more than 1 prior chemotherapy regimen or any other systemic 
therapy for recurrent/metastatic PDAC and who had tumor progression following prior 
standard first-line 5-FU-containing or gemcitabine-containing chemotherapy.
Duration of treatment
Treatment in both cohorts will be administered until confirmed PD, unacceptable toxicity, 
withdrawal of consent, or another discontinuation criterion is met.  In cases of toxicity and at 
the Investigator’s discretion, patients will be permitted to stop treatment with one agent of 
their combination therapy regimen and continue treatment with the other agent as 
monotherapy, using the same dose and regimen as previously administered.  These patients 
may continue to receive MEDI4736 alone (until confirmed PD, withdrawal of consent, or 
another discontinuation criterion is met), or nab-paclitaxel + gemcitabine alone (Cohort 1 
only) or AZD5069 alone (Cohort 2 only) (until the first assessment of disease progression 
[ie, unconfirmed PD], withdrawal of consent, or another discontinuation criterion is met).
Patients who have discontinued all study treatment will enter follow-up.
Investigational product, dosage, and mode of administration
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine chemotherapy

1.5 g MEDI4736 via intravenous (IV) infusion every 4 weeks (q4w), starting at 
Week 0, until confirmed PD or another discontinuation criterion is met.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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
125 mg/m2 nab-paclitaxel and 1000 mg/m2 gemcitabine via IV infusion, both 
administered on Days 1, 8 and 15 of each 28-day cycle (ie, 1 cycle = weekly for 3
weeks, then 1 week off) until confirmed PD or another discontinuation criterion is 
met (Patients receiving nab-paclitaxel + gemcitabine as monotherapy, without 
MEDI4736, will receive treatment until the first assessment of disease progression 
[ie, unconfirmed PD], withdrawal of consent, or another discontinuation criterion is 
met).
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069

1.5 g MEDI4736 via IV infusion q4w, starting at Week 0, until confirmed PD or 
another discontinuation criterion is met.

The current recommended Phase 2 dose (RP2D) determined for AZD5069 in the 
dose escalation phase of  Study D5660C00004 will be employed.  This regimen 
entails initial dosing of AZD5069 at 80 mg po bid with defined dose reduction 
criteria based on peripheral blood neutrophil counts.  Details of these criteria are 
described in Secion 6.7.3. Dosing will continue until confirmed PD or another 
discontinuation criterion is met. 
Statistical methods
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine
Safety and tolerability, and the occurrence of dose limiting toxicity, will be evaluated through 
adverse events (AEs), physical examinations, laboratory and vital sign measures, and 
electrocardiograms.  Secondary endpoints, including objective response rate (ORR), duration 
of response (DoR), disease control rate (DCR), and progression-free survival (PFS), will be 
summarized based on Investigator assessments according to RECIST 1.1.  PFS, overall 
survival (OS), and DoR will be described using programmed listings due to the capping of 
enrollment at 3 patients for this arm.
Similarly, immunogenicity results will be provided as a programmed listing capturing which 
patients develop detectable anti-MEDI4736, anti-nab-paclitaxel or anti-gemcitabine 
antibodies.
PK concentration data will be listed for each patient and each dosing day.
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069
Safety and tolerability will be evaluated through adverse events (AEs), physical examinations, 
laboratory and vital sign measures, and electrocardiograms, using summary statistics.  
Secondary endpoints, including ORR, DoR, DCR, PFS, proportion of patients alive and 
progression-free after 3 months (PFS3) and proportion of patients alive and progression-free 
after 6 months (PFS6), will be summarized based on Investigator assessments according to 
RECIST 1.1.  PFS, PFS3, PFS6, OS, proportion of patients alive at 6 months from first dose 
(OS6), proportion of patients alive at 12 months (OS12), and DoR rates and their medians will 


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
15(176)
be calculated and plotted using Kaplan-Meier estimates, with 95% CIs.  Efficacy parameters 
will also be summarized and explored as appropriate according to PD-L1 expression levels.  
PK concentration data will be listed for each patient and each dosing day, and a summary 
provided for all evaluable patients.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
16(176)
TABLE OF CONTENTS
TITLE PAGE............................................................................................................1
VERSION HISTORY...............................................................................................2
PROTOCOL SYNOPSIS........................................................................................10
TABLE OF CONTENTS........................................................................................16
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..............................23
1.
INTRODUCTION ..................................................................................27
1.1
Background and rationale for conducting this study ................................27
1.1.1
Immunotherapies ....................................................................................29
1.1.2
MEDI4736..............................................................................................29
1.1.3
AZD5069................................................................................................31
1.1.4
Rationale for conducting this study .........................................................32
1.2
Rationale for study design, doses and control groups...............................34
1.2.1
MEDI4736 dose rationale .......................................................................34
1.2.1.1
Rationale for fixed dosing .......................................................................36
1.2.2
Rationale for combination MEDI4736 and chemotherapy (nab-paclitaxel + 
gemcitabine) ...........................................................................................36
1.2.3
Rationale for combination of MEDI4736 and AZD5069 .........................38
1.2.4
AZD5069 dose rationale .........................................................................38
1.3
Benefit/risk and ethical assessment .........................................................40
1.3.1
Potential benefits.....................................................................................40
1.3.1.1
MEDI4736..............................................................................................40
1.3.1.2
AZD5069................................................................................................40
1.3.2
Potential risks .........................................................................................41
1.3.2.1
MEDI4736..............................................................................................41
1.3.2.2
AZD5069................................................................................................41
1.3.2.3
Overall benefit and risk assessment.........................................................42
1.4
Study design ...........................................................................................43
1.4.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy..........................................................................................44
1.4.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069........................44
2.
STUDY OBJECTIVES...........................................................................46
2.1
Primary objectives ..................................................................................46
2.1.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy..........................................................................................46
2.1.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069........................46
2.2
Secondary objectives...............................................................................46
2.2.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy..........................................................................................46


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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2.2.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069........................47
2.3
Exploratory objectives ............................................................................47
2.3.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy..........................................................................................47
2.3.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069........................47
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL.........48
3.1
Inclusion criteria .....................................................................................48
3.2
Exclusion criteria ....................................................................................50
3.3
Patient enrollment ...................................................................................53
3.4
Procedures for handling incorrectly enrolled patients ..............................53
3.5
Methods for assigning treatment groups..................................................54
3.6
Methods for ensuring blinding ................................................................54
3.7
Methods for unblinding...........................................................................54
3.8
Restrictions.............................................................................................54
3.9
Discontinuation of investigational product ..............................................56
3.9.1
Procedures for discontinuation of a patient from investigational product .56
3.10
Criteria for withdrawal............................................................................57
3.10.1
Screen failures ........................................................................................57
3.10.2
Withdrawal of the informed consent........................................................57
3.11
Discontinuation of the study....................................................................57
4.
STUDY PLAN AND TIMING OF PROCEDURES................................58
4.1
Enrollment/screening period ...................................................................70
4.2
Treatment period.....................................................................................70
4.3
Follow-up period.....................................................................................70
5.
STUDY ASSESSMENTS.......................................................................70
5.1
Efficacy assessments...............................................................................71
5.1.1
Central reading of scans ..........................................................................72
5.2
Safety assessments..................................................................................72
5.2.1
Laboratory safety assessments.................................................................72
5.2.2
Physical examination ..............................................................................74
5.2.3
Electrocardiograms .................................................................................74
5.2.4
Vital signs...............................................................................................74
5.2.5
Other safety assessments.........................................................................75
5.3
Other assessments...................................................................................76
5.3.1
ECOG performance status.......................................................................76


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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5.4
Pharmacokinetics ....................................................................................76
5.4.1
Collection of samples..............................................................................76
5.4.2
Determination of drug concentration of nab-paclitaxel, gemcitabine, and 
AZD5069................................................................................................76
5.4.3
Storage and destruction of pharmacokinetic samples for nab-paclitaxel, 
gemcitabine, and AZD5069.....................................................................77
5.4.4
Determination of drug concentration of MEDI4736 ................................77
5.4.5
Storage and destruction of pharmacokinetic samples for MEDI4736.......77
5.4.6
Collection of samples to measure the presence of ADAs.........................77
5.4.7
Storage and destruction of ADA samples ................................................77
5.5
Biomarker analysis..................................................................................78
5.5.1
Collection of samples..............................................................................78
5.5.1.1
Collection of samples for evaluation of potential patient selection 
markers...................................................................................................78
5.5.1.2
Collection of blood samples from Cohort 2 (AZD5069 plus MEDI4736) 
for exploratory analyses ..........................................................................80
5.5.2
Management of biomarker data...............................................................81
5.5.3
Storage, re-use, and destruction of biomarker samples ............................81
5.5.4
Labeling and shipment of biological samples ..........................................82
5.5.5
Chain of custody of biological samples ...................................................82
5.5.6
Withdrawal of informed consent for donated biological samples.............82
5.6
Pharmacogenetics ...................................................................................83
5.6.1
Collection of pharmacogenetic samples...................................................83
5.6.2
Storage, re-use and destruction of pharmacogenetic samples...................83
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT..................84
6.1
Definition of adverse events....................................................................84
6.2
Definitions of serious adverse event ........................................................84
6.3
Recording of adverse events....................................................................85
6.3.1
Time period for collection of adverse events ...........................................85
6.3.2
Follow-up of unresolved adverse events..................................................85
6.3.3
Variables.................................................................................................85
6.3.4
Causality collection.................................................................................86
6.3.5
Relationship to protocol procedures ........................................................87
6.3.6
Adverse events based on signs and symptoms.........................................87
6.3.7
Adverse events based on examinations and tests .....................................87
6.3.8
Hy’s Law ................................................................................................88
6.3.9
Disease progression.................................................................................88
6.3.10
New cancers............................................................................................88
6.3.11
Deaths.....................................................................................................88
6.4
Reporting of serious adverse events ........................................................88
6.5
Overdose.................................................................................................89
6.6
Pregnancy ...............................................................................................90


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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6.6.1
Maternal exposure...................................................................................90
6.6.2
Paternal exposure....................................................................................90
6.7
Management of IP-related toxicities........................................................91
6.7.1
MEDI4736..............................................................................................91
6.7.1.1
Adverse events of special interest (AESIs)..............................................92
6.7.2
Nab-paclitaxel + gemcitabine..................................................................93
6.7.3
AZD5069................................................................................................93
6.8
Study governance and oversight..............................................................97
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ........97
7.1
Identity of investigational product(s).......................................................97
7.1.1
MEDI4736..............................................................................................97
7.1.2
Nab-paclitaxel + gemcitabine..................................................................98
7.1.3
AZD5069................................................................................................98
7.2
Dose and treatment regimens ..................................................................98
7.2.1
Treatment regimens.................................................................................98
7.2.1.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy..........................................................................................98
7.2.1.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069........................99
7.2.2
Duration of treatment ............................................................................100
7.2.3
Enrollment and stopping criteria for Cohort 1 (first-line, Phase Ib, 
MEDI4736 + nab-paclitaxel + gemcitabine chemotherapy) ...................101
7.2.4
Definition of dose-limiting toxicity for Cohort 1 (first-line, Phase Ib, 
MEDI4736 + nab-paclitaxel + gemcitabine chemotherapy) ...................101
7.2.5
Definition of dose-limiting toxicity for Cohort 2 (MEDI4736 + 
AZD5069).............................................................................................103
7.3
Labelling...............................................................................................106
7.4
Storage..................................................................................................107
7.5
Compliance...........................................................................................107
7.6
Accountability.......................................................................................107
7.7
Concomitant and other treatments .........................................................107
7.7.1
Other concomitant treatment .................................................................111
7.8
Post study access to study treatment......................................................111
8.
STATISTICAL ANALYSES BY ASTRAZENECA.............................111
8.1
Statistical considerations .......................................................................111
8.2
Sample size estimate .............................................................................111
8.2.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy........................................................................................111
8.2.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069......................112
8.3
Definitions of analysis sets....................................................................113


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
20(176)
8.3.1
Full analysis set.....................................................................................114
8.3.2
Safety analysis set.................................................................................114
8.3.3
PK analysis set......................................................................................114
8.3.4
Efficacy analysis set..............................................................................114
8.4
Outcome measures for analyses.............................................................115
8.4.1
Calculation or derivation of efficacy variables.......................................115
8.4.1.1
RECIST 1.1-based endpoints ................................................................115
8.4.1.2
Primary endpoints.................................................................................116
8.4.2
Calculation or derivation of safety variables..........................................116
8.4.2.1
Adverse events......................................................................................116
8.4.2.2
Other significant adverse events............................................................116
8.4.2.3
Safety assessments................................................................................117
8.4.2.4
Secondary endpoints .............................................................................117
8.4.3
Calculation or derivation of pharmacokinetic variables .........................120
8.4.3.1
Population pharmacokinetics and exposure-response/safety analysis.....120
8.4.3.2
Pharmacokinetic  analysis .....................................................................120
8.4.3.3
Immunogenicity analysis.......................................................................120
8.4.4
Calculation or derivation of biomarker variables ...................................121
8.5
Methods for statistical analyses.............................................................121
8.5.1
Efficacy data.........................................................................................121
8.5.1.1
Duration of response .............................................................................121
8.5.1.2
Disease control rate...............................................................................122
8.5.1.3
Progression-free survival.......................................................................122
8.5.1.4
Proportion of patients with progression-free survival after 3 months and 
6 months ...............................................................................................122
8.5.1.5
Overall survival.....................................................................................122
8.5.1.6
Proportion of patients alive at 6 and 12 months .....................................122
8.5.2
Safety data ............................................................................................122
8.5.3
Pharmacokinetic data ............................................................................123
8.5.3.1
Immunogenicity analysis.......................................................................123
8.5.4
Biomarker data......................................................................................123
8.5.5
Interim analysis.....................................................................................123
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA............123
9.1
Training of study site personnel ............................................................123
9.2
Monitoring of the study.........................................................................124
9.2.1
Source data ...........................................................................................124
9.2.2
Study agreements..................................................................................124
9.2.3
Archiving of study documents...............................................................125
9.3
Study timetable and end of study...........................................................125
9.4
Data management by AstraZeneca or delegate ......................................125
10.
ETHICAL AND REGULATORY REQUIREMENTS..........................126
10.1
Ethical conduct of the study ..................................................................126


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
21(176)
10.2
Patient data protection...........................................................................126
10.3
Ethics and regulatory review .................................................................126
10.4
Informed consent ..................................................................................127
10.5
Changes to the protocol and informed consent form..............................127
10.6
Audits and inspections ..........................................................................127
11.
LIST OF 
REFERENCES
...................................................................................................................
129..............................................................................................................
LIST OF TABLES
Table 1
Highly Effective methods of contraception (<1% failure rate).................. 55
Table 2
Schedule of assessments for Cohort 1 (first-line, Phase Ib, MEDI4736 + 
nab-paclitaxel + gemcitabine chemotherapy) treatment period................. 59
Table 3
Schedule of assessments for Cohort 2 (second-line, Phase II, MEDI4736 + 
AZD5069)............................................................................................... 63
Table 4
Schedule of follow up assessments for Cohort 1 (first-line, Phase Ib, 
MEDI4736 + nab-paclitaxel + gemcitabine chemotherapy)...................... 67
Table 5
Schedule of follow up assessments for Cohort 2 (second-line, Phase II, 
MEDI4736 + AZD5069) ......................................................................... 68
Table 6
Clinical chemistry (serum or plasma) ....................................................... 73
Table 7
Hematology ............................................................................................. 73
Table 8
Urinalysis................................................................................................. 73
Table 9
Dose modifications for toxicity (non neutropenic and non liver toxicity 
events)..................................................................................................... 94
Table 10 Dose modifications for elevations in liver function tests........................... 94
Table 11 Prohibited medications and foods for patients who receive AZD5069 .... 110
Table 12 Probability of observing toxicity event................................................... 112
Table 13 Probability of observing toxicity events in 6 or 16 patients..................... 112
Table 14 Posterior Probabilities of True DLT Incidence > 33% with Various 
Priors..................................................................................................... 113
Table 15 Summary of outcome variables and analysis populations ....................... 114
Table 16 Summary of methods of assessment ....................................................... 145
Table 17 Evaluation of target lesions .................................................................... 149


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Table 18 Evaluation of  non-target lesions ............................................................ 150
Table 19 Overall Visit Response........................................................................... 151
Table 20   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) 1 November 2017 Version ................. 153
LIST OF FIGURES
Figure 1 Cohort 1 (first-line, Phase Ib MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy) design.............................................................................. 44
Figure 2 Cohort 2 (second-line, Phase II MEDI4736 + AZD5069) design.............. 45
Figure 3 Dose-reductions levels for AZD5069 toxicity management...................... 95
Figure 4 Management of neutropenic toxicities...................................................... 95
Figure 5 Cohort 1 dosing schedule ......................................................................... 99
Figure 6 Cohort 2 dosing schedule ....................................................................... 100
LIST OF APPENDICES
Appendix A  Additional Safety Information........................................................... 135
Appendix B  International Airline Transportation Association (IATA) 6.2 Guidance 
Document.............................................................................................. 138
Appendix C..........   Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 139
Appendix D  Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors).................. 144
Appendix E..   MEDI4736 Dosing Modification and Toxicity Management Guidelines
Immune-Mediated, Infusion Related, And Non Immune-Mediated 
Reactions............................................................................................... 153


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
23(176)
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study clinical study protocol.
Abbreviation or 
special term
Explanation
β-hCG
beta-Human chorionic gonadotropin
5-FU
Fluoropyrimidine
ADA
Antidrug antibody
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the plasma drug concentration-time curve
AUCss
Area under the plasma drug concentration-time curve at steady state
β-hCG
Beta-human chorionic gonadotropin
BCRP
Breast cancer resistance protein
bid
Twice daily
BoR
Best objective response
BP
Blood pressure
CD
Cluster of differentiation
CI
Confidence interval
COPD
Chronic obstructive pulmonary disease
CR
Complete response
CSA
Clinical Study Agreement
CSP
Clinical study protocol
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
CTL
Cytotoxic T lymphocytes
CTLA-4
Cytotoxic T lymphocyte-associated antigen 4
CXCL17
Chemokine (C-X-C motif) ligand 17
CXCR2
CXC chemokine receptor-2
CYP
Cytochrome P450
DCR
Disease control rate


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
24(176)
Abbreviation or 
special term
Explanation
DLT
Dose-limiting toxicity
DoR
Duration of response
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EGFR
Epidermal growth factor receptor
ESMO
European Society for Medical Oncology
EU
European Union
FOLFIRINOX
Multidrug combination of leucovorin, fluorouracil, irinotecan, and 
oxaliplatin
fT3
Free triiodothyronine
fT4
Free thyroxine
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
hCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
HR
Hazard ratio
IB
Investigator’s Brochure
ICAM2
Intercellular adhesion molecule 2
ICF
Informed consent form
ICH
International Conference on Harmonisation
IFN-γ
Interferon-gamma
IgG
Immunoglobulin G
IHC
Immunohistochemical
IL
Interleukin
IP
Investigational Product 
irAE
Immune-related adverse event
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
ITT
Intent-to-treat
IV
Intravenous
IVRS
Interactive Voice Response System


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
25(176)
Abbreviation or 
special term
Explanation
IWRS
Interactive Web Response System
LFT
Liver function test
mAb
Monoclonal antibody
MDSC
Myeloid-derived suppressor cells
MedDRA
Medical Dictionary for Regulatory Activities
MHC
Major histocompatibility complex
MHLW
Ministry of Health, Labor, and Welfare
miRNA
Micro-ribonucleic acid
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
NCI
National Cancer Institute
NE
Not evaluable
NSCLC
Non-small-cell lung cancer
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
OS6
Proportion of patients alive at 6 months from enrollment
OS12
Proportion of patients alive at 12 months from enrollment
PBMC
Peripheral blood mononuclear cells
PD
Progressive disease
PD-1
Programmed cell death 1 
PDAC
Pancreatic ductal adenocarcinoma
PD-L1
Programmed cell death ligand 1
PFS
Progression-free survival
PFS3
Proportion of patients with progression-free survival after 3 months
PFS6
Proportion of patients with progression-free survival after 6 months
P-gp
P-glycoprotein
PI
Principal Investigator 
PK
Pharmacokinetics
PR
Partial response
PS
Performance status
q2w
Every 2 weeks


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
26(176)
Abbreviation or 
special term
Explanation
q3w
Every 3 weeks
q4w
Every 4 weeks
q6w
Every 6 weeks
q8w
Every 8 weeks
q12w
Every 12 weeks
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST
Response Evaluation Criteria in Solid Tumors 
RNA
Ribonucleic acid
RT-qPCR
Reverse transcription quantitative polymerase chain reaction 
SAE
Serious adverse event 
SAP
Statistical analysis plan
SD
Stable disease
SoC
Standard of care
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
WBDC
Web Based Data Capture
WT
Weight


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all 
pancreatic tumors, is a malignancy with an extremely poor prognosis, as shown by a 1-year 
survival rate of around 18% for all stages of the disease and an estimated 5-year survival rate 
of less than 5%.  The low survival rates associated with PDAC primarily reflect the fact that 
tumors progress rapidly with few specific symptoms and are thus at an advanced stage at 
diagnosis in most patients (almost 80% of patients at diagnosis; Hidalgo et al 2015).
Metastatic PDAC is one of the most aggressive and highly lethal malignancies.  Although it 
constitutes only about 3% of all cancers in the United States (US), it is the fourth leading 
cause of cancer deaths in both men and women and is responsible for 7% of all cancer-related 
deaths.  The death rate from the disease rose from 5 per 100000 in 1930 to more than 10 per 
100000 in 2003.  The American Cancer Society estimates that in the US in 2014, about 
39590 people (20170 men and 19420 women) will die of pancreatic cancer 
(Dragovich et al 2014). In the absence of predisposing conditions, such as familial pancreatic 
cancer and chronic pancreatitis, pancreatic cancer is unusual in persons younger than 45 years.  
After age 50 years, the frequency of pancreatic cancer increases linearly.  The median age at 
diagnosis is 69 years in whites and 65 years in blacks; some single-institution data reported 
from large cancer centers suggest that the median age at diagnosis in both sexes has fallen to 
63 years.
The poor prognosis reflects the limited treatment options available, highlighting the need for 
the development of newer therapeutic options.  Very few patients with truly localized disease 
can be cured by surgery.  Inoperable patients sometimes undergo surgery for symptom relief 
(eg, bypass or stent implantation, splanchnicectomy), but the main treatment is radiation and 
chemotherapy.  Radiation therapy is used to control local symptoms like pain but has no 
proven effect on overall survival (OS)  (Thota et al 2014).
Despite recent advances in chemotherapeutics and in our understanding of the molecular 
biology of pancreatic cancer, there has been limited progress in therapeutic options for 
metastatic disease.  Over the past 4 decades, studies of several combination therapies have 
demonstrated minimal or no survival benefit compared with gemcitabine alone as first-line 
therapy.  Gemcitabine monotherapy had been the standard of care (SoC) for patients with 
metastatic pancreatic cancer for several years until combination therapy with gemcitabine plus 
erlotinib was shown to increase median survival by approximately 2 weeks.  A Phase III trial 
of gemcitabine versus fluoropyrimidine (5-FU) as first-line therapy in patients with advanced 
or metastatic adenocarcinoma of the pancreas reported a significant improvement in survival 
among patients treated with gemcitabine (median survival durations were 5.65 and 
4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively [p=0.0025]).  The 
survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients 
(Burris et al 1997).


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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The National Cancer Institute of Canada performed a Phase III trial (CAN-NCIC-PA3 
[NCT00026338]) that compared gemcitabine alone versus the combination of gemcitabine 
and erlotinib (100 mg/day) for first-line treatment in patients with advanced or metastatic 
pancreatic carcinomas.  The corresponding median survival rate for patients receiving 
erlotinib was 6.2 months versus 5.9 months for patients receiving placebo.  The 1-year 
survival rate for patients receiving erlotinib was 23% versus 17% for patients receiving 
placebo (Moore et al 2007).  However, the modest survival benefit was tempered by a 
significant side effect profile and the high cost of treatment (Moore et al 2007).  Later, the 
multidrug combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) 
was noted to provide an increased median survival of 4.3 months versus gemcitabine; 
however, given its side effect profile, it is available only to a select group of patients with 
advanced pancreatic cancer.  The patients were randomly assigned to receive FOLFIRINOX 
or gemcitabine.  The median OS was 11.1 months in the FOLFIRINOX group compared with 
6.8 months in the gemcitabine group (hazard ratio [HR] for death =0.57; 95% confidence 
interval [CI], 0.45 to 0.73; p<0.001).  Median progression-free survival (PFS) was 6.4 months 
in the FOLFIRINOX group and 3.3 months in the gemcitabine group (HR for disease 
progression =0.47; 95% CI, 0.37 to 0.59; p<0.001; Conroy et al 2011).
Recently, the gemcitabine plus nab-paclitaxel combination was shown to increase median 
survival by 1.8 months, with increased OS at 1 and 2 years; adverse effects were reasonable 
and included cytopenias and peripheral neuropathy.  The multi-center, international Phase III 
trial (NCT00844649) included 861 patients with previously untreated metastatic pancreatic 
adenocarcinoma.  The patients were randomly assigned to receive gemcitabine and 
nab-paclitaxel or gemcitabine monotherapy.  The median OS was 8.5 months in the 
nab-paclitaxel/gemcitabine group compared with 6.7 months in the gemcitabine group (HR 
for death=0.72; 95% CI, 0.62 to 0.83; p<0.001).  Median PFS was 5.5 months in the 
nab-paclitaxel/gemcitabine group and 3.7 months in the gemcitabine group (HR for disease 
progression=0.69; 95% CI, 0.58 to 0.82, p<0.001; Von Hoff et al 2013).
The current National Comprehensive Cancer Network recommendations suggest acceptable 
first-line chemotherapy combinations for patients with good performance status (ie, Eastern 
Cooperative Oncology Group [ECOG] performance status [PS] of 0 or 1), good pain 
management, patent biliary stent, and adequate nutritional intake; these combinations include 
FOLFIRINOX, nab-paclitaxel + gemcitabine, and gemcitabine plus erlotinib.  The only 
recommended first-line chemotherapy option for patients with poor PS is gemcitabine 
monotherapy.  The guidelines for choosing an appropriate treatment regimen for patients with 
metastatic pancreatic cancer thus remain ambiguous, and in the absence of a randomized trial 
comparing the combination regimens head to head, the dilemma remains regarding 
appropriate first-line therapy for these patients.
Invariably, regardless of choice of first-line therapy, patients with advanced/metastatic disease 
will progress, and at that point, the choice of treatment becomes considerably murkier.  
According to results from a US cooperative group trial (CALGB 80303), fewer than half of 
patients with advanced pancreatic cancer went on to receive any additional therapy after 
progressing on first-line study treatment.  This reflects, in part, the fact that patients in this 


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setting frequently demonstrate significant clinical deterioration and a decline in PS and are no 
longer deemed appropriate candidates for further anticancer therapy.
Currently, there is no firmly established standard chemotherapy for patients after progression 
on first-line treatment.  A variety of cytotoxic agents, either alone or in combination, have 
been evaluated, although primarily in the context of small single-arm or retrospective studies.  
Most regimens have been associated with median PFS in the range of 2 to 4 months, OS 
ranges between 4 and 8 months, and different response rates varying from 10% to 20%, 
highlighting the very poor prognosis of patients who are candidates for such treatment 
(Walker and Ko 2014).  Targeted therapies studied in this chemotherapy-refractory setting, 
meanwhile, have produced even worse efficacy results (Li et al 2014, Walker and Ko 2014).  
The combination of 5-FU and oxaliplatin has been shown to confer a benefit in the second-
line setting after first-line gemcitabine in a small clinical trial and can be considered as a 
treatment option in this setting.  In patients treated with first-line FOLFIRINOX who can 
receive second-line chemotherapy after progression, gemcitabine can be considered as an 
option (NCCN Pancreatic Adenocarcinoma Guidelines).  Despite some progress, enrollment 
of patients with pancreatic cancer in clinical trials for all lines of treatment should be 
encouraged to further improve the systemic treatment of this disease (Seufferlein et al 2012).
1.1.1
Immunotherapies
It is increasingly understood that cancers are recognized by the immune system, and under 
some circumstances, the immune system may control or even eliminate tumors 
(Dunn et al 2004).  Studies in mouse models of transplantable tumors have demonstrated that 
manipulation of co-stimulatory or co-inhibitory signals can amplify T-cell responses against 
tumors (Peggs et al 2009).  This amplification may be accomplished by blocking co-inhibitory 
molecules, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed 
cell death 1 (PD-1), from binding with their ligands, B7 or B7-homolog 1 (B7-H1) 
(programmed cell death ligand 1 [PD-L1]).
1.1.2
MEDI4736
MEDI4736 is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that inhibits the binding of PD-L1 and is being developed by 
AstraZeneca/MedImmune for use in the treatment of cancer (MedImmune is a wholly owned 
subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca 
throughout this document). MEDI4736 may also be referred to by its recently agreed on, non-
proprietary name (durvalumab) in this protocol and elsewhere. As MEDI4736 is an 
engineered mAb, it does not induce antibody-dependent cellular cytotoxicity or complement-
dependent cytotoxicity.  The proposed mechanism of action for MEDI4736 is interference of 
the interaction of PD-L1.
PD-L1 is frequently found to be expressed on many cancers with a high frequency, up to 88% 
in some cancer types.  Tumors expressing PD-L1 can render cytotoxic T lymphocytes (CTLs) 
inactive or nonfunctional through engagement of the inhibitory receptor of PD-1.  Pancreatic 
cancers that are PD-L1 positive have been found to have significantly poorer 1-year 
postoperative survival and OS compared to tumors that are PD-L1 negative (Nomi et al 2007). 


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Results of several preclinical models have demonstrated that blockade of PD-1 or PD-L1, or 
the use of PD-1-deficient T cells, can result in profound immune-mediated tumor control in 
many experimental systems (Blank et al 2006, Iwai et al 2002, Iwai et al 2005).
During the last decade, there has been a progressively increased interest in studying the 
therapeutic potential of immune therapy in PDAC.  Several lines of evidence documenting the 
immune dysfunction associated with PDAC support the hypothesis that immunotherapy can 
alter the process of carcinogenesis (Fokas et al 2015).
In particular, preclinical and clinical studies in PDAC have indicated that blockades of 
immune checkpoints can have a positive effect on antitumor immunity.  In fact, PD-L1-
expression is directly related to a poorer prognosis and reduced number of tumor-infiltrating 
T lymphocytes, particularly cluster of differentiation (CD) 8(+) T cells.  mAbs against PD-L1 
or PD-1 induced a substantial antitumor effect on murine pancreatic cancer in vivo.  PD-L1 
blockades promoted CD8(+) T-cell infiltration into the tumor and induced local immune 
activation.  Furthermore, the combination of anti-PD-L1 mAb and gemcitabine exhibited a 
significant synergistic effect on murine pancreatic cancer and resulted in complete response 
(CR) without overt toxicity (Nomi et al 2007).  Available clinical data derived from a clinical 
trial evaluating a single agent showed a modest clinical activity together with a tolerable 
safety profile, suggesting the possibility to evaluate an alternative development strategy, such 
as combination with different compounds.
Treatment of 14 patients with PDAC with BMS-936559, a novel anti-PD-L1 antibody, 
showed no response in any of the treated patients (Brahmer et al 2012).  Similarly, in a 
Phase II trial in 27 patients with locally advanced or metastatic PDAC receiving the 
anti-CTLA-4 agent ipilimumab, there were no responders by Response Evaluation Criteria in 
Solid Tumors (RECIST), but a patient experienced a delayed response after initial progressive 
disease (PD; Pardoll 2012, Royal et al 2010).  Preliminary data from 
Study CD ON-MEDI4736-1108 (referred to hereafter as Study 1108), a Phase I multi-arm 
expansion study of MEDI4736, showed 2 partial responses (PRs) in 29 evaluable patients with 
PDAC (Segal et al 2014).
As an antibody that blocks the interaction between PD-L1 and its receptors, MEDI4736 may 
relieve PD-L1-dependent immunosuppressive effects and, therefore, enhance the cytotoxic 
activity of antitumor T cells.  This hypothesis is supported by emerging clinical data from 
other mAbs targeting the PD-L1/PD-1 pathway, which provide early evidence of clinical 
activity and a manageable safety profile (Brahmer et al 2012, Topalian et al 2012).  To date, 
the responses tend to be more frequent in patients with tumors that express PD-L1 
(PD-L1-positive), although, importantly, responses are also seen in patients with tumors that 
are non/low expressors of PD-L1.
To date durvalumab has been given to more than 6000 patients as part of ongoing studies 
either as monotherapy or in combination with other anti-cancer agents. Details on the safety 
profile of durvalumab monotherapy are summarized in Section 1.3.2.1 and Section 6.7. Refer 
to the current durvalumab Investigator’s Brochure for a complete summary of non-clinical and 
clinical information including safety, efficacy and pharmacokinetics.


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1.1.3
AZD5069
AZD5069 is a highly selective and potent small-molecule CXC chemokine receptor-2 
(CXCR2) antagonist.  CXCR2 was recently identified as a novel target for modulating tumor 
immunity (Di Mitri et al 2014, Highfill et al 2014).  Tumor signaling of PD-1 (CD279) on 
T cells and expansion of myeloid-derived suppressor cells (MDSCs) are major mechanisms of 
tumor immune escape.  CXCR2 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 antitumor effects 
in established tumors (Highfill et al 2014).
Studies have suggested that CXCR2 is expressed in various PDAC cell lines and is primarily 
involved in enhancing the proliferation and survival of cancer cells through the autocrine and 
paracrine effect (Steele et al 2016, Takamori et al 2000). Specifically, expression of CXCR2 is 
increased in later stages of PDAC, indicating that CXCR2 is involved with the growth and 
proliferation of this tumor type (Hussain et al 2010).  Based on these findings, blocking the 
CXCR2 pathway could be used therapeutically to enhance antitumor immune responses in 
patients with PDAC. Results of multiple nonclinical studies have supported this hypothesis, as 
well.  Blocking the CXCR2 complex reduced cell proliferation and cell invasion of PDAC 
cells (Wang et al 2013) and has also been demonstrated to prolong survival in a state-of-the-
art GEMM model of pancreatic cancer (Steele et al 2016).
Most recently, preliminary data from the dose escalation part the D5660C00004 trial in solid 
tumor patients treated in combination with AZD5069 and MEDI4736 has been obtained.  As 
of 7 July 2016, safety and limited efficacy information from 11 subjects initially treated with 
AZD5069 40 mg bid and an additional 12 subjects started on AZD5069 80 mg bid was 
available.    During this portion of the trial, an initial RP2D of 80 mg po bid in combination 
with durvalumab was agreed upon by the safety review committee.    
AZD5069 was also previously evaluated in Phase I studies involving healthy volunteers, as 
well as patients with chronic obstructive pulmonary disease (COPD) and with bronchiectasis.  
There have also been 2 Phase II studies in patients with chronic or neutrophilic asthma.  A 
Phase Ib/II study (Study D5660C00004) of AZD5069 in combination with MEDI4736 in 
patients with advanced solid malignancies and squamous cell carcinoma of the head and neck 
is currently being conducted under Investigational New Drug Application 125391.
As of April 2015, AZD5069 has been studied in 8 completed Phase I clinical studies in a total 
of 255 healthy volunteers, of whom 202 received AZD5069 (single doses up to 200 mg; 
multiple doses up to 80 mg twice daily (bid) for up to 7 days and 100 mg bid for up to 
6.5 days).  Three 4-week studies have been conducted in patients: 87 patients with COPD 
(Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stage II to III) who 
received50 mg and 80 mg bid/placebo,  52 patients with bronchiectasis (80 mg bid/placebo), 
and 5 patients with neutrophilic asthma (45 mg bid).  A Phase II efficacy study in 640 patients 
with persistent uncontrolled asthma has also been completed (478 patients received AZD5069 


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at doses of 5 mg bid, 15 mg bid, or 45 mg bid, while 162 patients received placebo for 6 
months).
Details on the safety profile of AZD5069 are summarized in section 1.3.2.2.  Refer also to the 
current AZD5069 IB for a complete summary of nonclinical and clinical information.  No 
additional expected risks from the combination of AZD5069 with durvalumab treatment have 
been identified at this time.
1.1.4
Rationale for conducting this study
PDAC patients have poor outcomes, as a consequence of the very aggressive nature of the 
disease, and the limited activity of current treatment options, thus there is a significant unmet 
medical need for additional treatment options for use in this patient population.  In addition, 
although clinical experience with MEDI4736 is limited, currently available data from the 
MEDI4736 first in human study (Study 1108) indicate encouraging response rates and 
duration of response (DoR) with a manageable safety profile in patients with a variety of solid 
malignancies, including a heterogeneous population of heavily pretreated patients with 
pancreatic cancer treated with MEDI4736 as monotherapy.
Chemotherapy, a mainstay intervention for cancer since the 1940s, has the potential to debulk 
the primary tumor mass and, therefore, can be used to alter the tumor microenvironment, 
thereby making it more receptive to an effective immune response.
Although chemotherapeutic drugs induce their primary damage in many different ways, most 
of them kill tumor cells by the induction of apoptosis.  The massive apoptosis induced by 
chemotherapy could release pro-inflammatory mediators, such as heat-shock proteins, that act 
as danger signals and can activate dendritic cells through the toll-like receptor signaling 
pathways, thus engaging the innate immune response.  It could also induce cytokine 
production patterns typical of the T-helper, type I phenotype, thereby promoting effective 
cytotoxic T-cell responses (Zwierzina 2008).
There is evidence that tumor-derived antigens induce tolerance during tumor progression.  In 
mice, for example, persistent presentation of a tumor antigen causes cytotoxic T cells that 
were once active against the antigen to become tolerant, resulting in tumor outgrowth.  
Interestingly, functional capacities are regained when T cells are transferred to an antigen-free 
environment.  The elimination of persistent tolerogenic tumor antigen environment via 
chemotherapy-induced debulking may play a role in generating an effective immune response 
(Drake 2012).
Another way in which cytotoxic drugs can make the tumor microenvironment more conducive 
to an effective immune response is by restoring the expression of tumor antigens or major 
histocompatibility complex (MHC) molecules that have been lost during tumor progression or 
upregulating the expression of costimulatory molecules (B7-1 and B7-2), thereby rendering 
the tumor cells themselves as more efficient antigen presenting cells.  Others (5-fluorouracil 
and cisplatin) sensitize tumor cells to CTL-mediated apoptosis through Fas- or 
perforin/granzyme-mediated pathways (Emens and Jaffee 2005).


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Chemotherapy, even at conventional doses, can eliminate MDSC and Tregs, thus removing 
some of the immune suppressive factors present in cancer patients.  Cytotoxic drugs can 
modulate systemic mechanisms of active immune suppression or amplify expansion of 
antigen-specific T-cell expansion via cytoreduction by influencing the homeostasis of the 
hematopoietic compartment through transient lymphodepletion followed by rebound 
replenishment of immune cell pools (Emens and Jaffee 2005).
Moreover, cytoreductive chemotherapy generates a plethora of tumor-associated antigens, 
which are expressed in the context of MHC molecules on antigen-presenting cells and can 
potentially initiate antigen-specific T-cell activation.  Furthermore, tumors carry many 
mutations, and there is clear evidence that most tumors express neo-antigens against which the 
host has a capacity to react.  Conventional chemotherapy could unmask additional tumor 
neo-antigens and thus increase the amount of material available for cross-priming (Emens and 
Jaffee 2005).
This immune response is driven by the accumulation of dendritic cells in the tumor, followed 
by their maturation, migration to lymph nodes, and priming of tumor-specific CD8+ CTL in a 
type I interferon-dependent manner.  An antigen density within the tumor is an important 
determinant of the outcome of immune surveillance following chemotherapy 
(Kang et al 2013).
In this setting, immunotherapy has the potential to mount an ongoing and dynamic immune 
response that can kill tumor cells for an extended time after the conventional therapy has been 
administered.  This long-lasting response is potentially able to completely eradicate tumor 
cells rather than producing only a temporary killing of cells, in contrast to standard 
chemotherapy.  The most promising immune-based treatments are mAbs that act as 
checkpoint inhibitors (eg, MEDI4736), adoptive cell therapy (eg, T cells expressing chimeric 
antigen receptors), and vaccines (eg, sipuleucel-T).
CXC chemokines display pleiotropic effects in mediating immune response, angiogenesis, and 
metastases and deregulation of CXC chemokines occurs in late-stage PDAC 
(Fokas et al 2015).  The CXCR2 ligand, CXCL5, is overexpressed in patients with PDAC and 
is significantly correlated with advanced disease stage and poor outcome.  CXCR2-knockout 
mice harboring PDAC presented impaired recruitment of endothelial progenitor cells from 
bone marrow that resulted in decreased angiogenesis and tumor growth.  (Hiraoka et al 2011) 
showed that the chemokine (C-X-C motif) ligand 17 (CXCL17) mediated intratumoral 
infiltration of immature dendritic cells, while the intercellular adhesion molecule 2 (ICAM2) 
facilitated CD8+ cell-mediated cytotoxicity and tumor cell killing.  Interestingly, during 
tumorigenesis progression from precursor lesions to PDAC, downregulation of CXCL17 and 
ICAM2 tempered immune response that led to immune tolerance.  Furthermore, blockade of 
TGF-β receptor II in a mutant Kras mouse model resulted in an aggressive disease phenotype 
with increased secretion of CXCL1 and CXCL5 ligands.  Of note, CXCR2 expression was 
higher in stromal fibroblasts compared to epithelial cells, whereas signaling attenuation using 
a CXCR2 inhibitor decreased vessel density and improved survival in tumor-bearing mice.


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Recent work from Highfill and others (Highfill et al 2014) shows that murine 
rhabdomyosarcoma (RMS) primarily induces the expansion of granulocytic 
CXCR2+CD11b+Ly6Ghi MDSCs, and demonstrates that CXCR2 is required for trafficking of 
these MDSCs to the tumor bed. 
In addition, a study reported by Steele et al. demonstrated an important potential role for 
CXCR2 in pancreatic ductal adenocarcinoma (Steele et al 2016).  Their work demonstrated 
that high expression of CXCR2 at the tumor border was associated with more rapid 
progression in 44 patients.  Using a genetically modified mouse model of this disease (KPC 
mice, LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre), these investigators further demonstrated 
the presence of CXCR2-expressing myeloid cells within developing tumors and that 
simultaneous small molecule inhibition of CXCR2 by AZ13381758, (an AZD5069 congener) 
and gemcitabine can significantly enhance survival.
MDSC-mediated suppression of antitumor immunity is a local phenomenon limited to the 
tumor bed because inhibition of MDSC trafficking to the tumor enhances the potency of PD-1 
checkpoint blockade (Highfill et al 2014).  This work identifies CXCR2 as a new target for 
therapies aimed at inhibiting MDSC recruitment and provides a rationale for combining 
immune checkpoint inhibitors with agents designed to prevent MDSC-mediated immune 
suppression for cancer therapy.
Based on the preliminary clinical efficacy and safety data observed in the pancreatic cancer 
cohort of Study 1108, this study is being conducted to determine the safety and tolerability of 
the combination of MEDI4736 with chemotherapy or novel anticancer agents in patients with 
PDAC.
1.2
Rationale for study design, doses and control groups
This study will utilize an open-label design due to the different treatment administration 
schedules and treatment durations.
1.2.1
MEDI4736 dose rationale
A dose of MEDI4736 20 mg/kg every 4 weeks (q4w) is supported by in-vitro data, 
non-clinical activity, clinical pharmacokinetics (PK)/pharmacodynamics, biomarkers, and 
activity data from Study 1108 in patients with advanced solid tumors (ongoing first-time-
in-humans study) and from a Phase I trial performed in Japanese patients with solid tumor 
(NCT01938612).
PK/Pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 0.1 to 10 mg/kg every 2 weeks (q2w) or 15 mg/kg every 3 weeks (q3w), MEDI4736 
exhibited non-linear (dose-dependent) PK consistent with target-mediated drug disposition. 
The PK approached linearity at ≥3 mg/kg q2w, suggesting near complete target saturation 
(membrane-bound and soluble PD-L1 [sPD-L1]), and further shows that the MEDI4736 
dosing frequency can be adapted to a particular regimen given the linearity seen at higher 


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doses than 3 mg/kg. The expected half-life with doses ≥3 mg/kg q2w is approximately 
21 days. A dose-dependent suppression in peripheral sPD-L1 was observed over the dose 
range studied, consistent with engagement of MEDI4736 with PD-L1. Dose-related changes 
in a variety of peripheral biomarkers have been observed over the dose range of 0.1 to 
15 mg/kg. A low level of immunogenicity has been observed. No patients have experienced 
immune-complex disease following exposure to MEDI4736. For further information on 
immunogenicity, please see the current IB.
A population PK model was developed using the data from Study 1108 (doses=0.1 to 
10 mg/kg q2w or 15 mg/kg q3w; Fairman et al 2014).  Multiple simulations indicate that a 
similar overall exposure is expected following both 10 mg/kg q2w and 20 mg/kg q4w 
regimens, as represented by area under the plasma drug concentration-time curve (AUC) at 
steady state (AUCss) (4 weeks).  Median maximum plasma concentration at steady state 
(Cmax,ss) is expected to be higher with 20 mg/kg q4w (~1.5 fold), and median trough plasma 
concentration at steady state (Ctrough,ss) is expected to be higher with 10 mg/kg q2w 
(~1.25 fold).  Clinical activity with the 20 mg/kg q4w dosing regimen is anticipated to be 
consistent with 10 mg/kg q2w with the proposed similar dose of 20 mg/kg q4w expected to 
(a) achieve complete target saturation in majority of patients; (b) account for anticipated 
variability in PK, pharmacodynamics, and clinical activity in diverse cancer populations; 
(c) maintain sufficient PK exposure in case of ADA impact; and (d) achieve PK exposure that 
yielded maximal antitumor activity in animal models.
Given the similar AUC and modest differences in median peak and trough levels at steady 
state, the observation that both regimens maintain complete sPD-L1 suppression at trough, 
and the available clinical data, the 20 mg/kg q4w and 10 mg/kg q2w regimens are expected to 
have similar efficacy and safety profiles, supporting further development with a dose of 
20 mg/kg q4w.
Clinical data
Overall, cumulatively, 765 out of 1,744 patients (43.9%) reported SAEs in the monotherapy 
programme.  The most frequently reported SOCs were Neoplasms Benign, Malignant and 
Unspecified (including Cysts And Polyps) (n = 218; 12.5%) [likely in relation to the 
underlying cancer], Respiratory, Thoracic and Mediastinal Disorders (n = 195 11.2%) and 
Infections and Infestations (n = 163 9.3%).  The most frequently reported SAEs were 
Dyspnoea (n=62), Pneumonia (n=53) and NSCLC (n=50) (artefact most likely representing 
progressive disease rather than an SAE).  Possible immune-mediated adverse events (AEs) 
included: GI events (diarrhoea, colitis, enteritis, enterocolitis, pancreatitis and pancreatitis 
acute), endocrine events (adrenal insufficiency, hyperthyroidism, hypothyroidism, and 
hypopituitarism), hepatic events (autoimmune hepatitis, hepatitis, hepatocellular injury, 
hepatotoxicity, hyperbilirubinemia, liver injury and hepatic laboratory abnormality SAEs), 
renal events (acute kidney injury, renal failure) and respiratory events (ILD and pneumonitis).  
Other SAEs reported were axonal neuropathy (1), myocarditis (1) and tumour flare (1).
Partial efficacy data are available for Study CD-ON-MEDI4736-1108. Tumor assessments 
were based on RECIST v1.1 (Eisenhauer et al 2009). A total of 456 of 694 subjects with 


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advanced solid tumors treated with durvalumab 10 mg/kg Q2W were evaluable for response 
(defined as having ≥24 weeks follow-up, measurable disease at baseline, and ≥1 follow-up 
scan, or discontinued due to disease progression or death without any follow-up scan). In PD-
L1 unselected patients, the ORR, based on investigator assessment per RECIST v1.1, ranged 
from 0% in uveal melanoma to 20.0% in bladder cancer, and DCR-24w ranged from 4.2% in 
TNBC to 39.1% in advanced cutaneous melanoma.). PD-L1 status was known for 383 of the 
456 response evaluable subjects. Across the PD-L1-positive tumors, ORR was highest (> 
10%) for bladder cancer, advanced cutaneous melanoma, HCC (33.3% each), NSCLC 
(26.7%), and SCCHN (18.2%).  Moreover, in the PD-L1-positive subset, DCR-24w was 
highest (> 10%) in advanced cutaneous melanoma.  Response rates to durvalumab 10 mg/kg 
IV Q2W among 30 patients with pancreatic adenocarcinoma at more than 24 weeks of 
followup were 2/30 subjects treated (6.7%), with a disease control rate of 5/30 (16.7%). 
1.2.1.1
Rationale for fixed dosing
A population PK model was developed for MEDI4736 using monotherapy data from 
Study 1108 (Phase I study; N=292; doses=0.1 to 10 mg/kg q2w or 15 mg/kg q3w; solid 
tumors).  Population PK analysis indicated only a minor impact of body weight (WT) on the 
PK of MEDI4736 (coefficient of ≤0.5).  The impact of body WT-based (10 mg/kg q2w) and 
fixed dosing (750 mg q2w) of MEDI4736 was evaluated by comparing predicted steady state 
PK concentrations (5th, median, and 95th percentiles) using the population PK model.  A fixed 
dose of 750 mg was selected to approximate 10 mg/kg (based on a median body WT of 
approximately 75 kg).  A total of 1000 patients were simulated using a body WT distribution 
of 40 to 120 kg.  Simulation results demonstrated that body WT-based and fixed dosing 
regimens yield similar median steady state PK concentrations with slightly less overall 
between-patient variability with the fixed dosing regimen.
Similar findings have been reported by others (Narwal et al 2013, Ng et al 2006, 
Wang et al 2009, Zhang et al 2012).  Wang and colleagues investigated 12 mAbs and found 
that fixed and body size-based dosing perform similarly, with fixed dosing being better for 
7 of 12 antibodies (Wang et al 2009).  In addition, they investigated 18 therapeutic proteins 
and peptides and showed that fixed dosing performed better for 12 of 18 in terms of reducing 
the between-patient variability in PK/pharmacodynamics parameters (Zhang et al 2012).
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors.  Given the expectation of similar PK exposure and variability, 
AstraZeneca considered it feasible to switch to fixed dosing regimens.  Based on an average 
body WT of 75 kg, a fixed dose of 1.5 g q4w MEDI4736 (equivalent to 20 mg/kg q4w) is 
included in the current study.
1.2.2
Rationale for combination MEDI4736 and chemotherapy (nab-paclitaxel + 
gemcitabine)
The use of combination chemotherapy has been a mainstay of oncology therapy by 
distributing different stages of the cell reproduction cycle.  Recently, targeted agents have 
been combined rationally with other targeted or chemotherapeutic agents, and current 


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investigations are now adding immunotherapeutics to broaden responses as well as to treat 
resistance.
Cytotoxic chemotherapy have been shown to modulate the immune response by several 
mechanisms such as stimulating T-cell activation via increasing the expression of MHC-1 
molecules (Liu et al 2010), stimulating dendritic cell maturation (Liu et al 2010), inducing 
immunogenic cell death, a form of cell death that induces dendritic cells to stimulate tumor 
antigen presentation to T cells (Kroemer et al 2013); and reducing the immunosuppressive 
function of regulatory T cells (Zhang et al 2008) and MDSCs (Kodumudi et al 2010).  
Combining MEDI4736, a PD-L1 antagonist, with cytotoxic agents, such as nab-paclitaxel and 
gemcitabine, may provide complementary benefit in mounting an effective antitumor 
immunity by promoting the antigen presentation, increasing the production of protective T 
cells and overcoming immunosuppression in the tumor bed (Mellman et al 2011).  A variety 
of approaches for combining PD-1 pathway blockers with other agents have been explored 
over the past few years in an effort to both improve the efficacy of therapy and/or position the 
treatment regimen for testing in treatment-naïve patients with a variety of cancers.  
Approaches have included combinations with other checkpoint inhibitors (such as 
ipilimumab), immunostimulatory cytokines (eg, interferon-gamma [IFN-γ]), cytotoxic 
chemotherapy, anti-angiogenic inhibitors, and small-molecule molecularly targeted therapies, 
many with promising results and an acceptable toxicity profile (Philips and Atkins 2015).
CheckMate 012 [ClinicalTrials.gov identifier: NCT01454102] is a multi-arm Phase I study of 
nivolumab with various anticancer agents or as monotherapy.  Preliminary results from 
4 treatment arms from this study have been presented recently at the 2014 American Society 
of Clinical Oncology annual meeting.
In the platinum doublet arm, where 3 platinum-based chemotherapy regimens (cisplatin + 
gemcitabine, cisplatin + pemetrexed, and carboplatin + paclitaxel) were combined with 
nivolumab (n=56 patients), the ORR was 33% to 50%, 24-week PFS 36% to 71% and 1-year 
OS was 59% to 87% (Antonia et al 2014b).  No DLTs were seen in the first 6 weeks of 
treatment, but 45% of patients had Grade 3 or 4 toxicities and 7% (n=4 patients) had
pneumonitis.  Based on these preliminary results, the antitumor activity of first-line nivolumab 
in combination with platinum doublets is highly promising.  In the erlotinib and nivolumab 
arm, chemotherapy-naïve patients (n=21 patients) with epidermal growth factor receptor 
(EGFR) mutations were enrolled.  A total of 20 patients had prior treatment with first-line 
erlotinib.  The ORR was 19%, and the 24-week PFS was 51% (Rizvi et al 2014).  
Interestingly, of those with acquired erlotinib resistance, 3 patients (15%) had a PR, 9 patients 
(45%) achieved stable disease (SD), and 1 patient had an unconventional immune-related 
response.  Grade 3 toxicities were reported in 19% of patients (there were no Grade 4 
toxicities).  Common side effects included skin rash, fatigue, paronychia, diarrhea, and skin 
fissures.  While this combination has shown encouraging activity, the data are preliminary and 
validation and comparison with the third-generation EGFR tyrosine-kinase inhibitors in 
tumors harboring T790M mutations is still needed.  Further work on the interaction between 
tumors harboring T790M mutations and the tumor microenvironment and immune 
checkpoints would also be of interest.


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Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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1.2.3
Rationale for combination of MEDI4736 and AZD5069
Combining a PD-L1 antagonist, MEDI4736, with an agent targeting immunosuppression in 
the tumor bed, AZD5069, is a complementary antitumor strategy, as the 
2 immunotherapeutics may reasonably be expected to restore effective antitumor immunity by 
two separate but related mechanisms: these are promoting the effector function of T-cell 
responses (MEDI4736) and hindering immune escape in the tumor bed (AZD5069).
The combination of MEDI4736 with AZD5069 will be tested in this study to evaluate the 
safety and tolerability in patients the second-line treatment of patients with PDAC, a patient 
population with a limited benefit from chemotherapy.  PK, immunomodulatory, and PD 
parameters, as well as clinical activity and biomarkers that may correlate with activity or 
prospectively identify patients likely to respond to the various treatments, will also be 
evaluated.  The results from this study will form the basis for decisions for future studies.
1.2.4
AZD5069 dose rationale
The recommended Phase 2 dose levels (RP2D) of AZD5069 as determined in Study 
D5660C00004 (SCORES study) will be employed. 
This entails initial dosing of AZD5069 at 80 mg po bid in combination with durvalumab using 
defined dose reduction criteria based on peripheral blood neutrophil counts.  Details of this 
management are described Section 6.7.3.  Briefly, it entails starting at AZD5069 80 mg bid 
and carefully monitoring neutrophil counts during the first weeks of treatment.  Short dosing 
holds are the first response to absolute neutrophil counts <0.5 x 109/l (referred to hereafter as 
Grade 4 neutrophil reductions).      
In the face of prolonged Grade 4 neutrophil reductions unresponsive to dose holds, use of G-
CSF is allowed twice at any given dose level;   subsequent dose reductions to the next lower 
dosing level (80 mg bid40 mg bid or 40 mg bid20 mg bid) are then mandated.  Of note, 
Grade 3 neutrophil reductions (ANC 0.5-1.0 x 109/l) without clinically significant infection 
are tolerated within the dose reduction scheme.  
This dosing regime was developed over more than one year of experience treating patients in 
the SCORES trial without serious infectious complications of AZD5069 neutrophil reductions 
as described below.  
In the SCORES study, an initially established RP2D of AZD5069 40 mg bid was arrived after 
observation of a single dose limiting toxicity of Grade 3 neutropenia without infectious 
complications (9 patients initially treated at that dose level).  Among the 11 mixed solid tumor 
patients who received AZD5069 + Durvalumab at the next dosing level (80 mg bid), 2 
exhibited reversible Grade 3 or 4 neutropenia again not associated with infectious 
complications during the DLT evaluation window;  one complete remission of a tumor type 
(ER+ breast cancer) rarely responsive to PD-(L)1 inhibition was also observed.  
Because reduced peripheral blood neutrophil counts associated with CXCR2 inhibition by 
AZD5069 result from redistribution of mature neutrophils (myelokathexis or failure of bone 


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
39(176)
marrow release) and not from absolute reductions in the total body pool of granulocytes 
available to respond to infectious agents, the Safety Review Committee in the SCORES trial 
subsequently decided to enroll an additional cohort of up to 12 evaluable patients under a new 
dosing schedule for AZD5069 (80 mg bid with scheduled dose holds and titration for each 
patient).  Based on the absence of clinically significant infections in six additional patients and 
also on the accumulating experience with AZD5069 in oncology patients, the dosing scheme 
beginning with AZD5069 80 mg po bid reproduced and outlined in Section 6.7.3 here was 
declared the new RP2D.
Preliminary efficacy results in the SCORES trial suggest potential benefit from the 
combination of AZD5069 with Durvalumab.  As of 7 July 2016, 23 patients with mixed solid 
tumors had received AZD5069 in combination with MEDI4736 for a minimum of 6 weeks. 
These included 11 patients at 40 mg bid and 12 at 80 mg bid. Preliminary data at that time 
suggested 1 patient in the AZD5069 40 mg bid cohort had stable disease as a best response. 
There were 3 patients with stable disease, 2 patients with partial responses, and 1 patient with 
a complete response in the AZD5069 80 mg bid cohort. Efficacy analysis of these patients is 
ongoing.
Due to the very acute, rapidly progressive nature of pancreatic ductal adenocarcinoma, 
patients in the D4198C00003 study will begin receiving both AZD5069 and Durvalumab on 
day 1 of the first treatment cycle (no initial 7 day run-in on AZD5069 alone, as in the 
D5660C00004 study). Dosing will continue until confirmed PD or another discontinuation 
criterion is met.  
In study D5660C00004, following a single dose administration, maximum AZD5069 plasma 
concentrations (Cmax) were observed with a median time to maximum (Tmax) occurring at 2 
hrs (range: 0.5-8 hr). As assessed by geometric mean CV%, there was moderate between-
subject variability in Cmax and AUC, with values ranging from 31 to 46%. As the dose 
increased from 40 mg (capsule) to 80 mg (tablet), Cmax and AUC0-8, increased by 2.9 and 
2.57 fold, respectively. A similar trend was observed with the metabolite AZ13587715 PK..
In further support of the proposed dosing, a significant body of data from healthy volunteers 
and pulmonary patients also describes the safety of AZD5069 during long term 
administration.  As of April 2015, AZD5069 had  been studied in 8 completed Phase I clinical 
studies in a total of 255 healthy volunteers, of whom 202 received AZD5069 (single doses up 
to 200 mg; multiple doses up to 80 mg bid for up to 7 days and 100 mg bid for up to 6.5 days).  
In addition, three major trials in pulmonary patients were completed in 87 patients with COPD 
(GOLD Stage II-III) (50 mg and 80 mg bid/placebo), 52 patients with bronchiectasis (80 mg 
bid/placebo), and in a Phase II efficacy study in 640 patients with persistent uncontrolled 
asthma (478 patients received AZD5069 at doses of 5 mg, 15 mg bid, or 45 mg bid, while 162 
patients received placebo for 6 months).  In the asthma trial, approximately 70% of patients 
enrolled during the first portion of the study completed a planned optional 6-month safety 
extension, even though that portion of the study was terminated early due to a lack of efficacy.  
A small study of 4 patients involving comparison of neutrophils in sputum, serum, and 
bronchial tissue in patients with neutrophilic asthma has also been completed.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
40(176)
In these pulmonary studies, up to ~30% decreases in blood neutrophil counts were seen in 
pulmonary patients (COPD, bronchiectasis and asthma studies) without evidence of any 
increase in infections that might have been related to drop in neutrophil counts.  For further 
information concerning the healthy volunteer and pulmonary studies, please consult the 
current version of the Investigators Brochure for AZD5069.
1.3
Benefit/risk and ethical assessment
The following sections include summaries of the potential benefits and risks associated with 
MEDI4736 monotherapy and AZD5069 monotherapy, respectively, prior to the overall 
benefit/risk assessment.
1.3.1
Potential benefits
1.3.1.1
MEDI4736
The majority of the safety and efficacy data currently available for MEDI4736 are based on 
the first time in-human, single-agent study (Study 1108) in patients with advanced solid 
tumors.  Updated efficacy data from Study 1108 were presented at the European Society for 
Medical Oncology 2014 Congress.  As of 21 August 2014, 373 patients with all tumor types 
were evaluable for response analysis, including 352 patients receiving 10 mg/kg MEDI4736 
q2w.  The DCR at 12 weeks in patients receiving 10 mg/kg MEDI4736 q2w was 33%, and the 
ORR was 10%.  Greater DCR at 12 weeks (47% versus 28%) and ORR (22% versus 5%) 
were observed in PD-L1-positive versus PD-L1-negative patients.  Responses were ongoing in 
92% of patients, with an objective response duration ranging from 0.1 to 32 weeks 
(Segal et al 2014).  Of the 29 evaluable PDAC patients treated in Study 1108, 2 patients had 
PRs (Segal et al 2014).
1.3.1.2
AZD5069
AZD5069 is being evaluated in the D5660C00004 (SCORES) trial and so far a complete 
remission in one patient with a tumor type (ER+ breast cancer) that rarely responds to PD-
(L)1 blockade alone has been identified.  In addition, a strong basis for expecting efficacy has 
been documented in preclinical literature for a number of tumor types (pancreatic, 
rhabdomyosarcoma, prostate).  Blocking the CXCR2 complex has reduced cell proliferation 
and CXCR2 expression is increased in later stages of PDAC, so strong antagonism to this 
chemokine receptor may favorably affect host cell immune responses to PDAC tumors.  
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 TANs 
and MDSCs, which have been hypothesized to play an important role in the tumor 
microenvironment, potentially downregulating host immune responses to malignancies as well 
as affecting tumor cell senescence.  
Additional data on patients with solid tumors will be available from Study D5660C00004 
prior to initiation of treatment in this study. 


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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1.3.2
Potential risks
1.3.2.1
MEDI4736
Risks with MEDI4736 (durvalumab) include, but are not limited to, diarrhea/colitis and 
intestinal perforation, pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I 
diabetes mellitus, hypophysitis and adrenal insufficiency) hepatitis/increases in transaminases, 
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, hypersensitivity 
reactions and infections/serious infections. 
For information on all identified and potential risks with MEDI4736 (durvalumab) please 
always refer to the current version of the MEDI4736 (durvalumab) IB.
In monotherapy clinical studies AEs (all grades) reported very commonly (≥ 10% of patients) 
are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back 
pain, pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, rash, and pruritus. 
Approximately 9% of patients experienced an AE that resulted in permanent discontinuation 
of MEDI4736 (durvalumab) and approximately 6% of patients experienced an SAE that was 
considered to be related to MEDI4736 (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 (please see Section 6.7).
A detailed summary of MEDI4736 (durvalumab) monotherapy AE data can be found in the 
current version of the MEDI4736 (durvalumab) IB.
1.3.2.2
AZD5069
Identified risks that are currently regarded as expected terms for regulatory reporting purposes 
and comprise the reference safety information for AZD5069 are as follows:
Respiratory indications (non-oncology)

Neutropenia

Neutrophil count decreased
A reduction in blood neutrophil counts has been seen in healthy volunteers and patients
participating in respiratory studies with AZD5069. Data from healthy volunteers indicate a 
dose related effect. The reductions in blood neutrophil counts have been asymptomatic, with 
a return to baseline values following the completion of the dosing regimen. In some cases this 
reduction in blood neutrophil counts led to neutrophil levels falling below the lower limit of 
the laboratory reference range.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
42(176)
While reduction of neutrophils in peripheral blood or sputum could have an impact on host 
defense with regard to infections, studies with AZD5069 in healthy subjects, and in 
respiratory patients with COPD, bronchiectasis, and asthma did not show an increased rate of 
overall infections compared with placebo.  The reduction in blood neutrophil counts in these 
patients was modest in magnitude compared to that associated with cytoreductive therapeutics 
commonly employed in oncology clinics.  
Oncology indications
So far in the clinical program of AZD5069 in oncology indications, although reductions in 
peripheral blood neutrophil counts have been observed in the ongoing D5660C00004 trial, 
these have been non serious, reversible, and not associated with significant  clinical 
symptoms. No serious reports suggestive of neutrophil count decreased or neutropenia have 
been reported to data cut-off. Therefore, in the oncology indications, neutropenia/neutrophil 
count decreased is not currently considered expected for regulatory reporting purposes.
For information on potential risks of AZD5069 and further information on the safety profile of 
AZD5069, please refer to the current AZD5069 IB Section 6, Summary of data and guidance 
for the Investigators.
1.3.2.3
Overall benefit and risk assessment
There remains a significant unmet medical need for additional treatment options for patients 
with metastatic PDAC.
The combination of nab-paclitaxel + gemcitabine has been approved in patients with newly 
diagnosed advanced pancreatic cancer based on the data generated from the 861 patients 
enrolled in the Phase III MPACT trial, demonstrating a median OS of 8.5 months (95% CI, 
7.89 to 9.53) for the nab-paclitaxel + gemcitabine group compared with 6.7 months (95% CI, 
6.01 to 7.23) for the gemcitabine monotherapy group (HR for death =0.72; 95% CI, 0.62 to 
0.83; p<0.001).  In the nab-paclitaxel + gemcitabine group, the median duration (range) of 
treatment was 3.9 months (0.1 to 21.9 months) compared with 2.8 months (0.1 to 
21.5 months) in the gemcitabine group.  The most frequently reported nonhematologic AEs 
related to treatment with the nab-paclitaxel + gemcitabine combination included fatigue 
(54%), alopecia (50%), and nausea (49%).  Grade 3 or higher neutropenia, leukopenia, 
fatigue, and peripheral neuropathy were reported more often in the nab-paclitaxel + 
gemcitabine group compared with the gemcitabine monotherapy group.  Peripheral 
neuropathy was the AE with the most notable difference between the 2 treatment groups.  It 
was cumulative and rapidly reversible in most patients after temporary discontinuation of 
nab-paclitaxel and subsequent dose reduction.  None of the patients experienced Grade 4 
peripheral neuropathy.  The rate of discontinuation of nab-paclitaxel due to peripheral 
neuropathy (all grades) was 8%.  Overall, 10% of the patients had a dose reduction of 
nab-paclitaxel as a result of peripheral neuropathy.
While this will be the first study investigating the treatment of AZD5069 (in combination with 
MEDI4736) in patients with metastatic PDAC and further data in patients with solid tumors 


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
43(176)
will be available from Study D5660C00004, data in other CXCR2 inhibitors showed 
retardation of tumor progression both alone and in combination with docetaxel 
(Di Mitri et al 2014).  Additionally, preclinical animals models have demonstrated the 
blocking both CXCR2 and PD-L1 versus PD-L1 blockade alone demonstrated significant 
antitumor effects in established tumors (Highfill et al 2014).  Reduction of neutrophils in 
peripheral blood has been reported in AZD5069 trials and in general in this class of compound 
and could have an impact on host defense with regard to infections.  However, so far studies 
with AZD5069 in healthy patients and in patients with COPD and bronchiectasis did not 
shown an increased rate of overall infections compared with placebo.
Treatment with agents targeting PD-1/PD-L1 (such as MEDI4736) has shown activity in 
several tumor types in a subset of patients deriving meaningful and durable benefit.  Efficacy 
data for patients treated with MEDI4736 monotherapy in the pancreatic cancer cohort have 
shown some clinical activity.  Thus, combining MEDI4736 with chemotherapy, AZD5069, or 
other agents may potentially offer complementary antitumor benefit to this patient population.
The study design aims to minimize potential risks, and intensive monitoring, including early 
safety assessment, is in place for those risks deemed to be most likely based on prior 
experience with the IPs (including MEDI4736, nab-paclitaxel, gemcitabine, and AZD5069).
No important risks have been identified in the human studies of AZD5069 to date.
The toxicity profile of MEDI4736 monotherapy includes fatigue, nausea, diarrhea, decreased 
appetite, dyspnea, pyrexia, AST or ALT increases, amylase and lipase increases, rash and 
pruritus, and other immune-mediated reactions, which were mostly reversible and manageable 
by the available protocol treatment guidelines.
The rationale for this study is supported by the available nonclinical and clinical safety data, 
the limited survival benefit provided by the currently available treatment options to patients, 
the limited life expectancy due to malignant disease, the activity seen with MEDI4736 in this 
tumor type, and the strength of the scientific hypotheses evaluating (1) the safety and 
tolerability of adding MEDI4736 to first-line SoC and (2) MEDI4736 + AZD5069 
combination therapy treatments in second-line therapy.  Based on these considerations, the 
proposed treatments may have the potential to provide meaningful clinical benefit by 
generating durable clinical responses, thereby improving quality of life and potentially 
extending survival.
1.4
Study design
This study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and 
antitumor activity of MEDI4736 in combination with chemotherapy and novel anticancer 
agents in patient with PDAC. This study will consist of two independent study cohorts. Cohort 
1 is a first-line, Phase Ib assessment of MEDI4736 in combination with chemotherapy. Cohort 
2 is a second-line, Phase II assessment of MEDI4736 + AZD5069 with a safety run-in.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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1.4.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy
Cohort 1 is a Phase Ib, open-label, dose exploration assessment of the safety, tolerability, 
antitumor activity, and PK of MEDI4736 in combination with the nab-paclitaxel + 
gemcitabine chemotherapy regimen in patients with metastatic PDAC who are treatment-
naïve (defined as no prior exposure to systemic chemotherapy, targeted therapy, 
immunotherapy, or investigational agents [except adjuvant or neoadjuvant therapy if 
>6 months from last treatment]) (Von Hoff et al 2013).  A schematic diagram of the Cohort 1 
as initially designed Figure 1.
To date, 3 patients have been enrolled into a safety run-in period to evaluate safety, 
tolerability, and antitumor activity.  All three patients tolerated therapy through the study’s 
defined DLT window.  Their treatment and evaluation with respect to primary and secondary 
objectives will continue until such time as unacceptable toxicity or progressive disease is 
observed.  Enrollment of this cohort is currently closed due to portfolio decisions that are not 
related to safety or observed efficacy.  See Section 7.2.4 for details on the definition of DLTs.
Doses and treatment regimens are described in Section 7.2.  Assessments will be conducted as 
indicated in Table 2 and Table 4
Figure 1
Cohort 1 (first-line, Phase Ib MEDI4736 + nab-paclitaxel + 
gemcitabine chemotherapy) design
1.4.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069
Cohort 2 is a Phase II, open-label, multicenter assessment of the safety and preliminary 
antitumor activity of MEDI4736 in combination with AZD5069 in patients with metastatic 
PDAC whose disease has progressed on a 5-FU-containing or gemcitabine-containing first-


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
45(176)
line chemotherapy.  Cohort 2 will enroll approximately 16 evaluable patients.  A schematic 
diagram of the Cohort 2 design is shown in Figure 2.
Initially, approximately 6 patients will be enrolled into a safety run-in period to evaluate 
safety, tolerability, and antitumor activity.  After the initial 6 patients complete 1 treatment 
cycle, if no unexpected toxicity meeting DLT criteria, approximately 10 additional patients 
will be enrolled to determine preliminary antitumor activity.  All patients in this cohort, 
including those in the safety run-in, will be included in the preliminary antitumor activity 
analysis.
Doses and treatment regimens are further described in Section 7.2.  Assessments will be 
conducted as indicated in Table 3 and Table 5.
Figure 2
Cohort 2 (second-line, Phase II MEDI4736 + AZD5069) design


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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2.
STUDY OBJECTIVES
2.1
Primary objectives
2.1.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy
Primary objective:
Outcome measure:
To assess the safety and tolerability of 
MEDI4736 in combination with nab-paclitaxel 
+ gemcitabine
Occurrence of dose-limiting toxicities
AEs, physical examinations, laboratory findings 
(including clinical chemistry, hematology, and 
urinalysis), vital signs (including blood pressure and 
pulse), electrocardiograms (ECGs)
2.1.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069
Primary objective:
Outcome measure:
To assess the safety, toleratility and ORR for 
MEDI4736 + AZD5069 in combination.
Occurrence of dose-limiting toxicities AEs, physical 
examinations, laboratory findings (including clinical 
chemistry, hematology, and urinalysis), vital signs 
(including blood pressure and pulse), 
electrocardiograms (ECGs), and ORR using 
Investigator assessments according to RECIST 1.1.
2.2
Secondary objectives
2.2.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy
Secondary objectives:
Outcome measures:
To assess the efficacy of MEDI4736 in 
combination with nab-paclitaxel + gemcitabine 
in terms of ORR, DoR, DCR, PFS, and OS 
ORR, DoR, DCR, and PFS using Investigator 
assessments according to RECIST 1.1OS
To assess the PK of MEDI4736 and the 
combination of MEDI4736 and nab-paclitaxel 
+ gemcitabine 
Concentration of MEDI4736/nab-paclitaxel + 
gemcitabine in blood and noncompartmental PK 
parameters (such as peak concentration and trough, as 
data allow; sparse sampling only)


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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2.2.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069
Secondary objectives:
Outcome measures:
To further assess the efficacy of MEDI4736 
+AZD5069 in terms of DoR, DCR, PFS, 
PFS3, PFS6, OS, OS6, and OS12
DoR, DCR, PFS, PFS3, and PFS6 in all patients using 
Investigator assessments according to RECIST 1.1,  
OS, OS6, and OS12
To investigate the relationship between PD-L1 
expression by IHC and efficacy parameters
ORR, DoR, DCR, and PFS across PD-L1 expression 
using Investigator assessments according to 
RECIST 1.1, OS
To investigate the immunogenicity of 
MEDI4736 in combination with AZD5069
Presence of ADAs for MEDI4736 (confirmatory 
results: positive or negative; titers)
To assess the PK of MEDI4736 and the 
combination of MEDI4736 and AZD5069 
Concentration of MEDI4736/AZD5069 in blood and 
noncompartmental PK parameters (such as peak 
concentration and trough, as data allow; sparse 
sampling only)
2.3
Exploratory objectives
2.3.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy
Not applicable.
2.3.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069
Exploratory objectives:
Outcome measures:
Evaluate changes in blood-borne biomarkers 
that may correlate with treatment or clinical 
response
Assessments may include, but are not limited to, 
measurement of gene expression, immune cell types, 
soluble factors such as cytokines and chemokines, T-
cell receptor repertoire, circulating tumor DNA and 
activation and proliferation markers at baseline and 
with treatment.
Evaluate tumor-based biomarkers in archival 
tumor samples that may correlate with 
treatment or prospectively identify patients 
likely to respond to treatment 
Assessments may include tumor genetics, 
characterisation of immune infiltrates, gene expression 
signatures, T cell repertoire, or other stratification 
markers.
To collect and store deoxyribonucleic acid 
(DNA) for future exploratory research 
Future exploratory research may include but is not 
limited to exploration of genes/genetic variation that 
may influence response (i.e. distribution, safety, 
tolerability and efficacy) to treatment.


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Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Exploratory objectives:
Outcome measures:
Collect and store tumor, blood, plasma, and 
serum samples or analyse surplus blood or 
tissue including patient-specific archival tumor 
tissue, if available
Samples may be used 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 need for a 
protocol amendment.
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
Patients must meet all of the following criteria:
1.
Age ≥18 years at the time of screening.
2.
Written informed consent and any locally required authorization (eg, Health 
Insurance Portability and Accountability Act [HIPAA] in the US, European Union 
[EU] Data Privacy Directive in the EU) obtained from the patient/legal 
representative prior to performing any protocol-related procedures, including 
screening evaluations.
3.
Histologically or cytologically confirmed PDAC that has metastasized.  Other 
pancreatic malignancies [eg, acinar cell carcinomas, adenosquamous carcinomas, 
and neuroendocrine islet cell neoplasms] are excluded from the study.)
Cohort 1 (first-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine chemotherapy): 
treatment-naïve patients with metastatic PDAC who have received no previous systemic 
chemotherapy, targeted therapy, immunotherapy, or investigational agents (except adjuvant or 
neoadjuvant therapy if progression occurred >6 months from last treatment or surgery, 
respectively)
Cohort 2:  Patients with metastatic PDAC will have received no more than 1 prior systemic 
chemotherapy regimen. 
4.
Life expectancy ≥ 12 weeks.


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Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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5.
ECOG PS of 0 or 1
6.
At least 1 lesion, not previously irradiated, that can be accurately measured at 
baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have 
short axis ≥15 mm) with computed tomography (CT) or magnetic resonance 
imaging (MRI) scan and that is suitable for accurate repeated measurements.
7.
Adequate organ and bone marrow function as defined below:
−
Hemoglobin ≥9 g/dL
−
Albumin ≥3 g/dL
−
Absolute neutrophil count ≥1500/mm3  [≥1.5 x 109/l]
−
Platelet count ≥100000/mm3  [≥100 x 109/l] 
−
Serum bilirubin ≤1.5 × the upper limit of normal (ULN).  This will not apply to 
patients with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of 
evidence of hemolysis or hepatic pathology), who will be allowed in 
consultation with their physician.
−
ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST 
≤5 × ULN
−
Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥40 mL/min as 
determined by the Cockcroft-Gault equation
8.
Evidence of post-menopausal status or negative urinary or serum pregnancy test for 
female premenopausal patients.  Women will be considered post-menopausal if they 
are amenorrheic for 12 months without an alternative medical cause.  The following 
age specific requirements apply:
−
Women <50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more without an alternative medical cause, 
following cessation of exogenous hormonal treatments and if they have 
luteinizing hormone and follicle-stimulating hormone levels in the post-
menopausal range for the institution or underwent surgical sterilization 
(bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
−
Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more without an alternative medical
cause, following cessation of all exogenous hormonal treatments, had radiation-
induced menopause with last menses >1 year ago, had chemotherapy-induced 
menopause with last menses >1 year ago, or underwent surgical sterilization 
(bilateral oophorectomy, bilateral salpingectomy or hysterectomy).


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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9. Ability to undergo during screening a tumor biopsy (mandatory during screening period or 
taking place <45 days before beginning treatment) that is adequate for biomarker analysis.  
See Section 3.3 for further specifics concerning tissue samples.
3.2
Exclusion criteria
Any of the following criteria would exclude the patient from participation in the study:
1.
Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal 
therapy for cancer treatment.  Concurrent use of hormonal therapy for noncancer-
related conditions (eg, hormone replacement therapy) is acceptable.  Note: Local 
treatment of isolated lesions for palliative intent is acceptable (eg, local surgery or 
radiotherapy).
2.
Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, 
whichever is shorter, prior to the first dose of study treatment.
3.
Concurrent enrollment in another clinical study, unless it is an observational 
(noninterventional) clinical study or during the follow-up period of an 
interventional study.
4.
Receipt of last dose of an approved (marketed) anticancer therapy (chemotherapy, 
targeted therapy, biologic therapy, mAb, etc) within 21 days prior to the first dose 
of study treatment.  If sufficient wash-out time has not occurred due to the schedule 
or PK properties of an agent, a longer wash-out period will be required, as agreed 
by AstraZeneca and the Investigator.
5.
Major surgical procedure (as defined by the Investigator) within 21 days prior to the 
first dose of IP.  Note: Local surgery of isolated lesions for palliative intent is 
acceptable.  For patients with biliary obstruction caused by PDAC, the intervention 
of stent placement or percutaneous biliary drainage is allowed.
6.
Patients weighing less than 30 kg.
7.
History of leptomeningeal carcinomatosis.
8.
Ascites requiring intervention (eg, need for paracentesis or Tenckhoff catheter)
9.
Brain metastases or spinal cord compression.  Patients with suspected brain 
metastases at screening should have a CT/MRI of the brain prior to study entry.
10.
Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy 
with the exception of alopecia, vitiligo, and the laboratory values defined in the 
inclusion criteria.  (Patients with irreversible toxicity not reasonably expected to be 


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exacerbated by treatment with MEDI4736 may be included after consultation with 
the Study Physician.)
11.
Current or prior use of immunosuppressive medication within 14 days before the 
first dose of MEDI4736.  The following are exceptions to this criterion:
−
Intranasal, inhaled, or topical steroids; or local steroid injections 
(eg, intra-articular injection)
−
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or equivalent
−
Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication) and chemotherapy induced nausea and vomiting
12.
Cohort 2 only: Has received any potent and moderate cytochrome P450 (CYP)3A4 
inhibitors, potent and moderate CYP3A4 inducers, P-glycoprotein (P-gp) substrates 
(digoxin and dabigatran), breast cancer resistance protein (BCRP) substrates 
(topotecan), sensitive CYP2B6 substrates (bupropion and efavirenz), warfarin and 
coumarin derivatives, or herbal supplements (see Section 7.7 for list of drugs) 
within 14 days of the first dose of study treatment
13.
History of organ transplant that requires use of immunosuppressive agents.
14.
Active autoimmune disorders , or prior documented severe autoimmune or 
inflammatory disorders requiring immunosuppressive treatment (including 
inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis with the 
exception of diverticulosis, celiac disease, irritable bowel syndrome, or other 
serious gastrointestinal chronic conditions associated with diarrhea); systemic lupus 
erythematosus; Wegener syndrome (granulomatosis with polyangiitis), Graves’ 
disease; rheumatoid arthritis, hypophysitis, uveitis, etc. The following are 
exceptions to this criterion:
−
Patients with vitiligo or alopecia
−
diabetes mellitus type I or resolved childhood asthma/athopy
−
Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement 
−
Any chronic skin condition that does not require systemic therapy
−
Patients without active disease in the last 5 years may be included but only after 
consultation with the study physician
15.
Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 


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angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic 
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social 
situations that would limit compliance with study requirement, substantially 
increase risk of incurring AEs or compromise the ability of the patient to give 
written informed consent.
16.
Other malignancy within 5 years except for noninvasive malignancies such as 
cervical carcinoma in situ, non-melanomatous carcinoma of the skin, prostate 
cancer or ductal carcinoma in situ of the breast that has/have been surgically cured.
17.
Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
≥470 ms calculated from 3 ECG reports (within 5 minutes at least 1 minute apart).
18.
History of active primary immunodeficiency.
19.
Active infection including tuberculosis (clinical evaluation that includes clinical 
history, physical examination and radiographic findings, and TB testing in line with 
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), 
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies).  
Patients with a past or resolved HBV infection (defined as the presence of hepatitis 
B core antibody [anti-HBc] and absence of HBsAg) are eligible.  Patients positive 
for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is 
negative for HCV RNA.  
20.
Active infection including hepatitis B, hepatitis C, or human immunodeficiency 
virus (HIV).
21.
Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.  Note: 
Patients, if enrolled, should not receive live attenuated vaccine during the study and 
up to 30 days after the last dose of any IPs.
22.
Female patients who are pregnant or breastfeeding, or male or female patients of 
reproductive potential who are not employing an effective method of birth control 
(see Section 3.8).
23.
Known allergy or hypersensitivity to IP formulations or to other human monoclonal 
antibodies.
24.
Any condition that, in the opinion of the Investigator, would interfere with 
evaluation of IP or interpretation of patient safety or study results.
25.
Prior exposure to immune-mediated therapy, including, but not limited to, other 
anti-CTLA 4, anti-PD-1, anti PD-L1, or anti PD-L2 antibodies, therapeutic 
anticancer vaccines, or prior randomization or treament in previous MEDI4736 
and/or tremelimumab clinical trials regardless of treatment arm assignment.


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Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrollment
Investigators should keep a record, the patient screening log, of patients who entered 
screening.
At screening/baseline (Days -28 to -1), the Investigators or suitably trained delegate will:
1.
Obtain signed informed consent before any study specific procedures are 
performed.
2.
Obtain a unique 7-digit enrollment number, beginning with ‘E#’ (ie, the “E-Code”).  
Enrollment numbers will start at 001 in each center, and go up sequentially. This
number is the patient’s unique identifier and is used to identify the patient on the
electronic Case Report Forms (eCRFs).
3.
Determine patient eligibility (see Sections 3.1 and 3.2)
Note: In Cohort 2 only, patients must be able to undergo a tumor biopsy during screening 
(mandatory).   Tumor lesions used for biopsies should not be target lesions.  Samples with 
limited tumor content and fine needle aspirate specimens are not acceptable.  Specimens from 
metastatic bone lesions are typically unacceptable unless there is a significant soft tissue 
component.   More specific details of collecting tumor biopsy samples can be found in the 
laboratory/pathology manual. 
Patients in both cohorts will begin treatment on Day 1.  Patients must not be treated unless all 
eligibility criteria have been met.
If a patient withdraws from participation in the study, then his or her enrollment code cannot 
be reused. Withdrawn patients will not be replaced after the DLT period in cohort 1 and the 
safety run-in period for cohort 2. Patients in cohort 1 could be replaced if they do not meet the 
evaluable patient criteria (section 7.2.3) or withdraw from study during the DLT period (28 
days) for reason other than toxicity. Patients in cohort 2 could be replaced during the safety 
run-in period if they do not complete the first cycle because of withdrawal from the study for 
reason other than toxicity related to the study drug.
3.4
Procedures for handling incorrectly enrolled patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  Patients who 
are enrolled but subsequently found not to meet all the eligibility criteria must not be initiated 
on treatment and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is incorrectly started on treatment 
or subsequently fails to meet study criteria after initiation, the Investigator should inform the 
AstraZeneca Study Physician immediately, and a discussion should occur between the 


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AstraZeneca Study Physician and the Investigator regarding whether to continue or 
discontinue the patient from treatment.  The AstraZeneca study physician must ensure all 
decisions are appropriately documented.
3.5
Methods for assigning treatment groups
At baseline, patients who satisfy all the entry criteria to participate in Cohort 1 or Cohort 2 
will be enrolled sequentially in that cohort.  The cohorts will run at separate times.
Every effort should be made to minimize the time between enrollment and starting study drug.  
It is recommended that patients commence study drug as soon as possible after enrollment.
If a patient discontinues participation in the study, then their enrollment code cannot be 
reused.
3.6
Methods for ensuring blinding
This is an open-label study.
3.7
Methods for unblinding
This is an open-label study.
3.8
Restrictions
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after.  Restricted therapies are described in Section 7.7.
1.
Female patients of childbearing potential who are sexually active with a 
nonsterilized male partner must use at least one highly effective method of 
contraception from screening and must agree to continue using such precautions for 
180 days after the final dose of IP (MEDI4736 and/or AZD5069). Patients 
receiving MEDI4736 in combination with nab-paclitaxel + gemcitabine (Cohort 1) 
must follow the contraceptive method guidelines reported in this paragraph, for 
their respective sex, from screening and for a minimum of 180 days, or according to 
local contraceptive recommendations for nab-paclitaxel or gemcitabine (whichever 
is longer) after last dose of therapy. Cessation of birth control after this point 
should be discussed with a responsible physician. Not engaging in sexual activity is 
an acceptable practice; however, periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of birth control. In addition, female 
patients should refrain from breastfeeding and egg cell donation throughout this 
period.
−
Females of childbearing potential are defined as those who are not surgically 
sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete 
hysterectomy) or postmenopausal (defined as 12 months with no menses 
without an alternative medical cause).


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−
It is strongly recommended for non-sterilised  male partners of a female patient 
to use a male condom plus spermicide throughout this period.
2.
Nonsterilized males who are sexually active with a female partner of childbearing 
potential must use use a male condom plus spermicide from screening through 180 
days after receipt of the final dose of IP. Not engaging in sexual activity is an 
acceptable practice; however, occasional abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of contraception. In addition, male 
patients must refrain from sperm donation for 180 days after the final dose of IP, or 
according to local recommendations for nab-paclitaxel or gemcitabine (whichever is 
longer) for patients in cohort 1.
3.
It is strongly recommended for  female partners (of childbearing potential)  of male 
patients to use a highly effective method of contraception throughout this period 
(Table 1).  Highly effective methods of contraception are described in Table 1. A 
highly effective method of contraception is defined as one that results in a low 
failure rate (ie, less than 1% per year) when used consistently and correctly. Not all 
methods of acceptable contraception are highly effective. Note that some 
contraception methods are not considered highly effective (e.g. male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or 
without spermicide; non-copper containing intrauterine device; progestogen-only 
oral hormonal contraceptive pills where inhibition of ovulation is not the primary 
mode of action [excluding Cerazette/desogestrel which is considered highly 
effective]; and triphasic combined oral contraceptive pills).
4.
All patients: Patients should not donate blood while participating in this study and 
for 6 months following the last dose of study treatment.
Table 1
Highly Effective methods of contraception (<1% failure rate)
Barrier/Intrauterine methods
Hormonal methods
Copper T intrauterine device
Levonorgesterel-releasing intrauterine system 
(eg, Mirena®)d
Etonogestrel implants: e.g. Implanon or Norplan 
Intravaginal device: e.g. ethinylestradiol and 
etonogestrel 
Medroxyprogesterone injection: e.g. Depo-
Provera 
Normal and low dose combined oral 
contraceptive pill 
Norelgestromin/ethinylestradiol transdermal 
system
Cerazette (desogestrel) 
a
This is also considered a hormonal method.


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3.9
Discontinuation of investigational product
An individual patient will not receive any further IP if any of the following occur in the 
patient in question:
1.
Withdrawal of consent from further treatment with IP
2.
Lost to follow-up
3.
An AE that, in the opinion of the Investigator or the Sponsor, contraindicates 
further dosing
4.
Any AE that meets criteria for discontinuation as defined in Section 6 and Section
7.2
5.
Patient is determined to have met 1 or more of the exclusion criteria or failed to 
meet all of the inclusion criteria for study participation at study entry and 
continuing IP dosing might constitute a safety risk
6.
Pregnancy or intent to become pregnant
7.
Patient noncompliance that, in the opinion of the Investigator or Sponsor, warrants 
withdrawal from study medication (eg, refusal to adhere to scheduled visits)
8.
Initiation of alternative anticancer therapy, including another investigational agent
9.
Confirmed PD. Patients receiving nab-paclitaxel + gemcitabine or AZD5069 as 
single agent therapy will discontinue treatment at first assessment of PD [ie, 
unconfirmed PD].
3.9.1
Procedures for discontinuation of a patient from investigational product
At any time, patients are free to discontinue the IP without prejudice to further treatment.  A 
patient who decides to discontinue the IP will always be asked about the reason(s) for 
withdrawal and the presence of any AEs.  If possible, they will be seen and assessed by an 
Investigator.  AEs will be followed up (see Section 6).  All study drugs provided to the 
patients should be returned by the patient.  The AstraZeneca Study Physician should be 
notified of any ongoing AE that may delay treatment or necessitate permanent discontinuation 
of treatment.
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment.  Patients who are 
permanently discontinued will enter follow-up (see Table 4and Table 5).  All patients will be 
followed up for survival until the end of the study.  Patients who decline to return to the site 
for follow-up evaluations (see Table 4and Table 5) should be contacted by telephone every 
2 months as an alternative.
If a patient is withdrawn from study, see Section 3.10.


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3.10
Criteria for withdrawal
3.10.1
Screen failures
Screen failures are patients who do not fulfill the eligibility criteria for the study and, 
therefore, must not be enrolled.  These patients should have the reason for study withdrawal 
recorded as “eligibility criteria not fulfilled” (ie, patient does not meet the required 
inclusion/exclusion criteria).  This reason for study withdrawal is only to be used to for screen 
failures (ie, patients who failed screening procedures).  Screen-failed patients may be 
rescreened once.  Patients being rescreened should be assigned with a new enrollment code.
3.10.2
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment.
Patients who withdraw consent for further participation in the study will not receive any 
further IP or further study observation, with the exception of follow-up for survival, which 
will continue until the end of the study unless the patient has expressly withdrawn his or her 
consent to survival follow-up.  Note that the patient may be offered additional tests or tapering 
of treatment to withdraw safely.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AE.  The Investigator will follow up AEs outside of the clinical study until resolution.
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 3.11), such that there is insufficient information to 
determine the patient’s status at that time.  Patients who refuse continuing participation in the 
study, including telephone contact, should be documented as “withdrawal of consent” rather 
than “lost to follow-up.”  Investigators should document attempts to re-establish contact with 
missing patients throughout the study period.  If contact with a missing patient is 
re-established, the patient should not be considered lost to follow-up and any evaluations 
should resume according to the protocol.
Patients who decline to return to the site for follow-up evaluations (see Table 4 and Table 5) 
should be contacted by telephone every 2 months as an alternative.  Withdrawn patients will 
not be replaced.  
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial patients are placed at 
undue risk because of clinically significant findings that meet any of the following criteria:

Meet individual stopping criteria or are otherwise considered significant

Are assessed as causally related to study drug,

Are not considered to be consistent with continuation of the study


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In addition, Cohort 2 may be stopped if the criteria to proceed are not met (see Section 8.2.2).  
Regardless of the reason for termination, all data available for the patients at the time of 
discontinuation of follow-up must be recorded in the eCRFs.  All reasons for discontinuation 
of treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.  If this study is discontinued, all other studies involving 
MEDI4736 will remain open to enrollment and screening, if deemed appropriate by the 
Sponsor.
4.
STUDY PLAN AND TIMING OF PROCEDURES
The procedures for the screening and treatment periods in this study are presented in Table 2
and Table 3, and the procedures for the follow-up period are presented in Table 4and Table 5.


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Table 2
Schedule of assessments for Cohort 1 (first-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy) treatment period
Screening
C1
C2
C3
C4, C5, C6, etc
Window for each assessment: ±3 days, window for tumor 
assessment: ±7 days
For 
details 
see 
Section
Day
-28 to -1
1
8
15
1
8
15
1
8
15
1
8
15
Week (on Day 1 of the week)
-4 to -1
0
1
2
4
5
6
8
9
10
12
13
14
Informed consent
Written informed consent: study 
procedures/assignment of patient identification 
number
X
4.1
Study Procedures
Physical examination (full)a
X
X
X
X
5.2.2
Targeted physical exam (based on symptoms)a
At all visits and as clinically indicated
5.2.2
Vital signs (pre-, during, and post-infusion 
vital signs assessments)b
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2.4
Electrocardiogramc
X
As clinically indicated
5.2.3
Concomitant medications
X
X
All visits
7.7
Demography
X
4.1
Medical and surgical history
X
4.1
History of tobacco and alcohol use
X
4.1
Laboratory assessments
Serum or plasma chemistry (complete clinical 
chemistry panel including liver enzymes)d
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2.1
Hematologyd
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2.1


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Screening
C1
C2
C3
C4, C5, C6, etc
Window for each assessment: ±3 days, window for tumor 
assessment: ±7 days
For 
details 
see 
Section
Day
-28 to -1
1
8
15
1
8
15
1
8
15
1
8
15
Week (on Day 1 of the week)
-4 to -1
0
1
2
4
5
6
8
9
10
12
13
14
Thyroid function tests (TSH, fT3, and fT4)e
X
X
X
X
X
5.2.1
Urinalysisf
X
X
X
X
X
5.2.1
Hepatitis B and C; HIV
X
5.2.1
Urine hCG or serum β-hCGg
Xh
X
h
As clinically indicated
5.2.5
Coagulation parametersi
X
As clinically indicated
5.2.1
Monitoring
ECOG performance status
X
X
X
X
X
5.3.1
AE/SAE assessment
X
X
All visits
6.3
Treatment administration 
MEDI4736j
X
X
X
X
7.2.1.1
Gemcitabinej
X
X
X
X
X
X
X
X
X
X
X
X
7.2.1.1
Nab-paclitaxelj
X
X
X
X
X
X
X
X
X
X
X
X
7.2.1.1
Other laboratory assessments and assays
Mandatory tumor biopsy (newly acquired or 
archival <3 years old)l
X
5.5.1.1
Archival tumor sample, if available, for 
patients who submit a newly acquired biopsy 
at screening
X
5.5.1.1


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Screening
C1
C2
C3
C4, C5, C6, etc
Window for each assessment: ±3 days, window for tumor 
assessment: ±7 days
For 
details 
see 
Section
Day
-28 to -1
1
8
15
1
8
15
1
8
15
1
8
15
Week (on Day 1 of the week)
-4 to -1
0
1
2
4
5
6
8
9
10
12
13
14
Tumor assessment (CT or MRI)m
X
q8w for the first 48 weeks relative to first infusion, and q12w 
thereafter, until confirmed disease progression
5.1
Note: Assessments to be performed at the times stipulated in the table and as clinically required in the management of the patient.
Note: All assessments to be performed pre-infusion unless stated otherwise.
a
Body weight recorded at all physical examinations.
b
Blood pressure and pulse will be evaluated prior to the beginning of infusion with MED4736, approximately 30 minutes during the infusion with MEDI4736 (halfway 
through infusion), and 1 hour after the end of infusion with MEDI4736 (prior to start of nab-paclitaxel). Blood pressure and pulse will be evaluated upon completion of 
infusion with nab-paclitaxel and gemcitabine. Body temperature and respiratory rate will be evaluated pre-dose (prior to each infusion for each component IP). Vital sign 
assessment should implement on designated time point -5 minutes for pre-dose, ±5 minutes during treatment and +5 minutes post infusion.
c
Abnormal ECGs and the ECG obtained at screening will require triplicate results. 
d
If screening laboratory assessments are performed within 3 days prior to first dose they do not need to be repeated at Day 1. Results for safety bloods must be available 
and reviewed before commencing an infusion. Gamma glutamyltransferase tested at screening, Day 1 (to be tested only if Day 1 is more than 3 days from screening visit) 
and as clinically indicated. 
e
fT3 and fT4 will only be measured if TSH is abnormal or if there is clinical suspicion of an adverse event related to the endocrine system.
f
Urinalysis performed at screening, Day 1, every 4 weeks, and as clinically indicated.  If screening urinalysis is performed within 3 days prior to Day 1 it does not need to 
be repeated at Day 1. 
g
Pre-menopausal female patients of childbearing potential only.
h
Women of childbearing potential are required to have a pregnancy test within 7 days prior to the first dose of study drug.  Pregnancy tests may occur on Day 1, but results 
must be available and reviewed by the treating physician or Investigator prior to commencing an infusion.
i
Coagulation tests: activated partial thromboplastin time and international normalized ratio – only performed at screening and as clinically indicated. 
j
Patient will receive MEDI4736 as a 60-minute infusion, administered prior to chemotherapy every 4 weeks until confirmed PD, unacceptable toxicity, withdrawal of 
consent, or another discontinuation criterion is met.  The recommended dose of nab-paclitaxel is 125 mg/m2 intravenously on Days 1, 8 and 15 of each 28-day cycle and 
1000 mg/m2 gemcitabine on Days 1, 8 and 15 of each 28-day cycle immediately after nab-paclitaxel.  Patients may continue to receive MEDI4736 alone until confirmed 
PD, and nab-paclitaxel + gemcitabine alone until first assessment of PD.
k
To be performed in Cycle 4 only.
l
The newly acquired or archival (<3 years) sample must be received by the central laboratory prior to dosing.  Sample is mandatory if medically feasible.
m
RECIST assessments will be performed using CT/MRI assessments of the chest and abdomen, pelvis only when suspected or documented disease involvement. 
Additional anatomy may be imaged based on signs and symptoms of individual patients.  Baseline assessments should be performed no more than 28 days before start of 
study treatment, and ideally should be performed as close as possible to the start of study treatment.  Follow-up assessments will be performed q8w ±7 days for the first 
48 weeks (relative to the date of the first infusion) and then q12w ±7 days until confirmed objective disease progression per RECIST 1.1.  The confirmatory scans should 
preferably be performed at the next scheduled visit (relative to the date of the first infusion) and no less than 4 weeks after the initial assessment disease progression (in 


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the absence of clinically significant deterioration).  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to 
perform the subsequent assessments at their scheduled visits (relative to the date of the first infusion).  All confirmatory scans should be recorded on the database.  


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Table 3
Schedule of assessments for Cohort 2 (second-line, Phase II, MEDI4736 + AZD5069)
Screening
C1
C2
C3
C4, C5, C6, etc
For details 
see Section
Window for each assessment: ±3 days, window for tumor assessment: ±7 days
Day
-28 to -1
1
8
1
8
1
1
Week (on Day 1 of the week)
-4 to -1
0
1
4
5
8
12
Written informed consent: study procedures/assignment 
of patient identification number
X
4.1
Study Procedures
Physical examination (full)a
X
5.2.2
Targeted physical exam (based on symptoms)a
X
X
X
5.2.2
Vital signs (pre-, during, and post-infusion vital signs 
assessments)b
X
X
X
X
X
5.2.4
Electrocardiogramc
X
X
X
X
X
5.2.3
Concomitant medications
X
X
All visits
7.7
Demography
X
4.1
Medical and surgical history
X
4.1
History of tobacco and alcohol use
X
4.1
Laboratory assessments
Serum or plasma chemistry (complete clinical 
chemistry panel including liver enzymes)d
X
X
X
X
X
5.2.1
Hematologyd
X
X
X
X
X
X
X
5.2.1
Thyroid function tests (TSH, fT3, and fT4)e
X
X
X
X
X
5.2.1
Urinalysisf
X
X
X
X
X
5.2.1
Hepatitis B and C; HIV
X
5.2.1
Urine hCG or serum β-hCGg
Xh
Xh
As clinically indicated
5.2.5
Coagulation parametersi
X
As clinically indicated
5.2.1


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
64(176)
Screening
C1
C2
C3
C4, C5, C6, etc
For details 
see Section
Window for each assessment: ±3 days, window for tumor assessment: ±7 days
Day
-28 to -1
1
8
1
8
1
1
Week (on Day 1 of the week)
-4 to -1
0
1
4
5
8
12
Monitoring
ECOG performance status
X
X
X
X
X
5.3.1
AE/SAE assessment
X
X
All visits
6.3
Pharmacokinetics
MEDI4736 PK sample (serum)
Xj
Xj
Xj
Xj,k
5.4.2
AZD5069 PK sample (plasma)
Xj
Xj
Xj
Xj,k
5.4.2
Treatment administration 
MEDI4736l
X
X
X
X
7.2.1.2
AZD5069l
Twice daily
7.2.1.2
Other laboratory assessments and assays
Immunogenicity assessment for MEDI4736 only (ADA 
sampling [including ADA neutralizing antibodies] to 
identify ADA responses in patient circulation)
X
X
X
Xk
5.4.6
Circulating soluble factors (serum)
X
X
Xm
5.5.1.1
Circulating soluble factors (plasma)
X
X
Xm
5.5.1.1
Mandatory tumor biopsy (newly acquired)n
X
Xo
5.5.1.1
Archival tumor sample
X
5.5.1.1
MDSC
X
X
X
X
5.5.1.2
miRNA/mRNA (to examine immune cell gene 
expression profiles in circulation)
X
X
5.5.1.2
PBMCs
X
X
X
X
5.5.1.2
Pharmacogenetic (PGx) Sample
Xp
5.6.1
ctDNA (plasma)
X
Xr
X
Xs
5.5.1.2


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
65(176)
Screening
C1
C2
C3
C4, C5, C6, etc
For details 
see Section
Window for each assessment: ±3 days, window for tumor assessment: ±7 days
Day
-28 to -1
1
8
1
8
1
1
Week (on Day 1 of the week)
-4 to -1
0
1
4
5
8
12
Tumor assessment (CT or MRI)q
X
q6w for the first 48 weeks relative to first infusion, and q12w thereafter, until
confirmed disease progression
5.1
Note: Assessments to be performed at the times stipulated in the table and as clinically required in the management of the patient.
Note: All assessments to be performed pre-infusion unless stated otherwise.
a
Body weight recorded at all physical examinations.
b
Blood pressure and pulse will be evaluated prior to the beginning of the infusion, 30 minutes during infusion (halfway through infusion), and at the end of the infusion. A 
1-hour observation period is recommended after the first infusion of MEDI4736. If no clinically significant infusion reactions are observed during or after the first 
infusion, subsequent infusion observation periods can be at the Investigator’s discretion (suggested 30 minutes after infusion). These assessments should be followed for 
each of the component infusions. Body temperature and respiratory rate will be evaluated pre-dose (prior to each infusion). Vital sign assessment should implement on 
designated time point -5 minutes for pre-dose, ±5 minutes during treatment and +5 minutes post infusion
c
Abnormal ECGs and the ECG obtained at screening will require triplicate results. 
d
If screening laboratory assessments are performed within 3 days prior to first dose they do not need to be repeated at Day 1. Results for safety bloods must be available 
and reviewed before commencing an infusion. At any time per the Investigator’s clinical judgment, more frequent serum or plasma chemistry, hematology, or LFT 
monitoring are allowed as clinically indicated. Gamma glutamyltransferase tested at screening, Day 1 (to be tested only if Day 1 is more than 3 days from screening visit) 
and as clinically indicated. 
e
fT3 and fT4 will only be measured if TSH is abnormal or if there is clinical suspicion of an adverse event related to the endocrine system.
f
Urinalysis performed at screening, Day 1, every 4 weeks, and as clinically indicated.  If screening urinalysis is performed within 3 days prior to Day 1 it does not need to 
be repeated at Day 1. 
g
Pre-menopausal female patients of childbearing potential only.
h
Women of childbearing potential are required to have a pregnancy test within 7 days prior to the first dose of study drug.  Pregnancy tests may occur on Day 1, but results 
must be available and reviewed by the treating physician or Investigator prior to commencing an infusion.
i
Coagulation tests: activated partial thromboplastin time and international normalized ratio – only performed at screening and as clinically indicated.
j
On Cycle 1 Day 1 and Cycle 7 Day 1 (Week 24 ), PK samples will be collected pre-dose (within 60 minutes prior to treatment with any IP) and at the 
end of infusion (within 10 minutes after end of MEDI4736 infusion). On Cycle 2 Day 1 (Week 4), Cycle 3 Day 1 (Week 8), and Cycle 4 Day 1 (Week 
12), PK samples will be collected pre-dose (within 60 minutes prior to treatment with any IP only). On the day pre-dose PK samples are collected, the 
morning dose of AZD5069 must be administered at the study center and the exact time of administration recorded.
k
To be performed in Cycles 4 and 7 only.
l
Patients will receive MEDI4736 as a 60 minute infusion, administered prior to chemotherapy every 4 weeks until confirmed PD, unacceptable toxicity, withdrawal of 
consent, or another discontinuation criterion is met.  Patients will receive AZD5069 bid (ie, in the morning and in the evening of each day).  AZD5069 should be 
administered 2 hours before or 2 hours after food.  MEDI4736 infusions will take place in the morning at least 30 minutes after the morning administration of AZD5069.  
Patients may continue to receive MEDI4736 alone until confirmed PD, and AZD5069 alone until first assessment of PD.
m
To be performed in Cycle 4 only.
n
The newly acquired (mandatory during screening period or taking place <45 days before beginning treatment).  An optional tumor biopsy on progression may 
also be obtained.  


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
66(176)
o
Newly acquired tumor sample to be collected at Week 4 (-1 week/+2 weeks)  
p
A single 9ml sample of venous blood for genetic analysis will be collected at pre-dose of Cycle 1 Day 1. The date and time of collection of each sample will be recorded. 
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual.
q        RECIST assessments will be performed using CT/MRI assessments of the chest and abdomen, pelvis only when suspected or documented disease involvement. 
Additional anatomy may be imaged based on signs and symptoms of individual patients.  Baseline assessments should be performed no more than 28 days before start of 
study treatment, and ideally should be performed as close as possible to the start of study treatment.  Follow-up assessments will be performed q6w ±7 days for the first 
48 weeks (relative to the date of the first infusion) and then q12w ±7 days until confirmed objective disease progression per RECIST 1.1.  The confirmatory scans should 
preferably be performed at the next scheduled visit (relative to the date of the first infusion) and no less than 4 weeks after the initial assessment of disease progression (in 
the absence of clinically significant deterioration).  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to 
perform the subsequent assessments at their scheduled visits (relative to the date of the first infusion).  All confirmatory scans should be recorded on the database.  
r
ctDNA should be collected pre-dose at C1D1
s
ctDNA should be collected on Day 1 of odd cycles, from C5 onward.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
67(176)
Table 4
Schedule of follow up assessments for Cohort 1 (first-line, Phase Ib, MEDI4736 + nab-paclitaxel + 
gemcitabine chemotherapy)
Evaluation
Time since last dose of IP
Day (±3)
Months (±1 week)
12 months and 
every 2 months
(±2 weeks)
For details 
see Section
30
2
3
4
6
8
10
Physical examinationa
X
5.2.2
Vital signs (temperature, respiratory rate, blood pressure, and pulse)
X
5.2.4
Weight
X
5.2.2
AE/SAE assessment
X
X
X
6.3
Concomitant medications
X
X
X
7.7
Survival status: for all patients, including phone contact with patients 
who refuse to return for evaluations and agree to be contactedb
X
X
X
X
X
X
5.1
Urine hCG or serum β-hCG
X
5.2.5
Hematology
X
X
X
5.2.1
Serum or plasma chemistry 
X
X
X
5.2.1
Thyroid function tests (TSH, fT3, and fT4)c
X
5.2.1
Tumor assessment (CT or MRI)
For patients who discontinue study treatment due to toxicity (or symptomatic 
deterioration), tumor assessments should be performed relative to the date of first 
infusion as follows: q8w ±7 days for the first 48 weeks and q12w ±7 days thereafter 
(per Table 2) until confirmed PD by RECIST 1.1.  Please refer to Table 2 for timings 
of confirmatory scans.  
5.1
a
Full physical exam.
b
Post-progression, patients will be followed for survival contact every 2 months (8 weeks) until death or until the end of the study.
c
fT3 and fT4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
68(176)
Table 5
Schedule of follow up assessments for Cohort 2 (second-line, Phase II, MEDI4736 + AZD5069)
Evaluation
Time since last dose of IP
Day (±3)
Months (±1 week)
12 months and 
every 2 months
(±2 weeks)
For details 
see Section
30
2
3
4
6
8
10
Physical examinationa
X
5.2.2
Vital signs (temperature, respiratory rate, blood pressure, and pulse)
X
5.2.4
Weight
X
5.2.2
AE/SAE assessment
X
X
X
6.3
Concomitant medications
X
X
X
7.7
Subsequent anticancer therapy
X
X
X
X
X
X
X
X
5
Survival status: for all patients, including phone contact with patients 
who refuse to return for evaluations and agree to be contactedb
X
X
X
X
X
X
5.1
Urine hCG or serum β-hCG
X
5.2.5
Hematology
X
X
X
5.2.1
Serum or plasma chemistry 
X
X
X
5.2.1
Thyroid function tests (TSH, fT3, and fT4)c
X
5.2.1
Pharmacokinetic assessment (MEDI4736 only)
X
5.4.2
Immunogenicity assessment for MEDI4736 only (ADA sampling 
[including ADA neutralizing antibodies] to identify ADA responses 
in patient circulation)
X
X
5.4.6
Circulating soluble factors 
X
5.5.1.2
miRNA/mRNA (to examine immune cell gene expression profiles in 
circulation)
X
5.5.1.2
PBMCs
X
5.5.1.2
ctDNA (plasma)
X
5.5.1.2


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
69(176)
Evaluation
Time since last dose of IP
Day (±3)
Months (±1 week)
12 months and 
every 2 months
(±2 weeks)
For details 
see Section
30
2
3
4
6
8
10
Tumor assessment (CT or MRI)
An optional tumor biopsy upon evidence of PD should be performed according to 
institutional practice.  It is accepted that any biopsy procedure should be technically 
feasible and not associated with unacceptable clinical risk.
For patients who discontinue study treatment due to toxicity (or symptomatic 
deterioration), tumor assessments should be performed relative to the date of first 
infusion as follows: q6w ± 7days for the first 48 weeks and q12w ± 7 days thereafter 
(per Table 3) until confirmed PD by RECIST 1.1.  Please refer to Table 3 for timings 
of confirmatory scans.  
5.1
a
Full physical exam.
b
Post-progression, patients will be followed for survival contact every 2 months (8 weeks) until death or until the end of the study.
c
fT3 and fT4 will only be measured if TSH is abnormal.  They should also be measured if there is clinical suspicion of an AE related to the endocrine system.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
70(176)
4.1
Enrollment/screening period
At screening, consenting patients are assessed to ensure that they meet eligibility criteria. 
Patients who do not meet these criteria must not be enrolled in the study.  All screening and 
enrollment procedures will be performed according to the assessment schedules in Table 2 and
Table 3.
Written informed consent and any locally required privacy act document authorization must 
be obtained prior to performing any protocol-specific procedures, including screening/baseline 
evaluations.  All patients will be required to provide consent to supply a sample of their tumor 
(archival or newly acquired biopsy) for entry into this study.  For Cohort 2, tumor biopsies 
and archival tissue (the latter only if available) are mandatory for entry into the study (see 
Table 3 for details).  This consent is included in the main patient informed consent form 
(ICF).
Screening/baseline evaluations may be performed over more than 1 visit.
The timing of ECGs and vital sign assessments should be such that it allows the blood draw 
(eg, PK blood sample) to occur at the timepoints indicated in Table 2 through Table 5
4.2
Treatment period
All procedures to be conducted during the treatment period for both cohorts will be performed 
according to the assessment schedules (see Table 2 and Table 3). 
Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: ECG, vital signs, and then blood draws.  The 
timing of the first 2 assessments should be such that it allows the blood draw (eg, PK blood 
sample) to occur at the timepoints indicated in Table 2 and Table 3.
4.3
Follow-up period
All procedures to be conducted during the follow-up period for both cohorts will be performed 
according to the assessment schedule (see Table 4 and Table 5).
Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: ECG, vital signs, and then blood draws.  The 
timing of the first 2 assessments should be such that it allows the blood draw (eg, PK blood 
sample) to occur at the exact nominal time. 
5.
STUDY ASSESSMENTS
A Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The Investigator will ensure that data are recorded on the eCRFs as specified in the 
study protocol and in accordance with the instructions provided.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
71(176)
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA). 
The Investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be 
archived at the study site.
The Investigator will record data on the observations, tests, and assessments specified in the 
protocol on the eCRFs provided by AstraZeneca.  The CRF will be accompanied with 
“Instructions for the Investigator,” which should be followed.  These instructions provide 
guidance for the recording of study data in the eCRF, including how to change data 
incorrectly recorded.
5.1
Efficacy assessments
RECIST 1.1 criteria will be used to assess patient response to treatment by determining ORR, 
DoR, DCR, PFS, proportion of patients alive and progression-free after 3 months (PFS3), and 
proportion of patients alive and progression-free after 6 months (PFS6).  The RECIST 1.1 
guidelines for measurable, nonmeasurable, target, and non-target lesions and the objective 
tumor response criteria (CR, PR, SD, or PD) are presented in Appendix D.  OS, proportion of 
patients alive at 6 months from enrollment (OS6), and proportion of patients alive at 
12 months from enrollment (OS12) will also be evaluated.
The methods of assessment of tumor burden used at baseline are CT and/or MRI scans of the 
chest and abdomen; scans of the pelvis should only be done when there is suspected or 
documented disease involvement.  Any other areas of disease involvement should be 
additionally imaged based on the signs and symptoms of individual patients.
The baseline assessments should be performed no more than 28 days before start of study 
treatment, and ideally should be performed as close as possible to the start of study treatment.  
Efficacy for all patients will be assessed by objective tumor assessments every 8 weeks 
(q8w ±7 days; Cohort 1) or every 6 weeks (q6w ±7 days; Cohort 2) for the first 48 weeks 
relative to the date of the first infusion, and q12w ±7 days thereafter until confirmed objective 
disease progression.  If an unscheduled assessment is performed and the patient has not 
progressed, every attempt should be made to perform the subsequent assessments at his or her 
scheduled visits.
A confirmatory scan is required following the initial demonstration of PD in patients receiving 
MEDI4736 as monotherapy or in combination with nab-paclitaxel + gemcitabine or 
AZD5069; confirmation is not required for patients receiving nab-paclitaxel + gemcitabine or 
AZD5039 monotherapy.  The confirmatory scan should occur preferably at the next scheduled 
visit and no earlier than 4 weeks after the initial assessment of PD in the absence of clinically 
significant deterioration.  Treatment will continue between the initial assessment of 
progression and confirmation for progression.
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to 
progression, then the patient should still continue to be followed until confirmed objective 
disease progression.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
72(176)
Categorization of objective tumor response assessment will be based on the RECIST 1.1 
criteria of response: CR, PR, SD, and PD.  Target lesion progression will be calculated in 
comparison to when the tumor burden was at a minimum (ie, smallest sum of diameters 
previously recorded on study).  In the absence of progression, tumor response (CR or PR) and 
SD will be calculated in comparison to the baseline tumor measurements obtained before 
starting treatment.
Objective tumor response (CR or PR) should be confirmed preferably at the next scheduled 
visit and not less than 4 weeks after the visit when the response was first observed.
Following confirmed progression, patients should continue to be followed up for survival 
every 2 months (8 weeks) as outlined in the follow-up schedules of assessments (Table 4 and
Table 5).  In addition, all patients will be contacted in the week following data cutoff to 
confirm survival status.
It is important to follow the assessment schedule as closely as possible.  Refer to the study 
plans (Table 2 and Table 3 [screening and the treatment period], and Table 4 and Table 5
[follow up]) and Appendix D.
5.1.1
Central reading of scans
For both cohorts, an Investigator’s assessment of all scans using RECIST 1.1 will be 
conducted (see Section 8.5 for the analysis methods). Sites will be required to store electronic 
copies of all scans.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the times indicated in the assessment schedules and as clinically indicated (see 
Table 2 through Table 5).
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a 
licensed clinical laboratory according to local standard procedures.  Sample tubes and sample 
sizes may vary depending on the laboratory method used and routine practice at the site.  
Urine pregnancy tests may be performed at the site using a licensed test (urine or serum 
pregnancy test).  Abnormal clinically significant laboratory results should be repeated as soon 
as possible (preferably within 24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection, and results (values, units, and reference ranges) will 
be recorded on the appropriate eCRF.
The laboratory values to be measured are presented in Table 6 (clinical chemistry) Table 7
(hematology), and Table 8 (urinalysis).


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
73(176)
Table 6
Clinical chemistry (serum or plasma)
Albumin
Glucose
Alkaline phosphatase
Lactate dehydrogenase
Alanine aminotransferase
Lipase
Amylase
Magnesium
Aspartate aminotransferase
Potassium
Bicarbonate
Sodium
Calcium 
Total bilirubina
Chloride
Total protein
Creatinine
Urea or blood urea nitrogen, depending on local 
practice
Gamma glutamyltransferaseb
Uric acid
a
If total bilirubin is ≥2 × ULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and 
indirect bilirubin
b
At baseline and as clinically indicated
Table 7
Hematology
Basophils
Mean corpuscular volume
Eosinophils
Monocytes
Hematocrit
Neutrophils
Hemoglobin
Platelet count
Lymphocytes
Red blood cell count
Mean corpuscular hemoglobin
Total white cell count
Mean corpuscular hemoglobin concentration
Note: Coagulation parameters: activated partial thromboplastin time and international normalized ratio to be 
assessed at baseline and as clinically indicated
Table 8
Urinalysis
Bilirubin
pH
Blood
Protein
Glucose
Specific gravity
Ketones
Color and appearance
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high power field for 
red blood cells


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
74(176)
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer to 
Appendix C for further instructions.  These cases should be reported as SAEs if, after 
evaluation, they meet the criteria for a Hy’s Law case or if any of the individual liver test 
parameters fulfill any of the SAE criteria.  All patients with an elevated AST, ALT, or 
bilirubin value (the latter at ≥1.5 × ULN) at the time of the last dose of study treatment should 
have a further liver chemistry profile (AST, ALT, bilirubin, and alkaline phosphatase) 
performed 30 days (±3 days) after permanent discontinuation of study treatment.  Results for 
safety blood assessments must be available and reviewed before commencing an infusion.
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF.  Situations in which laboratory safety results should be 
reported as AEs are described in Section 6.3.8.
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from study treatment must have further tests performed until the laboratory values have 
returned to Grade 1 or 2, unless these values are not likely to improve because of the 
underlying disease.
5.2.2
Physical examination
Physical examinations will be performed according to the assessment schedules (see Table 2
through Table 3).  Targeted physical examinations are to be utilized by the Investigator on the 
basis of clinical observations and symptomatology.  All physical examinations will include 
body weight measurement.  Situations in which physical examination results should be 
reported as AEs are described in Section 6.3.7.
5.2.3
Electrocardiograms
Resting 12-lead ECGs will be recorded according to the assessment schedules (see Table 2
and Table 3 ).  ECGs should be obtained after the patient has been in a supine position for 
5 minutes and should be recorded while the patient remains in that position.
For Cohort 1, ECGs will be recorded at screening and as clinically indicated.
For Cohort 2, 12-Lead ECGs will be recorded in triplicate at screening and day 1 of each 
treatment cycle. 
Abnormal ECGs and the ECG obtained at screening will require triplicate results.  In case of 
clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 additional 
12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm 
prolongation.  
Situations in which ECG results should be reported as AEs are described in Section 6.3.7.
5.2.4
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules (see Table 2 through Table 5)


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
75(176)
On infusion days, patients will be monitored during and after infusion of IP as presented in the 
bulleted list below.
Supine BP will be measured after the patient has rested for at least 5 minutes.
For Cohort 1, BP and pulse will be evaluated prior to the beginning of infusion with 
MED4736, approximately 30 minutes during the infusion with MEDI4736 (halfway through 
infusion), and 1 hour after the end of infusion with MEDI4736 (prior to start of 
nab-paclitaxel). Blood pressure and pulse will be evaluated upon completion of infusion with 
nab-paclitaxel and gemcitabine.
For Cohort 2, BP and pulse will be evaluated prior to the beginning of the infusion, 
30 minutes during infusion (halfway through infusion), and at the end of the infusion.  A 
1-hour observation period is recommended after the first infusion of MEDI4736.  If no 
clinically significant infusion reactions are observed during or after the first infusion, 
subsequent infusion observation periods can be at the Investigator’s discretion (suggested 
30 minutes after infusion).  These assessments should be followed for each of the component 
infusions.
Body temperature and respiratory rate will be evaluated pre-dose (prior to each infusion).
Vital sign assessment should implement on designated time point -5 minutes for pre-dose, ±5 
minutes during treatment and +5 minutes post infusion.
Two or more BP readings should be taken at 2-minute intervals and averaged.  If the first 
2 diastolic readings differ by more than 5 mmHg, an additional reading should be obtained 
and the measurements should be averaged.  The date and time of collection and measurement 
will be recorded on the appropriate eCRF.  Additional monitoring with assessment of vital 
signs is at the discretion of the Investigator per standard clinical practice or as clinically 
indicated.
Situations in which vital signs results should be reported as AEs are described in Section
6.3.7.
5.2.5
Other safety assessments
Pregnancy tests on either urine (human chorionic gonadotropin [hCG]) or blood (serum 
beta-human chorionic gonadotropin [β-hCG]) samples will be performed for premenopausal 
women of childbearing potential at the times specified in the assessment schedule (see Table 2
through Table 5).  Tests will be performed by the hospital’s local laboratory.  If results are 
positive, the patient is ineligible and must be discontinued from treatment.  In the event of a 
suspected pregnancy during the study, the test should be repeated.
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies, HIV antibodies, thyroid-stimulating hormone, free 
triiodothyronine, and free thyroxine.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
76(176)
5.3
Other assessments
5.3.1
ECOG performance status
ECOG PS will be assessed at the times specified in the assessment schedules (see Table 2 and
Table 3) based on the following:
0=Fully active, able to carry on all pre-disease performance without restriction
1=Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2=Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3=Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4=Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5=Dead
Any significant changes from baseline or screening must be reported as an AE.
5.4
Pharmacokinetics
5.4.1
Collection of samples
Blood samples for determination of MEDI4736 concentration in serum, and nab-paclitaxel,  
gemcitabine and AZD5069 concentration in plasma will be obtained according to the 
assessment schedules (see Table 2 through Table 5).
Details on sample processing, handling, shipment, and storage are provided in the Laboratory 
Manual.
5.4.2
Determination of drug concentration of nab-paclitaxel, gemcitabine, and 
AZD5069
Samples for determination of nab-paclitaxel, gemcitabine, and AZD5069 will be analyzed by 
Covance on behalf of Clinical Bioanalysis Alliance, AstraZeneca R&D, using appropriate 
bioanalytical methods.
Full details of the analytical methods used will be described in separate bioanalytical reports.  
All samples still within the known stability of the analytes of interest at the time of receipt by 
the bioanalytical laboratory will be analyzed.
Details on sample processing, handling, shipment, and storage are provided in the Laboratory 
Manual.


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5.4.3
Storage and destruction of pharmacokinetic samples for nab-paclitaxel, 
gemcitabine, and AZD5069
PK samples will be disposed of after the Bioanalytical Report finalization or 6 months after 
issuance of the draft Bioanalytical Report (whichever is earlier), unless requested for future 
analyses.
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 clinical study 
report (CSR) but separately in a bioanalytical validation report.
5.4.4
Determination of drug concentration of MEDI4736
Samples for determination of MEDI4736 concentration in serum will be analyzed by a 
designated third party laboratory on behalf of AstraZeneca.  Samples will be collected, 
labeled, stored, and shipped as detailed in the Laboratory Manual.  Full details of the 
analytical method used will be described in a separate Bioanalytical Validation Report.
5.4.5
Storage and destruction of pharmacokinetic samples for MEDI4736
Samples will be stored for a maximum of 15 years from the end of study, after which they will 
be destroyed.  
PK samples may be disposed of or destroyed and anonymized by pooling.  Additional 
analyses may be conducted on the anonymized, pooled PK samples to further evaluate and 
validate the analytical method.  Results from such analyses may be reported separately from 
the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR, but will 
be reported separately in a bioanalytical validation report.
Any residual back up PK samples may be used for future exploratory biomarker research (in 
this case, residual back-up PK samples will be shipped to AstraZeneca-assigned Biobank).
5.4.6
Collection of samples to measure the presence of ADAs
The presence of ADAs for MEDI4736 will be assessed in serum samples taken according to 
the assessment schedules (see Table 2 through Table 5).
Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for 
MEDI4736 using validated assays.  Tiered analysis will be performed to include screening, 
confirmatory, and titer assay components, and positive-negative cut points previously 
statistically determined from drug-naive validation samples will be used.
5.4.7
Storage and destruction of ADA samples
Samples will be stored for a maximum of 15 years from the end of study, after which they will 
be destroyed.  


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ADA samples may be disposed of or destroyed and anonymized by pooling. Additional 
analyses may be conducted on the anonymized, pooled samples to further evaluate and 
validate the analytical method.  Results from such analyses may be reported separately from 
the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR but will 
be reported separately in a bioanalytical validation report.
Any residual back-up ADA samples may be used for future exploratory biomarker research 
(in this case, residual back-up PK samples will be shipped to AstraZeneca-assigned Biobank).
5.5
Biomarker analysis
The patient’s consent to the use of donated biological samples is mandatory.  For Cohort 1, 
only clinical chemistry, anti-drug antibody determinations (MEDI4736), and pharmacokinetic 
parameters (MEDI4736, gemcitabine, and paclitaxel) will be measured where collected.  For 
Cohort 2 only, the uses of these samples will in addition include the biomarker measurements 
described below.
Mandatory tumor and blood sample collections for the purpose of evaluating exploratory 
biomarkers (potential patient selection and  mechanistic biomarkers) are described in Section
5.5.1.  Samples will be taken according to the assessment schedules (see Table 2 through
Table 5).
Biomarkers that have demonstrated the potential to identify patients who are likely to respond 
to treatment with IP (from other MEDI4736 monotherapy or other combination therapy 
studies) may be investigated to determine a patient’s biomarker status and for possible 
correlation with efficacy endpoints in an exploratory analysis outside the scope of the CSR.  
Exploratory biomarker research will not form part of the CSR.  The results may be pooled 
with biomarker data from other MEDI4736 monotherapy or MEDI4736 combination therapy 
studies to test existing hypotheses or to generate hypotheses to be tested in future studies.  
There will be no exploratory biomarker research on samples from Cohort 1 patients.
5.5.1
Collection of samples
Any sample collections listed in this section may be discontinued at any time during the study 
at the Sponsor’s discretion.  See Table 2 to 5 for a schedule of sample collections. 
Details of sample collection, processing, shipping, and storage for all sample collections 
below will be described in the Laboratory Manual.   
5.5.1.1
Collection of samples for evaluation of potential patient selection markers
There will be no exploratory biomarker research on samples from Cohort 1 patients. For 
Cohort 2, provisions of biopsy tissue are as follows:


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
MANDATORY: Provision of a tumor biopsy, formalin-fixed and embedded in 
paraffin, for the purpose of PD-L1 expression analyses and for enabling exploratory 
analyses (Cohort 2 only) as described in the proceeding section.  A newly acquired 
tumor biopsy is  mandatory during screening period or taking place <45 days before 
beginning treatment.  
Samples should be collected via an image-guided core needle (18 gauge or larger is 
preferred).  Where institutional practice, in this setting, uses a smaller gauge needle, 
samples should be submitted in sufficient number to ensure that a valid result can be 
achieved.
When tissue is acquired for this study, effort should be made to maximize viable 
tumor for downstream analyses.  
Tumor lesions planned for biopsy should may be used as index lesions for 
assessment of disease.

Cohort 2 only, MANDATORY on treatment biopsy: on-treatment collection of 
tumor biopsies are required if clinically feasible at the timepoints indicated in Table
3 and Table 5. On treatment biopsy timing may be refined with emerging PK and/or 
pharmacodynamic data during the course of the trial.  Failure to to obtain sufficient 
on-treatment tumor samples after making best efforts to biopsy the tumor will not 
be considered a protocol deviation.  The Investigator must consult with the Study 
Physician if such sampling is not feasible.

Cohort 2 only, MANDATORY archived tumor tissue:  Archived tumor tissue 
(formalin-fixed, paraffin-embedded) for evaluation of tumor genetics and/or tumor 
PD-L1 expression, where such samples exist in a quantity sufficient to allow for 
analysis.

Cohort 2 only, OPTIONAL: Tumor biopsy at the time of progression is encouraged.  
Additional tumor biopsies collected as part of clinical care (eg, for mixed responses 
or upon PD) can be submitted for further analysis.  
Tumor lesions planned for biopsy should not be used as index lesions for 
assessment of disease.
See the Laboratory Manual for further details of requirements.
Tissue obtained as part of screening procedures for establishing PD-L1 expression may be 
analyzed for additional, exploratory markers /signatures at baseline and on-treatment that may 
correlate with response or treatment.  These include but are not limited to tumor genetics, gene 
expression signatures (e.g. IFN-gamma signature), markers of immune suppression or 
activation (e.g. FoxP3 T regulatory cells, increased CD8 T effector cells, ARG1 or other 
markers of MDSCs that may change on treatment, particularly in response to AZD5069 


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therapy (Highfill et al 2014), markers of stromal architecture changes (Steele et al 2016) and T 
cell repertoire changes.
Tumor biopsies will be stored at AstraZeneca Research and Development or an appropriate 
vendor selected by AstraZeneca.  Core biopsies and/or archived tissue may be used for 
correlative studies such as IHC assay for e.g. immune or stromal analysis, tumor mutation 
analysis, ribonucleic acid (RNA) analysis, proteomic analysis, immunophenotyping, and 
assessment of immunodiversity.  Samples will be collected, labeled, stored, and shipped as 
detailed in the Laboratory Manual.
5.5.1.2
Collection of blood samples from Cohort 2 (AZD5069 plus MEDI4736) for 
exploratory analyses 
Blood for exploratory biomarker analyses will be obtained according to the assessment 
schedules presented in Table 3 and Table 5.  Details for collection, volumes, storage, and 
shipment of biologic samples are presented in a separate Laboratory Manual.
Pharmacodynamic changes in biomarker measures will be monitored, when applicable.  
Baseline measures and early, on-treatment changes will be correlated with outcomes.  All 
samples collected for such exploratory analyses will be stored at the site, a reference 
laboratory, or at Sponsor’s facilities and may be used for subsequent research relevant to 
evaluating response to immunotherapy.
The exploratory blood biomarker plan is described by sample type below.
Whole blood gene expression (miRNA/mRNARNA)
Whole blood samples will be obtained at baseline and on-treatment as outlined in Table 3 and 
Table 5 from all patients.  These samples will be used to evaluate gene expression and/or  
immunophenotypic changes based on genomic DNA methylation patterns associated with 
clinical response or treatment using nucleic acid-directed methods.  Changes reflecting a 
potential increase in an active immune response, e.g. TH1 response, are likely to be a focus.  
Similar procedures may be completed using select peripheral blood mononuclear cell (PBMC) 
samples described below.
Circulating Myeloid derived suppressor cells (MDSC)
Flow cytometry will be carried out to quantify baseline and on-treatment circulating MDSC 
subtypes as baseline or decrease from baselinemay predict clinical benefit from therapy 
(Highfill et al 2014). 
Peripheral blood mononuclear cells
Whole blood samples will be collected for preparation of PBMCs and storage for potential 
downstream analyses.  A variety of assays may be pursued, including immune cell 
composition/activation status analyses by flow cytometry, T-cell functional assays (eg, 
ELISPOT), receptor occupancy analyses to measure target engagement, tetramer analyses to 


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monitor antigen-specific T cells, RNA/miRNA expression, and/or the assessment of the 
diversity and clonality of T-cell receptor gene rearrangements using deoxyribonucleic acid.
Soluble factors
Serum and plasma will be obtained at baseline and on- treatment as outlined in 3 and 4. The 
concentrations of a panel of cytokines and chemokines will be assessed. Focus is likely to be 
given to factors involved in Th1-driven immune responses, including IFN-γ,  CXCL9, and 
CXCL10 and factors associated with AZD5069 treatment (e.g. rises in CXCL8 and CXCL1). 
High pretreatment expressions (concentrations) of such factors may indicate active immune 
responses that may be augmented by checkpoint inhibitor immunotherapies; correlations with 
outcome data may identify patients likely to receive benefit or, alternatively,identifypatients 
likely to suffer drug-related AEs.  Plasma samples may also be used to evaluate circulating 
free DNA (cfDNA) as a potential patient selection or clinical response marker.
Serum and plasma may also be used for the detection/quantification of autoantibodies (against 
tumor-associated antigens). Seroconversion following treatment could be used as an indicator 
of overcoming tolerance.  Pretreatment seropositivity against specific antigens may provide 
predictive value, particularly when combined with data regarding the presence of antigen-
specific T cells (Yuan et al 2011).  Therefore, select candidate autoantibody measures may be 
evaluated for associations with clinical benefit and for directing PBMC-based, antigen-
directed measures as described for PBMCs above.
Circulating tumor DNA
A 10mL blood sample will be taken at each of the timepoints to provide plasma and will be 
used for the extraction and analysis of circulating tumor DNA (ctDNA), for the analysis of 
predictive biomarkers, pharmacodynamic biomarkers to interrogate changes in genetic 
alterations and potential mechanisms of resistance and for diagnostic purposes.  
5.5.2
Management of biomarker data
The biomarker data will have unknown clinical significance.  AstraZeneca will not provide 
biomarker research results to patients, their family members, any insurance company, any 
employer, clinical study Investigator, general physician, or any other third party, unless 
required to do so by law.  The patient’s samples will not be used for any purpose other than 
those described in the study protocol.
Individual patients will not be identified in any report or publication resulting from this work.  
The data and results of this research may be reviewed with collaborators and published, but 
neither the patient’s name nor any other personal identifiers will appear in any publication or 
report.
5.5.3
Storage, re-use, and destruction of biomarker samples
Samples will be stored for a maximum of 15 years from the end of study, after which they will 
be destroyed.  Summaries and analyses for exploratory biomarkers will be documented in a 
separate analysis plan and will be reported outside the CSR in a separate report.  The results of 


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this biomarker research may be pooled with biomarker data from other studies involving 
MEDI4736 or AZD5069 to generate hypotheses to be tested in future research.
5.5.4
Labeling and shipment of biological samples
The Principal Investigator (PI) will ensure that samples are labeled and shipped in accordance 
with the Laboratory Manual and the Biological Substance, Category B, Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria); 
see Appendix B.
Any samples identified as infectious materials in Category A will not be shipped, and no 
further samples will be taken from the involved patients unless agreed upon with AstraZeneca 
and appropriate labeling, shipment, and containment provisions are approved.
5.5.5
Chain of custody of biological samples
A full chain of custody will be maintained for all samples throughout their life cycle.
The PI at each site will keep full traceability of collected biological samples from the patients, 
while in storage at the site until shipment or disposal (where appropriate), and will keep 
documentation of receipt of arrival.
The sample receiver will keep full traceability of the samples, while in storage and during use 
until used or disposed of or until further shipment, and will keep documentation of receipt of 
arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, and auditing of external laboratory providers.
Samples retained for further use will be registered in the AstraZeneca-assigned Biobank 
during the entire life cycle.
5.5.6
Withdrawal of informed consent for donated biological samples
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of or destroyed, and the action will be documented.  If samples have already been 
analyzed, AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological samples is an integral part of the study, then the patient is 
withdrawn from further study participation.
The PI will:

Ensure that AstraZeneca is immediately notified of the patient’s withdrawal of 
informed consent to the use of donated samples

Ensure that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of, or destroyed and that the action is documented.


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
Ensure that the laboratory(ies) holding the samples is/are immediately informed 
about the withdrawn consent and that samples are disposed of or destroyed, the 
action is documented, and the signed document is returned to the study site.

Ensure that the patient and AstraZeneca are informed about the sample disposal
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
5.6
Pharmacogenetics
5.6.1
Collection of pharmacogenetic samples
The subject’s consent to participate in the pharmacogenetic research components of the study 
is mandatory.  
The blood sample for genetic research will ideally be obtained from the subjects at Day 1 
Cycle 1, prior to dosing.  Although genotype is a stable parameter, early sample collection is 
preferred to avoid introducing bias through excluding subjects who may withdraw due to an 
adverse event (AE), such subjects would be important to include in any genetic analysis.  If for 
any reason the sample is not drawn at Day 1 Cycle 1, it may be taken at any visit until the last 
study visit.  Only one sample should be collected per subject for genetics during the study. 
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual.
5.6.2
Storage, re-use and destruction of pharmacogenetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality.  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.  DNA 
is a finite resource that may be used up during analyses.  The results of any further analyses 
will be reported either in the Clinical Study Report itself or as an addendum, or separately in a 
scientific report or publication.
For all samples irrespective of the type of coding used the DNA will be extracted from the 
blood sample.  The DNA sample will be assigned a unique number replacing the information 
on the sample tube. Thereafter, the DNA sample will be identifiable by the unique DNA 
number only.  The DNA number is used to identify the sample and corresponding data at the 
AstraZeneca genetics laboratories, or at the designated contract laboratory.  No personal 
details identifying the individual will be available to any person (AstraZeneca employee or 
contract laboratory staff working with the DNA.)
The samples and data for genetic analysis in this study will be single coded.  The link between 
the subject enrolment/randomisation code and the DNA number will be maintained and stored 
in a secure environment, with restricted access within the Clinical Genotyping Group 
Laboratory Information Management System (LIMS) at AstraZeneca.  The link will be used 
to identify the relevant DNA samples for analysis, facilitate correlation of genotypic results 


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with clinical data, allow regulatory audit and to trace samples for destruction in the case of 
withdrawal of consent when the subject has requested disposal/destruction of collected 
samples not yet analysed. 
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section.
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, ECG).  In clinical studies, an AE 
can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered.
The term AE is used to include both serious and nonserious AEs.
6.2
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, and washout, 
follow-up), that fulfills 1 or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix AAppendix A
Additional 
Safety Information
.


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6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
AEs (including AESIs) and SAEs will be collected from the time the informed consent is 
signed through 90 days after the last dose of the last study treatment.
6.3.2
Follow-up of unresolved adverse events
During the course of the study, all AEs (including AESIs) and SAEs should be proactively 
followed up for each patient. Every effort should be made to obtain a resolution for all events, 
even if the events continue after discontinuation or study completion.
Any AEs that are unresolved at the patient’s last visit in the study are followed up 
by the Investigator for as long as medically indicated, but without further 
recording in the eCRF.  AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if 
judged to be necessary.
6.3.3
Variables

AE (verbatim)

The date when the AE started and stopped

The maximum CTCAE grade reported

Changes in CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the IPs (yes or no)

Action taken with regard to IPs

Administration of treatment for the AE

Whether the AE caused the patient’s withdrawal from the study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date the AE met criteria for SAE

Date the Investigator became aware of the SAE

Seriousness criteria fulfilled


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
Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Whether an autopsy was performed

Causality assessment in relation to study procedure(s)

Causality assessment in relation to Other Medication

Description of the AE
The grading scales found in the revised NCI CTCAE, Version 4.03, will be utilized for all 
events with an assigned CTCAE grading.  For those events without assigned CTCAE grades, 
the recommendation in the CTCAE criteria that converts mild, moderate, and severe events 
into CTCAE grades should be used.  A copy of CTCAE, Version 4.03 can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
6.3.4
Causality collection
The Investigator will assess causal relationship between the IP and each AE and answer “yes” 
or “no” to the question, “Do you consider that there is a reasonable possibility that the event 
may have been caused by the investigational product?”
For SAEs 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 AAppendix A
Additional Safety Information
.


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6.3.5
Relationship to protocol procedures
The Investigator is also required to provide an assessment of the relationship of SAEs to 
protocol procedures on the SAE report form.  This includes both non-treatment–emergent 
(ie, SAEs that occur prior to the administration of IP) and treatment-emergent SAEs.  A 
protocol-related SAE may occur as a result of a procedure or intervention required during the 
study (eg, blood collection).  The following guidelines should be used by Investigators to 
assess the relationship of SAEs to the protocol:

Protocol related: The event occurred due to a procedure or intervention that was 
described in the protocol for which there is no alternative etiology present in the 
patient’s medical record.

Not protocol related: The event is related to an etiology other than the procedure or 
intervention that was described in the protocol.  The alternative etiology must be 
documented in the study patient’s medical record.
6.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: “Have you had any health problems since the previous visit/you 
were last asked?” or revealed by observation will be collected and recorded in the eCRF.  
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
6.3.7
Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests and vital signs will be summarized in the 
CSR.  Deterioration, as compared to baseline, in protocol-mandated laboratory values and 
vital signs should, therefore, only be reported as AEs if they fulfill any of the SAE criteria or 
if they are considered the reason for discontinuation of treatment with the IPs.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE, and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin 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 that is unequivocally due to disease progression should not 
be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical 
examination, as compared with the baseline assessment, will be reported as an AE.


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6.3.8
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need 
to be reported as SAEs. Please refer to Appendix C for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law.
6.3.9
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied.  It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease.  The development of 
new, or progression of, existing metastasis to the primary cancer under study should be 
considered as disease progression and not an AE.  Events that are unequivocally due to 
disease progression should not be reported as an AE during the study.
6.3.10
New cancers
The development of a new cancer should be regarded as an SAE.  New primary cancers are 
those that are not the primary reason for the administration of the study treatment and have 
been identified after the patient’s inclusion in this study.
6.3.11
Deaths
All deaths that occur during the study, or within the protocol-defined follow-up period after 
the administration of the last dose of study treatment, must be reported as follows:

Death clearly resulting from disease progression should be reported to the Study 
Physician at the next monitoring visit and should be documented in the eCRF.  It 
should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to the Study Physician as an SAE 
within 24 hours.  The report should contain a comment regarding the 
co-involvement of PD, if appropriate, and should assign main and contributory 
causes of death.

Deaths with an unknown cause should always be reported as an SAE.  A 
post-mortem may be helpful in the assessment of the cause of death, and if 
performed, a copy of the post-mortem results should be forwarded to AstraZeneca 
Drug Safety or its representative within the usual timeframes.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IPs or to the 
study procedure(s). All SAEs will be recorded in the eCRF.


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If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day, that is, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel should inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day, that is, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel 
reports an SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed.
The reference documents for definition of expectedness/listedness are the IB for MEDI4736.
The PI 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.
6.5
Overdose
Use of IP in doses in excess of that specified in the protocol is considered to be an overdose.  
There is currently no specific treatment in the event of overdose of IP, and possible symptoms 
of overdose are not established.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigators or other site personnel should inform appropriate AstraZeneca representatives 
immediately or no later than 24 hours of when he or she becomes aware of it.


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Study Code D4198C00003
Edition Number 5.0
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The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply (see 
Section 6.4).  For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, that is, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy, and the PREGOUT is 
used to report the outcome of the pregnancy.
6.6.2
Paternal exposure
Male patients must refrain from fathering a child or donating sperm during the study and for 
180 days following the last dose.
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) occurring from the date of the first dose should, if possible, be 
followed up and documented.
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the patient’s partner.  Therefore, the local study 


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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.
6.7
Management of IP-related toxicities
The following general guidance should be followed for management of toxicities.

Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity if required).

If the symptoms promptly resolve with supportive care, consideration should be 
given to continuing the same dose of the assigned IP along with appropriate 
continuing supportive care. If medically appropriate, dose modifications are 
permitted.

All dose modifications should be documented with clear reasoning and 
documentation of the approach taken.

All toxicities will be graded according to NCI CTCAE, Version 4.03.
6.7.1
MEDI4736
The following general guidance should be followed for management of toxicities:

Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity if required)

If the symptoms promptly resolve with supportive care, consideration should be 
given to continuing the same dose of the assigned IP along with appropriate 
continuing supportive care. If medically appropriate, dose modifications are 
permitted (see Sections 6.7.2 and 6.7.3 and the Dosing Modification and Toxicity 
Management Guidelines in Appendix E).

All dose modifications should be documented with clear reasoning and 
documentation of the approach taken.
In addition, there are certain circumstances in which MEDI4736 should be permanently 
discontinued (see section 3.9 of this protocol and the Dosing Modification and Toxicity 
Management Guidelines in Appendix E).
Following the first dose of IP, subsequent administration of MEDI4736 can be modified based 
on toxicities observed as described in the Dosing Modification and Toxicity Management 
Guidelines in Appendix E of the protocol. These guidelines have been prepared by the 
Sponsor to assist the Investigator in the exercise of his/her clinical judgment in treating these 
types of toxicities. These guidelines apply to AEs considered causally related to MEDI4736 
regimen by the reporting investigator.Dose reductions are not permitted. In case of doubt, the 
Investigator should consult with the Study Physician.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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6.7.1.1
Adverse events of special interest (AESIs)
Adverse events of special interest (AESIs) are events of scientific and medical interest specific 
to the further understanding of the MEDI4736 safety profile and require close monitoring and 
rapid communication by the Investigator to AstraZeneca.  MEDI4736 AESIs may be serious 
or non-serious.  The rapid reporting of these AESIs allows ongoing analysis of these events in 
order to characterize and understand them in association with the use of this IP.
AESIs for MEDI4736 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 MEDI4736 monotherapy 
and combination therapy. An immune-related adverse event (irAE) is defined as an adverse 
event that is associated with drug exposure and is consistent with an immune-mediated 
mechanism of action and where there is no clear alternate aetiology. Serologic, immunologic, 
and histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or 
other etiologic causes of the irAE.
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Physician.
AESIs observed with MEDI4736 include:

Diarrhea/Colitis and intestinal perforation

Pneumonitis / ILD

Hepatitis/transaminase increases

Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal 
insufficiency, hyper- and hypothyroidism and type I diabetes mellitus)Rash / 
Dermatitis

Nephritis / Blood creatinine increases

Pancreatitis / serum lipase and amylase increases 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, pericarditis, sarcoidosis, uveitis 
and other events involving the eye, skin, haematological and rheumatological 
events.


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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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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 
version of the MEDI4736 Investigator Brochure. More specific guidelines for their evaluation 
and treatment are described in detail in Appendix E.
Information on MEDI4736 AESIs and guidelines for the management of immune-mediated 
reactions, infusion-related reactions, and non-immune-mediated reactions for MEDI4736 are 
provided in the Dosing Modification and Toxicity Management Guidelines in Appendix E.  
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.
6.7.2
Nab-paclitaxel + gemcitabine
Nab-paclitaxel and gemcitabine are associated with a number of unwanted effects. In case an 
AE can reasonably be attributed to nab-paclitaxel or gemcitabine, dose adjustment should be 
attempted before adjusting the MEDI4736 dose. Management of severe and/or intolerable 
suspected adverse reactions may require dose alterations and should be performed in 
agreement with the Summary of Product Characteristics and hospital protocol procedure.
Toxicities related to nab-paclitaxel + gemcitabine treatment should be managed as per local 
guidelines and the relevant approved labelling.
6.7.3
AZD5069
AZD5069, an inhibitor of CXCR2, acts by modulating neutrophil migration. Therefore, 
effects on blood neutrophil count, including reduction in their number (neutropenia), 
infections (especially requiring administration of outpatient oral or IV antibiotics) are deemed 
events of special interest, as are ECG abnormalities occuring after treatment with AZD5069.
Patients will initiate dosing of AZD5069 as 80 mg BID oral tablets.  If a patient experiences a 
clinically significant and/or unacceptable toxicity, dosing of AZD5069 will be interrupted or 
the dose reduced with supportive therapy administered as required.  For non neutropenic 
toxicities, if the toxicity resolves or reverts to a lower CTCAE grade within 21 days of onset 
and the patient is showing clinical benefit, dosing may be resumed as per Table 9 and Table
10 for events other than neutropenia associated with AZD5069.  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 and the patient should be followed up for safety.
A maximum of 2 dose reductions from 80 mg bid (Figure 3) will be allowed for an individual 
patient.  If the dose reduction is not tolerated, study treatment should be permanently 


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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discontinued and the patient should be followed up for safety.  The lowest dose of AZD5069  
that may be administered is 20 mg BID.
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. 
Table 9
Dose modifications for toxicity (non neutropenic and non liver toxicity 
events)
Examples (including and not limited to)
Toxicity
Recovery
Re-dosing
Notes
Grade 3
G2a ≤21 days
Restart at dose level -1 
If second event, then 
discontinue drug
G2a  >21 days
Discontinue study drug 
treatment
Grade 4
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.
Table 10
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 event discontinue 
drug
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.  Until this discussion occurs, dosing of study treatment must be interrupted 
temporarily.    


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Figure 3
Dose-reductions levels for AZD5069 toxicity management
Management of neutropenia associated with AZD5069 should be according to Figure 4.  It 
entails carefully monitoring neutrophil counts during the first weeks of treatment,  with short 
dosing holds as the first response to absolute neutrophil counts <0.5 x 109/l (Grade 4 
neutrophil reductions).      
In the face of prolonged Grade 4 neutrophil reductions unresponsive to dose holds, use of G-
CSF is allowed twice at any given dose level;   subsequent dose reductions to the next lower 
dosing level (80 mg bid40 mg bid or 40 mg bid20 mg bid) are then mandated.  Of note, 
Grade 3 neutrophil reductions (ANC 0.5-1.0 x 109/l) without clinically significant infection 
are tolerated within the dose reduction scheme.  
Figure 4
Management of neutropenic toxicities
Toxicity management for Grade 3 and Grade 4 AZD5069- related neutropenic events is as 
illustrated below in the Panels A and B.
AZD5069 40 mg BID
Dose reduction (-2)
AZD5069 20 mg BID
AZD5069 80 mg BID
Dose reduction (-1)


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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PANEL A
PANEL B


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Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
97(176)
6.8
Study governance and oversight
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
AstraZeneca will supply MEDI4736 and AZD5069.  Nab-paclitaxel and gemcitabine will be 
sourced locally.
Investigational product
Dosage form and strength
MEDI4736
50 mg/mL solution for infusion after dilution
Nab-paclitaxel
IV (as sourced locally)
Gemcitabine
IV (as sourced locally)
AZD5069
AZD5069
10 mg tablets for oral use
40 mg tablets for oral use
7.1.1
MEDI4736
MEDI4736 will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL MEDI4736, 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume 
(w/v) polysorbate 80; it has a pH of 6.0.  The nominal fill volume is 10 mL. Investigational 
product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen.
Preparation of MEDI4736 doses for administration with an IV bag
The dose of MEDI4736 for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
MEDI4736 vial to the start of administration should not exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
A dose of 1.5 g will be administered using an IV bag containing 0.9% (w/v) saline or 5%
(w/v) dextrose, with a final MEDI4736 concentration ranging from 1 to 20 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. Remove 
30.0 mL of IV solution from the IV bag prior to addition of MEDI4736. Next, 30.0 mL of 
MEDI4736 (ie, 1.5 g of MEDI4736) is added to the IV bag such that final concentration is 


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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within 1 to 20 mg/mL (IV bag volumes 100 to 1000 mL). Mix the bag by gently inverting to 
ensure homogeneity of the dose in the bag.
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.
In the event that either preparation time or infusion time exceeds the time limits outlined in 
the table, a new dose must be prepared from new vials.  MEDI4736 does not contain 
preservatives, and any unused portion must be discarded.
No incompatibilities between MEDI4736 and polyvinylchloride, or polyolefin IV bags have 
been observed.
All details can be found in the Drug Handling Instructions.
7.1.2
Nab-paclitaxel + gemcitabine
The nab-paclitaxel + gemcitabine will be sourced as commercially available material/locally 
sourced, prescribed according to local regulations, and will be administered according to 
prescribing information or treatment guidance in general use by the Investigating site.  Under 
certain circumstances when local sourcing is not feasible, nab-paclitaxel + gemcitabine will be 
supplied centrally by AstraZeneca.  This will be labeled with local language translated text in 
accordance with regulatory guidelines.
7.1.3
AZD5069
AZD5069 will be supplied as 40-mg and 10-mg oral tablets.
7.2
Dose and treatment regimens
7.2.1
Treatment regimens
7.2.1.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy
Patients in Cohort 1 will receive 1.5 g MEDI4736 by IV infusion q4w (ie, Day 1 of each 
28-day cycle).
The recommended dose of nab-paclitaxel in combination with gemcitabine is 125 mg/m2 via 
IV infusion over 30 minutes on Days 1, 8, and 15 of each 28-day cycle.  The concurrent 
recommended dose of gemcitabine is 1000 mg/m2 via IV infusion over 30 minutes 
immediately after the completion of nab-paclitaxel administration on Days 1, 8, and 15 of 
each 28-day cycle.  The tumor assessment schedule will not be altered (ie, assessments will 
continue to be q8w ±7 days relative to the date of first infusion per Table 2).
MEDI4736 will be administered first as a 1-hour infusion.  The nab-paclitaxel + gemcitabine 
infusion will start approximately 1 hour after the end of the MEDI4736 infusion.  
Nab-paclitaxel will be administered first as a 30- to 40-minute infusion, immediately followed 
by gemcitabine as a 30- to 40-minute infusion.


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Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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The dosing schedule for Cohort 1 is presented in Figure 5. The duration of treatment is 
described in Section 7.2.2.
Figure 5
Cohort 1 dosing schedule
7.2.1.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069
Patients in Cohort 2 will receive 1.5 g MEDI4736 by IV infusion q4w (ie, Day 1 of each 
28-day cycle) and AZD5069 administered at a starting dose of 80 mg orally bid (with dose 
reductions to 40 mg bid or 20 mg bid for toxicity allowable) in the morning and the evening of 
each day; see Figure 6.
The morning dose of AZD5069 will be administered at least 30 minutes before the infusion of 
MEDI4736.  A 1-hour observation period is recommended after the first infusion of 
MEDI4736.  If no clinically significant infusion reactions are observed during or after the first 
infusion, subsequent infusion observation periods can be at the Investigator’s discretion 
(suggested 30 minutes after infusion).
In all cases, AZD5069 should be administered with at least two hours of fasting before and 
one hour fasting after each dose (3 hour interval without food consumption) at approximately 
the same time each day (within a +/- 2 hours window).  Patients may have glucose (sugar 
tablets) and/or juice (except for grapefruit juices or juices containing grapefruit or Seville 
oranges) if they show 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.  This fasting restriction may be 
removed only when data showing there is no clinically relevant effect of food on the PK of 
AZD5069 becomes available.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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The duration of treatment is described in Section 7.2.2.
Figure 6
Cohort 2 dosing schedule
7.2.2
Duration of treatment
Treatment in both cohorts will be administered beginning on Day 1 until the following 
conditions are met:
1.
Confirmed PD
2.
Unacceptable toxicity
3.
Withdrawal of consent, or
4.
Another discontinuation criterion is met
In cases of toxicity and at the Investigator’s discretion, patients will be permitted to stop 
treatment with one agent of their combination therapy regimen and continue treatment with 
the other agent as monotherapy, using the same dose and regimen as previously administered.  
These patients may continue to receive MEDI4736 alone (until confirmed PD, withdrawal of 
consent, or another discontinuation criterion is met), or nab-paclitaxel + gemcitabine alone 
(Cohort 1 only) or AZD5069 alone (Cohort 2 only) until the first assessment of disease 
progression [ie, unconfirmed PD], withdrawal of consent, or another discontinuation criterion 
is met.
Patients who the Sponsor and Investigator determine may not continue treatment will enter 
follow-up. Patients who have discontinued treatment due to toxicity or symptomatic 
deterioration, or who have commenced subsequent anticancer therapy, will be followed up via 
telephone for death until end of study.


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Treatment through initial assessment of progression is allowed only with MEDI4736 as 
monotherapy or in combination with AZD5069 and nab-paclitaxel/gemcitabine.  Treatment 
through initial progression is not permitted for monotherapy AZD5069 and nab-
paclitaxel/gemcitabine alone.  The Investigator should ensure that patients do not have any 
significant, unacceptable, or irreversible toxicities that indicate that continuing treatment will 
not further benefit the patient. The Investigator should ensure that patients still meet all of the 
inclusion criteria and none of the exclusion criteria for this study and that these patients meet 
the following specific criteria for treatment in the setting of PD:

Written informed consent to continue treatment in the setting of PD. This consent 
document will specify that treatment beyond initial evidence of PD is not the 
standard-of-care and that alternative treatment options, either locally licensed 
treatments or other clinical trials, are available for this patient population.

Absence of clinical symptoms or signs indicating clinically significant disease 
progression and no decline in ECOG PS to >1.

Absence of rapid disease progression or threat to vital organs or critical anatomical 
sites (eg, central nervous system metastasis, respiratory failure due to tumor 
compression, or spinal cord compression) requiring urgent alternative medical 
intervention.
7.2.3
Enrollment and stopping criteria for Cohort 1 (first-line, Phase Ib, MEDI4736 
+ nab-paclitaxel + gemcitabine chemotherapy)
Initially, 3 patients will be enrolled into Cohort 1.  The DLT period is defined as the first 
treatment cycle (28 days). The population evaluable for safety will consist of all patients who 
complete the first treatment cycle (DLT period, as described above) and/or discontinue study 
treatment early due to a DLT and who have not missed ≥2 administrations of gemcitabine.
Because Cohort 1 is now limited to 3 patients who have completed the evaluation period, no 
further consideration of DLT is required.  
7.2.4
Definition of dose-limiting toxicity for Cohort 1 (first-line, Phase Ib, 
MEDI4736 + nab-paclitaxel + gemcitabine chemotherapy)
A DLT is defined as any of the below listed laboratory abnormalities or AEs clearly related to 
the administration of MEDI4736 occurring during the DLT period.
The following will be considered a DLT regardless of duration or reversibility:

Liver transaminase elevation ≥ 5 × but ≤ 8× ULN that does not downgrade to Grade 
2 within 5 days after onset with optimal medical management, including systemic
corticosteroids

Transaminase elevation > 8× ULN or total bilirubin > 5 × ULN


Clinical Study Protocol
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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Patients experiencing a DLT during the DLT period may continue treatment after dose 
adjustment (see Section 6.7) if there is a potential benefit from treatment.
Immune-related adverse events (irAEs)

Any Grade 4 irAE not attributed to local tumor response (eg, inflammatory reaction 
attributed to local tumor response or inflammatory reaction at sites of metastatic 
disease or lymph nodes).

Any Grade ≥3 colitis 

Any ≥ Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 7 days of the
initiation of maximal supportive care.

Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to 
Grade ≤1 or baseline status (for patients who entered the study with an existing 
laboratory abnormality) within 14 days.
Non-Immune-related Adverse Event (Non-irAE)

Any Grade ≥3 non-irAE toxicity that does not downgrade to Grade ≤1 or baseline 
status (for patients who entered the study with an existing laboratory abnormality) 
within 14 days.
The definition of DLT excludes the following conditions:

Vitiligo, alopecia, rash, and Grade 3 electrolyte abnormalities that are reversed with 
appropriate medical intervention within 7 days or derived from a suboptimal 
prophylactic and curative therapy.

Grade 4 electrolyte abnormalities lasting less than 24 hours.

Grade 3 and 4 toxicity nausea, vomiting, and diarrhea lasting less than 72 hours. 
Grade 3 and 4 diarrhea will be considered DLTs if considered as an irAE.

Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy, and the patient is asymptomatic.

Grade 3 inflammatory reaction attributed to a local antitumor response 
(eg, inflammatory reaction at sites of metastatic disease or lymph nodes).

Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management.


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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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
Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 5 days. Grade 3 or Grade 4 febrile neutropenia 
that can be reasonably attributed to background chemotherapy (Section 6.7.2).

Grade 3 or 4 lymphopenia

Grade 4 thrombocytopenia (platelet count ≤25000/mm3 [≤25 x 109/l]) or Grade 3 
thrombocytopenia (platelet count 25000-50000/mm3 [25-50 x 109/l]) not associated 
with any bleeding, not requiring transfusion, lasting less than 7 days, and/or can be 
reasonably attributed to background chemotherapy (Section 6.7.2).
irAEs are defined as AEs of an immune nature (ie, inflammatory) in the absence of a clear 
alternative etiology.  In the absence of a clinically significant abnormality, repeat laboratory 
testing will be conducted to confirm significant laboratory findings prior to designation as a 
DLT.  Laboratory abnormalities that are not deemed to be clinical significant will not be 
considered a DLT.
7.2.5
Definition of dose-limiting toxicity for Cohort 2 (MEDI4736 + AZD5069)
For patients in Cohort 2 to be deemed evaluable, a patient must have received 50% of planned 
doses of AZD5069 during the DLT evaluation period as well as the MEDI4736 infusion and 
have remained active on trial at the end of Day 28 of the study cycle 1. 
The DLT evaluation period for Cohort 2 will be defined as the time from the first dose of 
AZD5069 and MEDI4736 to the end of Cycle 1 (ie, 28 days total) or until a patient 
experiences a DLT, whichever occurs first.
Dose-limiting toxicity criteria for MEDI4736:
A DLT is defined as any of the below listed laboratory abnormalities or AEs clearly related 
to the administration of MEDI4736 occurring during the DLT period.
The following will be considered a DLT regardless of duration or reversibility:

Liver transaminase elevation ≥ 5 × but ≤ 8× ULN that does not downgrade to Grade 
2 within 5 days after onset with optimal medical management, including systemic
corticosteroids.

Transaminase elevation > 8× ULN or total bilirubin > 5 × ULN
Patients experiencing a DLT during the DLT period may continue treatment after dose 
adjustment (see Section 6.7) if there is a potential benefit from treatment.
Immune-related adverse events (irAEs)


Clinical Study Protocol
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
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
Any Grade 4 irAE not attributed to local tumor response (eg, inflammatory reaction 
attributed to local tumor response or inflammatory reaction at sites of metastatic 
disease or lymph nodes).

Any Grade ≥3 colitis 

Any ≥Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 7 days of the
initiation of maximal supportive care.

Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to 
Grade ≤1 or baseline status (for patients who entered the study with an existing 
laboratory abnormality) within 14 days.
Non-Immune-related Adverse Event (Non-irAE)

Any Grade ≥3 non-irAE toxicity that does not downgrade to Grade ≤1 or baseline 
status (for patients who entered the study with an existing laboratory abnormality) 
within 14 days.
The definition of DLT excludes the following conditions:

Vitiligo, alopecia, rash, and Grade 3 electrolyte abnormalities that are reversed with 
appropriate medical intervention within 7 days or derived from a suboptimal 
prophylactic and curative therapy.

Grade 4 electrolyte abnormalities lasting less than 24 hours.

Grade 3 and 4 toxicity nausea, vomiting, and diarrhea lasting less than 72 hours. 
Grade 3 and 4 diarrhea will be considered DLTs if considered as an irAE.

Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy, and the patient is asymptomatic.

Grade 3 inflammatory reaction attributed to a local antitumor response 
(eg, inflammatory reaction at sites of metastatic disease or lymph nodes).

Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management.

Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 5 days. Grade 3 or Grade 4 febrile neutropenia 
that can be reasonably attributed to background chemotherapy (Section 6.7.2).

Grade 3 or 4 lymphopenia.


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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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
Grade 4 thrombocytopenia (platelet count ≤25000/mm[≤25 x 109/l]) or Grade 3 
thrombocytopenia (platelet count 25000-50000/mm3 [25-50 x 109/l]) not associated 
with any bleeding, not requiring transfusion, lasting less than 7 days, and/or can be 
reasonably attributed to background chemotherapy (Section 6.7.2).
irAEs are defined as AEs of an immune nature (ie, inflammatory) in the absence of a clear 
alternative etiology.  In the absence of a clinically significant abnormality, repeat laboratory 
testing will be conducted to confirm significant laboratory findings prior to designation as a 
DLT.  Laboratory abnormalities that are not deemed to be clinical significant will not be 
considered a DLT.
Dose-limiting toxicity criteria for AZD5069:
A DLT is defined as any AE that occurs from the first dose of AZD5069 up to the end the 
DLT evaluation period, that is judged by the Investigator to be  AZD5069 related (ie, 
unrelated to PD, intercurrent illness, or concomitant medications), and that is assessed as 
grade 3 or worse according to the National Cancer Institute (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)
Total bilirubin 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:


Clinical Study Protocol
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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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−
If in the context of grade 3 febrile neutropenia (ie, absolute neutrophil count 
[ANC] 500-1000/mm3 [0.5-1.0 x 109/l] 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 (ie, ANC <500/mm3  [ <0.5 x 
109/l] with life-threatening consequences that indicate urgent intervention);
−
If assessed as grade 3 or worse (ie, ANC 0.5-1.0 x 109/l) 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 (ie, ANC <500/mm3 [0.5 x 109/l]) for more than 5 days.

Thrombocytopenia will be considered a DLT only:
−
If assessed as grade 3 or worse (ie, platelet count <50000/mm3 [<50 x 109/l]) 
and associated with bleeding, or
−
If assessed as grade 4 (ie, platelet count <25000/mm3 [<25 x 109/l]).
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 AZD5069 related (ie, causality rated as possible 
or greater) that requires study treatment to be discontinued for more than 10 consecutive days 
will be considered a DLT.Management of toxicity for MEDI4736 related events is described 
in Appendix E
Management of neutropenia associated with AZD5069 is described in Section 6.7.3.
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfill GMP Annex 13 requirements for labelling.  
Label text will be translated into local language.
Labels will be provided as either a single panel label or as multi-language booklet labels.


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Edition Number 5.0
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7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  The IP 
label on the pack/bottle/carton specifies the appropriate storage.  Storage is also described in 
the IB.
7.5
Compliance
The administration of all study drugs (including IPs) should be recorded in source 
documentation and in the appropriate sections of the eCRF.
Patients should return all unused medication and empty containers to the Investigator.
Treatment compliance will be assured by site reconciliation of medication dispensed and 
returned.
7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.  The 
study personnel will account for all study drugs.  The administration of all medications 
(including study drug) and details of treatment with investigational product should be 
recorded in the appropriate sections of the eCRF.
Drug accountability should be performed until the patient stops study treatment completely.  
Study site personnel will account for all study drugs received at the site, for all unused study 
drugs, and for appropriate destruction of study drugs.  Certificates of delivery, destruction, and 
return should be signed.
Study drug will not be distributed to the study site until the contract is concluded between the 
study site and AstraZeneca.  The IP Storage Manager is responsible for managing the study 
drug from receipt by the study site until the return of all unused study drug to AstraZeneca.  
AstraZeneca will provide the study documents “Procedures for drug accountability” and 
“Procedures for drug storage,” which describe the specific requirements.  The Investigator(s) 
is responsible for ensuring that the patient has returned all unused study drug.
7.7
Concomitant and other treatments
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical phase of the study (final study visit).  Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in source documentation and in the eCRF.
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator.
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables.  Refer to Section 6.7 for guidance on management of IP-related toxicities.


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Study Code D4198C00003
Edition Number 5.0
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Prohibited medication/class of drug:
Usage:
Any investigational anticancer therapy 
concurrent with those under investigation in 
this study
Should not be given during the study
mAbs against PD-1, PD-L1, and PD-L2, 
CXCR2 inhibitors, and therapeutic anticancer 
vaccines through 90 days after the last dose 
during the study
Should not be given during the study 
Any concurrent chemotherapy, radiotherapy 
(except for local treatment of isolated lesions, 
excluding target lesions, for palliative intent 
[eg, by local surgery or radiotherapy]), 
immunotherapy, biologic therapy, or hormonal 
therapy for cancer treatment.  
Should not be given during the study.  (Concurrent 
use of hormones for noncancer related conditions 
[eg, insulin for diabetes and hormone replacement 
therapy] is acceptable.)  
Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or 
equivalent, azathioprine, and tumor necrosis 
factor alpha (TNF-α) blockers.  
Should not be given during the study.  (Use of 
immunosuppressive medications for the management 
of IP-related AEs or in patients with contrast allergies 
is acceptable.  In addition, use of inhaled, topical, or 
intranasal corticosteroids is permitted.  Temporary 
uses of corticosteroids for concurrent illnesses 
[eg, food allergies or CT scan contrast 
hypersensitivity,] are acceptable upon discussion with 
the Study Physician.)
Live attenuated vaccines 
Should not be given within 30 days of dosing of IP
Herbal and natural remedies 
Should be avoided during the study (with the 
exception of homeopathic remedies, which could be 
used following discussion with the Investigator)
Rescue/supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) 
deemed necessary to provide adequate 
prophylactic or supportive care except for 
those medications identified as “prohibited” as 
listed above.  
To be administered as prescribed by the Investigator
Best supportive care (including antibiotics, 
nutritional support, growth factor support, anti-
emetic, correction of metabolic disorders, 
optimal symptom control, and pain 
management [including palliative radiotherapy, 
etc]) 
Should be used when necessary for all patients
Opioids 
Can be used but with caution and under medical 
control after discussion with the Study Physician


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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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As detailed in the IB for AZD5069, patients who are treated with AZD5069 should avoid 
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, Seville orange or grapefruit products, and any herbal medications.  Please 
refer to local prescribing information for other drugs that may interact with either 
nab-paclitaxel or gemcitabine.
For each patient enrolled in Cohort 2, 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.
See Table 11 for 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.
Patients administered AZD5069 alone and in combination with MEDI4736 must not consume 
Seville orange marmalade, Seville orange juice, grapefruit, grapefruit juice, grapefruit 
marmalade, or other Seville orange or grapefruit products. In addition the use of cannabinoids 
must be avoided in patients administered AZD 5069 alone and in combination with 
MEDI4736.
Any further questions regarding concomitant treatments in patients treated with AZD5069 
should be referred to the Study Physician.


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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
110(176)
Table 11
Prohibited medications and foods for patients who receive AZD5069
Class
Examples (including and not limited to)
Potent/moderate CYP3A4 
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 CYP3A4 
inducers
Avasimibe
Bosentan
Carbamazepine
Efavirenz
Etravirine
Modafinil
Nafcillin
Phenytoin 
Rifampin
St. John’s wort
Sensitive CYP2B6 substrates
Bupropion
Efavirenz
P-gp substrates with narrow 
therapeutic index
Digoxin
Dabigatran
Coumarin derivatives
Acenocoumarol
Phenprocoumon
Warfarin
BCRP substrates that reduce 
blood neutrophils
Topotecan
Any herbal medications


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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
111(176)
Table 11
Prohibited medications and foods for patients who receive AZD5069
Class
Examples (including and not limited to)
Seville orange or grapefruit 
products
Seville orange marmalade
Seville orange juice
Grapefruit
Grapefruit juice
Grapefruit marmalade
7.7.1
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF.
7.8
Post study access to study treatment
After the final analysis, AstraZeneca will continue to supply open-label drug to patients 
receiving AZD5069 and MEDI4736 therapy up to completion of a patient’s treatment period 
(see Section 7.2).
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
A comprehensive statistical analysis plan (SAP) within 3 months of the first enrolled patient 
and any subsequent amendments will be documented, with final amendments completed prior 
to reporting of the data.
8.2
Sample size estimate
8.2.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy
The sample size is set to screen patients for major toxicity that occurs in a large portion of the 
population, using the conventional 3 + 3 design.  The total number of patients in dose level 1 
is 3 patients.
Based on binomial probabilities, the probability of observing 0 or more patients with a toxicity 
event in 3 patients (6 patients respectively) can be seen in Table 12.


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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Table 12
Probability of observing toxicity event
Incidence 
of DLTs
Probability of observing X out of Y (X/Y) patients with DLT
0/3
≤1/3
≥2/3
0/6
≤1/6
≥2/6
30%
34.30%
78.40%
21.60%
11.80%
42.00%
58.00%
50%
12.50%
50.00%
50.00%
1.60%
10.90%
89.10%
70%
2.70%
21.60%
78.40%
0.10%
1.10%
98.90%
8.2.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069
The sample size is set to screen patients for major toxicity that occurs in a large portion of the 
population, using the approximately 6 to 16 evaluable patients in total.  A cohort of 6 patients 
will be recruited sequentially at the planned dose level.  Should safety and tolerability be 
acceptable (if there are 3 or fewer patients exhibiting DLT criteria) following assessment of 
the initial 6 patients, approximately 10 further patients will be recruited, to target 
approximately 16 evaluable patients in total. 
Based on binomial probabilities, the probability of observing 0 or more patients with a toxicity 
event in 6 patients (6 patients respectively) can be seen in Table 13.
Table 13
Probability of observing toxicity events in 6 or 16 patients
Incidence 
of DLTs
Probability of observing X out of Y (X/Y) patients with DLT
0/6
≤1/6
≤2/6
≥3/6
≤2/16
≥3/16
1%
94.10%
99.90%
100%
0%
98.90%
1.10%
5%
73.50%
96.70%
99.80%
0.20%
81.10%
18.90%
10%
53.10%
88.60%
98.40%
1.60%
51.50%
48.50%
20%
26.20%
65.50%
90.10%
9.90%
14.10%
85.90%
30%
11.80%
42%
74.40%
25.60%
2.60%
97.40%
50%
1.60%
10.90%
34.40%
65.60%
0%
100%
70%
0.10%
1.10%
7%
93%
0%
100%
When the true incidence is 30% the chance of observing at least 3 DLTs out of 6 patients is 
25.6% assuming no prior information.  
While the estimates in Table 13 are true for the assumed true DLT incidences, there is prior 
information in the AZD5069 program.  In particular there have been 23 patients treated with 


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Edition Number 5.0
Date 08 February 2018
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at least one of the durvalumab combinations in Trial D5660C00004.  About half of the 
patients treated with the AZD5069/durvalumab combination were treated with a tolerated dose 
which will continue to be developed, the empirical priors were discounted by about 50%.  The 
table below presents posterior probabilities that the true DLT incidence is at least 33%.  Three 
sets of posterior proibabilities are shown.  The posterior priobabilities based on a non-
informative prior are presented as an initial case.  Since we do have prior data, the more 
relevant posterior probabilities are shown in the last two columns of Table 14.  The 
probabilities under Trial 4 amendment 2 reflect the DLT information documented in the 
current version of the AZD5069 IB.  In the last column, posterior probabilities based on the 
original (more conservative) DLT definition are presented.
Table 14
Posterior Probabilities of True DLT Incidence > 33% with Various 
Priors
Data
Non-informative
Trial 4
Amendment 2
Trial 4 original
(conservative)
0/6 DLT
6.06%
0.05%
1.45%
1/6 DLT
26.96%
0.51%
5.56%
2/6 DLT
57.83%
2.57%
14.82%
3/6 DLT
83.18%
8.31%
30.02%
4/6 DLT
95.66%
19.63%
49.09%
5/6 DLT
99.35%
36.34%
67.86%
6/6 DLT
99.96%
55.55%
82.66%
With 3 patients out of 6 experiencing DLTs there is a 30.02% chance that the true DLT 
incidence is > 33% under the original Trial D5660C00004 DLT definition, which was 
changed to accommodate an Oncology population as opposed to the original COPD 
population.  The data supporting this change is outlined in the current AZD5069 IB.  With this 
in mind, the same posterior probability quoted for 3 patients out of 6 experiencing DLTs, the 
posterior probability that the true incidence is at least 33% is only 8.31%. Based on this, we 
will continue Cohort 2 in this trial if in 6 patients we see no more than 3 DLTs.  
8.3
Definitions of analysis sets
Definitions of the analysis sets for each outcome variable are provided in Table 15


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Edition Number 5.0
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Table 15
Summary of outcome variables and analysis populations
Outcome variable
Population
Efficacy data
ORR 
Efficacy Analysis Set
DoR, DCR, PFS, PFS3, PFS6, OS, OS6, OS12, 
and symptom endpoints
Efficacy Analysis Set
Demography
Safety Analysis Set
PK data
PK analysis set
Safety Data
Exposure
Safety analysis set
AEs
Safety analysis set
Laboratory measurements
Safety analysis set
ECOG PS
Safety analysis set
Vital signs
Safety analysis set
8.3.1
Full analysis set
The Full Analysis Set will include all patients enrolled to receive treatment (ie, the intent-to-
treat [ITT] population) and will classify them on the basis of allocated treatment, regardless of 
the treatment actually received.  Patients who were enrolled to receive treatment who did not 
subsequently go on to receive study treatment are included in the ITT population.
8.3.2
Safety analysis set
All patients who received at least 1 dose of IP and for whom any post-dose data are available 
will be included in the Safety Analysis Set.  PK analysis set
8.3.3
PK analysis set
All patients who received at least 1 dose of IP per protocol for whom any post-dose data are 
available and who do not violate or deviate from the protocol in ways that would significantly 
affect the PK analyses will be included in the PK Analysis Set.  The population will be 
defined by the Study Physician, Pharmacokineticist, and Statistician prior to any analyses 
being performed.
8.3.4
Efficacy analysis set
The Efficacy analysis set (EAS) will include patients who received at least 1 dose of IP and 
with no important protocol deviation that could impact the efficacy evaluation.  These 
deviations will be discussed and stated during the Data Review Meeting prior to database lock 
(DBL).


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8.4
Outcome measures for analyses
8.4.1
Calculation or derivation of efficacy variables
8.4.1.1
RECIST 1.1-based endpoints
Investigator RECIST 1.1-based assessments
All RECIST assessments, whether scheduled or unscheduled, will be included in the 
calculations.  This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy.
At each visit, patients will be programmatically assigned a RECIST 1.1 overall visit response 
of CR, PR, SD, or PD depending on the status of their disease compared with baseline and 
previous assessments.  Baseline will be assessed within the 28 days prior to the treatment start 
date.  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 not evaluable (NE) unless there is evidence of progression, in which case the 
response will be assigned as PD.  Endpoints (of ORR, DoR, DCR, PFS, PFS3, and PFS6) will 
be derived from the overall visit response date and the scan dates.
Progression of TLs will be calculated in comparison to when the tumor burden was at a 
minimum (ie, smallest sum of diameters previously recorded on study, including baseline). In 
the absence of progression, tumor response (CR, PR, SD) will be calculated in comparison to 
the baseline tumor measurements obtained before starting treatment.
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 nonmissing 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 nonmissing TL diameters would result in PD (ie, if 
using a value of 0 for missing lesions the sum of diameters has still increased by
>20% or more compared to 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.


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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 nonpathological) 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 to 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.
Stable disease 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.
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.
Please refer to Appendix D for the definitions of CR, PR, SD, NE, and PD.
8.4.1.2
Primary endpoints
8.4.2
Calculation or derivation of safety variables
8.4.2.1
Adverse events
Data from all cycles of treatment will be combined in the presentation of safety data.  AEs 
(both in terms of Medical Dictionary for Regulatory Activities [MedDRA] preferred terms 
and CTCAE grade) will be listed individually by patient.
Any AE occurring before treatment with IP will be included in the data listings but will not be 
included in the summary tables of AEs.  Any AE occurring within 90 days of discontinuation 
of IP (ie, the last dose of a given IP therapy) may be included in the AE summaries, but the 
majority of those summaries will omit the AEs observed after a patient has received further 
therapy for cancer.  Further details will be provided in the SAP.  Any events in this period that 
occur after a patient has received further therapy for cancer (following discontinuation of IP) 
will be flagged in the data listings.
A separate data listing of AEs occurring more than 90 days after discontinuation of IP will be 
produced.  These events will not be included in AE summaries.
8.4.2.2
Other significant adverse events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and AEs leading to discontinuation.  Based on 
the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered other significant adverse 
events (OAEs) and reported as such in the CSR.  A similar review of laboratory/vital 
signs/ECG data will be performed for identification of OAEs.  Examples of these are marked 


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hematological and other laboratory abnormalities, and certain events that lead to intervention 
(other than those already classified as serious) or significant additional treatment.
8.4.2.3
Safety assessments
For the change from baseline summaries for vital signs, laboratory data, ECGs, and physical 
examination, the baseline value will be the latest result obtained prior to the start of study 
treatment.
The QTcF will be derived during creation of the reporting database using the reported ECG 
values (RR and QT).
QTcF = QT/RR^ (1/3) where RR is in seconds
Corrected calcium will be derived during creation of the reporting database using the 
following formulas:
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – albumin (G/L)] × 0.02)
The denominator used in laboratory summaries will only include evaluable patients, in other 
words, those who had sufficient data to have the possibility of an abnormality.
For example:

If a CTCAE criterion involves a change from Baseline, evaluable patients would 
have both 1 pre-dose and at least 1 post-dose value recorded

If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient need only have 1 post-dose-value recorded.
The denominator in vital signs data should include only those patients with recorded data.
8.4.2.4
Secondary endpoints
Duration of response
DoR (per RECIST 1.1 as assessed by Investigator assessment) will be defined as the time 
from the date of first documented response until the first date of documented progression or 
death in the absence of disease progression.  The end of response should coincide with the 
date of progression or death from any cause used for the RECIST 1.1 PFS endpoint, based on 
Investigator assessment.
The time of the initial response will be defined as the latest of the dates contributing toward 
the first visit response of CR or PR.  If a patient does not progress following a response, then 
their DoR will be censored at the PFS censoring time.  DoR will not be defined for those 
patients who do not have documented response.


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Additionally, DoR will be obtained using the algorithm described, but following a 
modification where any objective progression requires confirmation.  Therefore, the end of 
response should coincide with the date of progression or death from any cause.  The time of 
the initial response will be defined as the latest of the dates contributing toward the first visit 
response of PR or CR.  Note that the time of initial response may be after an unconfirmed 
progression.
Disease control rate
DCR at 6 or 12 months is defined as the percentage of patients who have a best objective 
response (BoR) of CR or PR in the first 6 or 12 months, respectively, or who have 
demonstrated SD for a minimum interval of 24 or 48 weeks, respectively (-7 days, ie, 161 or 
329 days, respectively), following the start of study treatment.DCR will be determined 
programmatically based on RECIST 1.1 using Investigator assessments and all data up until 
the first progression event. This will use all data up until the first progression event. 
Progression-free survival (PFS)
PFS (per RECIST 1.1 using Investigator assessments) will be defined as the time from the 
date of first dose until the date of objective disease progression or death (by any cause in the 
absence of progression) regardless of whether the patient withdraws from allocated therapy or 
receives another anticancer therapy prior to progression. Patients who have not progressed or 
died at the time of analysis will be censored at the time of the latest date of assessment from 
their last evaluable RECIST 1.1 assessment. However, if the patient progresses or dies after 
2 or more missed visits, the patient will be censored at the time of the latest evaluable 
RECIST 1.1 assessment. If the patient has no evaluable visits or does not have baseline data, 
they will be censored at Day 1 unless they die within 2 visits of baseline.
The PFS time will always be derived based on scan/assessment dates not visit dates.
RECIST 1.1 assessments/scans contributing towards a particular visit may be performed on 
different dates.  The following rules will be applied:

For investigational assessments, the date of progression will be determined based on 
the earliest of the RECIST assessment/scan dates of the component that indicates 
progression.

When censoring a patient for PFS, the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment.
Note: For target lesions, only the latest scan date is recorded out of all scans performed at that 
assessment for the target lesions, and similarly for non-target lesions, only the latest scan date 
is recorded out of all scans performed at that assessment for the non-target lesions.
PFS based on RECIST 1.1 modified for confirmation of progression will be performed for 
exploratory purposes using the algorithm described above for the RECIST 1.1 Investigator 
assessments, but following a modification whereby any objective disease progression must be 


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confirmed by the next scheduled scan.  The confirmatory scan is preferably at the next 
regularly scheduled imaging visit and must be no sooner than 4 weeks after the initial 
suspected progression.  If disease progression is confirmed (or disease progression occurs and 
no further scans are recorded) then the date of progression will be when it was originally 
observed.  Patients with a single disease progression and no further tumor assessment scans 
will be treated as PD in the analysis.  In the absence of significant clinical deterioration, the 
investigational site is advised to continue the patient on study therapy until progression has 
been confirmed.  If progression is not confirmed, the patient should continue study therapy 
and on-treatment assessments.
Proportion of patients alive and progression-free after 3 months
The PFS rate at 3 months (PFS3) will be calculated using Kaplan-Meier estimates.  Tumor 
progression will be determined based on Investigator assessment and RECIST 1.1.
Proportion of patients alive and progression-free after 6 months
The PFS rate at 6 months (PFS6) will be calculated using Kaplan-Meier estimates.  Tumor 
progression will be determined based on Investigator assessment and RECIST 1.1.
Overall survival
OS is defined as the time from the date of initial treatment until death due to any cause.  Any 
patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive.
Note: Survival calls will be made in the week following the date of data cut-off for the 
analysis, and if patients are confirmed to be alive or if the death date is post the data cut-off 
date, these patients will be censored at the date of data cut-off. Death dates may be found by 
checking publicly available death registries.
Proportion of patients alive at 6 months
The OS6 will be defined as the Kaplan-Meier estimate of OS at 6 months.
Proportion of patients alive at 12 months
The OS12 will be defined as the Kaplan-Meier estimate of OS at 12 months.
Best objective response
BoR is calculated based on the overall visit responses from each RECIST assessment, 
described in Appendix D.  It is the best response a patient has had during their time in the 
study up until RECIST progression (or confirmed progression where applicable) or the last 
evaluable assessment in the absence of RECIST progression.
Categorization of BoR will be based on RECIST (Appendix D) using the following response 
categories: CR, PR, SD, PD, and NE.


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BoR will be determined programmatically based on RECIST using all Investigator assessment 
data up until the first progression event.  Furthermore, it will be determined programmatically 
based on RECIST modified for confirmation of progression.  This will use all data up until the 
progression event that is used for the analysis (ie, unconfirmed progressions are not 
considered progression events, which means that the BoR may be after an unconfirmed 
progression for some patients).
For patients whose progression event is death, BoR will be calculated based upon all 
evaluable RECIST assessments prior to death.
For patients who die with no evaluable RECIST assessments, if the death occurs within 17 
weeks (ie, 16 weeks ±7 days) weeks for Cohort 1 and 13 weeks (ie, 12 weeks ±7 days) for 
Cohort 2 after enrollment, then BoR will be assigned to the PD category. For patients who die 
with no evaluable RECIST assessments, if the death occurs >17 weeks (ie, 16 weeks ±7 days) 
for Cohort 1 and >13 weeks (ie, 12 weeks ±7 days) for Cohort 2 after the date of enrollment, 
then BoR will be assigned to the NE category.
Progression events that have been censored due to them being >17 weeks for Cohort 1 and 
>13 weeks for Cohort 2 after the last evaluable assessment will not contribute to the BoR 
derivation.
8.4.3
Calculation or derivation of pharmacokinetic variables
8.4.3.1
Population pharmacokinetics and exposure-response/safety analysis
A population PK model analysis might be performed using a nonlinear mixed-effects 
modelling approach if data allowed. The impact of physiologically-relevant patient 
characteristics (covariates) and disease on PK will be evaluated. The relationship between the 
PK exposure and the effect on safety and efficacy endpoints will be evaluated. The results of 
such an analysis will be reported in a separate report. The PK, pharmacodynamics, 
demographic, safety, and efficacy data collected in this study may also be combined with 
similar data from other studies and explored using population PK and/or PK-
pharmacodynamic methods.
8.4.3.2
Pharmacokinetic  analysis
The actual sampling times will be used in the PK calculations. PK concentration data and 
summary statistics will be tabulated. Individual and mean blood concentration-time profiles 
will be generated.  The following PK parameters will be determined after the first and steady-
state doses: peak and trough concentration (as data allow). Samples below the lower limit of 
quantification will be treated as missing in the analyses.
8.4.3.3
Immunogenicity analysis
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patient who develop detectable ADAs against MEDI4736 when they are treated 
with MEDI4736 in combination with nab-paclitaxel + gemcitabine or MEDI4736 in 
combination with AZD5069.  The immunogenicity titer and presence of neutralizing ADAs 


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will be reported for samples confirmed positive for the presence of ADAs. The effect of 
immunogenicity on PK, pharmacodynamics, efficacy, and safety will be evaluated, if the data 
allow.
8.4.4
Calculation or derivation of biomarker variables
Biomarker status, as defined in the exploratory objectives, will be assessed for evaluable 
patients in each cohort according to prespecified criteria that will be detailed in the SAP.
8.5
Methods for statistical analyses
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
cohort.  Continuous variables will be summarized by the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Categorical variables will be 
summarized by frequency counts and percentages for each category.  Unless otherwise stated, 
percentages will be calculated out of the population total for the corresponding cohort. 
Since Cohort 1 enrollment was stopped with only 3 patients, data from this cohort will be 
listed only.
8.5.1
Efficacy data
Objective response rate
Objective Response rate (ORR) (per RECIST 1.1) is defined as the number (%) of patients 
with a confirmed overall response of CR or PR and will be based on the Efficacy Analysis 
Set. A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 visit 
and confirmed by repeat imaging, preferably at the next regularly scheduled imaging visit and 
not less than 4 weeks after the visit when the response was first observed with no evidence of 
progression between the initial and CR/PR confirmation visit. Therefore, data obtained up 
until progression, or the last evaluable assessment in the absence of progression, will be 
included in the assessment of ORR. Any patient who discontinues treatment without 
progression, receives a subsequent therapy, and then responds will not be included as 
responders in the ORR.
The Objective Response rate (ORR) will be estimated with 95% exact CIs. The 
programmatically derived ORR will be based on Investigator assessments, and using all scans 
regardless of whether they were scheduled or not. 
The analysis population for ORR will be the efficacy Analysis Set.
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR) .
8.5.1.1
Duration of response
Descriptive data (relevant to Cohorts 1 and 2) will be provided for the DoR in responding 
patients, including the associated Kaplan-Meier curves (without any formal comparison of 
cohorts or p-value attached).


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8.5.1.2
Disease control rate
The DCR will be summarized (ie, number of patients).
8.5.1.3
Progression-free survival
Kaplan-Meier plots of PFS will be presented for each cohort  Summaries of the number and 
percentage of patients experiencing a PFS event and the type of event (RECIST 1.1 or death) 
will be provided along with median PFS for each cohort (if calculable).
8.5.1.4
Proportion of patients with progression-free survival after 3 months and 
6 months
The PFS3 and PFS6 will be calculated using Kaplan-Meier estimates, as the cumulative 
probability of progression-free survival to each of those time periods for each cohort. 
Estimates of PFS3 and PFS6 will each be presented with 95% CIs. Median progression-free 
survival and plots of PFS rates over time will also be presented, based on the Kaplan-Meier 
estimates.
8.5.1.5
Overall survival
Kaplan-Meier plots of OS will be presented for each cohort.  Summaries of the number and 
percentage of patients who have died, are still in survival follow-up, are lost to follow-up, and 
have withdrawn consent will be provided along with median OS for each cohort (if 
calculable).
8.5.1.6
Proportion of patients alive at 6 and 12 months
The OS6, and OS12, will be calculated using Kaplan-Meier estimates of the cumulative 
probability of survival at each of those time periods for each cohort.  The survival estimates of 
OS6 and OS12 will be presented with 95% CIs.  Median survival and survival plots over time 
will also be produced and presented, based on Kaplan-Meier estimates.
8.5.2
Safety data
Safety and tolerability data will be presented by cohort using the safety population.
Data from all cycles of treatment will be combined in the presentation of safety data.  AEs 
(both in terms of MedDRA preferred terms and CTCAE grade) will be listed individually by 
patient.  The number of patients experiencing each AE will be summarized by cohort and 
CTCAE grade.  Additionally, data presentations of the rate of AEs per person-years at risk 
may be produced.
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, vital signs, and ECGs.  Exposure to MEDI4736, nab-paclitaxel + gemcitabine, 
and AZD5069 will be summarized.  Time on study and MEDI4736, nab-paclitaxel + 
gemcitabine, and AZD5069 combination therapy dose delays/interruptions will also be 
summarized.  At the end of the study, appropriate summaries of all safety data will be 
produced, as defined in the SAP.


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8.5.3
Pharmacokinetic data
PK concentration data will be listed for each patient and each dosing day, and a summary 
provided for all evaluable patients.
8.5.3.1
Immunogenicity analysis
Immunogenicity results will be listed by patient and a summary will be provided of the 
number and percentage of patients who develop detectable anti-MEDI4736, 
anti-nab-paclitaxel, anti-gemcitabine, or anti-AZD5069 antibodies.  The immunogenicity titer 
and neutralizing ADA data will be listed for samples confirmed positive for the presence of 
anti-MEDI4736, anti-nab-paclitaxel, anti-gemcitabine, or anti-AZD5069 antibodies.
The effect of immunogenicity on PK, pharmacodynamics, efficacy, and safety will be 
evaluated if data allow.
If the data are suitable, the relationship between PK exposure and efficacy/safety parameters 
may be investigated graphically or using an appropriate data modelling approach.
8.5.4
Biomarker data
The relationship of PD-L1 expression and if applicable, of exploratory biomarkers to ORR, 
DoR, DCR, OS, PFS, PFS3, and PFS6 will be presented for a subset of patients in the efficacy 
analysis set who are evaluable for each biomarker.
This will be assessed using similar summary and graphical representations to those that are 
outlined for the efficacy outputs in Sections 8.5.1
PD-L1 expression determined by IHC assay will be reported in the CSR.  Summaries and 
analyses for exploratory biomarkers will be documented in a separate analysis plan and will 
be reported outside the CSR in a separate report.
8.5.5
Interim analysis
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine chemotherapy
Not applicable.
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069
Not applicable.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first patient is enrolled in the study, an AstraZeneca representative will review and 
discuss the requirements of the clinical study protocol (CSP) and related documents with the 


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investigational staff and train them in any study-specific procedures, including use of 
IVRS/IWRS and WBDC.
The PI will ensure that appropriate training relevant to the study is given to all of these staff 
and that any new information relevant to the performance of this study is forwarded to the 
staff involved.
The PI will maintain a record of all individuals involved in the study (medical, nursing, and 
other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, biological samples are handled in 
accordance with the Laboratory Manual, and that study drug accountability checks 
are being performed

Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study), including verification of informed consent of participating patients.  This 
will require direct access to all original records for each patient (eg, clinic charts)

Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed of or 
destroyed accordingly, and the action is documented and reported to the patient.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the center need information and advice about the study conduct.
9.2.1
Source data
Refer to the CSA for location of source data.
Source data are any data generated as a result of the patient’s inclusion in the study (including 
run-in and/or follow-up related to the study) and include all related medical examinations and 
other records.
9.2.2
Study agreements
The PI at each center should comply with all the terms, conditions, and obligations of the CSA 
for this study.  In the event of any inconsistency between this CSP and the CSA, the terms of 


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CSP shall prevail with respect to the conduct of the study and the treatment of patients.  In all 
other respects not relating to study conduct or treatment of patients, the terms of the CSA shall 
prevail.
Agreements between AstraZeneca and the PI should be in place before any study-related 
procedures can take place or before any patients are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.3
Study timetable and end of study
The end of the study is defined as “the last visit of the last patient undergoing the study.”  The 
Investigator will be notified by the Sponsor when recruitment is complete.
The study is expected to start in Q1 2016 and to end by Q4 2018.
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP) or if recruitment is slow.  AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study involving MEDI4736.
9.4
Data management by AstraZeneca or delegate
Data management will be performed by a chosen vendor according to the Data Management 
Plan.  AEs and medical/surgical history will be classified according to the terminology of the 
latest version of MedDRA.  Medications will be classified according to the AstraZeneca Drug 
Dictionary.  Classification coding will be performed by the chosen vendor.
The data collected through third party sources will be obtained and reconciled against study 
data.
Data queries will be raised for inconsistent, impossible, or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, signed, and locked, clean file will be declared.  Any 
treatment-revealing data may thereafter be added, and the final database will be locked.
Serious adverse event reconciliation


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SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data associated with human biological samples
Data associated with human biological samples will be transferred from laboratories internal 
or external to AstraZeneca.
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
Patient data protection
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation.  In some cases, such wording will be in a separate accompanying document.
10.3
Ethics and regulatory review
An EC/IRB should approve the final study protocol, including the final version of the ICF and 
any other written information and/or materials to be provided to the patients.  The Investigator 
will ensure the distribution of these documents to the applicable EC/IRB and to the study site 
staff.
The opinion of the EC/IRB should be given in writing.  The Investigator should submit the 
written approval to AstraZeneca before enrollment of any patient into the study.
The EC/IRB should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the EC/IRB annually.
Before enrollment of any patient into the study, the final study protocol, including the final 
version of the ICF, should be approved by the national regulatory authority or a notification to 
the national regulatory authority should be approved, 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, EC/IRBs, and PIs with safety 
updates/reports according to local requirements.
Each PI is responsible for providing the EC/IRB with reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the IP.  AstraZeneca will provide 
this information to the PI so that he or she can meet these reporting requirements.
10.4
Informed consent
The PI(s) at each center will:

Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk, and benefit of the study

Ensure each patient is notified that her or she is free to discontinue from the study at 
any time

Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided

Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study

Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File

Ensure a copy of the signed ICF is given to the patient

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the ICF that is approved by an EC/IRB.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the PI and 
AstraZeneca.  If it is necessary for the study protocol to be amended, the amendment should 
be submitted to the Head of the Study Site and be approved by its IRB.  If applicable, 
AstraZeneca should submit a notification to the regulatory authority before it is implemented.  
If a protocol amendment requires a change to a particular center’s ICF, then AstraZeneca and 
the center’s IRB should be notified.  Approval of the revised ICF by AstraZeneca and by the 
IRB is required before the revised form is used.  If an administrative change is required, such 
a change should be notified to or approved by each IRB according to local requirements.
10.6
Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an EC/IRB may perform 
audits or inspections at the center, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 


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documents, to determine whether these activities were conducted, and to determine if data 
were recorded, analyzed, and accurately reported according to the protocol, GCP, ICH 
guidelines, and any applicable regulatory requirements.  The Investigator will contact 
AstraZeneca immediately if contacted by a regulatory agency about an inspection at the 
center.


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11.
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Di Mitri D, Toso A, Chen JJ, Sarti M, Pinton S, Jost TR, et al. Tumour-infiltrating Gr-1+ 
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Drake CG. Combination immunotherapy approaches. Ann Oncol 2012;23(Suppl 8):viii41-6.
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
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Emens and Jaffee 2005
Emens LA, Jaffee EM. Leveraging the activity of tumor vaccines with cytotoxic 
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Fairman et al 2014
Fairman D, Narwal R, Liang M, Robbins PB, Schneider A, Chavez C, et al. Pharmacokinetics 
of MEDI4736, a fully human anti-PDL1 monoclonal antibody, in patients with advanced solid 
tumours. J Clin Oncol, 2014 ASCO Annual Meeting Abstracts; 32(5s):(Suppl; abstr 2602).
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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 patient 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 patient’s 
death.  “Life-threatening” does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the patient or may require 
medical intervention to prevent 1 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.
Examples of such events are:

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse


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A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
The following factors should be considered 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 patient actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? OR could the AE be anticipated from its pharmacological 
properties?

Dechallenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another etiology 
such as the underlying disease, other drugs, or other host or environmental factors.

Rechallenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped?  AstraZeneca would not normally recommend or support 
a rechallenge.

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship?
A “reasonable possibility” could be considered to exist for an AE where 1 or more 
of these factors exist.
In contrast, there would not be a “reasonable possibility” of causality if none of the 
above criteria apply or where there is evidence of exposure and a reasonable 
time course but any dechallenge (if performed) is negative or ambiguous or 
there is another more likely cause of the AE.
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?
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility.


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MEDI4736 DRUG-DRUG INTERACTIONS
There is no information to date on drug-drug interactions with MEDI4736 either pre-clinically 
or in patients.  As MEDI4736 is a monoclonal antibody and therefore a protein, it will be 
degraded to small peptides and amino acids and will be eliminated by renal and 
reticuloendothelial clearance.  It is therefore not expected that MEDI4736 will induce or 
inhibit the major drug metabolising cytochrome P450 pathways.  As a result, there are no 
expected pharmacokinetic drug-drug interactions.  The mechanism of action of MEDI4736 
involves binding to PD-L1, and therefore significant pharmacodynamic drug interactions with 
the commonly administered concomitant medications are not expected.  Despite this, 
appropriate clinical monitoring in all of the planned clinical studies will be conducted to 
evaluate any potential drug-drug interactions.


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Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labeling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories.  For transport purposes the classification of infectious substances according to 
risk groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B, or 
Exempt.  There is no direct relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability or life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens, eg, Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are, eg, Hepatitis A, B, C, D, and E viruses, 
human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable

Samples routinely transported by road or rail are subject to local regulations that 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used.


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Appendix C
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.  Specific guidance on the managing liver abnormalities can 
be found in Section 5.2.1 of the protocol and in the Dosing Modification and Toxicity 
Management Guidelines.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 × upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in alkaline phosphatase 
(ALP).
Hy’s Law (HL)
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.
For PHL and HL to be met the elevation in transaminases must precede or be coincident with 
(ie, on the same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
Identification of potential hy’s law cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:


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
ALT ≥3 × ULN

AST ≥3 × ULN

TBL ≥2 × ULN
If a central laboratory is used
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative).
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:

Request a repeat of the test (new blood draw) by the central laboratory

Complete the appropriate unscheduled laboratory 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 Appendix C for definition) 
by reviewing laboratory reports from all previous visits (including both central and 
local laboratory results)
If a local laboratory is 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 (Appendix C for definition) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF
Follow-up
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 


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


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


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The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:

Was the alternative cause for the previous occurrence of PHL criteria being met 
found to be the disease under study, eg, chronic or progressing malignant disease, 
severe infection or liver disease, or did the patient meet PHL criteria prior to 
starting study treatment and at their first on study treatment visit as described in 
Appendix C
If No: follow the process described in Appendix C
If Yes:
Determine if there has been a significant change in the patient’s condition# compared with 
when PHL criteria were previously met

If there is no significant change, no action is required

If there is a significant change, follow the process described in Appendix C
# A “significant” change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or total bilirubin) in isolation or 
in combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
References
FDA Guidance for Industry (issued July 2009) “Drug-induced liver injury: Premarketing 
clinical evaluation”: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf.


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Appendix D
Guidelines for Evaluation of Objective Tumor Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumors)
Introduction
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 guidelines (Eisenhauer et al 2009) for the D4198C00003 study with regards to 
Investigator assessment of tumor burden including protocol-specific requirements for this 
study.
Definition of measurable, non-measurable, target and non-target lesions
Only patients with measurable disease at baseline should be included in the study.  
Measurable disease is defined by the presence of at least one measurable (by RECIST 1.1) 
lesion which has not been previously irradiated.  A tumor lesion in a previously irradiated 
field can be assessed as measurable disease provided the lesion has been deemed to 
demonstrate progression.
Measurable:
A lesion, not previously irradiated per the protocol prior to enrollment, that can be accurately 
measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must 
have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging 
(MRI) and which is suitable for accurate repeated measurements.  A tumor lesion in a 
previously irradiated field can be assessed as measurable disease provided the lesion has been 
deemed to demonstrate progression.
Non-measurable:

All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis at baseline1).

Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by CT or 
MRI.

Previously irradiated lesions that have not demonstrated progression2

Brain metastasis
                                               
1 Nodes with <10 mm short axis are considered non-pathological and should not be recorded or followed as 
non-target lesions (NTLs).
2 Localized post-radiation changes which affect lesion sizes may occur.  Therefore, lesions that have been 
previously irradiated and have not demonstrated progression will not be considered measurable and must be 
selected as NTL at baseline and followed up as part of the NTL assessment.


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Special cases:

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.  Blastic lesions are considered non-measurable.

Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present 
in the same patient, these should be selected as target lesions (TLs).
Target lesions:
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline.
Non-target lesions:
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.
Methods of assessment
The same method of assessment and the same technique should be used to characterize 
each identified and recorded lesion at baseline and during follow-up visits.
A summary of the methods to be used for RECIST assessment is provided in Table 16, and 
those excluded from tumor assessments for this study are highlighted with the rationale 
provided.
Table 16
Summary of methods of assessment
Target lesions 
Non-target lesions
New lesions
CT (preferred)
MRI
CT (preferred)
MRI
Clinical examination 
X-ray, Chest X-ray
CT (preferred)
MRI
Clinical examination 
X-ray, Chest X-ray
Ultrasound
Bone scan
FDG-PET
CT  Computed tomography; FDG-PET  18-Fluoro-deoxyglucose positron emission tomography; MRI  Magnetic 
resonance imaging.
CT and MRI
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TL selected for response assessment and to assess NTL and identification 
of any new lesions.
In the D4198C00003 study, the methods of assessment of tumor burden used at baseline and 
follow-up visits are CT / MRI of the chest and abdomen, pelvis only when suspected or 


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documented disease involvement.  Any other areas of disease involvement should be 
additionally imaged based on the signs and symptoms of individual patients.  CT examination 
with intravenous contrast media administration is the preferred method.  MRI should be used 
where CT is not feasible or it is medically contra-indicated.  For brain lesion assessment, MRI 
is the preferred method.
Clinical examination
In the D4198C00003 study, clinical examination will not be used for assessment of TL.  
Clinically detected lesions can be selected as TLs if they are assessed by CT or MRI scans.  
Clinical examination can be used to assess NTL and to identify the presence of new lesions.
X-ray
Plain X-ray
In the D4198C00003 study plain X-ray may be used as a method of assessment for bone NTL 
and to identify the presence of new bone lesions.
Ultrasound
In the D4198C00003 study, ultrasound examination will not be used for assessment of TL and 
NTL as it is not a reproducible method, does not provide an accurate assessment of tumor size 
and it is subjective and operator dependent.  Ultrasound examination can, however, be used to 
identify the presence of new lesions.  If new clinical symptoms occur and an ultrasound is 
performed then new lesions should be confirmed by CT or MRI examination.
Endoscopy and laparoscopy
In the D4198C00003 study, endoscopy and laparoscopy will not be used for tumor 
assessments as they are not validated in the context of tumor assessment.
Tumor markers
In the D4198C00003 study, tumor markers will not be used for tumor response assessments as 
per RECIST 1.1.
Cytology and histology
In the D4198C00003 study histology will not be used as part of the tumor response 
assessment as per RECIST 1.1.
Isotopic bone scan
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment.
In the D4198C00003 study, isotopic bone scans may be used as a method of assessment to 
identify the presence of new bone lesions at follow-up visits.  New lesions will be recorded 
where a positive hot-spot that was not present on the baseline bone scan assessment is 
identified on a bone scan performed at any time during the study.  The Investigator should 
consider the positive hot-spot to be a significant new site of malignant disease and represent 


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true disease progression in order to record the new lesion.  Confirmation by CT, MRI and 
X-ray is recommended where bone scan findings are equivocal.
FDG-PET scan
In the D4198C00003 study, 18-Fluoro-deoxyglucose positron emission tomography 
(FDG-PET) scans may be used as a method for identifying new lesions, according with the 
following algorithm:  New lesions will be recorded where there is positive 
18-Fluoro-deoxyglucose uptake3 not present on baseline FDG-PET scan or in a location 
corresponding to a new lesion on CT/MRI at the same follow-up visit.  If there is no baseline 
FDG-PET scan available, and no evidence of new lesions on CT/MRI scans then follow-up 
CT/MRI assessments should be continued, scheduled as per protocol or clinical indicated, in 
order to confirm new lesions.
Tumor response evaluation
Schedule of evaluation
RECIST assessments will be performed using CT/MRI assessments of the chest and abdomen, 
and the pelvis only when suspected or when there is documented disease involvement.  
Additional anatomy should be imaged based on signs and symptoms of individual patients at 
baseline and follow-up.  Baseline assessments should be performed no more than 28 days 
before the start of study treatment, and ideally should be performed as close as possible to the 
start of study treatment (see Table 2 and Table 3 of the Clinical Study Protocol).  Follow-up 
assessments will be performed every 8 weeks (±7 days; Cohort 1) or every 6 weeks (±7 days; 
Cohort 2) for the first 48 weeks relative to the date of the first infusion, and every 12 weeks 
±7 days thereafter until confirmed objective disease progression.  In Cohort 1, if Day 15 
treatment administration is delayed due to patient toxicity (see Clinical Study Protocol 
Section 7.2.1.1), tumor assessments will not be altered (ie, assessments will continue to be 
every 8 weeks ±7 days relative to the date of first infusion per Table 2 of the Clinical Study 
Protocol).
Additional assessments will be performed post confirmed objective disease progression for 
patients remaining on assigned treatment, re-treatment, or until subsequent cancer therapy 
according to the clinical study protocol.
Any other sites at which new disease is suspected should also be adequately imaged at 
follow-up.
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits.  This 
schedule is to be followed in order to minimize any unintentional bias caused by some patients 
being assessed at a different frequency than other patients.
Target lesions
Documentation of target lesions
                                               
3 A positive FDG-PET scan lesion should be reported only when an uptake greater than twice that of the 
surrounding tissue is observed.


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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 two or more parts, then record the sum of the diameters of those 
parts. 

If two or more TLs merge then the sum of the diameters of the combined lesion 
should be recorded for one of the lesions and 0 mm recorded for the other lesion(s).  

If a TL is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned.  If an accurate measure can be given, this 
should be recorded, even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate 
of the size of the lesion. 

When a TL has had any intervention eg, radiotherapy, embolization, surgery, during 
the study, the size of the TL should still be provided where possible.
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL (see Table 17).


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Table 17
Evaluation of target lesions
Complete Response (CR)
Disappearance of all TLs since baseline.  Any pathological lymph 
nodes selected as TLs must have a reduction in short axis to 
<10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking 
as reference the baseline sum of diameters
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD
Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.
Not Evaluable (NE)
Only relevant if any of the TLs were not assessed or not evaluable 
or had a lesion intervention at this visit.  Note: if the sum of 
diameters meets the progressive disease criteria, progressive 
disease overrides not evaluable as a TL response
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; SD  Stable disease; 
TL  Target lesion.
Non-target lesions
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.  At each visit an overall assessment of the NTL response should be 
recorded by the Investigator.  This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit (Table
18).


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Table 18
Evaluation of  non-target lesions
Complete response (CR)
Disappearance of all NTLs since baseline.  All lymph nodes must 
be non-pathological in size (<10 mm short axis).
Non CR/Non PD
Persistence of one or more NTL.
Progression (PD)
Unequivocal progression of existing NTLs.  Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions.  In all cases the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy.
Not evaluable (NE)
Only relevant when one or some of the NTLs were not assessed 
and, in the Investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit.
Note: for patients without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression 
criteria have not been met.
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; NTL  Non-target 
lesion; TL  Target lesion.
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of stable disease or 
partial response in TLs, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest “increase” in the size of 1 or more NTLs is usually not 
sufficient to qualify for unequivocal progression status.
New lesions
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression.
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than 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.
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.
Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 19
Table 19
Overall Visit Response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
CR
Non CR/Non PD 
No
PR
CR
NE
No 
PR
PR
Non PD or NE
No
PR
SD 
Non PD or NE
No
SD
NE
Non PD or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR  Complete response, PR  Partial response, SD  Stable disease, PD  Progression of disease, NE  Not evaluable, 
NA  Not applicable (only relevant if there were no non-target lesions at baseline).
Confirmation of Progression
In the D4198C00003 study, imaging for confirmation of response (complete response or 
partial response) should be performed at next scheduled visit (and no less than 4 weeks) 
following the date the criteria for response were first met.
Disease progression requires confirmation.  The confirmatory scan should occur preferably at 
the next scheduled visit and no earlier than 4 weeks after the initial assessment of progression 
of disease (PD) in the absence of clinical deterioration.
Progression would be considered confirmed if the following criteria are met:

≥20% increase in the sum diameters of TLs compared with the nadir at 
2 consecutive visits with an absolute increase of 5mm (1)

And/or significant progression (worsening) of NTLs or new lesions at the 
confirmatory PD time-point compared with the first time point where progression of 
NTLs or new lesions identified


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
And/or additional new unequivocal lesions at the confirmatory PD time-point 
compared with the first time point new lesions identified.
(1) The assessment of progression requires a ≥20% increase in the sum diameters of target 
lesions at the first progression timepoint relative to the nadir.  The nadir is the smallest sum of 
diameters, and this may be at baseline or subsequent follow-up assessments.  The 
confirmatory scan confirms the persistence of the ≥20% increase relative to the nadir.  The 
minimum absolute increase in the sum of diameters of target lesions is at least 5 mm at both 
assessments.
In the absence of significant clinical deterioration the Investigator should continue assigned 
treatment until progression is confirmed.  If progression is not confirmed, then the patient 
should continue on assigned treatment and on treatment assessments.
If a patient discontinues treatment (and/or receives a subsequent cancer therapy) prior to 
progression, then the patient should still continue to be followed until confirmed objective 
disease progression.
Central Review
The Contract Research Organization appointed by AstraZeneca will provide specification for 
radiological imaging protocols in standard acquisition guidelines documentation.
References
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.


Clinical Study Protocol Appendix F
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Appendix E
MEDI4736 Dosing Modification and Toxicity Management Guidelines Immune-Mediated, 
Infusion Related, And Non Immune-Mediated Reactions
Table 20   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) 1 November 2017 Version
General Considerations
Dose Modifications
Toxicity Management
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03.
In addition to the criteria for permanent discontinuation of study drug/study 
regimen based on CTC grade/severity (table below), permanently discontinue 
study drug/study regimen for the following conditions:

Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per 
day (or equivalent) within 12 weeks after last dose of study drug/study 
regimen

Recurrence of a previously experienced Grade 3 treatment-related AE 
following resumption of dosing
Grade 1
No dose modification
Grade 2
Hold study drug/study regimen dose until Grade 2 resolution to 
Grade ≤1.
If toxicity worsens, then treat as Grade 3 or Grade 4.
Study drug/study regimen can be resumed once event stabilizes to 
Grade ≤1 after completion of steroid taper.
Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study 
drug/study regimen on the following conditions:
1.
The event stabilizes and is controlled.
2.
The patient is clinically stable as per Investigator or treating 
physician’s clinical judgement.
3.
Doses of prednisone are at ≤10 mg/day or equivalent.
Grade 3
Depending on the individual toxicity, study drug/study regimen 
may be permanently discontinued. Please refer to guidelines below.
Grade 4
Permanently discontinue study drug/study regimen.
It is recommended that management of immune-mediated adverse events (imAEs)
follows the guidelines presented in this table:
−
It is possible that events with an inflammatory or immune mediated 
mechanism could occur in nearly all organs, some of them not noted 
specifically in these guidelines.
−
Whether specific immune-mediated events (and/or laboratory indicators of 
such events) are noted in these guidelines or not, patients should be 
thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, and infections) to a possible immune-
mediated event. In the absence of a clear alternative etiology, all such events 
should be managed as if they were immune related. General 
recommendations follow.
−
Symptomatic and topical therapy should be considered for low-grade (Grade 
1 or 2, unless otherwise specified) events.
−
For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3) 
events, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent.
−
Some events with high likelihood for morbidity and/or mortality – e.g., myo-
carditis, or other similar events even if they are not currently noted in the 
guidelines – should progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is Grade 2, and if 
clinical suspicion is high and/or there has been clinical confirmation. 
Consider, as necessary, discussing with the study physician, and promptly 
pursue specialist consultation.
−
If symptoms recur or worsen during corticosteroid tapering (28 days of 
taper), increase the corticosteroid dose (prednisone dose [e.g., up to 2 to 
4 mg/kg/day PO or IV equivalent]) until stabilization or improvement of 
symptoms, then resume corticosteroid tapering at a slower rate (>28 days of 
taper).
−
More potent immunosuppressives such as TNF inhibitors (e.g., infliximab) 
(also refer to the individual sections of the imAEs for specific type of 


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Note: For Grade ≥3 asymptomatic amylase or lipase levels, hold study drug/study 
regimen, and if complete work up shows no evidence of pancreatitis, study 
drug/study regimen may be continued or resumed.
Note: Study drug/study regimen should be permanently discontinued in Grade 3 
events with high likelihood for morbidity and/or mortality – e.g., myocarditis, or 
other similar events even if they are not currently noted in the guidelines. 
Similarly, consider whether study drug/study regimen should be permanently 
discontinued in Grade 2 events with high likelihood for morbidity and/or mortality 
– e.g., myocarditis, or other similar events even if they are not currently noted in 
the guidelines – when they do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper
Note: There are some exceptions to permanent discontinuation of study drug for 
Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus). 
immunosuppressive) should be considered for events not responding to 
systemic steroids. Progression to use of more potent immunosuppressives 
should proceed more rapidly in events with high likelihood for morbidity 
and/or mortality – e.g., myocarditis, or other similar events even if they are 
not currently noted in the guidelines – when these events are not responding 
to systemic steroids.
−
With long-term steroid and other immunosuppressive use, consider need for 
Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis 
carinii pneumonia) prophylaxis, gastrointestinal protection, and glucose 
monitoring.
−
Discontinuation of study drug/study regimen is not mandated for Grade 
3/Grade 4 inflammatory reactions attributed to local tumor response 
(e.g., inflammatory reaction at sites of metastatic disease and lymph nodes). 
Continuation of study drug/study regimen in this situation should be based 
upon a benefit-risk analysis for that patient.
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; IV intravenous; NCI 
National Cancer Institute; PO By mouth.
Pediatric Considerations
Dose Modifications
Toxicity Management
The criteria for permanent discontinuation of study drug/study regimen based on 
CTC grade/severity is the same for pediatric patients as it is for adult patients, as 
well as to permanently discontinue study drug/study regimen if unable to reduce 
corticosteroid ≤a dose equivalent to that required for corticosteroid replacement 
therapy within 12 weeks after last dose of study drug/study regimen
−
All recommendations for specialist consultation should occur with a 
pediatric specialist in the specialty recommended.
−
The recommendations for dosing of steroids (i.e., mg/kg/day) and for IV IG 
and plasmapheresis that are provided for adult patients should also be used 
for pediatric patients.
−
The infliximab 5 mg/kg IV dose recommended for adults is the same as
recommended for pediatric patients ≥ 6 years old.  For dosing in children 
younger than 6 years old, consult with a pediatric specialist.
−
For pediatric dosing of mycophenolate mofetil, consult with a pediatric 
specialist.
−
With long-term steroid and other immunosuppressive use, consider need for 
PJP prophylaxis, gastrointestinal protection, and glucose monitoring.


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aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD.
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event (NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Pneumonitis/Interstitial 
Lung Disease (ILD)
Any Grade
General Guidance
For Any Grade:
−
Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients should be evaluated with imaging and pulmonary 
function tests, including other diagnostic procedures as 
described below.
−
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up, and high- resolution CT scan.
Grade 1
(asymptomatic, clinical 
or diagnostic 
observations only; 
intervention not 
indicated)
No dose modifications required. 
However, consider holding study 
drug/study regimen dose as clinically 
appropriate and during diagnostic work-
up for other etiologies.
For Grade 1 (radiographic changes only):
−
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, pulse oximetry (resting and exertion), and 
laboratory work-up and then as clinically indicated.
−
Consider Pulmonary and Infectious disease consult.
Grade 2
(symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL)
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1.

If toxicity worsens, then treat as 
Grade 3 or Grade 4.

If toxicity improves to Grade ≤1, 
then the decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper.
For Grade 2 (mild to moderate new symptoms):
−
Monitor symptoms daily and consider hospitalization.
−
Promptly start systemic steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV equivalent).
−
Reimage as clinically indicated.
−
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started
−
If still no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.
−
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 


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treatment of cancer-related infections [Category 2B 
recommendation])a
−
Consider pulmonary and infectious disease consult.
−
Consider, as necessary, discussing with study physician.
Grade 3 or 4
(Grade 3: severe 
symptoms; limiting 
self-care ADL; oxygen 
indicated)
(Grade 4: life-
threatening respiratory 
compromise; urgent 
intervention indicated 
[e.g., tracheostomy or 
intubation])
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4 (severe or new symptoms, new/worsening 
hypoxia, life-threatening):
−
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent.
−
Obtain Pulmonary and Infectious disease consult; consider, as 
necessary, discussing with study physician.
−
Hospitalize the patient.
−
Supportive care (e.g., oxygen).
−
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks’ dose) started. 
Caution: rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.
−
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and, in particular, anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections 
[Category 2B recommendation]).a
Diarrhea/Colitis
Any Grade
General Guidance
For Any Grade:
−
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes 
in bowel habits such as increased frequency over baseline or 
blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs, and ileus).
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections), including testing for clostridium 
difficile toxin, etc.
−
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order to 
prevent potential progression to higher grade event.
−
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis.


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Grade 1
(Diarrhea: stool 
frequency of <4 over 
baseline per day)
(Colitis: asymptomatic; 
clinical or diagnostic 
observations only)
No dose modifications.
For Grade 1:
−
Monitor closely for worsening symptoms.
−
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment.
Grade 2
(Diarrhea: stool 
frequency of 4 to 6 
over baseline per day) 
(Colitis: abdominal 
pain; mucus or blood in 
stool)
Hold study drug/study regimen until 
resolution to Grade ≤1

If toxicity worsens, then treat as 
Grade 3 or Grade 4.

If toxicity improves to Grade ≤1, 
then study drug/study regimen can 
be resumed after completion of 
steroid taper.
For Grade 2:
−
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide.
−
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.
−
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
GI consult should be obtained for consideration of further 
workup, such as imaging and/or colonoscopy, to confirm 
colitis and rule out perforation, and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started.
−
If still no improvement within 3 to 5 days despite 2 to 4 
mg/kg IV methylprednisolone, promptly start 
immunosuppressives such as infliximab at 5 mg/kg once 
every 2 weeksa. Caution: it is important to rule out bowel 
perforation and refer to infliximab label for general guidance 
before using infliximab.
−
Consider, as necessary, discussing with study physician if no 
resolution to Grade ≤1 in 3 to 4 days.
−
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Grade 3 or 4
(Grade 3 diarrhea: 
stool frequency of ≥7 
over baseline per day;
Grade 4 diarrhea: life 
threatening 
Grade 3
Permanently discontinue study 
drug/study regimen for Grade 3 if 
toxicity does not improve to Grade ≤1 
within 14 days; study drug/study regimen 
For Grade 3 or 4:
−
Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent.
−
Monitor stool frequency and volume and maintain hydration.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
158(176)
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation.
consequences)
(Grade 3 colitis: severe 
abdominal pain, 
change in bowel habits, 
medi-cal intervention 
indi-cated, peritoneal 
signs;
Grade 4 colitis: life-
threatening 
consequences, urgent 
intervention indicated)
can be resumed after completion of 
steroid taper.
Grade 4
Permanently discontinue 
study drug/study regimen. 
−
Urgent GI consult and imaging and/or colonoscopy as 
appropriate.
−
If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (e.g., infliximab at 5 mg/kg 
once every 2 weeks). Caution: Ensure GI consult to rule out 
bowel perforation and refer to infliximab label for general 
guidance before using infliximab.
−
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Hepatitis 
(elevated LFTs)
Infliximab should not be 
used for management of 
immune-related hepatitis.
Any Grade
General Guidance
For Any Grade:
−
Monitor and evaluate liver function test: AST, ALT, ALP, 
and TB.
−
Evaluate for alternative etiologies (e.g., viral hepatitis, 
disease progression, concomitant medications).
Grade 1
(AST or ALT >ULN 
and ≤3.0×ULN and/or 
TB > ULN and  
≤1.5×ULN)

No dose modifications.

If it worsens, then treat as Grade 2 
event.
For Grade 1:
−
Continue LFT monitoring per protocol.
Grade 2
(AST or 
ALT >3.0×ULN and 
≤5.0×ULN and/or 
TB >1.5×ULN and  
≤3.0×ULN)

Hold study drug/study regimen dose 
until Grade 2 resolution to Grade ≤1.

If toxicity worsens, then treat as 
Grade 3 or Grade 4.

If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
regimen after completion of steroid 
taper.
For Grade 2:
−
Regular and frequent checking of LFTs (e.g., every 1 to 2 
days) until elevations of these are improving or resolved.
−
If no resolution to Grade ≤1 in 1 to 2 days, consider, as 
necessary, discussing with study physician.
−
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent.
−
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional work up and start prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day.
−
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (i.e., mycophenolate mofetil).a Discuss 
PLEASE SEE 
shaded area 
immediately below
this section to find
guidance for
management of
“Hepatitis (elevated 
LFTS)” in HCC 
patients


Clinical Study Protocol Appendix F
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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
159(176)
with study physician if mycophenolate mofetil is not 
available. Infliximab should NOT be used.
−
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Grade 3 or 4
(Grade 3: AST or 
ALT >5.0×ULN and 
≤20.0×ULN and/or 
TB >3.0×ULN and  
≤10.0×ULN)
(Grade 4: AST or 
ALT >20×ULN and/or 
TB >10×ULN)
For Grade 3:
For elevations in transaminases 
≤8 × ULN, or elevations in bilirubin 
≤5 × ULN:

Hold study drug/study regimen dose 
until resolution to Grade ≤1 or 
baseline

Resume study drug/study regimen if 
elevations downgrade to Grade ≤1 or 
baseline within 14 days and after 
completion of steroid taper.

Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade ≤1 or 
baseline within 14 days
For elevations in transaminases 
>8 × ULN or elevations in bilirubin >5 × 
ULN, discontinue study drug/study 
regimen.
Permanently discontinue study 
drug/study regimen for any case meeting 
Hy’s law criteria (AST and/or ALT >3 × 
ULN + bilirubin >2 × ULN without 
initial findings of cholestasis (i.e., 
elevated alkaline P04) and in the absence 
of any alternative cause.b
For Grade 4:
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:
−
Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent.
−
If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy (i.e., 
mycophenolate mofetil). Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be 
used.
−
Perform hepatology consult, abdominal workup, and imaging 
as appropriate.
−
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
160(176)
Hepatitis 
(elevated LFTs)
Infliximab should not be 
used for management of 
immune-related hepatitis.
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any 
time) occurs in setting 
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation
Any Grade
General Guidance
For Any Grade:
−
Monitor and evaluate liver function test: AST, ALT, ALP, 
and TB.
−
Evaluate for alternative etiologies (e.g., viral hepatitis, 
disease progression, concomitant medications, worsening of 
liver cirrhosis [e.g., portal vein thrombosis]).
−
For HBV+ patients: evaluate quantitative HBV viral load, 
quantitative HBsAg, or HBeAg
−
For HCV+ patients: evaluate quantitative HCV viral load
−
Consider consulting hepatologist/Infectious disease specialist 
regarding change/implementation in/of antiviral medications 
for any patient with an elevated HBV viral load >2000 IU/ml
−
Consider consulting hepatologist/Infectious disease specialist 
regarding change/implementation in/of antiviral HCV 
medications if HCV viral load increased by ≥2-fold
−
For HCV+ with HBcAB+: Evaluate for both HBV and HCV 
as above
Grade 1
(Isolated AST or ALT 
>ULN and ≤5.0×ULN, 
whether normal or 
elevated at baseline) 

No dose modifications.

If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat as 
Grade 2 event.
For all grades, see instructions at bottom 
of shaded area if transaminase rise is not 
isolated but (at any time) occurs in 
setting of either increasing bilirubin or 
signs of DILI/liver decompensation
Grade 2
(Isolated AST or ALT 
>5.0×ULN and 
≤8.0×ULN, if normal 
at baseline)

Hold study drug/study regimen dose 
until Grade 2 resolution to Grade ≤1 
or baseline.
For Grade 2:
−
Regular and frequent checking of LFTs (e.g., every 1 to 3 
days) until elevations of these are improving or resolved.
−
Recommend consult hepatologist; consider abdominal 
ultrasound, including Doppler assessment of liver perfusion.
THIS shaded area 
is guidance only for
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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(Isolated AST or ALT 
>2.0×baseline and 
≤12.5×ULN, if 
elevated >ULN at 
baseline)

If toxicity worsens, then treat as 
Grade 3 or Grade 4.
If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
regimen after completion of steroid taper.
−
Consider, as necessary, discussing with study physician.
−
If event is persistent (>3 to 5 days) or worsens, and 
investigator suspects toxicity to be immune-mediated AE, 
recommend to start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.
−
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional workup and treatment with IV methylprednisolone 
2 to 4 mg/kg/day.
−
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, consider additional 
abdominal workup (including liver biopsy) and imaging (i.e., 
liver ultrasound), and consider starting immunosuppressives 
(i.e., mycophenolate mofetil).a Discuss with study physician 
if mycophenolate mofetil is not available. Infliximab should 
NOT be used.
Grade 3
(Isolated AST or ALT 
>8.0×ULN and 
≤20.0×ULN, if normal 
at baseline)
(Isolated AST or ALT 
>12.5×ULN and 
≤20.0×ULN, if  
elevated >ULN at 
baseline)

Hold study drug/study regimen dose 
until resolution to Grade ≤1 or 
baseline

Resume study drug/study regimen if 
elevations downgrade to Grade ≤1 or 
baseline within 14 days and after 
completion of steroid taper.

Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade ≤1 or 
baseline within 14 days
Permanently discontinue study 
drug/study regimen for any case meeting 
Hy’s law criteria, in the absence of any 
alternative cause.b
For Grade 3:
−
Regular and frequent checking of LFTs (e.g., every 1-2 days) 
until elevations of these are improving or resolved.
−
Consult hepatologist (unless investigator is hepatologist); 
obtain abdominal ultrasound, including Doppler assessment 
of liver perfusion; and consider liver biopsy.
−
Consider, as necessary, discussing with study physician.
−
If investigator suspects toxicity to be immune-mediated, 
promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent.
−
If no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, obtain 
liver biopsy (if it has not been done already) and promptly 
start treatment with immunosuppressive therapy 
(mycophenolate mofetil). Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be 
used.
−
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a


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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Grade 4
(Isolated AST or ALT 
>20×ULN,  whether 
normal or elevated at 
baseline)
Permanently discontinue study 
drug/study regimen.
For Grade 4:
Same as above 
(except would recommend obtaining liver biopsy early)
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 2×baseline, if 
>ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR):
-
Manage dosing for Grade 1 transaminase rise as instructed for Grade 2 transaminase rise
-
Manage dosing for Grade 2 transaminase rise as instructed for Grade 3 transaminase rise
-
Grade 3-4: Permanently discontinue study drug/study regimen
Nephritis or renal 
dysfunction
(elevated serum 
creatinine)
Any Grade
General Guidance
For Any Grade:
−
Consult with nephrologist.
−
Monitor for signs and symptoms that may be related to 
changes in renal function (e.g., routine urinalysis, elevated 
serum BUN and creatinine, decreased creatinine clearance, 
electrolyte imbalance, decrease in urine output, or 
proteinuria).
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression or infections).
−
Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2), in 
order to prevent potential progression to higher grade event.
Grade 1
(Serum creatinine > 1 
to 1.5 × baseline; > 
ULN to 1.5 × ULN)
No dose modifications.
For Grade 1:
−
Monitor serum creatinine weekly and any accompanying 
symptoms.

If creatinine returns to baseline, resume its regular 
monitoring per study protocol.

If creatinine worsens, depending on the severity, 
treat as Grade 2, 3, or 4.
−
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics.


Clinical Study Protocol Appendix F
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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Grade 2
(serum creatinine >1.5 
to 3.0 × baseline; >1.5 
to 3.0 × ULN)
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 

If toxicity worsens, then treat as 
Grade 3 or 4.

If toxicity improves to Grade ≤1 or 
baseline, then resume study 
drug/study regimen after completion 
of steroid taper.
For Grade 2:
−
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics.
−
Carefully monitor serum creatinine every 2 to 3 days and as 
clinically warranted.
−
Consult nephrologist and consider renal biopsy if clinically 
indicated.
−
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent.
−
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
additional workup should be considered and prompt treatment 
with IV methylprednisolone at 2 to 4 mg/kg/day started.
−
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
−
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol.
Grade 3 or 4
(Grade 3: serum 
creatinine 
>3.0 × baseline; >3.0 
to 6.0 × ULN;
Grade 4: serum 
creatinine >6.0 × ULN)
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:
−
Carefully monitor serum creatinine on daily basis.
−
Consult nephrologist and consider renal biopsy if clinically 
indicated.
−
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.
−
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
additional workup should be considered and prompt treatment 
with IV methylprednisolone 2 to 4 mg/kg/day started.
−
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Rash
(excluding bullous skin 
formations)
Any Grade
(refer to NCI CTCAE 
v 4.03 for definition of 
severity/grade 
depending on type of 
skin rash)
General Guidance
For Any Grade:
−
Monitor for signs and symptoms of dermatitis (rash and 
pruritus).
−
IF THERE IS ANY BULLOUS FORMATION, THE 
STUDY PHYSICIAN SHOULD BE CONTACTED AND
STUDY DRUG DISCONTINUED.
Grade 1
No dose modifications.
For Grade 1:
−
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream).
Grade 2
For persistent (>1 to 2 weeks) Grade 2 
events, hold scheduled study drug/study 
regimen until resolution to Grade ≤1 or 
baseline.

If toxicity worsens, then treat as 
Grade 3.

If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of 
steroid taper.
For Grade 2:
−
Obtain dermatology consult.
−
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream).
−
Consider moderate-strength topical steroid.
−
If no improvement of rash/skin lesions occurs within 3 to 
5 days or is worsening despite symptomatic treatment and/or 
use of moderate strength topical steroid, consider, as 
necessary, discussing with study physician and promptly start 
systemic steroids such as prednisone 1 to 2 mg/kg/day PO or 
IV equivalent.
−
Consider skin biopsy if the event is persistent for >1 to 
2 weeks or recurs.
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline.
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
Grade ≤1 or baseline within 30 days, 
then permanently discontinue study 
drug/study regimen.
For Grade 4:
For Grade 3 or 4:
−
Consult dermatology.
−
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent.
−
Consider hospitalization.
−
Monitor extent of rash [Rule of Nines].
−
Consider skin biopsy (preferably more than 1) as clinically 
feasible.
−
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PJP treatment (refer to current NCCN guidelines for 


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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Permanently discontinue study 
drug/study regimen.
treatment of cancer-related infections [Category 2B 
recommendation]).a
−
Consider, as necessary, discussing with study physician.
Endocrinopathy
(e.g., hyperthyroidism, 
hypothyroidism,  Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section)
Any Grade
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
v4.03 for defining the 
CTC grade/severity)
General Guidance
For Any Grade:
−
Consider consulting an endocrinologist for endocrine events.
−
Consider, as necessary, discussing with study physician.
−
Monitor patients for signs and symptoms of endocrinopathies. 
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, polydipsia, polyuria, hypotension, and 
weakness.
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including brain 
metastases, or infections).
−
Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, free T3 and free T4 and 
other relevant endocrine and related labs (e.g., blood glucose 
and ketone levels, HgA1c).
−
For modest asymptomatic elevations in serum amylase and 
lipase, corticosteroid treatment is not indicated as long as 
there are no other signs or symptoms of pancreatic 
inflammation.
−
If a patient experiences an AE that is thought to be possibly 
of autoimmune nature (e.g., thyroiditis, pancreatitis, 
hypophysitis, or diabetes insipidus), the investigator should 
send a blood sample for appropriate autoimmune antibody 
testing.
Grade 1
No dose modifications.
For Grade 1 (including those with asymptomatic TSH elevation):
−
Monitor patient with appropriate endocrine function tests.
−
For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment of 
early-morning ACTH, cortisol, TSH and free T4; also 
consider gonadotropins, sex hormones, and prolactin levels, 
as well as cosyntropin stimulation test (though it may not be 
useful in diagnosing early secondary adrenal insufficiency).
−
If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently out 
of range in 2 subsequent measurements, include free T4 at 


Clinical Study Protocol Appendix F
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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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subsequent cycles as clinically indicated and consider 
consultation of an endocrinologist.
Grade 2
For Grade 2 endocrinopathy other than 
hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until patient is clinically stable.

If toxicity worsens, then treat as 
Grade 3 or Grade 4.
Study drug/study regimen can be 
resumed once event stabilizes and after 
completion of steroid taper.
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions:
1.
The event stabilizes and is 
controlled.
2.
The patient is clinically stable as 
per investigator or treating 
physician’s clinical judgement.
3.
Doses of prednisone are 
≤10 mg/day or equivalent.
For Grade 2 (including those with symptomatic endocrinopathy):
−
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and 
as clinically indicated, consider pituitary scan.
−
For all patients with abnormal endocrine work up, except 
those with isolated hypothyroidism or Type 1 DM, and as 
guided by an  endocrinologist, consider short-term 
corticosteroids (e.g., 1 to 2 mg/kg/day methylprednisolone or 
IV equivalent) and prompt initiation of treatment with 
relevant hormone replacement (e.g., hydrocortisone, sex 
hormones).
−
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids.
−
Isolated Type 1 diabetes mellitus (DM) may be treated with 
appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids.
−
Once patients on steroids are improving, gradually taper  
immunosuppressive steroids (as appropriate and with 
guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment 
(refer to current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]).a
−
For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory 
assessments/MRI as clinically indicated.
Grade 3 or 4
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until endocrinopathy symptom(s) 
are controlled. 
Study drug/study regimen can be 
resumed once event stabilizes and after 
completion of steroid taper.
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
For Grade 3 or 4:
−
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and 
as clinically indicated, consider pituitary scan. Hospitalization 
recommended.
−
For all patients with abnormal endocrine work up, except 
those with isolated hypothyroidism or Type 1 DM, and as 
guided by an  endocrinologist, promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or equivalent, as well as 
relevant hormone replacement (e.g., hydrocortisone, sex 
hormones).


Clinical Study Protocol Appendix F
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Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
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can be retreated with study drug/study 
regimen on the following conditions:
1.
The event stabilizes and is 
controlled.
2.
The patient is clinically stable as 
per investigator or treating 
physician’s clinical judgement.
3.
Doses of prednisone are 
≤10 mg/day or equivalent.
−
For adrenal crisis, severe dehydration, hypotension, or shock, 
immediately initiate IV corticosteroids with mineralocorticoid 
activity.
−
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids.
−
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids.
−
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with 
guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment 
(refer to current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]).a
Neurotoxicity
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre)
Any Grade
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v4.03 
for defining the CTC 
grade/severity)
General Guidance
For Any Grade:
−
Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, metabolic 
syndromes, or medications).
−
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness).
−
Consider appropriate diagnostic testing (e.g., electromyogram 
and nerve conduction investigations).
−
Perform symptomatic treatment with neurological consult as 
appropriate.
−
Grade 1
No dose modifications.
For Grade 1:
−
See “Any Grade” recommendations above.
Grade 2
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to Grade 
≤1.
For sensory neuropathy/neuropathic pain, 
consider holding study drug/study 
regimen dose until resolution to Grade 
≤1.
For Grade 2:
−
Consider, as necessary, discussing with the study physician.
−
Obtain neurology consult.
−
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine).
−
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day 
PO or IV equivalent.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
168(176)
If toxicity worsens, then treat as 
Grade 3 or 4.
Study drug/study regimen can be 
resumed once event improves to Grade 
≤1 and after completion of steroid taper.
−
If no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day prednisone PO or IV equivalent, consider 
additional workup and promptly treat with additional 
immunosuppressive therapy (e.g., IV IG).
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 30 
days.
For Grade 4:
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:
−
Consider, as necessary, discussing with study physician.
−
Obtain neurology consult.
−
Consider hospitalization.
−
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent.
−
If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and promptly 
treat with additional immunosuppressants (e.g., IV IG).
−
Once stable, gradually taper steroids over ≥28 days.
Peripheral neuromotor 
syndromes
(such as Guillain-Barre 
and myasthenia gravis)
Any Grade
General Guidance
For Any Grade:
−
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients 
may unpredictably experience acute decompensations that 
can result in substantial morbidity or in the worst case, death. 
Special care should be taken for certain sentinel symptoms 
that may predict a more severe outcome, such as prominent 
dysphagia, rapidly progressive weakness, and signs of 
respiratory insufficiency or autonomic instability.
−
Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, metabolic 
syndromes or medications). It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in patients with 
underlying cancer, due to the multiple potential confounding 
effects of cancer (and its treatments) throughout the neuraxis. 
Given the importance of prompt and accurate diagnosis, it is 
essential to have a low threshold to obtain a neurological 
consult.
−
Neurophysiologic diagnostic testing (e.g., electromyogram 
and nerve conduction investigations, and “repetitive 
stimulation” if myasthenia is suspected) are routinely 


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
169(176)
indicated upon suspicion of such conditions and may be best 
facilitated by means of a neurology consultation.
−
It is important to consider that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. Patients requiring treatment should be 
started with IV IG and followed by plasmapheresis if not 
responsive to IV IG.
Grade 1
No dose modifications.
For Grade 1:
−
Consider, as necessary, discussing with the study physician.
−
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described above.
−
Obtain a neurology consult.
Grade 2
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if it does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency or 
autonomic instability.
For Grade 2:
−
Consider, as necessary, discussing with the study physician.
−
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described above.
−
Obtain a neurology consult
−
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine).
MYASTHENIA GRAVIS:
o
Steroids may be successfully used to treat 
myasthenia gravis. It is important to consider that 
steroid therapy (especially with high doses) may 
result in transient worsening of myasthenia and 
should typically be administered in a monitored 
setting under supervision of a consulting 
neurologist.
o
Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or IV
IG. Such decisions are best made in consultation 
with a neurologist, taking into account the unique 
needs of each patient.
o
If myasthenia gravis-like neurotoxicity is present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis.
GUILLAIN-BARRE:


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
170(176)
o
It is important to consider here that the use of 
steroids as the primary treatment of Guillain-Barre 
is not typically considered effective.
o
Patients requiring treatment should be started with 
IV IG and followed by plasmapheresis if not 
responsive to IV IG.
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 30 
days or if there are signs of respiratory 
insufficiency or autonomic instability.
For Grade 4:
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4 (severe or life-threatening events):
−
Consider, as necessary, discussing with study physician.
−
Recommend hospitalization.
−
Monitor symptoms and obtain neurological consult.
MYASTHENIA GRAVIS:
o
Steroids may be successfully used to treat 
myasthenia gravis. They should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist.
o
Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or IV 
IG.
o
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis.
GUILLAIN-BARRE:
o
It is important to consider here that the use of 
steroids as the primary treatment of Guillain-Barre 
is not typically considered effective.
o
Patients requiring treatment should be started with 
IV IG and followed by plasmapheresis if not 
responsive to IV IG.
Myocarditis
Any Grade
General Guidance
Discontinue drug permanently if biopsy-
proven immune-mediated myocarditis.
For Any Grade:
−
The prompt diagnosis of immune-mediated myocarditis is 
important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function. 
−
Consider, as necessary, discussing with the study physician.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
171(176)
−
Monitor patients for signs and symptoms of myocarditis (new 
onset or worsening chest pain, arrhythmia, shortness of 
breath, peripheral edema). As some symptoms can overlap 
with lung toxicities, simultaneously evaluate for and rule out 
pulmonary toxicity as well as other causes (e.g., pulmonary 
embolism, congestive heart failure, malignant pericardial 
effusion). A Cardiology consultation should be obtained 
early, with prompt assessment of whether and when to 
complete a cardiac biopsy, including any other diagnostic 
procedures.
−
Initial work-up should include clinical evaluation, BNP, 
cardiac enzymes, ECG, echocardiogram (ECHO), monitoring 
of oxygenation via pulse oximetry (resting and exertion), and 
additional laboratory work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO to assess wall motion 
abnormalities when needed.
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections)
Grade 1
(asymptomatic with 
laboratory (e.g., BNP) 
or cardiac imaging 
abnormalities)
No dose modifications required unless 
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen is 
held, resume after complete resolution to 
Grade 0.
For Grade 1 (no definitive findings):
-
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms,  BNP, cardiac enzymes, ECG, ECHO, pulse 
oximetry (resting and exertion), and laboratory work-up as 
clinically indicated.
-
Consider using steroids if clinical suspicion is high.
Grade 2, 3 or 4
(Grade 2: Symptoms 
with mild to moderate 
activity or exertion)
(Grade 3: Severe with 
symptoms at rest or 
with minimal activity 
or exertion; 
intervention indicated)
- If Grade 2 -- Hold study drug/study 
regimen dose until resolution to 
Grade 0. If toxicity rapidly improves 
to Grade 0, then the decision to 
reinitiate study drug/study regimen 
will be based upon treating 
physician’s clinical judgment and 
after completion of steroid taper. If 
toxicity does not rapidly improve, 
permanently. discontinue study 
drug/study regimen.
For Grade 2-4:
−
Monitor symptoms daily, hospitalize.
−
Promptly start IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent after Cardiology consultation has determined 
whether and when to complete diagnostic procedures 
including a cardiac biopsy.
−
Supportive care (e.g., oxygen).
−
If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
172(176)
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate 
aminotransferase; BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; 
(Grade 4: Life-
threatening 
consequences; urgent
intervention indicated 
(e.g., continuous IV 
therapy or mechanical 
hemodynamic 
support))
If Grade 3-4, permanently discontinue 
study drug/study regimen.
−
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Myositis/Polymyositis 
(“Poly/myositis”)
Any Grade
General Guidance
For Any Grade:
−
Monitor patients for signs and symptoms of poly/myositis. 
Typically, muscle weakness/pain occurs in proximal muscles 
including upper arms, thighs, shoulders, hips, neck and back, 
but rarely affects the extremities including hands and fingers; 
also difficulty breathing and/or trouble swallowing can occur 
and progress rapidly. Increased general feelings of tiredness 
and fatigue may occur, and there can be new-onset falling, 
difficulty getting up from a fall, and trouble climbing stairs, 
standing up from a seated position, and/or reaching up.
−
If poly/myositis is suspected, a Neurology consultation 
should be obtained early, with prompt guidance on diagnostic 
procedures. Myocarditis may co-occur with poly/myositis; 
refer to guidance under Myocarditis. Given breathing 
complications, refer to guidance under Pneumonitis/ILD. 
Given possibility of an existent (but previously unknown) 
autoimmune disorder, consider Rheumatology consultation.
−
Consider, as necessary, discussing with the study physician.
−
Initial work-up should include clinical evaluation, creatine 
kinase, aldolase, LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein level, urine 
myoglobin, and additional laboratory work-up as indicated, 
including a number of possible rheumatological/antibody 
tests (i.e., consider whether a rheumatologist consultation is 
indicated and could guide need for rheumatoid factor, 
antinuclear antibody, anti-smooth muscle, antisynthetase 
[such as anti-Jo-1], and/or signal-recognition particle 
antibodies). Confirmatory testing may include 
electromyography, nerve conduction studies, MRI of the 


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
173(176)
muscles, and/or a muscle biopsy. Consider Barium swallow 
for evaluation of dysphagia or dysphonia.
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections).
Grade 1
(mild pain)
- No dose modifications.
For Grade 1:
−
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated.
−
Consider Neurology consult.
−
Consider, as necessary, discussing with the study physician.
Grade 2
(moderate pain 
associated with 
weakness; pain limiting 
instrumental activities 
of daily living [ADLs])
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
- Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency.
For Grade 2:
−
Monitor symptoms daily and consider hospitalization.
−
Obtain Neurology consult, and initiate evaluation.
−
Consider, as necessary, discussing with the study physician.
−
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly 
start IV methylprednisolone 2 to 4 mg/kg/day systemic 
steroids along with receiving input from Neurology 
consultant 
−
If clinical course is not rapidly progressive, start systemic 
steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV 
equivalent); if no improvement within 3 to 5 days, continue 
additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day
−
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.
−
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Grade 3 or 4
(pain associated with 
severe weakness; 
For Grade 3:
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
For Grade 3 or 4 (severe or life-threatening events):
−
Monitor symptoms closely; recommend hospitalization.
−
Obtain Neurology consult, and complete full evaluation.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
174(176)
imAE immune-mediated adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic 
resonance imaging; NCI  National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as 
Pneumocystis carinii pneumonia); PO  By mouth; T3 Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating 
hormone; ULN Upper limit of normal.
limiting self-care 
ADLs)
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 30 
days or if there are signs of respiratory 
insufficiency.
For Grade 4:
- Permanently discontinue study 
drug/study regimen.
−
Consider, as necessary, discussing with the study physician.
−
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from Neurology 
consultant.
−
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.
−
Consider whether patient may require IV IG, plasmapheresis.
−
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
175(176)
Infusion-Related Reactions
Severity Grade of the 
Event (NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Any Grade
General Guidance
For Any Grade:
−
Manage per institutional standard at the discretion of investigator.
−
Monitor patients for signs and symptoms of infusion-related 
reactions (e.g., fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (e.g., generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia).
Grade 1 or 2
For Grade 1:
The infusion rate of study drug/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the event.
For Grade 2:
The infusion rate of study drug/study regimen may be decreased 
50% or temporarily interrupted until resolution of the event.
Subsequent infusions may be given at 50% of the initial 
infusion rate.
For Grade 1 or 2:
−
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator.
−
Consider premedication per institutional standard prior to 
subsequent doses.
−
Steroids should not be used for routine premedication of Grade ≤2 
infusion reactions.
Grade 3 or 4
For Grade 3 or 4:
Permanently discontinue study drug/study regimen.
For Grade 3 or 4:
−
Manage severe infusion-related reactions per institutional 
standards (e.g., IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid).
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and AZD5069
Study Code D4198C00003
Edition Number 5.0
Date 08 February 2018
176(176)
Non–Immune-Mediated Reactions
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
Any Grade
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant.
Treat accordingly, as per institutional standard.
Grade 1
No dose modifications.
Treat accordingly, as per institutional standard.
Grade 2
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline.
Treat accordingly, as per institutional standard.
Grade 3
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline.
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to 
≤Grade 1 or baseline within 14 days, resume study drug/study 
regimen administration. Otherwise, discontinue study drug/study 
regimen.
Treat accordingly, as per institutional standard.
Grade 4
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the Sponsor.).
Treat accordingly, as per institutional standard.
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.”
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d4198c00003-csp-v5
Document Title:
D4198C00003 Clinical Study Protocol version 5
Document ID:
Doc ID-003649109
Version Label:
2.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
13-Feb-2018 22:46 UTC
Author Approval
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Author Approval
12-Feb-2018 19:43 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D4198C00003
Edition Number
1
Date
02Aug2018
A Phase Ib and II Open-Label, Multi-Center Study of MEDI4736 
Evaluated in Different Combinations in Patients with Metastatic Pancreatic 
Ductal Adenocarcinoma


PPD
PPD


PPD
PPD


Statistical Analysis Plan 
Study Code D4198C00003
Edition Number 1
Date 02Aug2018
4
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................3
TABLE OF CONTENTS.....................................................................................4
TABLE OF TABLES...........................................................................................7
TABLE OF FIGURES .........................................................................................7
LIST OF ABBREVIATIONS ..............................................................................8
AMENDMENT HISTORY................................................................................ 11
1.
STUDY DETAILS............................................................................................. 11
1.1
Study objectives.................................................................................................11
1.1.1
Primary objective............................................................................................... 11
1.1.1.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy.....................................................................................................11
1.1.1.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069...................................11
1.1.2
Secondary objectives.......................................................................................... 11
1.1.2.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy.....................................................................................................11
1.1.2.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069...................................12
1.1.3
Exploratory objectives ....................................................................................... 12
1.1.3.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy.....................................................................................................12
1.1.3.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069...................................12
1.2
Study design ......................................................................................................13
1.2.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy.....................................................................................................13
1.2.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069...................................14
1.3
Number of subjects ............................................................................................ 15
1.3.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy.....................................................................................................15
1.3.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069...................................15
2.
ANALYSIS SETS ............................................................................................. 16
2.1
Definition of analysis sets .................................................................................. 16
2.2
Deviations..........................................................................................................19
3.
PRIMARY AND SECONDARY VARIABLES................................................. 20


Statistical Analysis Plan 
Study Code D4198C00003
Edition Number 1
Date 02Aug2018
5
3.1
Derivation of RECIST visit responses ................................................................ 20
3.1.1
Target lesions (TLs)........................................................................................... 21
3.1.2
Non-Target Lesions (NTLs) and new lesions...................................................... 26
3.1.3
Overall visit response......................................................................................... 27
3.2
Outcome Variables............................................................................................. 27
3.2.1
Primary endpoints.............................................................................................. 27
3.2.1.1
Objective response rate ...................................................................................... 27
3.2.1.2
Safety co-primary endpoints............................................................................... 28
3.2.2
Secondary endpoints .......................................................................................... 28
3.2.2.1
Duration of response .......................................................................................... 28
3.2.2.2
Disease control rate............................................................................................ 28
3.2.2.3
Progression-free survival.................................................................................... 29
3.2.2.4
Proportion of patients alive and progression-free after 3 months......................... 30
3.2.2.5
Proportion of patients alive and progression-free after 6 months......................... 30
3.2.2.6
Overall survival..................................................................................................30
3.2.2.7
Proportion of patients alive at 6 months.............................................................. 31
3.2.2.8
Proportion of patients alive at 12 months............................................................ 31
3.2.2.9
Best objective response ...................................................................................... 31
3.3
Safety variables..................................................................................................32
3.3.1
Dose-limiting toxicity ........................................................................................ 32
3.3.2
Adverse events...................................................................................................32
3.3.3
Laboratory assessment ....................................................................................... 33
3.3.4
Electrocardiograms ............................................................................................ 34
3.3.5
Vital signs..........................................................................................................34
3.3.6
Time to first subsequent therapy from discontinuation of study treatment...........34
3.3.7
Treatment exposure............................................................................................ 35
3.3.8
Dose intensity ....................................................................................................35
3.3.9
General considerations for safety assessments.................................................... 36
3.4
Pharmacokinetic and Immunogenicity variables................................................. 38
3.4.1
Pharmacokinetic noncompartmental analysis ..................................................... 38
3.4.2
Immunogenicity analysis.................................................................................... 38
3.5
Biomarker variables ........................................................................................... 38
4.
ANALYSIS METHODS.................................................................................... 38
4.1
General principles .............................................................................................. 38
4.2
Analysis methods............................................................................................... 40
4.2.1
Multiplicity (Not Applicable)............................................................................. 41
4.2.2
Primary endpoints.............................................................................................. 41
4.2.2.1
Objective response rate ...................................................................................... 41
4.2.2.2
Safety co-primary endpoints............................................................................... 41
4.2.3
Secondary endpoints .......................................................................................... 41
4.2.3.1
Objective response rate ...................................................................................... 41
4.2.3.2
Duration of response .......................................................................................... 41


Statistical Analysis Plan 
Study Code D4198C00003
Edition Number 1
Date 02Aug2018
6
4.2.3.3
Disease control rate............................................................................................ 41
4.2.3.4
Progression-free survival.................................................................................... 41
4.2.3.5
Proportion of patients with progression-free survival after 3 months and 6 
months ............................................................................................................... 41
4.2.3.6
Overall survival..................................................................................................42
4.2.3.7
Proportion of patients alive at 6 and 12 months .................................................. 42
4.2.3.8
Best objective response ...................................................................................... 42
4.2.3.9
Change in tumor size.......................................................................................... 42
4.2.4
Safety data .........................................................................................................42
4.2.5
Pharmacokinetic data ......................................................................................... 47
4.2.5.1
Immunogenicity analysis.................................................................................... 47
4.2.6
Biomarker data...................................................................................................47
4.2.7
Demographic and baseline characteristics data................................................... 48
4.2.8
Treatment exposure............................................................................................ 49
4.2.9
ECOG PS...........................................................................................................49
4.2.10
Subsequent Therapy........................................................................................... 49
5.
TIMING OF ANALYSES.................................................................................. 49
5.1
Cohort 1............................................................................................................. 50
5.2
Cohort 2............................................................................................................. 50
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 50
7.
REFERENCES ..................................................................................................51
8.
APPENDIX .......................................................................................................52


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TABLE OF TABLES
PAGE
Table 1 
Probability of observing toxicity events.................................................15
Table 2 
Probability of observing toxicity events in 6 or 16 patients....................16
Table 3 
Summary of outcome variables and analysis populations.......................18
Table 4 
Evaluation of target lesions ...................................................................22
Table 5 
Example of scaling................................................................................25
Table 6 
Evaluation of non-target lesions ............................................................26
Table 7 
Overall visit response............................................................................27
Table 8
Initial intended doses.............................................................................36
Table 9  
Pre-planned statistical to be conducted..................................................40
Table 10 
Details of changes from the clinical study protocol................................50
TABLE OF FIGURES
PAGE
Figure 1
Cohort 1 (first-line, Phase Ib MEDI4736 + nab-paclitaxel + 
gemcitabine chemotherapy) design........................................................14
Figure 2
Cohort 2 (second-line, Phase II MEDI4736 + AZD5069) design...........15


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LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
ADA
Antidrug antibody
AE
Adverse event
AESI
Adverse event of special interest
AJCC
American Joint Committee on Cancer
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AZDD
AZ drug dictionary
BMI
Body mass index
BoR
Best objective response
BP
Blood pressure
CI
Confidence interval
CR 
Complete response
CRF
Case report form
CSP
Clinical study protocol
CSR
Clinical study report
CT
Computed tomography
CTC/CTCAE
Common terminology criteria for adverse event
CV
Coefficient of variation
DBL
Database lock
DBP
Diastolic blood pressure
DCO
Data cut-off
DCR
Disease control rate
DLT 
Dose-limiting toxicity
DoR
Duration of response
DRM
Data review meeting
EAS
Efficacy analysis set
ECG
Electrocardiogram
ECOG
Eastern cooperative oncology group


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Abbreviation or 
special term
Explanation
FAS
Full analysis set
fT3
Free triiodothyronine
fT4
Free thyroxine
IHC
Immunohistochemical
ILD
Interstitial lung disease
IP
Investigational product
irAE
Immune-related adverse events
ITT
Intent-to-treat
LD
Longest diameter
LDH
Lactate dehydrogenase
MedDRA
Medical dictionary for regulatory activities
MRI
Magnetic resonance imaging
NA
Not applicable
NE
Not evaluable
NTL
Non-target lesion
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
OS6
Proportion of patients alive at 6 months from enrollment
OS12
Proportion of patients alive at 12 months from enrollment
PD
Progressive disease
PDAC 
Pancreatic ductal adenocarcinoma
PD-L1
Programmed death ligand 1
PDx
Pharmacodynamics
PFS
Progression-free survival
PFS3
Proportion of patients with progression-free survival after 3 months
PFS6
Proportion of patients with progression-free survival after 6 months
PK 
Pharmacokinetics
PKS
Pharmacokinetics analysis set
PR
Partial response
PS
Performance status
q6w
Every 6 weeks


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Abbreviation or 
special term
Explanation
q8w
Every 8 weeks
q12w
Every 12 weeks
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RDI
Relative dose intensity
RECIST 1.1
Response Evaluation Criteria In Solid Tumours, Version 1.1
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SD
Stable disease
SI
International System
SRC
Safety Review Committee
TEAE
Treatment emergent adverse event
TL
Target lesion
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
WHO
World health organization


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AMENDMENT HISTORY
Date
Brief description of change
02Aug2018
N/A
1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objective
1.1.1.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy
Primary objective:
Outcome measure:
To assess the safety and tolerability of 
MEDI4736 in combination with nab-paclitaxel + 
gemcitabine
Occurrence of dose-limiting toxicities
AEs, physical examinations, laboratory findings
(including clinical chemistry, hematology, and
urinalysis), vital signs (including blood pressure 
and pulse), electrocardiograms (ECGs)
1.1.1.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069
Primary objective:
Outcome measure:
To assess the safety, tolerability and ORR for 
MEDI4736 + AZD5069 in combination 
Occurrence of dose-limiting toxicities AEs, 
physical examinations, laboratory findings 
(including clinical chemistry, hematology, and 
urinalysis), vital signs (including blood pressure 
and pulse), electrocardiograms (ECGs), and ORR 
using Investigator assessments according to 
RECIST 1.1.
1.1.2
Secondary objectives
1.1.2.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy
Secondary objectives:
Outcome measures:
To assess the efficacy of MEDI4736 in 
combination with nab-paclitaxel + gemcitabine in 
terms of ORR, DoR, DCR, PFS, and OS
ORR, DoR, DCR, and PFS using Investigator 
assessments according to RECIST 1.1 
OS
To assess the PK of MEDI4736 and the 
combination of MEDI4736 and nab-paclitaxel + 
gemcitabine
Concentration of MEDI4736/nab-paclitaxel +
gemcitabine in blood and noncompartmental PK
parameters (such as peak concentration and 
trough, as data allow; sparse sampling only)


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1.1.2.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069
Secondary objectives:
Outcome measures:
To further assess the efficacy of MEDI4736
+AZD5069 in terms of DoR, DCR, PFS, PFS3,
PFS6, OS, OS6, and OS12
DoR, DCR, PFS, PFS3, and PFS6 in all patients
using Investigator assessments according to
RECIST 1.1
OS, OS6, and OS12
To investigate the relationship between PD-L1
expression by IHC and efficacy parameters
ORR, DoR, DCR, and PFS across PD-L1 
expression using Investigator assessments 
according to RECIST 1.1
OS
To investigate the immunogenicity of MEDI4736 
in combination with AZD5069
Presence of ADAs for MEDI4736 (confirmatory
results: positive or negative; titers)
To assess the PK of MEDI4736 and the
combination of MEDI4736 and AZD5069
Concentration of MEDI4736/AZD5069 in blood 
and noncompartmental PK parameters (such as 
peak concentration and trough, as data allow; 
sparse sampling only)
1.1.3
Exploratory objectives
1.1.3.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy
Not applicable.
1.1.3.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069
Exploratory objectives:
Outcome measures:
Evaluate changes in blood-borne biomarkers that 
may correlate with treatment or clinical response
Assessments may include, but are not limited to, 
measurement of gene expression immune cell 
types, soluble factors such as cytokines and
chemokines, T-cell receptor repertoire, 
circulating tumor DNA and activation and 
proliferation markers at baseline and with 
treatment.
Evaluate tumor-based biomarkers in archival 
tumor samples that may correlate with treatment 
or prospectively identify patients likely to 
respond to treatment 
Assessments may include tumor genetics, 
characterisation of immune infiltrates, gene 
expression signatures, T cell repertoire, or other 
stratification markers.
To collect and store deoxyribonucleic acid 
(DNA) for future exploratory research 
Future exploratory research may include but is 
not limited to exploration of genes/genetic 
variation that may influence response (i.e. 
distribution, safety, tolerability and efficacy) to 
treatment.
Collect and store tumor, blood, plasma, and 
serum samples or analyse surplus blood or tissue 
including patient-specific archival tumor tissue, if 
Samples may be used for potential future 
exploratory research into factors that may 
influence development of the tumor or response 


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available
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 need for a protocol amendment.
1.2
Study design
This study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and 
antitumor activity of MEDI4736 in combination with chemotherapy and novel anticancer 
agents in patients with pancreatic ductal adenocarcinoma (PDAC). This study will consist of 
two independent study cohorts. Cohort 1 is a first-line, Phase Ib assessment of MEDI4736 in 
combination with chemotherapy. Cohort 2 is a second-line, Phase II assessment of MEDI4736 
+ AZD5069 with a safety run-in.
1.2.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy
Cohort 1 is a Phase Ib, open-label, dose exploration assessment of the safety, tolerability, 
antitumor activity, and pharmacokinetics (PK) of MEDI4736 in combination with the         
nab-paclitaxel + gemcitabine chemotherapy regimen in patients with metastatic PDAC who 
are treatment naïve (defined as no prior exposure to systemic chemotherapy, targeted therapy, 
immunotherapy, or investigational agents [except adjuvant or neoadjuvant therapy if >6 
months from last treatment]) (Von Hoff et al 2013). A schematic diagram of the Cohort 1 as 
initially designed is shown in Figure 1.
Doses and treatment regimens are described in Section 7.2 of the Clinical study protocol 
(CSP). Assessments will be conducted as indicated in Table 2 and Table 4 of the CSP.


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Figure 1
Cohort 1 (first-line, Phase Ib MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy) design
1.2.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069
Cohort 2 is a Phase II, open-label, multicenter assessment of the safety and preliminary 
antitumor activity of MEDI4736 in combination with AZD5069 in patients with metastatic 
PDAC whose disease has progressed on a 5-FU-containing or gemcitabine-containing       
first-line chemotherapy. Cohort 2 will enroll approximately 16 evaluable patients. A 
schematic diagram of the Cohort 2 design is shown in Figure 2.
Initially, approximately 6 evaluable patients will be enrolled into a safety run-in period to 
evaluate safety, tolerability, and antitumor activity. After the 6 initial evaluable patients 
complete 1 treatment cycle, if no unexpected toxicity meet DLT criteria, approximately 10 
additional evaluable patients will be enrolled to determine preliminary antitumor activity. All 
patients in this cohort, including those in the safety run-in, will be included in the preliminary 
antitumor activity analysis. See Section 7.2.5 of the CSP (version 5.0, 08Feb2018) for details 
on the definition of DLTs.
Doses and treatment regimens are described in Section 7.2 of the CSP. Assessments will be
conducted as indicated in Table 3 and Table 5 of the CSP.


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Figure 2
Cohort 2 (second-line, Phase II MEDI4736 + AZD5069) design
1.3
Number of subjects
1.3.1
Cohort 1: First-line, Phase Ib, MEDI4736 + nab-paclitaxel + gemcitabine 
chemotherapy
The sample size is set to screen patients for major toxicity that occurs in a large portion of the 
population, using the conventional 3 + 3 design. The total number of patients in dose level 1 is 
3 patients.
Based on binomial probabilities, the probability of observing 0 or more patients with a toxicity
event in 3 patients (6 patients respectively) can be seen in Table 1.
Table 1
Probability of observing toxicity events
Incidence of
DLTs
Probability of observing X out of Y (X/Y) patients with DLT
0/3
≤1/3
≥2/3
0/6
≤1/6
≥2/6
30%
34.30%
78.40%
21.60%
11.80%
42.00%
58.00%
50%
12.50%
50.00%
50.00%
1.60%
10.90%
89.10%
70%
2.70%
21.60%
78.40%
0.10%
1.10%
98.90%
1.3.2
Cohort 2: Second-line, Phase II, MEDI4736 + AZD5069
The sample size is set to screen patients for major toxicity that occurs in a large portion of the 
population, using the approximately 6 to 16 evaluable patients in total. A cohort of 6 evaluable
patients will be recruited sequentially at the planned dose level. Should safety and tolerability 
be acceptable (if there are 3 or fewer patients exhibiting DLT criteria) following assessment of 


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the initial 6 evaluable patients, approximately 10 further evaluable patients will be recruited, 
to target approximately 16 evaluable patients in total.
Based on binomial probabilities, the probability of observing 0 or more patients with a toxicity 
event in 6 patients (16 patients respectively) can be seen in Table 2.
Table 2
Probability of observing toxicity events in 6 or 16 patients
Incidence of
DLTs
Probability of observing X out of Y (X/Y) patients with DLT
0/6
≤1/6
≤2/6
≥3/6
≤2/16
≥3/16
1%
94.10%
99.90%
100%
0%
98.90%
1.10%
5%
73.50%
96.70%
99.80%
0.20%
81.10%
18.90%
10%
53.10%
88.60%
98.40%
1.60%
51.50%
48.50%
20%
26.20%
65.50%
90.10%
9.90%
14.10%
85.90%
30%
11.80%
42%
74.40%
25.60%
2.60%
97.40%
50%
1.60%
10.90%
34.40%
65.60%
0%
100%
70%
0.10%
1.10%
7%
93%
0%
100%
2.
ANALYSIS SETS
2.1
Definition of analysis sets
Full analysis set
The full analysis set (FAS) will include all patients enrolled to receive treatment and will 
classify them on the basis of allocated treatment, regardless of the treatment actually received. 
Patients who were enrolled to receive treatment who did not subsequently go on to receive 
study treatment are included in the FAS population.
Safety analysis set
All patients who received at least 1 dose of investigational product (IP) and for whom any 
post-dose data are available will be included in the safety analysis set, according to the 
treatment they actually received. Study population and demography data description will be 
produced on the Safety analysis set. When assessing safety and tolerability, summaries will be 
produced based on the Safety analysis set.
DLT evaluable set
For Cohort 1, the DLT evaluable set will include all patients who completed the DLT 
evaluation period and/or discontinued study treatment early due to a DLT and who have not 
missed ≥2 administrations of gemcitabine.
For Cohort 2, the DLT evaluable set will include patients who received 50 % of planned doses 
of AZD5069 during the DLT period as well as the MEDI4736 infusion and remained active 
on study at the end of Day 28 of the study Cycle 1.


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The DLT evaluation period is defined as the time from the first dose of MEDI4736 for Cohort 
1 (resp. MEDI4736 and AZD5069 for Cohort 2) to the end of Cycle 1 (i.e., 28 days in total) or 
until a patient experiences a DLT or discontinues treatment during Cycle 1, whichever occurs 
first. Patients will be presented according to the treatment they actually received.
Efficacy Analysis Set
The Efficacy analysis set (EAS) will include patients who received at least 1 dose of IP and 
with no important protocol deviation that could impact the efficacy evaluation. Patients will 
be presented according to the treatment they actually received.
These deviations will be discussed and stated during the Data Review Meeting prior to 
database lock (DBL).
PK analysis set
All patients who received at least 1 dose of IP per protocol for whom any post-dose data are 
available and who do not violate or deviate from the protocol in ways that would significantly 
affect the PK analyses will be included in the PK analysis set (PKS). Patients will be 
presented according to the treatment they actually received.
The population will be defined by the Study Physician, Pharmacokineticist, and Statistician 
prior to any analyses being performed.
Definitions of the analysis sets for each outcome variable are provided in Table 3.


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Table 3
Summary of outcome variables and analysis populations
Outcome variable
Population
Efficacy data
  ORR
Efficacy Analysis Set
  DoR*, DCR, PFS, PFS3, PFS6, OS, OS6, OS12  Efficacy Analysis Set
Study population/Demography data
  Patient disposition
All subjects
  Demography characteristics
Safety Analysis Set
  Baseline and disease characteristics
Safety Analysis Set
  Important deviations 
Safety Analysis Set
  Medical/Surgical history
Safety Analysis Set
  Previous anti-cancer therapy 
Safety Analysis Set
  Concomitant medications/procedures
Safety Analysis Set
  Subsequent anti-cancer therapy
Safety Analysis Set
  WHO PS
Safety Analysis Set
PK data
  PK data
PK Analysis Set
Immunogenicity
  Immunogenicity data
Safety Analysis Set
Safety data
  Exposure
Safety Analysis Set
  AEs
Safety Analysis Set
  DLT
Safety Analysis Set
  Laboratory measurements
Safety Analysis Set
  ECOG PS
Safety Analysis Set
  Vital signs
Safety Analysis Set
* Patients who are evaluable for the analysis of DoR are those identified as responders for the ORR analysis.


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2.2
Deviations
A list of protocol deviations will be reviewed including the impact on the analysis sets and 
decisions regarding how to handle these deviations will be documented by the study team 
physician, pharmacokineticist and statistician prior to database lock. Important protocol 
deviations may include, but are not limited to: not meeting eligibility criteria, non-
performance of important assessments, use of prohibited medications, develop discontinuation 
criteria but not withdrawn from study or discontinued IP as appropriate etc.
Important protocol deviations will be identified from 2 sources: the deviations collected at 
sites in IMPACT and the deviations programmatically obtained using data collected in the 
database.
  + 
The following programmable general categories will be considered as important deviations 
and be listed and discussed in the clinical study report (CSR) for both cohorts. 

Deviation 1: Patients enrolled but who did not receive study treatment.

Deviation 2: Patients who deviate from key entry criteria as per the CSP. These are 
inclusion criteria 3, 5, 6 and exclusion criteria 1, 3, 4.

Deviation 3: Baseline RECIST (Response Evaluation Criteria In Solid Tumours)
scan > 28 days before the start of study treatment.

Deviation 4: No baseline RECIST 1.1 assessment on or before the start of study 
treatment.

Deviation 5: Received prohibited concomitant medications (including other anti-
cancer agents). Please refer to the CSP section 7.7. This will be used as a guiding 
principle for the physician review of all medications prior to database lock to 
identify those likely have an impact on efficacy.
In addition to the programmatic determination of the deviations above, monitoring notes or 
summaries will be reviewed to determine any important post entry deviations that are not 
identifiable via programming, and to check that those identified via programming are correctly 
classified. Even the list above is not exhaustive, the final classification of deviations will be 
made at the data review meeting (DRM) prior to database lock or data freeze. Decisions made 
at the DRM will be documented and approved by AstraZeneca prior to analysis.
PDs recorded in 
IMPACT 
[Reviewed & 
Important PDs 
identified]
Important PDs 
identified using 
programming 
Important PDs reported 
in listing and summary 
tables


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Deviation 1 will lead to exclusion from the Safety analysis set. Any deviation considered to 
impact upon PK will lead to exclusion from the PKS.
Errors in treatment dispensing will also be summarized and listed separately to the important 
protocol deviations. 
The summary will also include the number of patients who receive no treatment whatsoever 
for a period of time due to errors in dispensing of medication. Note, this is not due to 
tolerability issues where patients may stop taking drug.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Derivation of RECIST visit responses
For all subjects, the RECIST tumor response data will be used to determine each subject’s
visit response according to RECIST version 1.1. It will also be used to determine if and when 
a subject has progressed in accordance with RECIST and also their best objective response. 
Baseline radiological tumor assessments are to be performed no more than 28 days before the 
start of study treatment and ideally as close as possible to the start of study treatment.
For Cohort 1, tumor assessments are then performed every 8 weeks (q8w) ±7 days for the first 
48 weeks (relative to the date of the first infusion) and then every 12 weeks (q12w) ±7 days 
until confirmed objective disease progression per RECIST 1.1
For Cohort 2, tumor assessments are then performed every 6 weeks (q6w) ±7 days for the first 
48 weeks (relative to the date of the first infusion) and then q12w ±7 days until confirmed 
objective disease progression per RECIST 1.1
If an unscheduled assessment is performed, and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits. This schedule 
is to be followed in order to minimize any unintentional bias caused by some patients being 
assessed at a different frequency than other patients.
All RECIST assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy. For patients who discontinue IP due to toxicity in the 
absence of confirmed objective progression, objective tumor assessments per the scheduled 
assessments should be continued as planned until confirmed objective disease progression.
A confirmatory scan is required following the initial demonstration of PD. The confirmatory 
scan should occur preferably at the next scheduled visit and no earlier than 4 weeks after the 
initial assessment of PD in the absence of clinically significant deterioration. Treatment will 
continue between the initial assessment of progression and confirmation for progression.
Objective tumor response (CR or PR) should be confirmed preferably at the next scheduled
visit and not less than 4 weeks after the visit when the response was first observed.
Categorization of objective tumor response assessment will be based on the RECIST 1.1 
criteria of response: complete response (CR), partial response (PR), stable disease (SD), or 
progressive disease (PD). At each visit, patients will be programmatically assigned a response 


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based on tumor assessments provided by the investigator for target lesions, non-target lesions 
and new lesions. Target lesion progression will be calculated in comparison to when the tumor 
burden was at a minimum (i.e., smallest sum of diameters previously recorded on study). In 
the absence of progression, tumor response (CR or 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, then the patient will be assigned a visit 
response of not evaluable (NE; unless there is evidence of progression, in which case the 
response will be assigned as PD). Endpoints of objective response rate (ORR), duration of 
response (DoR), disease control rate (DCR), progression-free survival (PFS), proportion of 
patients with progression-free survival after 3 months (PFS3), and proportion of patients with 
progression-free survival after 6 months (PFS6) will be derived from the overall visit response 
date and the scan dates.
Note that overall responses as per Investigator opinion will not be used for any endpoint based 
on RECIST criteria.
Please refer to Appendix D of the CSP for the definitions of CR, PR, SD, NE, and PD and for 
more details regarding the tumor assessment.
3.1.1
Target lesions (TLs)
Measurable disease is defined as having at least one measurable lesion, not previously 
irradiated, which is ≥ 10 mm in the longest diameter (except lymph nodes which must have 
short axis ≥ 15 mm) with CT or MRI and which is suitable for accurate repeated 
measurements.
A subject can have a maximum of 5 measurable lesions recorded at baseline with a maximum 
of 2 lesions per organ (representative of all lesions involved suitable for accurate repeated 
measurement) and these are referred to as target lesions (TLs). If more than one baseline scan 
is recorded then measurements from the one that is closest and prior to start of study treatment 
will be used to define the baseline sum of TLs. It may be the case that, on occasion, the largest 
lesion does not lend itself to reproducible measurement in which circumstance the next largest 
lesion, which can be measured reproducibly, should be selected.
All other lesions (or sites of disease) not recorded as TL should be identified as non-target 
lesions (NTL) at baseline. Measurements are not required for these lesions, but their status 
should be followed at subsequent visits.
Measurable disease (i.e. at least one TL) is one of the entry criteria for the study. However, if 
a patient with non-measurable disease is enrolled in the study, the evaluation of overall visit 
responses will be based on the overall NTL assessment and the absence/presence of new 
lesions. If a patient does not have measurable disease at baseline then the TL visit response 
will be not applicable (NA).


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Table 4
Evaluation of target lesions
Visit Reponses
Description
Complete Response (CR)
Disappearance of all TLs since baseline. Any pathological lymph 
nodes selected as TLs must have a reduction in short axis to 
<10mm.
Partial response (PR)
At least a 30% decrease in the sum of diameters of TLs, taking as 
reference the baseline sum of diameters as long as criteria for PD 
are not met
Stable disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD
Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at 
least 5mm.
Not Evaluable (NE)
Only relevant if any of the TLs were not assessed or not evaluable
or had a lesion intervention at this visit. Note: if the sum of
diameters meets the progressive disease criteria, progressive
disease overrides not evaluable as a TL response
Not applicable (NA)
No TLs are recorded at baseline
CR Complete response; PR Partial response; PD Progression of disease; NE Not evaluable; SD Stable disease; 
TL Target lesion.
Rounding of TL data
For calculation of PD and PR for TLs percentage changes from baseline and previous 
minimum should be rounded to 1 decimal place before assigning a TL response. For example 
19.95% should be rounded to 20.0% but 19.94% should be rounded to 19.9%.
Missing TL data
For a visit to be evaluable, all TL measurements should be recorded. However, a visit 
response of PD should still be assigned if any of the following occurred:

A new lesion is recorded.

A NTL visit response of PD is recorded.

The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute 
increase of ≥ 5mm, from nadir even assuming the non-recorded TLs have 
disappeared.
Note: the nadir can only be taken from assessments where all the TLs had a lesion diameter 
recorded.


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Lymph nodes
For lymph nodes, if the size reduces to < 10mm then these are considered non-pathological. 
However a size will still be given and this size should still be used to determine the TL visit 
response as normal. In the special case where all lymph nodes are < 10mm and all other TLs 
are 0mm then although the sum may be >0mm the calculation of TL response should be 
categorized as a CR.
TL visit responses subsequent to CR
A CR can only be followed by CR, PD or NE. If a CR has occurred then the following rules at 
the subsequent visits must be applied:

Step 1: If all lesions meet the CR criteria (i.e. 0mm  or < 10mm for lymph nodes) 
then response will be set to CR irrespective of whether the criteria for PD of TL is 
also met i.e. if a lymph node longest diameter (LD) increases by 20% but remains < 
10mm.

Step 2: If some lesion measurements are missing but all other lesions meet the CR 
criteria (i.e. 0mm or < 10mm for lymph nodes) then response will be set to NE 
irrespective of whether, when referencing the sum of TL diameters, the criteria for 
PD are also met.

Step 3: If not all lesions meet the CR criteria and the sum of lesions meets the 
criteria for PD then response will be set to PD.

Step 4: If after steps 1 – 3 a response can still not be determined the response will 
be set to remain as CR.
TL too big to measure
If a TL becomes too big to measure this should be indicated in the database and a size (‘x’) 
above which it cannot be accurately measured should be recorded. If using a value of x in the 
calculation of TL response would not give an overall visit response of PD, then this will be 
flagged and reviewed by the study team blinded to treatment assignment. It is expected that a 
visit response of PD will remain in the vast majority of cases.
TL too small to measure
If a TL becomes too small to measure a value of 5mm will be entered into the database and 
used in TL calculations, unless the radiologist has indicated and entered a smaller value that 
can be reliably measured. If a TL response of PD results then this will be reviewed by the 
study team blinded to treatment assignment.
Irradiated lesions/lesion intervention
Previously irradiated lesions (i.e. lesion irradiated prior to entry into the study) should be 
recorded as NTLs and should not form part of the TL assessment.
Any TL (including lymph nodes), which has had intervention during the study (for example, 
irradiation / palliative surgery / embolization), should be handled in the following way and 


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once a lesion has had intervention then it should be treated as having intervention for the 
remainder of the study noting that an intervention will most likely shrink the size of tumors:

Step 1: the diameters of the TLs (including the lesions that have had intervention) 
will be summed and the calculation will be performed in the usual manner. If the 
visit response is PD this will remain as a valid response category.

Step 2: If there was no evidence of progression after step 1, treat the lesion diameter 
(for those lesions with intervention) as missing and if 1/3 of the TLs have missing 
measurements then scale up as described in the ‘Scaling’ section below. If the 
scaling results in a visit response of PD then the patient would be assigned a TL 
response of PD.

Step 3: If after both steps PD has not been assigned, then, if appropriate, a scaled 
sum of diameters will be calculated (as long as 1/3 of the TLs have missing 
measurements), treating the lesion with intervention as missing, and PR or SD then 
assigned as the visit response. Patients with intervention are evaluable for CR as 
long as all non-intervened lesions are 0 (or <10mm for lymph nodes) and the lesions 
that have been subject to intervention also have a value of 0 recorded. If scaling up 
is not appropriate due to too few non-missing measurements then the visit response 
will be set as NE.
At subsequent visits the above steps will be repeated to determine the TL and overall visit 
response. When calculating the previous minimum, lesions with intervention should be treated 
as missing and scaled up where appropriate (as per step 2 above).
Scaling (applicable only for irradiated lesions/lesion intervention)
If > 1/3 of TL measurements are treated as missing (because of intervention) then TL response 
will be NE, unless the sum of diameters of non-missing TL 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 to nadir and the sum of TLs has increased by ≥5mm from nadir).
If ≤ 1/3 of the TL measurements are treated as missing (because of intervention) then the 
results will be scaled up (based on the sizes at the nadir visit to give an estimated sum of 
diameters and this will be used in calculations; this is equivalent to comparing the visit sum of 
diameters of the non-missing lesions to the nadir sum of diameters excluding the lesions with 
missing measurements.


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Table 5
Example of scaling
Lesion
Longest diameter at nadir 
visit (mm)
Longest diameter at follow-up 
visit (mm)
1
2
3
4
5
7.2
6.7
4.3
8.6
2.5
7.1
6.4
4.0
8.5
Intervention
Sum
29.3
26
Lesion 5 is missing at the follow-up visit.
The sum of lesions 1-4 at the follow-up is 26 mm. The sum of the corresponding lesions at 
nadir visit is 26.8 mm.
Scale up as follows to give an estimated TL sum of 28.4 mm:
mm
4.
28
3.
29
8.
26
26


CR will not be allowed as a TL response for visits where there is missing data. Only PR, SD 
or PD (or NE) could be assigned as the TL visit response in these cases. However, for visits 
with 1/3 lesion assessments not recorded, the scaled up sum of TLs diameters will be 
included when defining the nadir value for the assessment of progression.
Lesions that split in two
If a TL splits in two, then the LDs of the split lesions should be summed and reported as the 
LD for the lesion that split.
Lesions that merge
If two TLs merge, then the LD of the merged lesion should be recorded for one of the TL 
sizes and the other TL size should be recorded as 0cm.
Change in method of assessment of TLs
CT, MRI and clinical examination are the only methods of assessment that can be used within 
a trial, with CT and MRI being the preferred methods and clinical examination only used in 
special cases. If a change in method of assessment occurs between CT and MRI this will be 
considered acceptable and no adjustment within the programming is needed.
If a change in method involves clinical examination (e.g. CT changes to clinical examination 
or vice versa), any affected lesions should be treated as missing.


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3.1.2
Non-Target Lesions (NTLs) and new lesions
At each visit an overall assessment of the NTL response should be recorded by the 
investigator. This section provides the definitions of the criteria used to determine and record 
overall response for NTL at the investigational site at each visit.
NTL response will be derived based on the Investigator’s overall assessment of NTLs as 
follows:
Table 6
Evaluation of non-target lesions
Visit Responses
Description
Complete response (CR)
Disappearance of all NTLs since baseline. All lymph nodes 
non-pathological in size (<10 mm short axis).
Non CR/Non PD
Persistence of one or more NTL.
Progression (PD)
Unequivocal progression of existing NTLs. Unequivocal 
progression may be due to an important progression in one 
lesion only or in several lesions. In all cases the progression 
MUST be clinically significant for the physician to consider 
changing (or stopping) therapy.
Not Evaluable (NE)
Only relevant when one or some of the NTLs were not 
assessed and, in the Investigator's opinion, they are not able to 
provide an evaluable overall NTL assessment at this visit.
Note: for patients without TLs at baseline, this is relevant if 
any of the NTLs were not assessed at this visit and the 
progression criteria have not been met.
CR Complete response; PR Partial response; PD Progression of disease; NE Not evaluable; NTL Non-target 
lesion; TL Target lesion.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of SD or PR in 
TLs, the overall tumor burden has increased sufficiently to merit a determination of disease 
progression. A modest ‘increase’ in the size of one or more NTLs is usually not sufficient to 
qualify for unequivocal progression status.
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression.
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: i.e. not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumor.
New lesions will be identified via a Yes/No tick box. The absence and presence of new lesions 
at each visit should be listed alongside the TL and NTL visit responses.
A new lesion indicates progression so the overall visit response will be PD irrespective of the 
TL and NTL response.


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If the question ‘Any new lesions since baseline’ has not been answered with Yes or No and 
the new lesion details are blank this is not evidence that no new lesions are present, but should 
not overtly affect the derivation.
Symptomatic progression is not a descriptor for progression of NTLs: it is a reason for 
stopping study therapy and will not be included in any assessment of NTLs.
Patients with ‘symptomatic progression’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumor
assessments where possible until objective disease progression is observed.
3.1.3
Overall visit response
Table 7 defines how the previously defined TL and NTL visit responses will be combined 
with new lesion information to give an overall visit response.
Table 7
Overall visit response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
CR
Non-CR/Non-PD
No
PR
CR
NE
No
PR
PR
Non-PD or NE
No
PR
SD
Non-PD or NE
No
SD
NE
Non-PD or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR Complete response, PR Partial response, SD Stable disease, PD Progression of disease, NE Not evaluable, 
NA Not applicable (only relevant if there were no non-target lesions at baseline).
For each visit, including any unscheduled tumor assessment, the overall response will be 
programmatically derived from TL/NTL/NL assessments based on Investigator assessments.
3.2
Outcome Variables
Initiation of subsequent anti-cancer therapy includes radiotherapy.
3.2.1
Primary endpoints
3.2.1.1
Objective response rate
ORR will be based on the programmatically derived overall response, using all scans 
regardless of whether they were scheduled or not.
ORR (per RECIST 1.1) is defined as the number (%) of patients with a confirmed overall 
response of CR or PR and will be based on the Efficacy Analysis Set. A confirmed response 
of CR/PR means that a response of CR/PR is recorded at 1 visit and confirmed by repeat 


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imaging, preferably at the next regularly scheduled imaging visit and not less than 4 weeks
after the visit when the response was first observed with no evidence of progression between 
the initial and CR/PR confirmation visit. Therefore, data obtained up until confirmed
progression, or the last evaluable assessment in the absence of confirmed progression, will be 
included in the assessment of ORR. Note that the response may be after an unconfirmed 
progression.
Any patient who discontinues treatment without progression, receives a subsequent therapy
and then responds will not be included as responders in the ORR.
The overall responses as per Investigator will be listed only.
3.2.1.2
Safety co-primary endpoints
The safety co-primary endpoints are described in Section 3.3
3.2.2
Secondary endpoints
3.2.2.1
Duration of response
DoR (per RECIST 1.1 as assessed by Investigator assessment) will be defined as the time 
from the date of first documented response until the first date of documented confirmed 
progression or death in the absence of disease progression (i.e. date of PFS event or censoring 
- date of first response + 1). The end of response should coincide with the date of progression,
death from any cause or censoring used for the RECIST 1.1 PFS endpoint, based on
Investigator assessment.
The time of the initial response will be defined as the latest of the dates contributing toward
the first visit response of CR or PR. Note that the time of initial response may be after an 
unconfirmed progression. If a patient does not progress following a response, then their DoR 
will be censored at the PFS censoring time. DoR will not be defined for those patients who do 
not have documented response.
3.2.2.2
Disease control rate
DCR at 6 months is defined as the percentage of patients who have a best objective response 
(BoR) of CR or PR in the first 6 months (i.e. 24+1=25 weeks to allow for a late assessment 
within the assessment window) or who have demonstrated SD for a minimum interval of 24
weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 161 
days) following the start of treatment.
DCR at 12 months is defined as the percentage of patients who have a BoR of CR or PR in the 
first 12 months (i.e. 48+1=49 weeks to allow for a late assessment within the assessment 
window) or who have demonstrated SD for a minimum interval of 48 weeks (minus 1 week to 
allow for an early assessment within the assessment window, i.e. 329 days) following the start 
of treatment.
DCR will be determined based on programmatically derived RECIST 1.1 assessments and all 
data up until the first progression event. 


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3.2.2.3
Progression-free survival
PFS (per RECIST 1.1 using Investigator assessments) will be defined as the time from the 
date of first dose until the date of objective disease progression or death (by any cause in the 
absence of progression) regardless of whether the patient withdraws from allocated therapy or 
receives another anticancer therapy prior to progression.
Patients who have not progressed or died at the time of analysis will be censored at the time of 
the latest date of assessment from their last evaluable RECIST 1.1 assessment. However, if the 
patient progresses or dies after 2 or more missed visits, the patient will be censored at the time 
of the latest evaluable RECIST 1.1 assessment. If the patient has no evaluable visits or does 
not have baseline data, they will be censored at Day 1 unless they die within 2 visits of 
baseline.
Given the scheduled visit assessment scheme (i.e. eight-weekly for the first 48 weeks then 
twelve-weekly thereafter for cohort 1, six-weekly for the first 48 weeks then twelve-weekly 
thereafter for cohort 2) the definition of 2 missed visits will change as detailed below.
Cohort 1
If the previous RECIST assessment is less than study day 274 (i.e. week 39) then two missing 
visits will equate to 18 weeks since the previous RECIST assessment, allowing for early and 
late visits (i.e., 2 x 8 weeks + 1 week for an early assessment + 1 week for a late assessment = 
18 weeks). If the two missed visits occur over the period when the scheduled frequency of 
RECIST assessments changes from eight-weekly to twelve-weekly this will equate to 22 
weeks (i.e., take the average of 8 and 12 weeks which gives 10 weeks and then apply same 
rationale hence 2 x 10 weeks + 1 week for an early assessment + 1 week for a late assessment 
= 22 weeks). The time period for the previous RECIST assessment will be from study days 
274 to 344 (i.e. week 39 to week 49). From week 49 onwards (when the scheduling changes to 
twelve-weekly assessments), two missing visits will equate to 26 weeks (i.e. 2 x 12 weeks + 1
week for an early assessment + 1 week for a late assessment = 26 weeks). 
Cohort 2
If the previous RECIST assessment is less than study day 274 (i.e. week 39) then two missing 
visits will equate to 14 weeks since the previous RECIST assessment, allowing for early and 
late visits (i.e., 2 x 6 weeks + 1 week for an early assessment + 1 week for a late assessment = 
14 weeks). If the two missed visits occur over the period when the scheduled frequency of 
RECIST assessments changes from six-weekly to twelve-weekly this will equate to 20 weeks 
(i.e., take the average of 6 and 12 weeks which gives 9 weeks and then apply same rationale 
hence 2 x 9 weeks + 1 week for an early assessment + 1 week for a late assessment = 20 
weeks). The time period for the previous RECIST assessment will be from study days 274 to 
344 (i.e. week 39 to week 49). From week 49 onwards (when the scheduling changes to 
twelve-weekly assessments), two missing visits will equate to 26 weeks (i.e. 2 x 12 weeks + 1 
week for an early assessment + 1 week for a late assessment = 26 weeks). 
If the patient has no evaluable visits or does not have baseline data, they will be censored at 
date of first dose unless they die within 2 visits of first dose (16 weeks plus 1 week allowing 
for a late assessment within the visit window for Cohort 1, 12 weeks plus 1 week allowing for 
a late assessment within the visit window for Cohort2).


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The PFS time will always be derived based on scan/assessment dates not visit dates.
RECIST 1.1 assessments/scans contributing towards a particular visit may be performed on
different dates. The following rules will be applied:

For investigational assessments, the date of progression will be determined based on 
the earliest of the RECIST assessment/scan dates of the component that indicates 
progression.

When censoring a patient for PFS, the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment.
Note: For target lesions, only the latest scan date is recorded out of all scans performed at that 
assessment for the target lesions, and similarly for non-target lesions, only the latest scan date 
is recorded out of all scans performed at that assessment for the non-target lesions.
3.2.2.4
Proportion of patients alive and progression-free after 3 months
The PFS rate at 3 months (PFS3) will be calculated using Kaplan-Meier estimates. Tumor 
progression will be determined based on Investigator assessment and RECIST 1.1.
3.2.2.5
Proportion of patients alive and progression-free after 6 months
The PFS rate at 6 months (PFS6) will be calculated using Kaplan-Meier estimates. Tumor 
progression will be determined based on Investigator assessment and RECIST 1.1.
3.2.2.6
Overall survival
Overall survival (OS) is defined as the time from the date of first dose until death due to any 
cause (i.e. date of death or censoring – date of first dose + 1). Any patient not known to have 
died at the time of analysis will be censored based on the last recorded date on which the 
patient was known to be alive.
Note: Survival calls will be made in the week following the date of data cut-off (DCO) for the 
analysis, and if patients are confirmed to be alive or if the death date is post the DCO date, 
these patients will be censored at the date of DCO. The status of ongoing, withdrawn (from 
the study) and “lost to follow-up” patients at the time of the final OS analysis should be 
obtained by the site personnel by checking the patient’s notes, hospital records, contacting the 
patient’s general practitioner and checking publicly-available death registries. In the event that 
the patient has actively withdrawn consent to the processing of their personal data, the vital 
status of the patient can be obtained by site personnel from publicly-available resources where 
it is possible to do so under applicable local laws.
Note that for any OS analysis performed prior to the final OS analysis, in the absence of 
survival calls being made, it may be necessary to use all relevant case report form (CRF)
fields to determine the last recorded date on which the patient was known to be alive for those 
patients still on treatment (since the SURVIVE module is only completed for patients off 
treatment).


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3.2.2.7
Proportion of patients alive at 6 months
The proportion of patients alive at 6 months from enrollment (OS6) will be defined as the 
Kaplan-Meier estimate of OS at 6 months.
3.2.2.8
Proportion of patients alive at 12 months
The proportion of patients alive at 12 months from enrollment (OS12) will be defined as the 
Kaplan-Meier estimate of OS at 12 months.
3.2.2.9
Best objective response
BoR is calculated based on the overall visit responses from each RECIST assessment, 
described in Appendix D of the CSP. It is the best response a patient has had during their time 
in the study up until RECIST confirmed progression or the last evaluable assessment in the 
absence of RECIST confirmed progression.
Categorization of BoR will be based on RECIST (cf. Appendix D of the CSP) using the 
following response categories: CR, PR, SD, PD, and NE.
CR or PR must be confirmed. For determination of a best response of SD, the earliest of the 
dates contributing towards a particular overall visit assessment will be used. 
SD should be recorded:

Cohort 1: at least 8 weeks minus 1 week, i.e. at least 49 days (to allow for the 
assessment window), after first dosing. 

Cohort 2: at least 6 weeks minus 1 week, i.e. at least 35 days (to allow for the 
assessment window), after first dosing. 
For CR/PR, the initial overall visit assessment which showed a response will use the latest of 
the dates contributing towards a particular overall visit assessment.
BoR will be determined programmatically based on RECIST using all Investigator assessment 
data up until the first confirmed progression event. This will use all data up until the 
progression event that is used for the analysis (i.e., unconfirmed progressions are not 
considered progression events, which means that the BoR may be after an unconfirmed 
progression for some patients). The denominators for each case will be consistent with those 
used in the ORR analysis.
For patients whose progression event is death, BoR will be calculated based upon all 
evaluable RECIST assessments prior to death.
For patients who die with no evaluable RECIST assessments, if the death occurs ≤17 weeks 
for cohort 1 and ≤13 weeks for cohort 2 (i.e., 2*8 weeks and 2*6 weeks respectively +1 week 
to allow for a late assessment within the assessment window) after enrollment, then BoR will 
be assigned to the PD category. For patients who die with no evaluable RECIST assessments, 
if the death occurs >17 weeks for cohort 1 and >13 weeks for cohort 2 (i.e., 2*8 weeks and 
2*6 weeks respectively +1 week) after the date of enrollment, then BoR will be assigned to 
the NE category.


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Progression events that have been censored due to them being >17 weeks for Cohort 1 and 
>13 weeks for Cohort 2 after the last evaluable assessment will not contribute to the BoR 
derivation.
3.3
Safety variables
3.3.1
Dose-limiting toxicity
DLT criteria for MEDI4736 are defined for Cohort 1 and Cohort 2 in Section 7.2.4 and 
Section 7.2.5 of the CSP.
DLT criteria for AZD5069 are defined for Cohort in Section 7.2.5 of the CSP.
DLT status, based on a SRC review, are collected in the Adverse events eCRF page.
3.3.2
Adverse events
AEs and SAEs will be collected throughout the study, from the time the informed consent is
signed through 90 days after the last dose of IP. Data from all cycles of treatment will be 
combined in the presentation of safety data. The medical dictionary for regulatory activities 
(MedDRA) (using the latest or current MedDRA version) will be used to code the AEs. AEs 
will be graded according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE Version 4.03).
A treatment emergent adverse event (TEAE) is an AE with an onset date or a pre-existing AE 
worsening following the first dose of study treatment through to 90 days after the last dose of 
IP.
Causally related to treatment events are those assessed by the investigator (as collected in the 
eCRF) and will also include events with missing responses which default causally related. 
If any component of experimental combinations under study is discontinued, then the overall 
action taken is considered to be “drug discontinued”. 
Other significant adverse events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as serious adverse events (SAEs) and AEs leading to 
discontinuation. Based on the expert’s judgment, significant AEs of particular clinical 
importance may, after consultation with the global patient safety physician, be considered 
other significant adverse events (OAEs) and reported as such in the CSR. A similar review of 
laboratory/vital signs/ECG data will be performed for identification of OAEs. 
Examples of these are marked hematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious) or significant 
additional treatment.
AEs of special interest
Some clinical concepts (including some selected individual preferred terms and higher level 
terms) have been considered “AEs of special interest” (AESI) to the MEDI4736 program. 
These AESIs have been identified as
diarrhea/colitis
and intestinal perforation, 
pneumonitis/ILD (Interstitial lung disease), hepatitis/transaminase increases, endocrinopathies


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(i.e. 
events 
of 
hypophysitis/hypopituitarism, 
adrenal 
insufficiency, 
hyper-
and 
hypothyroidism, and hypothyroidism and type I diabetes mellitus), rash/dermatitis, 
nephritis/blood creatinine increases, pancreatitis/serum lipase and amylase increases, 
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, pericarditis, sarcoidosis, 
uveitis and other events involving the eye, skin, haematological and rheumatological events. 
For AZD5069, an inhibitor of CXCR2, which acts by modulating neutrophil migration, any 
infections 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. Other categories may be added or existing terms may be merged as necessary.
An AstraZeneca medically qualified expert after consultation with the global patient safety 
physician has reviewed the AEs of interest and identified which preferred terms contribute to 
each AESI. At the time of the analyses, all AESI categories as present in the most recent 
version of the AESI identification file for MEDI4736 program will be described; the file 
might include AESI categories for MEDI4736 and/or AZD5069 molecules. A further review 
will take place prior to DBL to ensure any further terms not already included are captured 
within the categories.
3.3.3
Laboratory assessment
Change from baseline in hematology and clinical chemistry variables will be calculated for 
each post-dose visit on treatment. CTC grades will be defined at each visit according to the 
CTC grade criteria using project ranges after conversion of lab result to corresponding 
preferred units. The following parameters have CTC grades defined for both high and low 
values: potassium, sodium, magnesium, glucose and corrected calcium so high and low CTC
grades will be calculated.
Corrected calcium will be derived during creation of the reporting database using the 
following formulas:
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – albumin (g/L)] × 0.02)
Creatinine clearance will be derived according to the Cockcroft-Gault formula (Cockcroft and 
Gault 1976).
Absolute values will be compared to the project reference range and classified as low (below 
range), normal (within range or on limits of range) and high (above range).


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The maximum or minimum on-treatment value (depending on the direction of an adverse 
effect) will be defined for each laboratory parameter as the maximum (or minimum) post-dose 
value at any time.
Local reference ranges will be used for the primary interpretation of laboratory data at the
local laboratory. Project reference ranges will be used throughout for reporting purposes.
For example:

If a CTCAE criterion involves a change from Baseline, evaluable patients would 
have both 1 pre-dose and at least 1 post-dose value recorded

If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient need only have 1 post-dose-value recorded.
3.3.4
Electrocardiograms
Resting 12-lead ECG data at screening and during treatment period will be used for reporting. 
For derivation of post baseline visit values considering visit window and to handle multiple 
records present in any visit window, derivation rules as described in Section 3.3.9 below will 
be used.
The QT interval corrected for heart rate using Fridericia’s formula (QTcF) will be derived 
during creation of the reporting database using the reported ECG values (RR and QT).
QTcF (msec) = QT (msec) /RR^ (1/3) where RR is in seconds
The variable automatically derived in the database will be used in the analysis.
For triplicate ECGs, the mean of the three ECG assessments will be used to determine the 
value at that time point. In addition, the worst overall ECG evaluation will be considered at 
that time point.
3.3.5
Vital signs
Vital signs data obtained up until the 30 days from date of last dose of study treatment or until 
initiation of the first subsequent therapy following discontinuation of treatment (whichever 
occurs first), will be used for reporting. 
For derivation of post-baseline visit values considering visit window and to handle multiple 
records, derivation rules as described in Section 3.3.9 below will be used.
3.3.6
Time to first subsequent therapy from discontinuation of study treatment
Time to subsequent therapy from date of last dose is defined as the time from the date of 
discontinuation of study treatment to the start date of the first subsequent therapy after 
discontinuation of treatment. Any patient not known to have had a first subsequent therapy 
will not have this calculation performed.


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3.3.7
Treatment exposure
Exposure will be defined separately for each IP as follows:
Total (or intended) exposure of MEDI4736

Total (or intended) exposure=last dose date +27 days where dose >0 mg or death or 
DCO date, whichever occurs first – first dose date +1. 
Total (or intended) exposure of AZD5069

Total (or intended) exposure=last dose date where dose >0 mg or death or DCO date, 
whichever occurs first – first dose date +1.
Actual exposure of study treatment

Actual exposure = intended exposure – total duration of dose interruptions, where 
intended exposure will be calculated as above.
A dose interruption is defined as 

any length of time where the patient has not taken any of the planned dose (taking 
into account the scheduled off treatment period), for MEDI4736,

any length of time where the patient has not taken any of the planned daily dose, for 
AZD5069.
Doses interruptions as collected in the eCRF (Action taken <molecule>=Dose interrupted in 
each Exposure form) will be used for analysis.
For actual exposure on MEDI4736, only valid doses will be considered when identifying the 
dose interruptions. A dose will be considered as valid when the dose is non null and the 
volume after and before infusion are not equal.
Dose reductions of MEDI4736 are not permitted per Section 6.7 of the CSP. The actual 
exposure calculation makes no adjustment for any dose reductions that may have occurred.
Exposure will also be measured by the number of cycles initiated. For both cohorts, a cycle 
corresponds to a period of 28 days. If a cycle is prolonged for any reason, this should still be 
counted as one cycle. A cycle will be counted if treatment is started even if the full dose is not 
delivered.
3.3.8
Dose intensity
Relative dose intensity (RDI) is the percentage of the actual dose delivered relative to the 
intended dose through to treatment discontinuation.
Relative dose intensity (RDI) will be defined as follows:
RDI = 100% * d/D, where d is the actual cumulative dose delivered up to the actual last day of 
dosing and D is the intended cumulative dose up to the actual last day of dosing. When 


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accounting for the calculation of intended cumulative dose, 3 days should be added to the date 
of last dose to reflect the protocol allowed window for dosing.
As per CSP, the initial intended doses are described in Table 8 below:
Table 8
Initial intended doses
MEDI4736
Nab-paclitaxel
Gemcitabine
AZD5069
Cohort 1
1.5g
125 mg/m²
1 000 mg/m²
-
Cohort 2
1.5 g
-
-
20 mg or 40 mg or 
80 mg
For AZD5069, the recommended dose of 80mg bid was approved as initial dose.
Dose modifications are described in CSP Appendix E for MEDI4736, and Sections 6.7.2 and 
6.7.3 for nab-paclitaxel+gemcitabine and AZD5069 respectively. They will not affect the RDI 
derivation.
3.3.9
General considerations for safety assessments
Time windows will need to be defined for any presentations that summarize values by visit. 
The following conventions should also apply:

The time windows should be exhaustive so that data recorded at any time point has 
the potential to be summarized. Inclusion within the time window should be based 
on the actual date and not the intended date of the visit.

All unscheduled visit data should have the potential to be included in the 
summaries.
The window for the visits following baseline will be constructed in such a way that the upper 
limit of the interval falls half way between the two visits (the lower limit of the first post-
baseline visit will be Day 2). If an even number of days exists between two consecutive visits 
then the upper limit will be taken as the midpoint value minus 1 day.
The following formula can be considered:

Upper bound (Visit_x)= Day(Visit_x)+integer part of ((Day(Visit_x+1) –
Day(Visit_x))/2)

Lower bound (Visit_x)=2 for first post-baseline visit
          
  =Upper bound (Day(Visit_x-1)) +1 otherwise
An example is displayed in the appendix (Section 8).
Note: Due to the differing assessment schedules the visit windows will be different for the 
different study treatments and endpoints.


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
Data collected between the start of treatment and the relevant follow-up period
(including the permitted time-window for a late assessment) following the last dose 
of study treatment will be considered as on treatment

For summaries showing the maximum or minimum values, the maximum/minimum 
value recorded on treatment will be used (regardless of where it falls in an interval).

Listings should display all values contributing to a time point for a patient.

For visit based summaries:

If there is more than one value per patient within a time window then the 
closest value to the scheduled visit date should be summarized, or the earlier in 
the event the values are equidistant from the nominal visit date. The listings 
will highlight the value for that patient that went into the summary table, 
wherever feasible. Note: in summaries of extreme values all post baseline 
values collected are used including those collected at unscheduled visits 
regardless of whether or not the value is closest to the scheduled visit date.

When several timepoints are planned within the same visit (for instance vital 
signs are planned pre-, during and post-infusion), data from all timepoints will 
be summarized. In case of unscheduled assessments, the same algorithm as 
above will be applied.

For summaries at a patient level, all values should be included, regardless of 
whether they appear in a corresponding visit based summary, when deriving a 
patient level statistic such as a maximum.

Baseline will be defined as the last non-missing measurement prior to dosing with 
study treatment. For laboratory data and weight assessments, any assessments made 
on day 1 will be considered pre-dose. For ECOG, data collected on Day 1 will be 
considered as baseline. Alternatively, if two visits are equally eligible to assess 
patient status at baseline (e.g., screening and baseline assessments both on the same 
date prior to first dose with no washout or other intervention in the screening 
period), the average will be taken as a baseline value. For non-numeric laboratory 
tests (i.e. some of the urinalysis parameters) where taking an average is not possible 
then the closest pre-dose value will be taken as baseline. In the scenario where there 
are two assessments on day 1, one with time recorded and the other without time 
recorded, the one with time recorded would be selected as baseline. Study day will 
be calculated in relation to date of first treatment.
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of “< x” (i.e., below the lower limit of quantification) or > x (i.e., above the upper limit 
of quantification) will be imputed as “x” in the calculation of summary statistics but displayed 
as “< x” or “> x” in the listings.


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3.4
Pharmacokinetic and Immunogenicity variables
Analyses to evaluate the pharmacokinetics and immunogenicity of MEDI4736/AZD5069 will 
be performed by AstraZeneca/MedImmune Clinical Pharmacology group or designee.
3.4.1
Pharmacokinetic noncompartmental analysis
Calculation of PK parameters will be performed at Covance. The actual sampling times will 
be used in the PK calculations. The peak and trough concentration PK parameters only will 
be determined after the first and steady-state doses (as data allow). Samples below the lower 
limit of quantification will be treated as missing in the analyses.
3.4.2
Immunogenicity analysis
The immunogenicity titer and presence of neutralizing ADAs will be reported for samples 
confirmed positive for the presence of ADAs.
The effect of immunogenicity on PK, pharmacodynamics, efficacy, and safety will be 
evaluated, if the data allow.
3.5
Biomarker variables
Programmed cell death ligand 1 (PD-L1) expression status (positive, negative) will be 
retrieved from the item “Total Positive Cells (%)” available in the raw database.
4.
ANALYSIS METHODS
Enrollment of Cohort 1 is currently closed due to portfolio decisions that are not related to 
safety or observed efficacy. Data from Cohort 1 will be listed only (including derived 
variables).
For the analyses described during Section 4, where applicable and data allow, listings will be 
generated for Cohort 1 and Cohort 2.  Associated Tables and Figures will be produced for 
Cohort 2 only.
4.1
General principles
The general principles as mentioned below will be followed throughout the study:

Descriptive statistics will be used for all variables, as appropriate, and will be 
presented by cohort. Continuous variables will be summarized by the number of 
observations, mean, standard deviation, median, minimum, and maximum. 
Categorical variables will be summarized by frequency counts and percentages for 
each category. 

Unless otherwise stated, percentages will be calculated out of the population total 
for the corresponding cohort.

For continuous data the mean and median will be rounded to 1 additional decimal 
place compared to the original data. The standard deviation will be rounded to 2 


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additional decimal places compared to the original data. Minimum and maximum 
will be displayed with the same accuracy as the original data.

For PK data the geometric mean and coefficient of variation (CV) will be presented 
to 4 significant figures (sf), minimum and maximum will be presented to 3 sf and n 
will be presented as an integer. 

For categorical data, percentages will be rounded to 1 decimal place.

SAS® version 9.4 will be used for all analyses.
Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of investigational product, except for efficacy variables. For efficacy variables, 
baseline is defined as the last visit prior to first dose.
Concomitant medications will be medications taken at least once from the first dosing date 
until 90 days after the last dose of the study treatment. Medications with missing start or end 
dates will also be assumed to be concomitant (whatever is the ongoing status).
Age will be derived for analysis purpose as: year(<reference date>) - year(date of birth), -1 if 
“day and month” of the reference date is before “day and month” of the date of birth, with 
inform consent date as reference date. 
Handling of missing/incomplete dates
The original incomplete or missing dates will be presented in the listings also.

Adverse events: all AEs will be considered as treatment-emergent unless the 
opposite can be clearly stated. Imputation will be done only in the context of 
identifying TEAEs.

Concomitant medications: all medications will be considered as concomitant unless 
the opposite can be clearly stated.
No other imputation will be made.
In practice, original incomplete or missing dates for adverse events and medications will be 
imputed as below:

Missing day: Impute the 1st of the month unless year and month is same as
year and month of first dose of study drug then impute first dose date

Missing day and month: impute 1st January unless year is the same as first 
dose date then impute first dose date

Completely missing – impute first dose date unless the end date suggests it 
could have started prior to this in which case impute the 1st January of 
the same year as the end date.
When imputing a start date ensure that the new imputed date is sensible i.e. is prior to the end 
date of the AE or med.


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The following other general principles will also apply:

All data collected will be listed.

Efficacy data will be summarized and analyzed based on the Efficacy Analysis Set. 
PK data will be summarized and analyzed based on the PKS. Safety and treatment 
exposure data will be summarized on the Safety analysis set. Study population and 
demography data will be summarized based upon the Safety analysis set.
4.2
Analysis methods
Results of all statistical analysis will be presented using a 80% confidence interval (CI) unless 
otherwise stated.
Populations to be considered for each endpoint are detailed in Table 3.
The following table (Table 9) details which endpoints are to be subjected to formal statistical 
analysis.
Table 9
Pre-planned statistical to be conducted
Type of endpoint
Endpoints analyzed
Notes
Cohort 2
Objective response 
rate
Exact 80% CI using Investigator RECIST 1.1 
assessments
Primary
Exact 60% CI using Investigator RECIST 1.1 
assessments
Duration of response
Descriptive data including Kaplan-Meier curves 
using Investigator RECIST 1.1 assessments
Secondary
Disease Control Rate
Summarized n (%) and 80% CI
Secondary
Progression-free 
survival
Kaplan-Meier estimates and plots
Median PFS
Events summary
Secondary
PFS3
PFS estimate at 3 months with 80%CI
Secondary
PFS6
PFS estimate at 6 months with 80%CI
Secondary
Overall survival
Kaplan-Meier estimates and plot
Median OS
Events summary
Secondary
Proportion of patients 
alive at 6 months
OS estimate at 6 months with 80%CI
Secondary
Proportion of patients 
alive at 12 months
OS estimate at 12 months with 80%CI
Secondary


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Target lesion size
Descriptive data on percent change from baseline
Waterfall plot on best percentage change
Spider plot on percentage change
Secondary
4.2.1
Multiplicity (Not Applicable)
4.2.2
Primary endpoints
4.2.2.1
Objective response rate
The efficacy co-primary endpoint for Cohort 2 (ORR) will be estimated with 80% exact 
Clopper-Pearson CIs. 
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR). The number (%) of patients with a confirmed response and the number (%) 
of patients with a single visit response (i.e., an unconfirmed response) will also be presented.
For internal decision-making support, the primary analysis will be repeated with 60% exact 
Clopper-Pearson CIs.
4.2.2.2
Safety co-primary endpoints
Analysis methods for the safety co-primary endpoints are described in Section 4.2.4
4.2.3
Secondary endpoints
4.2.3.1
Objective response rate
ORR is a secondary endpoint for Cohort 1. This endpoint is described in Section 4.2.2.
4.2.3.2
Duration of response
Descriptive data will be provided for the DoR in responding patients, including the associated 
Kaplan-Meier curve if data allow.
4.2.3.3
Disease control rate
The DCR will be summarized (i.e., number of patients) with 80% CI. Summary statistics (i.e., 
number of patients [%] and 80% CIs) on DCR at 6 and 12 months will be produced.
4.2.3.4
Progression-free survival
Kaplan-Meier plot of PFS will be presented. Summaries of the number and percentage of 
patients experiencing a PFS event and the type of event (RECIST 1.1 or death), are still in 
survival follow-up, are lost to follow-up and have withdrawn consent will be provided along 
with median PFS (if calculable). Median progression-free survival will also be presented, 
based on the Kaplan-Meier estimates.
4.2.3.5
Proportion of patients with progression-free survival after 3 months and 6 
months
The PFS3 and PFS6 will be calculated using Kaplan-Meier estimates, as the cumulative 
probability of progression-free survival to each of those time periods. Estimates of PFS3 and 
PFS6 will each be presented with 80% CIs.


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4.2.3.6
Overall survival
Kaplan-Meier plot of OS will be presented. Summaries of the number and percentage of 
patients who have died, are still in survival follow-up, are lost to follow-up, and have 
withdrawn consent will be provided along with median OS (if calculable).
4.2.3.7
Proportion of patients alive at 6 and 12 months
The OS6, and OS12, will be calculated using Kaplan-Meier estimates of the cumulative
probability of survival at each of those time periods. The survival estimates of OS6 and OS12 
will be presented with 80% CIs. 
4.2.3.8
Best objective response
For each treatment arm, best objective response (BoR) will be summarized by n (%) for each 
category (CR, PR, SD, PD and NE). No formal statistical analyses are planned for BoR.
4.2.3.9
Change in tumor size
The absolute values and percentage change in target lesion tumor size from baseline will be 
summarized using descriptive statistics and presented at each timepoint. The best change in 
target lesion tumor size from baseline, (where best change in target lesion size is the 
maximum reduction from baseline or the minimum increase from baseline in the absence of a 
reduction) will also be summarized.
Tumor size will also be presented graphically using waterfall plots, to present each patient’s 
best percentage change in tumor size as a separate bar, with the bars ordered from the largest 
increase to the largest decrease. Reference lines at the +20% and -30% change in tumor size 
levels will be added to the plots, which correspond with the definitions of progression and 
‘partial’ response respectively. Additional waterfall plots showing percentage change in tumor 
size at specific timepoints may be produced if it is felt that these are warranted to provide 
greater clarity.
Additionally, ‘spider’ plots will be produced. This depicts each patient’s percentage change in 
tumor size as a line over time.
4.2.4
Safety data
Safety and tolerability data will be presented using the Safety analysis set. Safety data will be 
summarized only. No formal statistical analyses will be performed on the safety data.
Data from all cycles of treatment will be combined in the presentation of safety data. AEs 
(both in terms of MedDRA preferred terms and CTCAE grade) will be listed individually by 
patient. The number of patients experiencing each AE will be summarized by CTCAE grade. 
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, vital signs, and ECGs. Exposure to MEDI4736, nab-paclitaxel + gemcitabine, 
and AZD5069 will be summarized. Time on study and MEDI4736, nab-paclitaxel + 
gemcitabine, and AZD5069 combination therapy dose interruptions will also be summarized. 
The following sections describe the planned safety summaries. However, additional safety 
tables may be required to aid interpretation of the safety data.


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DLTs
The proportion of patients with at least one DLT will be displayed considering the tick box of 
the AE page.
AEs
All AEs, both in terms of current MedDRA preferred term and CTCAE grade, will be 
summarized descriptively by count (n) and percentage (%). The majority of the AE 
summaries, unless otherwise stated, will be based on treatment-emergent AEs. Any AE 
occurring before study treatment (i.e. before the administration of the first dose on Study Day 
1) will be included in the AE listings, but will not be included in the summary tables (unless 
otherwise stated). These will be referred to as ‘pre-treatment’. 
AEs observed up until 90 days following discontinuation of the IP (i.e., the last dose of 
MEDI4736 or nab-paclitaxel or gemcitabine or AZD5069) or until the initiation of the first 
subsequent anticancer therapy following discontinuation of treatment (whichever occurs first) 
will be used for reporting of all of the AE summary tables. 
However, to assess the longer term toxicity profile, all of the AE summaries will also be 
produced containing AEs observed up until 90 days following discontinuation of the IP (i.e. 
without taking subsequent therapy into account).
A small selection of AE summaries may also be produced containing AEs observed from 
initiation of the first subsequent therapy following discontinuation of study treatment until    
90 days following discontinuation of IPs (i.e. summarizing those AEs experienced by patients 
taking subsequent therapy during the AE collection follow-up window post discontinuation of 
study treatment). These outputs will only be produced if the number of AEs observed warrant 
the inclusion of such outputs for interpretational purposes. Any data post 90 days last dose for 
IPs will be presented in a separate summary that presents any events that occur prior to dosing 
or starting more than 90 days after discontinuing treatment.
All reported AEs will be listed along with the date of onset, date of resolution (if AE is 
resolved) and investigator’s assessment of severity and relationship to study drug. Any event 
that occurs after a patient has received further therapy for cancer will be flagged. A separate 
data listing of AEs occurring more than 90 days after discontinuation of IP will be produced.
Frequencies and percentages of patients reporting each preferred term will be presented (i.e. 
multiple events per patient will not be accounted for apart from on the episode level 
summaries).
Summary information (the number and percent of patients by system organ class and preferred 
term) will be tabulated for:

All AEs

All AEs causally related to study treatment (as determined by the reporting 
investigator)

AEs by maximum CTCAE grade


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
AEs with CTCAE grade 3 or higher

AEs with CTCAE grade 3 or higher, causally related to study treatment (as 
determined by the reporting investigator)

AEs with outcome of death

AEs with outcome of death causally related to study treatment (as determined by 
the reporting investigator)

AEs by outcome

All SAEs

All SAEs causally related to study treatment (as determined by the reporting 
investigator)

SAEs leading to discontinuation of study treatment

AEs leading to discontinuation of study treatment

AEs leading to discontinuation of study treatment, causally related to study 
treatment (as determined by the reporting investigator)

AEs leading to hospitalization

Other significant AEs

Other significant AEs causally related to study treatment (as determined by the 
reporting investigator)

Immune mediated AEs (as determined by the reporting investigator)

Infusion reaction AEs (as determined by the reporting investigator)
An overall summary of the number and percentage of patients in each category will be 
presented. In addition, a truncated AE table of most common AEs and another table showing 
most common AEs with CTCAE grade 3 or higher, showing all events that occur in at least 
5% of patients overall will be summarized by preferred term, by decreasing frequency. This 
cut-off may be modified after review of the data. When applying a cut-off (i.e., x %), the raw 
percentage should be compared to the cut-off, no rounding should be applied first (i.e., an AE 
with frequency of 4.9% will not appear if a cut-off is 5%). Summary statistics showing the 
time to onset and the duration of the first AE will also be presented.
Deaths
A listing of all deaths will be provided, on the FAS.


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Adverse events of special interest
Preferred terms used to identify adverse events of special interest (as defined in Section 3.3.2) 
will be listed before DBL and documented in the study master file. Grouped summary tables 
will be produced and may also show the individual preferred terms which constitute each 
AESI grouping. For each ‘grouped’ term, the number (%) of patients experiencing any of the 
specified terms will be presented by maximum CTCAE grade. Groupings will be based on 
preferred terms provided by the medical team prior to DBL, and a listing of the preferred 
terms in each grouping will be provided.
Additional summaries of the above-mentioned grouped AE categories will include number 
(%) of patients who have:

At least one adverse event of special interest presented by outcome

At least one adverse event of special interest causally related to study treatment

At least one adverse event of special interest leading to discontinuation of study 
treatment
A summary of total duration (days) of AESI will be provided for events which have an end 
date and this will be supported by summaries of ongoing AESIs at death and, separately, at 
DCO.
Additionally, there will be several summaries of AESIs requiring concomitant treatment, and 
particularly the relationship of AESIs to the use of immunosuppressive agents (i.e., depicting 
which AESI triggered immunosuppressive use) and, separately, to the use of 
immunosuppressive agents at high doses.
Laboratory assessment
Data obtained up until the last assessment during follow-up, as detailed in Appendix 2,
following discontinuation of the IP or until the initiation of the first subsequent therapy 
following discontinuation of treatment (whichever occurs first) will be used for reporting. 
Data summaries will be provided in International System (SI) of units. The denominator used 
in laboratory summaries of CTC grades will only include evaluable patients, in other words 
those who had sufficient data to have the possibility of an abnormality.
Scatter plots (shift plots) of baseline to maximum value on treatment will be produced for lab 
parameters where data is available, including for example but not exclusive to: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total 
bilirubin, corrected calcium, lactate dehydrogenase (LDH), magnesium, sodium, potassium, 
glucose, creatinine, urea or blood urea nitrogen (depending on local practice), and thyroid-
stimulating hormone (TSH), free triiodothyronine (fT3) and free thyroxine (fT4).
Scatter plots (shift plots) of baseline to minimum value on treatment will be produced for: 
hemoglobin, lymphocyte (count, absolute); neutrophils (count, absolute); platelet count; 
albumin, total protein, corrected calcium, magnesium, sodium, potassium, glucose and TSH, 
fT3 and fT4.


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Shift tables for laboratory values by worst CTC grade will be produced, and for specific 
parameters separate shift tables indicating hyper- and hypo- directionality of change will be 
produced. The laboratory parameters for which CTC grade shift outputs will be produced are:

Hematology: hemoglobin, total white cell count, lymphocytes (absolute count), 
neutrophils (absolute count), platelets

Clinical chemistry: ALT, AST, ALP, total bilirubin, albumin, magnesium – hypo 
and – hyper, sodium – hypo and – hyper, potassium – hypo and – hyper, corrected 
calcium – hypo and – hyper, glucose – hypo and hyper, creatinine
For the parameters with no CTCAE grading that are listed in the CSP, shift tables from 
baseline to maximum, and baseline to minimum value on-treatment will be provided. 
All shift plots will be produced with appropriate reference lines.
Liver Enzyme Elevations and Hy's law
The following summaries will include the number (%) of patients who have:

Elevated ALT, AST, and total bilirubin at any point during the study following the 
start of study treatment

ALT ≥ 3x –≤5x, > 5x –≤8x, > 8x –≤10x,  > 10x–≤20x, and > 20x ULN 

AST ≥3x –≤5x, > 5x –≤8x, > 8x –≤10x, > 10x–≤20x, and > 20x ULN 

Total bilirubin ≥2x–≤ 3x, > 3x –≤ 5x, > 5x ULN 

ALT or AST ≥3x - ≤5x, >5x - ≤8x, >8x - ≤10x, >10x - ≤20x and >20x ULN 

ALT or AST ≥3x ULN and Total bilirubin ≥2x ULN (Potential Hy’s law). 
Note: The onset date of ALT or AST elevation should be prior to or on the date 
of Total Bilirubin elevation.
Liver biochemistry test results over time for patients with elevated ALT or AST (i.e. ≥ 3x 
ULN), and elevated total bilirubin (i.e. ≥ 2x ULN) (at any time) will be plotted. Individual 
patient data where ALT or AST (i.e. ≥ 3x ULN) plus total bilirubin (i.e. ≥ 2x ULN) are 
elevated at any time will be listed also.
Plots of ALT and AST vs. total bilirubin will also be produced with reference lines at 3×ULN 
for ALT, AST, and 2×ULN for total bilirubin. In each plot, the maximum values on treatment 
will be reported, ALT/AST will be on the horizontal axis and total bilirubin will be in the 
vertical axis.
ECG assessment
Shift plots to minimum and maximum observation on treatment will be produced for each of 
the ECG parameters presenting mean QT duration, mean RR duration, and QTcF. The 


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reviewing physician will determine what is worth further consideration, for example ECG data 
at screening and during treatment period may be included in the summary tables for RR, QT 
and QTcF. Overall evaluation of ECG is collected in terms of normal or abnormal, and the 
relevance of the abnormality is termed as “clinically significant” or “not clinically 
significant”. QTcF changes (values of >450, >480, and >500; increase/decrease of >30, >60, 
and >90 from baseline to any time; and value >450 and increase of > 30 and value >500 and 
increase of >60) during treatment will be summarized.
Vital signs
Summary tables will include data up to the 30-day follow-up period or until the initiation of 
the first subsequent anticancer therapy following discontinuation of treatment (whichever 
occurs first).
Vital signs parameters (systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse 
rate, temperature, respiratory rate and weight) will be summarized over time in terms of 
absolute values and changes from baseline at each scheduled visit.
Box plots for absolute values and change from baseline in SBP, DBP, pulse rate, temperature, 
respiratory rate and weight will be presented, if warranted after data review
Time to Subsequent Therapy from discontinuation of study treatment
This will be listed only. 
4.2.5
Pharmacokinetic data
Pharmacokinetic concentration data will be listed for each patient and each dosing day, and a 
summary provided by nominal visit/time point for all evaluable patients in the PKS. In 
addition, a box plot for different cycles of trough and peak will be produced.
4.2.5.1
Immunogenicity analysis
Immunogenicity results will be listed by patient and a summary will be provided of the 
number and percentage of patients who develop detectable anti-MEDI4736, anti-nab-
paclitaxel, anti-gemcitabine and ADZ5069 antibodies, if applicable, based on the Safety 
analysis set. If available, the immunogenicity titer and neutralizing ADA data will be listed for 
samples confirmed positive for the presence of anti-MEDI4736 antibodies.
The effect of immunogenicity on PK, PDx, efficacy and safety will be evaluated if data allow. 
These outputs will be produced by AstraZeneca/MedImmune Clinical Pharmacology group or 
designee.
4.2.6
Biomarker data
If sufficient data are available, the relationship of PD-L1 expression and of exploratory 
biomarkers to ORR, DoR, DCR, OS, and PFS will be presented for a subset of patients in the 
EAS population who are evaluable for each biomarker.
This will be assessed using similar summary and graphical representations to those that are 
outlined for the efficacy outputs.
PD-L1 expression determined by immunohistochemistry will be reported in the CSR. 
Summaries and analyses for exploratory biomarkers will be documented in a separate analysis 


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plan and will be reported outside the CSR in a separate report. These outputs will be produced 
by AstraZeneca/MedImmune Biomarker group or designee.
4.2.7
Demographic and baseline characteristics data
The following will be summarized for all patients in the Safety analysis set (unless otherwise 
specified):

Patient disposition (including screening failures and reason for screening failure)-
All subjects

Patient recruitment by country and center – All subjects

Important protocol deviations

Inclusion in analysis sets (FAS, Safety analysis set, PKS, DLT evaluable set, EAS)
- FAS

Demographics (derived age, age group [<50, ≥50-< 65, ≥65-<75 and ≥ 75 years], 
sex, race, ethnicity)

Patient characteristics at baseline (height, weight, weight group [<70, ≥70 - ≤90 and 
> 90 kg], body mass index (BMI) and body mass index group [<18.5, ≥18.5 - <25.0, 
≥25.0 - <30, ≥30.0)

Previous disease-related treatment modalities

Number of regimens of previous chemotherapy at baseline

Disease characteristics at baseline (ECOG Performance status (PS), primary tumor 
location, histology type, tumor grade, American Joint Committee on Cancer
(AJCC) stage, pancreas cancer location and overall disease classification, best 
response to previous therapy, time from informed consent to first dose [≤ 14 days, 
14 days < to ≤ 21 days, 21 days < to ≤ 42 days, > 42 days])

Extent of disease at baseline

Disease related medical history (past and current combined)

Relevant surgical history

Time from most recent disease progression to start of study treatment

Disallowed concomitant medications

Allowed concomitant medications


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
Nicotine use, categorized (never, current, former) and descriptive statistics by type 
of substance use
The AZ drug dictionary (AZDD) will be used for concomitant medication coding.
4.2.8
Treatment exposure
The following summaries related to study treatment will be produced for the Safety analysis 
set:

Total exposure (weeks) of each molecule.

Actual exposure (weeks) of each molecule.

Total number of cycles received (i.e. at least some drug administered).

Number of dose reductions of AZD5069 along with reasons, and number of dose 
interruptions of MEDI4736 and AZD5069. Dose interruptions will be based on 
investigator initiated dosing decisions. In addition, interruptions due to AEs and due 
to reasons other than AEs will be summarized separately.

Number of infusions received (MEDI4736).

Number of cycles with AZD5069 administration

Number of administrations (AZD5069)

RDI of MEDI4736 and AZD5069.

Exposure over time will be plotted.
The total and actual exposures will also be expressed as total treatment years, defined as the 
total across all patients in the analysis set.
4.2.9
ECOG PS
ECOG PS will be summarized over time.
4.2.10
Subsequent Therapy
Subsequent therapies received after discontinuation of study treatment will have summaries 
produced, together with number of regimens received.
5.
TIMING OF ANALYSES
No interim analysis is planned.


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5.1
Cohort 1
The timing for Cohort 1 will follow the Cohort 2 Primary and Follow-up analyses timing (see 
Section 5.2).
5.2
Cohort 2
A safety review will occur when the 6 initial patients complete 1 treatment cycle, before the 
decision to expand to 10 additional patients, in order to observe if any unexpected toxicity has 
occurred other than that observed in Study D5660C0004. Medics/safety will review the data 
collected from RAVE; Safety TLFs will be produced for that purpose with Safety listings as a 
minimum.
A decision was made not to perform a Primary analysis (6 months after the last 10 additional 
subjects recruited have Cycle 2 Day 15 assessments).
The full TLF package will be produced at the time of the final DBL (planned 12 months after 
the last of the 10 additional subjects is recruited).
Patient listings will be produced for patients still on study at the time of the follow-up 
analysis. These listings will be produced from RAVE.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
Table 10
Details of changes from the clinical study protocol
Protocol
SAP
Explanation
Section 
5.2.3
Section 3.3.4
For Cohort 1, ECGs will be recorded at screening and as 
clinically indicated.
For Cohort 2, 12-Lead ECGs will be recorded in 
triplicate at screening and day 1 of each treatment cycle. 
Triplicates are collected at screening for both cohorts, as 
mentioned in CSP Tables 2 and 3 footnote [c]
Section 
8.2.2
Section 1.3.2
Based on binomial probabilities, the probability of observing 0 
or more patients with a toxicity event in 6 patients (6 patients 
respectively) can be seen in Table 2.
Sentence updated in the SAP with the right number of patients: 
“… with a toxicity event in 6 patients (16 patients 
respectively)…”.
Section 8
Section 4.2
95%CI replaced with 80%CI due to small sample size
Section 
8.5.1.1
Section 4.2.3.2
Descriptive statistics produced for Cohort 2 only since only 
listings to be produced as mentioned in CSP Section 8.5
Section 
8.5.1.3
Section 4.2.3.4
Only for Cohort 2 since only listings to be produced as 
mentioned in CSP Section 8.5
Section 
Section 4.2.3.5
Only for Cohort 2 since only listings to be produced as 


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8.5.1.4
mentioned in CSP Section 8.5
Section 
8.5.1.5
Section 4.2.3.6
Only for Cohort 2 since only listings to be produced as 
mentioned in CSP Section 8.5
Section 
8.5.1.6
Section 4.2.3.7
Only for Cohort 2 since only listings to be produced as 
mentioned in CSP Section 8.5
Section 
8.4.2.4, 
Section 
8.5.1
Section 3.2.2.1
Section 4.2.3.2
DoR: CSP Section 8.4.2.4 mentions “until the first date of 
documented progression” for the main analysis and “with 
confirmation of progression” for the sensitivity analysis
SAP sections are updated to perform the main analysis 
considering the requirement for a confirmed progression.
No analysis modified for unconfirmed progression will be 
conducted due to lack of meaningful contribution to the 
interpretation of the data.
Section 
8.4.2.4, 
Section 
8.5.1
Section 3.2.2.3
Section 4.2.3.4
PFS: CSP Section 8.4.2.4 mentions “until the date of objective 
disease progression” for the main analysis and “with 
confirmation of progression” for the sensitivity analysis
SAP sections are updated to perform the main analysis 
considering the absence of requirement for a confirmed 
progression.
No analysis modified for confirmed progression will be 
conducted.
Section 
8.4.2.4,
Section 
8.5.1
Section 3.2.2.9
Section 4.2.3.8
BOR: CSP Section 8.4.2.4 mentions “until the first progression 
event” for the main analysis and “with confirmation of 
progression” for the sensitivity analysis
SAP sections are updated to perform the main analysis 
considering the requirement for a confirmed progression.
No analysis modified for unconfirmed progression will be 
conducted due to lack of meaningful contribution to the 
interpretation of the data.
7.
REFERENCES
Cockcroft and Gault 1976
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron
1976; 16(1):31-41.
Pintilie M 
Competing risks: A practical perspective. Wiley.
Von Hoff et al 2013
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival
in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med
2013; 369(18):1691-703.


Statistical Analysis Plan 
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52
CTCAE v4.03
A copy of CTCAE, Version 4.03 can be downloaded from the Cancer Therapy Evaluation 
Program website (http://ctep.cancer.gov).
8.
APPENDIX
Appendix 1: Visit windows
For example, the visit windows for vital signs data for Cohort 1 (visits on Day 1, 8, 15 of each 
cycle):
Cycle
Day 
cycle
Day
Lower
Upper
1
8
8
2
11
1
15
15
12
22
2
1
29
23
32
2
8
36
33
39
2
15
43
40
50
3
1
57
51
60
3
8
64
61
67
3
15
71
68
78
4
1
85
79
88
4
8
92
89
95
4
15
99
96
106
5
1
113
107
116
5
8
120
117
123
5
15
127
124
134
6
1
141
135
144
6
8
148
145
151
6
15
155
152
162
7
1
169
…
Appendix 2: Follow-up period for laboratory parameters
Cohort 1
Cohort 2
Urine hCG or serum β-hCG
30 days (±3)
30 days (±3)


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Hematology
90 days (±7)
90 days (±7)
Serum or plasma chemistry 
90 days (±7)
90 days (±7)
Thyroid function tests (TSH, fT3, and fT4)
30 days (±3)
30 days (±3)