Clinical trial NCT02558894
Conditions: Metastatic Pancreatic Ductal Adenocarcinoma
Keywords: Pancreatic Ductal Adenocarcinoma, PDAC
Sponsor: AstraZeneca
Start date: 2015-11-16; Completion date: 2017-06-15
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase II Open-Label, Multi-Center Study of MEDI4736 Evaluated as Single Agent or in Combination with Tremelimumab in Patients with Metastatic Pancreatic Ductal Adenocarcinoma.

Detailed description:
This is a Phase II, open-label, multi-center study to determine the efficacy and safety of MEDI4736 evaluated as single agent or in combination with tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) whose disease has progressed on fluoropyrimidine containing or gemcitabine-containing first-line chemotherapy.This study will consist of Part A, lead-in, as well as a possible expansion Part B.

Arms: arm 1: MEDI4736 via IV infusion. arm 2: MEDI4736+tremelimumab via IV infusion.
Interventions: intervention 1: MEDI4736 monotherapy intervention 2: tremelimumab+MEDI4736
Intervention descriptions: intervention 1: MEDI4736 via IV infusion. intervention 2: tremelimumab+MEDI4736 via IV infusion.

Protocol documents:
Prot_000.pdf: 
33'
33'


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
2(131)
PROTOCOL SYNOPSIS
A Phase II Open-Label, Multi-Center Study of MEDI4736 Evaluated as 
Single Agent or in Combination with Tremelimumab in Patients with 
Metastatic Pancreatic Ductal Adenocarcinoma
International Coordinating Investigators
 
Number of patients planned
This study will consist of Part A, Lead-in, as well as a possible Part B, non-randomized 
expansion (Part B: Expansion) or a possible Part B, randomized controlled study
(Part B: RCT).  This study will initially enroll approximately 60 patients to receive 
MEDI4736 monotherapy or MEDI4736 + tremelimumab combination therapy (Part A:
Lead-in). Depending on the data in each arm from Part A, a non-randomized expansion phase 
may be initiated (Part B: Expansion approximately 140 additional patients, 70 patients per 
arm) and/or a randomized, controlled study (Part B: Randomized, controlled trial ([RCT]) 
may be initiated to compare MEDI4736 monotherapy and/or MEDI4736 + tremelimumab 
combination to Standard of Care (SoC; approximately 375 total additional patients, 125 
patients per arm).
Study period
Phase of development
Estimated date of first patient enrolled
Q4 2015
II
Estimated date of last patient completed
Q3 2020
II
Study design
This is a Phase II, open-label, multi-center study to determine the efficacy and safety of 
MEDI4736 evaluated as single agent or in combination with tremelimumab in patients with 
metastatic pancreatic ductal adenocarcinoma (PDAC) whose disease has progressed on
5-FU-containing or gemcitabine-containing first-line chemotherapy.  Initially, patients will be 
enrolled and randomized (1:1) to treatment with MEDI4736 monotherapy or MEDI4736 + 
tremelimumab, until 30 patients have been randomized to treatment in each arm (Part A: 
Lead-in).  Patient recruitment and tumor assessment will be monitored on an ongoing basis.
The format of Part B will be determined based on the responses seen in the first 30 patients in 
each arm in Part A.  A protocol amendment will be made if criteria are met to proceed to 
33'


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
3(131)
Part B. The protocol amendment will include available data from Part A and any changes to 
study design and statistical plan, if needed.
!
Part B: Expansion.  If an ORR of >25% (ie, responses in ≥8 patients) is observed 
in the first 30 treated patients in either treatment arm in Part A (unless the totality of 
the data supports a different decision), after protocol amendment an additional 
70 patients will be enrolled in that arm, for a total of 100 evaluable patients per arm.
!
Part B: Randomized, controlled trial (RCT).  If an ORR of >15% and <25% 
(ie, response in ≥5 patients and <8 patients) is observed in the first 30 treated 
patients in either treatment arm in Part A, a randomized, controlled substudy may
be initiated after protocol amendment.
If Part B: RCT is initiated, this will be a randomized, controlled, open-label, multi-center, 
study to determine the efficacy and safety of MEDI4736 monotherapy and/or MEDI4736 + 
tremelimumab combination therapy versus SoC chemotherapy (1:1 or 1:1:1, depending on 
whether there are 2 or 3 treatment arms).  Approximately 125 additional patients per treatment 
arm will be planned for enrollment.  Treatment arms for MEDI4736 monotherapy and/or 
MEDI4736 + tremelimumab will only be included in the RCT if the corresponding treatment 
meets the appropriate criteria in Part A.  Randomization in Part B: RCT will be stratified by 
best response to prior first-line chemotherapy (complete response [CR], partial response [PR], 
or stable disease [SD]) versus no response (progressive disease [PD]) and according to prior 
first-line chemotherapy, 5-FU-containing versus gemcitabine-containing.
Tumor assessments will be performed every 6 weeks ±7 days for the first 48 weeks relative to 
the date of first infusion and then every 12 weeks ±7 days thereafter until confirmed PD, with 
categorization of objective tumor response by Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST 1.1).
Objectives
Part A: Lead-in and Part B: Expansion
Primary objective:
Outcome measure:
To assess the efficacy of MEDI4736 
monotherapy and MEDI4736 + tremelimumab 
combination therapy in terms of ORR
ORR in all patients using Investigator assessments 
according to RECIST 1.1
Secondary objectives:
Outcome measures:
To further assess the efficacy of the 
combination of MEDI4736 and tremelimumab 
and MEDI4736 alone 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


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
4(131)
Secondary objectives:
Outcome measures:
To assess the health-related QoL in metastatic 
PDAC patients treated with MEDI4736 + 
tremelimumab combination therapy and 
MEDI4736 monotherapy as measured by 
EORTC QLQ-C30 global QoL scale (Part B 
only)
Adjusted mean change from baseline in global QoL 
score from the EORTC QLQ-C30 questionnaire
To assess the disease-related symptoms in 
metastatic PDAC patients treated with 
MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy as 
measured by EORTC QLQ-PAN26 pancreatic 
pain scale (Part B only)
Adjusted mean change from baseline in pancreatic 
pain score from the EORTC QLQ-PAN26 
questionnaire
To investigate the immunogenicity of 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy
Presence of ADAs for MEDI4736 and tremelimumab 
(confirmatory results: positive or negative; titers)
To assess the PK of MEDI4736 monotherapy 
and MEDI4736 + tremelimumab combination 
therapy
Concentration of MEDI4736/tremelimumab in blood 
and noncompartmental PK parameters (such as peak 
concentration and trough, as data allow; sparse 
sampling only)
Safety objective:
Outcome measures:
To assess the safety and tolerability profile of 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy
AEs, physical examinations, laboratory findings 
(including clinical chemistry, hematology, and 
urinalysis), vital signs (including blood pressure and 
pulse), ECGs
Part B: Randomized, controlled trial
Primary objective:
Outcome measure:
To assess the efficacy of MEDI4736 
monotherapy and MEDI4736 + tremelimumab 
combination therapy compared to SoC in terms 
of OS
OS
Secondary objectives:
Outcome measures:
To further assess the efficacy of MEDI4736 
monotherapy and MEDI4736 + tremelimumab 
combination therapy compared to SoC in terms 
of ORR, DoR, DCR, PFS, PFS2, PFS3, and 
OS6, OS12
PFS, PFS2, PFS3, ORR, DoR, and DCR in all 
patients using Investigator assessments according to 
RECIST 1.1
OS6, OS12


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
5(131)
Secondary objectives:
Outcome measures:
To investigate the relationship between PD-L1 
expression by IHC and efficacy parameters
ORR, DoR, DCR, PFS3, and PFS6 across PD-L1 
expression using Investigator assessments according 
to RECIST 1.1
To assess the health-related QoL in metastatic 
PDAC patients treated with MEDI4736 + 
tremelimumab combination therapy and 
MEDI4736 monotherapy as measured by 
EORTC QLQ-C30 global QoL scale
Adjusted mean change from baseline in global QoL 
score from the EORTC QLQ-C30 questionnaire
To assess the disease-related symptoms in 
metastatic PDAC patients treated with 
MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy as 
measured by EORTC QLQ-PAN26 pancreatic 
pain scale 
Adjusted mean change from baseline in pancreatic 
pain score from the EORTC QLQ-PAN26 
questionnaire
To investigate the immunogenicity of 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy
Presence of ADAs for MEDI4736 and tremelimumab 
(confirmatory results: positive or negative; titers)
To assess the PK of MEDI4736 monotherapy 
and MEDI4736 + tremelimumab combination 
therapy
Concentration of MEDI4736/tremelimumab in blood 
and noncompartmental PK parameters (such as peak 
concentration and trough, as data allow; sparse 
sampling only)
Safety objective:
Outcome measures:
To assess the safety and tolerability profile of 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy compared 
to SoC
AEs, physical examinations, laboratory findings 
(including clinical chemistry, hematology, and 
urinalysis), vital signs (including blood pressure and 
pulse), ECGs
Target subject population
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 at least 2 months of 
prior standard first-line 5-FU-containing or gemcitabine-containing chemotherapy.
Duration of treatment
Patients in the Part A Lead-in or Part B will receive MEDI4736 monotherapy or MEDI4736 + 
tremelimumab combination therapy for a 12- month period or until discontinuation criteria are 
met.  Patients in the SoC arm of the Part B: Randomized, controlled trial will discontinue 
study drug at the first assessment of disease progression per RECIST 1.1.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
6(131)
Patients in the MEDI4736 monotherapy treatment arm who develop PD after completing 12 
months of therapy may restart their assigned treatment with the same treatment guidelines 
followed previously.  Patients in the MEDI4736 + tremelimumab arm may restart treatment if 
they complete the 4 dosing cycles with MEDI4736 + tremelimumab (with clinical benefit per 
Investigator judgement) but subsequently have confirmed progression of disease during or 
following treatment with MEDI4736 alone.  
Patients who have discontinued all study treatment will enter follow-up.
Investigational product, dosage, and mode of administration
MEDI4736 monotherapy treatment arm
!
1.5 g MEDI4736 via IV infusion q4w, starting at Week 0, for up to a total of 
12 months (up to 13 doses)
MEDI4736 + tremelimumab combination therapy treatment arm
!
1.5 g MEDI4736 by IV infusion q4w and 75 mg tremelimumab q4w by IV infusion 
starting at week 0 (up to 4 doses each), followed by 1.5 g MEDI4736 monotherapy 
by IV infusion q4w (starting on Week 16) to complete a total of 12 months of 
therapy (up to 9 additional doses) 
Standard of Care (Part B: Randomized, controlled trial only)
!
Gemcitabine-based or fluorouracil-based chemotherapy administered per local 
guidelines
Statistical methods
For each arm in Part A (Lead-in) of the study, once 15 patients have completed 2 
post-baseline tumor assessments (at Weeks 6 and 12), predictive probability will be calculated 
to assess the chance of observing at least 5 out of 30 responses (>15% ORR [CR or PR], 
and/or at least 15/30 DCR at 12 weeks (≥50% DCR12) in that arm.  If, predictive probability 
is below 10% for both endpoints, enrollment into the arm in which this happens will be 
stopped.  A different decision outside of these criteria may be made, if the totality of the data 
supports it.  Recruitment will continue while predictive probability is evaluated.  If enrollment 
into an arm is to be stopped based on <10% predictive probability, no new patients will be 
recruited, but patients who are already on study will continue in accordance with study 
guidelines.  If enrollment is fast enough so that, by the time 15 patients are evaluable (Weeks 
6 and 12 tumor assessment data available), all 30 patients per arm have already been 
randomized, then the predictive probability calculations will not be carried out.  
If the ORR in Part A is >25% (ie, ≥8 responses from 30 patients in an arm), then an additional 
70 patients will be enrolled to that arm (Part B: Expansion) to evaluate ORR in 100 patients in 
total (unless the totality of the data supports a different decision).  In the Part B: Expansion 
study, the primary endpoint, ORR, will be evaluated using a 2-sided, 95% Clopper-Pearson 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
7(131)
confidence interval to the observed ORR in the expanded cohort of 100 patients. With 
100 patients, there will be >90% power to reject the null hypothesis of a 10% response rate 
assuming a true response rate of 25% at 5% (2-sided) significance level (critical value ORR of 
16.7%), while also providing adequate patients to reasonably characterize the safety profile of 
the expanded arm(s).  A 10% response rate is considered a reasonable assumption for the 
average response rate achieved by current therapies in second-line advanced pancreatic cancer 
(Rahma et al 2013).
If the ORR in Part A is >15% (ie, ≥5 responses from 30 treated patients in an arm), then a 
randomized, controlled substudy may be initiated (Part B: RCT).  If initiated, this substudy
will be a randomized, open- label, multi-center, study to determine the efficacy and safety of 
MEDI4736 monotherapy and/or MEDI4736 + tremelimumab combination therapy versus SoC 
chemotherapy (randomized 1:1 or 1:1:1, depending on whether there are 2 or 3 treatment 
arms) with a primary endpoint of OS. If both arms move forward to part B, then the primary 
comparison will be conducted on MEDI4736 + tremelimumab combination therapy versus 
SoC chemotherapy.  Approximately 125 additional patients per treatment arm will be planned 
for enrollment in this Part B: RCT. Treatment for MEDI4736 monotherapy and/or 
MEDI4736 + tremelimumab will only be included in the RCT if the corresponding treatment 
meets the appropriate criteria for Part A.  A final decision to initiate the randomized portion of 
the study will be made after evaluation of all available efficacy and safety data from the 
lead-in phase, and may not be limited to the decision rules provided in the protocol.  With 
125 patients per arm for a 2-arm study, 196 events (78% maturity) would provide 90% power 
to detect a true average hazard ratio of 0.63 at a 2-sided 5% significance level (critical value 
for hazard ratio of 0.75). This assumes a median OS in the SoC arm of 5 months and a 
2-month delay in survival curves separating.  The data from Part B: RCT will be analyzed 
separately and will not be pooled with Part A for the purpose of statistical analysis.  
For Part B: RCT, the randomization schedule will be stratified by best response to prior 
first-line chemotherapy (CR, PR, or SD) versus no response (PD), and by prior first-line 
chemotherapy, 5FU-containing versus gemcitabine-containing. The primary endpoint, OS, 
will be compared between treatments based on the hazard ratio, with 95% confidence 
intervals.  The hazard ratio will be estimated using a stratified log rank test.  If both arms are 
taken forward from Part A, then the primary comparison will be to compare MEDI4736 + 
tremelimumab combination therapy versus SoC.  MEDI4736 monotherapy versus SoC will be 
compared hierarchically in order to strongly control the type I error. Full details of the 
multiple testing procedure will be provided in the SAP.  
Secondary endpoints, including DoR, DCR, PFS, PFS2, PFS3 and PFS6, will be summarized 
based on Investigator assessments according to RECIST 1.1.  PFS, PFS2, PFS3, PFS6, OS, 
OS6, OS12, and DoR rates and their medians will be calculated and plotted using 
Kaplan-Meier estimates, with 95% confidence intervals.  Safety and tolerability will be 
evaluated through AEs, physical examinations, laboratory and vital sign measures, and 
electrocardiograms, using summary statistics.  Disease-related symptoms and health-related 
quality of life will be assessed through an analysis of the EORTC QLQ-C30 global quality of 
life (QoL) and QLQ-PAN26 pancreatic pain scales.  Adjusted mean change from baseline in 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
8(131)
global QoL score will be analyzed using a mixed model for repeated measures (MMRM) 
analysis of all of the post-baseline scores for each visit and will be presented by treatment 
group.  As a supportive analysis, global QoL improvement rate will be analyzed using a 
logistic regression model.  An exploratory analysis will examine adjusted mean change from 
baseline on EORTC QLQ-C30 functioning domains (physical, role, cognitive, emotional, and 
social) and on EORTC QLQ-C30 and QLQ-PAN26 symptom scales/items (including 
pancreatic pain, fatigue, nausea, weight loss [difficulty gaining weight/loss of appetite], and 
jaundice).  EORTC QLQ-C30 and QLQ-PAN26 compliance (overall compliance and by visit 
compliance) will be summarized for each treatment group.  


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
9(131)
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
PROTOCOL SYNOPSIS.........................................................................................2
TABLE OF CONTENTS.........................................................................................9
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................16
1.
INTRODUCTION .................................................................................................21
1.1
Background and rationale for conducting this study .............................................21
1.1.1
Immunotherapies....................................................................................................23
1.1.2
MEDI4736 .............................................................................................................23
1.1.3
Tremelimumab.......................................................................................................25
1.1.4
MEDI4736 in combination with tremelimumab....................................................25
1.1.5
Rationale for conducting this study .......................................................................26
1.2
Rationale for study design, doses and control groups............................................28
1.2.1
MEDI4736 and tremelimumab dose and treatment regimen justification.............28
1.2.1.1
MEDI4736 + tremelimumab combination therapy dose rationale ........................28
1.2.1.2
Rationale for 4 cycles of combination therapy followed by MEDI4736 
monotherapy ..........................................................................................................30
1.2.1.3
MEDI4736 monotherapy dose rationale................................................................31
1.2.1.4
Rationale for fixed dosing......................................................................................32
1.3
Benefit/risk and ethical assessment........................................................................33
1.3.1
Potential benefits....................................................................................................33
1.3.1.1
MEDI4736 .............................................................................................................33
1.3.1.2
Tremelimumab.......................................................................................................34
1.3.1.3
MEDI4736 + tremelimumab..................................................................................34
1.3.2
Potential risks.........................................................................................................34
1.3.2.1
MEDI4736 .............................................................................................................34
1.3.2.2
Tremelimumab.......................................................................................................35
1.3.2.3
MEDI4736 + tremelimumab..................................................................................36
1.3.3
Overall benefit and risk assessment.......................................................................36
1.4
Study design...........................................................................................................38
2.
STUDY OBJECTIVES..........................................................................................42
2.1
Primary objective...................................................................................................42
2.2
Secondary objectives .............................................................................................42
2.3
Safety objectives ....................................................................................................44
2.4
Exploratory objectives ...........................................................................................44


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
10(131)
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL.....................45
3.1
Inclusion criteria ....................................................................................................45
3.2
Exclusion criteria ...................................................................................................47
3.3
Patient enrollment and randomization ...................................................................49
3.4
Procedures for handling incorrectly enrolled or randomized patients...................50
3.5
Methods for assigning treatment groups................................................................51
3.6
Methods for ensuring blinding...............................................................................51
3.7
Methods for unblinding..........................................................................................51
3.8
Restrictions ............................................................................................................51
3.9
Discontinuation of investigational product............................................................52
3.9.1
Procedures for discontinuation of a patient from investigational product.............53
3.10
Criteria for withdrawal...........................................................................................53
3.10.1
Screen failures........................................................................................................53
3.10.2
Withdrawal of the informed consent......................................................................54
3.11
Discontinuation of the study..................................................................................54
4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................55
4.1
Enrollment/screening period..................................................................................65
4.2
Treatment period....................................................................................................65
4.3
Follow-up period....................................................................................................65
5.
STUDY ASSESSMENTS .....................................................................................65
5.1
Efficacy assessments..............................................................................................66
5.1.1
Central reading of scans.........................................................................................67
5.2
Safety assessments.................................................................................................67
5.2.1
Laboratory safety assessments...............................................................................67
5.2.2
Physical examination .............................................................................................69
5.2.3
ECG........................................................................................................................69
5.2.4
Vital signs ..............................................................................................................70
5.2.5
Other safety assessments........................................................................................70
5.3
Other assessments ..................................................................................................71
5.3.1
Patient reported outcomes (PRO) ..........................................................................71
5.3.1.1
EORTC QLQ-C30 .................................................................................................71
5.3.1.2
EORTC QLQ-PAN26............................................................................................71
5.3.1.3
PRO-CTCAE .........................................................................................................72
5.3.1.4
EQ-5D-5L ..............................................................................................................72
5.3.2
Administration of the patient-reported outcome questionnaires............................73
5.3.3
ECOG performance status .....................................................................................74


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
11(131)
5.3.4
Health resource use................................................................................................74
5.4
Pharmacokinetics ...................................................................................................75
5.4.1
Collection of samples.............................................................................................75
5.4.2
Determination of drug concentration of MEDI4736 and tremelimumab ..............75
5.4.3
Storage and destruction of pharmacokinetic samples for MEDI4736 and 
tremelimumab ........................................................................................................75
5.4.4
Collection of samples to measure the presence of ADAs......................................75
5.4.5
Storage and destruction of ADA samples..............................................................75
5.5
Biomarker analysis.................................................................................................76
5.5.1
Collection of samples.............................................................................................76
5.5.1.1
Collection of biomarker samples for evaluation of patient selection ....................76
5.5.1.2
Exploratory biomarker data ...................................................................................77
5.5.2
Management of biomarker data .............................................................................80
5.5.3
Storage, re-use, and destruction of biological samples..........................................80
5.5.4
Labeling and shipment of biological samples........................................................80
5.5.5
Chain of custody of biological samples.................................................................80
5.5.6
Withdrawal of informed consent for donated biological samples .........................81
5.6
Pharmacogenetics ..................................................................................................81
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................81
6.1
Definition of adverse events ..................................................................................82
6.2
Definitions of serious adverse event......................................................................82
6.3
Recording of adverse events ..................................................................................82
6.3.1
Time period for collection of adverse events.........................................................82
6.3.2
Follow-up of unresolved adverse events................................................................82
6.3.3
Variables ................................................................................................................83
6.3.4
Causality collection................................................................................................84
6.3.5
Relationship to protocol procedures ......................................................................84
6.3.6
Adverse events based on signs and symptoms.......................................................84
6.3.7
Adverse events based on examinations and tests...................................................85
6.3.8
Hy’s Law................................................................................................................85
6.3.9
Disease progression ...............................................................................................85
6.3.10
New cancers...........................................................................................................85
6.3.11
Deaths ....................................................................................................................86
6.4
Reporting of serious adverse events.......................................................................86
6.5
Overdose ................................................................................................................87
6.6
Pregnancy...............................................................................................................87
6.6.1
Maternal exposure..................................................................................................87
6.6.2
Paternal exposure...................................................................................................88
6.7
Management of IP-related toxicities......................................................................88
6.7.1
MEDI4736 and MEDI4736 + tremelimumab........................................................89
6.7.2
Standard of care .....................................................................................................89


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
12(131)
6.8
Study governance and oversight ............................................................................89
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................89
7.1
Identity of investigational product(s).....................................................................89
7.1.1
MEDI4736 .............................................................................................................90
7.1.2
Tremelimumab.......................................................................................................90
7.2
Dose and treatment regimens.................................................................................91
7.2.1
Treatment regimens ...............................................................................................91
7.2.2
Duration of treatment.............................................................................................92
7.3
Labelling ................................................................................................................94
7.4
Storage ...................................................................................................................94
7.5
Compliance ............................................................................................................95
7.6
Accountability........................................................................................................95
7.7
Concomitant and other treatments .........................................................................95
7.7.1
Other concomitant treatment..................................................................................97
7.8
Post study access to study treatment......................................................................97
8.
STATISTICAL ANALYSES BY ASTRAZENECA............................................97
8.1
Statistical considerations........................................................................................97
8.2
Sample size estimate..............................................................................................97
8.3
Definitions of analysis sets ....................................................................................99
8.3.1
Full analysis set......................................................................................................99
8.3.2
Safety analysis set..................................................................................................99
8.3.3
PK analysis set .....................................................................................................100
8.4
Outcome measures for analyses...........................................................................100
8.4.1
Calculation or derivation of efficacy variables....................................................100
8.4.1.1
RECIST 1.1-based endpoints...............................................................................100
8.4.1.2
Primary endpoints ................................................................................................101
8.4.1.3
Secondary endpoints ............................................................................................101
8.4.2
Calculation or derivation of safety variables .......................................................104
8.4.2.1
Adverse events.....................................................................................................104
8.4.2.2
Other significant adverse events ..........................................................................104
8.4.2.3
Safety assessments...............................................................................................105
8.4.3
Calculation or derivation of patient-reported outcome variables.........................105
8.4.3.1
EORTC QLQ-C30 ...............................................................................................105
8.4.3.2
EORTC QLQ-PAN26..........................................................................................108
8.4.3.3
Calculation or derivation of healthy state utility (EQ-5D-5L).............................108
8.4.4
Calculation or derivation of pharmacokinetic variables ......................................108
8.4.4.1
Population pharmacokinetics and exposure-response/safety analysis.................108
8.4.4.2
Pharmacokinetic noncompartmental analysis......................................................109
8.4.4.3
Immunogenicity analysis .....................................................................................109


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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8.4.5
Calculation or derivation of biomarker variables ................................................109
8.4.6
Calculation or derivation of pharmacogenetic variables......................................109
8.5
Methods for statistical analyses ...........................................................................109
8.5.1
Analysis of the primary variables ........................................................................111
8.5.2
Analysis of the secondary variables.....................................................................113
8.5.2.1
Duration of response............................................................................................113
8.5.2.2
Disease control rate..............................................................................................113
8.5.2.3
Progression-free survival .....................................................................................114
8.5.2.4
Progression-free survival2 (second progression).................................................114
8.5.2.5
Proportion of patients with progression-free survival after 3 months and 
6 months...............................................................................................................114
8.5.3
Proportion of patients alive at 6 and 12 months...................................................114
8.5.4
Patient-reported outcomes ...................................................................................114
8.5.4.1
EORTC QLQ-C30 ...............................................................................................114
8.5.4.2
EORTC QLQ-PAN26..........................................................................................115
8.5.4.3
PRO-CTCAE .......................................................................................................116
8.5.5
Safety data............................................................................................................116
8.5.6
Pharmacokinetic data...........................................................................................117
8.5.6.1
Immunogenicity analysis .....................................................................................117
8.5.7
Pharmacokinetic/pharmacodynamic relationships...............................................117
8.5.8
Biomarker data.....................................................................................................117
8.5.9
Healthcare resource use .......................................................................................117
8.5.10
Interim analysis....................................................................................................118
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ........................118
9.1
Training of study site personnel...........................................................................118
9.2
Monitoring of the study .......................................................................................118
9.2.1
Source data...........................................................................................................119
9.2.2
Direct access to source data in Japan...................................................................119
9.2.3
Study agreements.................................................................................................119
9.2.4
Archiving of study documents.............................................................................119
9.3
Study timetable and end of study.........................................................................119
9.4
Data management by AstraZeneca or delegate....................................................120
10.
ETHICAL AND REGULATORY REQUIREMENTS.......................................120
10.1
Ethical conduct of the study.................................................................................120
10.2
Patient data protection..........................................................................................121
10.3
Ethics and regulatory review................................................................................121
10.4
Informed consent .................................................................................................122
10.5
Changes to the protocol and informed consent form...........................................122
10.6
Audits and inspections .........................................................................................123


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Edition Number 1
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11.
LIST OF REFERENCES.....................................................................................124
LIST OF TABLES
Table 1
Effective methods of contraception (2 methods must be used)................52
Table 2
Schedule of assessments for treatment and retreatment periods for 
MEDI4736 and MEDI4736 + tremelimumab (12 months)......................56
Table 3
Schedule of assessments: follow-up for patients who have 
completed treatment and achieved disease control (until confirmed 
progression of disease) .............................................................................61
Table 4
Schedule of assessments: follow-up for patients who have 
discontinued study treatment due to confirmed progression of 
disease and patients who have discontinued due to toxicity in the 
absence of confirmed progression of disease ...........................................63
Table 5
Clinical chemistry (serum or plasma).......................................................68
Table 6
Hematology ..............................................................................................68
Table 7
Urinalysis..................................................................................................69
Table 8
Illustrative stopping boundaries for ORR and DCR12 based on 
15 evaluable patients (both criteria to be met to stop an arm)..................98
Table 9
Summary of outcome variables and analysis populations........................99
Table 10
Mean change and visit response in health related quality of life............106
Table 11
Preplanned statistical and sensitivity analyses to be conducted.............110
LIST OF FIGURES
Figure 1
Phase II, MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy - study design .................................39
Figure 2
Phase II, MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy - study flow chart............................40
Figure 3
MEDI4736 monotherapy dosing schedule ...............................................91
Figure 4
MEDI4736 + tremelimumab combination therapy dosing schedule........92


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Edition Number 1
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LIST OF APPENDICES
Appendix A
Signatures
Appendix B
Additional Safety Information 
Appendix C
IATA 6.2 Guidance Document
Appendix D
Pharmacogenetics Research
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law
Appendix F
Guidelines for Evaluation of Objective Tumor Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumors)
Appendix G
Patient Reported Outcomes


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Edition Number 1
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study clinical study protocol.
Abbreviation or 
special term
Explanation
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
BCRP
Breast cancer resistance protein
BICR
Blinded Independent Central Review
BoR
Best objective response
BP
Blood pressure
BSC
Best supportive care
CD
Cluster of differentiation
CI
Confidence interval
Cmax
Maximum plasma concentration
Cmax,ss
Maximum plasma concentration at steady state
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
Ctrough
Trough plasma concentration
Ctrough,ss
Trough plasma concentration at steady state


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Edition Number 1
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Abbreviation or 
special term
Explanation
DCR
Disease control rate
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid 
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
EDoR
Expected Duration of Response
EORTC
European Organisation for Research and Treatment of Cancer
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer quality of 
life core questionnaire
EORTC QLQ-PAN26
European Organisation for Research and Treatment of Cancer quality of 
life questionnaire pancreatic cancer module
EQ-5D-5L
EuroQol 5-dimension, 5-level health state utility index
EU
European Union
FAS
Full analysis set
FDA
Food and Drug Administration
FOLFIRINOX
Multidrug combination of leucovorin, fluorouracil, irinotecan, and 
oxaliplatin
fT3
Free triiodothyronine
fT4
Free thyroxine
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
hCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
HR
Hazard ratio
HRQoL
Health-related quality of life
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IFN-γ
Interferon-gamma


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Abbreviation or 
special term
Explanation
IgG
Immunoglobulin G
IHC
Immunohistochemical
IL
Interleukin
IMT
Immunomodulatory therapy
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
IWRS
Interactive Web Response System
LFT
Liver function test
LIMS
Laboratory Information Management System
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 randomization/enrollment
OS12
Proportion of patients alive at 12 months from randomization/enrollment
PBMC
Peripheral blood mononuclear cells
PD
Progressive disease
PD-1
Programmed cell death 1 


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Edition Number 1
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Abbreviation or 
special term
Explanation
PDAC
Pancreatic ductal adenocarcinoma
PD-L1
Programmed cell death ligand 1
PFS
Progression-free survival
PFS2
Progression-free survival2; time from the date of randomization to the 
earliest progression event(s) subsequent to that used for the PFS endpoint 
or death
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
PGx
Pharmacogenetic
PI
Principal Investigator 
PK
Pharmacokinetics
PR
Partial response
PRO
Patient-reported outcomes
PRO-CTCAE
Patient-reported outcomes version of the Common Terminology Criteria for 
Adverse Events
PS
Performance status
q2w
Every 2 weeks
q3w
Every 3 weeks
q4w
Every 4 weeks
q6w
Every 6 weeks
q8w
Every 8 weeks
q12w
Every 12 weeks
QoL
Quality of life
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RCT
Randomized controlled trial
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
SNP
Single nucleotide polymorphism


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Drug Substance MEDI4736 and Tremelimumab
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Edition Number 1
Date 17 August 2015
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Abbreviation or 
special term
Explanation
SoC
Standard of care
sPD-L1
Soluble programmed cell death ligand 1
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
WBDC
Web Based Data Capture
WT
Weight


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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).  


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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).  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).
Results of several preclinical models have demonstrated that blockade of PD-1 or PD-L1, or 


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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 
(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.
MEDI4736 has been given to humans as part of ongoing studies as a single drug or in 
combination with other drugs.  As of 14 July 2014, 509 patients have been enrolled and 
treated in 10 ongoing clinical studies on MEDI4736 (with 5 studies using MEDI4736 as 
monotherapy and 5 studies using MEDI4736 in combination therapy). Details on the safety 
profile of MEDI4736 are summarized in Section 1.3.2.1. Refer to the current MEDI4736 


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Edition Number 1
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Investigator’s Brochure (IB) for a complete summary of nonclinical and clinical information; 
see Section 6.7 for guidance on management of MEDI4736-related toxicities.
1.1.3
Tremelimumab
Tremelimumab, a CTLA-4 mAb of the IgG 2 kappa isotype, is an immunomodulatory therapy 
(IMT) that is being developed by AstraZeneca for use in the treatment of cancer.  
Tremelimumab is a human IgG 2 mAb directed against CTLA-4.   
Binding of CTLA-4 to its target ligands (B7-1 and B7-2) provides a negative regulatory 
signal, which limits T-cell activation.  Anti-CTLA-4 inhibitors antagonize the binding of 
CTLA-4 to B7 ligands and enhance human T-cell activation as demonstrated by increased 
cytokine (interleukin [IL]-2 and interferon–gamma [IFN-∀]) production in vitro in whole 
blood or peripheral blood mononuclear cell (PBMC) cultures (Tarhini and Kirkwood 2008).  
In addition, blockade of CTLA-4 binding to B7 by anti-CTLA-4 antibodies results in 
markedly enhanced T-cell activation and antitumor activity in animal models, including 
killing of established murine solid tumors and induction of protective antitumor immunity.  
(Refer to the current tremelimumab IB for more information.)  Therefore, it is expected that 
treatment with an anti-CTLA-4 antibody, such as tremelimumab, will lead to increased 
activation of the human immune system, increasing antitumor activity in patients with solid 
tumors. At the same time, it is unlikely that anti-CTLA-4 monotherapy will lead to long-term 
cures in the majority of patients as single agent. In this regard, a recently completed Phase II 
trial in patients with locally advanced or metastatic pancreatic cancer (NCT00836407) showed 
that anti-CTLA-4 monotherapy is ineffective in this patient population, only one patient 
experienced a delayed response after initial progressive disease (Royal et al 2010).
An extensive program of nonclinical and clinical studies has been conducted for 
tremelimumab both as monotherapy and combination therapy with conventional anticancer 
agents to support various cancer indications using different dose schedules.  As of the data 
cutoff date of 12 November 2014 (for all studies except Study D4190C00006, which has a 
cutoff date of 4 December 2014), 1010 patients have received tremelimumab monotherapy 
(excluding 497 patients who have been treated in the blinded Phase IIb study, D4880C00003) 
and 197 patients have received tremelimumab in combination with other agents.  More than 
800 of these patients had melanoma and were treated at a dose of 15 mg/kg every 90 days.  
Details on the safety profile of tremelimumab monotherapy are summarized in 
Section 1.3.2.2.  Refer to the current tremelimumab IB for a complete summary of nonclinical 
and clinical information; see Section 6.7 for guidance on management of tremelimumab-
related toxicities. 
Tremelimumab exhibited a biphasic pharmacokinetic (PK) profile with a long-terminal phase 
half-life of 22 days.  Overall, a low incidence of antidrug antibodies (ADAs; <6%) was 
observed in treatment with tremelimumab.  
1.1.4
MEDI4736 in combination with tremelimumab
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity 
(Pardoll 2012) because the mechanisms of action of CTLA-4 and PD-1 are nonredundant; 


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Edition Number 1
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therefore, AstraZeneca is also investigating the use of MEDI4736 + tremelimumab 
combination therapy for the treatment of cancer.
Study D4190C00006 is a Phase Ib dose-escalation study to establish safety, 
PK/pharmacodynamics, and preliminary antitumor activity of MEDI4736 + tremelimumab 
combination therapy in patients with advanced non-small-cell lung cancer (NSCLC).  The 
dosing schedule utilized is MEDI4736 every 2 or 4 weeks (q2w; q4w) up to Week 48 
(12 months), combined with tremelimumab q4w up to Week 24 for 7 doses, then 
tremelimumab every 12 weeks (q12w) for 2 additional doses for up to 12 months.  The study 
is ongoing and continues to accrue.  
As of 27 January 2015, a total of 74 patients have been treated in the study, including 
58 patients on the q4w dosing schedule and 16 patients on the q2w dosing schedule.  Patients 
have received between 1 and 13 doses of MEDI4736 and between 1 and 9 doses of 
tremelimumab.  Details on the safety profile of MEDI4736 + tremelimumab combination 
therapy are summarized in Sections 1.2.1 and 1.3.2.3.  Refer to the current MEDI4736 IB and 
tremelimumab IB for a complete summary of nonclinical and clinical information; see 
Section 6.7 for guidance on management of MEDI4736 + tremelimumab-related toxicities.
As of 27 January 2015 in Study D4190C00006, an approximately dose-proportional increase 
in PK exposure (maximum plasma concentration [Cmax], trough plasma concentration [Ctrough], 
and area under the plasma drug concentration-time curve from time zero to Day 28 post-dose 
[AUC0-28day]) of both MEDI4736 and tremelimumab was observed over the dose range of 3 to 
20 mg/kg MEDI4736 q4w or q2w and 1 to 10 mg/kg tremelimumab q4w.  Four of 60 patients 
were ADA positive for either anti-MEDI4736 or anti-tremelimumab antibodies 
post-treatment; MEDI4736 PK was impacted in only 2 of these 4 patients.  Complete soluble 
programmed cell death ligand 1 (sPD-L1) suppression (surrogate for PD-L1 targeting) was 
observed in almost all patients over the dose range of 3 to 20 mg/kg of MEDI4736 q4w or 
q2w.
1.1.5
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.  
Combining multiple immunotherapy agents has been shown to result in improved response 
rates relative to monotherapy, for example, the concurrent administration of nivolumab and 
ipilimumab to patients with advanced melanoma induced higher objective response rates 
(ORRs) than those obtained with single-agent therapy.  Importantly, responses appeared to be 
deep and durable (Wolchok et al 2013).  The rationale for evaluating the combination of 


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MEDI4736 with tremelimumab is that the mechanisms of CTLA-4 and PD-1 are 
nonredundant, suggesting that targeting both may have additive or synergistic activity 
(Pardoll 2012).  Similar results have been observed in an ongoing study of MEDI4736 + 
tremelimumab in NSCLC (Antonia et al 2014a), with further updated details presented in this 
clinical study protocol (CSP).
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 cytotoxic T lymphocytes (CTL)-mediated apoptosis 
through Fas- or perforin/granzyme-mediated pathways (Emens and Jaffee 2005).
Chemotherapy, even at conventional doses, can eliminate myeloid-derived suppressor cells 
(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 


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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 2013Kang 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 and tremelimumab), adoptive cell therapy (eg, T cells 
expressing chimeric antigen receptors), and vaccines (eg, sipuleucel-T).
Based on the preliminary clinical efficacy and safety data observed in the pancreatic cancer 
cohort of Study 1108 and the preliminary efficacy, safety, and tolerability data of MEDI4736 
+ tremelimumab combination therapy in Study D4190C00006 (a Phase Ib/II study of 
MEDI4736 + tremelimumab combination in NSCLC), this study is being conducted to
determine the safety and efficacy of the combination of MEDI4736 with tremelimumab and 
MEDI4736 as monotherapy in a Phase II setting in 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 and tremelimumab dose and treatment regimen justification
1.2.1.1
MEDI4736 + tremelimumab combination therapy dose rationale
The MEDI4736 + tremelimumab combination therapy doses and regimen selected for this 
study are based on the goal of selecting an optimal combination dose of MEDI4736 and 
tremelimumab that would yield sustained target suppression (sPD-L1), demonstrate promising 
efficacy, and have an acceptable safety profile.  
Pharmacokinetics/Pharmacodynamics data
In order to reduce the dosing frequency of MEDI4736 to align with the q4w dosing of 
tremelimumab, while ensuring an acceptable PK/pharmacodynamics, safety, and efficacy 
profile, cohorts in Study D4190C00006 were narrowed to 15 and 20 mg/kg MEDI4736 q4w.  
PK simulations from the MEDI4736 monotherapy data indicated that a similar area under the 
plasma drug concentration-time curve at steady state (AUCss; 4 weeks) was expected 
following both 10 mg/kg q2w and 20 mg/kg q4w MEDI4736.  The observed MEDI4736 PK 
data from the D4190C00006 study were well in line with the predicted monotherapy PK data 
developed preclinically.  This demonstrates similar exposure of MEDI4736 20 mg/kg q4w and 


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10 mg/kg q2w, with no alterations in PK when MEDI4736 and tremelimumab (doses ranging 
from 1 to 3 mg/kg) are dosed together.  While the median maximum plasma concentration at 
steady state (Cmax,ss) is expected to be higher with 20 mg/kg q4w (approximately 1.5 fold) and 
median trough concentration at steady state (Ctrough,ss) is expected to be higher with 10 mg/kg 
q2w (approximately 1.25 fold), this is not expected to impact the overall safety and efficacy 
profile, based on existing preclinical and clinical data.
Monotonic increases in pharmacodynamic activity were observed with increasing doses of 
tremelimumab relative to the activity observed in patients treated with MEDI4736 
monotherapy.  There was evidence of augmented pharmacodynamic activity relative to 
MEDI4736 monotherapy with combination doses containing 1 mg/kg tremelimumab,
inclusive of both the 15 and 20 mg/kg MEDI4736 plus 1 mg/kg tremelimumab combinations.  
Clinical data
As of 27 January 2015, a total of 74 patients with advanced NSCLC have been treated in 
Study D4190C00006.  The 74 patients have received between 1 and 9 doses of tremelimumab 
and between 1 and 13 doses of MEDI4736.  Various dose combinations were explored, with 
doses of tremelimumab ranging from 1 to 10 mg/kg and doses of MEDI4736 ranging from 
3 to 20 mg/kg.  Fifty-eight of these patients were in the q4w dosing schedule and 16 patients 
were in the q2w dosing schedule, with the goal of identifying the dose combination that best 
optimizes the risk:benefit profile in an acceptable range of PK and pharmacodynamic values.
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse 
events (AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs.  
Between the 10 mg/kg MEDI4736 + 1 mg/kg tremelimumab and 10 mg/kg MEDI4736 + 
3 mg/kg tremelimumab cohorts treated at the q2w schedule, the number of patients reporting 
any AE, Grade 3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg 
MEDI4736 + 3 mg/kg tremelimumab cohort than the 10 mg/kg MEDI4736 + 1 mg/kg 
tremelimumab cohort.  A similar pattern was noted in the q4w regimens, suggesting that, as 
the dose of tremelimumab increased above 1 mg/kg, a higher rate of treatment-related events 
may be anticipated.  Further, the SAEs frequently attributed to immunotherapy, pneumonitis 
and colitis, were more commonly seen in cohorts using either 3 mg/kg or 10 mg/kg of 
tremelimumab compared to the 1-mg/kg dose cohorts.  Together, these data suggest that a 
combination using a tremelimumab dose of 1 mg/kg appeared to minimize the rate of toxicity 
when combined with MEDI4736.  As a result, all combination doses utilizing either the 3 or 
10-mg/kg doses of tremelimumab were eliminated in the final dose selection.
In contrast, cohorts assessing higher doses of MEDI4736 with a constant dose of 
tremelimumab did not show an increase in the rate of AEs.  The data suggested that increasing 
doses of MEDI4736 may not impact the safety of the combination as much as the 
tremelimumab dose.  Further, safety data between the 10-mg/kg and 20-mg/kg cohorts were 
similar, with no change in safety events with increasing dose of MEDI4736.
In Study D4190C00006, of all treatment cohorts, the cohort of 11 patients treated in the 
20 mg/kg MEDI4736 + 1 mg/kg tremelimumab group had the fewest AEs, Grade ≥3 AEs, 
SAEs, and treatment discontinuations due to AEs, but still showed strong evidence of clinical 


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activity.  This cohort had a lower number of treatment-related Grade ≥3 AEs or treatment 
related SAEs.  No dose-limiting toxicities (DLTs) were reported.  
Preliminary clinical activity of the MEDI4736 and tremelimumab combination did not appear 
to change with increasing doses of tremelimumab.  The 15- and 20-mg/kg MEDI4736 q4w 
cohorts demonstrated objective responses at all doses of tremelimumab, and increasing doses 
of tremelimumab did not provide deeper or more rapid responses.
Efficacy data suggested that the 20 mg/kg MEDI4736 + 1 mg/kg tremelimumab dose cohort 
may demonstrate equivalent clinical activity to other dose combinations.  A total of 5 of 
11 patients in the 20 mg/kg MEDI4736 + 1 mg/kg tremelimumab cohort were evaluable for 
efficacy with at least 8 weeks of follow-up.  Of these, there were 2 patients (40%) with PR, 
1 patient (20%) with SD, and 1 patient (20%) with PD.  (The fifth patient had only a single 
scan, which was conducted outside the window for these evaluations.)
Additionally, of all cohorts, the 20 mg/kg MEDI4736 + 1 mg/kg tremelimumab dose cohort 
had the fewest AEs, Grade ≥3 AEs, SAEs, and treatment discontinuations due to AEs, but still 
showed some evidence of clinical activity.  All together, the data suggested that a 20 mg/kg 
MEDI4736 + 1 mg/kg tremelimumab dose combination should be selected for further 
development.  
1.2.1.2
Rationale for 4 cycles of combination therapy followed by MEDI4736 
monotherapy
Long-term follow up on melanoma patients treated with ipilimumab, an anti-CTLA-4 
targeting antibody (dosed every 3 weeks for 4 doses and then discontinued), shows that 
patients responding to ipilimumab derive long-term benefit, with a 3-year OS rate of 
approximately 22%.  Furthermore, the survival curve in this population reached a plateau at 
3 years and was maintained through 10 years of follow up (Schadendorf et al 2013). 
Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies: 
!
Nivolumab (anti-PD-1) was dosed q2w for up to 96 weeks in a large Phase I 
dose-escalation and expansion study, and showed responses were maintained for a 
median of 22.94 months for melanoma (doses 0.1 mg/kg to 10 mg/kg), 17 months 
for NSCLC (doses 1, 3, and 10 mg/kg), and 12.9 months for renal cell carcinoma 
patients (doses 1 and 10 mg/kg) at the time of data analysis (Brahmer et al 2014, 
Drake et al 2013, Hodi et al 2014).  Furthermore, responses were maintained 
beyond treatment discontinuation in the majority of patients who stopped 
nivolumab treatment (either due to protocol specified end of treatment, CR, or 
toxicity) for up to 56 weeks at the time of data analysis (Topalian et al 2014). 
!
MPDL3280a (anti-PD-L1) and the combination of nivolumab with ipilimumab, in 
which patients were dosed for a finite time period and responses maintained beyond 
treatment discontinuation have been reported (Herbst et al 2013, Wolchok et al 
2013).


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Similar long term results may be expected with use of other immune-mediated cancer 
therapeutics including anti-CTLA-4 antibodies such as tremelimumab, anti PD-L1 antibodies 
such as MEDI4736, or the combination of the two. 
The MEDI4736 + tremelimumab combination regimen will be administered for 4 doses 
followed by 1.5 g MEDI4736 monotherapy q4w.
1.2.1.3
MEDI4736 monotherapy dose rationale
A dose of MEDI4736 20 mg/kg q4w is supported by in-vitro data, non-clinical activity, 
clinical PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients 
with advanced solid tumors (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 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 
sPD-L1), and further shows that the MEDI4736 dosing frequency can be adapted to a 
particular regimen given the linearity seen at higher 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.  Of the 220 patients who received MEDI4736 monotherapy and for whom 
PK/ADA data were available as of14 July 2014, 5 were ADA positive, with an impact on 
PK/pharmacodynamics reported in 1 patient at 3 mg/kg.  
Data from Study 006 (Phase I trial in NSCLC patients using the combination of MEDI4736 
and tremelimumab) also show an approximately dose-proportional increase in PK exposure 
for MEDI4736 over the dose range of 3 to 20 mg/kg MEDI4736 q4w or q2w.  (For further 
information on PK observations in Study 006, please refer to Section 1.2.1).  
The observed MEDI4736 PK data from the combination study were well in line with the 
predicted monotherapy PK data (5th median and 95th percentiles) for a q4w regimen.  (For 
further information on PK observations in Study 006, please refer to Section 1.2.1).
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 AUCss (4 weeks).  Median Cmax,ss is expected to be higher with 
20 mg/kg q4w (~1.5 fold) and median 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 


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(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 area under the plasma drug concentration-time curve (AUC) and modest 
differences in median peak and trough levels at steady state, the observation that both 
regimens maintain complete sPD-L1 suppression at trough, 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
As of 8 April 2015, there is initial safety data for 16 patients receiving the 20 mg/kg q4w
dosing regimen (12 patients from Study 1108 and 4 patients from the Japan Phase I trial).  The 
toxicities observed with 20 mg/kg q4w are consistent with the 10 mg q2w regimen, and there 
were no DLTs observed.  Of the 12 patients in Study 1108, 42% of patients have experienced 
any grade AE, with 2 being Grade 3 and above (17%).  None of the Grade 3 and higher events 
was considered treatment-related.  No patients on the Japan Phase I trial have experienced a 
Grade 3 or above AE.  At present, the data do not suggest that the safety profile of MEDI4736 
will be different in the 20 mg/kg q4w dosing regimen when compared to 10 mg/kg q2w 
regimen.  In fact, as of 14 July 2014, 393 patients enrolled in Study 1108 have received 
MEDI4736, predominantly at 10 mg/kg q2w (either in the dose-escalation or dose-expansion 
phase of the study).  Data presented at the European Society for Medical Oncology (ESMO) 
meeting 2014 with a later cutoff of 21 August 2014 showed that MEDI4736 was well 
tolerated at all doses in the NSCLC subset of patients enrolled into Study 1108, with 
drug-related Grade ≥3 AEs reported in 3% of patients and drug-related AEs leading to 
discontinuation reported in 1% of patients.  No drug-related colitis or hyperglycemia of any 
grade, no Grade ≥3 pneumonitis reported, and no drug-related AEs leading to death were 
reported (Antonia et al 2014b).  No DLTs were observed up to a dose of 10 mg/kg q2w or 
15 mg/kg q3w.
Efficacy data on the NSCLC patients in Study 1108, presented at ESMO 2014 (cutoff date of 
21 August 2014), showed a DCR at 12 weeks of 41% and ORR of 16% among 162 evaluable 
patients, with activity observed in both squamous and non-squamous histologies.  The ORR 
was higher (25%; 12 CR/PR; n=48) in patients with PD-L1 positive tumors, defined as those 
with ≥25% of tumor cells with membrane staining for PD-L1, compared to patients with 
PD-L1 negative tumors (10%; 7 CR/PR; n=74) (Antonia et al 2014b).  
1.2.1.4
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 


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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.  
Similarly, a population PK model was developed for tremelimumab using data from Phase I 
through Phase III studies (N=654; doses=0.01 to 15 mg/kg q4w or every 90 days; metastatic 
melanoma; Wang et al 2014).  A population PK model indicated minor impact of body WT on 
the PK of tremelimumab (coefficient of ≤0.5).  The WT-based (1 mg/kg q4w) and fixed 
dosing (75 mg/kg q4w; based on a median body WT of approximately 75 kg) regimens were 
compared using predicted PK concentrations (5th, median, and 95th percentiles) using a 
population PK model in a simulated population of 1000 patients with a body WT distribution 
of 40 to 120 kg.  Similar to MEDI4736, simulations indicated that both body WT-based and 
fixed dosing regimens of tremelimumab 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) and 
75 mg q4w tremelimumab (equivalent to 1 mg/kg q4w) is included in the current study.
1.3
Benefit/risk and ethical assessment
The following sections include summaries of the potential benefits and risks associated with 
MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy, 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%) 


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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). Other mAbs targeting the PD-L1/PD-1 pathway have shown clinical 
activity in this indication, as summarized in Section 1.1.4.
1.3.1.2
Tremelimumab
In a single-arm, Phase II study (Study A3671008) of tremelimumab administered at 15 mg/kg 
every 90 days to patients with refractory melanoma, an response rate of 7% and a median OS 
of 10 months in the second-line setting (as compared to approximately 6 months with best 
supportive care reported from a retrospective analysis; Korn et al 2008) were observed 
(Kirkwood et al 2010).  In a randomized, open-label, first-line Phase III study of 
tremelimumab (administered at 15 mg/kg every 90 days) versus chemotherapy (dacarbazine or 
temozolomide) in advanced melanoma (Study A3671009), results of the final analysis showed 
a response rate of 11% and a median OS of 12.58 months in this first-line setting as compared 
to 10.71 months with standard chemotherapy; however, these results were not statistically 
significant (Ribas et al 2013).  Additionally, in a Phase II maintenance study (Study 
A3671015) in patients with Stage IIIB or IV NSCLC that have responded or remained stable, 
PFS at 3 months was 22.7% in the tremelimumab arm (15 mg/kg) compared with 11.9% in the 
best supportive care arm (Study A3671015).
1.3.1.3
MEDI4736 + tremelimumab 
The preclinical and clinical justification for this combination as noted in Section 1.2.1 also 
supports the synergy of this combination.  Available data, such as those presented by Wolchok 
et al, suggest that the combination of agents targeting PD-1/PD-L1 and CTLA-4 may have 
profound and durable benefits in patients with melanoma (Wolchok et al 2013).  Furthermore, 
preliminary efficacy data from Study D4190C00006 have demonstrated that this combination 
is clinically active and well tolerated.  As of 27 January 2015, 53 patients were evaluable for 
response across various MEDI4736 + tremelimumab dose regiments.  Of these, 
12 (23%) patients had a best response of PR and 14 (26%) patients had a best response of SD.  
In the MEDI4736 20 mg/kg + tremelimumab 1 mg/kg q4w cohort, a total of 5 of 11 patients 
were evaluable for efficacy with at least 8 weeks of follow-up.  Of these, there were 
2 (40%) patients with PR, 1 (20%) patient with SD, and 1 (20%) patient with PD.
1.3.2
Potential risks
1.3.2.1
MEDI4736
Potential risks, based on the mechanism of action of MEDI4736 and related molecules, 
include immune-mediated reactions, such as enterocolitis, dermatitis, hepatitis/hepatotoxicity,
endocrinopathy, pneumonitis, and neuropathy or neurologic events.  Additional important 
potential risks include infusion-related reactions, hypersensitivity, anaphylaxis or serious 
allergic reactions, serious infections, and immune complex disease.  Of the 393 patients with 
advanced solid tumors including PDAC treated with 10 mg/kg q2w in Study 1108 (as of the 
current IB, Edition 7.0, cutoff date of 14 July 2014), 331 (84.2%) patients had at least 1 AE 
regardless of causality.  Treatment-related AEs were reported for 162 (41.2%) of 393 patients.  


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The most frequently reported (≥2% of patients) AEs assessed by the Investigator as treatment 
related (including all National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Event [CTCAE] grades) were fatigue (13.5%); nausea (8.4%); diarrhea, decreased 
appetite, and rash (5.3% each); vomiting (4.8%); pruritus (4.1%); dyspnea (3.8%); pyrexia 
(3.1%); hypothyroidism, increased alanine aminotransferase [ALT], increased aspartate 
aminotransferase [AST], and cough (2.5% each); myalgia (2.3%); and abdominal pain and 
dizziness (2.0% each).  Two patients discontinued treatment due to AEs assessed by the 
Investigator as treatment related (pneumonitis and increased transaminases).  Grade 3 events 
assessed by the Investigator as treatment related that occurred in 2 or more patients were 
fatigue (4 patients); increased gamma-glutamyltransferase (3 patients); and vomiting, 
increased ALT, increased AST, and arthralgia (2 patients each).  There were 2 patients with 
Grade 4 events (hypercalcemia and fatigue) assessed by the Investigator as treatment related 
and 1 patient with a Grade 5 event assessed by the Investigator as treatment related 
(angiopathy).  For further details on the safety profile of MEDI4736 as monotherapy or 
combination therapy, please refer to the current IB. 
Other mAbs targeting the PD-1/PD-L1 pathway are currently in clinical development.  Among 
the most frequent AEs noted with treatment with these antibodies are fatigue, rash, diarrhea, 
and pruritus.  Immune-mediated AEs of Grade ≥3 reported include pneumonitis, diarrhea, 
increased ALT, and increased AST.  Other relevant risks include those associated with 
biological and immunotherapeutic agents, including infusion reactions and acute 
immunoglobulin E-mediated allergic reactions.
1.3.2.2
Tremelimumab
Potential risks, based on the mechanism of action of MEDI4736 and related molecules 
(ipilimumab) include potentially immune-mediated reactions that can result in an 
inflammatory response in any organ or tissue including the liver, gastrointestinal (GI) tract, 
thyroid glands, pancreas, skin, nervous system, respiratory tract, and adrenal glands.  The 
profile of AEs and the spectrum of event severity have remained stable across the 
tremelimumab clinical program and are consistent with the pharmacology of the target.  To 
date, no tumor type or stage appears to be associated with unique AEs (except for vitiligo that 
appears to be confined to patients with melanoma).  Overall, 944 (97.0%) of the 973 patients 
treated with tremelimumab monotherapy as of the data cutoff date of 12 November 2014 
experienced at least 1 AE.  The events resulted in discontinuation of tremelimumab in 
10.0% of patients, were serious in 36.5%, were Grade ≥3 in severity in 49.8%, were fatal in 
67.7%, and were considered to be treatment related in 79.1% of patients. Among the overall 
fatal cases (67.7%) reported in the patients treated with tremelimumab monotherapy, the most 
frequent cause of death was ascribed to the patient’s underlying malignant disease (61.8%), 
whereas the remaining causes included other or unknown/missing (7.1%), and due to 
investigational product (IP; 0.5%). The most frequent Grade ≥3 AEs (all causality) reported 
in ≥ 2% of subjects (in decreasing order of frequency) were diarrhea, fatigue, colitis, disease 
progression, dyspnea, dehydration/nausea/vomiting, abdominal pain, decreased appetite, and 
asthenia. The events of diarrhea, abdominal pain, and colitis occurred at a higher rate in the 10 
mg/kg group, whereas fatigue, disease progression, dyspnea, dehydration, nausea, vomiting, 
decreased appetite, and asthenia were reported more frequently in the 15 mg/kg group.  


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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Treatment-related AEs were reported at similar rates in the 10 and 15 mg/kg groups (81.8%
and 80.0%, respectively), and were mostly Grade 1 or 2 in severity (≥ Grade 3 treatment-
related AEs reported in 26.1% of subjects). The most frequent treatment-related AEs (in > 5% 
of subjects) were diarrhea (41.2%), rash (27.2%), pruritus (25.1%), fatigue (23.8%), nausea 
(21.9%), vomiting (13.5%), decreased appetite (11.3%), headache (7.2%), pyrexia (7.0%), 
abdominal pain (6.7%), and colitis (5.5%). 
1.3.2.3
MEDI4736 + tremelimumab 
No safety studies in animals have been performed combining tremelimumab with MEDI4736.  
As both CTLA-4 and PD-L1 have mechanisms of actions that enhance activation of immune 
cells, their potential to induce cytokine release was tested in a whole-blood assay system.  
MEDI4736 and tremelimumab, either alone or in combination, did not induce cytokine release 
in blood from any donor.
Evaluation of the safety of MEDI4736 + tremelimumab in the ongoing Study D4190C00006, 
in patients with NSCLC, has so far shown a manageable safety and tolerability profile of the 
combination therapy. 
Overall, 62 (83.8%) of the 74 patients reported an AE regardless of causality.  The most 
frequently (10 or more patients) reported AEs were fatigue (37.8%; 28 patients); diarrhea 
(32.4%; 24 patients); amylase increased and pruritus (16.2%; 12 patients); decreased appetite, 
dyspnea, nausea, and rash (14.9%; 11 patients each), and headache and pyrexia (13.5%; 
10 patients).  Additional safety results from this study are presented in Section 1.2.1 and the 
MEDI4736 IB (Edition 7.0).
In the literature (Wolchok et al 2013), using the combination of the same class of drugs 
(eg, anti-PD-1 and anti-CTLA4 antibodies), specifically nivolumab + ipilimumab in a study 
involving patients with malignant melanoma, the safety profile of this combination had shown 
occurrences of AEs assessed by the Investigator as treatment-related in 93% of treated 
patients, with the most frequent events being rash (55% of patients), pruritus (47% of 
patients), fatigue (38% of patients), and diarrhea (34% of patients).  Grade 3 or 4 AEs, 
regardless of causality, were noted in 72% of patients, with Grade 3 or 4 events assessed by 
the Investigator as treatment-related in 53%.  The most frequent of these Grade 3 or 4 events 
assessed by the Investigator as treatment-related include increased lipase (13% of patients), 
AST (13% of patients), and ALT levels (11% of patients).  Frequent Grade 3 or 4 selected 
AEs assessed by the Investigator as treatment-related in the combination therapy included 
hepatic events (15% of patients), GI events (9% of patients), and renal events (6% of patients).  
Isolated cases of pneumonitis and uveitis were also observed. 
1.3.3
Overall benefit and risk assessment
There remains a significant unmet medical need for additional treatment options for patients 
with metastatic PDAC. 
Treatment with agents targeting PD-1/PD-L1 (such as MEDI4736) or CTLA-4 (such as 
tremelimumab) has shown activity in several tumor types in a subset of patients deriving 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
37(131)
meaningful and durable benefit.  Efficacy data for patients treated with MEDI4736 
monotherapy in the pancreatic cancer cohort have shown some clinical activity.  Additionally, 
MEDI4736 + tremelimumab combination therapy has shown clinical activity in patients with 
recurrent or metastatic squamous cell cancer of the head and neck.  Preliminary data generated 
from patients with NSCLC treated with MEDI4736 + tremelimumab combination therapy 
have also shown early signs of clinical activity, and data from competitors indicate that the 
combination may act synergistically (Wolchok et al 2013).  Thus, these agents may potentially 
offer 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, tremelimumab, and SoC).
The toxicity profile of the combination MEDI4736 + tremelimumab includes fatigue, colitis, 
diarrhea, 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.  
In particular, based on the specific mechanism of action of MEDI4736 and tremelimumab 
leading to T-cell activation and proliferation, there is the possibility of observing immune-
related AEs (irAEs) during the conduct of this study.  Potential irAEs may be similar to those 
seen with the use of ipilimumab, BMS-936558, and BMS-936559 and may include immune-
mediated enterocolitis, pneumonitis, dermatitis, hepatitis, and endocrinopathies 
(Brahmer et al 2012, Hodi et al 2010, Topalian et al 2012).  Patients should be monitored for 
signs and symptoms of irAEs.  In the absence of an alternate etiology (eg, infection or PD), an 
immune-related etiology should be considered for signs or symptoms of pneumonitis, 
enterocolitis, dermatitis, hepatitis, and endocrinopathy.  It is recommended that management 
of irAEs follow the guidelines outlined in Section 6.7.
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 the safety and tolerability 
of (1) MEDI4736 monotherapy and (2) MEDI4736 + tremelimumab 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 (QoL) and potentially extending survival.  
Furthermore, preclinical and clinical evidence indicate that the combination of PD-1/PD-L1 
and CTLA-4 targeting agents may provide antitumor activity, with additional synergy from 
the combination (Wolchok et al 2013).  Therefore, the investigation of the potential 
therapeutic efficacy of MEDI4736 monotherapy and the combination of MEDI4736 and 
tremelimumab in patients with PD-L1-positive and -negative tumors is acceptable, and the 
overall benefit/risk assessment supports the proposed study design.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
38(131)
1.4
Study design
This is a second-line Phase II study assessing MEDI4736 monotherapy and
MEDI4736 + tremelimumab combination therapy.  
This is a Phase II, open-label, multi-center study to determine the efficacy and safety of 
MEDI4736 evaluated as single agent or in combination with tremelimumab in patients with 
metastatic PDAC whose disease has progressed on a 5-FU-containing or gemcitabine-
containing first-line chemotherapy.  A schematic diagram of the overall study design is shown 
in Figure 1, and a detailed study flow chart is shown in Figure 2. Patients will be enrolled
globally.  
Initially, patients will be enrolled in the study and randomized (1:1) to treatment with 
MEDI4736 monotherapy or MEDI4736 + tremelimumab, until 30 patients have been 
randomized to treatment in each arm (Part A: Lead-in).  Randomization will be stratified 
according to best response to prior first-line chemotherapy (CR, PR, or SD) versus no 
response (PD) and according to prior first-line chemotherapy, 5-FU-containing versus 
gemcitabine-containing.  Patient recruitment and tumor assessment will be monitored on an 
ongoing basis.  
The format of Part B will be determined based on the responses seen in the first 30 patients in 
each arm in Part A. A protocol amendment will be made if criteria are met to proceed to 
Part B. The protocol amendment will include available data from Part A and any changes to 
study design and statistical plan, if needed.
1.
Part B: Expansion.  If an ORR of >25% (ie, responses in ≥8 patients) is observed 
in the first 30 treated patients in either treatment arm in Part A (unless the totality of 
the data support a different decision), after protocol amendment an additional 
70 patients will be enrolled in that arm, for a total of 100 evaluable patients per arm.  
2.
Part B: Randomized, controlled trial (RCT).  If an ORR of >15% and <25% 
(ie, response in ≥5 patients and <8 patients) is observed in the first 30 treated 
patients in either treatment arm in Part A, a randomized, controlled substudy may
be initiated after protocol amendment.  
If initiated, Part B: RCTwill be an open-label, multi-center, study to determine the efficacy 
and safety of MEDI4736 monotherapy and/or MEDI4736 + tremelimumab combination 
therapy versus SoC chemotherapy in patients with metastatic PDAC who have failed 5-FU-
containing or gemcitabine-containing first-line chemotherapy.  Approximately 125 additional 
patients per treatment arm will be planned for enrollment.  Treatment arms for MEDI4736 
monotherapy and/or MEDI4736 + tremelimumab will only be included in the Part B: RCT if 
the corresponding treatment meets the appropriate ORR criteria in Part A.  If initiated, the data 
from Part B: RCT will be analyzed separately and will not be pooled with Part A for the 
purpose of statistical analysis.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
39(131)
Patients will be randomized in Part B: RCT with a 1:1 or 1:1:1 ratio (depending on whether 
there are 2 or 3 treatment arms) in a stratified manner according to their best response to prior 
first-line chemotherapy (CR, PR, or SD) versus no response (PD) and according to prior first-
line chemotherapy, 5-FU-containing versus gemcitabine-containing.  Doses and treatment 
regimens are described in Section 7.2.  Assessments will be conducted as indicated in Table 2,
Table 3, and Table 4.
Figure 1
Phase II, MEDI4736 monotherapy and MEDI4736 + tremelimumab 
combination therapy - study design


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
40(131)
Figure 2
Phase II, MEDI4736 monotherapy and MEDI4736 + tremelimumab 
combination therapy - study flow chart 
a
Disease progression needs to be confirmed.  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 clinical 
deterioration.  Administration of study treatment will continue between the initial assessment of progression 
and confirmation of progression.  Patients treated through progression must meet the criteria described in 
Section 7.2.2.  Patients with confirmed PD who continue to receive study treatment at the discretion of the 
Investigator (following consultation with the Sponsor) can receive study treatment for a maximum of 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
41(131)
12 months.  Patients in the SoC arm of Part B: RCT will discontinue study drug at the first assessment of 
disease progression per RECIST 1.1.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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2.
STUDY OBJECTIVES
2.1
Primary objective
Part A: Lead-in and Part B: Expansion
Primary objective:
Outcome measure:
To assess the efficacy of MEDI4736 
monotherapy and MEDI4736 + tremelimumab 
combination therapy in terms of ORR
ORR in all patients using Investigator assessments 
according to RECIST 1.1a,b
a
All images will be collected and stored for possible future central re-analysis.
b
Sensitivity analyses of ORR will be performed based on Investigator assessment according to RECIST 1.1 
modified for confirmation of progression.
Part B: Randomized, controlled trial
Primary objective:
Outcome measure:
To assess the efficacy of MEDI4736 
monotherapy and MEDI4736 + tremelimumab 
combination therapy compared to SoC in terms 
of OS
OS
2.2
Secondary objectives
Part A: Lead-in and Part B: Expansion
Secondary objectives:
Outcome measures:
To further assess the efficacy of the 
combination of MEDI4736 and tremelimumab 
and MEDI4736 alone 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 1.1a
OS, OS6, and OS12
To assess the health-related QoL in metastatic 
PDAC patients treated with MEDI4736 + 
tremelimumab combination therapy and 
MEDI4736 monotherapy as measured by 
EORTC QLQ-C30 global QoL scale (Part B 
only)
Adjusted mean change from baseline in global QoL 
score from the EORTC QLQ-C30 questionnaire
To assess the disease-related symptoms in 
metastatic PDAC patients treated with 
MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy as 
measured by EORTC QLQ-PAN26 pancreatic 
pain scale (Part B only)
Adjusted mean change from baseline in pancreatic 
pain score from the EORTC QLQ-PAN26 
questionnaire


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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To investigate the immunogenicity of 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy
Presence of ADAs for MEDI4736 and tremelimumab 
(confirmatory results: positive or negative; titers)
To assess the PK of MEDI4736 monotherapy 
and MEDI4736 + tremelimumab combination 
therapy
Concentration of MEDI4736/tremelimumab in blood
and noncompartmental PK parameters (such as peak 
concentration and trough, as data allow; sparse 
sampling only)
a
All images will be collected and stored for possible future central re-analysis.
Part B: Randomized, controlled trial
Secondary objectives:
Outcome measures:
To further assess the efficacy of MEDI4736 
monotherapy and MEDI4736 + tremelimumab 
combination therapy compared to SoC in terms 
of ORR, DoR, DCR, PFS, PFS2, PFS3, OS6, 
and OS12
PFS, PFS2, PFS3, ORR, DoR, and DCR in all 
patients using Investigator assessments according to 
RECIST 1.1a
OS6, OS12
To investigate the relationship between PD-L1 
expression by IHC and efficacy parameters
ORR, DoR, DCR, PFS3, and PFS6 across PD-L1 
expression using Investigator assessments according 
to RECIST 1.1
To assess the health-related QoL in metastatic 
PDAC patients treated with MEDI4736 + 
tremelimumab combination therapy and 
MEDI4736 monotherapy as measured by 
EORTC QLQ-C30 global QoL scale
Adjusted mean change from baseline in global QoL 
score from the EORTC QLQ-C30 questionnaire
To assess the disease-related symptoms in 
metastatic PDAC patients treated with 
MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy as 
measured by EORTC QLQ-PAN26 pancreatic 
pain scale 
Adjusted mean change from baseline in pancreatic 
pain score from the EORTC QLQ-PAN26 
questionnaire
To investigate the immunogenicity of 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy
Presence of ADAs for MEDI4736 and tremelimumab 
(confirmatory results: positive or negative; titers)
To assess the PK of MEDI4736 monotherapy 
and MEDI4736 + tremelimumab combination 
therapy
Concentration of MEDI4736/tremelimumab in blood 
and noncompartmental PK parameters (such as peak 
concentration and trough, as data allow; sparse 
sampling only)
a
All images will be collected and stored for possible future central re-analysis.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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2.3
Safety objectives
Part A: Lead-in and Part B Expansion
Safety objective:
Outcome measures:
To assess the safety and tolerability profile of 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy
AEs, physical examinations, laboratory findings 
(including clinical chemistry, hematology, and 
urinalysis), vital signs (including blood pressure and 
pulse), ECGs
Part B: Randomized, controlled trial
Safety objective:
Outcome measures:
To assess the safety and tolerability profile of 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy compared 
to SoC
AEs, physical examinations, laboratory findings 
(including clinical chemistry, hematology, and 
urinalysis), vital signs (including blood pressure and 
pulse), ECGs
2.4
Exploratory objectives  
Part A: Lead-in, Part B: Expansion, and Part B: Randomized, controlled trial
Exploratory objectives:
Outcome measures:
To assess the efficacy of MEDI4736 and 
tremelimumab and MEDI4736 alone according 
to irRECISTa
ORR, DoR, DCR, PFS, PFS3, and PFS6 using BICR 
assessments according to irRECISTa
ORR, DoR, DCR, PFS3, and PFS6 in patients with 
PD-L1-positive tumors and patients with 
PD-L1-negative tumors using BICR assessments 
according to irRECIST (Part B: RCT only)a
To assess tolerability directly by patient self-
reporting of specific PRO-CTCAE symptoms
(Part B only)
Pre-selected PRO-CTCAE items (not more than 30) 
considered relevant to patients with metastatic PDAC
treated with MEDI4736 or tremelimumab or SoC
To collect blood and tissue samples for 
defining biological responses to MEDI4736 or 
MEDI4736-tremelimumab and for identifying 
candidate markers that may correlate with 
likelihood of clinical benefit
Serum sPD-L1
Circulating soluble factors (eg, cytokines and 
autoantibodies)
miRNA/mRNA
T cell and MDSC phenotyping
SNP genotyping


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
45(131)
Exploratory objectives:
Outcome measures:
To collect and store DNA according to each 
country’s local and ethical procedures for 
future exploratory research into genes/genetic 
variation that may influence response 
(ie, distribution, safety, tolerability, and 
efficacy) to study treatments and/or 
susceptibility to disease (optional genetics 
component)
Correlation of polymorphisms with variation in PK, 
pharmacodynamics, safety, or response parameters 
observed in patients treated with MEDI4736 and the 
combination of MEDI4736 and tremelimumab, 
and/or susceptibility to disease
To assess change in performance status in 
metastatic PDAC patients treated with 
MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy as 
measured by the ECOG performance status 
scale
ECOG performance status
To describe and evaluate resource use 
associated with assigned treatments and 
underlying disease (Part B only)
Health resource utilization methods including 
HOSPAD, concomitant medications, and the AE 
module of the electronic case report form (eCRF)
To explore the impact of treatment and disease 
state on health state utility using the EuroQol 
5-dimension, 5-level health state utility index 
(EQ-5D-5L) (Part B only)
The EQ-5D-5L will be used to derive health state 
utility based on patient-reported data.
Note: Exploratory objective analyses may be reported separately from the main clinical study report.
a
This analysis will be conducted only if central review data are generated at a future timepoint.  
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.  (For patients aged <20 years and enrolled in Japan, a written 
informed consent should be obtained from the patient and his or her legally 
acceptable representative.)


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
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Edition Number 1
Date 17 August 2015
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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.)
4.
No more than 1 prior chemotherapy regimen or any other systemic therapy for 
recurrent/metastatic PDAC.  One other prior line of therapy administered either in a 
prior adjuvant, neoadjuvant, or definitive chemoradiation setting is permitted.  In 
addition, patients must have tumor progression following prior standard first-line 
5-FU-containing or gemcitabine-containing chemotherapy.
5.
Life expectancy ≥12 weeks.
6.
ECOG PS of 0 or 1.  
7.
At least 1 lesion, not previously irradiated, that can be accurately measured at 
baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have 
short axis ≥15 mm) with computed tomography (CT) or magnetic resonance 
imaging (MRI) scan and that is suitable for accurate repeated measurements.
8.
No 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, and participation in previous MEDI4736 clinical trials.
9.
Adequate organ and bone marrow function as defined below:
#
Hemoglobin ≥9 g/dL
#
Albumin ≥3 g/dL
#
Absolute neutrophil count ≥1500/mm3
#
Platelet count ≥100000/mm3
#
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 ≥50 mL/min as 
determined by the Cockcroft-Gault equation
10.
Evidence of post-menopausal status or negative urinary or serum pregnancy test for 
female premenopausal patients.  Women will be considered post-menopausal if they 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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are amenorrheic for 12 months without an alternative medical cause.  The following 
age specific requirements apply: 
#
Women <50 years old would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and with luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution
#
Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, radiation-induced oophorectomy with last menses >1 year 
ago, chemotherapy-induced menopause with >1 year interval since last menses, 
or surgical sterilization (bilateral oophorectomy or hysterectomy).
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.
6.
Patients weighing less than 30 kg.
7.
History of leptomeningeal carcinomatosis.
8.
Ascites requiring intervention (eg, need for paracentesis or Tenckhoff catheter)


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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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 
exacerbated by treatment with MEDI4736 or tremelimumab 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 or tremelimumab.  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) 
12.
History of organ transplant that requires use of immunosuppressive agents.
13.
Active or prior documented autoimmune or inflammatory disorders (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) within the past 3 years prior 
to the start of treatment.  The following are exceptions to this criterion:
#
Patients with vitiligo or alopecia
#
Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement, or psoriasis not requiring systemic treatment 
14.
Uncontrolled intercurrent illness, including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric 
illness/social situations that would limit compliance with study requirement, 
substantially increase risk of incurring AEs from MEDI4736 or tremelimumab, or 
compromise the ability of the patient to give written informed consent.


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Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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15.
Other malignancy within 5 years except for noninvasive malignancies such as 
cervical carcinoma in situ, non-melanomatous carcinoma of the skin, or ductal 
carcinoma in situ of the breast that has/have been surgically cured.  
16.
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).
17.
History of active primary immunodeficiency.
18.
Active tuberculosis.
19.
Active infection including hepatitis B, hepatitis C, or human immunodeficiency 
virus (HIV).
20.
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.
21.
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).
22.
Known allergy or hypersensitivity to IP formulations or to other human monoclonal 
antibodies.
23.
Any condition that, in the opinion of the Investigator, would interfere with 
evaluation of IP or interpretation of patient safety or study results.
Genetics research study (optional)
Exclusion criteria for participation in the optional (DNA) genetics research component of the 
study include previous allogeneic bone marrow transplant and non-leukocyte depleted whole 
blood transfusion in 120 days of genetic sample collection.
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrollment and randomization
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, including optional consent for genetic research study.
2.
Obtain a unique 7-digit enrollment number, beginning with ‘E#’ (ie, the “E-Code”).  
This is obtained through the Interactive Voice Response System (IVRS)/Interactive 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
50(131)
Web Response System (IWRS).  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 eCRFs.
3.
Determine patient eligibility (see Sections 3.1 and 3.2)
Note: Patients must be able to undergo a newly acquired tumor biopsy during screening 
(strongly encouraged) or to provide an available tumor sample taken <3 years prior to 
screening.  The newly acquired or archival (<3 years) sample must be received by the central 
laboratory prior to dosing.  Tumor lesions used for newly acquired biopsies should not be 
target lesions, unless there are no other lesions suitable for biopsy.  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.  The tumor specimen should be of sufficient quantity to allow for PD-L1 IHC and 
other exploratory biomarker analyses and is preferred in formalin-fixed paraffin embedded 
blocks.
At randomization, once the patient is confirmed to be eligible, the Investigator or suitably 
trained delegate will complete a randomization call via the IVRS/IWRS.  Randomization 
numbers will be assigned strictly sequentially by IVRS/IWRS as patients are eligible for entry 
into the study.  The system will randomize the eligible patient to 1 of the 2 or 3 treatment 
groups (depending on the part of the study).  Randomization will be stratified according to 
best response to prior first-line chemotherapy (CR, PR, or SD) versus no response (PD) and 
according to prior first-line chemotherapy, 5-FU-containing versus gemcitabine-containing.
If the patient is ineligible and not enrolled/randomized, the IVRS/IWRS should be contacted 
to terminate the patient in the system as a screen failure. 
Patients 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 or
randomization code cannot be reused.  Withdrawn patients will not be replaced.
3.4
Procedures for handling incorrectly enrolled or randomized 
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 
randomized or initiated on treatment and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomized in error, 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 AstraZeneca Study Physician and the Investigator regarding 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
51(131)
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 will be centrally assigned to study drug 
by the IVRS/IWRS, according to the randomization scheme generated by the Biostatistics 
Group, AstraZeneca, or delegate.  The randomization scheme will be produced by a computer 
software program that incorporates a standard procedure for generating randomization 
numbers.  One randomization list will be produced for each of the randomization strata.  A 
blocked randomization will be generated, and all centers will use the same list in order to 
minimize any imbalance in the number of patients assigned to each treatment group in Part A. 
Patients will be identified to the IVRS/IWRS per country regulations.  Randomization/
enrollment codes will be assigned strictly sequentially, within each stratum, as patients 
become eligible for randomization.  The IVRS/IWRS Centralized Randomization Center will 
inform the pharmacist of the kit identification number to be allocated to the patient at the 
randomization visit.  
Every effort should be made to minimize the time between randomization/enrollment and 
starting study drug.  It is recommended that patients commence study drug as soon as possible 
after randomization/enrollment (ie, on the same day after randomization in the IVRS/IWRS 
system).
The Investigator will call/log in to the IVRS/IWRS for each subsequent dispensing visit for 
assignment of a new kit identification number.  The kit identification number dispensed at 
each visit will correspond to the treatment arm to which the patient was originally 
randomized/enrolled. 
If a patient discontinues participation in the study, then their enrollment/randomization 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:
1.
Female patients of childbearing potential who are sexually active with a 
nonsterilized male partner must use 2 methods of effective contraception from 
screening and must agree to continue using such precautions for 180 days after the 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
52(131)
final dose of IP; cessation of birth control after this point should be discussed with a 
responsible physician.  Periodic abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of birth control.
#
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).
#
Female patients must use 2 acceptable methods of effective contraception as 
described in Table 1.
#
It is strongly recommended for the male partner of a female patient to also use 
male condom plus spermicide throughout this period. 
#
Female patients must refrain from egg cell donation and breastfeeding while on 
study and for 180 days after your last dose of study drug.
2.
Nonsterilized males who are sexually active with a female partner of childbearing 
potential must use a male condom plus spermicide from Day 1 and for 180 days 
after receipt of the final dose of IP. It is strongly recommended for the female 
partner of a male patient to also use an effective method of contraception 
throughout this period.  In addition, male patients must refrain from sperm donation 
for 180 days after the final dose of study drug.  
3.
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
Effective methods of contraception (2 methods must be used)
Barrier Methods
Intrauterine Device Methods
Hormonal Methods
Male condom plus spermicide
Copper T
Implants
Cap plus spermicide
Progesterone Ta
Hormone shot or injection
Diaphragm plus spermicide
Levonorgestrel-releasing intrauterine 
system (eg, Mirena®)a
Combined pill
Minipill
Patch
a
This is also considered a hormonal method.
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


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
53(131)
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
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 and Investigator determination that the patient is no longer 
benefiting from treatment with IP. Patients enrolled in the SOC arm will 
discontinue study drug at the first assessment of disease progression.
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 3 and Table 4).  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 3 and Table 4) should be contacted by telephone every 2
months as an alternative.  
If a patient is withdrawn from study, see Section 3.10.
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 and randomized.  These patients should have the reason for study 
withdrawal recorded as “eligibility criteria not fulfilled” (ie, patient does not meet the required 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
54(131)
inclusion/exclusion criteria).  This reason for study withdrawal is only valid for screen failures 
(ie, not randomized patients).  Patients can be rescreened a single time, but they cannot be 
re-randomized. 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. 
The patient will return electronic PRO devices, if applicable.  
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 3 and Table 4) 
should be contacted by telephone every 2 months as an alternative.  Withdrawn patients will 
not be replaced.  When a patient is withdrawn from the study, study center personnel should 
call the IVRS/IWRS and register the patient withdrawal information.
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
In addition, the study may be stopped if the criteria to proceed are not met (see Section 8.2). 
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.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
55(131)
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 or tremelimumab 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 12-month treatment periods in this study are presented
in Table 2, and the procedures for the follow-up period are presented in Table 3 and Table 4.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
56(131)
Table 2
Schedule of assessments for treatment and retreatment periods for MEDI4736 and MEDI4736 + 
tremelimumab (12 months)
Screening
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
For details see 
Section
Window for each assessment: ±3 days, window for tumor assessment: ±7 days
Day
-28 to -1
1
15
1
15
1
1
1
1
1
1
1
1
1
1
1
Week (on Day 1 of the week)
-4 to -1
0
2
4
6
8
12
16
20
24
28
32
36
40
44
48
Informed consent
Consent: genetic sample and 
analysis (optional)
X
4.1
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
X
X
X
X
X
X
X
X
X
X
5.2.2
Vital signsb
X
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
X
5.2.1
Hematologyd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2.1
Thyroid function tests (TSH, fT3,
and fT4)e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2.1


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
57(131)
Screening
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
For details see 
Section
Window for each assessment: ±3 days, window for tumor assessment: ±7 days
Day
-28 to -1
1
15
1
15
1
1
1
1
1
1
1
1
1
1
1
Week (on Day 1 of the week)
-4 to -1
0
2
4
6
8
12
16
20
24
28
32
36
40
44
48
Urinalysisf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2.1
Hepatitis B and C; HIV
X
5.2.1
Urine hCG or serum β-hCGg
X
Xh
As clinically indicated
5.2.5
Coagulation parametersi
X
As clinically indicated
5.2.1
Monitoring
ECOG performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5.3.3
AE/SAE assessment
X
X
All visits
6.3
Pharmacokinetics
MEDI4736 PK sample (serum)j,k
X
X
X
X
5.4.2
Tremelimumab PK sample 
(serum)j,k
X
X
X
5.4.2
IP administration
Monotherapy arm
MEDI4736 (monotherapy)l
X
X
X
X
X
X
X
X
X
X
X
X
X
7.2.1
Combination therapy arm
MEDI4736 (combination therapy)l
X
X
X
X
X
X
X
X
X
X
X
X
X
7.2.1
Tremelimumabl
X
X
X
X
7.2.1
Quality of life assessments
EORTC QLQ-C30, EORTC 
QLQ-PAN26, and EQ-5D-
5Lm(Part B only)
X
X
X
X
X
X
X
5.3.1
PRO-CTCAEn (Part B only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5.3.1


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
58(131)
Screening
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
For details see 
Section
Window for each assessment: ±3 days, window for tumor assessment: ±7 days
Day
-28 to -1
1
15
1
15
1
1
1
1
1
1
1
1
1
1
1
Week (on Day 1 of the week)
-4 to -1
0
2
4
6
8
12
16
20
24
28
32
36
40
44
48
Health economics measurements
Hospital resource use module 
(HOSPAD) (Part B only)o
To be completed at each hospitalization
5.3.4
Other laboratory assessments and assays
Immunogenicity assessment 
(ADA sampling [including ADA 
neutralizing antibodies] to identify 
ADA responses in patient 
circulation)k
X
X
X
Xp
5.4.4
sPD-L1 concentration (to assess 
target engagement)
X
X
X
X
5.5.1.1
Circulating soluble factors
X
X
X
5.5.1.2
Mandatory tumor biopsy (newly 
acquired or archival <3 years old)q
X
Xr
5.5.1.1
Archival tumor sample, if 
available, for patients who submit 
a newly acquired biopsy at 
screening
X
5.5.1.1
SNP genotyping and MDSC
X
5.5.1.2
miRNA/mRNA (to examine 
immune cell gene expression 
profiles in circulation) and 
PBMCs
X
X
5.5.1.2
Tumor assessment (CT or MRI)s
X
q6w for the first 48 weeks relative to first infusion, and q12w thereafter, until confirmed disease 
progression
5.1
PGx sample (optional [DNA 
element])
X
5.6
a
Body weight recorded at all physical examinations.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
59(131)
b
Blood pressure and pulse will be evaluated at the beginning of the infusion, every 30 minutes during treatment, and in the 1 hour post-infusion observation period: 30 and 
60 minutes after the infusion (ie, 90 and 120 minutes from the start of the infusion) (±5 minutes) – for the first infusion only and then for subsequent infusions as 
clinically indicated.  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).  
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 Day 1 they do not need to be repeated at Day 1.  Results for safety bloods, serum or plasma 
chemistry and LFT enzymes must be available and reviewed before commencing an infusion.  At any time per the Investigator’s clinical judgment, more frequent LFT 
monitoring is allowed as clinically indicated.  Gamma glutamyltransferase tested at screening, Day 1 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 test 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 Day 1 and Week 12, 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 of end of 
infusion of MEDI4736 and within 10 minutes of end of infusion of tremelimumab [for patients receiving MEDI4736 + tremelimumab]). On Week 4, PK samples will be 
collected pre-dose (within 60 minutes prior to treatment with any IP) only. On Week 24, PK samples will be collected pre-dose (within 60 minutes prior to treatment 
with any IP) and at the end-of-infusion for MEDI4736 (within 10 minutes of end of infusion), with no sample for tremelimumab.
k
The follow-up samples (3 and 6 months) for each molecule are relative to the respective last dose.
l
Patients in the MEDI4736 monotherapy arm will receive MEDI4736 every 4 weeks for up to 12 months (up to 13 doses). Patients in the MEDI4736 + tremelimumab 
combination therapy arm will receive MEDI4736 and tremelimumab every 4 weeks for the first 4 months (up to 4 doses) followed by MEDI4736 every 4 weeks for the 
subsequent 8 months (up to 9 doses). For the combination arm only – tremelimumab will be administered first; the MEDI4736 infusion will start approximately 1 hour 
after the end of the tremelimumab infusion.  If there are no clinically significant concerns after the first cycle, and at the discretion of the physician, then for all other 
cycles MEDI4736 can be given immediately after the tremelimumab infusion has finished.  Patients who achieve and maintain disease control (ie, CR, PR, or SD) 
through to the end of the assigned IP 12-month treatment period may restart treatment with the combination upon evidence of PD, with or without confirmation, during 
follow-up.  Before restarting their assigned IP, the Investigator should ensure patients do not have any significant, unacceptable, or irreversible toxicities that indicate 
continuing treatment will not further benefit the patient, and that the patient still fulfills the eligibility criteria for this study, including re-consenting to restart IP.  To 
restart treatment, the patient must not have received an intervening systemic anticancer therapy after his or her assigned IP discontinuation.  Patients should have a 
baseline tumor assessment within 28 days of restarting their assigned IP treatment; all further scans should occur q6w ±7 days (relative to the date of restarting treatment)
and q12w ±7 days thereafter until study treatment is stopped (maximum of 12 months of further treatment).  If a patient derives clinical benefit from the combination of 
MEDI4736 + tremelimumab, per judgment of the Investigator, and subsequently progresses while undergoing treatment with MEDI4736 alone, MEDI4736 q4w and 
tremelimumab induction may be reinstituted for 4 doses 1 time only (follow the same treatment guidelines as during the first 12 months).
m
PROs (EORTC QLQ-C30, QLQ-PAN26, and EQ-5D-5L) will be collected during Part B only.  Patients will complete PROs using handheld electronic devices at study 
sites if assessment timepoint coincides with a study visit; otherwise patients will complete the PROs at home.  PROs should be completed prior to any other visit 
procedures to ensure that any such clinical interactions do not bias the patient’s response to the questionnaire items.  Please note that the EORTC QLQ-C30 and EORTC 
QLQ-PAN26 are administered as a single questionnaire. 
n
The PRO-CTCAE will be collected during Part B only.  PRO-CTCAE will only be administered in those countries where a linguistically validated version exists.
o
HOSPAD module should be completed by site staff whenever the patient has attended or been admitted to the hospital.  A reminder will be provided at each clinic visit.
p
ADAs for MEDI4736 only, not tremelimumab.
q
The newly acquired or archival (<3 years) sample must be received by the central laboratory prior to dosing.
r
Newly acquired tumor sample to be collected at Week 4 (-1 week/+2 weeks)


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
60(131)
s
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 complete 
response/partial response and 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.  For all patients who are treated through progression, the Investigator should ensure patients do not have any significant, 
unacceptable or irreversible toxicities that indicate continuing treatment will not further benefit the patient, and that the patient still fulfils eligibility criteria for this study 
including re-consenting to continue treatment.  For ‘re-treatment’ patients who go on to have a subsequent 12 months of treatment, the same assessments should be done 
as in the first 12-month treatment period with the exception of the PK, ADA, sPD-L1, SNP, MDSC, and nAB assessments, which do not need to be collected a second 
time.
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.
β-hCG  Beta-human chorionic gonadotropin; C  Cycle; fT3  Free triiodothyronine; fT4  Free thyroxine; hCG  Human chorionic gonadotropin; LFT  Liver function test; 
TSH  Thyroid-stimulating hormone; V  Visit.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
61(131)
Table 3
Schedule of assessments: follow-up for patients who have completed treatment and achieved disease 
control (until confirmed progression of disease)
Evaluation
Time since last dose of IP
Day (±3)
Months (±1 week)
12 months 
and every 
2 months
(±2 weeks)
30
2
3
4
6
8
10
Physical examinationa
X
Vital signs (temperature, respiratory rate, blood pressure, and pulse)
X
Weight
X
AE/SAE assessment
X
X
X
Concomitant medications
X
X
X
Hospital resource use module (HOSPAD) (Part B only)
To be completed at each hospitalization
ECOG performance status
At time points consistent with tumor assessments up to confirmed disease progression.  Upon 
confirmation of progression, ECOG performance status should also be collected at other site 
visits that the patient attends, if appropriate site staff are available to collect such information.  In 
addition, ECOG performance status should be provided when information on subsequent 
anticancer therapy is provided, where possible.
Subsequent anticancer therapy
X
X
X
X
X
X
X
X
Survival status: for all patients, including phone contact with patients who 
refuse to return for evaluations and agree to be contacted
X
X
X
X
X
X
Urine hCG or serum β-hCG
X
Hematology
X
X
X
Serum or plasma chemistry 
X
X
X
Thyroid function tests (TSH, fT3, and fT4)b
X
Pharmacokinetic assessment
X
Immunogenicity assessment (ADA sampling [including ADA neutralizing 
antibodies] to identify ADA responses in patient circulation)
X
X
sPD-L1 concentration (to assess target engagement)
X
EORTC QLQ-C30, EORTC QLQ-PAN26, and EQ-5D-5Lc (Part B only)
Every 8 weeks up to at least 6 months following disease progression


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
62(131)
Evaluation
Time since last dose of IP
Day (±3)
Months (±1 week)
12 months 
and every 
2 months
(±2 weeks)
30
2
3
4
6
8
10
PRO-CTCAEc,d (Part B only)
Every 4 weeks up to at least 6 months following disease progression
Tumor assessment (CT or MRI)
For patients who achieve disease control following 12 months of treatment, tumor assessments 
should be performed q12w ±7 days relative to the date of first infusion until confirmed PD by 
RECIST 1.1 by investigational site review.  Please refer to Table 2 for timings of confirmatory 
scans.  
a
Full physical exam
b
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.
c
PROs (EORTC QLQ-C30, QLQ-PAN26, and EQ-5D-5L) will be collected during Part B only.  PROs should be completed for least 6 months post-confirmed disease 
progression.  Post-progression, patients should complete PROs at home if necessary to minimize noncompliance.  PROs should be completed prior to any other visit 
procedures to ensure that any such clinical interactions do not bias the patient’s response to the questionnaire items. Please note that the EORTC QLQ-C30 and EORTC 
QLQ-PAN26 are administered as a single questionnaire.
d
The PRO-CTCAE will be collected during Part B only.  PRO-CTCAE will only be administered in those countries where a linguistically validated version exists.  
β-hCG  Beta-human chorionic gonadotropin; fT3 Free triiodothyronine; fT4  Free thyroxine; hCG  Human chorionic gonadotropin; sPD-L1  Soluble PD-L1; 
TSH Thyroid-stimulating hormone.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
63(131)
Table 4
Schedule of assessments: follow-up for patients who have discontinued study treatment due to confirmed 
progression of disease and patients who have discontinued due to toxicity in the absence of confirmed 
progression of disease
Evaluation
Time since last dose of IP
Day 
(±3)
Months (±1 week)
12 months and every 
2 months
(±2 weeks)
30
2
3
4
6
8
10
Physical examinationa
X
Vital signs (temperature, respiratory rate, blood pressure, and pulse)
X
Weight
X
AE/SAE assessment
X
X
X
Concomitant medications
X
X
X
Hospital resource use module (HOSPAD) (Part B only)
To be completed at each hospitalization
ECOG performance statusb 
X
X
X
Xb
Xb
Xb
Xb
Xb
Subsequent anticancer therapy
X
X
X
X
X
X
X
X
Survival status: for all patients, including phone contact with patients 
who refuse to return for evaluations and agree to be contactedc
X
X
X
X
X
X
Urine hCG or serum β-hCG
X
Hematology
X
X
X
Serum or plasma chemistry 
X
X
X
Thyroid function tests (TSH, fT3, and fT4)d
X
Pharmacokinetic assessment
X
Immunogenicity assessment (ADA sampling [including ADA 
neutralizing antibodies] to identify ADA responses in patient 
circulation)
X
X
sPD-L1 concentration (to assess target engagement)
X
Circulating soluble factors (to assess cytokines, chemokines, growth 
factors, and antibodies against tumor and self antigens in circulation)
X


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
64(131)
Evaluation
Time since last dose of IP
Day 
(±3)
Months (±1 week)
12 months and every 
2 months
(±2 weeks)
30
2
3
4
6
8
10
miRNA/mRNA (to examine immune cell gene expression profiles in 
circulation)
X
PBMCs
X
EORTC QLQ-C30, EORTC QLQ-PAN26, and EQ-5D-5Le (Part B
only)
Every 8 weeks up to at least 6 months following disease progression
PRO-CTCAEe,f (Part B only)
Every 4 weeks up to at least 6 months following disease progression
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 ±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.  
a
Full physical exam.
b
ECOG performance status should also be collected at other site visits that the patient attends, if appropriate site staff are available to collect such information.  In 
addition, ECOG performance status should be provided when information on subsequent anticancer therapy is provided, where possible.
c
Post-progression, patients will be followed for survival contact every 2 months (8 weeks) until death or until the end of the study.
d
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.
e
The EORTC QLQ-C30 and QLQ-PAN26 will be collected during Part B only.  PROs should be completed for least 6 months post-confirmed disease progression.  Post-
progression, patients should complete PROs at home if necessary to minimize noncompliance.  PROs should be completed prior to any other visit procedures to ensure 
that any such clinical interactions do not bias the patient’s response to the questionnaire items.  Please note that the EORTC QLQ-C30 and EORTC QLQ-PAN26 are 
administered as a single questionnaire.
f
The PRO-CTCAE will be collected during Part B only.  PRO-CTCAE will only be administered in those countries where a linguistically validated version exists.  
β-hCG  Beta-human chorionic gonadotropin; fT3  Free triiodothyronine; fT4  Free thyroxine; hCG  Human chorionic gonadotropin; sPD-L1  Soluble PD-L1; 
TSH  Thyroid-stimulating hormone.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
65(131)
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.
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.  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 4.
4.2
Treatment period
All procedures to be conducted during the 12-month treatment period will be performed 
according to the assessment schedules (see Table 2). 
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 through Table 4.
4.3
Follow-up period
All procedures to be conducted during the follow-up period will be performed according to 
the assessment schedule (see Table 3 and Table 4).
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.
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.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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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, PFS2, PFS3, and 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 F.  OS, OS6, and 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 6 weeks 
(q6w ±7 days) 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.  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.
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.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
67(131)
Following confirmed progression, patients should continue to be followed up for survival 
every 2 months (8 weeks) as outlined in the follow-up schedule of assessments (Table 4).  In 
addition, all patients will be contacted in the week following data cutoff to confirm survival 
status.
Patients randomized to the MEDI4736 monotherapy or MEDI4736 + tremelimumab arms who 
achieve and maintain disease control (ie, CR, PR, or SD) through to the end of the 12-month 
treatment period may restart treatment with their assigned IP upon evidence of PD, with or 
without confirmation, according to RECIST 1.1, during follow-up (patients receiving 
MEDI4736 + tremelimumab in combination may restart combination therapy following 
disease control lasting at least the first 4 cycles of combination therapy).  To restart treatment, 
the patient must not have received an intervening systemic anticancer therapy post 
discontinuation.  Patients who restart treatment must have a baseline tumor assessment within 
28 days of restarting treatment with IP; all further scans should occur q6w ±7 days (relative to 
the date of restarting treatment) and then q12w ±7 days thereafter until confirmed disease 
progression. All assessments in Table 2 will be followed for patients who continue to receive 
treatment. 
It is important to follow the assessment schedule as closely as possible.  Refer to the study 
plans (Table 2 [screening and the treatment period], Table 3 and Table 4 [follow up]) and 
Appendix F.
5.1.1
Central reading of scans
Investigator’s assessment of all scans using RECIST 1.1 will be conducted (see Section 8.5
for the analysis methods).  All images will be collected and stored with the imaging provider
for possible future central re-analysis at the discretion of the Sponsor.  Guidelines for image
collection, quality control, and storage will be provided in a separate document.  The 
management of patients will be based solely upon the results of assessment conducted by the 
Investigator.  When a Blinded Independent Central Review (BICR) is performed, three levels 
of review will be included in the radiology assessments: RECIST 1.1, RECIST 1.1 modified 
for confirmation of progression, and irRECIST 1.1.
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 4).
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).


Clinical Study Protocol
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Study Code D4198C00001
Edition Number 1
Date 17 August 2015
68(131)
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 5 (clinical chemistry) Table 6
(hematology), and Table 7 (urinalysis). 
Table 5
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 6
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


Clinical Study Protocol
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Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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Table 7
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
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer to 
Appendix E 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 4).  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
ECG
Resting 12-lead ECGs will be recorded according to the assessment schedules (see Table 2).  
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.
ECGs will be recorded at screening and as clinically indicated.
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 


Clinical Study Protocol
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Edition Number 1
Date 17 August 2015
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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 4).  
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.  
BP and pulse will be evaluated at the beginning of the infusion, every 30 minutes during 
treatment, and in the 1-hour post-infusion observation period: 30 and 60 minutes after the 
infusion (ie, 90 and 120 minutes from the start of the infusion) (±5 minutes) – for the first 
infusion only and then for subsequent infusions as clinically indicated.  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).  
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 4).  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
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Edition Number 1
Date 17 August 2015
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5.3
Other assessments
5.3.1
Patient reported outcomes (PRO)
“PRO” is an umbrella term referring to all outcomes and symptoms that are directly reported 
by the patient.  PROs have become a significant endpoint when evaluating effectiveness of 
treatments in clinical studies.  The following PROs will be administered in this study: EORTC 
QLQ-C30, EORTC QLQ-PAN26, the Patient-Reported Outcomes version of the Common 
Terminology Criteria for Adverse Events (PRO-CTCAE), and the EQ-5D-5L; see 
Appendix G).
The PRO instruments will be self-administered by the patients as ePROs using handheld 
devices at study sites or at home.  All assessments should be completed without assistance 
from site staff according to the assessment schedules (see Table 2, Table 3, and Table 4), 
before any other study procedures are conducted at a given visit.  Study coordinators should 
ensure that patients have completed the PRO assessment for that visit before the patient is 
seen by a study nurse or physician (unless these are the same person).  It takes approximately 
15 to 30 minutes for patients to complete the questionnaires; therefore, the burden to the 
patient is moderate.  If patients have had scans at an outside facility or missed a scheduled 
data collection site visit, PRO questionnaires should still be completed by the patient at home 
on that scheduled visit date.  
5.3.1.1
EORTC QLQ-C30
The EORTC QLQ-C30, Version 3 questionnaire is included for the purpose of assessing 
HRQoL and is a well-established measure of HRQoL/health status, and commonly used as an 
endpoint in cancer clinical trials.  It assesses HRQoL/health status through 9 multi-item 
scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales 
(fatigue, pain, and nausea and vomiting), and a global health and QoL scale.  Six single-item 
symptom measures are also included: dyspnea, insomnia, appetite loss, constipation, diarrhea, 
and financial difficulties (see Appendix G).  For each of the 15 domains, final scores are 
transformed such that they range from 0 to 100, where higher scores indicate greater 
functioning, greater HRQoL, or greater level of symptoms (Aaronson et al 1993).
5.3.1.2
EORTC QLQ-PAN26
For patients with pancreatic cancer, a disease-specific self-administered questionnaire for 
pancreatic cancer was developed (EORTC QLQ-PAN26; Appendix G) to be used in 
conjunction with the EORTC QLQ-C30 (Fitzsimmons and Johnson 1998, 
Fitzsimmons et al 2005).  The EORTC QLQ-PAN26 consists of 26 items that comprise 
7 multi-item scales (pancreatic pain [4 items], eating related [2 items], hepatic [2 items], 
altered bowel habit [2 items], body image [2 items], health care satisfaction [2 items], and 
sexuality [2 items]) and 10 single-item scales (swollen abdomen, taste changes, indigestion, 
flatulence, weight loss, loss of muscle strength, dry mouth, burden of treatment, fear of future 
health, and ability to plan future).  When items are grouped into domains rather than reporting 
specific items, it is important that the correct scoring algorithm is followed.  Higher scores 
represent more symptoms, except for health care satisfaction scale and sexuality scale where 


Clinical Study Protocol
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Edition Number 1
Date 17 August 2015
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higher scores represent greater satisfaction and sexuality. For change scores, a score of +5 is 
considered deterioration (except for the 2 scales mentioned above) and a score of -5 is 
considered as improvement.  Thus, final scores are transformed such that they range from 0 to 
100, where higher scores indicate greater functioning or greater level of symptoms (Aaronson 
et al 1993).
5.3.1.3
PRO-CTCAE
The PRO-CTCAE is included to address tolerability from the patients’ perspective.  It was 
developed by the NCI.  The PRO-CTCAE will only be administered in those countries where 
a linguistically validated version exists.  It was developed in recognition that collecting 
symptom data directly from patients using PRO tools can improve the accuracy and efficiency 
of symptomatic AE data collection.  This was based on findings from multiple studies 
demonstrating that physicians and nurses underestimate symptom onset, frequency, and 
severity in comparison with patient ratings (Basch et al 2009, Litwin et al 1998, Sprangers and 
Aaronson 1992).  These symptoms have been converted to patient terms (eg, CTCAE term 
“myalgia” converted to “aching muscles”).  For several symptoms, like fatigue and pain, 
additional questions are asked about symptom frequency, severity, and interference with usual 
activities.  The items included in the PRO CTCAE have undergone extensive qualitative 
review among experts and patients.  These items have been extensively evaluated by patients 
with cancer to be clear, comprehensible, and measuring the symptom of interest.  In this study, 
only items that are considered relevant for the trial, site of cancer, and cancer treatment are 
selected (see Appendix G).
5.3.1.4
EQ-5D-5L
The EQ-5D is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal 
(EuroQol Group 1990).  Applicable to a wide range of health conditions and treatments, it 
provides a simple descriptive profile and a single index value for health status that can be used 
in the clinical and economic evaluation of health care as well as in population health surveys.  
The questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression.  Each dimension has 5 response options (no problems, slight 
problems, moderate problems, severe problems, and extreme problems) that reflect increasing 
levels of difficulty (EuroQol Group 2013).
Since 2009, the EuroQol group has been developing a more sensitive version of the EQ-5D 
(the EQ-5D-5L) which expands the range of responses to each dimension from 3 to 5 levels of 
increasing severity (Herdman et al 2011).  Preliminary studies indicate that the 5L version 
improves upon the properties of the 3L measure in terms of reduced ceiling effect, increased 
reliability and an improved ability to differentiate between different levels of health (Janssen 
et al 2008a, Janssen et al 2008b, Pickard et al 2007).
The patient will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions.  The questionnaire also includes a visual 
analogue scale, where the patient will be asked to rate current health status on a scale of 0 to 
100, with 0 being the worst imaginable health state (see Appendix G).


Clinical Study Protocol
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5.3.2
Administration of the patient-reported outcome questionnaires
Patients will complete the PRO assessments by using a handheld electronic device (ePRO).
Each center must allocate the responsibility for the administration of the PRO instruments to a 
specific individual (eg, a research nurse or study coordinator) and, if possible, assign a 
back-up person to cover if that individual is absent.  The PRO questionnaires must be 
administered and completed at the clinic as per the schedule of assessments if the assessment 
timepoint coincides with a study visit; otherwise patients will complete the PROs at home.  
The PRO questionnaires will be administered on the days specified in the schedules of 
assessments (see Table 2, Table 3, and Table 4).  Post-progression, patients should complete 
PROs at home if necessary to minimize noncompliance.
The following best practice guidelines should be followed when collecting PRO data via an 
electronic device:
!
PRO questionnaires must be completed prior to any other study procedures 
(following informed consent) and before discussion of disease progression to avoid 
bias in the patient’s responses to the questions.
!
PRO questionnaires must be completed by the patient in private.
!
The research nurse or appointed site staff must explain to patients the value and 
relevance of study participation and inform them that these questions are being 
asked to find out, directly from them, how they feel.  The research nurse or 
appointed site staff should also stress that the information is confidential.  
Therefore, if the patients have any medical problems, they should discuss them with 
the doctor or research nurse separately from the ePRO assessment.
!
The research nurse or appointed site staff must train the patient on how to use the 
ePRO device, using the materials and training provided by the ePRO vendor, and 
provide guidance on whom to call if there are problems with the device.
!
The research nurse or appointed site staff must remind patients that there are no 
right or wrong answers and avoid introducing bias by not clarifying items.
!
The patient should not receive help from relatives, friends, or clinic staff to answer 
the PRO questionnaires.  If a patient uses visual aids (eg, spectacles or contact 
lenses) for reading and does not have them when he or she attends the clinic, the 
patient will be exempted from completing the PROs.  
!
Site staff must not read or complete the PRO questionnaires on behalf of the patient.  
If the patient is unable to read the questionnaire (eg, is blind or illiterate), that 
patient should be exempted from completing PRO questionnaires but may still 
participate in the study.  Patients exempted in this regard should be flagged 
appropriately by the site staff. 


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Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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!
The patient should be given sufficient time to complete the PRO questionnaires at 
his or her own speed.
!
The research nurse or appointed site staff or family member must monitor 
compliance; minimizing missing data is a key aspect of study success.  Compliance 
must be checked at each study visit and should be checked more frequently to 
identify problems early. If compliance drops below 85%, a check-in call from the 
site to ask the patient if he or she has any difficulties is highly recommended.
5.3.3
ECOG performance status
ECOG performance status will be assessed at the times specified in the assessment schedules 
(see Table 2 through Table 4) 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.
5.3.4
Health resource use
For the purposes of economic evaluation for payer submissions, it is necessary to capture 
healthcare resource use related to the treatment and the underlying disease.  Within the study, 
the following will be captured:
!
Hospital episodes captured by hospital resource use module (HOSPAD).  HOSPAD 
is an eCRF module completed by sites capturing information from patient’s medical 
records regarding the type of contact (hospitalizations, outpatient, day case), reason, 
and length of stay by ward type (including intensive care unit).
!
Treatment related to AEs (including the method of delivery of the treatment) 
captured in AE/SAE assessment module
!
Treatment not related to the study captured in concomitant medications eCRF


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Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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5.4
Pharmacokinetics
5.4.1
Collection of samples
Blood samples for determination of MEDI4736 and tremelimumab concentration in serum 
will be obtained according to the assessment schedules (see Table 2 through Table 4).
Details on sample processing, handling, shipment, and storage are provided in the Laboratory 
Manual.
5.4.2
Determination of drug concentration of MEDI4736 and tremelimumab
Samples for determination of MEDI4736 and tremelimumab 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.
5.4.3
Storage and destruction of pharmacokinetic samples for MEDI4736 and 
tremelimumab
PK samples will be disposed 5 to 10 years after the IPs are approved for marketing or formal 
discontinuation of clinical development of the IP.
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 Biobank; see details in 
the Laboratory Manual).
5.4.4
Collection of samples to measure the presence of ADAs
The presence of ADAs will be assessed in serum samples taken according to the assessment 
schedules (see Table 2 through Table 4). 
Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for 
MEDI4736 and tremelimumab 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. 
5.4.5
Storage and destruction of ADA samples
ADA samples will be disposed 5 to 10 years after the IPs are approved for marketing or 
formal discontinuation of clinical development of the IP.


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Drug Substance MEDI4736 and Tremelimumab
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Edition Number 1
Date 17 August 2015
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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 Biobank; see details 
in the Laboratory Manual).
5.5
Biomarker analysis 
The patient’s consent to the use of donated biological samples is mandatory.  
Mandatory tumor and blood biomarkers to be evaluated for the purpose of evaluation of 
patient selection and for exploratory analyses are described in Section 5.5.1.  Exploratory 
biomarkers may be evaluated as determined by additional data (see Section 5.5.1.2).  Samples 
will be taken according to the assessment schedules (see Table 2 through Table 4).
Biomarkers that have demonstrated the potential to identify patients who are likely to respond 
to treatment with IP (from other MEDI4736 monotherapy or MEDI4736 + tremelimumab 
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.
5.5.1
Collection of samples
5.5.1.1
Collection of biomarker samples for evaluation of patient selection
Provisions of tissue are as follows:
!
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 as described in the proceeding section.  A newly acquired tumor biopsy is 
strongly preferred; however, if not feasible with an acceptable clinical risk, an 
archival sample taken <3 years prior to screening can be submitted.  This sample 
must be received by the central laboratory prior to dosing.
Samples should be collected via an image-guided core needle (at least 18 gauge) or 
an excisional archival tumor biopsy sample. Where institutional practice in this 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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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 material 
for downstream analyses. Two cores, using an 18-gauge or larger needle, are 
required for determining PD-L1 expression levels.  These should be placed in 
formalin and processed to a single paraffin embedded block, as described in the 
Pathology Manual.  When a smaller gauge needle is used, the number of cores rises 
to 3 or 4. That written, and as a guidance, it is anticipated that 4 passes of a core 
needle will provide sufficient tissue. Whenever feasible, additional cores should be 
obtained and immediately frozen as described in the Laboratory Manual.
Tumor lesions planned for biopsy should not be used as index lesions for 
assessment of disease.
!
MANDATORY: If clinically feasible, on-treatment collection of tumor biopsies at 
the timepoints indicated in Table 2.  The Investigator must consult with the Study 
Physician if such sampling is not feasible.
!
OPTIONAL: If a newly acquired tumor sample is submitted during screening, an 
additional archived tumor tissue block (formalin-fixed, paraffin-embedded) is 
strongly encouraged, where such samples exist in a quantity sufficient to allow for 
analysis. 
!
The collection of tumor biopsies at the time of progression and prior to retreatment 
is strongly encouraged.  The biopsy procedure at retreatment should be omitted only 
if there is unacceptable clinical risk or the procedure is otherwise considered not 
feasible.  The Investigator must consult with the Study Physician prior to making 
the decision not to biopsy at retreatment.
Additional tumor biopsies collected as part of clinical care (eg, for mixed responses or upon 
PD) can be submitted for further analysis.
See the Laboratory Manual for further details of requirements.
Tumor biopsies will be stored at AstraZeneca Research and Development or an appropriate 
vendor selected by AstraZeneca.  Core biopsies may be used for correlative studies such as 
IHC assay, tumor mutation analysis, ribonucleic acid (RNA) analysis, proteomic analysis, 
immunophenotyping, and assessment of immunodiversity.  A brief outline of such analyses is 
provided in the exploratory biomarker data description in Section 5.5.1.2.  Samples will be 
collected, labeled, stored, and shipped as detailed in the Laboratory Manual.
5.5.1.2
Exploratory biomarker data
Blood and tumor samples for exploratory biomarker analyses will be obtained according to the 
assessment schedules presented in Table 2 through Table 4.  Details for collection, volumes, 
storage, and shipment of biologic samples are presented in a separate Laboratory Manual. 


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Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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Pharmacodynamic changes in biomarker measures will be monitored, when applicable.  
Baseline measures (and early, on-treatment changes) will be correlated with outcomes.  Note 
that samples will be obtained from patients enrolled to each treatment arm.  Data will be 
compared across treatment arms to determine if changes are specific to one treatment arm 
versus the other.  Similar comparisons will be made with baseline measures to determine if 
biomarkers (or combination of markers) are prognostic or may be candidate, predictive 
markers of outcomes associated with MEDI4736 monotherapy and MEDI4736 combination 
therapy.  
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 biomarker plan is described by sample type below.
Tumor markers (in formalin-fixed paraffin-embedded tissue)
Tissue obtained as part of screening procedures and for establishing PD-L1 expression will be 
analyzed for additional markers by IHC assay.  At a minimum, CD8 and CD4/FoxP3 
measures will be completed in an effort to enumerate cytotoxic versus regulatory T cells.  
Based on availability of tissue, a panel of additional, immune-relevant markers expressed on 
tumor-infiltrating lymphocytes or on tumor cells may be assessed.  Markers of special interest 
include, but are not limited to, Ox40, GITR, PD-L2, Tim-3, CD137, Lag-3, and markers that 
may identify MDSCs, which may change on treatment (Highfill et al 2014).
Tissues obtained at screening may be assessed also for somatic mutations and/or for an
interferon-gamma (IFN-γ) gene expression signature (eg, IFN-γ) by reverse transcription 
quantitative polymerase chain reaction (RT-qPCR), in situ hybridization, NanoString®, and/or 
similar methodologies. 
Whole blood for DNA/single nucleotide polymorphism genotyping
Genomic DNA will be extracted from whole blood obtained pretreatment from all patients.  
Genotyping of immunomodulatory genes such as PD-1, PD-L1, CTLA-4, and human 
leukocyte antigen loci may be completed to determine whether natural variation within such 
genes is associated with likelihood of clinical benefit and/or with likelihood of drug-related 
AEs.  Genes associated with solid tumor development, disease progression, or likelihood of 
tumor response to chemotherapy may, likewise, be investigated.  Genotyping will occur 
retrospectively, data will not be shared with patients, and results will not impact treatment 
decisions.
Genotypes may also be correlated with biomarker measures (eg, gene and/or protein 
expression) obtained from other sample types described in this exploratory biomarker section.  
A primary hypothesis is that different genotypes will be associated with different expression 
levels of factors within the PD-1 and CTLA-4 signaling pathways.  Such variations in 
expression may affect the ability of a patient to mount an appropriate immune reaction to a 
tumor and/or affect the likelihood of response to therapeutics targeting these pathways.  


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Therefore, genotyping may provide easy-to-measure baseline information regarding a 
patient’s immune system.  One goal of this research is to understand how such genetic 
information may be used to predict pharmacodynamic responses to therapy.
Whole blood gene expression (PaxGene-RNA)
Whole blood samples will be obtained before or after treatment as outlined in Table 2 through
Table 4 from all patients.  Total RNA will be prepared for quantification of RNA and/or 
miRNA expression using RT-qPCR, microarray, sequencing, or similar methodology. 
Focus is likely to be given to the expression of immunomodulatory genes previously found to 
be up-regulated in response to MEDI4736 and/or tremelimumab.  Pretreatment expression of 
such genes may indicate active immune responses that may be augmented by checkpoint 
inhibitor immunotherapies; correlations with outcome data will be completed on select 
candidate predictive markers with the aim of characterizing useful expression thresholds for 
identifying patients likely to receive benefit.  Similar procedures may be completed using 
select peripheral blood mononuclear cell (PBMC) samples described below.
Myeloid-derived suppressor cells
Flow cytometry will be completed on all patients to quantify pretreatment circulating MDSC 
subtypes.  Different MDSC count thresholds will be analyzed for their ability to predict 
clinical benefit from therapy.  
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, MDSC assessments in banked 
specimens, T-cell functional assays (eg, ELISPOT), receptor occupancy analyses to measure 
target engagement, tetramer analyses to monitor antigen-specific T cells, RNA/miRNA 
expression, and/or the assessment of the diversity and clonality of T-cell receptor gene 
rearrangements using DNA.  
Soluble factors (plasma)
Plasma will be obtained before or after treatment as outlined in Table 2 through Table 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 and interleukin 
(IL)-18.  High pretreatment expressions (concentrations) of such factors may indicate active 
immune responses that may be augmented by checkpoint inhibitor immunotherapies; 
correlations with outcome data will be completed on select candidate predictive markers, with 
an aim of characterizing useful expression thresholds for identifying patients likely to receive 
benefit or, alternatively, for identifying patients likely to suffer drug-related AEs. 
Similarly, the concentrations of a battery of immune cell ligands or receptors may be assessed.  
Proteins of special interest include CTLA4, PD-1, PD-L1, B7-1, B7-2, and IL6R.


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Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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Plasma may also be used for the detection/quantification of autoantibodies (against tumor-
associated antigens) on ProtoArray® or a similar assay platform containing antigens 
preselected based on documented expression in study indications.  Seroconversion following 
treatment will 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.
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 biological 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 
this biomarker research may be pooled with biomarker data from other studies involving 
MEDI4736 or tremelimumab 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 C.
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.


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Drug Substance MEDI4736 and Tremelimumab
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Edition Number 1
Date 17 August 2015
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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 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
!
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
Refer to Appendix D for details of the genetic research (optional DNA component).
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section.


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Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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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 B.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
AEs 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 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 


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Edition Number 1
Date 17 August 2015
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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
!
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


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Edition Number 1
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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 B.
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. 


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Edition Number 1
Date 17 August 2015
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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.
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 E 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.


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Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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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.
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. 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
87(131)
The reference documents for definition of expectedness/listedness are the IBs for MEDI4736 
and tremelimumab. 
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.
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.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
88(131)
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 
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 (see the Dosing Modification and Toxicity Management Guidelines).
!
All dose modifications should be documented with clear reasoning and 
documentation of the approach taken.
In addition, there are certain circumstances in which MEDI4736 and tremelimumab should be 
permanently discontinued (see Section 3.9 and the Dosing Modification and Toxicity 
Management Guidelines).


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
89(131)
Following the first dose of IP, subsequent administration of MEDI4736 and tremelimumab 
can be modified based on toxicities observed as described in the Dosing Modification and 
Toxicity Management Guidelines.  All toxicities will be graded according to NCI CTCAE, 
Version 4.03.  Dose reductions are not permitted. In case of doubt, the Investigator should 
consult with the Study Physician.  
6.7.1
MEDI4736 and MEDI4736 + tremelimumab
Adverse events of special interest (AESIs) are events of scientific and medical interest specific 
to the further understanding of the MEDI4736 and tremelimumab safety profile and require 
close monitoring and rapid communication by the Investigator to AstraZeneca.  MEDI4736 
and tremelimumab 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 these IPs. 
Information on MEDI4736 and MEDI4736 + tremelimumab AESIs and guidelines for the 
management of immune-mediated reactions, infusion-related reactions, and non-immune-
mediated reactions for MEDI4736 and MEDI4736 + tremelimumab are provided in the 
Dosing Modification and Toxicity Management Guidelines.
6.7.2
Standard of care
Toxicities related to SoC treatment in the RCT: Part B should be managed as per local 
guidelines and the relevant approved labelling.
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 tremelimumab. The SoC products (for Part B: RCT)
will be sourced locally.
Investigational product
Dosage form and strength
MEDI4736
50 mg/mL solution for infusion
Tremelimumab
20 mg/mL solution for infusion
SoC (for Part B: RCT only)
Treatment-dependenta
a
Under certain circumstances when local sourcing is not feasible, standard of care treatment may be supplied 
centrally through AstraZeneca.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
90(131)
7.1.1
MEDI4736
MEDI4736 will be supplied by AstraZeneca as a 500-mg vial for solution for infusion. The 
solution contains 50 mg/mL MEDI4736, 26 mM histidine/histidine hydrochloride, 275 mM 
trehalose dihydrate, and 0.02% (weight/volume) polysorbate 80; it has a pH of 6.0.  Total 
in-use storage time from needle puncture of MEDI4736 vial to the start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C (36°F to 46°F).  If 
the in-use storage time exceeds these limits, a new dose must be prepared from new vials.  
MEDI4736 does not contain preservatives, and any unused portion must be discarded.  
MEDI4736 vials should be stored at refrigerated temperatures (2°C to 8°C), and should 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.  Doses of 1.5 g will be administered using a 
bag containing 250 mL 0.9% (weight/volume) saline and delivered through an IV
administration set with a 0.2-μm in-line filter.  A volume of 0.9% (weight/volume) saline 
equal to the volume of MEDI4736 to be added to the IV bag must be removed from the bag 
prior to the addition of MEDI4736.  The calculated volume of MEDI4736 is then added to the 
IV bag, and the bag is mixed by gentle inversion to ensure homogeneity of the dose in the bag.
Preparations are to be in accordance with the study-specific drug handling instructions.
No incompatibilities between MEDI4736 and polyethylene, polypropylene, polyvinylchloride, 
or polyolefin copolymers have been observed.
7.1.2
Tremelimumab
Tremelimumab is supplied as a sterile solution for IV infusion, filled in 20-mL clear glass 
vials with a rubber stopper and aluminum seal.  Each vial contains 20 mg/mL (with a nominal 
fill of 20 mL, accounting to 400 mg/vial) of tremelimumab, in isotonic solution at pH 5.5.  
Tremelimumab vials should be stored at refrigerated temperatures (2°C to 8°C), and should 
not be frozen.
Product preparation and reconstitution of tremelimumab
The dose of tremelimumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique.  Total in-use storage time from needle 
puncture of the product vial to start of administration should not exceed 4 hours at room 
temperature or 24 hours at 2°C to 8°C (36°F to 46°F).  If in-use storage time exceeds these 
limits, a new dose must be prepared from new vials.  Tremelimumab does not contain 
preservatives, and any unused portion must be discarded.
Preparation of tremelimumab doses for administration with an IV bag
Doses of 75 mg will be administered using a bag containing 250 mL 0.9% (weight/volume) 
saline and delivered through an IV administration set with a 0.2-μm in-line filter.  A volume 
of 0.9% (weight/volume) saline equal to the volume of tremelimumab to be added to the IV 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
91(131)
bag must be removed from the bag prior to the addition of tremelimumab.  The calculated 
volume of tremelimumab is then added to the IV bag, and the bag is mixed by gentle inversion 
to ensure homogeneity of the dose in the bag.
Preparations are to be in accordance with the study-specific drug handling instructions.
7.2
Dose and treatment regimens
7.2.1
Treatment regimens
MEDI4736 monotherapy
Patients in the MEDI4736 monotherapy treatment arm will receive 1.5 g MEDI4736 via IV 
infusion q4w for up to 12 months (up to 13 doses).  See Figure 3.
Figure 3
MEDI4736 monotherapy dosing schedule
MEDI4736 + tremelimumab
Patients in the MEDI4736 + tremelimumab arm will receive 1.5 g MEDI4736 via IV infusion 
q4w for 4 months with 75 mg tremelimumab via IV infusion q4w for 4 doses (4 doses each).  
Patients will then continue with MEDI4736 monotherapy at 1.5 g q4w, beginning at Week 16, 
4 weeks after the last dose of combination therapy, up to a total of 9 additional doses, with the 
final dose at Week 48.  See Figure 4.
Tremelimumab will be administered first.  MEDI4736 infusion will start approximately 1 hour 
after the end of tremelimumab infusion.  The duration will be approximately 1 hour for each 
infusion.  A 1-hour observation period is recommended after the first infusion of MEDI4736 
and tremelimumab.  If no clinically significant infusion reactions are observed during or after 
the first cycle, subsequent infusion observation periods can be at the Investigator’s discretion 
(suggested 30 minutes after each MEDI4736 and tremelimumab infusion).


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
92(131)
Figure 4
MEDI4736 + tremelimumab combination therapy dosing schedule
Standard of care
Patients randomized to the SoC treatment arm of Part B: RCT will receive SoC treatment with 
a gemcitabine-based chemotherapy (for patients whose first-line chemotherapy was 
fluorouracil-based) or fluorouracil-based chemotherapy (for patients whose first-line 
chemotherapy was gemcitabine-based).  Treatment will be as per local guidelines.
7.2.2
Duration of treatment
Treatment will be administered beginning on Day 1.  
Patients in Part A or Part B will receive MEDI4736 monotherapy or MEDI4736 + 
tremelimumab combination for 12 months or until confirmed PD, unacceptable toxicity, 
withdrawal of consent, or another discontinuation criterion is met, or unless the criterion for 
initiating retreatment on MEDI4736 + tremelimumab combination therapy is met as described 
below. Patients enrolled in the SoC arm of Part B: RCT will discontinue study drug at the 
first assessment of disease progression per RECIST 1.1.  
Patients randomized to the MEDI4736 monotherapy or MEDI4736 + tremelimumab arms who 
meet the retreatment criteria below for their respective treatment arm will follow the same 
treatment guidelines followed during the initial 12-month treatment period, including the same 
dose and frequency of treatments and the same schedule of assessments, with the exception of 
the PK, ADA, sPD-L1, SNP, MDSC, and nAB assessments, which do not need to be collected 
a second time.  Retreatment will not be permitted for patients randomized to SoC treatment in 
Part B: RCT.  Crossover within the study will not be permitted.  Patients who meet the criteria 
for retreatment for their respective treatment arm may only receive retreatment once.
Patients randomized to monotherapy MEDI4736 may undergo retreatment in 1 clinical 
scenario, described below:


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
93(131)
1.
Patients who achieve or maintain disease control (ie, CR, PR, or SD) through to the 
end of the 12-month treatment period may restart their assigned treatment with 
MEDI4736 upon evidence of PD, with or without confirmation and according to 
RECIST 1.1, during follow-up.
Patients randomized to the combination of MEDI4736 and tremelimumab arm may undergo 
retreatment in 2 clinical scenarios, described below:
1.
Patients who achieve and maintain disease control (ie, CR, PR, or SD) through to 
the end of the 12-month treatment period may restart treatment with the 
combination upon evidence of PD, with or without confirmation and according to 
RECIST 1.1, during follow-up. 
2.
Patients who complete the 4 dosing cycles of the combination of MEDI4736 and 
tremelimumab portion of the regimen (with clinical benefit per Investigator 
judgment), but subsequently have evidence of PD during the MEDI4736 
monotherapy portion of the combination regimen, with or without confirmation 
according to RECIST 1.1, may restart treatment with the combination.
For both treatment arms, before restarting their assigned treatment, the Investigator should 
ensure that the patient:
1.
Does not have any significant, unacceptable, or irreversible toxicities that indicate 
continuing treatment will not further benefit the patient
2.
Still fulfills the eligibility criteria for this study, including re-consenting to restart IP
3.
Has not have received an intervening systemic anticancer therapy after their 
assigned treatment discontinuation
4.
Has had a baseline tumor assessment within 28 days of restarting their assigned 
treatment; all further scans should occur with the same frequency as during the 
initial 12 months of treatment (relative to the date of restarting treatment) until 
study treatment is stopped (maximum of 12 months of further treatment).
During the retreatment period, patients in the MEDI4736 + tremelimumab arm will resume 
MEDI4736 dosing at 1.5 g q4w with 75 mg of tremelimumab q4w for 4 doses each.  Patients 
will then continue with MEDI4736 monotherapy at 1.5 g q4w, beginning at Week 16, 4 weeks 
after the last dose of combination therapy, up to a total of 9 additional doses, with the final 
dose at Week 48.
Patients in the MEDI4736 monotherapy treatment arm will resume MEDI4736 dosing at 1.5 g
q4w for up to 12 months (up to 13 doses).
Patients who the Sponsor and Investigator determine may not continue treatment after 
confirmed PD during the 12-month initial treatment period or in the 12-month retreatment 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
94(131)
period 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 until confirmed disease progression or death (whichever occurs first).
Treatment through progression and retreatment in the MEDI4736 monotherapy or MEDI4736 
+ tremelimumab arms is at the Investigator’s discretion, and 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 or retreatment 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 performance status 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
A patient with confirmed progression randomized to the MEDI4736 arm cannot continue 
therapy with MEDI4736 or obtain retreatment with MEDI4736 if dosing is ongoing and the 
progression occurs in a target lesion that has previously shown a confirmed response. A 
patient with a confirmed progression randomized to the MEDI4736 + tremelimumab arm 
cannot continue therapy or obtain retreatment if dosing is ongoing in the combination portion 
of therapy and progression occurs in a target lesion that has previously shown a confirmed 
response.
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.
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.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
95(131)
7.5
Compliance
The administration of all study drugs (including IPs) should be recorded 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.
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 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.  
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 CTLA-4, PD-1, or PD-L1 
through 90 days after the last dose of IP
Should not be given during the study


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
96(131)
Prohibited medication/class of drug:
Usage:
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)
Drugs with laxative properties and herbal or 
natural remedies for constipation
Should be avoided through 90 days post-last dose of 
tremelimumab
Sunitinib
Should not be given through 90 days after the last 
dose of tremelimumab
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
BSC (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


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
97(131)
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 MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy up 
to completion of a patient’s treatment period (initial or repeat) (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
Part A: Lead-in and Part B: Expansion
Once 15 efficacy outcomes are observed in the first 15 patients in each arm (ie, a minimum 
follow-up of 2 post-baseline tumor assessments at Week 6 and Week 12), predictive 
probability will be used to calculate the chance of observing at least 5 out of 30 responses 
(≥15% CR/PR) in each arm, and at least 15 out of 30 patients achieving DCR at 12 weeks 
(≥50% DCR12).  This will make use of a Beta –Binomial posterior predictive distribution, 
where at the outset a non-informative prior is assumed for the ORR or DCR12 (Beta[1,1]), 
and a Beta-Binomial distribution can then be used to calculate the probability of achieving the 
required ORR or DCR from 30 evaluable patients given the data observed (see Table 8).  If
predictive probability is <10% for both ORR and DCR12, recruitment into the arm in which 
this happens will be stopped.  A different decision outside of these criteria may be made, if the 
totality of the data supports it.  Recruitment will continue while predictive probability is 
calculated.  If an arm is to be stopped following the predictive probability calculation, no new 
patients will be recruited to that arm, but patients who are already on study will continue in 
accordance with study guidelines outlined in Section 7.2.  If enrollment is fast enough so that, 
by the time 15 patients are evaluable (Weeks 6 and 12 tumor assessment data available), all 
30 patients per arm have already been randomized, then the predictive probability calculations 
will not be carried out.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
98(131)
Table 8
Illustrative stopping boundaries for ORR and DCR12 based on 
15 evaluable patients (both criteria to be met to stop an arm)
Endpoint
Stopping boundary (predictive probability)
ORR
0/15 (1.8%)
DCR12
<5/15 (5.3%)
If an ORR >25% (ie, ≥8 CR/PR) is recorded among the first 30 treated patients in either of the 
treatment arms in Part A (unless the totality of the data supports a different decision), an 
additional 70 patients will be enrolled in that arm, for a total of 100 evaluable patients per arm 
in the Part B: Expansion study.  
In Part B, 100 patients (30 from Part A plus an additional 70 from Part B) will provide 
>90% power for an exact test of a single proportion, assuming a null hypothesis (H0) of 
ORR=10%, and an alternative hypothesis (HA) of ORR=25%, at the 2-sided 0.05 alpha level. 
(Critical value, ORR = 16.7%), while also providing adequate patients to reasonably 
characterize the safety profile of the expanded arm(s).  A 10% response rate is considered a 
reasonable assumption for the average response rate achieved by current therapies in 
second-line advanced pancreatic cancer (Rahma et al 2013).
Part B: Randomized, controlled trial
Should the ORR in Part A in at least 1 arm be >15% (≥5/30 responses) then a randomized 
controlled trial may be initiated.  
If initiated, this will be a separate randomized, open- label, multi-center, study to determine 
the efficacy and safety of MEDI4736 monotherapy and/or MEDI4736 + tremelimumab 
combination therapy versus SoC chemotherapy (1:1:1 or 1:1) with primary endpoint of OS.  If 
both arms are taken forward from Part A, then the primary comparison will be to compare 
MEDI4736 + tremelimumab combination therapy versus SoC.  Approximately 125 additional 
patients per treatment arm will be randomized in this Part B: RCT. Treatment for MEDI4736 
monotherapy and/or MEDI4736 + tremelimumab will only be included in this RCT if the 
corresponding treatment meets the appropriate criteria in Part A. A final decision to initiate 
Part B (RCT) will be made after evaluation of all available efficacy and safety data from the 
lead in phase (Part A), and may not be limited to the decision rules provided in the protocol.  
The data from Part B: RCT will be analyzed separately and will not be pooled with Part A for 
the purpose of statistical analysis.
It is assumed that median OS on SoC chemotherapy will be 5 months. With an assumed 
2-month delay in the treatment effect of the experimental therapy emerging relative to SoC 
(ie, an HR of 1 for the first 2 months ) followed by an HR of 0.51 thereafter and a minimum 
follow-up time of 11.5 months from the end of patient recruitment, this yields an anticipated 
overall average HR of 0.63.  Under these assumptions, analysis would occur after 196 events 
in a 250-patient, 2-arm study (78% maturity, 196/250) and would be expected around 


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20.5 months after the first patient is randomized.  If the true average HR is 0.63, then with 
196 events the study will have 90% power to demonstrate a statistically significant difference 
at a 2-sided 5% significance level (critical value for HR of 0.75). 
Non-uniform accrual of patients (with k=1.5) over 9 months is assumed when estimating the 
analysis times.  The total proportion of patients randomized at time t [t≤9 months] following 
the start of the study is therefore assumed to be (t/9)1.5.
8.3
Definitions of analysis sets
Definitions of the analysis sets for each outcome variable are provided in Table 9.
Table 9
Summary of outcome variables and analysis populations
Outcome variable
Population
Efficacy data
ORR 
Full analysis set 
DoR, DCR, PFS, PFS2, PFS3, PFS6, OS, OS6, 
OS12, PROs, and symptom endpoints
Full analysis set 
Demography
Full analysis set
PK data
PK analysis set
Safety Data
Exposure
Safety analysis set
AEs
Safety analysis set
Laboratory measurements
Safety analysis set
ECOG performance status
Safety analysis set
Vital signs
Safety analysis set
8.3.1
Full analysis set 
The full analysis set will include all randomized patients (ie, the intent-to-treat [ITT] 
population) and will classify them on the basis of randomized or allocated treatment, 
regardless of the treatment actually received. Patients who were randomized but who did not 
subsequently go on to receive study treatment are included in the ITT population.  For the 
purposes of evaluating the data in Part A to expand into Part B, only patients who actually 
received at least 1 dose of study treatment will be included in the Full Analysis Set.
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.  When assessing safety and tolerability, 
summaries will be produced based on the Safety Analysis Set.


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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.
8.4
Outcome measures for analyses
8.4.1
Calculation or derivation of efficacy variables
The analysis of the primary endpoint for Part A: Lead-in) and Part B: Expansion, ORR, will 
be based on Investigator assessments according to RECIST 1.1.  Sensitivity analyses for this 
ORR in Part A: Lead-in and Part B: Expansion will be conducted based on Investigator 
assessment according to RECIST 1.1 modified for confirmation of progression.  OS will be 
evaluated as the primary endpoint in Part B: RCT.
The analyses of the secondary endpoints of ORR, DoR, DCR, PFS, PFS2, PFS3, and PFS6
will be based on Investigator assessments according to RECIST 1.1.  OS, OS6, and OS12 will 
also be evaluated as secondary endpoints.  
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 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, 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 ORR, DoR, DCR, PFS, PFS2, 
PFS3, and PFS6) will be derived from the overall visit response date and the scan dates.
Please refer to Appendix F for the definitions of CR, PR, SD, NE, and PD.
Storage of data for possible BICR of RECIST 1.1-based assessments
All radiological scans for all patients (including those at unscheduled visits or outside visit 
windows) will be stored for possible assessment by BICR.


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8.4.1.2
Primary endpoints
Objective response rate
The primary endpoint for Part A: lead-in and Part B: Expansion is ORR, which will be 
assessed according to Investigator assessment.  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 Full 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.
For sensitivity analysis, ORR will be assessed using the RECIST Investigator assessed tumor 
data following a modification where any objective progression requires confirmation.  
Therefore, data obtained up until confirmed progression, or the last evaluable assessment in 
the absence of a confirmed progression, will be included in the assessment of ORR.  Note that 
the response may be after an unconfirmed progression.
Overall survival
The primary endpoint for Part B: RCT is OS.  OS is defined as the time from the date of 
randomization 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.
8.4.1.3
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 3 or 12 months is defined as the percentage of patients who have a best objective 
response (BoR) of CR or PR in the first 3 or 12 months, respectively, or who have 
demonstrated SD for a minimum interval of 12 or 52 weeks, respectively (-7 days, ie, 105 or 
357 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 
progression event that is used for the analysis (ie, unconfirmed progressions are not 
considered progression events, which means that the BoR that contributes to the DCR may be 
after an unconfirmed progression for some patients).
Progression-free survival (PFS)
PFS (per RECIST 1.1 using Investigator assessments) will be defined as the time from the 
date of first dose/randomization 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/randomized 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 0 days 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. 


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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 
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.  For Part B: RCT, patients enrolled in the SoC arm will 
discontinue study drug at the first assessment of disease progression.
Progression-free survival2 (second progression) (PFS2)
Time from randomization to second progression (PFS2) is defined as the time from the date of 
randomization to the earliest of the progression event(s) subsequent to that used for the PFS 
endpoint or death.  Patients alive and for whom a second disease progression has not been 
observed should be censored at the last time known to be alive and without a second disease 
progression, that is, censored at the latest of the PFS or PFS2 assessment date if the patient has 
not had a second progression or death.
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.
Proportion of patients alive at 6 months from randomization/enrollment
The OS6 will be defined as the Kaplan-Meier estimate of OS at 6 months.
Proportion of patients alive at 12 months from randomization/enrollment 
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 F.  It is the best response a patient has had during their time in the 


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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 F) using the following response 
categories: CR, PR, SD, PD, and NE.
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 13 weeks 
(ie, 12 weeks ±7 days) after enrollment, then BoR will be assigned to the PD category.  For 
patients who die with no evaluable RECIST assessments, if the death occurs >13 weeks 
(ie, 12 weeks ±7 days) after the date of enrollment, then BoR will be assigned to the NE 
category.
Progression events that have been censored due to them being >13 weeks after the last 
evaluable assessment will not contribute to the BoR derivation.
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 


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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.
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.
8.4.3
Calculation or derivation of patient-reported outcome variables
PRO questionnaires will be assessed using the EORTC QLQ-C30 questionnaire, EORTC 
QLQ-PAN26 questionnaire, and PRO-CTCAE.  All items/questionnaires will be scored 
according to published scoring guidelines or the developer’s guidelines, if published 
guidelines are not available.  All PRO analyses will be based on the Full Analysis Set (FAS; 
ITT population), unless stated otherwise.
8.4.3.1
EORTC QLQ-C30
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional 
scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and 


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nausea/vomiting), 6 individual items (dyspnea, insomnia, appetite loss, constipation, diarrhea, 
and financial difficulties), and a global measure of health status (overall health and overall 
quality of life).  The EORTC QLQ-C30 will be scored according to the EORTC QLQ-C30 
scoring manual (Fayers et al 2001).  An outcome variable consisting of a score from 0 to 100 
will be derived for each of the symptom scales/symptom items, each of the functional scales, 
and the global health status scale in the EORTC QLQ-C30 according to the EORTC 
QLQ-C30 Scoring Manual.  Higher scores on the global health status and functioning scales 
indicate better health status/function, but higher scores on symptom scales/items represent 
greater symptom severity.
The change from baseline in HRQoL will be assessed using the EORTC QLQ-C30 global 
QoL scale, which includes 2 items from the EORTC QLQ-C30: “How would you rate your 
overall health during the past week?” (Item 29) and “How would you rate your overall QoL 
during the past week?” (Item 30).
Definition of clinically meaningful changes
Changes in score compared with baseline will be evaluated.  A minimum clinically 
meaningful change is defined as an absolute change in the score from baseline of ≥10 for 
scales/items from the EORTC QLQ-C30 (Osoba et al 1998).  For example, a clinically 
meaningful improvement in physical function (as assessed by EORTC QLQ-C30) is defined 
as an increase in the score from baseline of ≥10, whereas a clinically meaningful deterioration 
is defined as a decrease in the score from baseline of ≥10.  At each post-baseline assessment, 
the change in symptoms/functioning from baseline will be categorized as improvement, 
no change or deterioration as shown in Table 10.
Table 10
Mean change and visit response in health related quality of life
Score
Change from baseline
Visit response
EORTC QLQ-C30 Global quality 
of life score
≥+10
Improvement
≤-10
Deterioration
Otherwise
No change
EORTC QLQ-C30 symptom 
scales/items
≥+10
Deterioration
≤-10
Improvement
Otherwise
No change
EORTC QLQ-C30 functional 
scales
≥+10
Improvement
≤-10
Deterioration
Otherwise
No change
For each subscale, if <50% of the subscale items are missing, then the subscale score will be 
divided by the number of nonmissing items and multiplied by the total number of items on the 
subscales (Fayers et al 2001). If at least 50% of the items are missing, then that subscale will 


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be treated as missing. Missing single items are treated as missing. The reason for any missing 
questionnaire will be identified and recorded.  If there is evidence that the missing data are 
systematic, missing values will be handled to ensure that any possible bias is minimized.
Exploratory PRO endpoints
Time to symptom deterioration
For each of the symptoms scales in the EORTC QLQ-C30, time to symptom deterioration will 
be defined as the time from randomization until the date of the first clinically meaningful 
symptom deterioration (an increase in the score from baseline of ≥10) or death (by any cause) 
in the absence of a clinically meaningful symptom deterioration, regardless of whether the 
patient withdraws from study treatment or receives another anticancer therapy prior to 
symptom deterioration.  Death will be included as an event only if the death occurs within 
2 visits of the last PRO assessment where the symptom change could be evaluated.  
Patients whose symptoms (as measured by EORTC QLQ-C30) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at the 
time of their last PRO assessment where the symptom could be evaluated.  Also, if symptoms 
deteriorate after 2 or more missed PRO assessment visits or the patient dies after 2 or more 
missed PRO assessment visits, the patient will be censored at the time of the last PRO 
assessment where the symptom could be evaluated.  If a patient has no evaluable visits or does 
not have baseline data he or she will be censored at 0 days.  
Time to HRQoL/function deterioration
For HRQoL (as measured by EORTC QLQ-C30), time to deterioration will be defined as the 
time from the date of randomization until the date of the first clinically meaningful 
deterioration (a decrease in the function scales or the global health status/HRQoL from 
baseline of ≥10) or death (by any cause) in the absence of a clinically meaningful 
deterioration, regardless of whether the patient withdraws from study treatment or receives 
another anticancer therapy prior to HRQoL/function deterioration.  Death will be included as 
an event only if the death occurs within 2 visits of the last PRO assessment where the 
HRQoL/function change could be evaluated.  
Patients whose HRQoL (as measured by EORTC QLQ-C30) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at the 
time of their last PRO assessment where the HRQoL/function could be evaluated.  Also, if 
HRQoL deteriorates after 2 or more missed PRO assessment visits or the patient dies after 
2 or more missed PRO assessment visits, the patient will be censored at the time of the last 
PRO assessment where HRQoL/function could be evaluated.  If a patient has no evaluable 
visits or does not have baseline data he or she will be censored at 0 days.  
Symptom improvement rate
The symptom improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement (a decrease from baseline score ≥10 for EORTC QLQ-C30 symptom scales) in 


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that symptom from baseline.  The denominator will consist of a subset of the ITT population 
who has a baseline symptom score ≥10.
HRQoL/function improvement rate
The HRQoL/function improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement (an increase from baseline score ≥10 for EORTC QLQ-C30 functional scales 
and global health status/HRQoL) in that scale from baseline.  
8.4.3.2
EORTC QLQ-PAN26
For EORTC QLQ-PAN26, 7 multi-item subscales scores (pancreatic pain [4 items], eating 
related [2 items], hepatic [2 items], altered bowel habit [2 items], body image [2 items], health 
care satisfaction [2 items], sexuality [2 items]) and 10 single-item scales (swollen abdomen, 
taste changes, indigestion, flatulence, weight loss, loss of muscle strength, dry mouth, burden 
of treatment, fear of future health, and ability to plan future) will be derived as specified in the 
scoring manual.
8.4.3.3
Calculation or derivation of healthy state utility (EQ-5D-5L)
The EQ-5D-5L index comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression).  For each dimension, respondents select which 
statement best describes their health on that day from a possible 5 options of increasing levels 
of severity (no problems, slight problems, moderate problems, severe problems, and extreme 
problems).  A unique EQ-5D health state is referred to by a 5-digit code allowing for a total of 
3125 health states.  For example, state 11111 indicates no problems on any of the 
5 dimensions.  These data will be converted into a weighted health state index by applying 
scores from EQ-5D value sets elicited from general population samples (the base case will be 
the United Kingdom valuation set, with other country value sets applied in scenario analyses).  
Where values sets are not available, the EQ-5D-5L to EQ-5D-3L crosswalk will be applied.  
In addition to the descriptive system, respondents also assess their health on the day of 
assessment on a visual analogue scale, ranging from 0 (worst imaginable health) to 100 (best 
imaginable health).  This score is reported separately.  The evaluable population will comprise 
the FAS (ITT population).
8.4.4
Calculation or derivation of pharmacokinetic variables
8.4.4.1
Population pharmacokinetics and exposure-response/safety analysis
A population PK model analysis might be performed using a nonlinear mixed-effects 
modelling approach.  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.


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8.4.4.2
Pharmacokinetic noncompartmental 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.  PK parameters will be determined using standard noncompartmental 
methods.  The following PK parameters will be determined after the first and steady-state 
doses: peak and trough concentration (as data allow).  Samples below the lower limit of 
quantification will be treated as missing in the analyses.
8.4.4.3
Immunogenicity analysis
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against MEDI4736 monotherapy or
MEDI4736 in combination with tremelimumab.  The immunogenicity titer and presence of 
neutralizing ADAs will be reported for samples confirmed positive for the presence of ADAs.  
The effect of immunogenicity on PK, pharmacodynamics, efficacy, and safety will be 
evaluated, if the data allow.
8.4.5
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.
8.4.6
Calculation or derivation of pharmacogenetic variables
In the case of genetic data, only the date that the patient gave consent to participation in the 
genetic research and the date the blood sample was taken from the patient will be recorded in 
the eCRF and database.  The genetic data generated from the study will be stored in the 
AstraZeneca Laboratory Information Management System (LIMS) database or other 
appropriate system.  This database is a secure database, which is separate from the database 
used for the main study.  Some or all of the dataset from the main study may be duplicated 
within the AstraZeneca LIMS database for exploratory genetic analysis.  Data will be reported 
outside the CSR (please see Appendix D).
8.5
Methods for statistical analyses
The primary hypothesis being tested is that treatment with MEDI4736 in combination with 
tremelimumab or as MEDI4736 monotherapy, will deliver improved ORR compared to SoC 
in the treatment of patients with metastatic PDAC who have failed 5-FU-containing or 
gemcitabine-containing first-line chemotherapy.
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment group.  Continuous variables will be summarized by the number of observations, 
mean, standard deviation, median, minimum, and maximum.  Categorical variables will be 
summarized by frequency counts and percentages for each category.  Unless otherwise stated, 
percentages will be calculated out of the population total for the corresponding treatment arm. 


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Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of IP, except for efficacy variables.  For efficacy variables, baseline is defined as 
the last visit prior to treatment start date.
All data collected will be listed.  Efficacy and PRO data will be summarized and analyzed 
based on the FAS.  PK data will be summarized and analyzed based on the PK Analysis Set.  
Safety data will be summarized on the Safety Analysis Set.
All outputs will be summarized by treatment arm for all enrolled patients (ITT).   
Results of all statistical analysis will be presented using a 95% CI and 2-sided p-value, unless 
otherwise stated.
Table 11 details which endpoints are to be analyzed, together with preplanned sensitivity 
analyses indicating which analysis is regarded as primary for that endpoint.  Formal statistical 
analysis will be done only for ORR.  Nominal p-values will be provided for all other endpoint 
and sensitivity analyses.
Unless otherwise stated, data and endpoints derived from RECIST tumor assessments will 
refer Investigator assessed data.
Table 11
Preplanned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
Objective response rate
Summarized by treatment arm with lower 95% Clopper-Pearson confidence 
limits (Part A)
Part B: Expansion - Formal analysis using exact test for a binomial 
proportion, with 2-sided 95% Clopper-Pearson CI
Duration of response
Kaplan Meier plots and summaries
DCR
Summarized by treatment arm n (%) Parts A and B.
Best objective response
Summary statistics, N (%)
Progression free survival, PFS3, 
PFS6
Kaplan Meier plots, estimates and summaries as appropriate
Part B: RCT - Stratified log rank test
Overall survival, OS6, OS12
Kaplan Meier plots and summaries.
Part B: RCT - Stratified log rank test
Multiple testing strategy
For Part B: RCT, if both arms are taken forward from Part A, then the primary comparison 
will be to compare MEDI4736 + tremelimumab combination therapy versus SoC.  MEDI4736 
monotherapy versus SoC will be compared hierarchically in order to strongly control the type 
I error.  Full details of the multiple testing procedure will be provided in the SAP.  


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
111(131)
8.5.1
Analysis of the primary variables
Objective response rate
The primary endpoint (ORR) for Part A and Part B: Expansion (if initiated) will be estimated 
for each treatment arm with 95% exact CIs.  The primary analysis will be based on the 
programmatically derived ORR based on Investigator assessments, and using all scans 
regardless of whether they were scheduled or not.  An additional sensitivity analysis will be 
performed on programmatically derived ORR using Investigator data (RECIST modified for 
confirmation of progression) to determine if there is any difference when using progression 
confirmation rules.  
The primary analysis population for ORR will be the FAS.
Summaries will be produced that present the number and percentage of patients with a tumor
response (CR/PR).  The number (%) of patients with a confirmed response and the number 
(%) of patients with a single visit response (ie, an unconfirmed response) will also be 
presented.
Overall survival
Kaplan-Meier plots of OS will be presented for each treatment arm of the study.  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/treatment arm (if calculable). 
The OS6 will be summarized (using the Kaplan-Meier curve) and presented for each treatment 
arm.
For Part B: RCT, the primary OS analysis will be performed in the ITT population using a 
stratified log-rank test adjusting for response to prior chemotherapy and type of prior 
chemotherapy.  The effect of each experimental arm versus SoC treatment will be estimated 
by the HR together with its corresponding 95% CI and p-value.
The HR and its CI can be estimated from the stratified log-rank as follows (Berry et al 1991, 
Collett 2003, Selke and Siegmund 1983):
∃
%
&
∋
(
)
∗
V
U
HR
exp
∃∃
%
&
+
,
−
./0
1
./0
∋∋
(
)
+,−
#
∗
V
V
U
V
V
U
96
.1
exp
,
96
.1
exp
HR
for 
CI
95%


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
112(131)
Where 
2
2
2
#
∗
∗
i
ki
ki
k
k
k
e
d
U
U
)
,
(
1
1
is the stratified log-rank test statistic obtained from the 
SAS LIFETEST procedure,
2
∗
k
k
V
V
is its standard deviation, k denotes the stratum, and 
d1ki and e1ki are the observed and expected events in Group 1, stratum k.
The assumption of proportionality will be assessed.  Proportional hazards will be tested firstly 
by examining plots of complementary log-log (event times) versus log (time) and, if these 
raise concerns, by fitting a time-dependent covariate to assess the extent to which this 
represents random variation.  If a lack of proportionality is evident, the variation in treatment 
effect will be described by presenting piecewise HR calculated over distinct time-periods.  In 
such circumstances, the HR can still be meaningfully interpreted as an average HR over time 
unless there is extensive crossing of the survival curves.  If lack of proportionality is found, 
this may be is a result of treatment-by-covariate interactions, which will be investigated.
A sensitivity analysis for OS will examine the censoring patterns to rule out attrition bias, 
achieved by a Kaplan-Meier plot of time to censoring where the censoring indicator of OS is 
reversed.
Subgroup analyses will be conducted comparing OS between treatments in the following 
subgroups of the FAS:
!
Response to previous chemotherapy (CR/PR/SD vs PD)
!
Type of previous chemotherapy (5-FU-containing or gemcitabine-containing 
chemotherapy)
The HR (MEDI4736 or MEDI4736 + tremelimumab: SoC) and 95% CI in each subgroup will 
be calculated from a single Cox model.  These will be presented on a forest plot including the 
HR and 95% CI from the overall population. 
Other baseline variables may also be assessed if there is clinical justification or an imbalance 
is observed between the treatment arms.  The purpose of the subgroup analyses is to assess the 
consistency of treatment effect across expected prognostic factors.
The presence of quantitative interactions will be assessed by means of an overall global 
interaction test.  This will be performed in the overall population by comparing the fit of a 
Cox proportional hazards model including treatment, all covariates, and all covariate-by 
treatment interaction terms, with one that excludes the interaction terms and will be assessed 
at the 2-sided 10% significance level.  If the fit of the model is not significantly improved then 
it will be concluded that overall the treatment effect is consistent across the subgroups.
If the global interaction test is found to be statistically significant, an attempt to determine the 
cause and type of interaction will be made.  Stepwise backwards selection will be performed 
on the saturated model, whereby (using a 10% level throughout) the least significant 
interaction terms are removed one-by-one and any newly significant interactions re-included 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
113(131)
until a final model is reached where all included interactions are significant and all excluded 
interactions are nonsignificant.  Throughout this process all main effects will be included in 
the model regardless of whether the corresponding interaction term is still present.  This 
approach will identify the factors that independently alter the treatment effect and prevent 
identification of multiple correlated interactions.
Any quantitative interactions identified using this procedure will then be tested to rule out any 
qualitative interaction using the approach of Gail and Simon 1985.
If there are too few events available for a meaningful analysis of a particular subgroup (it is 
not considered appropriate to present analyses where there are less than 20 events in a 
subgroup), the relationship between that subgroup and OS will not be formally analyzed.  In 
this case, only descriptive summaries will be provided.
8.5.2
Analysis of the secondary variables
8.5.2.1
Duration of response
In order to analyze the DoR between treatment arms (only relevant for Part B randomized, 
controlled study), the Expected Duration of Response (EDoR) will be derived for each 
treatment arm (Ellis et al 2008).  The EDoR is the product of the proportion of patients 
responding to treatment and the mean DoR in responding patients and provides an estimate 
based on all randomized patients.  Treatments will be compared by calculating the ratio of
EDoRs, using an appropriate probability distribution (to be specified in the SAP) for DoR in 
responding patients.  Additionally, descriptive data will be provided for the DoR in 
responding patients, including the associated Kaplan-Meier curves (without any formal 
comparison of treatment arms or p-value attached).
8.5.2.2
Disease control rate
The DCR will be summarized (ie, number of patients).


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
114(131)
8.5.2.3
Progression-free survival
Kaplan-Meier plots of PFS will be presented for each treatment arm.  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 ca+lculable). 
Additionally, for Part B: RCT, formal comparative analysis of PFS will be carried out in the 
same way as for OS.
8.5.2.4
Progression-free survival2 (second progression)
For Part B: RCT, PFS2 will be summarized and analyzed in the same way as PFS.
8.5.2.5
Proportion of patients with progression-free survival after 3 months and 
6 months
The PFS and PFS6 will be calculated using Kaplan-Meier estimates, as the cumulative 
probability of progression-free survival to each of those two time periods.  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. 
8.5.3
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 95% CIs.  Median survival and survival plots over time will also be 
produced and presented, based on Kaplan-Meier estimates. 
8.5.4
Patient-reported outcomes
The analysis population for PRO data will be the PRO analysis set including patients with 
evaluable baseline EORTC QLQ-C30 and QLQ-PAN26 forms.  The HRQoL and pancreatic 
pain will be assessed through an analysis of the EORTC-QLQC30 global QoL and PAN-26 
pancreatic pain scales.
8.5.4.1
EORTC QLQ-C30
Adjusted mean change from baseline in global QoL score will be analyzed using a mixed 
model for repeated measures (MMRM) analysis of all of the post-baseline scores for each visit 
and will be presented by treatment group.  The study discontinuation visit and the safety 
follow-up visit will be excluded from this analysis. Restricted maximum likelihood (REML) 
estimation will be used. The model will include treatment, visit and treatment by visit 
interaction as explanatory variables and the baseline QoL score as a covariate. Treatment, visit 
and treatment by visit interaction will be fixed effects in the model.  The treatment by visit 
interaction will remain in the model regardless of significance.
An unstructured covariance matrix will be used to model the within-subject error and the 
Kenward-Roger approximation will be used to estimate the degrees of freedom. 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
115(131)
If the fit of the unstructured covariance structure fails to converge, the following covariance 
structures will be tried in order until convergence is reached: toeplitz with heterogeneity, 
autoregressive with heterogeneity, toeplitz, and autoregressive. 
The adjusted mean change from baseline estimates and corresponding 95% CIs will be 
presented by visit for each treatment group and corresponding plots over time will be 
presented.
As a supportive analysis, EORTC QLQ-C30 global QoL score improvement rate will be 
analyzed using a logistic regression model.  If the overall response rate is <5%, no analysis 
will be performed (note that if the response rate in only one of the treatment groups is <5% 
but ≥5% in the other treatment group then the analysis will still be performed). If the overall 
expected response rate is low (<20%) a Fisher’s exact test will be considered and mid p-values 
used. The results of the analysis will be presented in terms of an odds ratio together with its 
associated profile likelihood CIs and p-values (based on twice the change in log-likelihood 
resulting from the addition of a treatment factor to the model).
EORTC QLQ-C30 compliance (overall compliance and by visit compliance) will be 
summarized for each treatment group.
Descriptive statistics and graphs will be reported for the global QoL score by visits as well as 
unadjusted change in these scores from baseline. Summary tables of EORTC QLQ-C30 best 
overall QoL response as defined in Table 10 will be provided (improvement, deterioration, no 
change).
8.5.4.2
EORTC QLQ-PAN26
Patient-reported outcomes as measured by EORTC QLQ-PAN26 will be summarized 
descriptively; the change from baseline for domain, subscale scores, and individual items by 
treatment group at each time point and change from baseline will be explored. EORTC 
QLQ-PAN26 compliance (overall compliance and by visit compliance) will be summarized 
for each treatment group.
Exploratory analyses
Exploratory analyses examining adjusted mean change from baseline will be performed for 
EORTC QLQ-C30 functioning domains (physical, role, cognitive, emotional, and social) and 
for the individual EORTC QLQ-C30 and QLQ-PAN26 symptom scales/items (with a 
particular focus on pancreatic pain, fatigue, nausea, weight loss [difficulty gaining weight/loss 
of appetite], and jaundice), using the same MMRM model described for the global QoL score.
Descriptive statistics and graphs will be reported for the EORTC QLQ-C30 functioning 
domains and EORTC QLQ-C30 and QLQ-PAN26 symptom scales/items (specifically 
pancreatic pain, fatigue, nausea, weight loss [difficulty gaining weight/loss of appetite], and 
jaundice).


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
116(131)
EORTC QLQ-C30: Time to symptom deterioration will be analyzed for each of the 
3 symptom scales (fatigue, pain, and nausea/vomiting) and the 5 individual symptom items 
(dyspnea, insomnia, appetite loss, constipation, and diarrhea).  Time to QoL/function 
deterioration will be analyzed for the 5 function scales (physical, role, emotional, cognitive, 
and social) and global health status/QoL.  This will be achieved by comparing treatment arms 
using a stratified log-rank test as described for the primary analysis of OS.  The sensitivity 
analysis to ascertain attrition bias will be performed as described for the primary analysis of 
OS.  However, subgroup analyses and treatment interaction testing will not be performed.  
The HR and 95% CI for each scale/item will be presented graphically on a forest plot.
A summary of the symptom improvement rate for each of the 3 symptom scales and the 
5 individual symptom items will be produced.  Similarly, a summary of QoL/function 
improvement rate for each of the 5 function scales (physical, role, emotional, cognitive, and 
social) and global health status/QoL will be produced.  Symptom improvement rate and 
QoL/function improvement rate will be analyzed by comparing between treatment arms using 
a logistic regression model as described for the analysis of ORR.  The odds ratio and 95% CI 
for each scale/item will be presented graphically on a forest plot.  
Time to deterioration will be presented using a Kaplan-Meier plot for each of the 3 symptom 
scales (fatigue, pain, and nausea/vomiting), 5 individual symptom items (dyspnea, insomnia, 
appetite loss, constipation, and diarrhea), 5 functional scales (physical, role, emotional, 
cognitive, and social), and global health status/QoL.  Summaries of the number and 
percentage of patients experiencing a clinically meaningful deterioration or death and the 
median time to deterioration will also be provided for each treatment arm.  
Summaries of original and change from baseline values of each symptom scale/item, the 
global HRQoL score, and each functional domain will be reported by visit for each treatment 
arm.  Graphical presentations may also be produced as appropriate.  Summaries of the number 
and percentage of patients in each response category at each visit for each ordinal item (in 
terms of the proportion of patients in the categories of improvement, no change, and 
deterioration as defined in Section 8.4.3.1) will also be produced for each treatment arm.
8.5.4.3
PRO-CTCAE
PRO-CTCAE data will be presented using summaries and descriptive statistics based on the 
FAS.  Further details will be provided in the SAP.
8.5.5
Safety data
Safety and tolerability data will be presented by treatment arm 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 treatment arm 
and CTCAE grade.  Additionally, data presentations of the rate of AEs per person-years at risk 
may be produced.  Any safety summaries examining retreatment with MEDI4736 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
117(131)
monotherapy and MEDI4736 + tremelimumab combination therapy will be produced 
separately.
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, vital signs, and ECGs.  Exposure to MEDI4736 monotherapy, MEDI4736 + 
tremelimumab combination therapy, and SoC will be summarized.  Time on study and
MEDI4736 monotherapy, MEDI4736 + tremelimumab combination therapy, and SoC
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. 
8.5.6
Pharmacokinetic data
PK concentration data will be listed for each patient and each dosing day, and a summary 
provided for all evaluable patients.
8.5.6.1
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 or 
anti-tremelimumab antibodies. The immunogenicity titer and neutralizing ADA data will be 
listed for samples confirmed positive for the presence of anti-MEDI4736 or 
anti-tremelimumab antibodies.  
The effect of immunogenicity on PK, pharmacodynamics, efficacy, and safety will be 
evaluated if data allow.
8.5.7
Pharmacokinetic/pharmacodynamic relationships
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.
8.5.8
Biomarker data
The relationship of PD-L1 expression and if applicable, of exploratory biomarkers to ORR, 
DoR, DCR, PFS, PFS2, PFS3, and PFS6 will be presented for a subset of patients in the ITT 
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 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.
8.5.9
Healthcare resource use
An exploratory health economic analysis of hospital episodes including type of contact 
(hospitalization, outpatient, or day case), reason, length of stay by ward type (including 
intensive care unit), procedures, and tests may be undertaken to examine the impact of disease 


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
118(131)
and treatment on resource use to primarily support the economic evaluation of MEDI4736 and 
MEDI4736 + tremelimumab in comparison to SoC.  The analysis will be reported separately.
8.5.10
Interim analysis
An interim analysis when 15 evaluable patients are observed in Part A will use predictive 
probability to determine whether either arm may stop (based on <10% predictive probability 
of meeting the minimum criteria to initiate Part B). Should it become obvious that the 
continuation criteria have been met prior to completion of enrollment of Part A, then the 
decision to initiate Part B (either Expansion or the RCT) may be made early.
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 CSP and related documents with the investigational staff and 
train them in any study-specific procedures and IVRS/IWRS, WBDC, and any electronic PRO 
systems to be utilized.
The PI will ensure that appropriate training relevant to the study is given to all of these staff 
and that any new information relevant to the performance of this study is forwarded to the 
staff involved.
The PI will maintain a record of all individuals involved in the study (medical, nursing, and 
other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to
!
Provide information and support to the Investigator(s)
!
Confirm that facilities remain acceptable
!
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, 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)


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
119(131)
!
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
Direct access to source data in Japan
The Head of the study site and the PI/Investigator will cooperate for monitoring and audit by 
AstraZeneca and accept inspection by the IRB or regulatory authorities. All study documents,
such as raw data, will be open for direct access to source data at the request of the monitor and 
the auditor of AstraZeneca, the IRB, or regulatory authorities.
The monitor(s) will verify data from the eCRFs against source data before the PI signs the 
eCRFs to ensure accuracy and completeness of documentation and ensure that the PI has 
submitted the eCRFs to AstraZeneca.  If the Investigator wishes to amend the collected 
eCRFs, the monitor will ensure that the PI has recorded the amendment with signature and 
date and provided this to AstraZeneca.
9.2.3
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 
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.
9.2.4
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 Q3 2015 and to end by Q3 2020.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
120(131)
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 or tremelimumab.
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
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data management of genotype data
Please see Appendix D for details.
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


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
121(131)
(ICH)/GCP, applicable regulatory requirements and the AstraZeneca policy on Bioethics and 
Human Biological Samples.
The applicable regulatory requirements in Japan are “Good Clinical Practice for Trials on 
Drugs” (Ministry of Health, Labor, and Welfare [MHLW] Ordinance No. 28, 27 March 1997, 
partially revised by MHLW Ordinance and their related notifications.
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.
Please see Appendix D for further details.
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.
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.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
122(131)
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.
For sites in Japan only
If any new information on the study medication becomes available that may influence the 
decision of the patient to continue the study, the Investigator(s) should inform the patient of 
such information immediately, record this in a written form, and confirm with the patient if he 
or she wishes to continue the participation in the study.  In addition, if the Investigator(s) 
deem it necessary to revise the ICF, he or she should revise it immediately (refer to 
Section 10.5).  The Investigator(s) should re-explain the patients using an updated ICF even if 
the patients have already been informed of the new information verbally.  Written informed 
consent to continue participation in the study should be provided separately.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.  If 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 Informed 
Consent Form, 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.


Clinical Study Protocol
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
123(131)
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 
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.
For Japan sites: All study data may undergo a reliability review and onsite-GCP inspection 
by the regulatory authorities. 


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Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 1
Date 17 August 2015
124(131)
11.
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Edition Number 1
Date 17 August 2015
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Edition Number 1
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Edition Number 1
Date 17 August 2015
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Edition Number 1
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Study Code D4198C00001
Edition Number 1
Date 17 August 2015
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Clinical Study Protocol Appendix B
Drug Substance
MEDI4736 and Tremelimumab
Study Code
D4198C00001
Edition Number
2
Date
17 August 2015
Appendix B
Additional Safety Information


Clinical Study Protocol Appendix B
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
2(4)
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


Clinical Study Protocol Appendix B
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
3(4)
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.


Clinical Study Protocol Appendix B
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
4(4)
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.


Clinical Study Protocol Appendix C
Drug Substance
MEDI4736 and
Tremelimumab
Study Code
D4198C00001
Edition Number
2
Date
17 August 2015
Appendix C
International Airline Transportation Association (IATA) 6.2 Guidance 
Document


Clinical Study Protocol Appendix C
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
2(2)
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.


Clinical Study Protocol Appendix D
Drug Substance
MEDI4736 and
Tremelimumab
Study Code
D4198C00001
Edition Number
2
Date
17 August 2015
Appendix D
Pharmacogenetics Research


Clinical Study Protocol Appendix D
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
2(7)
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
TABLE OF CONTENTS.........................................................................................2
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS............................3
1.
BACKGROUND AND RATIONALE....................................................................4
2.
GENETIC RESEARCH OBJECTIVES..................................................................4
3.
GENETIC RESEARCH PLAN AND PROCEDURES ..........................................4
3.1
Selection of genetic research population .................................................................4
3.1.1
Study selection record..............................................................................................4
3.1.2
Inclusion criteria ......................................................................................................4
3.1.3
Exclusion criteria .....................................................................................................4
3.1.4
Discontinuation of patients from this genetic research............................................5
3.2
Collection of samples for genetic research ..............................................................5
3.3
Coding and storage of DNA samples.......................................................................5
4.
ETHICAL AND REGULATORY REQUIREMENTS...........................................6
4.1
Informed consent .....................................................................................................6
4.2
Patient data protection..............................................................................................6
5.
DATA MANAGEMENT.........................................................................................6
6.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE .........................................................................................................................7
7.
LIST OF REFERENCES.........................................................................................7


Clinical Study Protocol Appendix D
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
3(7)
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation or 
special term
Explanation
CSR
Clinical Study Report
DNA
Deoxyribonucleic acid
LIMS
Laboratory information management system
PGx
Pharmacogenetics


Clinical Study Protocol Appendix D
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
4(7)
1.
BACKGROUND AND RATIONALE
AstraZeneca intends to perform genetic research in the MEDI4736 clinical development 
program to explore how genetic variations may affect the clinical parameters associated with 
this drug combination.  Collection of DNA samples from populations with well described 
clinical characteristics may lead to improvements in the design and interpretation of clinical 
trials and, possibly, to genetically guided treatment strategies.
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to MEDI4736, but also susceptibility to pancreatic ductal adenocarcinoma for 
which MEDI4736 may be evaluated.  Thus, this genetic research may involve study of 
additional un-named genes or gene categories, but only as related to pancreatic ductal 
adenocarcinoma and MEDI4736 treatment.
2.
GENETIC RESEARCH OBJECTIVES
The objective of this research is to collect and store DNA, derived from a blood sample, for 
future exploratory research into genes/genetic variation that may influence response 
(ie, distribution, safety, tolerability and efficacy) of MEDI4736 and/or susceptibility to 
pancreatic ductal adenocarcinoma.
3.
GENETIC RESEARCH PLAN AND PROCEDURES
3.1
Selection of genetic research population
3.1.1
Study selection record
All enrolled patients will be asked to participate in this genetic research (Substudy 3 only).  
Participation is voluntary, and if a patient declines to participate, there will be no penalty or 
loss of benefit.  The patient will not be excluded from any aspect of the main study.
3.1.2
Inclusion criteria
For inclusion in this genetic research, patients must fulfill all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and:
!
Provide informed consent for the genetic sampling and analyses.
3.1.3
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:
!
Previous allogeneic bone marrow transplant


Clinical Study Protocol Appendix D
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
5(7)
!
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection
3.1.4
Discontinuation of patients from this genetic research
Specific reasons for discontinuing a patient from this genetic research are:
Withdrawal of consent for genetic research:  patients may withdraw from this genetic research 
at any time, independent of any decision concerning participation in other aspects of the main 
study.  Voluntary discontinuation will not prejudice further treatment.  Procedures for 
discontinuation are outlined in Section 3.9 of the main Clinical Study Protocol.
3.2
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the patients at baseline after 
randomization.  Although genotype is a stable parameter, early sample collection is preferred 
to avoid introducing bias through excluding patients who may withdraw due to an adverse 
event (AE), as these patients would be important to include in any genetic analysis.  Only 
1 sample should be collected per patient for genetics during the study.  Samples will be 
collected, labelled, stored and shipped as detailed in the Laboratory Manual.
If the patient agrees to participate, a 9-mL blood sample will be collected.
3.3
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 
15 years from the date of last patient last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.
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 patient enrollment/randomization code and the DNA number will be maintained and 
stored in a secure environment, with restricted access WITHIN the Clinical Genotyping Group 
Laboratory Information Management System (LIMS) at AstraZeneca.  The link will be used 
to identify the relevant DNA samples for analysis, facilitate correlation of genotypic results 
with clinical data, allow regulatory audit and to trace samples for destruction in the case of 
withdrawal of consent.


Clinical Study Protocol Appendix D
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
6(7)
4.
ETHICAL AND REGULATORY REQUIREMENTS
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 10 of the main Clinical Study Protocol.
4.1
Informed consent
The genetic component of this study is optional, and the patient may participate in other 
components of the main study (Substudy 3 only) without participating in the genetic 
component.  To participate in the genetic component of the study, the patient must sign and 
date both the consent form for the main study (Substudy 3) and the genetic component of the 
study.  Copies of both signed and dated consent forms must be given to the patient and the 
original filed at the study center.  The Principal Investigator(s) is responsible for ensuring that 
consent is given freely and that the patient understands that he or she may freely discontinue 
from the genetic aspect of the study at any time.
4.2
Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data.  Also Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.
5.
DATA MANAGEMENT
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or third party contracted 
to work with AstraZeneca to analyze the samples.
The results from this genetic research may be reported separately from the CSR for the main 
study.
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.


Clinical Study Protocol Appendix D
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
7(7)
6.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
The number of patients that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A statistical 
analysis plan will be prepared where appropriate.
7.
LIST OF REFERENCES
None


Clinical Study Protocol Appendix E
Drug Substance
MEDI4736 and Tremelimumab
Study Code
D4198C00001
Edition Number
2
Date
17 August 2015
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
2(8)
TABLE OF CONTENTS
PAGE
TABLE OF CONTENTS.........................................................................................2
1.
INTRODUCTION ...................................................................................................3
2.
DEFINITIONS.........................................................................................................3
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES...................................4
4.
FOLLOW-UP ..........................................................................................................5
4.1
Potential Hy’s Law Criteria not met ........................................................................5
4.2
Potential Hy’s Law Criteria met ..............................................................................5
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES...............5
6.
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW CRITERIA 
ARE MET BEFORE AND AFTER STARTING STUDY TREATMENT ............6
7.
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL 
HY’S LAW ..............................................................................................................7
8.
REFERENCES ........................................................................................................8


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
3(8)
1.
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.
2.
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.


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
4(8)
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:
!
ALT ≥3 × ULN
!
AST ≥3 × ULN
!
TBL ≥2 × ULN
If a central laboratory is 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 Section 2 of this appendix 
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 (see Section 2 of this Appendix 
for definition) by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory CRF


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
5(8)
4.
FOLLOW-UP
4.1
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
4.2
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 
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
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW 
CASES
The instructions in this section should be followed for all cases where PHL criteria are met.
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.


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
6(8)
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. 
∀
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
6.
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW
CRITERIA ARE MET BEFORE AND AFTER STARTING 
STUDY TREATMENT 
This section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment. 
At the first on study treatment occurrence of PHL criteria being met the Investigator will:
!
Determine if there has been a significant change in the patients’ condition#
compared with the last visit where PHL criteria were met#


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
7(8)
∀
If there is no significant change no action is required
∀
If there is a significant change notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Section 4.2 of this Appendix
# A “significant” change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or 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.
7.
ACTIONS REQUIRED FOR REPEAT EPISODES OF 
POTENTIAL HY’S LAW
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
!
Was the alternative cause for the previous occurrence of PHL criteria being met 
found to be the disease under study, 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 
Section 6?
If No: follow the process described in Section 4.2 of this Appendix
If Yes:
Determine if there has been a significant change in the patient’s condition# compared with 
when PHL criteria were previously met
!
If there is no significant change, no action is required
!
If there is a significant change, follow the process described in Section 4.2 of this 
Appendix
# A “significant” change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or total bilirubin) in isolation or 
in combination, or a clinically relevant change in associated symptoms.  The determination of 


Clinical Study Protocol Appendix E
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Date 17 August 2015
8(8)
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
8.
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.


Clinical Study Protocol Appendix F
Drug Substance
MEDI4736 and Tremelimumab
Study Code
D4198C00001
Edition Number
2
Appendix Date
17 August 2015
Appendix F
Guidelines for Evaluation of Objective Tumor Response Using RECIST 1.1
Criteria (Response Evaluation Criteria in Solid Tumors)


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Appendix Date 17 August 2015
2(14)
TABLE OF CONTENTS
PAGE
TABLE OF CONTENTS.........................................................................................2
1.
INTRODUCTION ...................................................................................................4
2.
DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET 
AND NON-TARGET LESIONS.............................................................................4
3.
METHODS OF ASSESSMENT..............................................................................5
3.1
CT and MRI.............................................................................................................6
3.2
Clinical examination................................................................................................6
3.3
X-ray ........................................................................................................................6
3.3.1
Plain X-ray...............................................................................................................6
3.4
Ultrasound................................................................................................................6
3.5
Endoscopy and laparoscopy.....................................................................................7
3.6
Tumor markers.........................................................................................................7
3.7
Cytology and histology............................................................................................7
3.8
Isotopic bone scan....................................................................................................7
3.9
FDG-PET scan.........................................................................................................7
4.
TUMOR RESPONSE EVALUATION ...................................................................8
4.1
Schedule of evaluation.............................................................................................8
4.2
Target lesions...........................................................................................................8
4.2.1
Documentation of target lesions ..............................................................................8
4.2.2
Evaluation of target lesions......................................................................................9
4.3
Non-target lesions ..................................................................................................10
4.3.1
Evaluation of non-target lesions ............................................................................10
4.4
New lesions............................................................................................................11
4.5
Symptomatic deterioration.....................................................................................12
4.6
Evaluation of overall visit response.......................................................................12
5.
CONFIRMATION OF PROGRESSION ..............................................................13
6.
CENTRAL REVIEW.............................................................................................13
7.
REFERENCES ......................................................................................................14


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Appendix Date 17 August 2015
3(14)
LIST OF TABLES
Table 1
Summary of methods of assessment...........................................................6
Table 2
Evaluation of target lesions ......................................................................10
Table 3
Evaluation of non-target lesions...............................................................11
Table 4
Overall visit response ...............................................................................12


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Appendix Date 17 August 2015
4(14)
1.
INTRODUCTION
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 guidelines (Eisenhauer et al 2009) for the D4198C00001 study with regards to 
Investigator assessment of tumor burden including protocol-specific requirements for this 
study.
2.
DEFINITION OF MEASURABLE, NON-MEASURABLE, 
TARGET AND NON-TARGET LESIONS
Only patients with measurable disease at baseline should be included in the study.  
Measurable disease is defined by the presence of at least one measurable (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.
!
Lesions <2 cm biopsied within the screening period (fresh tumor biopsy)
                                                
1 Nodes with <10 mm short axis are considered non-pathological and should not be recorded or followed as 
non-target lesions (NTLs).


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Appendix Date 17 August 2015
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!
Previously irradiated lesions that have not demonstrated progression2
!
Brain metastasis
Special cases:
!
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.  Blastic lesions are considered non-measurable.
!
Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present 
in the same patient, these should be selected as target lesions (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.
3.
METHODS OF ASSESSMENT
The same method of assessment and the same technique should be used to characterize 
each identified and recorded lesion at baseline and during follow-up visits.
A summary of the methods to be used for RECIST assessment is provided in Table 1, and 
those excluded from tumor assessments for this study are highlighted with the rationale 
provided.
                                                
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.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Appendix Date 17 August 2015
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Table 1
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.
3.1
CT and MRI 
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TL selected for response assessment and to assess NTL and identification 
of any new lesions. 
In the D4198C00001 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 
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.
3.2
Clinical examination 
In the D4198C00001 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.
3.3
X-ray
3.3.1
Plain X-ray 
In the D4198C00001 study plain X-ray may be used as a method of assessment for bone NTL 
and to identify the presence of new bone lesions. 
3.4
Ultrasound 
In the D4198C00001 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.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Appendix Date 17 August 2015
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3.5
Endoscopy and laparoscopy 
In the D4198C00001 study, endoscopy and laparoscopy will not be used for tumor 
assessments as they are not validated in the context of tumor assessment.
3.6
Tumor markers 
In the D4198C00001 study, tumor markers will not be used for tumor response assessments as 
per RECIST 1.1.
3.7
Cytology and histology 
In the D4198C00001 study histology will not be used as part of the tumor response 
assessment as per RECIST 1.1. 
3.8
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment.  
In the D4198C00001 study, isotopic bone scans may be used as a method of assessment to 
identify the presence of new bone lesions at follow-up visits.  New lesions will be recorded 
where a positive hot-spot that was not present on the baseline bone scan assessment is 
identified on a bone scan performed at any time during the study.  The Investigator should 
consider the positive hot-spot to be a significant new site of malignant disease and represent 
true disease progression in order to record the new lesion.  Confirmation by CT, MRI and 
X-ray is recommended where bone scan findings are equivocal.
3.9
FDG-PET scan
In the D4198C00001 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.
                                                
3 A positive FDG-PET scan lesion should be reported only when an uptake greater than twice that of the 
surrounding tissue is observed.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Appendix Date 17 August 2015
8(14)
4.
TUMOR RESPONSE EVALUATION 
4.1
Schedule of evaluation
RECIST assessments will be performed using CT/MRI assessments of the chest and abdomen, 
pelvis only when suspected or 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 start of study 
treatment, and ideally should be performed as close as possible to the start of study treatment 
(see Table 2 of the Clinical Study Protocol).  Follow-up assessments will be performed every 
6 weeks (q6w±7 days) for the first 48 weeks relative to the date of the first infusion, and 
q12w±7 days thereafter until confirmed objective disease progression.  
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.
4.2
Target lesions
4.2.1
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), 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.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Appendix Date 17 August 2015
9(14)
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.
4.2.2
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL (see Table 2).


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Appendix Date 17 August 2015
10(14)
Table 2
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.
4.3
Non-target lesions
4.3.1
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.  At each visit an overall assessment of the NTL response should be 
recorded by the Investigator.  This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit (see 
Table 3).


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Appendix Date 17 August 2015
11(14)
Table 3
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.
4.4
New lesions
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression. 
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: 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.


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Appendix Date 17 August 2015
12(14)
4.5
Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.
Patients with “symptomatic deterioration” requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumor 
assessments where possible until objective disease progression is observed.
4.6
Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 4.
Table 4
Overall visit response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
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).


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Appendix Date 17 August 2015
13(14)
5.
CONFIRMATION OF PROGRESSION
In the D4198C00001 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
!
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.
6.
CENTRAL REVIEW
The Contract Research Organization appointed by AstraZeneca to perform the independent 
central review for this study will provide specification for radiological imaging protocols in 
standard acquisition guidelines documentation. 


Clinical Study Protocol Appendix F
Drug Substance MEDI4736 and Tremelimumab
Study Code D4198C00001
Edition Number 2
Appendix Date 17 August 2015
14(14)
7.
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 G
Drug Substance
MEDI4736 and Tremelimumab
Study Code
D4198C00001
Edition Number
2
Date
17 August 2015
Appendix G
Patient Reported Outcomes: EORTC QLQ-C30, EORTC QLQ-PAN26, 
PRO-CTCAE, and EQ-5D-5L


EORTC QLQ-C30 (version 3)
We are interested in some things about you and your health. Please answer all of the questions yourself by 
circling the number that best applies to you. There are no "right" or "wrong" answers. The information that you 
provide will remain strictly confidential. 
Please fill in your initials:
bbbb
Your birthdate (Day, Month, Year):
cececdde
Today's date (Day, Month, Year):  
31 cececdde
__________________________________________________________________________________________ 
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
1. 
Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4  
5. 
Do you need help with eating, dressing, washing  
 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
 
Please go on to the next page


During the past week:
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
For the following questions please circle the number between 1 and 7 that  
best applies to you 
29. 
How would you rate your overall health during the past week? 
 
 1 
2 
3 
4 
5 
6 
7 
 Very poor 
 
 
 
 
 
Excellent 
30. 
How would you rate your overall quality of life during the past week? 
 
 1 
2 
3 
4 
5 
6 
7 
 Very poor 
 
 
 
 
 
Excellent 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 


EORTC  QLQ - PAN26 
Patients sometimes report that they have the following symptoms or problems. Please indicate the 
extent to which you have experienced these symptoms or problems during the past week. Please 
answer by circling the number that best applies to you.   
During the past week:
Not 
A 
Quite 
Very 
 
 
at all 
little 
a bit 
much 
31. Have you had abdominal discomfort? 
1 
2 
3 
4 
32. Did you have a bloated feeling in your abdomen? 
1 
2 
3 
4 
33. Have you had back pain?  
1 
2 
3 
4 
34. Did you have pain during the night? 
1 
2 
3 
4 
35. Did you find it uncomfortable in certain positions 
(e.g. lying down)?  
1 
2 
3 
4 
36. Were you restricted in the types of food you can eat 
as a result of your disease or treatment?  
1 
2 
3 
4 
37. Were you restricted in the amounts of food you could eat 
as a result of your disease or treatment?  
1 
2 
3 
4 
38. Did food and drink taste different from usual?  
1 
2 
3 
4 
39. Have you had indigestion?  
1 
2 
3 
4 
40. Were you bothered by gas (flatulence)?  
1 
2 
3 
4 
41. Have you worried about your weight being too low?  
1 
2 
3 
4 
42. Did you feel weak in your arms and legs?  
1 
2 
3 
4 
43. Did you have a dry mouth?  
1 
2 
3 
4 
44. Have you had itching?  
1 
2 
3 
4 
45. To what extent was your skin yellow? 
1 
2 
3 
4 
46. Did you have frequent bowel movements? 
1 
2 
3 
4 
47. Did you feel the urge to move your bowels quickly? 
1 
2 
3 
4 
48. Have you felt physically less attractive as a result of  
your disease and treatment?  
1 
2 
3 
4 
Please go to the next page


During the past week:
Not 
A 
Quite 
Very 
 
 
at all 
little 
a bit 
much 
49. Have you been dissatisfied with your body?  
1 
2 
3 
4 
50. To what extent have you been troubled with side-effects  
from your treatment?  
1 
2 
3 
4 
51. Were you worried about your health in the future?  
1 
2 
3 
4 
52. Were you limited in planning activities, for example 
meeting friends, in advance?  
1 
2 
3 
4 
53. Have you received adequate support from your health  
care professionals? 
1 
2 
3 
4 
54. Has the information given about your physical condition 
and treatment been adequate?  
1 
2 
3 
4 
55. Have you felt less interest in sex?  
1 
2 
3 
4 
56. Have you felt less sexual enjoyment?  
1 
2 
3 
4 
 QLQ-C30-PAN26 Copyright 1999 EORTC Study Group on Quality of life. All rights reserved  (phase III module) 


UK (English) v.2 © 2009 EuroQol Group. EQ-5D™is a trade mark of the EuroQol Group
Health Questionnaire
English version for the UK


UK (English) v.2 © 2009 EuroQol Group. EQ-5D™is a trade mark of the EuroQol Group
2
Under each heading, please tick the ONE box that best describes your health TODAY
MOBILITY
I have no problems in walking about 

I have slight problems in walking about 

I have moderate problems in walking about 

I have severe problems in walking about 

I am unable to walk about 

SELF-CARE
I have no problems washing or dressing myself 

I have slight problems washing or dressing myself 

I have moderate problems washing or dressing myself 

I have severe problems washing or dressing myself 

I am unable to wash or dress myself 

USUAL ACTIVITIES (e.g. work, study, housework, 
family or leisure activities)
I have no problems doing my usual activities 

I have slight problems doing my usual activities 

I have moderate problems doing my usual activities 

I have severe problems doing my usual activities 

I am unable to do my usual activities 

PAIN / DISCOMFORT
I have no pain or discomfort 

I have slight pain or discomfort 

I have moderate pain or discomfort 

I have severe pain or discomfort 

I have extreme pain or discomfort 

ANXIETY / DEPRESSION
I am not anxious or depressed 

I am slightly anxious or depressed 

I am moderately anxious or depressed 

I am severely anxious or depressed 

I am extremely anxious or depressed 



UK (English) v.2 © 2009 EuroQol Group. EQ-5D™is a trade mark of the EuroQol Group
3
x
We would like to know how good or bad your health is 
TODAY.
x
This scale is numbered from 0 to 100.
x
100 means the best health you can imagine.
0 means the worst health you can imagine.
x
Mark an X on the scale to indicate how your health is TODAY.
x
Now, please write the number you marked on the scale in the 
box below. 
                    
YOUR HEALTH TODAY =
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The best health     
you can imagine
The worst health   
you can imagine


PATIENT-REPORTED OUTCOMES VERSION OF THE COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS (PRO-CTCAE) ITEM LIBRARY 
 
Attention/Memory 
 
Concentration* 
 
 
Memory 
 
Cutaneous 
Rash* 
 
Skin dryness 
 
Acne 
 
Hair loss* 
 
Hand-foot 
 
syndrome 
 
Hives 
 
Itching 
 
Nail loss 
 
Nail ridging 
 
Nail 
 
discoloration 
 
Sensitivity to 
 
sunlight 
 
Pressure sores 
 
Radiation skin 
 
reaction 
 
Skin darkening 
 
Stretch marks 
 
 
 
Cardio/Circulatory 
Swelling* 
Heart  
Palpitations 
Pain 
      General pain* 
      Headache* 
      Muscle pain 
Joint pain 
 
Gastro-Intestinal 
Taste changes* 
Decreased    
appetite* 
Nausea* 
Vomiting* 
Heartburn 
Gas 
Bloating 
 
Hiccups 
Constipation* 
Diarrhea* 
Abdominal  
pain 
Fecal  
incontinence 
 
 
Sleep/Wake 
Insomnia* 
 
 
Fatigue* 
 
Respiratory 
Shortness of       
breath* 
Cough 
Wheezing 
 
Gynecologic/Urinary 
 
Vaginal 
 
bleeding 
Missed 
menstrual 
periods 
Vaginal 
discharge 
Vaginal dryness 
Painful 
urination 
Urinary urgency 
Urinary 
frequency 
Change in usual 
urine color 
Urinary 
incontinence 
 
Neurological  
 
 
Numbness & 
 
tingling* 
 
Dizziness 
Mood 
      Anxious* 
      Discouraged 
       
              Sad* 
 
 
Miscellaneous 
      Breast swelling    
      and tenderness 
      Bruising 
      Chills 
      Increased    
      sweating 
      Decreased   
      sweating 
      Hot flashes 
      Nosebleed 
      Pain and  
      swelling at   
      injection site 
      Body odor  
 
 
 
Sexual 
      Achieve and       
      maintain    
      erection 
      Ejaculation 
      Desire 
      Orgasm 
      Pain w/sexual    
      Intercourse 
 
Visual/Perceptual 
Blurred vision 
Flashing lights 
Visual floaters 
Watery eyes 
Ringing ear 
 
Oral 
Dry mouth* 
Difficulty 
swallowing 
Mouth/throat 
sores* 
Cracking at the 
corners of the 
mouth 
(cheliosis) 
Voice quality 
changes 
Hoarseness 
*Denotes core item 

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D4198C00001
Edition Number
2.0
Date
27/Feb/2017
A Phase II Open-Label, Multi-Center Study of MEDI4736 Evaluated as 
Single Agent or in Combination with Tremelimumab in Patients with 
Metastatic Pancreatic Ductal Adenocarcinoma


33'
33'


33'


Statistical Analysis Plan 
Study Code D4198C00001
Edition Number 2.0
Date 27/Feb/2017
4
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
SIGNATURE OF STUDY STATISTICIAN ..........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN....................................3
TABLE OF CONTENTS.........................................................................................4
LIST OF ABBREVIATIONS..................................................................................7
AMENDMENT HISTORY ...................................................................................10
1.
STUDY DETAILS.................................................................................................10
1.1
Study objectives.....................................................................................................10
1.1.1
Primary objectives .................................................................................................10
1.1.2
Secondary objectives .............................................................................................11
1.1.3
Safety objectives ....................................................................................................11
1.1.4
Exploratory objectives ...........................................................................................11
1.2
Study design...........................................................................................................12
1.3
Number of subjects ................................................................................................15
2.
ANALYSIS SETS .................................................................................................15
2.1
Definition of analysis sets......................................................................................15
2.2
Deviations ..............................................................................................................16
3.
PRIMARY AND SECONDARY VARIABLES...................................................18
3.1
Derivation of RECIST Visit Response ..................................................................18
3.1.1
Target lesions (TLs)...............................................................................................19
3.1.2
Non-Target Lesions (NTLs) and new lesions........................................................24
3.1.3
Overall visit response.............................................................................................26
3.1.4
Independent Review (Not applicable)....................................................................26
3.2
Outcome variables .................................................................................................26
3.2.1
Primary endpoint - Objective Response Rate (ORR) ............................................26
3.2.2
Secondary endpoints ..............................................................................................27
3.2.2.1
Progression Free Survival......................................................................................27
Time to study discontinuation or Death.................................................................28
3.2.2.2
Proportion of patients alive and progression-free..................................................28
3.2.2.3
Overall Survival.....................................................................................................28
3.2.2.4
Proportion of patients alive....................................................................................29
3.2.2.5
Duration of Response.............................................................................................29
3.2.2.6
Best objective response..........................................................................................29


Statistical Analysis Plan 
Study Code D4198C00001
Edition Number 2.0
Date 27/Feb/2017
5
3.2.2.7
Change in tumor size .............................................................................................30
3.2.2.8
Disease Control Rate (DCR)..................................................................................31
3.3
Safety .....................................................................................................................31
3.3.1
Adverse events (AE)..............................................................................................31
Other significant adverse events ............................................................................32
AEs of special interest ...........................................................................................32
3.3.2
Treatment exposure................................................................................................33
Patients who permanently discontinue during a dose delay ..................................33
3.3.3
Dose intensity.........................................................................................................33
3.3.4
Time to first subsequent therapy from discontinuation of study treatment ...........34
3.3.5
Laboratory data ......................................................................................................34
3.3.6
ECGs......................................................................................................................35
3.3.7
Vital signs ..............................................................................................................36
3.3.8
General considerations for safety assessment........................................................36
3.4
Biomarker variables...............................................................................................39
3.5
Pharmacokinetic and Immunogenicity variables...................................................39
3.5.1
Population pharmacokinetics and exposure-response/safety analysis...................39
3.5.2
Pharmacokinetic non-compartmental analysis ......................................................39
3.5.3
Immunogenicity analysis .......................................................................................40
3.6
Health resource Use (Not applicable)....................................................................40
3.7
Pharmacogenetics ..................................................................................................40
4.
ANALYSIS METHODS .......................................................................................40
4.1
General principles ..................................................................................................40
4.2
Analysis methods...................................................................................................42
4.2.1
Multiplicity (Not applicable) .................................................................................42
4.2.2
Primary endpoint – Objective Response Rate .......................................................42
4.2.3
Duration of response..............................................................................................43
4.2.4
Disease control rate................................................................................................43
4.2.5
Progression-free survival .......................................................................................43
4.2.6
Overall survival......................................................................................................44
4.2.7
Change in tumor size .............................................................................................44
4.2.8
Healthcare resource use (Not applicable) ..............................................................44
4.2.9
Safety data..............................................................................................................44
Liver Enzyme Elevations and Hy's law .................................................................50
ECGs......................................................................................................................51
Vital signs ..............................................................................................................51
Time to subsequent therapy from discontinuation of study treatment...................51
Physical examination .............................................................................................51
Other safety data ....................................................................................................51
4.2.10
WHO performance status.......................................................................................52
4.2.11
PK/PDx data...........................................................................................................52
4.2.12
PK/PDx relationship ..............................................................................................52


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4.2.13
Biomarker data.......................................................................................................52
4.2.14
Demographic and baseline characteristics data .....................................................52
4.2.15
Treatment exposure................................................................................................54
Time on study ........................................................................................................54
4.2.16
Subsequent therapy................................................................................................54
5.
TIMING OF ANALYSES .....................................................................................54
5.1
Part A: Interim Analysis ........................................................................................54
5.2
Primary analyses ....................................................................................................55
6.
CHANGES OF ANALYSIS FROM PROTOCOL ...............................................55
6.1
Disease control rate................................................................................................55
6.2
Protocol amendment ..............................................................................................56
6.3
Part B: Expansion design.......................................................................................56
6.4
ePRO data ..............................................................................................................56
7.
REFERENCES ......................................................................................................56
8.
APPENDIX (NOT APPLICABLE).......................................................................57
LIST OF TABLES
Table 1
Summary of outcome variables and analysis populations........................16
Table 2
TL visit responses.....................................................................................20
Table 3
NTL visit Responses.................................................................................25
Table 4
Overall visit responses..............................................................................26
Table 5
PD-L1 status definition.............................................................................39
Table 6
Preplanned statistical and sensitivity analyses to be conducted...............42
LIST OF FIGURES
Figure 1
Phase II, MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy - study design .................................13
Figure 2
Phase II, MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy - study flow chart............................14


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LIST OF ABBREVIATIONS
The following abbreviations and special terms are used in this study analysis plan.
Abbreviation or 
special term
Explanation
5-FU
Fluoropyrimidine
ADA
Antidrug antibody
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT
Alanine aminotransferase
ALP
Alkaline phosphatase
AST
Aspartate aminotransferase
BICR
Blinded Independent Central Review
BoR
Best objective Response
CI
Confidence Interval
CR
Complete Response
CSP
Clinical Study Protocol
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Event
DBL
Database lock
DCO
Data cut-off
DCR
Disease Control Rate
DCR12
Disease Control Rate at 12 weeks
DNA
Deoxyribonucleic acid 
DoR
Duration of Response
d.p
Decimal place
DRM
Data Review Meeting
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EORTC
European Organisation for Research and Treatment of Cancer
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer quality of 
life core questionnaire


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Abbreviation or 
special term
Explanation
EORTC QLQ-PAN26
European Organisation for Research and Treatment of Cancer quality of 
life questionnaire pancreatic cancer module
EQ-5D-5L
EuroQol 5-dimension, 5-level health state utility index
FAS
Full Analysis Set
fT3
Free triiodothyronine
fT4
Free thyroxine
HR
Hazard Ratio
HRQoL
Health-Related Quality of Life
IHC
Immunohistochemical
IP
Investigational Product 
irAE
Immune-related adverse event
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
ITT
Intent-to-treat
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
MDSC
Myeloid-derived suppressor cells
MedDRA
Medical Dictionary for Regulatory Activities
miRNA
Micro-ribonucleic acid
MRI
Magnetic Resonance Imaging
mRNA
Messenger ribonucleic acid
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 randomization/enrollment
OS12
Proportion of patients alive at 12 months from randomization/enrollment
PD
Progressive Disease
PDx
Pharmacodynamics
PDAC
Pancreatic ductal adenocarcinoma
PD-L1
Programmed cell death ligand 1
PFS
Progression-free survival


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Abbreviation or 
special term
Explanation
PFS3
Proportion of patients with progression-free survival after 3 months
PFS6
Proportion of patients with progression-free survival after 6 months
PGx
Pharmacogenetic
PI
Principal Investigator 
PID
Percentage intended dose
PK
Pharmacokinetics
PR
Partial Response
PRO
Patient Reported Outcomes
PRO-CTCAE
Patient-Reported Outcomes version of the Common Terminology Criteria 
for Adverse Events 
q4w
Every 4 weeks
q6w
Every 6 weeks
q12w
Every 12 weeks
QoL
Quality of Life
QLQ
Quality of Life Questionnaire
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RCT
Randomized Controlled Trial
RDI
Relative Dose Intensity
RECIST
Response Evaluation Criteria in Solid Tumors 
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SD
Stable Disease
SNP
Single Nucleotide Polymorphism
SoC
Standard of Care
sPD-L1
Soluble programmed cell death ligand 1
TFST
Time to First Subsequent Therapy
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal


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AMENDMENT HISTORY
Date
Brief description of change
V1.0 (16FEB2016)
N/A
V2.0 (27/Feb/2017)
Part B related revision and other minor revisions
1.
STUDY DETAILS
This study consists of Part A, Lead-in, as well as a possible Part B, expansion (Part B: 
Expansion) and/or a possible Part B, randomized controlled study (Part B: RCT).
The purpose of this Statistical Analysis Plan (SAP) is to detail statistical methods and 
presentations for Part A: Lead-in and Part B: expansion only.
The format of Part B will be determined based on the responses seen in the first 30 patients in 
each arm in Part A. In the event a Part B: Expansion is initiated, data from Part A and Part B: 
Expansion will be combined. In the event a Part B: RCT is initiated, a separate SAP will be 
produced to detail the methods that will be applied.
This document has been prepared in conjunction with the Clinical Study Protocol (CSP) 
version 1 (17AUG2015) and is referring to the unique CRF template version 2.0 
(05NOV2015).
A protocol amendment will be made if criteria are met to proceed to Part B: RCT. The 
protocol amendment will include available data from Part A and any changes to study design 
and statistical plan, if needed.
1.1
Study objectives
1.1.1
Primary objectives
Primary objective:
Outcome measure:
To assess the efficacy of MEDI4736
monotherapy and MEDI4736 + 
tremelimumab
combination therapy in terms of ORR
ORR in all patients using Investigator 
assessments according to RECIST 1.1a,b
a All images will be collected and stored for possible future central re-analysis.
b Sensitivity analyses of ORR will be performed based on Investigator assessment according to RECIST 1.1 
modified for confirmation of progression.


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1.1.2
Secondary objectives
Secondary objective:
Outcome measure:
To further assess the efficacy of the
combination of MEDI4736 and 
tremelimumab
and MEDI4736 alone 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 1.1a
OS, OS6, and OS12
To assess the health-related QoL in metastatic 
PDAC patients treated with MEDI4736 + 
tremelimumab combination therapy and 
MEDI4736 monotherapy as measured by 
EORTC QLQ-C30 global QoL scale (Part B 
only)
Adjusted mean change from baseline in 
global QoL score from the EORTC QLQ-C30 
questionnaire 
To assess the disease-related symptoms in 
metastatic PDAC patients treated with 
MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy as 
measured by EORTC QLQ-PAN26 
pancreatic pain scale (Part B only)
Adjusted mean change from baseline in 
pancreatic pain score from the EORTC QLQ-
PAN26 questionnaire
To investigate the immunogenicity of 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy
Presence of ADAs for MEDI4736 and  
tremelimumab (confirmatory results: positive 
or negative; titers)
To assess the PK of MEDI4736 monotherapy
and MEDI4736 + tremelimumab combination
therapy
Concentration of MEDI4736/tremelimumab 
in blood and noncompartmental PK 
parameters (such as peak concentration and 
trough, as data allow; sparse sampling only)
a All images will be collected and stored for possible future central re-analysis.
1.1.3
Safety objectives
Safety objective:
Outcome measure:
To assess the safety and tolerability profile of
MEDI4736 monotherapy and MEDI4736 +
tremelimumab combination therapy
AEs, physical examinations, laboratory 
findings (including clinical chemistry, 
hematology, and urinalysis), vital signs 
(including blood pressure and pulse), ECGs
1.1.4
Exploratory objectives
Exploratory objectives:
Outcome measure:
To assess the efficacy of MEDI4736 and 
tremelimumab and MEDI4736 alone 
according to irRECISTa
ORR, DoR, DCR, PFS, PFS3, and PFS6 
using BICR assessments according to 
irRECISTa
To assess tolerability directly by patient self-
reporting of specific PRO-CTCAE symptoms 
Pre-selected PRO-CTCAE items (not more 
than 30) considered relevant to patients with 


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(Part B only)
metastatic PDAC treated with MEDI4736 or 
tremelimumab or SoC
To collect blood and tissue samples for 
defining biological responses to MEDI4736 
or MEDI4736-tremelimumab and for 
identifying candidate markers that may 
correlate with likelihood of clinical benefit
Serum sPD-L1
Circulating soluble factors (eg, cytokines and 
autoantibodies)
miRNA/mRNA
T cell and MDSC phenotyping
SNP genotyping
To collect and store DNA according to each 
country’s local and ethical procedures for 
future exploratory research into genes/genetic 
variation that may influence response (ie, 
distribution, safety, tolerability, and efficacy) 
to study treatments and/or susceptibility to 
disease (optional genetics component)
Correlation of polymorphisms with variation 
in PK, pharmacodynamics, safety, or 
response parameters observed in patients 
treated with MEDI4736 and the combination 
of MEDI4736 and tremelimumab, and/or 
susceptibility to disease
To assess change in performance status in 
metastatic PDAC patients treated with 
MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy as 
measured by the ECOG performance status 
scale
ECOG performance status
To describe and evaluate resource use 
associated with assigned treatments and 
underlying disease (Part B only)
Health resource utilization methods including 
HOSPAD, concomitant medications, and the 
AE module of the electronic case report form 
(eCRF)
To explore the impact of treatment and 
disease state on health state utility using the 
EuroQol 5-dimension, 5-level health state 
utility index (EQ-5D-5L) (Part B only)
The EQ-5D-5L will be used to derive health 
state utility based on patient-reported data.
Note: Exploratory objective analyses may be reported separately from the main clinical study report.
aThis analysis will be conducted only if central review data are generated at a future timepoint.
1.2
Study design
This is a second-line Phase II study assessing MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy.
This is a Phase II, open-label, multi-center study to determine the efficacy and safety of 
MEDI4736 evaluated as single agent or in combination with tremelimumab in patients with 
metastatic pancreatic ductal adenocarcinoma (PDAC) whose disease has progressed on 5-FU-
containing or gemcitabine-containing first-line chemotherapy. Initially, patients will be 
enrolled and randomized (1:1) to treatment with MEDI4736 monotherapy or MEDI4736 + 
tremelimumab, until 30 patients have been randomized to treatment in each arm (Part A: 
Lead-in). Randomization will be stratified according to best response to prior first-line 
chemotherapy (Complete response [CR], Partial Response [PR], or Stable Disease [SD]) 


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versus no response (PD) and according to prior first-line chemotherapy, 5-FU-containing
versus gemcitabine-containing. Patient recruitment and tumor assessment will be monitored 
on an ongoing basis. The format of Part B will be determined based on the responses seen in 
the first 30 patients in each arm in Part A. If both arms go to Part B: Expansion, Part B; 
Expansion will be randomized. If only one goes, Part B: Expansion will not be randomized. 
Only either Part B: Expansion or Part B: RCT will be initiated. A protocol amendment will be 
made if criteria are met to go to Part B: RCT. A schematic diagram of the overall study design 
is shown in Figure 1, and a detailed study flow cart is shown in Figure 2.
Figure 1
Phase II, MEDI4736 monotherapy and MEDI4736 + tremelimumab 
combination therapy - study design


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Figure 2
Phase II, MEDI4736 monotherapy and MEDI4736 + tremelimumab 
combination therapy - study flow chart 


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1.3
Number of subjects
Part A: Lead-in and Part B: Expansion. 
This study will initially enroll approximately 60 patients to receive MEDI4736 monotherapy 
or MEDI4736 + tremelimumab combination therapy (Part A: Lead-in). Depending on the data 
in each arm from Part A, an expansion phase may be initiated (Part B: Expansion 
approximately 140 additional patients, 70 patients per arm) and/or a randomized, controlled 
study (Part B: Randomized controlled trial [RCT]) may be initiated to compare MEDI4736 
monotherapy and/or MEDI4736 + tremelimumab combination to Standard of Care (SoC; 
approximately 375 total additional patients, 125 patients per arm).
If an ORR >25% (i.e., ≥8 CR/PR) is recorded among the first 30 treated patients in either of 
the treatment arms in Part A (unless the totality of the data supports a different decision), an 
additional 70 patients will be enrolled in that arm, for a total of 100 evaluable patients per arm 
in the Part B: Expansion study. If both arms meet the criterion of ORR > 25%, patients will be 
randomised to either arm.
In Part B: Expansion, 100 patients (30 from Part A plus an additional 70 from Part B) will 
provide >90% power for an exact test of a single proportion, assuming a null hypothesis (H0) 
of ORR=10%, and an alternative hypothesis (HA) of ORR=25%, at the 2-sided 0.05 alpha 
level (critical value, ORR = 16.7%), while also providing adequate patients to reasonably 
characterize the safety profile of the expanded arm(s). A 10% response rate is considered a 
reasonable assumption for the average response rate achieved by current therapies in second-
line advanced pancreatic cancer (Rahma et al 2013, see Section 7).
Part B: Randomized, controlled trial
Should the ORR in Part A in at least 1 arm be >15% (≥5/30 responses) and <25% (<8 
responses) then a randomized controlled trial may be initiated.  If initiated, this will be 
detailed in a separate SAP.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
Full Analysis Set (Intention to treat)
The Full Analysis Set (FAS) will include all randomized patients (i.e., the intent-to-treat [ITT] 
population) and will classify them on the basis of randomized or allocated treatment, 
regardless of the treatment actually received. Patients who were randomized but who did not 
subsequently go on to receive study treatment are included in the ITT population. For the 
purposes of evaluating the data in Part A to expand into Part B, only patients who actually 
received at least 1 dose of study treatment will be included in the FAS.


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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, according to the treatment they actually received. 
When assessing safety and tolerability, summaries will be produced based on the Safety 
Analysis Set.
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.
Definitions of the analysis sets for each outcome variable are provided in Table 1.
Table 1
Summary of outcome variables and analysis populations
Outcome variable
Population
Efficacy data
PFS
FAS (ITT population)
DoR, DCR, PFS, PFS3, PFS6, OS, OS6, OS12, 
PROs and symptoms endpoints (*)
FAS (ITT population)
Demography
FAS (ITT population)
PK data
PK Analysis Set
Safety data
Exposure
Safety Analysis Set
AEs
Safety Analysis Set
Laboratory measurements
Safety Analysis Set
ECOG performance status
Safety Analysis Set
Vital signs
Safety Analysis Set
(*) See Section 6
2.2
Deviations
The following general categories will be considered important deviations and be listed and 
discussed in the CSR as appropriate for the study. 
!
Deviation 1: Patients randomized (*) but who did not receive study treatment.
!
Deviation 2: Patients randomized who received treatment other than that to which 
they were randomized.


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!
Deviation 3: Patients who deviate from any of the key entry criteria as per the CSP. 
These are inclusion criteria 3, 4, 6, 7 and 8 and exclusion criteria 4, 11 and 20.
!
Deviation 4: Baseline RECIST scan > 28 days before start of randomized treatment.
!
Deviation 5: No baseline RECIST 1.1 assessment on or before date of first dose.
!
Deviation 6: 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.
(*): where applicable
In addition to the programmatic determination of the deviations above (based on the clinical 
database), 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. 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.
Deviation 1 will lead to exclusion from the Safety analysis set. None of the other deviations 
will lead patients being excluded from the analysis sets described in Section 2.1 (with the 
exception of the PK analysis set, if the deviation is considered to impact upon PK). 
Errors in treatment dispensing, in addition to incorrect stratifications, will also be summarized
and listed separately from the important protocol deviations. If a patient is not randomized or 
treated according to the randomization schedule, it is envisaged that there will be 2 
subcategories:
!
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.
!
The patient receives a treatment pack with a different code to their randomization
code. However, the actual treatment may still match the randomized treatment. For 
example, a patient is given randomization code 0001, which according to the 
randomization schedule is MEDI4736. However, at the randomization visit they are 
given treatment pack 0003, but this still contains MEDI4736.
The summary will include all patients with a dispensing error but will also include 
information on how many of those patients received at least one dose of the wrong treatment 
at any time. Patients who receive the wrong treatment at any time will be included in the 
Safety Analysis Set as described in Section 2.1. During the study, decisions on how to handle 
misrandomizations will be made on an individual basis with written instruction from the study 
team leader and/or statistician.


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3.
PRIMARY AND SECONDARY VARIABLES
3.1
Derivation of RECIST Visit Response
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. 
The methods of assessment of tumor burden used at baseline are computed tomography (CT)
and/or magnetic resonance imaging (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 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 CSP Appendix F.
Baseline radiological tumor assessments are to be performed no more than 28 days before the 
start of randomized treatment and ideally as close as possible to the start of study treatment. 
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 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/her 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.
Categorization of objective tumor response assessment will be based on the RECIST 1.1 
criteria of response: CR, PR, SD, and PD. At each visit, patients will be programmatically 
assigned a response 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 ORR, DoR, 
DCR, PFS, PFS3, and 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.


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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.
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.
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.
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 randomization 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 (NTLs) at baseline.  Measurements are not required for these lesions, but their status 
should be followed at subsequent visits.
TL response will be derived based on the Investigator’s overall assessment of TLs as follows 
(see Table 2):


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Table 2
TL visit responses
Visit Responses
Descriptions
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.
Stable disease (SD)
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD.
Progressive disease (PD)
At least a 20% increase in the sum of diameters of 
TLs taking as reference the smallest sum on study 
(this includes the baseline sum if that is the 
smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5%.
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.
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 (d.p.) 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 LD recorded. 
If there is at least one TL measurement missing and a visit response of PD cannot be assigned, 
the visit response is not evaluable (NE).


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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 over-
written 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 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.


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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 
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 subject 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 (as per step 2 above).


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Scaling (applicable only for irradiated lesions/lesion intervention)
If > 1/3 of TL measurements are 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 missing (because of intervention) then the results will be 
scaled up (based on the sizes at the nadir visit to give an estimated sum of diameters and this 
will be used in calculations; this is equivalent to comparing the visit sum of diameters of the 
non-missing lesions to the nadir sum of diameters excluding the lesions with missing 
measurements).
Example of scaling
Lesion
Longest diameter at nadir 
visit (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 28.4mm:
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.


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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.
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 (see Table 3):


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Table 3
NTL visit Responses
Visit Response
Description
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 NTLs.
Progressive Disease (PD)
Unequivocal progression of existing NTLs. 
Unequivocal progression may be due to an 
important progression in one lesion only or in 
several lesions. In all cases the progression MUST 
be clinically significant for the physician to 
consider changing (or stopping) therapy.
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 4 defines how the previously defined TL and NTL visit responses will be combined
with new lesion information to give an overall visit response.
Table 4
Overall visit responses
TARGET
NON-TARGET
NEW LESIONS
OVERALL VISIT 
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)
3.1.4
Independent Review (Not applicable)
3.2
Outcome variables
3.2.1
Primary endpoint - Objective Response Rate (ORR)
The primary endpoint of ORR, according to investigator assessment, is defined as the number 
(%) of subjects with at least one visit response of confirmed CR or PR and will be based on 
the FAS.


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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 visits. Therefore, data obtained up 
until progression, or last evaluable assessment in the absence of progression, will be included 
in the assessment of ORR. Patients who discontinue randomized treatment without 
progression, receive a subsequent anti-cancer therapy and then respond will not be included as 
responders in the ORR.
For sensitivity analysis, ORR will be assessed using the RECIST Investigator assessed tumor 
data following a modification where any objective progression requires confirmation. 
Therefore, data obtained up until confirmed progression, or last evaluable assessment in the 
absence of a confirmed progression, will be included in the assessment of ORR. Note that the 
response may be after an unconfirmed progression.
3.2.2
Secondary endpoints
3.2.2.1
Progression Free Survival
Progression free survival (PFS) is defined as the time from the date of randomization (for Part 
A, and Part B if randomization is applicable) or first dosing (for Part B if randomization is not 
applicable)until the date of objective disease progression or death (by any cause in the absence 
of progression) regardless of whether the subject withdraws from randomized therapy or 
receives another anti-cancer therapy prior to progression.
Subjects 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 subject progresses or dies after two or more missed visits, the subject will be censored at 
the time of the latest evaluable RECIST 1.1 assessment prior to the two missed visits.
Given the scheduled visit assessment scheme (i.e. six-weekly for the first 48 weeks then 
twelve-weekly thereafter)  the definition of 2 missed visits will change.  If the previous 
RECIST assessment is less than study day 288 (i.e. Week 41) 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 288 to 
344 (i.e. Week 41 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 a patient has no evaluable visit or does not have baseline data, he/she will be censored at 
date of randomization unless they die within 2 visits from randomization date (2 x 6 weeks + 1 
week for a late assessment).


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If the subject has no post-baseline evaluable visit or does not have baseline data they will be 
censored at date of first dose unless they die within 2 visits of first dose (12 weeks plus 1 
week allowing for a late assessment within the visit window).
The PFS time will always be derived based on scan/assessment dates not visit dates.
RECIST 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 dates of the component that triggered the progression
!
When censoring a subject for PFS the subject will be censored at the latest of the 
dates contributing to a particular overall visit assessment.
Note: For TLs, only the latest scan date is recorded out of all scans performed at that 
assessment for the TLs and similarly for NTLs only the latest scan date is recorded out of all 
scans performed at that assessment for the NTLs.
Time to study discontinuation or Death
Time to Study Discontinuation or Death is defined as the time from first dosing to the earlier 
of the date of study treatment discontinuation or death.  Any patient not known to have died at 
the time of analysis and not known to have discontinued study treatment will be censored 
based on the last recorded date on which the patient was known to be alive.
3.2.2.2
Proportion of patients alive and progression-free
The proportion of patients alive and progression free at 3 months (i.e., PF3) will be defined as 
the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by the site investigator) at 3 
months.
The proportion of patients alive and progression free at 6 months (i.e., PF6) will be defined as 
the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by the site investigator) at 6 
months.
3.2.2.3
Overall Survival
Overall survival (OS) is defined as the time from the date of randomization (for Part A, and 
Part B if randomization is applicable) or first dosing (for Part B if randomization is not 
applicable) until death due to any cause (i.e. date of death or censoring – date of first dosing or 
randomization + 1). Any subject not known to have died at the time of analysis will be 
censored based on the last recorded date on which the subject was known to be alive 
(SUR_DAT, recorded within the SURVIVE module of the eCRF). 
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 


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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 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).
3.2.2.4
Proportion of patients alive
The proportion of patients alive at 6 months (OS6) will be defined as the Kaplan-Meier 
estimate of OS at 6 months. 
The proportion of patients alive at 12 months (OS12) will be defined as the Kaplan-Meier 
estimate of OS at 12 months. 
3.2.2.5
Duration of Response
Duration of response (DoR) will be defined as the time from the date of first documented 
response until date of documented progression or death in the absence of disease progression, 
the end of response should coincide with the date of progression or death from any cause used 
for the PFS endpoint.  The time of the initial response will be defined as the latest of the dates 
contributing towards the first visit response of PR or CR.
If a subject does not progress following a response, then their duration of response will use the 
PFS censoring time. DoR will not be defined for those patients who do not have documented 
response.
Additionally, DoR will be obtained using the algorithm described (see Appendix F in the 
CSP), but following a modification where any objective progression requires confirmation. 
Therefore, the end of response should coincide with the date of progression or death for any 
cause. Note that the time of initial response may be after an unconfirmed progression. 
3.2.2.6
Best objective response 
Best objective response (BoR) is calculated based on the overall visit responses from each 
RECIST assessment, described in Appendix F in the CSP. It is the best response a patient has 
had following date of first dosing but prior to starting any subsequent cancer therapy and prior 
to RECIST progression or the last evaluable assessment in the absence of RECIST 
progression. 
Categorization of BoR will be based on RECIST using the following response categories: CR, 
PR, SD, PD, and NE.


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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 at least 6 weeks minus 1 week, i.e. at least 35 days (to allow for the assessment 
window), after the 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 from the overall visit response 
using all Investigator assessment data up until the first progression event. The denominator
will be consistent with the one used in the ORR analysis. 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 (i.e., 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 ≤13 weeks 
(i.e., 2*6 weeks + 1 week to allow for a late assessment within the assessment window) after 
the first dosing, then BoR will be assigned to the progression (PD) category. For patients who 
die with no evaluable RECIST assessments, if the death occurs >7 weeks (i.e., 6 weeks + 1 
week) after the first dosing then BoR will be assigned to the NE category.
Progression events that have been censored because they occurred more than two missed visits 
after the last evaluable assessment will not contribute to the BoR derivation. 
3.2.2.7
Change in tumor size
For supportive purposes percentage change from baseline in tumor size will be derived at each 
scheduled tumor assessment visit (i.e., Week 6, Week 12 etc… hereafter referred to as Week 
X for convenience). Best percentage change from baseline in tumor size will also be derived 
as the biggest decrease or the smallest increase in tumor size from baseline.
This is based on RECIST target lesion measurements taken at baseline and at the timepoint of 
interest. Tumor size is defined as the sum of the longest diameters of the target lesions. Target 
lesions are measurable tumor lesions. Baseline for RECIST is defined to be the last evaluable 
assessment prior to starting treatment (see Section 3.1 for more details). The change in target 
lesion tumor size at Week X will be obtained for each patient by taking the difference between 
the sum of the target lesions at Week X and the sum of the target lesions at baseline. To obtain 
the percentage change in target lesion tumor size at Week X the change in target lesion tumor
size is divided by the sum of the target lesions at baseline and multiplied by 100 (i.e. (Week X 
- baseline) / baseline * 100). More details on target lesions and measurements can be found in 
Section 3.1.


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Apply a window around the Week X visit: Whenever tumor size data for the Week X visit 
(Note: or visit at which progression was documented if before Week X) is available then this 
should be used in the analysis. A windowing rule will be applied and will follow the protocol 
allowed visit window; therefore any RECIST scan performed within ± 7 days of the protocol 
scheduled visit will be used for that visit.
The above derivations will be programmed for the investigator assessments based upon 
RECIST analysis.
3.2.2.8
Disease Control Rate (DCR)
Disease control rate at 3 months is defined as the percentage of patients who have a BoR of 
CR or PR in the first 3 months (i.e. 12+1=13 weeks to allow for a late assessment within the 
assessment window) or who have demonstrated SD for a minimum interval of 12 weeks 
(minus 1 week to allow for an early assessment within the assessment window, i.e., 77 days) 
following the start of treatment. Disease control rate at 6 months is defined as the percentage 
of patients who have a 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 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 
progression event that is used for the analysis.
3.3
Safety
Safety and tolerability will be assessed in terms of adverse events (AEs) (including serious 
adverse events [SAEs]), deaths, laboratory data, vital signs, electrocardiograms (ECGs) and 
exposure. These will be collected for all patients.
Data from the initial treatment period (i.e., the initial 12 months of treatment) and safety data 
from the retreatment period may also be summarized separately (see Section 4.1). ‘On 
treatment’ will be defined as assessments between date of start dose and 90 days following 
last dose of the study treatment on each period of treatment. The Safety Analysis Set will be 
used for reporting of safety data.
3.3.1
Adverse events (AE)
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 the study treatment.


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The Medical Dictionary for Regulatory Activities (MedDRA) (using the latest MedDRA 
version) will be used to code the AEs. AEs will be graded according to the National Cancer 
Institute Common Terminology Criteria for AEs (CTCAE Version 4.03). 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 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 
the study treatment. In the unlikely event of the components being administered separately 
then date of first dose/last dose will be considered as the earliest/latest dosing date of either 
component.
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 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
Adverse events of special interest (AESIs) are events of scientific and medical interest specific 
to the further understanding of the MEDI4736 and tremelimumab safety profile and require 
close monitoring and rapid communication by the Investigator to AstraZeneca. MEDI4736 
and tremelimumab 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 these IPs.
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.


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Some clinical concepts (including some selected individual preferred terms and higher level 
terms) have been considered “AEs of special interest” to the MEDI4736 program.  These 
AESIs have been identified as Pneumonitis, Colitis, Select hepatic events, Hypothyroidism, 
Hyperthyroidism, Hypophysitis, Adrenal Insufficiency, Dermatitis, Select renal events, Select 
pancreatic events, and Infusion related/Hypersensitivity/Anaphylactic reactions, Diarrhea, 
and Rash. 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. A further review will take place prior to Database lock (DBL) to ensure any 
further terms not already included are captured within the categories.
3.3.2
Treatment exposure
Exposure will be defined separately for the initial treatment period and for the re-treatment 
period as follows:
Total (or intended) exposure of study treatment
!
Total (or intended) exposure = last dose date +27 days where dose > 0 mg or death
or DCO, whichever  occurs first – first dose date + 1
Actual exposure of study treatment
!
Actual exposure = intended exposure – total duration of dose delays, where 
intended exposure will be calculated as above.
A dose delay is stated as soon as the infusion is not administered on the day planned per 
dosing scheduling.
Dose reductions 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 infusions received.
Patients who permanently discontinue during a dose delay
If a decision is made to permanently discontinue study treatment in-between cycles or during 
a dose delay then the date of last administration of study medication recorded will be used in 
the programming.
3.3.3
Dose intensity
For each molecule, standard dose intensity will be derived separately for the initial treatment 
period. 
Relative dose intensity (RDI) is the percentage of the actual dose intensity delivered relative 
to the intended dose intensity through to treatment discontinuation. 


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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.
As the treatment period is for a finite period of time, additional considerations need to be 
taken into account for the above calculations. In the absence of event by the end of the initial 
treatment period, the following censoring will be applied, relative to the first infusion in that 
period: earliest between the date of censoring used in the PFS and 
!
MEDI4736: end of period = 48 weeks (+1 week for late assessment)
!
Tremelimumab: end of period = 12 weeks (+1week for late assessment)
The standard dose intensity calculations above are focused upon standard agents that treat to 
progression and as the primary analysis is based upon RECIST 1.1 it is still appropriate to 
calculate these. However, due to the fact that there is the intention to treat through progression 
per the protocol there will be an additional measure of dose intensity to investigate the entire 
treatment period including the time period after progression:
!
Relative dose intensity (treatment through progression) (RDI2) = 100% * d/D, 
where d is the actual cumulative dose delivered up to the later of progression (or a 
censoring event) or the actual last day of dosing and D is the intended cumulative 
dose up to the later of progression (or a censoring event) or the actual last day of 
dosing.
The censoring event mentioned above is the date of censoring used in the PFS analysis.
3.3.4
Time to first subsequent therapy from discontinuation of study treatment
Time to first 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. Any 
palliative radiotherapy post discontinuation of study treatment should not be considered as 
subsequent cancer therapy. Any patient not known to have had a first subsequent therapy will 
not have this calculation performed.
3.3.5
Laboratory data
Laboratory data will be collected throughout the study, from screening to the follow-up visits 
as described in the CSP. Blood and urine samples for determination of hematology, clinical 
chemistry, and urinalysis will be collected as described in Section 5.2.1 of the CSP. For the 
definition of baseline and the derivation of post baseline visit values considering visit window 
and how to handle multiple records, derivation rules as described in Section 3.3.8 below will 
be used.


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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 local or project ranges as required, 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)] x 0.02)
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).
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.
Project reference ranges will be used throughout for reporting purposes.  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.
For example:
!
If a CTCAE criterion involves a change from baseline, evaluable patients would 
have both a pre-dose and at least 1 post-dose value recorded
!
If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient need only have 1 post dose-value recorded.
3.3.6
ECGs
ECG data are collected at screening and as clinically indicated while on study treatment. 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 3.3.8 below will 
be used.
At each time point the Investigator’s assessment of the ECG will be collected locally. Heart 
rate, duration of QRS complex, RR, PR and QT intervals will be collected centrally via a 
digital read. 
For triplicate ECGs, the mean of the three ECG assessments will be used to determine the 
value at that time point.


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3.3.7
Vital signs
Vital signs data obtained up until the 30 days (+3 days as per permitted time-window) from 
date of last dose of study treatment 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 3.3.8 below will be used.
3.3.8
General considerations for safety assessment
Time windows will be defined for any presentations that summarize values by visit. The 
following conventions will 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.
For example, the visit windows for vital signs data for MEDI4736 + tremelimumab 
combination therapy and MEDI4736 monotherapy (with 4 weeks between 
scheduled assessments) are:
(Week 4) Day 29, visit window 2 – 42
(Week 8) Day 57, visit window 43 – 70
(Week 12) Day 85, visit window 71 – 98
(Week 16) Day 113, visit window 99 – 126
(Week 20) Day 141, visit window 127 – 154
(Week 24) Day 169, visit window 155 – 182
(Week 28) Day 197, visit window 183 – 210
(Week 32) Day 225, visit window 211 – 238
(Week 36) Day 253, visit window 239 – 266
(Week 40) Day 281, visit window 267 – 294


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(Week 44) Day 309, visit window 295 – 322
(Week 48) Day 337, visit window 323 – 350
Note:  Due to the differing assessment schedules the visit windows will be different 
for the different study treatments and endpoints.
!
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 
should 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.
%
To prevent very large tables or plots being produced that contain many cells 
with meaningless data, for each treatment group visit data should only be 
summarized if the number of observations is greater than the minimum of 20 
and > 1/3 of patients dosed.
!
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 the re-treatment period, baseline is similarly defined as the last 
non-missing measurement prior to the first dose on the re-treatment period. For 
laboratory data and height/weight assessments, any assessments made on Day 1 will 
be considered pre-dose. 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 best value would be taken as baseline as this is the most conservative. 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. Where safety data are summarized over time, study day will be calculated 
in relation to date of first treatment. ECOG performed on Day 1 will be considered 
as baseline.


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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.  Additionally, adverse events that have missing causality 
(after data querying) will be assumed to be related to study drug.


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3.4
Biomarker variables
PD-L1 expression status (positive, negative) is defined in Table 5.
Table 5
PD-L1 status definition
Interpretation
Staining description
Positive for PD-L1
≥25% tumor cell membrane positivity for PD-L1 
at any intensity above background staining as 
noted on the corresponding negative control
OR
≥25% tumor associated immune cell positivity for 
PD-L1 at any intensity above background staining 
as noted on the corresponding negative control
Negative for PD-L1
<25% tumor cell membrane positivity for PD-L1 
at any intensity above background staining as 
noted on the corresponding negative control
AND
<25% tumor associated immune cell positivity for 
PD-L1 at any intensity above background staining 
as noted on the corresponding negative control
Abbr: PD-L1 Programmed cell death ligand 1
3.5
Pharmacokinetic and Immunogenicity variables
Samples for determination of MEDI4736 and tremelimumab concentration in serum will be 
analyzed by a designated third party laboratory on behalf of AstraZeneca.
3.5.1
Population pharmacokinetics and exposure-response/safety analysis
A population PK model analysis might be performed using a nonlinear mixed-effects 
modelling approach.  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 (PDx), 
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-PDx methods.
The mean PK profiles will be will be shown in a figure.
3.5.2
Pharmacokinetic non-compartmental analysis
PK concentration data and summary statistics will be tabulated by nominal visit/time point.  
Individual and mean blood concentration-time profiles will be generated.    Samples below the 
lower limit of quantification will be treated as missing in the analyses.


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3.5.3
Immunogenicity analysis
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against MEDI4736 monotherapy or 
MEDI4736 in combination with tremelimumab.  The immunogenicity titer and presence of 
neutralizing ADAs will be reported for samples confirmed positive for the presence of ADAs.  
The effect of immunogenicity on PK, pharmacodynamics, efficacy, and safety will be 
evaluated, if the data allow, but will be reported in a separate report.
3.6
Health resource Use (Not applicable)
3.7
Pharmacogenetics
A statistical analysis plan will be prepared where appropriate and reported outside the CSR.
4.
ANALYSIS METHODS
4.1
General principles
The below mentioned general principles will be followed throughout the study:
!
Descriptive statistics will be used for all variables, as appropriate. Continuous
variables will be summarised by the number of observations, mean, standard
deviation, median, minimum, and maximum. For log transformed data it is more
appropriate to present geometric mean, coefficient of variation (CV), median,
minimum and maximum. Categorical variables will be summarised by frequency
counts and percentages for each category.
!
Unless otherwise stated, percentages will be calculated out of the population total
and for each treatment group.
!
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
additional decimal places compared to the original data. Minimum and maximum
will be displayed with the same accuracy as the original data.
!
For categorical data, percentages will be rounded to 1 decimal place.
!
SAS® version 9.2 or above will be used for all analyses.
!
All analyses related to Part B described in this document are optional, unless 
this study really recruits patients for Part B.
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 treatment start date.


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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).
When the date of birth is incomplete due to local regulatory constraints, the age as collected in 
the eCRF will be used for analysis purpose.
Handling of missing/incomplete dates
The original incomplete or missing dates will be presented in the listings.
!
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.
The following other general principles will also apply:
!
All data collected will be listed.
!
Efficacy data will be summarized and analyzed based on the FAS. PK data will be 
summarized and analyzed based on the PK Analysis Set. Safety and treatment 
exposure data will be summarized based upon the Safety Analysis Set. Study 
population and demography data will be summarized based upon the FAS.
!
All outputs will be summarized by treatment arm for all enrolled patients (ITT). 
!
If any arm goes to Part B: Expansion, safety data collected during Part A and Part 
B: Expansion will be presented once, at the time of Part B: Expansion analysis. The 
decision for Part B is to be made on efficacy data, these will be presented at the 
time of Part A analysis (see Section 5.2) and thereafter pooled with Part B: 
Expansion data if any arm goes to Part B: Expansion. If any arm goes to Part B: 
Expansion, data collected during Part B: Expansion will not be presented 
separately.
!
Safety data will be summarized from the initial treatment period (i.e. the initial 12 
months of treatment). Safety data from the re-treatment period may also be 
summarized via a small set of headline summaries should there be sufficient 
number of patients re-treated to warrant this. Any safety summaries representing the 
re-treatment period will be based upon a subset of the Safety Analysis Set 
representing patients who have had at least one dose of study treatment in the re-
treatment period.


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Table 6 details which endpoints are to be analyzed, together with preplanned sensitivity 
analyses indicating which analysis is regarded as primary for that endpoint.  Formal statistical 
analysis will be done only for ORR for Part B: Expansion.
Unless otherwise stated, data and endpoints derived from RECIST tumor assessments will 
refer to Investigator assessed data.
Table 6
Preplanned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
Objective response rate
Summarized by treatment arm with lower 95% 
Clopper-Pearson confidence limits (Part A)
Part B: Expansion - Formal analysis using exact 
test for a binomial proportion, with 2-sided 95% 
Clopper-Pearson CI
Duration of response
Kaplan Meier plots and summaries
DCR
Summarized by treatment arm n (%).
Best objective response
Summary statistics, N (%)
Progression free survival, PFS3, PFS6
Kaplan Meier plots, estimates and summaries as 
appropriate
Overall survival, OS6, OS12
Kaplan Meier plots and summaries.
4.2
Analysis methods
4.2.1
Multiplicity (Not applicable)
4.2.2
Primary endpoint – Objective Response Rate
The ORR will be based on the programmatically derived RECIST using the Investigator 
tumor data.  An additional sensitivity analysis will be performed on programmatically derived 
ORR using Investigator data (RECIST modified for confirmation of progression) to determine 
if there is any difference when using progression confirmation rules.
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR) with lower 95% Clopper-Pearson confidence limits for Part A and with a 
formal analysis using exact test for a binomial proportion, with 2-sided 95% Clopper-Pearson 
confidence interval for part B: Expansion. For Part A primary analysis, the number and 
percentage of patients with a tumor response (and associated CI) will also be presented where 
unconfirmed responses are no longer excluded. Overall visit response data will be listed.  
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.


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4.2.3
Duration of response
Descriptive data will be provided for the DoR in responding patients.
If data allows, Kaplan-Meier plots of the proportion of patients in responders will be presented 
by treatment arm.
In addition, this will be produced for DoR when obtained while objective progression requires 
confirmation.
4.2.4
Disease control rate
Summary statistics (i.e., number of patients [%] with 95% CIs) on DCR at 3, 6 and 12 months 
will be produced by treatment arm. It will be provided for both overall and by Korea status 
(i.e. Korea and Non Korea).
4.2.5
Progression-free survival
Kaplan-Meier plots of PFS will be presented for each arm. 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 PFS for each cohort (if 
calculable). It will be provided for both overall and by Korea status (i.e. Korea and Non 
Korea).
Exploratory analysis
PFS based on RECIST 1.1 modified for confirmation of progression will be performed for 
exploratory purposes using the algorithm described in CSP Appendix F, but following a 
modification whereby any objective disease progression must be confirmed by the next 
scheduled scan (see Section 3.1). 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.
The same analysis as above will be performed for this exploratory analysis.
Proportion of patients alive and progression free after 3 months
The PFS rate at 3 months (PFS3) will be calculated using Kaplan-Meier estimates, as the 
cumulative probability of progression-free survival.  Estimate of PFS3 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.
Proportion of patients alive and progression free after 6 months
The same analysis as for PFS3 will be conducted for the PFS rate at 6 months (PFS6).


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4.2.6
Overall survival
Kaplan-Meier plots will be presented by treatment arm. Summaries of the number and 
percentage of patients who have died, those still in survival follow-up, those lost to follow-up, 
and those who have withdrawn consent will be provided. The summaries will be produced for 
Korean and non-Korean.
In addition, duration of follow-up will be summarized using medians:
!
In all patients: Time from first dosing to the date of death (i.e. overall survival) or to
the date of censoring for censored patients regardless of treatment arm.
Proportion of patients alive at 6 months from randomization/enrolment
The OS6 will be defined as the Kaplan-Meier estimate of OS at 6 months.
Proportion of patients alive at 12 months from randomization/enrolment
The OS12 will be defined as the Kaplan-Meier estimate of OS at 12 months.
4.2.7
Change in tumor size
The absolute values, change in TL tumor size from baseline and percentage change in TL 
tumor size from baseline will be summarized using descriptive statistics and presented at each 
timepoint for each treatment arm. 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 and 
presented for each treatment arm.
Tumor size will also be presented graphically using waterfall plots for each treatment arm, to 
present each subject’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 time points may be produced if it is felt 
that these are warranted to provide greater clarity.
4.2.8
Healthcare resource use (Not applicable)
4.2.9
Safety data
Safety and tolerability data will be presented by treatment arm using the safety population. 
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 treatment arm 
and CTCAE grade.  Additionally, data presentations of the rate of AEs per person-years at risk 


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may be produced.  Any safety summaries examining retreatment with MEDI4736 
monotherapy and MEDI4736 + tremelimumab combination therapy will be produced 
separately.
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, vital signs, and ECGs.  Exposure to MEDI4736 monotherapy, MEDI4736 + 
tremelimumab combination therapy will be summarized.  Time on study and MEDI4736 
monotherapy, MEDI4736 + tremelimumab combination therapy dose delays/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.
Adverse events
All AEs, both in terms of current MedDRA preferred term and CTCAE grade, will be 
summarized descriptively by count (n) and percentage (%) for each treatment group. The 
current MedDRA dictionary will be used for coding. The majority of the AE summaries, 
unless stated otherwise, will be based on TEAEs.  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’.  However, any AE occurring before the administration of the 
first dose on Study Day 1 that increases in severity after the first dose will be regarded as 
treatment emergent and thus will be included in the majority of summary tables.
AEs observed up until 90 days following discontinuation of the study treatment or until the 
initiation of the first subsequent anti-cancer therapy following discontinuation of treatment 
(whichever occurs first) will be used for reporting of all of the AE summary tables. This will 
more accurately depict AEs attributable to study treatment only as a number of AEs up to 90 
days following discontinuation of treatment are likely to be attributable to subsequent therapy.
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 study 
treatment (i.e. without taking subsequent anti-cancer therapy into account).
A selection of AE summaries may also be produced containing AEs (by system organ class 
and preferred term) observed from the initiation of the first subsequent anti-cancer therapy 
following discontinuation of study treatment until 90 days following discontinuation of the 
study treatment (i.e. summarising 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 study treatment
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.


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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. 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 any on episode level summaries which 
may be produced).
Summary information (the number and percent of patients by system organ class and preferred 
term separated by treatment group) will be tabulated for:
!
All AEs
!
All AEs causally related to study medication (as determined by the reporting 
investigator)
!
AEs with CTCAE grade 3 or higher
!
AEs with CTCAE grade 3 or higher, causally related to study medication (as 
determined by the reporting investigator)
!
AEs with outcome of death
!
AEs with outcome of death causally related to study medication (as determined by 
the reporting investigator)
!
AEs by outcome
!
All SAEs
!
All SAEs causally related to study medication (as determined by the reporting 
investigator)
!
SAEs leading to discontinuation of study medication
!
AEs leading to discontinuation of study medication
!
AEs leading to discontinuation of study medication, causally related to study 
medication (as determined by the reporting investigator)
!
AEs leading to hospitalization
!
AEs leading to dose delay of study medication
!
Other significant AEs
!
Other significant AEs causally related to study medication (as determined by the 
reporting investigator)


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!
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 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 may also be presented as appropriate.
Each AE event rate (per 100 patient years) will also be summarized by preferred term within 
each system organ class for the output summarizing all AEs. For each preferred term, the 
event rate is defined as the number of patients with that AE divided by the total drug exposure 
of patients at risk of AE. The denominator is calculated as the total over each patient of days 
from first dose to the earlier of the date of onset of the event or the last day of study 
medication.
Summaries of the number and percentage of patients will be provided by maximum reported 
CTCAE grade, system organ class, preferred term and treatment group.
Fluctuations observed in CTCAE grades during study will be listed for those AEs which are 
CTCAE ≥3.
In addition, all AEs will be listed.
Death
A summary of all deaths will be provided with number and percentage of patients by 
treatment group, categorized as:
1.
Total number of death (including deaths within 90 days after last dose of study 
medication and deaths occur outside of 90 days post dosing window)
2.
Death related to disease under investigation ONLY, as determined by investigator 
(including deaths within 90 days after last dose of study medication and deaths 
occur outside of 90 days post dosing window)
3.
TEAE with outcome of death ONLY and onset date prior to initiation of subsequent 
anti-cancer therapy
4.
AE with outcome of death ONLY and onset date falling after 90 days follow-up 
period or initiation of subsequent anti-cancer therapy (whichever is earlier) (1st 
summary)


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5.
Death related to disease under investigation, as determined by the investigator, and 
with TEAE with outcome of death and onset date prior to initiation of subsequent 
anti-cancer therapy
6.
Death related to disease under investigation, as determined by the investigator, and 
with AE with outcome of death and onset date falling after 90 days follow-up 
period or initiation of subsequent anti-cancer therapy (whichever is earlier)
7.
Death occurred 90 days after last dose or initiation of subsequent anti-cancer 
therapy (whichever is earlier), and unrelated to AE or disease under investigation
8.
Patients with unknown reason for death.
9.
Other deaths
Summaries 1, 2, 8 and 9 above will be produced twice: firstly accounting for subsequent 
therapy and, secondly, without taking subsequent therapy into consideration.
This summary will include AEs with start date up to 90 days after last dose or up to date of 
subsequent therapy, whichever occurs first.
Adverse events of special interest
Preferred terms used to identify adverse events of special interest (as defined in Section 3.3.1) 
will be listed before DBL and documented in the Study Master File. Grouped summary tables 
of certain MedDRA preferred terms will be produced and may also show the individual 
preferred terms which constitute each AESI grouping. 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.
Summaries of the above-mentioned grouped AE categories will include number (%) of 
patients who have:
!
At least one AESI presented by outcome
!
At least one AESI causally related to study medication
!
At least one AESI leading to discontinuation of study medication
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 
data cut-off.
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 


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which AESI triggered immunosuppressive use) and, separately, to the use of 
immunosuppressive agents at high doses.
Laboratory assessments
Data obtained up until the 3 months (+1 week for a late assessment, i.e. 3*30+7=97 days) 
following discontinuation of treatment or until the initiation of the first subsequent therapy 
will be used for reporting. This will more accurately depict laboratory toxicities attributable to 
study treatment only as a number of toxicities up to 97 days following discontinuation of 
study treatment are likely to be attributable to the subsequent therapy.
However, to assess the longer term toxicity profile, summaries of laboratory data will also be 
produced containing data collected up until 97 days following discontinuation of study 
treatment irrespective of whether subsequent therapy was administered during that period.
A small selection of summaries of laboratory data may also be produced containing data from 
initiation of the first subsequent therapy following discontinuation of study treatment until 97
days following discontinuation of study treatment (i.e. summarizing the laboratory data 
collected on patients taking subsequent therapy during the safety collection follow-up window 
post discontinuation of study treatment). These outputs will only be produced if the number of 
laboratory toxicities observed warrant the inclusion of such outputs for interpretational 
purposes. Any data post 97 days last dose for study treatment will not be summarized.
Data summaries will be provided in International System (SI) of units.
Scatter plots (shift plots) of baseline to maximum value/minimum value (as appropriate) on 
treatment (i.e. on-treatment is defined as data collected between the start of treatment and the 
relevant follow-up period following the last dose of study treatment) may be produced for 
certain parameters if warranted after data review (e.g. alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], alkaline phosphatase [ALP], total bilirubin, corrected 
calcium, lactate dehydrogenase [LDH], magnesium, sodium, potassium, glucose, creatinine, 
urea nitrogen, and thyroid stimulating hormone [TSH], free triiodothyronine [fT3] and free 
thyroxine [fT4]).
Scatter plots (shift plots) of baseline to minimum value on treatment (defined as above) may 
be produced for certain parameters if warranted after data review (e.g. hemoglobin, 
lymphocyte (count, absolute), neutrophils (count, absolute), platelet count, albumin, total 
protein, corrected calcium, magnesium, sodium, potassium, glucose and TSH, fT3 and fT4).
Box-plots of absolute values by week, and box-plots of change from baseline by week, may be 
presented for certain parameters if warranted after data review (e.g. hemoglobin, neutrophil 
(count, absolute), lymphocyte (count, absolute), platelet (count), AST, ALT, ALP, total 
bilirubin, albumin, total protein, corrected calcium, LDH, sodium, potassium, creatinine, urea 
nitrogen and TSH, fT3 and fT4).


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For continuous laboratory assessments including the thyroid test parameters TSH, fT3 and 
fT4, absolute value, change from baseline and percentage change from baseline will be 
summarized using descriptive statistics at each scheduled assessment time by actual treatment 
group. 
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, leukocytes, 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 worst value on-treatment will be provided. 
Additional summaries will include a shift table for urinalysis (bilirubin, blood, glucose, 
ketones, protein) comparing baseline value to maximum on-treatment value.
Shift tables showing baseline to maximum and baseline to minimum will be produced for 
TSH, fT3 and fT4.
Liver Enzyme Elevations and Hy's law
The following summaries will include the number (%) of patients who have:
!
Elevated ALT, AST, and Total bilirubin during the study
%
ALT ≥ 3x – ≤5x, > 5x – ≤8x, > 8x – ≤10x, > 10x – ≤20x, and > 20x Upper 
Limit of Normal (ULN) during the study
%
AST ≥3x – ≤5x, > 5x – ≤ 8x, > 8x – ≤10x, > 10x – ≤20x, and > 20x ULN 
during the study
%
Total bilirubin ≥2x – ≤3x, > 3x – ≤5x, > 5x ULN during the study
%
ALT or AST ≥3x – ≤5x, >5x – ≤8x, > 8x – ≤10x, > 10x – ≤20x,  and > 20x 
ULN during the study
%
ALT or AST ≥3x ULN and total bilirubin ≥2x ULN during the study (Potential 
Hy’s law): The onset date of ALT or AST elevation should be prior to or on the 
date of total bilirubin elevation


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!
Narratives will be provided in the CSR for patients who have ALT ≥3x ULN plus 
total bilirubin ≥2x ULN or AST ≥3x ULN plus total bilirubin ≥2x ULN at any 
visit.
For Hy’s Law criteria to be met, the elevation in transaminases must precede or be coincident 
with the elevation in total bilirubin (i.e. on the same day), but there is no specified timeframe 
within which the elevations in transaminases and total bilirubin must occur.
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 by treatment group will also be produced with 
reference lines at 3xULN for ALT, AST, and 2xULN for total bilirubin. In each plot, total 
bilirubin will be in the vertical axis.
ECGs
Overall evaluation of ECG is collected at screening and as clinically indicated while on study 
treatment in terms of normal or abnormal, and the relevance of the abnormality is termed as 
“clinically significant” or “not clinically significant”. A shift table of baseline evaluation to 
worst evaluation will be produced.
Vital signs
Vital signs data obtained up until the 30-day safety follow-up visit will be included in the 
summary tables.
Box plots for absolute values and change from baseline by week, may be presented for certain 
vital signs parameters if warranted after data review.
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, temperature, 
respiratory rate and weight) will be summarized over time in terms of absolute values and 
changes from baseline at each scheduled measurement by treatment group.
Time to subsequent therapy from discontinuation of study treatment
A descriptive summary will be produced for time to subsequent therapy from discontinuation 
of study treatment. This summary is supportive of the Adverse Event and Laboratory data 
outputs.
Physical examination
All individual physical examination data will be listed only.
Other safety data


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Data from positive pregnancy tests will be listed only.
4.2.10
WHO performance status
All WHO/ECOG performance status will be summarized over time.
4.2.11
PK/PDx data
Pharmacokinetic concentration data will be listed for each patient and each dosing day, and a 
summary provided for all evaluable patients in the PK analysis population. 
PK modeling will be performed outside of the CSR.
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 and anti-
tremelimumab antibodies based on the safety population. The immunogenicity titer and 
neutralizing ADA data will be listed for samples confirmed positive for the presence of anti-
MEDI4736 antibodies and/or anti-tremelimumab antibodies.
The effect of immunogenicity on PK, PDx, efficacy and safety will be evaluated if data allow
and such analysis will be performed outside of the CSR. 
4.2.12
PK/PDx relationship
If the data are suitable, the relationship between PK exposure and efficacy/safety parameters 
may be investigated graphically or using an appropriate data modeling approach. This will be 
performed outside of the CSR
4.2.13
Biomarker data
The relationship of PD-L1 expression and if applicable, of exploratory biomarkers to ORR, 
DoR, DCR, PFS, PFS3 and PFS6 will be presented for a subset of patients in the ITT 
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 in Section 4.2.2 to Section 4.2.5.
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.
4.2.14
Demographic and baseline characteristics data
The following will be summarized for all patients in the FAS (unless otherwise specified) by 
treatment group:
!
Patient disposition (including screening failures and reason for screening failure)
!
Important protocol deviations


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!
Inclusion in analysis populations
!
Demographics (derived age, derived age group[<50, ≥50 - < 65, ≥65 - < 75 years 
and ≥75 years], sex, race and ethnicityPatient characteristics at baseline (height, 
weight, weight group[<70kg, 70kg to 90 kg, >90kg], 
!
Patient recruitment by country and center
!
Previous disease-related treatment modalities
!
Number of regimens of previous chemotherapy at baseline
!
Disease characteristics at baseline (World Health Organization performance status, 
primary tumor location, histology type, tumor grade, American Joint Committee on 
Cancer staging, 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 ]). It will be provided for
both overall and by Korea status (i.e. Korea and Non Korea).
!
Extent of disease at baseline
!
Disease related medical history (past and current combined)
!
Relevant surgical history
!
Physical examination at baseline
!
Time from most recent disease progression to start of study treatment
!
Disallowed concomitant medications
!
Allowed concomitant medications
!
!
Nicotine use, categorized (never, current, former) and descriptive statistics by type 
of substance use
!
Stratification factors as per IVRS/IWRS and eCRF data
The AZ drug dictionary will be used for concomitant medication coding.
Patient disposition data will also be summarized at the time of OS analysis.


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4.2.15
Treatment exposure
The following summaries related to study treatment will be produced for the Safety Analysis 
Set by randomized treatment group, for the initial treatment period:
!
Total exposure (weeks) (*) .
!
Actual exposure (weeks) (*) .
!
Total number of cycles received (*).
!
Reasons for dose delays and infusion interruptions of MEDI4736 and 
tremelimumab. Dose interruptions will be based on investigator initiated dosing 
decisions.
!
Number of infusions received (*).
!
RDI (relative dose intensity) of MEDI4736 and tremelimumab.
In the combination therapy arm, all descriptions above will be provided separately for each 
molecule and, for those having (*), in total, where the maximum in either molecule will be 
reported. The total and actual exposures will also be expressed as total treatment years, 
defined as the total across all patients in the analysis set.
Data collected during the re-treatment will only be listed.
Time on study
Time on study is defined as the [study discontinuation date – randomization date +1] and will 
be summarized by treatment arm.
4.2.16
Subsequent therapy
Subsequent therapies received after discontinuation of study treatment will have summaries 
produced by treatment group, together with number of regimens received.
5.
TIMING OF ANALYSES
5.1
Part A: Interim Analysis
An interim analysis when 15 evaluable patients in each arm are observed in Part A will use 
predictive probability to determine whether either arm may stop (based on <10% predictive 
probability of meeting the minimum criteria to initiate Part B). Should it become obvious that 
the continuation criteria have been met prior to completion of enrolment of Part A, then the 
decision to initiate Part B (either Expansion or the RCT) may be made early.


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In each arm, once 15 patients have completed 2 post-baseline tumor assessments (at Week 6 
and 12), predictive probabilities will be calculated to assess the chance of observing at least 5 
out of 30 responses (>15% ORR), and (separately) the chance of observing at least 15/30 
DCR at 12 weeks (≥15 DCR12) in that arm. Only data from the 15 evaluable patients will 
initially support the predictive probabilities.
However in the event of treatment discontinuation, the impact of such patients on these 
predictive probabilities will be considered.
This will make use of a Beta-Binomial posterior predictive distribution, where at the outset a 
non-informative prior is assumed for the ORR or DCR12 (Beta[1,1]), and a Beta-Binomial 
distribution can then be used to calculate the probability of achieving the required ORR or 
DCR from 30 evaluable patients given data observed. 
If predictive probability is below 10% for both endpoints, enrolment into the arm in which this 
happens will be stopped. A different decision outside of these criteria may be made, if the 
totality of the data supports it. Recruitment will continue while predictive probability is 
evaluated. If enrolment into an arm is to be stopped based on <10% predictive probability, no 
new patients will be recruited, but patients who are already on study will continue in 
accordance with study guidelines. If enrolment is fast enough so that, by the time 15 patients 
are evaluable, all 30 patients per arm have already been randomized, then the predictive 
probability calculations will not be carried out.
5.2
Primary analyses
For both Part A and Part B: Expansion, a primary analysis will be performed when all subjects 
have completed the Week 18 visit or discontinued treatment. For Part A analysis, all data 
present at that time will be used for decision making on format for Part B.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
6.1
Disease control rate
As per CSP Section 8.4.1.3:
DCR at 3 or 12 months is defined as the percentage of patients who have a best objective 
response (BoR) of CR or PR in the first 3 or 12 months, respectively, or who have 
demonstrated SD for a minimum interval of 12 or 52 weeks, respectively (-7 days, ie, 105 or 
357 days, respectively), following the start of study treatment.
For DRC at 3 months, the “105 days” mentioned for minimum duration for SD will be 
replaced with “77 days” (see Section 3.2.2.8) since a 13-weeks minimum duration for SD 
(minus 1 to allow for an early assessment) corresponds to (13-1)*7=84 days.
In addition, DCR at 6 months will be provided to get an intermediate estimate.


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6.2
Protocol amendment
As per CSP Section 1.4:
The format of Part B will be determined based on the responses seen in the first 30 patients in 
each arm in Part A.  A protocol amendment will be made if criteria are met to proceed to 
Part B.
In order to clarify the sentence above, a protocol amendment is needed only if the data suggest 
that Part B: RCT is to be initiated.
6.3
Part B: Expansion design
As per CSP Synopsis,
This study will consist of Part A, Lead-in, as well as a possible Part B, non-randomized 
expansion (Part B: Expansion) or a possible Part B, randomized controlled study 
(Part B: RCT).
In order to clarify the sentence above, Part B: Expansion will be randomized if both arms 
initiated in Part A go to Part B: Expansion, but if only one goes, Part B: Expansion will not be 
randomized.
6.4
ePRO data
ePRO data will be collected only if Part B: RCT is initiated.
7.
REFERENCES
Aaronson et al 1993
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-76.
Fitzsimmons and Johnson 1998
Fitzsimmons D, Johnson CD. Quality of life after treatment of pancreatic cancer. Langenbecks 
Arch Surg 1998;383(2):145-51.
Fitzsimmons et al 2005
Fitzsimmons D, Kahl S, Butturini G, van Wyk M, Bornman P, Bassi C, et al. Symptoms and 
quality of life in chronic pancreatitis assessed by structured interview and the EORTC 
QLQ-C30 and QLQ-PAN26. Am J Gastroenterol 2005;100(4):918-26.
Rahma et al 2013
Rahma OE, Duffy A, Liewehr DJ, Steinberg SM, Greten TF. Second-line treatment in
advanced pancreatic cancer: a comprehensive analysis of published clinical trials. Ann Oncol
2013;24:1972-9


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8.
APPENDIX (NOT APPLICABLE)