Clinical trial NCT02352948
Conditions: Non - Small Cell Lung Cancer NSCLC
Sponsor: AstraZeneca
Start date: 2015-01-13; Completion date: 2023-08-30
Enrollment: 597 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a Phase III, randomised, open label, multi-centre study assessing the efficacy and safety of MEDI4736 (durvalumab) versus Standard of Care in NSCLC patients with PD-L1 positive tumours and the combination of MEDI4736 (durvalumab) plus tremelimumab (MEDI4736+treme) versus Standard of Care in NSCLC patients with PD-L1-negative tumours in the treatment of male and female patients with locally advanced or metastatic NSCLC (Stage IIIB-IV), who have received at least 2 prior systemic treatment regimens including 1 platinum-based chemotherapy regimen for NSCLC. Patients with known EGFR (Epidermal growth factor receptor) tyrosine kinase (TK) activating mutations and anaplastic lymphoma kinase (ALK) rearrangements are not eligible for the study (prospective testing is not planned within this study). The Standard of Care options are: an EGFR tyrosine kinase inhibitor (erlotinib \[TARCEVA®\]), gemcitabine or vinorelbine (NAVELBINE®)

Detailed description:
The study has an umbrella design with 2 sub-studies: sub-study A (randomizing patients with PD-L1 positive tumours 1:1 into MEDI4736 (durvalumab) vs. Standard of Care) and sub-study B (randomizing patients with PD-L1 negative tumours 2:3:1:2 into MEDI4736 (durvalumab) vs. MEDI4736 (durvalumab) plus tremelimumab vs. tremelimumab vs. Standard of Care. The two substudies may have different durations of recruitment periods due to differences in patient population (PD-L1 expression). They may not run concurrently with start and completion of recruitment potentially occurring at different time points.

Arms: arm 1: MEDI4736 (durvalumab) by intravenous infusion. Sub-study A for patients with PD-L1 positive tumors. arm 2: Investigator choice from Vinorelbine, Gemcitabine and Erlotinib. Sub-study A for patients with PD-L1 positive tumors. arm 3: MEDI4736 (durvalumab) by intravenous infusion and tremelimumab by intravenous infusion. Sub-study B for patients with PD-L1 negative tumors. arm 4: Investigator choice from Vinorelbine, Gemcitabine and Erlotinib. Sub-study B for patients with PD-L1 negative tumors. arm 5: MEDI4736 (durvalumab) by intravenous infusion. Sub-study B for patients with PD-L1 negative tumors. arm 6: tremelimumab by intravenous infusion. Sub-study B for patients with PD-L1 negative tumors.
Interventions: intervention 1: MEDI4736 (durvalumab) intervention 2: Vinorelbine intervention 3: Gemcitabine intervention 4: Erlotinib intervention 5: MEDI4736 (durvalumab) in combination with tremelimumab (anti-CTLA4) intervention 6: tremelimumab (anti-CTLA4)
Intervention descriptions: intervention 1: MEDI4736 (durvalumab) treatment by intravenous infusion intervention 2: Vinorelbine by intravenous infusion. Administered at a dose of 30 mg/m2 iv on Days 1, 8, 15 and 22 of a 28-day cycle. intervention 3: Gemcitabine by intravenous infusion. Administered at a dose of 1000 mg/m2 iv over 30 minutes on Days 1, 8, and 15 of a 28-day cycle. intervention 4: Erlotinib administered at a dose of 150 mg once daily as a tablet for oral administration intervention 5: MEDI4736 (durvalumab) in combination with tremelimumab (anti-CTLA4) treatment by intravenous infusion intervention 6: tremelimumab (anti-CTLA4) treatment by intravenous infusion

Protocol documents:
Prot_001.pdf: 
Revised Clinical Study Protocol 
Drug Substance 
Durvalumab (MEDI4736) 
Study Code 
D4191C00004 
Edition Number 
07.0 
Date 
08 January 2018 
A Phase III, Open-label, Randomised, Multi-centre, International Study of 
MEDI4736, Given as Monotherapy or in Combination with Tremelimumab, 
Determined by PD-L1 Expression, Versus Standard of Care in Patients with 
Locally Advanced or Metastatic Non-Small Cell Lung Cancer 
(Stage IIIB-IV) who Have Received at Least Two Prior Systemic Treatment 
Regimens Including One Platinum-based Chemotherapy Regimen and Do 
Not Have Known EGFR TK Activating Mutations or ALK Rearrangements 
(ARCTIC) 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden. 
EudraCT number: 2014-000338-46 
AstraZeneca Research and 
Development site representative 
; QuintilesIMS Ltd 
500 Brook Drive, Green Park, Reading 
United Kingdom 
Date 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
The following Amendment(s) and Administrative Changes are included in this revised protocol: 
Amendment No. 
Date of Amendment 
Local Amendment No: Date of Local Amendment 
01 
18 June 2014 
02 
28 July 2014 
03 
29 August 2014 
04 
27 March 2015 
05.1 
30 December 2015 
06 
31 August 2016 
07 
19 September 2017 
08 
08 January 2018 
PPD
PPD
PPD


Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
2 
Administrative 
Change No. 
Date of Administrative 
Change 
Local Administrative 
Change No. 
 Date of Local 
Administrative Change 
01 
05 February 2015 
02 
17 June 2015 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
3 
PROTOCOL SYNOPSIS 
 
A Phase III, Open-label, Randomised, Multi-centre, International Study of 
MEDI4736, Given as Monotherapy or in Combination with Tremelimumab, 
Determined by PD-L1 Expression, Versus Standard of Care in Patients with 
Locally Advanced or Metastatic Non-Small Cell Lung Cancer 
(Stage IIIB-IV) who Have Received at Least Two Prior Systemic Treatment 
Regimens Including One Platinum-based Chemotherapy Regimen and Do 
Not Have Known EGFR TK Activating Mutations or ALK Rearrangements 
(ARCTIC) 
 
 
International Coordinating Investigator 
Dr. David Planchard, Gustave Roussy, Department of Medical Oncology, Thoracic Group, 
114 Rue Édouard Vaillant, 94805 Villejuif, France.   
Study centre(s) and number of patients planned 
Approximately 1300 patients with locally advanced or metastatic non-small cell lung cancer 
(NSCLC; Stage IIIB-IV) will be recruited, and approximately 610 patients randomised, at 
approximately 250 sites in North America, Latin America, Asia, Europe, Australia and New 
Zealand.   
Study period 
 
Phase of development 
Estimated date of first patient enrolled 
Q1 2015 
III 
Estimated date of last patient completed 
Q4 2018 
III 
 
Objectives 
This study will consist of 2 sub-studies: Sub-study A will address the research hypotheses for 
MEDI4736 monotherapy in patients with programmed death ligand 1 (PD-L1)-positive 
tumours (where positive is defined as ≥25% of tumour cells with membrane staining 
[proprietary PD-L1 immunohistochemistry assay; Ventana Medical Systems, Inc]), and 
Sub-study B will address the research hypotheses for MEDI4736 plus tremelimumab 
(MEDI4736+tremelimumab) in patients with PD-L1-negative tumours (ie, those with <25% 
of tumour cells with membrane staining). 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
4 
The research hypotheses on the respective sub-studies will be assessed via the primary 
objectives in Sub-study A (NSCLC patients with PD-L1-positive tumours) and Sub-study B 
(NSCLC patients with PD-L1-negative tumours), which is to assess the efficacy of MEDI4736 
and MEDI4736+tremelimumab treatment compared with Standard of Care in terms of overall 
survival (OS) and progression free survival (PFS). 
Secondary efficacy objectives in each of the 2 sub-studies include evaluation of the proportion 
of patients alive at 12 months from randomisation (OS12), objective response rate (ORR), 
duration of response (DoR), the proportion of patients alive and progression free at 6 months 
from randomisation (APF6) and the proportion of patients alive and progression free at 
12 months from randomisation (APF12), and the time from randomisation to second 
progression (PFS2).  Other secondary objectives in each of the sub-studies include an 
assessment of safety and tolerability, pharmacokinetic (PK) exposure and immunogenicity, 
and patient reported outcomes.  Exploratory objectives are also included.   
Primary Objective: 
Outcome Measure: 
Sub-study A (PD-L1-positive population) 
To assess the efficacy of MEDI4736 monotherapy 
compared with Standard of Care in terms of OS and 
PFS 
Sub-study B (PD-L1-negative population) 
To assess the efficacy of MEDI4736+tremelimumab 
treatment compared with Standard of Care in terms of 
OS and PFS 
OSa 
PFS using investigator assessments according to 
RECIST 1.1a,b 
a 
In each of the Sub-studies A and B the assessment of PFS and OS will be considered co-primary objectives.   
b 
The co-primary analysis of PFS will be based on programmatically-derived PFS based upon investigator assessment.  
OS  Overall survival; PD-L1  Programmed death ligand 1; PFS  Progression free survival; RECIST  Response Evaluation 
Criteria In Solid Tumours. 
 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
5 
The following are the secondary objectives in Sub-study A (MEDI4736 monotherapy versus 
Standard of Care) and Sub-study B (MEDI4736+tremelimumab versus Standard of Care):  
Secondary Objective: 
Outcome Measure: 
To further assess the efficacy in terms of: OS12, 
ORR, DoR, APF6, APF12 and PFS2 
OS12 
ORR using investigator assessments according to 
RECIST 1.1a 
DoR using investigator assessments according to 
RECIST 1.1a 
APF6 and APF12 using investigator assessments 
according to RECIST 1.1a 
PFS2 as defined by local standard clinical practice 
 
To assess the safety and tolerability profile 
Adverse events, physical examinations, vital signs 
including blood pressure, pulse, electrocardiograms, 
and laboratory findings including clinical chemistry, 
haematology and urinalysis 
To assess the PK of MEDI4736 and tremelimumab 
Concentration of PK in blood and non-compartmental 
PK parameters (such as peak concentration and trough, 
as data allow) (sparse sampling) 
To investigate the immunogenicity of MEDI4736 
and tremelimumab  
ADA (confirmatory results: positive or negative; titres 
[ADA neutralising antibodies will also be assessed])  
To assess symptoms and health-related QoL using 
EORTC QLQ-C30 v3 and LC13 
EORTC QLQ-C30: Time to symptom deterioration 
(fatigue, pain, nausea/vomiting, dyspnoea, loss of 
appetite, insomnia, constipation, and diarrhoea).  Time 
to QoL/function deterioration (physical function, role 
function, emotional function, cognitive function, social 
function and global health status/QoL) 
LC13: Time to symptom deterioration (dyspnoea, 
cough, haemoptysis, chest pain, arm/shoulder pain, 
other pain) 
Changes in World Health Organisation Performance 
Status will also be assessed 
Sub-study B (PD-L1-negative population) 
To evaluate the efficacy of 
MEDI4736+tremelimumab treatment compared 
with a) MEDI4736 monotherapy and b) 
tremelimumab monotherapy  
PFSa, ORRa and DoRa using investigator assessments 
according to RECIST 1.1, and OS 
a 
Analysis of ORR, DoR, APF6 and APF12 will be based upon investigator assessment.  
ADA  Anti-drug antibody; APF6  Proportion of patients alive and progression free at 6 months from randomisation; 
APF12  Proportion of patients alive and progression free at 12 months from randomisation; DoR  Duration of response; 
EORTC QLQ-C30 European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire; 
LC13  Lung Cancer Module; ORR Objective response rate; OS12  Proportion of patients alive at 12 months from 
randomisation; PFS  Progression free survival; PFS2  Time from randomisation to second progression; PK  
Pharmacokinetic(s); QoL  Quality of Life; RECIST  Response Evaluation Criteria In Solid Tumours. 
 
In Sub-study B, PFS in MEDI4736+tremelimumab arm will be compared to each of the 
MEDI4736 and tremelimumab monotherapy arms as part of the contribution of components 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
6 
analysis.  This analysis is planned to be performed when approximately 158 PFS events are 
observed in the MEDI4736+tremelimumab and tremelimumab monotherapy arms.  However, 
for practical considerations, if this time is close to the time of the final PFS analysis, the 
contribution of components analysis will be conducted at the time of the PFS final analyses.  
This is considered a secondary objective of the study. 
The following exploratory objectives will be addressed in Sub-studies A and B: 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
7 
 
 
 
 
 
 
 
 
 
 
 
AE  Adverse event; EQ-5D-5L  EuroQoL 5-dimension, 5-level health state utility index; IFN  Interferon; IL  Interleukin; 
ORR Objective response rate; OS  Overall survival; PD-L1  Programmed death ligand 1; PDx  Pharmacodynamic(s); PFS  
Progression free survival; PK  Pharmacokinetic(s).   
 
Study design 
This study is a Phase III, randomised, open label, multi-centre study assessing the efficacy and 
safety of MEDI4736 versus Standard of Care in NSCLC patients with PD-L1-positive 
tumours, and the combination of MEDI4736+tremelimumab versus Standard of Care in 
NSCLC patients with PD-L1-negative tumours.  The study will enrol male and female patients 
with locally advanced or metastatic NSCLC (Stage IIIB-IV), who have received at least 
2 prior systemic treatment regimens including 1 platinum-based chemotherapy regimen for 
NSCLC.  Patients with known epidermal growth factor receptor (EGFR) tyrosine kinase (TK) 
activating mutations and anaplastic lymphoma kinase (ALK) rearrangements are not eligible 
for the study (prospective testing is not planned within this study).  Patients will be 
randomised in a 1:1 ratio in Sub-study A and a 3:2:2:1 ratio 
(MEDI4736+tremelimumab:MEDI4736:Standard of Care:tremelimumab) in Sub-study B. 
The original study design intended to recruit 250 patients to Sub-study A.  However, due to 
low patient accrual, the recruitment to Sub-study A was closed in Q1 2016 at which time 
126 patients had been randomised.  As a result, the analysis plan for Sub-study A was updated 
and is presented in Protocol Amendment 6.0, dated 31 August 2016.  
Sub-study A (patients with PD-L1-positive tumours): 
• 
MEDI4736 (10 mg/kg once every 2 weeks [Q2W] intravenously [iv] for up to 
12 months) (approximately 60 patients) 
• 
Standard of Care (restricted to erlotinib, gemcitabine or vinorelbine) (approximately 
60 patients).   
− 
Erlotinib: 150 mg once daily, orally 
− 
Gemcitabine: 1000 mg/m2 iv on Days 1, 8, and 15 of a 28-day cycle 
− 
Vinorelbine: 30 mg/m2 iv on Days 1, 8, 15 and 22 of a 28-day cycle.   
CCI


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
8 
Sub-study B (patients with PD-L1-negative tumours): 
• 
MEDI4736+tremelimumab (MEDI4736 20 mg/kg plus tremelimumab 1 mg/kg 
once every 4 weeks [Q4W] iv for up to 12 weeks [4 doses]) then MEDI4736 alone 
(10 mg/kg Q2W iv, starting at Week 16, for 34 weeks [18 doses]) (180 patients) 
• 
Standard of Care (see under Sub-study A) (120 patients) 
• 
MEDI4736 (10 mg/kg Q2W iv for up to 12 months) (120 patients) 
• 
Tremelimumab (10 mg/kg Q4W iv for 24 weeks then Q12W for 24 weeks) 
(60 patients). 
The sub-studies may not run concurrently with the start and completion of recruitment 
potentially occurring at different time points.  Assignment to the applicable sub-study will be 
preceded by the Pre-screening Period during which assessment of the patient’s PD-L1 status, 
based on a tumour sample, will take place.  After confirmation of PD-L1 status, patients will 
enter the main Screening Period within their assigned sub-study if it remains open for 
recruitment.  The study design is shown in diagram form in Figure 1. 
Figure 1 
Study design schema 
 
 
Details for all study procedures at Pre-screening, at Screening, during the Treatment Period and Follow-up are 
described within the applicable sections of the study protocol. 
Determination
of PD-L1 
status
PD-L1
positive
PD-L1
negative
Sub-study B
Day -42 to -1
Day 1
Randomisation
Pre-screening
Treatment  Period
Follow-up
Screening and 
Assignment to 
Sub-study
All patients will 
enter follow up.
For the 
immunotherapy 
arms re-
treatment  is 
allowed
for those who 
have disease 
control  after 
12 months of 
treatment but
progress during 
follow-up. For 
combination arm, 
re-treatment 
allowed after 
16 weeks but 
progress during 
MEDI4736 
monotherapy 
period
MEDI4736 monotherapy
(Up to 12 months)
Standard of Care
(For as long as getting clinical benefit)
MEDI4736 monotherapy 
(Up to 12 months)
Tremelimumab monotherapy
(Up to 12 months)
Day -28 to -1
PD-L1 = programmed death ligand 1
MEDI4736+tremelimumab
(Up to 12 months   [combination  for 
12 weeks; MEDI4736 monotherapy for 
34 weeks])
Standard of Care
(For as long as getting clinical benefit)
Sub-study A
1:1 ratio
3:2:2:1 ratio


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
9 
PD-L1 expression will be determined for all patients prior to randomisation.  Patients will be 
assigned to Sub-study A and Sub-study B, respectively based on PD-L1 tumour expression 
status (PD-L1 positive versus PD-L1 negative [based on an archival tumour sample or a recent 
tumour biopsy]).  Patients will be stratified at randomisation based on the Standard of Care 
treatment that they would be administered if randomised to the Standard of Care arm 
(2 categories: gemcitabine/vinorelbine versus erlotinib) and histology (2 categories: squamous 
versus all other).    
The primary objective of this study is to assess the efficacy of MEDI4736 monotherapy 
(patients with PD-L1-positive tumours) and MEDI4736+tremelimumab (patients with 
PD-L1-negative tumours) compared with Standard of Care in terms of OS and PFS (per 
RECIST 1.1 as assessed by the investigator). 
For Sub-study B, an interim analysis for OS will be performed.  The purpose of the OS 
interim analysis is to demonstrate superiority to support the primary objective in terms of OS. 
For Sub-study B, a contribution of components analysis will be performed when 
approximately 158 PFS events are observed in the MEDI4736+tremelimumab and 
tremelimumab monotherapy arms.  However, for practical considerations, if this time is close 
to the time of the final PFS analysis, the contribution of components analysis will be 
conducted at the time of the final PFS analysis.  The purpose of this analysis is to compare the 
monotherapy and combination dosing regimens to determine if the combination therapy (ie, 
MEDI4736+tremelimumab) is more efficacious than each of the monotherapy arms.  As these 
treatment comparisons are secondary and serve a different purpose to that of the primary 
comparisons, they are not included in the multiple testing procedure for the primary 
comparisons, and an alpha of 0.05 will be used for either PFS or OS without multiplicity 
adjustment. 
If the contribution of components analysis is performed prior to the final PFS analysis and the 
MEDI4736+tremelimumab arm is superior to either of the monotherapy arms, then that 
monotherapy arm may be dropped from the study and all patients on that treatment will be 
discontinued.  However, any patients on that treatment will have the opportunity to remain on 
treatment if they are gaining clinical benefit and if, after discussion with their treating 
physician, it is felt that this is the best treatment option for them. 
Sub-study A: Treatment with MEDI4736 10 mg/kg will commence on Day 1 following 
randomisation after confirmation of eligibility and will continue on a Q2W schedule for up to 
12 months.  Treatment should be discontinued prior to 12 months if there is confirmed 
progression of disease (PD) (unless the investigator considers the patient continues to receive 
benefit from treatment), initiation of alternative cancer therapy, unacceptable toxicity, 
withdrawal of consent, or other reasons to discontinue treatment occur.  Patients who have 
discontinued treatment due to toxicity, symptomatic deterioration or who have commenced 
subsequent anti-cancer therapy will be followed up until confirmed disease progression or 
death (whichever occurs first).  Study drug should be discontinued if there is confirmed PD 
while on treatment following a previous response (partial response [PR] or complete response 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
10 
[CR]) to study drug while on treatment (ie, the response and progression events both occurred 
while receiving study drug during the same treatment period). 
Sub-study B: Treatment with MEDI4736 or tremelimumab monotherapy, or the combination 
of MEDI4736 plus tremelimumab will commence on Day 1 following randomisation after 
confirmation of eligibility.  MEDI4736 will continue on a 10 mg/kg Q2W schedule when 
given as monotherapy for up to 12 months and tremelimumab when given as a monotherapy 
will continue on a 10 mg/kg Q4W schedule for 24 weeks then Q12W for a further 24 weeks.  
MEDI4736+tremelimumab in combination will be administered from Day 1 on a Q4W 
schedule up to 12 weeks (4 doses of MEDI4736 20 mg/kg and tremelimumab 1 mg/kg) after 
which MEDI4736 10 mg/kg alone will be administered on a Q2W schedule for 34 weeks 
starting at Week 16 (18 doses).   
In the monotherapy arms, treatment should be discontinued prior to 12 months (MEDI4736 
monotherapy) or 48 weeks (tremelimumab monotherapy) if there is confirmed PD (unless the 
investigator considers the patient continues to receive benefit from treatment), initiation of 
alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to 
discontinue treatment occur.  Patients who have discontinued treatment due to toxicity, 
symptomatic deterioration or who have commenced subsequent anti-cancer therapy will be 
followed up until confirmed disease progression or death (whichever occurs first).   
Study drug should be discontinued if there is confirmed PD while on treatment following a 
previous response (PR or CR) to study drug while on treatment (ie, the response and 
progression events both occurred while receiving study drug during the same treatment 
period). 
In the MEDI4736+tremelimumab combination arm, if a patient experiences PD, retreatment 
with the combination regimen (MEDI4736+tremelimumab) is allowed.  Retreatment in the 
combination arm can only occur if PD, with or without confirmation, occurs during the 
MEDI4736 monotherapy portion or after completion of 12 months of therapy.  During the 
retreatment period, the patient would resume MEDI4736 dosing at 20 mg/kg Q4W as during 
the initial induction period, along with 1 mg/kg of tremelimumab Q4W for 4 doses.  
Monotherapy with MEDI4736 would then resume at 10 mg/kg Q2W 4 weeks after the last 
combination dose is administered.  Retreatment will continue as long as the investigator 
judges the patient is deriving clinical benefit. 
Both Sub-study A and B: Treatment in the Standard of Care arm will commence on Day 1 
following randomisation after confirmation of eligibility and will continue on a 4-weekly 
schedule until PD (unless the investigator considers the patient continues to receive benefit 
from treatment), initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of 
consent or other reasons to discontinue treatment occur.   
Tumour assessments will be performed using computed tomography/magnetic resonance 
imaging.  The baseline assessment should be performed within the 28 days prior to 
randomisation.  Efficacy for all patients will be assessed by objective tumour assessments 
every 8 weeks for the first 48 weeks (relative to the date of randomisation) then every 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
11 
12 weeks thereafter until confirmed objective disease progression as defined by RECIST 1.1 
(irrespective of the reason for stopping treatment and/or subsequent therapy).  An exception 
would be those patients with confirmed PD that continue to receive MEDI4736 monotherapy, 
tremelimumab monotherapy or MEDI4736+tremelimumab at the discretion of the investigator 
(after consultation with the sponsor); these patients can receive treatment for a maximum of 
12 months during the initial treatment period but for as long as the investigator judges they are 
gaining clinical benefit during the retreatment phase, and will have scans every 8 weeks until 
study treatment is stopped, or, if they continue to receive re-treatment after the final DCO, 
patients should receive scans/RECIST and other assessments per local standard of care. 
A confirmatory scan is required following the initial demonstration of PD preferably at the 
next scheduled visit and no earlier than 4 weeks after the initial assessment of PD, unless the 
patient will be entering retreatment, whereby a confirmatory PD scan is not required.  In the 
absence of clinically significant deterioration the investigational site is advised to continue the 
patient on study treatment until progression has been confirmed.  In the Standard of Care arm, 
it is at the investigator’s discretion if a patient with uncertain PD continues treatment until PD 
is confirmed; however, a confirmatory scan is required for all patients in the Standard of Care 
arm even if a subsequent treatment is started.  If an unscheduled assessment is performed, and 
the patient has not progressed, every attempt should be made to perform the subsequent 
assessments at their scheduled visits.   
Following completion or discontinuation of treatment, patients will enter a follow-up period.  
Once a patient has had objective progression recorded and has discontinued study drug, the 
patient will be followed up for survival status every 2 months until death, withdrawal of 
consent or the end of the study.  Patients will also be assessed every 12 weeks for a second 
progression defined according to local standard clinical practice and may involve any of: 
objective radiological, symptomatic progression or death.  
Every effort should be made to obtain accurate follow-up information on patients whose PFS 
and OS data were not accurately recorded.  For example, in the case of PFS, the local 
investigator could provide their clinical assessment of progression if care is transferred 
elsewhere, and for OS an effort should be made to continue to follow and use death registries 
where necessary. 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be convened and will meet 
approximately 6 months after the study has started or 20 patients have been randomised to the 
combination arm on Sub-study B (whichever comes first) to review safety assessments and 
make recommendations to continue, amend, or stop the study based on safety findings.  The 
committee will meet approximately every 6 months thereafter.  The IDMC will also review:  
• 
The interim analysis for OS on Sub-study B 
• 
The contribution of components analysis for the immunotherapy arms if this 
analysis occurs before the primary PFS analysis. 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
12 
All patients who receive a dose of study treatment will be evaluated for safety and tolerability.  
Enrolment will continue unless there is an unexpected safety concern.  The study may be 
adjusted or suspended depending on the IDMC review outcome. 
Full details of the IDMC procedures and processes can be found in the IDMC Charter. 
Target patient population 
Male or female patients aged 18 years or older with histologically-documented or 
cytologically-documented Stage IIIB/Stage IV NSCLC (according to Version 7 of the 
International Association for the Study of Lung Cancer Staging Manual in Thoracic 
Oncology), or with recurrent or progressive disease following multimodal therapy (radiation 
therapy, surgical resection, or definitive chemoradiation therapy for locally advanced disease).  
Patients must have received at least 2 prior systemic treatment regimens to be eligible 
including a platinum-based chemotherapy regimen.  Patients with known EGFR TK activating 
mutations and ALK rearrangements are not eligible for the study.  Patients must have 
WHO Performance Status of 0 or 1. 
PD-L1 expression will be determined for all patients prior to randomisation. Patients with 
positive PD-L1 tumour expression status are eligible for Sub-study A, while patients with 
negative PD-L1 tumour expression status are eligible for Sub-study B. 
Investigational product, dosage and mode of administration 
MEDI4736 monotherapy arm (Sub-study A or Sub-study B) will receive MEDI4736 
10 mg/kg via a 60-minute iv infusion Q2W (±3 days) for up to 12 months.   
MEDI4736+tremelimumab arm (Sub-study B) will receive MEDI4736 20 mg/kg via a 
60-minute iv infusion plus tremelimumab 1 mg/kg via a 60-minute iv infusion Q4W (±3 days) 
for 12 weeks then MEDI4736 10 mg/kg alone via a 60-minute iv infusion Q2W for a further 
34 weeks.   
Tremelimumab monotherapy arm (Sub-study B) will receive tremelimumab 10 mg/kg via a 
60-minute iv infusion Q4W (±3 days) for 24 weeks then Q12W (±3 days) for a further 
24 weeks.   
Standard of Care, dosage and mode of administration 
In both Sub-study A and B patients randomised to the Standard of Care arm will receive one 
of the following treatments based on investigator choice: 
Gemcitabine 
Gemcitabine should be administered at a dose of 1000 mg/m2 iv over 30 minutes on Days 1, 8, 
and 15 (±3 days) of a 28-day cycle.   
Vinorelbine 
Vinorelbine should be administered at a dose of 30 mg/m2 iv on Days 1, 8, 15 and 22 
(±3 days) of a 28-day cycle.   


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
13 
Erlotinib 
Erlotinib should be administered at a dose of 150 mg once daily as a tablet for oral 
administration taken at least 1 hour before or 2 hours after the ingestion of food.   
Duration of treatment 
MEDI4736 monotherapy arm 
Treatment with MEDI4736 10 mg/kg will commence on Day 1 following randomisation after 
confirmation of eligibility and will continue on a Q2W schedule for up to 12 months.  The 
final administration of MEDI4736 will be at the Week 50 visit.   
Disease progression that occurs while on treatment requires confirmation.  In the absence of 
clinically significant deterioration, the investigational site is advised to continue the patient on 
study treatment until progression has been confirmed.  If progression is not confirmed, then 
the patient should continue on study treatment and on treatment assessments. 
Treatment should be discontinued prior to 12 months if there is confirmed PD (unless the 
investigator considers the patient continues to receive benefit from treatment), initiation of 
alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to 
discontinue treatment occur.   
Tremelimumab monotherapy arm 
Treatment with tremelimumab 10 mg/kg will commence on Day 1 following randomisation 
after confirmation of eligibility and will continue on a Q4W schedule for 24 weeks then 
Q12W for a further 24 weeks.   
Disease progression that occurs while on treatment requires confirmation.  In the absence of 
clinically significant deterioration, the investigational site is advised to continue the patient on 
study treatment until progression has been confirmed.  If progression is not confirmed, then 
the patient should continue on study treatment and on treatment assessments.   
Treatment should be discontinued prior to 48 weeks if there is confirmed PD (unless the 
investigator considers the patient continues to receive benefit from treatment), initiation of 
alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to 
discontinue treatment occur.   
MEDI4736+tremelimumab arm 
Treatment with MEDI4736 (20 mg/kg) plus tremelimumab (1 mg/kg) will commence on 
Day 1 following randomisation after confirmation of eligibility and will continue on a Q4W 
schedule for 12 weeks (4 doses of each).  After 4 doses, tremelimumab will be stopped and 
treatment with MEDI4736 (10 mg/kg) will continue on a Q2W schedule, starting at Week 16, 
for 34 weeks (18 doses).  The final administration of MEDI4736 on the 
MEDI4736+tremelimumab arm will be at the Week 50 visit.   


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
14 
In the combination arm, patients who achieve and maintain disease control (ie, CR, PR or SD) 
through to the end of the 4th cycle (Week 16, 4 weeks after the last dose of combination 
treatment) will continue with the planned treatment for this arm, ie, MEDI4736 10 mg/kg 
Q2W.  If patients should experience PD (according to RECIST 1.1), with or without 
confirmation, during the MEDI4736 monotherapy treatment, retreatment with the combination 
regimen may begin. 
Any patient who is restarting the combination treatment regimen will adhere to the same 
treatment guidelines followed during the initial treatment period (same treatment, same length 
and frequency of treatment, same assessments schedule).  Patients may only restart the 
treatment once. 
Treatment should be discontinued prior to 50 weeks if there is confirmed PD during the initial 
combination regimen (ie, during the first 4 cycles) or following the retreatment phase (unless 
the investigator considers the patient continues to receive benefit from treatment), initiation of 
alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to 
discontinue treatment occur.   
Rules for treatment discontinuation, interruption and retreatment option for both 
MEDI4736 and tremelimumab monotherapy arms, and MEDI4736+tremelimumab arm 
Patients who achieve and maintain disease control (ie, CR, PR, or SD) through to the end of 
the 12-month treatment period will enter follow-up.  When these patients experience evidence 
of PD, with or without confirmation, during follow-up and meet the criteria for treatment in 
the setting of PD, they will be given the option to restart their assigned immune-mediated 
cancer treatment (ie, MEDI4736 monotherapy, tremelimumab monotherapy or combination 
MEDI4736+tremelimumab) for as long as the investigator judges they are gaining clinical 
benefit with the same treatment guidelines followed during the initial 12-month treatment 
period.  Patients should have a baseline tumour assessment within 28 days before restarting 
their assigned immune-mediated cancer treatment; all further scans should occur every 
8 weeks (relative to the date of restarting treatment) until study treatment is stopped.  Only 
patients who the investigator determines do not have any significant, unacceptable, or 
irreversible toxicities, or would continue to receive benefit from therapy can restart a second 
treatment upon PD.   
Patients with confirmed progression in the MEDI4736 monotherapy or tremelimumab 
monotherapy arms cannot continue treatment or obtain retreatment if the progression occurred 
during dosing and after confirmed response (ie, the response and progression events both 
occurred while receiving active immune-mediated cancer treatment during the same treatment 
period).   
Retreatment in the combination arm can only occur if PD, with or without confirmation, 
occurs during the monotherapy portion or after completion of 12 months of treatment.  During 
the retreatment period, the patient would resume MEDI4736 20 mg/kg Q4W as during the 
initial induction period, along with tremelimumab 1 mg/kg Q4W for 4 doses.  Monotherapy 
with MEDI4736 10 mg/kg Q2W would then resume at 4 weeks after the last dose of 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
15 
combination treatment for as long as the investigator judges that the patient is gaining clinical 
benefit. 
For patients in the MEDI4736 or tremelimumab monotherapy arms or the 
MEDI4736+tremelimumab arm who have a dose interruption due to toxicity at any point in 
the treatment period may resume treatment and complete the treatment period accordingly as 
per applicable treatment arm duration. 
Patients who have confirmed PD during the initial treatment period in the MEDI4736 or 
tremelimumab monotherapy arms, or after restarting treatment and cannot continue to receive 
study drug, will enter follow-up.   
Patients with confirmed PD that continue to receive MEDI4736 monotherapy, tremelimumab 
monotherapy or who are in the MEDI4736+tremelimumab arm as originally intended, at the 
discretion of the investigator (following consultation with the sponsor), can receive treatment 
for a maximum of 12 months/48 weeks accordingly during the initial treatment period but for 
as long as the investigator judges they are gaining clinical benefit if they are a re-treatment 
patient.   
Standard of Care 
Treatment in the Standard of Care arm will commence on Day 1 following randomisation 
after confirmation of eligibility and will continue on a 4-weekly schedule until PD (unless the 
investigator considers the patient continues to receive benefit from treatment), initiation of 
alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to 
discontinue treatment occur.   
Treatment through PD in the Standard of Care arm is at the investigator’s discretion.  In cases 
of unequivocal progression the investigator should discontinue treatment, where it is uncertain 
if disease has progressed the investigator should decide whether (if in the absence of clinically 
significant deterioration) to continue the patient on treatment until progression has been 
confirmed.   


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
16 
Note: For all patients who receive study treatment through disease progression (not allowed if 
there is confirmed PD while on treatment following a previous response [PR or CR] while on 
treatment to study drug) and patients who achieve disease control (ie, CR, PR or SD) and 
restart MEDI4736 monotherapy, tremelimumab monotherapy or MEDI4736+tremelimumab 
upon evidence of PD (according to RECIST 1.1) during follow-up, the investigator should 
ensure patients do not have any significant, unacceptable or irreversible toxicities that indicate 
continuing treatment will not further benefit the patient.  The patient must continue to meet 
those inclusion and exclusion criteria that are relevant to treatment through disease 
progression and retreatment as specified in the protocol.  These patient informed consent 
documents will specify that treatment beyond initial evidence of PD or re-treatment following 
progression during follow up 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.  Patients with rapid tumour progression or with symptomatic progression that 
requires urgent medical intervention (eg, central nervous system metastasis, respiratory failure 
due to tumour compression, spinal cord compression) will not be eligible to continue to 
receive treatment.    
Outcome variable(s):  
See Objectives. 
Statistical methods 
The primary objective of this study is to assess the efficacy of MEDI4736 treatment 
(Sub-study A being concerned with MEDI4736 monotherapy and Sub-study B being primarily 
concerned with MEDI4736+tremelimumab) compared with Standard of Care in terms of OS 
and PFS.  Overall survival is defined as the time from the date of randomisation until death 
due to any cause.  Progression free survival (per RECIST 1.1 as assessed by the investigator) 
will be defined as the time from the date of randomisation until the date of objective disease 
progression or death (by any cause in the absence of progression) regardless of whether the 
patient withdraws from randomised therapy or receives another anti-cancer therapy prior to 
progression.  Thus, the 2 co-primary endpoints in this study are OS and PFS.  Sub-study A 
will be descriptive in nature with no statistical testing.  To control for type I error in 
Sub-study B, an alpha of 0.04 will be used for the analysis of OS and an alpha of 0.01 will be 
used for the analysis of PFS.  The study will be considered positive (a success) if either the 
PFS analysis results and/or the OS analysis results are statistically significant in Sub-study B. 
Secondary efficacy variables include: OS12, ORR, DoR, APF6, APF12 and PFS2. 
Efficacy data will be summarised and analysed on an Intent-to-Treat (ITT) basis and will 
compare the treatment arms on the basis of randomised treatment, regardless of the treatment 
actually received.  Patients who were randomised but did not subsequently go on to receive 
study treatment are included in the ITT population. 
A total of 126 patients will be randomised 1:1 to MEDI4736 or Standard of Care 
(gemcitabine, vinorelbine or erlotinib) in Sub-study A and approximately 480 patients will be 
randomised 3:2:2:1 to MEDI4736+tremelimumab or Standard of Care or MEDI4736 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
17 
monotherapy or tremelimumab monotherapy in Sub-study B.  The randomisation (via an 
Interactive Voice/Web Response System) will be stratified separately on each sub-study based 
on the Standard of Care treatment that they would be administered (2 categories: 
gemcitabine/vinorelbine versus erlotinib) and histology (2 categories: squamous versus all 
other). 
The primary PFS and interim OS analysis for superiority in Sub-study B (PD-L1-negative 
population) will be performed when approximately 244 PFS events have occurred from 
300 patients (81% maturity) who have been randomised to the MEDI4736+tremelimumab and 
Standard of Care arms.  Assuming the true average hazard ratio (HR) is 0.63 in 
PD-L1-negative population for PFS (corresponding to a 1.3-month improvement in median 
PFS from a control group median of 3 months), the PFS analysis will have 84% power to 
demonstrate a statistically significant difference for PFS, with a type I error of 0.01 (2-sided). 
The OS analysis in Sub-study A (PD-L1-positive population) will be performed when 
approximately 82 deaths have occurred from 126 patients (65% maturity).   
The OS analysis in Sub-study B (PD-L1-negative population) will be performed when 
approximately 205 deaths have occurred from the 300 patients (68% maturity) who have been 
randomised to MEDI4736+tremelimumab and Standard of Care.  Assuming the true average 
HR is 0.63 in PD-L1-negative population for OS (corresponding to a 4.4-month improvement 
in median OS from a control group median of 7 months), this analysis will have 89% power to 
demonstrate a statistically significant difference for OS, with an overall type I error of 0.04 
(2-sided). 
The boundaries for the treatment comparison at the interim and final analysis for OS on 
Sub-study B will be derived based upon the exact number of OS events using the Lan and 
DeMets approach that approximates the O-Brien Fleming spending function. 
For Sub-study B, a contribution of components analysis will be performed when 
approximately 158 PFS events are observed in the MEDI4736+tremelimumab and 
tremelimumab monotherapy arms.  However, for practical considerations, if this time is close 
to the time of the final PFS analysis, the contribution of components analysis will be 
conducted at the time of the final PFS analysis.  The MEDI4736+tremelimumab versus 
tremelimumab monotherapy treatment comparison is the primary comparison.  The 
MEDI4736+tremelimumab versus MEDI4736 monotherapy treatment comparison will also be 
performed at this time.  As these treatment comparisons are secondary and serve a different 
purpose to that of the primary comparisons, they are not included in the multiple testing 
procedure for the primary comparisons, and an alpha of 0.05 will be used for either PFS or OS 
without multiplicity adjustment. 
If the contribution of components analysis is performed prior to the final PFS analysis, the 
interim analyses for superiority of the MEDI4736+tremelimumab arm versus each 
monotherapy arm may be used to guide decisions on whether to discontinue either 
monotherapy arm or to continue the study without modification.   


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
18 
All interim analyses will be assessed by an IDMC. 
Overall survival will be analysed in Sub-study B using a stratified log-rank test adjusting for 
Standard of Care therapy type (gemcitabine/vinorelbine versus erlotinib) and histology 
(squamous versus all other).  The effect of treatment will be estimated by the HR together 
with its corresponding ([1-adjusted alpha] x 100)% CI (for the primary treatment comparison 
in each sub-study) and p-value for the ITT population.  Note that the alpha-adjusted CI and 
p-value will only be generated on Sub-study B.  The HR and 95% CI will be generated on 
Sub-study A. 
Progression free survival based upon the site investigator data will be analysed using the same 
methodology as described for the OS analyses.  The HR and 95% CI will be generated on 
Sub-study A.  The effect of treatment will be estimated by the HR, together with its 
corresponding 99% CI (for the primary treatment comparison in each sub-study) and p-value 
for the ITT population, for Sub-study B only. 
Safety data will be summarised descriptively and will not be formally analysed.   
End of Analysis Portion of Study 
At the time of the final DCO, the analysis portion of the clinical study will have been 
completed and all patients remaining in the study will be considered to have completed the 
analysis portion of the study. 
Patients in OS follow-up (progressed and have completed treatment) will be considered to 
have completed the study.  Patients in progression-free follow up (patients who have 
completed treatment and have not progressed and who are still potentially eligible for 
retreatment) may decide to continue in the study in progression-free follow up.  These patients 
would therefore remain eligible for possible future re-treatment upon progression if they meet 
re-treatment criteria and the investigator judges that the patient will gain clinical 
benefit.  Patients already receiving re-treatment at the time of final DCO for the study may 
continue receiving investigational product if the investigator judges that they are gaining 
clinical benefit. 
Scans will be collected in accordance with local clinical practice.  Patients in progression-free 
follow-up after the final DCO are to undergo sampling for local laboratory assessments in 
such a way that continued per-protocol re-treatment eligibility can be properly 
determined.  For patients receiving re-treatment after final DCO, it is recommended that the 
patients continue the scheduled site visits and investigators monitor the patient’s safety 
laboratory assessments prior to and periodically during treatment in order to manage AEs in 
accordance with the toxicity management guidelines (Refer to Section 5.5.3).  All data will be 
recorded on patient charts but will not otherwise be reported for the purposes of this study. 
For patients who either continue to receive treatment or begin re-treatment after the time of 
the final DCO, investigators will report all serious adverse events (SAEs) to 
AstraZeneca/MedImmune patient safety until 90 days after investigational product is 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
19 
discontinued.  Following the final DCO, SAE reporting applies only to patients who are active 
on the drug and within 90 days post the last dose.  In addition, in patients who are still in 
progression-free follow-up at the final DCO and who are eligible for future re-treatment (ie, 
the patient was randomised to investigational product, completed the initial 12 month 
treatment period and had SD, PR or CR at completion of 12 months of treatment), notification 
must be sent to QuintilesIMS if the patient dies (via the statement of death CRF) or if the 
patient goes onto receive another alternate systemic anti-cancer therapy and thus becomes 
ineligible for re-treatment. 
In the event that a roll-over or safety extension study will become available, patients currently 
receiving treatment with study drug or patients in progression-free follow-up may be 
transitioned to such a study, and the current study would end.  The roll-over or safety 
extension study would ensure treatment continuation with visits assessment per its protocol.  
Any patient that would be proposed to move to such study would be given a new Informed 
Consent. 
 
 
  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
20 
TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ........................................................................................................... 1 
PROTOCOL SYNOPSIS ......................................................................................... 3 
TABLE OF CONTENTS ....................................................................................... 20 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................... 29 
1. 
INTRODUCTION ................................................................................................. 33 
1.1 
Background ............................................................................................................ 33 
1.1.1 
Non-small cell lung cancer .................................................................................... 33 
1.1.2 
Immunotherapies .................................................................................................... 33 
1.1.2.1 
Clinical data for agents targeting PD-1 and PD-L1 ............................................... 36 
1.1.2.2 
Clinical data for agents targeting CTLA-4 ............................................................ 37 
1.1.3 
MEDI4736 ............................................................................................................. 38 
1.1.4 
Tremelimumab ....................................................................................................... 39 
1.1.5 
MEDI4736 in combination with tremelimumab .................................................... 40 
1.1.5.1 
Rationale for combination of anti-CTLA-4 and anti-PD-1/PD-L1 ........................ 40 
1.1.5.2 
Study D4190C00006 Phase Ib experience ............................................................. 42 
1.1.5.3 
Safety and efficacy on the overall Study D4190C00006 ....................................... 43 
1.1.5.4 
Safety and efficacy of dose of the combination of MEDI4736 20 mg/kg 
Q4W and tremelimumab 1 mg/kg Q4W ................................................................ 46 
1.1.6 
Genetic data ........................................................................................................... 47 
1.2 
Research hypothesis ............................................................................................... 47 
1.3 
Rationale for conducting this study ....................................................................... 48 
1.4 
Benefit/risk and ethical assessment........................................................................ 51 
1.4.1 
MEDI4736 monotherapy: Sub-study A ................................................................. 51 
1.4.2 
MEDI4736 monotherapy, tremelimumab monotherapy and MEDI4736 
plus tremelimumab: Sub-study B ........................................................................... 53 
1.4.3 
Summary of potential benefits and risks of other immunotherapy agents ............. 56 
1.4.4 
Summary benefit: risk statement ........................................................................... 56 
2. 
STUDY OBJECTIVES .......................................................................................... 58 
2.1 
Primary objective ................................................................................................... 58 
2.2 
Secondary objectives ............................................................................................. 58 
2.3 
Exploratory objectives ........................................................................................... 59 
3. 
STUDY PLAN AND PROCEDURES .................................................................. 61 
3.1 
Overall study design and flow chart ...................................................................... 61 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
21 
3.2 
Rationale for study design, doses and control groups .......................................... 110 
3.2.1 
Unmet need and potential role of immunotherapies in NSCLC .......................... 110 
3.2.2 
Potential role for MEDI4736 monotherapy (Sub-study A), and 
MEDI4736+tremelimumab, MEDI4736 monotherapy and tremelimumab 
monotherapy (Sub-study B) in the treatment of NSCLC ..................................... 110 
3.2.3 
Study design rationale .......................................................................................... 111 
3.2.3.1 
MEDI4736 monotherapy dose justification ......................................................... 111 
3.2.3.2 
Tremelimumab monotherapy dose justification .................................................. 112 
3.2.3.3 
Dose justification for the combination of MEDI4736 20 mg/kg IV Q4W 
with tremelimumab 1 mg/kg IV Q4W for 4 cycles ............................................. 113 
3.2.3.4 
Justification for Standard of Care as a comparator .............................................. 117 
3.2.3.5 
Rationale for patient selection (based on biomarkers) ......................................... 117 
3.2.3.6 
Rationale for study endpoints (efficacy) .............................................................. 120 
3.2.3.7 
Rationale for study endpoints (other exploratory endpoints) .............................. 121 
4. 
PATIENT SELECTION CRITERIA ................................................................... 121 
4.1 
Inclusion criteria .................................................................................................. 121 
4.2 
Exclusion criteria ................................................................................................. 124 
4.3 
Criteria for Treatment through Progression of Disease and Retreatment ............ 127 
5. 
STUDY CONDUCT ............................................................................................ 130 
5.1 
Restrictions during the study ............................................................................... 130 
5.2 
Patient enrolment and randomisation ................................................................... 132 
5.3 
Procedures for handling patients incorrectly enrolled or randomised or 
initiated on study treatment .................................................................................. 134 
5.4 
Blinding and procedures for unblinding the study ............................................... 135 
5.4.1 
Methods for ensuring blinding ............................................................................. 135 
5.4.2 
Methods for unblinding the study ........................................................................ 135 
5.5 
Treatments ............................................................................................................ 135 
5.5.1 
Identity of investigational product(s) ................................................................... 135 
5.5.1.1 
MEDI4736 ........................................................................................................... 136 
5.5.1.2 
Tremelimumab ..................................................................................................... 137 
5.5.1.3 
Standard of Care .................................................................................................. 139 
5.5.2 
Doses and treatment regimens ............................................................................. 140 
5.5.2.1 
MEDI4736 monotherapy (Sub-study A and Sub-study B) .................................. 140 
5.5.2.2 
MEDI4736+tremelimumab and tremelimumab monotherapy (Sub-study B) ..... 142 
5.5.2.3 
Monitoring of dose administration of MEDI4736 and/or tremelimumab ........... 145 
5.5.2.4 
Dose and schedule of agents in the Standard of Care arm ................................... 145 
5.5.2.5 
Treatment through progression of disease ........................................................... 146 
5.5.3 
Management of toxicity ....................................................................................... 147 
5.5.3.1 
Management of toxicity attributable to MEDI4736 monotherapy, 
tremelimumab monotherapy or MEDI4736+tremelimumab ............................... 148 
5.5.3.2 
Adverse events of special interest ........................................................................ 149 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
22 
5.5.3.3 
Management of toxicity attributable to agents in the Standard of Care arm ....... 150 
5.5.4 
Additional study drug .......................................................................................... 152 
5.5.5 
Labelling .............................................................................................................. 153 
5.5.6 
Storage ................................................................................................................. 153 
5.6 
Concomitant and post-study treatment(s) ............................................................ 154 
5.7 
Treatment compliance .......................................................................................... 155 
5.8 
Discontinuation of study treatment ...................................................................... 155 
5.8.1 
Procedures for discontinuation of a patient from study treatment ....................... 157 
5.8.2 
Assessments following withdrawal of study treatment........................................ 157 
5.9 
Withdrawal from study ........................................................................................ 159 
6. 
COLLECTION OF STUDY VARIABLES ......................................................... 160 
6.1 
Recording of data ................................................................................................. 160 
6.2 
Data collection at enrolment and follow-up ......................................................... 161 
6.2.1 
Enrolment procedures .......................................................................................... 161 
6.2.2 
Follow-up procedures .......................................................................................... 162 
6.2.2.1 
Survival follow-up ............................................................................................... 163 
6.2.2.2 
Second progression .............................................................................................. 163 
6.3 
Efficacy ................................................................................................................ 164 
6.4 
Safety ................................................................................................................... 167 
6.4.1 
Definition of adverse events ................................................................................ 167 
6.4.2 
Definitions of serious adverse event .................................................................... 168 
6.4.3 
Recording of adverse events ................................................................................ 168 
6.4.4 
Reporting of serious adverse events..................................................................... 173 
6.4.5 
Laboratory safety assessment .............................................................................. 174 
6.4.6 
Physical examination ........................................................................................... 176 
6.4.7 
ECG ...................................................................................................................... 177 
6.4.8 
Vital signs ............................................................................................................ 178 
6.4.8.1 
Pulse and blood pressure ...................................................................................... 179 
6.4.8.2 
Temperature, respiratory rate and oxygen saturation........................................... 179 
6.4.9 
Other safety assessments ...................................................................................... 180 
6.5 
Patient reported outcomes .................................................................................... 180 
6.5.1 
EORTC QLQ-C30 ............................................................................................... 181 
6.5.2 
Lung Cancer Module ........................................................................................... 181 
6.5.3 
EuroQoL 5-dimension, 5-level health state utility index ..................................... 181 
6.5.4 
Administration of patient reported outcomes questionnaires .............................. 182 
6.5.5 
Patient interviews (optional) ................................................................................ 183 
6.6 
Pharmacokinetics and ADA (MEDI4736, tremelimumab and 
MEDI4736+tremelimumab arms only) ................................................................ 184 
6.6.1 
Collection of PK samples and determination of drug concentration ................... 184 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
23 
6.6.2 
Collection of samples to measure for the presence of ADA and ADA 
neutralising antibodies ......................................................................................... 184 
6.7 
Biomarker analysis ............................................................................................... 185 
6.7.1 
Collection of PD-L1 expression data for sub-study assignment .......................... 185 
6.7.2 
Collection of exploratory biomarker data ............................................................ 187 
6.7.2.1 
Blood borne biomarkers ....................................................................................... 187 
6.7.2.2 
Tumour samples ................................................................................................... 187 
6.7.2.3 
Genomic analysis ................................................................................................. 188 
6.7.3 
Management of exploratory biomarker data ........................................................ 188 
6.8 
Pharmacogenetics ................................................................................................ 188 
6.9 
Health economics ................................................................................................. 188 
7. 
BIOLOGICAL SAMPLING PROCEDURES ..................................................... 189 
7.1 
Volume of blood .................................................................................................. 189 
7.2 
Handling, storage and destruction of biological samples .................................... 193 
7.2.1 
Pharmacokinetic, immunogenicity and/or pharmacodynamic (soluble 
PD-L1) samples ................................................................................................... 194 
7.2.2 
Pharmacogenetic samples .................................................................................... 194 
7.3 
Labelling and shipment of biohazard samples ..................................................... 194 
7.4 
Chain of custody of biological samples ............................................................... 194 
7.5 
Withdrawal of informed consent for donated biological samples ....................... 195 
8. 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 195 
8.1 
Ethical conduct of the study ................................................................................. 195 
8.2 
Patient data protection .......................................................................................... 196 
8.3 
Ethics and regulatory review................................................................................ 196 
8.4 
Informed consent ................................................................................................. 197 
8.5 
Changes to the protocol and informed consent form ........................................... 198 
8.6 
Audits and inspections ......................................................................................... 199 
9. 
STUDY MANAGEMENT BY ASTRAZENECA .............................................. 199 
9.1 
Pre-study activities ............................................................................................... 199 
9.2 
Training of study site personnel ........................................................................... 199 
9.3 
Monitoring of the study ....................................................................................... 200 
9.4 
Study agreements ................................................................................................. 200 
9.5 
Study timetable and end of study ......................................................................... 201 
9.5.1 
Treatment after final Overall Survival data cut-off ............................................. 201 
10. 
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE .................... 202 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
24 
11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA, OR DELEGATE ................................................................... 203 
11.1 
Calculation or derivation of efficacy variable(s) ................................................. 203 
11.1.1 
RECIST 1.1-based endpoints ............................................................................... 203 
11.1.2 
Co-primary endpoints .......................................................................................... 203 
11.1.2.1 Overall survival .................................................................................................... 203 
11.1.2.2 Progression free survival ...................................................................................... 204 
11.1.3 
Proportion of patients alive at 12 months (OS12) ............................................... 204 
11.1.4 
Objective response rate ........................................................................................ 205 
11.1.5 
Duration of response ............................................................................................ 205 
11.1.6 
Proportion of patients alive and progression free at 6 months ............................. 205 
11.1.7 
Proportion of patients alive and progression free at 12 months ........................... 205 
11.1.8 
Time from randomisation to second progression (PFS2) .................................... 205 
11.2 
Calculation or derivation of safety variable(s) ..................................................... 206 
11.2.1 
Adverse events ..................................................................................................... 206 
11.2.2 
Other significant adverse events (OAEs) ............................................................. 206 
11.2.3 
Safety assessments ............................................................................................... 207 
11.3 
Calculation or derivation of patient reported outcome variables ......................... 207 
11.3.1.1 EORTC QLQ-C30 ............................................................................................... 207 
11.3.1.2 Lung cancer module 13 ........................................................................................ 210 
11.3.1.3 Calculation or derivation of health state utility (EQ-5D-5L) ............................... 211 
11.4 
Calculation or derivation of pharmacokinetic variables ...................................... 212 
11.4.1 
PK non-compartmental analysis .......................................................................... 212 
11.4.2 
Population PK and exposure-response/safety analysis ........................................ 212 
11.4.3 
Immunogenicity analysis ..................................................................................... 212 
11.5 
Calculation or derivation of biomarker variable(s) .............................................. 212 
11.6 
Calculation or derivation of pharmacogenetic variables...................................... 212 
11.7 
Calculation or derivation of health economic variables....................................... 213 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
BY ASTRAZENECA .......................................................................................... 213 
12.1 
Description of analysis sets .................................................................................. 213 
12.1.1 
Full analysis set .................................................................................................... 214 
12.1.2 
Safety analysis set ................................................................................................ 214 
12.1.3 
PK analysis set ..................................................................................................... 214 
12.2 
Methods of statistical analyses ............................................................................. 214 
12.2.1 
Multiple testing strategy ...................................................................................... 218 
12.2.2 
Co-primary endpoints .......................................................................................... 220 
12.2.2.1 Overall survival .................................................................................................... 220 
12.2.2.2 Progression free survival ...................................................................................... 222 
12.2.3 
Objective response rate ........................................................................................ 223 
12.2.4 
Duration of response ............................................................................................ 223 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
25 
12.2.5 
Proportion of patients alive and progression free at 6 months ............................. 223 
12.2.6 
Proportion of patients alive and progression free at 12 months ........................... 224 
12.2.7 
Time from randomisation to second progression ................................................. 224 
12.2.8 
Patient reported outcomes .................................................................................... 224 
12.2.8.1 EORTC QLQ-C30 ............................................................................................... 225 
12.2.8.2 LC13 .................................................................................................................... 225 
12.2.8.3 EuroQol 5-Dimension 5-Level questionnaire ...................................................... 226 
12.2.9 
Healthcare resource use ....................................................................................... 226 
12.2.10 
Safety data ............................................................................................................ 227 
12.2.11 
PK data (MEDI4736 monotherapy, MEDI4736+tremelimumab and 
tremelimumab monotherapy arms only) .............................................................. 227 
12.2.12 
PK/PDx relationships (MEDI4736 monotherapy, 
MEDI4736+tremelimumab and tremelimumab monotherapy arms only) .......... 227 
12.2.13 
Biomarker data ..................................................................................................... 227 
12.2.14 
Interim analysis .................................................................................................... 228 
12.3 
Determination of sample size ............................................................................... 229 
12.4 
Independent data monitoring committee.............................................................. 230 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ................................................................................................ 231 
13.1 
Medical emergencies, AstraZeneca/MedImmune and QuintilesIMS 
contacts ................................................................................................................ 231 
13.2 
Overdose .............................................................................................................. 232 
13.3 
Pregnancy ............................................................................................................. 233 
13.3.1 
Maternal exposure ................................................................................................ 233 
13.3.2 
Paternal exposure ................................................................................................. 234 
14. 
LIST OF REFERENCES ..................................................................................... 235 
 
LIST OF TABLES 
Table 1 
Cohorts in Study D4190C00006 .............................................................. 42 
Table 2 
Rate Summary of All Adverse Events in the Q4W Cohorts, As-
treated Population, Study D4190C00006 ................................................. 44 
Table 3 
Schedule of study procedures for the MEDI4736 monotherapy 
arm in Sub-study A and Sub-study B: Screening and Treatment 
Period (up to 12 months, maximum of 26 doses. Last infusion at 
Week 50)................................................................................................... 73 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
26 
Table 4 
Schedule of study procedures for the tremelimumab monotherapy 
arm in Sub-study B: Screening and Treatment Period (up to 48 
weeks, maximum of 9 doses of tremelimumab. Last infusion at 
Week 48)................................................................................................... 79 
Table 5 
Schedule of study procedures for the MEDI4736+tremelimumab 
arm in Sub-study B: Screening and Treatment Period (up to 50 
weeks, maximum of 22 doses of MEDI4736 and 4 doses of 
tremelimumab. Last infusion at Week 50) ............................................... 84 
Table 6 
Follow-up for patients who have completed the treatment period 
for MEDI4736 monotherapy, tremelimumab monotherapy and 
MEDI4736+tremelimumab and achieved disease control and 
patients who have discontinued study drug due to toxicity or a 
reason other than confirmed progression of disease ................................. 91 
Table 7 
Follow-up for patients who have discontinued MEDI4736 
monotherapy, tremelimumab monotherapy and 
MEDI4736+tremelimumab due to confirmed progression of 
disease ....................................................................................................... 95 
Table 8 
Schedule of study procedures for patients treated with vinorelbine 
or gemcitabine in the Standard of Care arm (a cycle=4 weeks): 
Screening and Treatment Period............................................................... 98 
Table 9 
Schedule of study procedures for patients treated with erlotinib in 
the Standard of Care arm (a cycle=4 weeks): Screening and 
Treatment Period .................................................................................... 103 
Table 10 
Follow-up for patients in the Standard of Care arm ............................... 108 
Table 11 
Effective methods of contraception (2 methods must be used) .............. 131 
Table 12 
List of investigational products for this study ........................................ 135 
Table 13 
MEDI4736 in-use stability and infusion times ....................................... 137 
Table 14 
Tremelimumab in-use stability and infusion times ................................ 139 
Table 15 
Standard of Care ..................................................................................... 139 
Table 16 
Dose reduction for gemcitabine for myelosuppression in NSCLC ........ 150 
Table 17 
Vinorelbine dosing based on neutrophil counts ..................................... 151 
Table 18 
Vinorelbine dosing based on total bilirubin ........................................... 151 
Table 19 
Haematology ........................................................................................... 175 
Table 20 
Clinical chemistry (serum or plasma) ..................................................... 175 
Table 21 
Urinalysisa............................................................................................... 176 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
27 
Table 22 
Volume of blood to be drawn from each patient in the MEDI4736 
monotherapy arm (Sub-study A and B) in the first 3 months on 
treatment ................................................................................................. 190 
Table 23 
Volume of blood to be drawn from each patient in the 
tremelimumab monotherapy arm (Sub-study B) in the first 
3 months on treatment ............................................................................ 191 
Table 24 
Volume of blood to be drawn from each patient in the 
MEDI4736+tremelimumab arm (Sub-study B) in the first 
3 months on treatment ............................................................................ 192 
Table 25 
Volume of blood to be drawn from each patient in the Standard of 
Care arms in the first 3 months on treatment.......................................... 193 
Table 26 
Mean change and visit response in health related quality of life ............ 208 
Table 27 
Visit Response for HRQoL and disease-related symptoms ................... 211 
Table 28 
Summary of outcome variables and analysis populations ...................... 213 
Table 29 
Formal statistical analyses to be conducted and pre-planned 
sensitivity analyses ................................................................................. 216 
 
LIST OF FIGURES 
Figure 1 
Study design schema .................................................................................. 8 
Figure 2 
Study design schema ................................................................................ 62 
Figure 3 
Study flow chart (for patients randomised to MEDI4736 
monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab) ..................................................................... 69 
Figure 4 
Study flow chart (for patients randomised to Standard of Care) .............. 71 
Figure 5 
Schema for MEDI4736+tremelimumab treatment ................................. 144 
Figure 6 
Multiple testing procedures for controlling the type 1 error rate for 
Sub-study B ............................................................................................ 219 
 
LIST OF APPENDICES 
 
 
 
  
 
 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
28 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
29 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ADA 
Anti-drug antibody 
AE 
Adverse event (see definition in Section 6.4.1) 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
APF6 
Proportion of patients alive and progression free at 6 months from 
randomisation  
APF12 
Proportion of patients alive and progression free at 12 months from 
randomisation 
APTT 
Activated partial thromboplastin time  
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
BoR 
Best objective response 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum serum concentration 
CR 
Complete response 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTLA-4 
Cytotoxic T-lymphocyte antigen 4 
DCO 
Data cut-off 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid  
DoR 
Duration of response 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
30 
Abbreviation or 
special term 
Explanation 
EDoR 
Expected Duration of Response 
EDTA 
disodium edetate dihydrate  
EGFR 
Epidermal growth factor receptor 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer 30-item core 
quality of life questionnaire 
EQ-5D 
EuroQoL 5-dimension utility index 
EQ-5D-5L 
EuroQoL 5-dimension, 5-level health state utility index  
ESMO 
European Society of Medical Oncology 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FTIH 
First-Time-In-Human 
GCP 
Good Clinical Practice 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
HRA 
Health Research Associates, Inc 
HRQoL 
Health Related Quality of Life 
IASLC 
International Association for the Study of Lung Cancer 
IB 
Investigator Brochure 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IFN 
Interferon 
Ig 
Immunoglobulin 
IL 
Interleukin 
IMT 
immunomodulatory therapy 
INR 
International normalised ratio  
International 
Co-ordinating 
Investigator 
If a study is conducted in several countries the International Co-ordinating 
Investigator is the investigator co-ordinating the investigators and/or 
activities internationally.  
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
31 
Abbreviation or 
special term 
Explanation 
iv 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LC13 
Lung Cancer Module; 13-item self-administered questionnaire from the 
EORTC for lung cancer  
LIMS 
Laboratory Information Management System 
MedDRA 
Medical Dictionary for Regulatory Activities 
miRNA 
Micro RNA 
mAb 
Monoclonal antibody 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger RNA 
MTD 
Maximum tolerated dose 
NE 
Not evaluable 
NSCLC 
Non-small cell lung cancer 
OAE 
Other significant adverse event (see definition in Section 11.2.2) 
ORR 
Objective response rate 
OS 
Overall survival 
OS12 
Proportion of patients alive at 12 months from randomisation 
PD 
Progression of disease 
PD-1 
Programmed death 1 
PD-L1 
Programmed death ligand 1 
PDx 
Pharmacodynamic(s) 
PFS 
Progression free survival 
PFS2 
Time from randomisation to second progression 
PGx 
Pharmacogenetic(s) 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PRO 
Patient reported outcome(s) 
PVC 
Polyvinyl chloride  
Q2W, Q4W, Q12W 
Every 2 weeks, every 4 weeks, every 12 weeks 
QoL 
Quality of Life 
QTc 
QT interval corrected for heart rate 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
32 
Abbreviation or 
special term 
Explanation 
R&D 
Research and Development 
RECIST 
Response Evaluation Criteria In Solid Tumours 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event (see definition in Section 6.4.2). 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
sPD-L1   
Soluble programmed death ligand 1 
SUSAR 
Suspected Unexpected Serious Adverse Reaction(s) 
T3 
Triiodothyronine 
T4 
Thyroxine 
TK 
Tyrosine kinase 
TKI 
Tyrosine kinase inhibitor 
T-cell 
T lymphocyte 
TMGs 
Dose Modification and Toxicity Management Guidelines 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WBDC 
Web Based Data Capture 
WHO 
World Health Organisation 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
33 
1. 
INTRODUCTION 
Investigators should be familiar with the current MEDI4736 and tremelimumab Investigator 
Brochures (IB). 
1.1 
Background 
1.1.1 
Non-small cell lung cancer 
Lung cancer has been the most common cancer in the world for several decades, and by 2008, 
there were an estimated 1.61 million new cases, representing 12.7% of all new cancers.  It was 
also the most common cause of death from cancer, with 1.38 million deaths (18.2% of the 
total) (GLOBOCAN 2008).  Non-small cell lung cancer (NSCLC) represents approximately 
80% to 85% of all lung cancers.  Unfortunately, at the time of diagnosis, approximately 70% 
of patients with NSCLC already have advanced or metastatic disease not amenable to surgical 
resection.  Furthermore, a significant percentage of patients with early stage NSCLC who 
have undergone surgery subsequently develop distant recurrence and die as a result of their 
lung cancer (Pisters and Le Chevalier 2005).   
Despite advances in the diagnosis, imaging, staging and treatment of NSCLC, the estimated 
overall 5-year survival for patients in Europe continues to be low (11%) 
(D’Addario et al 2010).  Once patients have treatment failure following initial therapy, the 
outlook for those with refractory advanced NSCLC is extremely poor, with response to further 
systemic treatment of <10% (GLOBOCAN 2008, Hanna et al 2004) and median survival of 
approximately 6 months.  
Common third-line treatment for NSCLC in major global markets includes: vinorelbine 
(NAVELBINE®), tyrosine kinase inhibitors (TKIs such as erlotinib [TARCEVA®] and 
gefitinib [IRESSA®]), pemetrexed (ALIMTA®), and docetaxel (TAXOTERE®) for 
non-squamous NSCLC, and vinorelbine, TKIs, gemcitabine and docetaxel (TAXOTERE®) for 
squamous NSCLC (Decisions Resources 2013).  For these patients, clinical trials, 
experimental treatment, or best supportive care are among the treatment options  
(Azzoli et al 2009, Syrigos et al 2011). 
1.1.2 
Immunotherapies 
The immune system can identify tumour-associated antigens and eliminate the cancerous cells 
expressing them and thus plays an important role in preventing and combating the growth of 
tumours.  This process of tumour immune surveillance is believed to result in a co-evolution 
of the tumour and immune response termed immunoediting, which is thought to follow 
3 stages (Swann and Smyth 2007).   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
34 
• 
During the initial phase of elimination, the innate and adaptive immune systems 
detect and eliminate tumour cells.  Elimination can result in complete clearance of 
tumour cells as is seen in rare cases of spontaneous regression of melanoma 
(Kalialis et al 2009).   
• 
However, if elimination is incomplete, the immune system and tumour may enter a 
state of equilibrium.  During this second phase of immunoediting, the immune 
response selectively eliminates susceptible tumour cells and may prevent tumour 
progression.  As the equilibrium phase persists, the tumour may evolve mechanisms 
to avoid or attenuate the immune response.   
• 
The emergence of tumour cells with reduced immunogenicity or enhanced 
immunosuppressive mechanisms leads to the escape phase of immunoediting.  
During the escape phase, many factors may contribute to the failure of the immune 
system to control tumour growth including the expression of immune-inhibitory 
molecules, presence of immunosuppressive regulatory T lymphocytes (T-cells) or 
immunosuppressive cytokines within the tumour microenvironment, and 
down-regulation of major histocompatibility molecules and tumour antigens leading 
to reduced antigen presentation and recognition.  
Blockade of negative regulatory signals to T-cells such as cytotoxic T-lymphocyte antigen 4 
(CTLA-4) and programmed death ligand 1 (PD-L1) has also shown promising clinical 
activity.  Ipilimumab binds to CTLA-4 and prevents the interaction of CTLA-4 with cluster of 
differentiation (CD) 80 and CD86, resulting in enhanced T-cell activation and proliferation 
(Lipson and Drake 2011).  Ipilimumab was granted United States (US) Food and Drug 
Administration (FDA) approval in 2011 for the treatment of metastatic melanoma and is 
currently under investigation for several other malignancies.   
PD-L1 (B7 homolog 1 [B7-H1], CD274) is part of a complex system of receptors and ligands 
that are involved in controlling T-cell activation.  In normal tissue, PD-L1 is expressed on 
T-cells, B lymphocytes (B-cells), dendritic cells, macrophages, mesenchymal stem cells, bone 
marrow-derived mast cells, as well as various nonhaematopoietic cells (Keir et al 2008).  The 
normal function of PD-L1 is to regulate the balance between T-cell activation and tolerance 
through interaction with 2 receptors, programmed death 1 (PD-1, CD279) and CD80 (B7-1).  
PD-L1 is also expressed by tumours and acts at multiple sites to help tumours evade detection 
and elimination by the host immune system.  In the lymph nodes, PD-L1 on antigen 
presenting cells binding to PD-1 (CD279) or CD80 (B7-1) on activated T-cells, delivers an 
inhibitory signal to the T-cell (Keir et al 2008, Park et al 2010).  Likewise, binding of CD80 
on antigen presenting cells to PD-L1 on T-cells leads to inhibitory signalling in the T-cell.  
These and bidirectional interactions between CD80 and PD-L1, expressed on both antigen 
presenting cells and T-cells, lead to further inhibition of T-cell activation.  These interactions 
result in reduced T-cell activation and fewer activated T-cells in the circulation.  In the tumour 
microenvironment, PD-L1 expressed on tumour cells binds to PD-1 on activated T-cells 
reaching the tumour.  This delivers an inhibitory signal to those T-cells, preventing them from 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
35 
killing the target tumour cells, and thus protecting the tumour from immune elimination 
(Zou and Chen 2008).  
PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88% in some 
types of cancer.  In a number of these cancers, including lung (Mu et al 2011), renal 
(Krambeck et al 2007, Thompson et al 2005, Thompson et al 2006), pancreatic  
(Loos et al 2008, Nomi et al 2007, Wang et al 2010), and ovarian cancers  
(Hamanishi et al 2007), the expression of PD-L1 is associated with reduced survival and an 
unfavourable prognosis.  In ovarian cancer, for example, the 5-year survival rate in patients 
with low levels of PD-L1 was 80.2%, compared with 52.6% in patients with high levels of 
PD-L1 (Hamanishi et al 2007).  In lung cancer, only 20% of patients with tumours expressing 
PD-L1 survived for more than 3 years, compared with 49% of patients with tumours lacking 
PD-L1 (Mu et al 2011).  Based on these data, and on data for expression of PD-L1 on the 
surface of human tumours generated using proprietary immunohistochemistry methods for 
assessment, MEDI4736 has the potential to affect multiple types of solid tumours, including 
those with a high incidence rate and some less common types with limited treatment options 
and poor outcomes.  
The levels of tumour-infiltrating cells, and more specifically cytotoxic T-cells, have been 
correlated to improved prognosis in a number of cancers including colorectal, melanoma, and 
lung cancers (Pagès et al 2010), suggesting that an anti-tumour immune response is beneficial 
to patients.  In vitro, an antibody that blocks the interaction between PD-L1 and its receptors 
can relieve PD-L1-dependent immunosuppressive effects and enhance the cytotoxic activity 
of anti-tumour T-cells (Blank et al 2006).  Based on these findings, an anti-PD-L1 antibody 
could be used therapeutically to enhance anti-tumour immune responses in patients with 
cancer.  Results of several preclinical studies using mouse tumour models support this 
hypothesis, where antibodies directed against PD-L1, or its receptor PD-1, showed 
anti-tumour activity (Hirano et al 2005, Iwai et al 2002, Okudaira et al 2009,  
Zhang et al 2008). 
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, interferon [IFN]-γ) production in vitro in whole blood or peripheral blood 
mononuclear cells 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 
anti-tumour activity in animal models, including killing of established murine solid tumours 
and induction of protective anti-tumour immunity (see current tremelimumab IB).  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 anti-tumour activity in patients 
with solid tumours. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
36 
1.1.2.1 
Clinical data for agents targeting PD-1 and PD-L1 
A Phase I clinical study of the anti-PD-1 antibody nivolumab (BMS-936558/MDX-1106) was 
conducted in 39 patients (Brahmer et al 2010).  No dose limiting toxicities (DLTs) were 
observed and a maximum tolerated dose (MTD) was not identified.  Efficacy data for 
nivolumab indicate an objective response rate (ORR) of 19% for NSCLC patients with 
squamous histology and 15% for NSCLC patients with non-squamous histology  
(Brahmer et al 2013).  In a large Phase I study of nivolumab in 296 patients, treatment-related 
adverse events (AEs) were observed at all dose levels studied (Topalian et al 2012).  The most 
frequent treatment-emergent AEs of any grade observed during this study were fatigue (24%), 
rash (12%), diarrhoea (11%) and pruritus (10%).  Immune-mediated AEs of ≥Grade 3 
occurred in 6% of patients and included pneumonitis (1%), diarrhoea (1%), alanine 
aminotransferase (ALT) increased (1%), and aspartate aminotransferase (AST) increased 
(1%).  Of note, 3 deaths due to pneumonitis were assessed as related to study drug. 
MK-3475, another anti-PD-1 monoclonal antibody (mAb), is being evaluated in Phase I and II 
studies, with data from a study of 135 patients with advanced melanoma recently reported 
(Hamid et al 2013).  Efficacy data for MK-3475 in NSCLC has indicated an ORR of 24% by 
immune-related response criteria (irRC) (21% by Response Evaluation Criteria in Solid 
Tumours [RECIST]) after 2 previous NSCLC treatment regimens.  Preliminary median 
overall survival (OS) was 51 weeks (Garon et al 2013).  The most frequent treatment-related 
AEs of any grade observed in the study of 135 patients with advanced melanoma recently 
reported by Hamid et al 2013 were fatigue (30%), rash and pruritus (21% each), diarrhoea 
(20%), myalgia (12%), headache, asthenia, nausea, and elevated AST (10% each).  Grade 3 or 
higher treatment-related AEs were reported in 13% of patients and included rash (2%), 
pruritus, hypothyroidism, diarrhoea, abdominal pain, fatigue, decreased appetite, elevated 
AST and renal failure (1% each). 
Clinical data have also been reported from a Phase I clinical study of the anti-PD-L1 antibody, 
BMS-936559 (MDX-1105).  Preliminary data for BMS-936559 (MDX-1105) indicates an 
ORR of 8% for NSCLC patients with squamous histology and 11% for NSCLC patients with 
non-squamous histology.  The most frequently observed treatment-related AEs of any grade 
were similar to those observed with BMS-936558 and included fatigue (16%), infusion-
related reaction (10%), diarrhoea (9%), rash (7%), arthralgia (7%), pruritus (6%) and nausea 
(6%) (Brahmer et al 2012).  Immune-mediated AEs of ≥Grade 3 occurred in 5% of patients.  
Pneumonitis was not reported in this study. 
Data for MPDL3280A, another anti-PD-L1 antibody in development in NSCLC patients, was 
presented by L Horn at The World Conference on Lung Cancer 2013.  These data showed an 
ORR in smokers of 26%; versus 10% in never smokers and 23% in patients with epidermal 
growth factor receptor (EGFR) wild type mutation status and 23% in patients who were EGFR 
mutation positive.  Safety data from 171 patients enrolled in a Phase I study of MPDL3280A 
has also been presented (Herbst et al 2013).  In this ongoing study, the most frequently 
reported AEs, regardless of causality, were fatigue (43%), cough (26%), diarrhoea (26%), 
nausea (25%), decreased appetite (25%), headache (25%), constipation (23%), dyspnoea 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
37 
(23%), pyrexia (22%), arthralgia (19%), rash (18%), and insomnia (18%).  Grade 3 or 4 
treatment-related AEs were reported in 13% of patients.  No DLTs were observed and an 
MTD was not identified. 
Studies of other agents targeting the PD-1/PD-L1 pathway are also in early stage development 
with limited data available.  CT-011 (an anti-PD-1 mAb), has been evaluated in a Phase I 
study in advanced haematologic malignancies (Berger et al 2008).  In this study of 17 patients, 
CT-011 was well tolerated and no treatment-related toxicities were reported.  No MTD was 
identified in this population.  The most frequent AE was diarrhoea, which occurred in 
2 patients.   
1.1.2.2 
Clinical data for agents targeting CTLA-4 
Ipilimumab is currently approved for the treatment of unresectable or metastatic melanoma.  
Ipilimumab is being studied in a number of other cancer indications and in combination with 
various anti-cancer agents. 
Ipilimumab has been studied in NSCLC in combination with either chemotherapy or in 
ongoing trials in combination with anti-PD-1/PD-L1 agents.  Ipilimumab was studied in a 
randomised, double-blind, trial evaluating the efficacy and safety of ipilimumab in 
combination with paclitaxel/carboplatin compared to paclitaxel/carboplatin alone in 
previously untreated patients with lung cancer.  In this study ipilimumab was given either 
concurrently or sequentially with the platinum doublet chemotherapy and was continued in a 
maintenance schedule (10 mg/kg every 3 months) after discontinuation of chemotherapy until 
progression or undue toxicity. 
Ipilimumab showed promising results in this first-line NSCLC Phase II study.  The median 
immune-related progression-free survival was 5.7 months for the phased ipilimumab arm 
versus 4.6 months for chemotherapy alone (hazard ratio [HR] = 0.72, p = 0.05) and 
5.5 months for the concurrent ipilimumab arm versus 4.63 months for chemotherapy alone 
(HR = 0.81, p = 0.13.  The main AEs were immune-related, such as hypophysitis, enterocolitis 
and hyperthyroidism.  Phase III studies are ongoing (Lynch et al 2012). 
In addition to the first-line NSCLC Phase II study, a Phase I trial examining the use of phased 
ipilimumab with platinum-based chemotherapy in Japanese patients demonstrated a response 
rate of 60% in 10 evaluable NSCLC patients (Nokihara H 2013). 
Interim results were presented at the American Society of Clinical Oncology (ASCO) 2014 on 
a study of 2 different dosing regimens of ipilimumab in combination with nivolumab in 
2 cohorts of squamous and non-squamous first-line NSCLC patients.  Objective response rate 
ranged from 11 to 33% across the 4 different arms based on histology and dosing regimens.  
Progression free survival (PFS) rates at 24 weeks ranged from 20 to 51%.  Grade 3 and 4 
treatment-related events were reported in 49% of patients across the treatment arms 
(Antonia et al 2014 ASCO). 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
38 
1.1.3 
MEDI4736 
Refer to the current MEDI4736 IB for a complete summary of non-clinical and clinical 
information; see Section 5.5.3 of this protocol for guidance on management of potential 
MEDI4736-related toxicities. 
MEDI4736 is a human mAb of the immunoglobulin (Ig)G1 kappa subclass that inhibits 
binding of PD-L1 and is being developed by AstraZeneca/MedImmune for use in the 
treatment of cancer.  MEDI4736 is developed as an immunomodulatory therapy (IMT) within 
the pharmaco-therapeutic group of the anti-neoplastic agents.  The proposed mechanism of 
action for MEDI4736 is interference of the interaction of PD-L1, expressed on cancer cells 
and a subset of leukocytes, with the PD-1 (CD279) and B7-1 (CD80) molecules on 
antigen-presenting cells and T-cells.  By binding to PD-L1 on tumour cells, the mechanism of 
action of MEDI4736 includes stimulation/re-engagement of the patient’s anti-tumour immune 
response. 
MEDI4736 has been given to humans as part of ongoing studies as a single drug or in 
combination with other drugs.  As of July 2015, a total of 1883 patients have been enrolled 
and treated with MEDI4736 in 30 ongoing sponsor and collaborative clinical studies: 
13 employing MEDI4736 as monotherapy and 17 as combination therapy.  No studies have 
yet been completed.   
The majority of the safety data currently available for MEDI4736 are based on the 
First-Time-in-Human (FTIH), single-agent study (Study CD-ON-MEDI4736-1108; referred to 
hereafter as Study 1108) in patients with advanced solid tumours.  As of 14 July 2014, 
393 patients enrolled in Study 1108 have received MEDI4736 at 10 mg/kg every 2 weeks 
(Q2W; either in the dose-escalation or dose-expansion phase of the study).  Of these 
393 patients, 331 (84.2%) had at least 1 AE (regardless of causality.  Overall, the most 
frequently reported (≥10% of patients) AEs (all grades) were fatigue, nausea, dyspnoea, 
decreased appetite, constipation, diarrhoea, vomiting, cough, pyrexia, back pain, and rash.    
Approximately half (48.1%) of these AEs were Grade 1 to 2 in severity and manageable by 
general treatment guidelines as described in the current MEDI4736 study protocols.  Grade 3 
or higher AEs were noted in 141 of 393 patients (35.9%).  These events occurring in more 
than 1% of patients were dyspnoea (5.1%); increased gamma-glutamyltransferase (3.3%); 
fatigue, general physical health deterioration, increased AST, and back pain (2.3% each); 
anaemia and dehydration (1.8% each); and abdominal pain, vomiting, sepsis, syncope, sepsis, 
and hypotension (1.3% each). 
Treatment-related AEs were reported for 162 of 393 patients (41.2%).  The most frequently 
reported (≥2% of patients) treatment-related AEs (all grades) were fatigue (13.5%); nausea 
(8.4%); diarrhoea, decreased appetite, and rash (5.3% each); vomiting (4.8%); pruritus (4.1%); 
dyspnoea (3.8%); pyrexia (3.1%); hypothyroidism (2.8%); increased ALT, increased AST, 
and cough (2.5% each); myalgia (2.3%); and abdominal pain and dizziness (2.0% each).  No 
DLTs have been reported.  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
39 
A total of 229 serious adverse events (SAEs), regardless of causality, have been reported in 
123 of 393 patients (31.3%) treated with 10 mg/kg MEDI4736 Q2W.  The SAEs reported for 
5 or more patients were dyspnoea, general physical health deterioration, pyrexia, abdominal 
pain, back pain, dehydration, pleural effusion, and sepsis.  
The important potential risks, based on the mechanism of action of MEDI4736, as well as data 
from studies of relevant or similar therapies, include immune-mediated reactions, such as 
enterocolitis, dermatitis, hepatotoxicity, endocrinopathy, pneumonitis, and other events such 
as serious infections, infusion-related reactions, anaphylaxis or serious allergic reaction and 
immune complex disease.  
Data presented at the European Society for Medical Oncology (ESMO) 2014 with a later cut-
off 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; drug-related AEs leading to discontinuation reported in 1% of patients; no drug-
related colitis or hyperglycaemia of any grade and no Grade ≥3 pneumonitis were reported 
and no drug-related AEs leading to death were reported (Antonia et al 2014 ESMO).  
Efficacy data on the NSCLC patients in Study 1108, presented at ESMO 2014 (cut-off date of 
21 August 2014), showed a disease control rate 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 in patients with PD-L1 positive (≥25% of tumour cells with 
membrane staining for PD-L1) tumours (25%; 12 complete response [CR]/partial 
response [PR]; n=48) compared to patients with PD-L1 negative tumours (10%; 7 CR/PR; 
n=74) (Antonia et al 2014 ESMO).  Updated safety and efficacy data from Study 1108 was 
presented at international oncology conferences (Rizvi et al 2015 ASCO).  Overall, a low 
incidence of anti-drug antibody (ADA) has been observed.  Of the 220 patients who received 
MEDI4736 monotherapy and for whom PK/ADA data were available as of July 2014, 5 were 
detected to be ADA positive, with an impact on PK/pharmacodynamics (PDx) reported in 
1 patient.  
Complete updated clinical data on MEDI4736 is found in the current IB. 
1.1.4 
Tremelimumab 
Refer to the tremelimumab IB for a complete summary of non-clinical and clinical 
information; see Section 5.5.3 for guidance on management of potential tremelimumab-related 
toxicities. 
Tremelimumab, a CTLA-4 mAb of the IgG2 kappa isotype, is an IMT that is being developed 
by AstraZeneca/MedImmune for use in the treatment of cancer.  Tremelimumab is a human Ig 
G2 mAb directed against CTLA-4.  CTLA-4 is a critical regulatory signal for T-cell expansion 
and activation following an immune response, and it serves as a natural braking mechanism 
that maintains T-cell homeostasis.  During T-cell activation, T-cells upregulate CTLA-4, 
which binds to B7 ligands on antigen-presenting cells, sending an inhibitory signal that limits 
T-cell activation.  Tremelimumab blocks the inhibitory signal resulting from CTLA-4 binding 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
40 
to B7, leading to prolongation and enhancement of T-cell activation and expansion.  Thus, the 
mechanism of action of tremelimumab is indirect and is applied through enhancing 
T-cell-mediated immune response.   
An extensive programme of non-clinical and clinical studies has been conducted for 
tremelimumab both as monotherapy and combination therapy with conventional anti-cancer 
agents to support various cancer indications using different dose schedules.  Tremelimumab 
has been administered as a single-agent treatment to patients participating in 11 sponsored 
clinical studies, 3 of which are ongoing.  In total, more than 1400 patients with a variety of 
tumour types have been treated with tremelimumab given alone or in combination with other 
anti-cancer agents in 34 sponsored clinical studies. 
Currently available data from the tremelimumab monotherapy clinical development 
programme suggests response rates that are more modest than the anti-PD-L1 approach, with 
a manageable but more pronounced toxicity profile in patients with a variety of solid 
malignancies, including patients with advanced NSCLC.  Study A3671015, a Phase II, 
randomised, open-label trial examining tremelimumab 15 mg/kg every 90 days versus Best 
Supportive Care in advanced NSCLC patients who had completed first-line platinum-based 
chemotherapy, demonstrated PFS at 3 months of 10/44 in the tremelimumab arm (22.7%; 90% 
confidence interval [CI] 12.9%, 35.5%) and 5/42 in the Best Supportive Care arm (11.9%; 
90% CI 4.8%, 23.4%).  There were 3 patients who had a partial response (PR) in the 
tremelimumab arm, including 1 patient who had crossed over from the Best Supportive Care 
arm after progression of disease (PD), and there were no PR in the Best Supportive Care arm.  
Of note, all of these responding patients had squamous disease. 
Details on the safety profile of tremelimumab monotherapy are summarized in Section 1.4.2 
of the protocol.  Although the majority of the safety data for tremelimumab are based on 
mesothelioma and melanoma subject data, the mechanism of action for these risks is thought 
to be immune-mediated, reflective of the pharmacology of tremelimumab, and consistent with 
the safety profile of anti-CTLA-4 antibodies.  Therefore, these safety risks are thought to be 
applicable to most subjects with solid tumours.   
Complete updated clinical data including safety, efficacy and pharmacokinetic data can be 
found in the current version of the tremelimumab IB.  
Emerging data from Study D4190C00006 in advanced NSCLC show that the combination of 
MEDI4736 and tremelimumab has a manageable safety profile (see Section 1.1.5). 
1.1.5 
MEDI4736 in combination with tremelimumab  
1.1.5.1 
Rationale for combination of anti-CTLA-4 and anti-PD-1/PD-L1 
There are data suggesting that anti-tumour T-cells express multiple inhibitory receptors, a 
finding mirrored in murine models of chronic viral infections.  The hypothesis for evaluating 
the combination of an anti-PD-L1 agent with an anti-CTLA-4 agent in the clinic is supported 
by pre-clinical data in mouse models of transplantable solid tumours that show superior 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
41 
anti-tumour activity of combination therapy over monotherapy (Curran et al 2010,  
Mangsbo et al 2010).  Pre-clinical data indicate that the mechanisms of activation of known 
sites for activity of CTLA-4 and PD-1 are non-redundant and therefore targeting both 
pathways may have additive or synergistic activity (Pardoll 2012).  
In a relevant mouse model of melanoma, single blockade of either CTLA-4 or PD-1 enhanced 
the infiltration of activated T-cells into tumours, but the T-cells accumulated high levels of 
unblocked negative co-receptors that eventually limited their expansion.  Blocking CTLA-4, 
PD-1 and PD-L1 simultaneously allowed T-cells to continue to survive and proliferate, and 
resulted in enhanced infiltration, activation and cytokine production, thereby reducing 
tumour-induced immune suppression and promoting tumour rejection (Drake 2012).  In a 
study by Curran et al 2010, vaccination with irradiated B16 melanoma cells expressing the 
Flt3-ligand (Fvax) combined with antibody blockade of the negative T-cell co-stimulatory 
receptor CTLA-4 promoted rejection of pre-implanted tumours.  However, despite CTLA-4 
blockade, T-cell proliferation and cytokine production can be inhibited by the interaction of 
PD-1 with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-1.  The study 
showed that the combination of CTLA-4 and PD-1 blockade was more than twice as effective 
as either agent alone in promoting the rejection of B16 melanomas in conjunction with Fvax 
(Curran et al 2010). 
The concurrent administration of ipilimumab (anti-CTLA-4 mAb) and nivolumab (anti-PD-1 
mAb) in the clinic was recently evaluated in a Phase I trial that demonstrated impressive 
preliminary evidence of improved benefit in advanced melanoma patients.  The overall 
response rate (modified World Health Organisation [WHO] criteria) was 53% at the MTD, 
including 3 patients with a complete response (CR), and all responding patients experienced a 
≥80% decline in tumour burden at 12 weeks.  Across all dose levels in this dose-escalation 
study, the response rate was 40%.  The response seen appeared to be both rapid and deep.  
Also, responses to the combined therapy were generally durable and were observed even in 
patients whose treatment was terminated early because of AEs (Wolchok et al 2013). 
The combination was tolerated, but there were more Grade 3 or 4 events compared to 
historical data on either agent when given alone.  These events were manageable.  Grade 3 
or 4 AEs related to therapy occurred in 53% of patients.  The events reported were 
qualitatively similar to previous experience with monotherapy as immune events and were 
generally reversible (Wolchok et al 2013).  Improving the safety profile of such combinations, 
however, will be important. 
Preliminary data from a Phase I study of ipilimumab and nivolumab in first-line NSCLC 
showed an ORR of 11 to 33% and a PFS rate at 24 weeks of 20 to 51% across different 
histologies and looking at different dose combinations of the 2 agents  
(Antonia et al 2014 ASCO). 
In conclusion, the pre-clinical and clinical research suggests that combinations of 
immunotherapy agents may generate superior anti-tumour activity compared to single agent 
immunotherapy, which may translate into higher and more durable rates of response.  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
42 
Therefore, concurrent targeting of immunologic checkpoints with multiple 
inhibitory/stimulatory molecules may enhance efficacy. 
1.1.5.2 
Study D4190C00006 Phase Ib experience 
Study D4190C00006 is an ongoing Phase Ib dose-escalation and dose-expansion study of 
MEDI4736 in combination with tremelimumab in patients with advanced NSCLC.  Patients 
with histologically- or cytologically-confirmed locally advanced or metastatic NSCLC, with at 
least 1 measurable lesion, with adequate organ and marrow function, and with Eastern 
Cooperative Oncology Group performance status of 0-1, are eligible.  Patients cannot have 
had more than 3 prior lines of therapy in the metastatic setting including standard of care.   
Two dosing schedules are being evaluated in this study: a once every 4 weeks (Q4W) 
schedule (MEDI4736 Q4W up to Week 48 plus tremelimumab Q4W up to Week 24 then once 
every 12 weeks [Q12W] until Week 48) and an alternative Q2W schedule for 18 doses or until 
Week 36.   
The first patient in Cohort 1a was dosed in October 2013.  As of 27 January 2015, a total of 
74 patients have been treated in the study with a minimum of 3 patients in each cohort as 
detailed in Table 1.  
Table 1 
Cohorts in Study D4190C00006  
Cohort 
MEDI4736 
Tremelimumab 
Patients Treated 
Q4W Dosing Schedule 
1a 
3 mg/kg 
1 mg/kg 
3 
2a 
10 mg/kg 
1 mg/kg 
3 
3a 
15 mg/kg 
1 mg/kg 
12 
3b 
10 mg/kg 
3 mg/kg 
3 
4 
20 mg/kg 
1 mg/kg 
11 
4a 
15 mg/kg 
3 mg/kg 
11 
5 
15 mg/kg 
10 mg/kg 
9 
5a 
20 mg/kg 
3 mg/kg 
6 
Q4W Total 
 
 
58 
Q2W Dosing Schedule 
8 
10 mg/kg 
1 mg/kg 
6 
9 
10 mg/kg 
3 mg/kg 
10 
Q2W Total 
 
 
16 
Overall Total 
 
 
74 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
43 
Patients have received between 1 and 9 doses of tremelimumab and between 1 and 13 doses of 
MEDI4736.   
1.1.5.3 
Safety and efficacy on the overall Study D4190C00006 
As of the 27 January 2015 cut-off date, 2 patients out of 6 treated in the Q4W MEDI4736 
20 mg/kg and tremelimumab 3 mg/kg (M20/T3; Cohort 5a) experienced a DLT.  The DLTs 
were: (1) increased AST (Grade 3) on Day 29 of Cycle 1 and (2) increased amylase (Grade 3) 
and increased lipase (Grade 4) occurring on Day 9 of Cycle 1.  Adverse events regardless of 
causality were reported in 62 of the 74 patients (83.8%) across all dose cohorts.  Adverse 
events were considered related to treatment in 50 patients (67.6%).  Twenty-four of these 
events were Grade 1 or Grade 2, with Grade ≥3 events reported in 26 patients (35.1% of total 
population).  No consistent pattern in the nature, frequency, or severity of AEs has been noted 
with escalating doses of the combination. 
With the exception of the 20 mg/kg MEDI4736 and 1 mg/kg tremelimumab (M20/T1) cohort, 
all patients within each Q4W cohort had at least 1 AE (Table 2).  Across the Q4W dose 
cohorts in which tremelimumab was administered at 1 mg/kg, rates of treatment related AEs, 
Grade 3 and 4 AEs, and SAEs were least frequent in the M3/T1 cohort.  Grade 3 
treatment-related AEs and were highest in the M20/T3 cohort.  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
44 
 
Table 2 
Rate Summary of All Adverse Events in the Q4W Cohorts, As-treated Population, Study D4190C00006  
Adverse Event Outcome 
(MedDRA V 17.1)  
M3/T1 
(N = 3) 
n (%) 
M10/T1 
(N = 3) 
n (%) 
M15/T1 
(N = 12) 
n (%) 
M10/T3 
(N = 3) 
n (%) 
M20/T1 
(N = 11) 
n (%) 
M15/T3 
(N = 11) 
n (%) 
M15/T10 
 (N = 9) 
n (%) 
M20/T3 
(N = 6) 
n (%) 
Total 
(N = 58) 
n (%) 
1 or more event  
3 (100) 
3 (100) 
12 (100) 
3 (100) 
7 (63.6) 
11 (100) 
9 (100) 
6 (100) 
54 (93.1) 
1 or more Grade 3 event  
0 
2 (66.7) 
9 (75.0) 
3 (100) 
3 (27.3) 
5 (45.5) 
7 (77.8) 
6 (100) 
35 (60.3) 
1 or more Grade 4 event  
0 
1 (33.3) 
1 (8.3) 
1 (33.3) 
1 (9.1) 
0 
0 
1 (16.7) 
5 (8.6) 
1 or more serious event  
1 (33.3) 
2 (66.7) 
7 (58.3) 
2 (66.7) 
2 (18.2) 
7 (63.6) 
7 (77.8) 
6 (100) 
34 (58.6) 
1 or more event leading to 
discontinuation of study drug  
1 (33.3) 
1 (33.3) 
2 (16.7) 
2 (66.7) 
0 
5 (45.5) 
3 (33.3) 
5 (83.3) 
19 (32.8) 
Death  
0 
1 (33.3) 
1 (8.3) 
0 
0 
2 (18.2) 
0 
2 (33.3) 
6 (10.3) 
1 or more related event  
1 (33.3) 
3 (100) 
7 (58.3) 
3 (100) 
7 (63.6) 
9 (81.8) 
8 (88.9) 
5 (83.3) 
43 (74.1) 
1 or more ≥Grade 3 related 
event  
0 
2 (66.7) 
5 (41.7) 
2 (66.7) 
2 (18.2) 
4 (36.4) 
4 (44.4) 
5 (83.3) 
24 (41.4) 
1 or more related serious event  
0 
1 (33.3) 
3 (25.0) 
2 (66.7) 
2 (18.2) 
5 (45.5) 
4 (44.4) 
5 (83.3) 
22 (37.9) 
1 or more related event leading 
to discontinuation of study drug  
0 
1 (33.3) 
1 (8.3) 
2 (66.7) 
0 
4 (36.4) 
3 (33.3) 
4 (66.7) 
15 (25.9) 
Death related to study drug  
0 
1 (33.3) 
0 
0 
0 
0 
0 
1 (16.7) 
2 (3.4) 
MedDRA  Medical Dictionary for Regulatory Activities; M(x)/T(y)  MEDI4736 (x) mg/kg and tremelimumab (y) mg/kg; Q4W  every 4 weeks.  
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
45 
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); diarrhoea 
(32.4%; 24 patients); amylase increased and pruritus (16.2%; 12 patients); decreased appetite, 
dyspnoea, nausea and rash (14.9%; 11 patients each), and headache and pyrexia (13.5%; 
10 patients).  
Twenty of the 62 patients who experienced AEs regardless of causality had events that were 
Grade 1 or 2 in severity.  Forty-two of the 62 patients reported ≥Grade 3 events.  The most 
frequently reported ≥Grade 3 events (in 3 or more patients) were diarrhoea (7 patients); colitis 
(6 patients); increased lipase (4 patients); and anaemia, increased ALT, increased AST, 
dehydration and pneumonitis (3 patients each).  
Fifty of the 74 patients reported a treatment-related AE.  The most frequently reported 
treatment-related AEs were fatigue (24.3%; 18 patients); diarrhoea (21.6%; 16 patients); 
increased ALT (13.5%, 10 patients); pruritus (12.2%; 9 patients); and rash (10.8%; 8 patients).  
Twenty-four of the 50 patients who experienced treatment-related AEs reported Grade 1 or 
2 events only.  Twenty-six of the 50 patients reported ≥Grade 3 events.  The most frequently 
reported treatment-related ≥Grade 3 events (in 3 or more patients) were colitis and diarrhoea 
(6 patients each), increased lipase (4 patients), and increased ALT, increased AST and 
pneumonitis (3 patients each). 
Within the total study population, 21 patients (28.4%) discontinued treatment due to AEs.  
The most frequent AEs (more than 1 patient) leading to treatment discontinuation were colitis 
(5 patients); pneumonitis (4 patients); diarrhoea (3 patients); and increased AST and dyspnoea 
(2 patients each).  The episodes of colitis, diarrhoea, increased AST, and pneumonitis were all 
considered to be treatment related.  The percentage of patients with AEs leading to 
discontinuation was highest in the M20/T3 cohort (83.3%, 5/6). 
Eleven patients (14.9%) have died, of which 9 were due to disease and 2 to treatment-related 
toxicities (Grade 5 polymyositis and Grade 5 neuromuscular disorder [verbatim term]).  Ten 
of the 11 patients died within 90 days after the last dose. 
In Study D4190C00006, PK (n=55), ADA (n=60), and soluble PD-L1 (sPD-L1; n=69) data 
were collected from 10 cohorts following Q4W or Q2W regimens.  An approximately 
dose-proportional increase in PK exposure (maximum plasma concentration [Cmax] 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.  The observed 
PK exposures of MEDI4736 and tremelimumab following combination were in line with 
respective monotherapy data, indicating no PK interaction between these 2 agents.  
Four of 60 patients (2 at 15 mg/kg MEDI4736 Q4W plus 10 mg/kg tremelimumab Q4W, 
1 each at 15 mg/kg MEDI4736 Q4W plus 1 mg/kg tremelimumab Q4W and 10 mg/kg 
MEDI4736 Q4W plus 3 mg/kg tremelimumab Q4W) were ADA positive for either 
anti-MEDI4736 or anti-tremelimumab antibodies post-treatment.  MEDI4736 PK was 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
46 
impacted in only 2 of 4 patients following 15 mg/kg MEDI4736 Q4W plus 1 mg/kg 
tremelimumab Q4W and 15 mg/kg MEDI4736 Q4W plus 10 mg/kg tremelimumab Q4W.  
One of 53 patients (15 mg/kg MEDI4736 Q4W plus 1 mg/kg tremelimumab Q4W) was ADA 
positive with no impact on PK.  
Following MEDI4736 in combination with tremelimumab, complete sPD-L1 suppression 
(surrogate for PD-L1 targeting) was observed in almost all patients over the dose range of 3 to 
20 mg/kg MEDI4736 Q4W or Q2W.  In 2 patients (1 patient each at 10 mg/kg MEDI4736 
Q4W plus 1 mg/kg tremelimumab Q4W and 15 mg/kg MEDI4736 Q4W plus 1 mg/kg 
tremelimumab Q4W), showed partial sPD-L1 suppression at some visits followed by 
complete suppression after repeated dosing.  One patient following 15 mg/kg MEDI4736 
Q4W plus 10 mg/kg tremelimumab Q4W showed partial suppression on Day 29 and was 
ADA positive with an impact on PK.  No clear dose-dependent changes in sPD-L1 were 
identified over the dose range of 3 to 20 mg/kg MEDI4736 Q4W or Q2W.  
As of the 27 January 2015 cut-off date, a total of 53 of 74 patients were evaluable for efficacy 
with at least 8-weeks of follow-up.  Of these, there were 12 patients (23%) with PR, 14 
patients (26%) with stable disease (SD), and 19 patients (36%) with progressive disease (PD) 
as assessed by RECIST guidelines v1.1 (Eisenhauer et al 2009). 
Other active combination studies of MEDI4736 and tremelimumab include 
Study LUD2013-003, which is an open-label, dose-escalation, and dose-expansion study in 
adults with advanced solid tumours (3 patients were enrolled as of 18 February 2014, with no 
safety data yet available as of this cut-off date). 
Updated information on the safety and efficacy profile of MEDI4736+tremelimumab 
combination therapy are provided in the current MEDI4736 and tremelimumab IBs. 
1.1.5.4 
Safety and efficacy of dose of the combination of MEDI4736 20 mg/kg Q4W 
and tremelimumab 1 mg/kg Q4W 
As of the 27 January 2015 cut-off date, in Study D4190C00006, in the 20 mg/kg MEDI4736 
and 1 mg/kg tremelimumab cohort, 11 patients have received 1 to 5 doses of tremelimumab 
and MEDI4736.  Seven patients (63.6%) reported at least 1 AE.  Adverse events reported by 
more than 1 patient were fatigue (4 patients) and diarrhoea, blood thyroid stimulating 
hormone increased, decreased appetite, and dizziness (2 patients each).  All 7 of these patients 
reported at least 1 treatment-related AE, with each event reported by 1 patient each. 
Three patients (27.3%) experienced Grade 3 or higher AEs regardless of causality.  These 
events were sepsis, ALT increased, AST increased, blood potassium decreased, haemoglobin 
decreased, lipase increased, platelet count decreased, and sciatica (1 patient each).  Two of the 
3 patients experienced Grade 3 or higher AEs that were treatment-related.  These AEs were 
sepsis, ALT increased, AST increased, lipase increased, and platelet count decreased 
(1 patient each). 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
47 
Two patients (18.2%) experienced a total of 6 SAEs (colitis, sepsis, increased ALT, increased 
AST, decreased platelet count, and depressed level of consciousness).  
There were no AEs leading to treatment discontinuation.  No patient in this cohort died due to 
an AE.  
A total of 5 of 11 patients were evaluable for efficacy as of the 27 January 2015 cut-off date, 
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 progressive disease (PD).  (Note: One of the 5 
patients initially deemed to be evaluable was subsequently determined to have had a scan 
outside of the analysis window; efficacy results for this patient were not available at the time 
of data cut-off [DCO].)  Updated safety and efficacy data from D4190C00006 was presented 
at international oncology conferences (Antonia et al 2015 ASCO, Rizvi et al 2015 SITC).  
Overall, the safety profile of 20 mg/kg MEDI4736 in combination with 1 mg/kg 
tremelimumab continues to be manageable and supports further development of the 
combination at this dose (see Dosing Modification and Toxicity Management Guidelines in 
Section 5.5.3). 
1.1.6 
Genetic data  
The pharmacogenetic (PGx) research elements of this study (relating to deoxyribonucleic acic 
[DNA]) are optional.  Refer to Appendix D. 
1.2 
Research hypothesis 
The research hypothesis for this study is to determine whether: 
• 
MEDI4736 10 mg/kg (Q2W via iv infusion for up to 12 months) shows improved 
efficacy in terms of OS and PFS compared with Standard of Care in the treatment 
of patients with locally advanced or metastatic PD L1–positive (where positive is 
defined as ≥25% of tumour cells with membrane staining [proprietary PD-L1 
immunohistochemistry assay; Ventana Medical Systems, Inc]), NSCLC 
(Stage IIIB-IV), who have received at least 2 prior systemic treatment regimens 
including 1 platinum-based chemotherapy regimen for NSCLC.   
• 
MEDI4736 20 mg/kg plus tremelimumab 1 mg/kg (Q4W iv for up to 12 weeks) 
then MEDI4736 10 mg/kg (Q2W iv for up to 34 weeks) shows improved efficacy in 
terms of OS and PFS compared with Standard of Care in the treatment of patients 
with locally advanced or metastatic PD L1–negative (ie, those with <25% of tumour 
cells with membrane staining) NSCLC (Stage IIIB-IV), who have received at least 
2 prior systemic treatment regimens including 1 platinum-based chemotherapy 
regimen for NSCLC. 
This will be assessed via the primary objective of this study, which is to assess the efficacy, in 
terms of OS and PFS, of MEDI4736 versus Standard of Care in the PD-L1-positive patient 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
48 
population or MEDI4736 plus tremelimumab (MEDI4736+tremelimumab) compared with 
Standard of Care in the PD-L1-negative patient population. 
Secondary efficacy objectives for both sub-studies include evaluation of the proportion of 
patients alive at 12 months from randomisation (OS12), ORR, duration of response (DoR), the 
proportion of patients alive and progression free at 6 months from randomisation (APF6) and 
the proportion of patients alive and progression free at 12 months from randomisation 
(APF12), and the time from randomisation to second progression (PFS2).  Other secondary 
objectives for both sub-studies include an assessment of safety and tolerability, MEDI4736 
and tremelimumab PK exposure, immunogenicity, and patient reported outcomes (PRO).  
Exploratory objectives are also included.  Additionally Sub-study B will investigate whether 
MEDI4736+tremeliminab is superior to each of its constituent components through separate 
comparisons with MEDI4736 monotherapy and tremelimumab monotherapy.  If appropriate, 
and depending upon the results and timing of the contribution of components analysis, there is 
scope for the same comparisons to be repeated at the time of final analysis across further 
efficacy endpoints as well as comparisons with the Standard of Care therapy.  
Section 12.3 provides information on how the sample size for the study was determined. 
1.3 
Rationale for conducting this study 
Current therapies for advanced NSCLC have poor outcomes (low 5-year survival [11%], poor 
response to systemic treatment for patients with refractory advanced NSCLC [<10%], with 
median survival of approximately 6 months) (D’Addario et al 2010, GLOBOCAN 2008, 
Hanna et al 2004).  There is still a significant unmet medical need for additional treatment 
options for use in this patient population (see Section 1.1.1).   
Although clinical experience with MEDI4736 alone, tremelimumab alone and with the 
combination of MEDI4736 plus tremelimumab is limited, currently available data from the 
MEDI4736 monotherapy clinical development programme indicates encouraging response 
rates and DoR, with a manageable safety profile in patients with a variety of solid 
malignancies, including patients with advanced NSCLC.  Data on MEDI4736 monotherapy 
presented at ESMO 2014 showed an ORR of 16% in the overall NSCLC patient population 
and a 25% ORR in the PD-L1-positive subset of patients (Antonia et al 2014 ESMO).  More 
recent data has been presented at international oncology conferences (Rizvi et al 2015 ASCO).  
Please refer to latest MEDI4736 IB for complete details of efficacy of MEDI4736 across all 
clinical programs. 
Currently available data from the tremelimumab monotherapy clinical development 
programme suggests response rates that are more modest than the anti-PD-L1 approach, with 
a manageable but more pronounced toxicity profile in patients with a variety of solid 
malignancies, including patients with advanced NSCLC.  Study A3671015, a Phase II, 
randomised, open-label trial examining tremelimumab 15 mg/kg every 90 days versus Best 
Supportive Care in advanced NSCLC patients who had completed first-line platinum-based 
chemotherapy, demonstrated PFS at 3 months of 10/44 in the tremelimumab arm (22.7%; 90% 
CI 12.9%, 35.5%) and 6/42 in the Best Supportive Care arm (11.9%; 90% CI 6.4%, 26.3%).  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
49 
There were 3 patients who had a PR in the tremelimumab arm, including 1 patient who had 
crossed over from the Best Supportive Care arm after PD, and there were 0 PR in the Best 
Supportive Care arm.  Of note, all of these responding patients had squamous disease.  As 
discussed in Section 1.1.5.1, non-clinical and clinical research suggests that combinations of 
IMT agents may generate superior anti-tumour activity, compared to single-agent 
immunotherapy, which may translate into higher and more durable rates of response.  As a 
result, concurrent targeting of immunologic checkpoints with multiple inhibitory/stimulatory 
molecules may enhance efficacy.  Early data from Study D4190C00006 (MEDI4736 in 
combination with tremelimumab) has shown an acceptable and manageable safety profile, 
including at the proposed dose for this study of 20 mg/kg MEDI4736 and 1 mg/kg 
tremelimumab.  Efficacy data are limited but there are early signs of clinical activity in an 
advanced/metastatic NSCLC patient population.  Published data from a combination of other 
PD-1 and CTLA-4 inhibitors have demonstrated impressive preliminary evidence of improved 
benefit in melanoma patients, with a response rate of 53% at the MTD; all responding patients 
experienced a ≥80% decline in tumour burden at 12 weeks.  Preliminary data from a Phase I 
study of ipilimumab and nivolumab in first-line NSCLC showed an ORR of 11 to 33% and a 
PFS rate at 24 weeks of 20 to 51% across different histologies and looking at different dose 
combinations of the 2 agents (Antonia et al 2014 ASCO). 
Current experience from studies with single-agent IMTs that target the PD-1/PD-L1 pathway 
suggest that clinical responses may be enhanced in a subset of patients and that it might be 
beneficial to enrich the patient population by selecting patients likely to respond to therapy.  
To date, no assay has been established or validated, and no single approach has proven 
accurate for patient enrichment for anti-PD-1/PD-L1 agents.  However, independent data from 
multiple sources using different assays and scoring methods suggests that PD-L1 expression 
on tumour cells and or tumour-infiltrating cells may be associated with greater clinical benefit.  
For example, data presented by Roche at the Annual Meeting of the ASCO 2013 
(Powderly et al 2013) suggested that PD-L1 expression on infiltrating lymphocytes in 
NSCLC, melanoma and renal cell carcinoma patient cohorts is associated with greater clinical 
benefit from anti-PD-L1 treatment.  Using a proprietary assay for PD-L1 
immunohistochemistry, a 36% ORR was observed in patients who had PD-L1–positive 
tumours, with 50% of patients with PD-L1–positive tumours having SD and 33% having PRs.  
Similarly, in data presented at the Annual Meeting of the ASCO 2013 by Bristol-Myers 
Squibb (Grosso et al 2013), PD-L1 staining, when assessed using a different method and 
scoring algorithm, appeared to be associated with greater clinical benefit in patients treated 
with nivolumab (anti-PD-1).  A 44% ORR was observed in patients with PD-L1-positive 
tumours versus a 17% ORR in patients with PD-L1-negative tumours.  Additionally, patients 
with tumours that were PD-L1 positive had a higher PFS (9.1 versus 2.0 months) and OS than 
patients with PD-L1-negative tumours (21 versus 12 months).   
Also, in a data set presented by Merck & Co at the World Conference on Lung Cancer  
(Garon et al 2013), analysis of the relationship between PD-L1 expression status and response 
rates in a cohort of patients with NSCLC indicated that tumour samples displaying high levels 
of PD-L1 expression (according to their assay criteria) were associated with response rates of 
67% (6/9; per irRC) and 57% (4/7; per RECIST 1.1).  In contrast, tumour samples expressing 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
50 
zero/low levels of PD-L1 were associated with response rates of 4% (1/24; per irRC) and 9% 
(2/22; per RECIST 1.1).   
Data on MEDI4736 presented at ESMO 2014 showed an ORR of 16% in the overall NSCLC 
patient population and a 25% ORR in the PD-L1-positive subset of patients  
(Antonia et al 2014 ESMO).  More recent data has been presented at international oncology 
conferences (Rizvi et al 2015 ASCO).  Therefore, it appears that the selection of patients 
based on PD-L1 expression within the tumour microenvironment may improve the probability 
and/or quality of responses to PD-1 pathway-targeting agents and, therefore, may have merit 
as a patient enrichment tool. 
Based on this information, the likelihood of response to MEDI4736 monotherapy is expected 
to be higher in patients with PD-L1-positive tumours. 
While the Ventana PD-L1 assay is expected to successfully select NSCLC patients with 
PD-L1-positive tumour for response with MEDI4736 monotherapy, a few NSCLC patients 
with PD-L1-negative tumours have been noted to achieve a response with MEDI4736 in the 
FTIH study (Antonia et al 2014 ESMO).  This is not surprising as PD-L1, as a biomarker, has 
limitations due to its dynamic and heterogeneous nature.  Therefore, until a more selective 
biomarker is identified, and considering the heavy toxicity burden of Standard of Care and the 
MEDI4736 AE profile, MEDI4736 monotherapy in NSCLC patients with PD-L1-negative 
tumours should be explored.   
Separately, it has been noted earlier that a Phase II study examining tremelimumab in 
advanced NSCLC patients produced a trend toward improved PFS at 3 months and a 4.8% PR 
rate.  The more intensive tremelimumab treatment regimen of 10 mg/kg Q4W has not been 
examined as monotherapy in NSCLC.  Tremelimumab at a concentration of 30 μg/mL 
enhanced IL-2 release (in vitro) and showed anti-tumour activity (in vivo), and was 
consequently identified as the target concentration.  As a result, PK simulations indicate that 
at a dose of 10 mg/kg Q4W for 6 months, approximately 90% of patients are expected to be 
above this target level of 30 μg/mL during the induction phase.  An enhanced AUC at this 
dose may offer greater exposure which may confer benefit beyond what was noted in Study 
A3671015.  Therefore, this study will explore tremelimumab monotherapy at a dose of 
10 mg/kg Q4W for 24 weeks followed by 10mg/kg Q12W up to an additional 24 weeks.   
Expression of PD-L1 may have less bearing when a combination of checkpoint inhibitors is 
utilised.  A study investigating the combination of a PD-1 inhibitor (nivolumab) and a 
CTLA-4 inhibitor (ipilimumab) in patients with melanoma suggested that the combination of 
CTLA-4 and PD-1 blockade may be active regardless of tumoural PD-L1 expression 
(Wolchok et al 2013).  Early data from Study D4190C00006 (combination of MEDI4736 plus 
tremelimumab) has shown consistent clinical activity in an advanced/metastatic NSCLC 
patient population.  The combination of 2 immune checkpoint mAb inhibitors is likely to 
increase the frequency and/or severity of some toxicities, such as immune-mediated toxicities.  
Emerging safety data from these early phase combination studies suggests this to be the case.  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
51 
Examination of the combination of MEDI4736 plus tremelimumab is important to clearly 
define the activity and safety profile compared to Standard of Care. 
Therefore, NSCLC patients with PD-L1-negative tumours are a subset of patients with limited 
therapeutic options with a high unmet need, who may have a greater signal of activity from 
the combination of MEDI4736 plus tremelimumab versus MEDI4736 monotherapy or 
tremelimumab monotherapy.  As the toxicity profile varies amongst these therapies, 
exploration of the combination of MEDI4736 plus tremelimumab versus either of the 
constituent components as monotherapy agents is an important study that will clearly establish 
the proper risk benefit for each therapy. 
1.4 
Benefit/risk and ethical assessment 
Refer to the current IBs for information on the potential benefits of MEDI4736 and 
tremelimumab and an assessment of the potential and known risks.   
Lung cancer is an aggressive, heterogeneous, and complex disease that is often detected at an 
advanced stage, with no curative option for the majority of patients.  Despite advances in the 
diagnosis, imaging, staging and treatment of NSCLC, the estimated overall 5-year survival for 
patients in Europe continues to be low (11%) and the outlook for those with refractory 
advanced NSCLC is extremely poor (D’Addario et al 2010, GLOBOCAN 2008,  
Hanna et al 2004).  Common third-line treatment for NSCLC in major global markets 
includes: vinorelbine, TKIs and gemcitabine (Decisions Resources 2013).  For these patients, 
clinical trials, experimental treatment, or best supportive care are among the considered 
treatment options (Azzoli et al 2009, Syrigos et al 2011). 
1.4.1 
MEDI4736 monotherapy: Sub-study A 
MEDI4736 has been given to humans as part of ongoing studies where it is given either as a 
single drug or in combination with other drugs.  The majority of the safety data currently 
available for MEDI4736 is based on the FTIH, single agent study 1108 in patients with 
advanced solid tumours.  As of 14 July 2014, a total of 414 patients have entered into this 
study, of which 393 had received MEDI4736 at 10 mg/kg Q2W.  The most frequently 
reported (≥10% of patients) treatment-emergent AEs (all grades) were fatigue, dyspnoea, 
nausea, constipation and decreased appetite.  The majority of these treatment-emergent AEs 
were Grades 1 to 2 in severity and manageable by the general treatment guidelines as 
described in the current MEDI4736 study protocols.  Treatment-related AEs were reported for 
162 of 393 patients (41.2%).  The most frequently reported (≥2% of patients) 
treatment-related AEs (all grades) were fatigue (13.5%); nausea (8.4%); diarrhoea, decreased 
appetite, and rash (5.3% each); vomiting (4.8%); pruritus (4.1%); dyspnoea (3.8%); pyrexia 
(3.1%); hypothyroidism (2.8%); increased ALT, increased AST, and cough (2.5% each); 
myalgia (2.3%); and abdominal pain and dizziness (2.0% each).  No DLTs have been 
reported.   
Data presented at ESMO 2014 with a later cut-off of 21 August 2014 showed that MEDI4736 
was well tolerated at all doses in the NSCLC subset of patients enrolled into Study 1108, with 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
52 
drug-related Grade ≥3 AEs reported in 3% of patients; drug-related AEs leading to 
discontinuation reported in 1% of patients; no drug-related colitis or hyperglycaemia of any 
grade and no Grade ≥3 pneumonitis were reported and no drug-related AEs leading to death 
were reported (Antonia et al 2014 ESMO).  More recent data has been presented at 
international oncology conferences (Rizvi et al 2015 ASCO).  For further details on the safety 
data on MEDI4736, please refer to the current IB. 
Potential risks based on the mechanism of action of MEDI4736 and related molecules include 
immune-mediated reactions such as enterocolitis, dermatitis, hepatotoxicity, endocrinopathy, 
pneumonitis and neuropathy.  As with the administration of any foreign protein and/or other 
biologic agents, other important potential risks include anaphylaxis/anaphylactoid/ 
hypersensitivity reactions, serious infections, infusion reactions, immune-complex disease and 
the development of ADAs.  Anti-drug antibodies could result in immune-complex disease 
with manifestations such as arthralgias, serum sickness, and vasculitis and/or could result in 
altered MEDI4736 levels or activity.   
Among the most frequent treatment-related AEs noted with other mAbs targeting the 
PD-1/PD-L1 pathway are fatigue, rash, diarrhoea and pruritus.  Reported immune-mediated 
AEs of ≥Grade 3 include pneumonitis, diarrhoea, ALT increased and AST increased. 
Promising evidence of clinical activity has been observed for molecules similar to MEDI4736, 
including other mAbs targeting the PD-1/PD-L1 pathway.  In these studies, encouraging 
response rates and durable responses have been observed across a range of tumour types 
(Berger et al 2008, Brahmer et al 2010, Gordon et al 2013, Robert et al 2011, 
Topalian et al 2012).  
Evidence of clinical activity has also been observed with MEDI4736.  Of the 414 patients 
treated with MEDI4736 (all dose levels), 169 patients were evaluable for response analysis, 
which included patients who had at least 24 weeks of follow-up as of 14 July 2014 and had 
either at least 1 post-baseline tumour assessment or experienced clinical PD or death.  
Nineteen patients (11.2%) had a best overall response of CR/PR (confirmed and 
unconfirmed).  The DCR (CR + PR + SD ≥12 weeks) was 32% (54 of 169 patients).  
Programmed cell death ligand 1 status (based on Ventana/MedImmune assay) was known for 
143 of 169 evaluable patients, of whom 30 were PD-L1 positive.  A best overall response of 
CR/PR (confirmed and unconfirmed) was observed in 7 of 30 (23.3%) PD-L1-positive 
patients and in 6 of 113 (5.3%) PD-L1-negative patients.  
Of the 184 patients with NSCLC treated with MEDI4736 (all dose levels), 49 patients were 
evaluable for response analysis.  Seven patients (14.3%) had a best overall response of CR/PR 
(confirmed and unconfirmed).  The DCR was 36.7% (18 of 49 patients).  Programmed cell 
death ligand 1 status (based on Ventana assay) was known for 26 of the 49 evaluable patients 
(the 26 patients were treated with MEDI4736 10 mg/kg Q2W), of whom 8 were PD-L1 
positive.  A best overall response of CR/PR (confirmed and unconfirmed) was reported in 3 of 
8 (37.5%) PD-L1-positive patients and in 1 of 18 (5.6%) PD L1-negative patients. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
53 
Efficacy data on the NSCLC patients in Study 1108, presented at ESMO 2014 (cut-off date of 
21 August 2014), showed a disease control rate 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 in patients with PD-L1 positive (≥25% of tumour cells with 
membrane staining for PD-L1) tumours (25%; 12 CR/PR; n=48) compared to patients with 
PD-L1 negative tumours (10%; 7 CR/PR; n=74) (Antonia et al 2014 ESMO).  More recent 
data has been presented at international oncology conferences (Rizvi et al 2015 ASCO).  
Please refer to latest MEDI4736 IB for complete details of efficacy of MEDI4736 across all 
clinical programs. 
As discussed in Section 1.3, current experience from studies with single-agent IMTs that 
target the PD-1/PD-L1 pathway suggest that clinical responses may be enhanced in a subset of 
any given patient population and that it might be beneficial to enrich the patient population by 
selecting patients likely to respond to therapy.  Data from multiple sources using different 
assays and scoring methods suggests that PD-L1 expression on tumour cells and or 
tumour-infiltrating cells may be associated with greater clinical benefit.  It appears that the 
selection of patients based on PD-L1 expression within the tumour microenvironment may 
improve the probability and/or quality of responses to PD-1 pathway-targeting agents and, 
therefore, may have merit as a patient enrichment tool. 
Based on this information, the likelihood of response to MEDI4736 monotherapy is expected 
to be higher in NSCLC patients with PD-L1-positive tumours; nonetheless, responses were 
also noted in a few NSCLC patients with PD-L1-negative tumours. 
In view of the potential for MEDI4736 to have anti-tumour activity in the NSCLC patient 
population with PD-L1-positive and negative tumours, the risk-benefit assessment favours the 
proposed enrolment of patients with PD-L1 positive tumours into Sub-study A, MEDI4736 
monotherapy versus Standard of Care, and patients with PD-L1-negative tumours into 
Sub-Study B, MEDI4736+tremelimumab in combination versus Standard of Care (see 
Section 1.4.2). 
1.4.2 
MEDI4736 monotherapy, tremelimumab monotherapy and MEDI4736 plus 
tremelimumab: Sub-study B 
The benefits and risks of MEDI4736 given as a monotherapy agent are discussed in 
Section 1.4.1. 
Tremelimumab has been administered as a single-agent treatment to patients participating in 
11 sponsored clinical studies, 3 of which are ongoing.  In total, more than 1400 patients with a 
variety of tumour types have been treated with tremelimumab given alone or in combination 
with other anti-cancer agents in 34 sponsored clinical studies. 
Risks with tremelimumab monotherapy are gastrointestinal effects (colitis, diarrhoea, 
enterocolitis and intestinal perforation); endocrine disorders (hypo and hyperthyroidism, 
hypophysitis and adrenal insufficiency); skin effects (rash and pruritus); elevations in lipase 
and amylase; other gastrointestinal events (ulcerative colitis, dehydration, nausea and 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
54 
vomiting); hepatic events (hepatitis and liver enzyme elevations); pneumonitis and interstitial 
lung disease; clinical manifestations of pancreatitis; nervous system events (encephalitis, 
peripheral motor and sensory neuropathies, Guillain-Barre and proximal muscle weakness); 
cytopenias (thrombocytopenia, anemia and neutropenia); infusion-related reactions, 
anaphylaxis and allergic reactions; renal events (renal failure, acute kidney injury, nephritis, 
nephrotic syndrome, autoimmune nephritis and electrolyte abnormalities such as 
hypokalaemia); autoimmune diseases (autoimmune arthritis, Sjogren's syndrome and giant 
cell temporal arteritis); hyperglycaemia and diabetes mellitus; and pyrexia.   
Further information on the identified and potential risks can be found in the current version of 
the tremelimumab IB. 
Using pooled data from monotherapy clinical studies, AEs (all grades) reported very 
commonly (≥10% of patients) were diarrhoea, nausea, fatigue, pruritus, decreased appetite, 
rash, vomiting, dyspnoea, constipation, cough, pyrexia, abdominal pain, decreased weight, 
headache, asthenia and anaemia.  Approximately 16% of patients experienced an AE that 
resulted in permanent discontinuation of tremelimumab and approximately 45% of patients 
experienced an SAE. 
The majority of the updated reference safety information for tremelimumab is based on data 
from the mesothelioma (Study D4880C00003 [DETERMINE]) and melanoma (legacy data 
from tremelimumab mesothelioma/melanoma multiple dose pools) subject data, but is 
consistent with the safety profile of anti-CTLA-4 antibodies and expected to be applicable to 
most subjects with solid tumours.  A detailed summary of these studies and the tremelimumab 
monotherapy AE data can be found in the current version of the tremelimumab IB. 
Although clinical experience with the single agent, tremelimumab, in NSCLC is limited, a 
Phase II study (A3671015) examining tremelimumab (15 mg/kg every 90 days) as 
maintenance treatment post-platinum doublet chemotherapy in advanced NSCLC patients 
produced a trend toward improved PFS at 3 months and a 4.8% PR rate.  The more intensive 
tremelimumab treatment regimen of 10 mg/kg Q4W has not been examined as monotherapy 
in NSCLC.  In this study (Study D4191C00004), tremelimumab will be given at a dose of 
10 mg/kg Q4W for 24 weeks and then 10 mg/kg Q12W for up to a further 24 weeks.  The 
enhanced AUC offered by this greater exposure may confer benefit beyond what was seen in 
the previous Phase II study. 
As discussed in Section 1.1.5, data from the dose-escalation combination study of MEDI4736 
plus tremelimumab in NSCLC patients have shown an acceptable and manageable safety 
profile in an advanced/metastatic NSCLC patient population, and signs of clinical activity 
have been seen.  As of 27 January 2015, 53 patients have at least 8 weeks of follow-up data.  
Twelve patients had best overall responses of PR and 14 patients had SD as assessed by 
RECIST. 
As of 27 January 2015, AEs regardless of causality were reported in 62 of the 74 patients 
(83.8%) across all dose cohorts.  Adverse events were considered related to treatment in 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
55 
50 patients (67.6%).  Twenty-four of the 50 patients who experienced treatment-related AEs 
reported Grade 1 or 2 events only.  Twenty-six of the 50 patients reported ≥Grade 3 events. 
Data in the literature from combinations of the same class of drugs showed higher response 
rates than those obtained with single-agent therapy, and these responses appeared to be rapid 
and deep.  Also, responses to combined therapy were generally durable and were observed 
even in patients whose treatment was terminated early because of AEs (Wolchok et al 2013). 
Also, as previously discussed in Section 1.3, the selection of patients based on PD-L1 
expression within the tumour microenvironment may improve the likelihood of response to 
MEDI4736 monotherapy in patients with PD-L1-positive tumours; however, patients with 
PD-L1-negative tumours also showed clinical benefit. 
In Study A3671015, patients with advanced NSCLC given tremelimumab had limited benefit 
and a trend toward improved PFS at 3 months.  The approach of using 10 mg/kg Q4W to 
enhance AUC merits testing on a larger scale as monotherapy. 
Expression of PD-L1 may have less bearing when a combination of checkpoint inhibitors is 
utilised.  A study investigating the combination of a PD-1 inhibitor (nivolumab) and a 
CTLA-4 inhibitor (ipilimumab) in patients with melanoma suggested that the combination of 
CTLA-4 and PD-1 blockade may be active regardless of tumoural PD-L1 expression 
(Wolchok et al 2013).   
With the proliferation of agents targeting the NSCLC patients with PD-L1 positive tumours, 
the NSCLC patients with PD-L1–negative tumours represent an unmet medical need with 
limited therapeutic options and it is imperative that different monotherapeutic and 
combinatorial approaches be examined.  It is also of importance to assess the efficacy of the 
combination versus each of its separate components when administered as monotherapy 
agents. 
Emerging safety data from these early studies exploring the combination of immune 
checkpoint inhibitors indicate an increased frequency and/or severity of some toxicities, such 
as immune-related toxicities; which are manageable based on immune-related toxicity 
management guidelines.  
Therefore, Sub-study B offers NSCLC patients with PD-L1-negative expressing tumours 
acceptable therapeutic options with manageable safety profiles. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
56 
1.4.3 
Summary of potential benefits and risks of other immunotherapy agents 
Other mAbs targeting the PD-1/PD-L1 pathway are currently in clinical development.  Among 
the most frequent treatment-related AEs noted with these antibodies are fatigue, rash, 
diarrhoea and pruritus.  Immune-mediated AEs of ≥Grade 3 reported include pneumonitis, 
diarrhoea, ALT increased and AST increased. 
Other relevant risks include those associated with biological and immunotherapy agents.  
Ipilimumab and tremelimumab are both immunomodulatory antibodies that target CTLA-4 
and have been studied extensively across multiple tumour types.  Ipilimumab is marketed for 
the treatment of metastatic or unresectable melanoma based on improvements in OS as a 
single agent and in combination with chemotherapy.  Immune-mediated AEs of Grade 3 or 
higher observed during Phase III studies of ipilimumab occurred in 15% of patients and 
included enterocolitis (7%), hepatitis (2%), dermatitis (2.5%) and endocrinopathy (1.8%) 
(YERVOY™ prescribing information).  Adverse events similar to those reported with 
ipilimumab were observed during the clinical development of tremelimumab in melanoma, 
with diarrhoea (40%), pruritus (23%), rash (22%), nausea (22%) and fatigue (17%) being the 
most common (Kirkwood et al 2010).  Grade 3 or higher AEs observed were diarrhoea (11%), 
fatigue (2%), rash (1%), nausea (1%), vomiting (1%) and anorexia (1%). 
Promising evidence of clinical activity has been observed for molecules similar to 
tremelimumab and MEDI4736, including other mAbs targeting the CTLA-4 and PD-1/PD-L1 
pathways, respectively.  In these studies, encouraging response rates and durable responses 
have been observed across a range of tumour types (Berger et al 2008, Brahmer et al 2010, 
Gordon et al 2013, Robert et al 2011, Topalian et al 2012,  
YERVOY™ prescribing information, OPDIVO® prescribing information,  
KEYTRUDA® prescribing information). 
1.4.4 
Summary benefit: risk statement 
Lung cancer is an aggressive, heterogeneous, and complex disease that is often detected at an 
advanced stage, with no curative option for the majority of patients.  Despite advances in the 
diagnosis, imaging, staging and treatment of NSCLC, the estimated overall 5-year survival for 
patients in Europe continues to be low (11%) and the outlook for those with refractory 
advanced NSCLC is extremely poor (D’Addario et al 2010, Hanna et al 2004).  There remains 
a significant unmet medical need for additional treatment options for NSCLC patients, 
especially in the third-line or greater setting where treatment options are limited.   
Emerging clinical data show that MEDI4736 has an acceptable and manageable safety profile, 
and the potential for MEDI4736 to have anti-tumour activity in the NSCLC population with 
PD-L1-positive tumours supports a risk-benefit assessment that favours the proposed 
enrolment of such patients into MEDI4736 monotherapy in Sub-study A of this study.   
In NSCLC patients with PD-L1-negative tumours, MEDI4736 monotherapy is expected to 
confer limited efficacy with a manageable safety profile consistent with the FTIH study 
(Study 1108; see Section 1.1.3).  Emerging data from the tremelimumab clinical development 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
57 
programme suggest that tremelimumab monotherapy appears to have anti-tumour activity 
alongside a manageable safety profile in an advanced cancer population.  While response rates 
are generally low (approximately 10%), in those patients who do respond the responses are 
generally durable, lasting several months.  The enhanced AUC and exposure of the 
tremelimumab 10 mg/kg Q4W regimen may enhance efficacy while retaining a manageable 
safety profile. 
Although limited in scope, the emerging data for the combination of MEDI4736 plus 
tremelimumab suggests an acceptable and manageable safety profile.  There are early signs of 
clinical efficacy, and data in the literature from combinations of the same class of drugs 
showed higher response rates than those obtained with single-agent therapy, with responses 
that appear to be rapid and deep.  Also, responses to the combination therapy were generally 
durable and were observed even in patients whose treatment was terminated early because of 
AEs (Wolchok et al 2013).   
For patients with PD-L1-negative tumours, the risk-benefit assessment favours the proposed 
enrolment of these patients into the MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736 plus tremelimumab in Sub-study B of this study. 
All patients will be closely monitored and are able to stop treatment at any time if they choose 
to do so, or if the investigator judges it is in the best interest of the patient.  Additionally, in 
the event of unmanageable toxicity, directions for delaying an infusion or permanently 
stopping MEDI4736 monotherapy, tremelimumab monotherapy or MEDI4736 combined with 
tremelimumab are provided.  
Finally, the safety of patients in this study will be assessed by an Independent Data 
Monitoring Committee (IDMC) via ongoing safety assessments.  The committee will meet 
approximately 6 months after the study has started or 20 patients have been randomised to the 
combination arm (whichever comes first) to review the safety data from the study.  The IDMC 
will meet approximately every 6 months thereafter.  In addition for Sub-study B, an interim 
contribution of components analysis may be reviewed by the IDMC to determine whether the 
MEDI4736+tremelimumab arm is superior to each of the MEDI4736 monotherapy and 
tremelimumab monotherapy arms in turn.  If the MEDI4736+tremelimumab arm is superior to 
either or both of the monotherapy arms, then the applicable monotherapy arms may be 
dropped from Sub-study B.  If either or both monotherapy arms are dropped any patients on 
treatment will have the opportunity to remain on treatment if they are gaining clinical benefit 
and if, after discussion with their treating physician, it is felt that this is the best treatment 
option for them. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
58 
2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Primary Objective: 
Outcome Measure: 
Sub-study A (PD-L1-positive population) 
To assess the efficacy of MEDI4736 monotherapy 
compared with Standard of Care in terms of OS and 
PFS 
Sub-study B (PD-L1-negative population) 
To assess the efficacy of MEDI4736+tremelimumab 
treatment compared with Standard of Care in terms of 
OS and PFS 
OSa 
PFS using investigator assessments according to 
RECIST 1.1a,b 
a 
In each of the Sub-studies A and B the assessment of PFS and OS will be considered co-primary objectives.   
b 
The co-primary analysis of PFS will be based on programmatically-derived PFS based upon investigator assessment.  
For the analyses to be conducted, see Section 12.2.2. 
OS  Overall survival; PD-L1  Programmed death ligand 1; PFS  Progression free survival; RECIST  Response Evaluation 
Criteria In Solid Tumours. 
 
2.2 
Secondary objectives 
The following are the secondary objectives in Sub-study A (MEDI4736 monotherapy versus 
Standard of Care) and Sub-study B (MEDI4736+tremelimumab versus Standard of Care):  
Secondary Objective: 
Outcome Measure: 
To further assess the efficacy in terms of: OS12, 
ORR, DoR, APF6, APF12 and PFS2 
OS12 
ORR using investigator assessments according to 
RECIST 1.1a 
DoR using investigator assessments according to 
RECIST 1.1a 
APF6 and APF12 using investigator assessments 
according to RECIST 1.1a 
PFS2 as defined by local standard clinical practice 
 
To assess the safety and tolerability profile 
Adverse events, physical examinations, vital signs 
including blood pressure, pulse, electrocardiograms, 
and laboratory findings including clinical chemistry, 
haematology and urinalysis 
To assess the PK of MEDI4736 and tremelimumab 
Concentration of PK in blood and non-compartmental 
PK parameters (such as peak concentration and trough, 
as data allow) (sparse sampling) 
To investigate the immunogenicity of MEDI4736 
and tremelimumab  
ADA (confirmatory results: positive or negative; titres 
[ADA neutralising antibodies will also be assessed])  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
59 
Secondary Objective: 
Outcome Measure: 
To assess symptoms and health-related QoL using 
EORTC QLQ-C30 v3 and LC13 
EORTC QLQ-C30: Time to symptom deterioration 
(fatigue, pain, nausea/vomiting, dyspnoea, loss of 
appetite, insomnia, constipation, and diarrhoea).  Time 
to QoL/function deterioration (physical function; role 
function; emotional function; cognitive function; social 
function and global health status/QoL) 
LC13: Time to symptom deterioration (dyspnoea, 
cough, haemoptysis, chest pain, arm/shoulder pain, 
other pain) 
Changes in World Health Organisation Performance 
Status will also be assessed 
Sub-study B (PD-L1-negative population) 
To evaluate the efficacy of 
MEDI4736+tremelimumab treatment compared 
with a) MEDI4736 monotherapy and b) 
tremelimumab monotherapy  
PFSa, ORRa and DoRa using investigator assessments 
according to RECIST 1.1, and OS 
a 
Analysis of ORR, DoR, APF6 and APF12 will be based upon investigator assessment.  For the analyses to be 
conducted, see Sections 12.2.3, 12.2.4, 12.2.5 and 12.2.6. 
ADA  Anti-drug antibody; APF6  Proportion of patients alive and progression free at 6 months from randomisation; APF12  
Proportion of patients alive and progression free at 12 months from randomisation; DoR  Duration of response; EORTC 
QLQ-C30 European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire; LC13  
Lung Cancer Module; ORR Objective response rate; OS12  Proportion of patients alive at 12 months from randomisation; 
PFS  Progression free survival; PFS2  Time from randomisation to second progression; PK  Pharmacokinetic(s); QoL  Quality 
of Life; RECIST  Response Evaluation Criteria In Solid Tumours; WHO  World Health Organisation. 
 
In Sub-study B, PFS in MEDI4736+tremelimumab arm will be compared to each of the 
MEDI4736 and tremelimumab monotherapy arms as part of the contribution of components 
analysis.  This analysis is planned to be performed when approximately 158 PFS events are 
observed in the MEDI4736+tremelimumab and tremelimumab monotherapy arms.  However, 
for practical considerations, if this time is close to the time of the final PFS analysis, the 
contribution of components analysis will be conducted at the time of the final PFS analysis.  
This is considered a secondary objective of the study.   
2.3 
Exploratory objectives 
The following exploratory objectives will be addressed in Sub-studies A and B: 
 
 
 
 
 
 
 
  
 
 
 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
60 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE  Adverse event; EQ-5D-5L  EuroQoL 5-dimension, 5-level health state utility index; IFN  Interferon; IL  Interleukin; 
ORR Objective response rate; OS  Overall survival; PD-L1  Programmed death ligand 1; PDx  Pharmacodynamic(s); PFS  
Progression free survival; PK  Pharmacokinetic(s).   
 
With regards to PD-L1 expression determined by immunohistochemistry, this will be reported 
in the Clinical Study Report (CSR).  
 
 
 
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
61 
3. 
STUDY PLAN AND PROCEDURES 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. 
3.1 
Overall study design and flow chart 
This study is a Phase III, randomised, open label, multi-centre study assessing the efficacy and 
safety of MEDI4736 versus Standard of Care in NSCLC patients with PD-L1-positive 
tumours and the combination of MEDI4736 plus tremelimumab (MEDI4736+tremelimumab) 
versus Standard of Care in NSCLC patients with PD-L1-negative tumours.  The study will 
enrol male and female patients with locally advanced or metastatic NSCLC (Stage IIIB-IV), 
who have received at least 2 prior systemic treatment regimens including 1 platinum-based 
chemotherapy regimen for NSCLC.  Patients with known EGFR tyrosine kinase (TK) 
activating mutations and anaplastic lymphoma kinase (ALK) rearrangements are not eligible 
for the study (prospective testing is not planned within this study).   
Approximately 1300 patients will be recruited, with approximately 610 patients expected to be 
randomised (126 patients in Sub-study A and 480 patients in Sub-study B) at approximately 
250 sites worldwide.  The original study design intended to recruit 250 patients to 
Sub-study A.  However, due to low patient accrual, the recruitment to Sub-study A was closed 
in Q1 2016 at which time 126 patients had been randomised.  As a result, the analysis plan for 
Sub-study A was updated and is presented in Protocol Amendment 6.0, dated 31 August 2016.  
Patients will be randomised in a 1:1 ratio in Sub-study A and a 3:2:2:1 ratio 
(MEDI4736+tremelimumab:MEDI4736:Standard of Care:tremelimumab) in Sub-study B.  
Sub-study A (patients with PD-L1-positive tumours): 
• 
MEDI4736 (10 mg/kg Q2W iv for up to 12 months) (approximately 60 patients) 
• 
Standard of Care (restricted to the erlotinib, gemcitabine or vinorelbine) 
(approximately 60 patients).  For each agent 4 weeks equates to 1 cycle of 
treatment. 
− 
Erlotinib: 150 mg once daily as a tablet for oral administration taken at least 
1 hour before or 2 hours after the ingestion of food 
− 
Gemcitabine: 1000 mg/m2 iv over 30 minutes on Days 1, 8, and 15 of a 28-day 
cycle 
− 
Vinorelbine: 30 mg/m2 iv on Days 1, 8, 15 and 22 of a 28-day cycle.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
62 
Sub-study B (patients with PD-L1-negative tumours): 
• 
MEDI4736+tremelimumab (MEDI4736 20 mg/kg plus tremelimumab 1 mg/kg 
Q4W iv for up to 12 weeks [4 doses]) then MEDI4736 alone (10 mg/kg Q2W iv, 
starting at Week 16, for 34 weeks [18 doses]) (180 patients) 
• 
Standard of Care (see under Sub-study A) (120 patients) 
• 
MEDI4736 (10 mg/kg Q2W iv for up to 12 months) (120 patients) 
• 
Tremelimumab (10 mg/kg Q4W iv for 24 weeks then Q12W for 24 weeks) 
(60 patients). 
The sub-studies may not run concurrently with the start and completion of recruitment 
potentially occurring at different time points.  Assignment to the applicable sub-study will be 
preceded by the Pre-screening Period during which assessment of the patient’s PD-L1 status, 
based on a tumour sample, will take place.  After confirmation of PD-L1 status, patients will 
enter the main Screening Period within their assigned sub-study if it remains open for 
recruitment.  The study design is shown in diagram form in Figure 2. 
Figure 2 
Study design schema 
 
 
Study procedures at Screening and during the Treatment Period for MEDI4736 monotherapy in Sub-studies A 
and B are presented in Table 3, and for tremelimumab monotherapy and MEDI4736+tremelimumab in 
Sub-study B in Table 4 and Table 5.  Follow-up procedures for patients who have completed MEDI4736 
monotherapy, tremelimumab monotherapy or MEDI4736+tremelimumab and achieved disease control, and for 
Determination
of PD-L1 
status
PD-L1
positive
PD-L1
negative
Sub-study B
Day -42 to -1
Day 1
Randomisation
Pre-screening
Treatment  Period
Follow-up
Screening and 
Assignment to 
Sub-study
All patients will 
enter follow up.
For the 
immunotherapy 
arms re-
treatment  is 
allowed
for those who 
have disease 
control  after 
12 months of 
treatment but
progress during 
follow-up. For 
combination arm, 
re-treatment 
allowed after 
16 weeks but 
progress during 
MEDI4736 
monotherapy 
period
MEDI4736 monotherapy
(Up to 12 months)
Standard of Care
(For as long as getting clinical benefit)
MEDI4736 monotherapy 
(Up to 12 months)
Tremelimumab monotherapy
(Up to 12 months)
Day -28 to -1
PD-L1 = programmed death ligand 1
MEDI4736+tremelimumab
(Up to 12 months   [combination  for 
12 weeks; MEDI4736 monotherapy for 
34 weeks])
Standard of Care
(For as long as getting clinical benefit)
Sub-study A
1:1 ratio
3:2:2:1 ratio


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
63 
patients who have discontinued MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab due to toxicity or a reason other than confirmed PD are presented in Table 6.  
Follow-up procedures for patients who have discontinued MEDI4736 monotherapy, tremelimumab monotherapy 
or MEDI4736+tremelimumab due to confirmed PD are presented in Table 7.  Study procedures for patients 
treated with vinorelbine or gemcitabine in the Standard of Care arm are presented in Table 8.  Study procedures 
for patients treated with erlotinib in the Standard of Care arm are presented in Table 9.  Follow-up procedures for 
patients treated with Standard of Care are presented in Table 10.   
 
Patients must have histologically- or cytologically-documented Stage IIIB/Stage IV NSCLC 
(according to Version 7 of the International Association for the Study of Lung Cancer 
(IASLC) Staging Manual in Thoracic Oncology  
[IASLC Staging Manual in Thoracic Oncology]), or recurrent or progressive disease 
following multimodal therapy (radiation therapy, surgical resection, or definitive 
chemoradiation therapy for locally advanced disease).  Patients with advanced or metastatic 
NSCLC must have received at least 2 prior systemic treatment regimens to be eligible 
including a platinum-based chemotherapy regimen. 
PD-L1 expression will be determined for all patients prior to randomisation.  Patients will be 
assigned to Sub-study A and Sub-study B respectively based on PD-L1 tumour expression 
status (PD-L1 positive versus PD-L1 negative [based on an archival tumour sample or a recent 
tumour biopsy]).  Patients will be stratified at randomisation based on the Standard of Care 
treatment that they would be administered if randomised to the Standard of Care arm 
(2 categories: gemcitabine/vinorelbine versus erlotinib) and histology (2 categories: squamous 
versus all other). 
The primary objective of this study is to assess the efficacy of MEDI4736 monotherapy 
(patients with PD-L1-positive tumours) and MEDI4736+tremelimumab (patients with 
PD-L1-negative tumours) compared with Standard of Care in terms of OS and PFS (per 
RECIST 1.1 as assessed by the investigator).   
For Sub-study B, an interim analysis for OS will be performed.  The purpose of the OS 
interim analysis is to demonstrate superiority to support the primary objective in terms of OS.   
For Sub-study B, a contribution of components analysis will be performed when 
approximately 158 PFS events are observed in the MEDI4736+tremelimumab and 
tremelimumab monotherapy arms.  However, for practical considerations, if this time is close 
to the time of the final PFS analysis, the contribution of components analysis will be 
conducted at the time of the final PFS analysis.  The purpose of this analysis is to compare the 
monotherapy and combination dosing regimens to determine if the combination therapy (ie, 
MEDI4736+tremelimumab) is more efficacious than each of the monotherapy arms.  As these 
treatment comparisons are secondary and serve a different purpose to that of the primary 
comparisons, they are not included in the multiple testing procedure for the primary 
comparisons, and an alpha of 0.05 will be used for either PFS or OS without multiplicity 
adjustment. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
64 
If the contribution of components analysis is performed prior to the final PFS analysis and the 
MEDI4736+tremelimumab arm is superior to either of the monotherapy arms, then that 
monotherapy arm may be dropped from the study and all patients on that treatment will be 
discontinued.  However, any patients on that treatment will have the opportunity to remain on 
treatment if they are gaining clinical benefit and if, after discussion with their treating 
physician, it is felt that this is the best treatment option for them.   
Sub-study A: Treatment with MEDI4736 10 mg/kg will commence on Day 1 following 
randomisation after confirmation of eligibility and will continue on a Q2W schedule for up to 
12 months.  Treatment should be discontinued prior to 12 months if there is confirmed PD 
(unless the investigator considers the patient continues to receive benefit from treatment), 
initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other 
reasons to discontinue treatment occur.  Patients who have discontinued treatment due to 
toxicity, symptomatic deterioration or who have commenced subsequent anti-cancer therapy 
will be followed up until confirmed disease progression or death (whichever occurs first).  
Study drug should be discontinued if there is confirmed PD while on treatment following a 
previous response (PR or CR) to study drug while on treatment (ie, the response and 
progression events both occurred while receiving study drug during the same treatment 
period). 
Sub-study B: Treatment with MEDI4736 or tremelimumab monotherapy, or the combination 
of MEDI4736+tremelimumab will commence on Day 1 following randomisation after 
confirmation of eligibility.  MEDI4736 will continue on a 10 mg/kg Q2W schedule when 
given as monotherapy for up to 12 months and tremelimumab when given as a monotherapy, 
will continue on a 10 mg/kg Q4W schedule for 24 weeks then Q12W for a further 24 weeks.  
MEDI4736+tremelimumab in combination will be administered from Day 1 on a Q4W 
schedule up to 12 weeks (4 doses of MEDI4736 20 mg/kg and tremelimumab 1 mg/kg) after 
which MEDI4736 10 mg/kg alone will be administered on a Q2W schedule for 34 weeks 
starting at Week 16 (18 doses).   
In the monotherapy arms in Sub-study B, treatment should be discontinued prior to 12 months 
(MEDI4736 monotherapy) or 48 weeks (tremelimumab monotherapy) if there is confirmed 
PD (unless the investigator considers the patient continues to receive benefit from treatment), 
initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other 
reasons to discontinue treatment occur.  Patients who have discontinued treatment due to 
toxicity, symptomatic deterioration or who have commenced subsequent anti-cancer therapy 
will be followed up until confirmed disease progression or death (whichever occurs first).   
Study drug should be discontinued if there is confirmed PD while on treatment following a 
previous response (PR or CR) to study drug while on treatment (ie, the response and 
progression events both occurred while receiving study drug during the same treatment 
period). 
In the combination arm, if a patient experiences PD, retreatment with the combination 
regimen (MEDI4736+ tremelimumab) is allowed.  Retreatment in the combination arm can 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
65 
only occur if PD, with or without confirmation, occurs during the MEDI4736 monotherapy 
portion or after completion of 12 months of therapy.  During the retreatment period, the 
patient would resume MEDI4736 dosing at 20 mg/kg Q4W as during the initial induction 
period, along with 1 mg/kg of tremelimumab Q4W for 4 doses.  Monotherapy with 
MEDI4736 would then resume at 10 mg/kg Q2W 4 weeks after the last combination dose is 
administered for as long as the investigator judges they are gaining clinical benefit. 
Both Sub-study A and B: Treatment in the Standard of Care arm will commence on Day 1 
following randomisation after confirmation of eligibility and will continue on a 4-weekly 
schedule until PD (unless the investigator considers the patient continues to receive benefit 
from treatment), initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of 
consent, or other reasons to discontinue treatment occur.   
Tumour assessments using computed tomography (CT)/magnetic resonance imaging (MRI) 
will be performed every 8 weeks at the times specified in Table 3, Table 4, Table 6 and 
Table 7 for patients receiving MEDI4736 and tremelimumab monotherapy, Table 5, Table 6 
and Table 7 for patients receiving MEDI4736+tremelimumab, and Table 8 (for patients 
receiving gemcitabine or vinorelbine), Table 9 (for patients receiving erlotinib), and Table 10 
(follow-up period for all patients in the Standard of Care arm) for patients receiving Standard 
of Care.  The baseline assessment should be performed within the 28 days prior to 
randomisation.  Response Evaluation Criteria In Solid Tumours 1.1 measurements (using 
investigator assessments) will be used to derive the co-primary variable of PFS and secondary 
variables of ORR, DoR, APF6, APF12 and PFS2.  Categorisation of objective tumour 
response assessment will be based on the RECIST 1.1 criteria of response: CR, PR, SD and 
PD.   
Once a patient has had objective progression recorded and has discontinued study drug, the 
patient will be followed up for survival status every 2 months until death, withdrawal of 
consent or the final DCO. 
Sensitivity analyses will be performed on PFS, ORR and DoR based on tumour information 
recorded in the clinical database by the investigator according to RECIST 1.1 (Sub-study B).  
See Section 6.3 and Appendix F for further information regarding RECIST tumour 
assessments in this study.   
The study flow charts are presented in Figure 3 (for patients randomised to MEDI4736 
monotherapy, tremelimumab monotherapy or MEDI4736+tremelimumab) and Figure 4 (for 
patients randomised to Standard of Care). 
It is important to follow the assessment schedules as closely as possible.  The schedule of 
study procedures at Screening and during the Treatment Period for MEDI4736 monotherapy 
is presented in Table 3, for tremelimumab monotherapy in Table 4 and for 
MEDI4736+tremelimumab in Table 5.  The schedule of follow-up procedures for patients 
who have completed MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab and achieved disease control, and patients who have discontinued 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
66 
MEDI4736 monotherapy, tremelimumab monotherapy or MEDI4736+tremelimumab due to 
toxicity or a reason other than confirmed PD is presented in Table 6.  The schedule of follow-
up procedures for patients who have discontinued MEDI4736 monotherapy, tremelimumab 
monotherapy or MEDI4736+tremelimumab due to confirmed PD is presented in Table 7.   
The schedule of study procedures for patients treated with vinorelbine or gemcitabine in the 
Standard of Care arm is presented in Table 8.  The schedule of study procedures for patients 
treated with erlotinib in the Standard of Care arm is presented in Table 9.  The schedule of 
follow-up procedures for patients treated with Standard of Care is presented in Table 10.   
Every effort should be made to obtain accurate follow-up information on patients whose PFS 
and OS data were not accurately recorded.  For example, in the case of PFS, the local 
investigator could provide their clinical assessment of progression if care transfers elsewhere, 
and for OS an effort should be made to continue to follow and use death registries where 
necessary.  
Guidelines for the management of toxicities are described in Section 5.5.3. 
 
Treatment delays 
All visits should be conducted based on the schedules provided in Table 3 to Table 10, unless 
otherwise indicated. 
For all treatment arms 
• 
Tumour efficacy (RECIST 1.1) assessments dates are not affected by dose delays, 
and remain as originally scheduled, because they are based on the date of 
randomisation (not the date of therapy). 
• 
All other scheduled assessments must be performed relative to the start of the 
dosing cycle such that all laboratory procedures required for dosing should be 
performed within 3 days prior to dosing. 
For MEDI4736 monotherapy, tremelimumab monotherapy or MEDI4736+tremelimumab 
combination arms 
Patients may delay dosing under certain circumstances: 
• 
Dosing may be delayed due to either an immune or a non-immune-related AE 
(irAE) as per Toxicity Management Guidelines (Refer to Section 5.5.3). 
• 
If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible. 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
67 
• 
Dosing intervals of subsequent cycles in the combination arm may be shortened as 
clinically feasible and in line with the treatment windows in order to gradually align 
treatment cycles with the schedule of tumour efficacy (RECIST 1.1) assessments. 
Independent Data Monitoring Committee 
An IDMC will be convened and will meet approximately 6 months after the study has started 
or 20 patients have been randomised to the combination arm on Sub-study B (whichever 
comes first) to review safety assessments and make recommendations to continue, amend, or 
stop the study based on safety findings.  The committee will meet approximately every 
6 months thereafter.  The IDMC will also review: 
• 
The interim analysis for OS on Sub-study B (see Section 12.2.14) 
• 
The contribution of components analysis for the immunotherapy arms if this 
analysis occurs before the primary PFS analysis. 
All patients who receive a dose of study treatment will be evaluated for safety and tolerability.  
Enrolment will continue unless there is an unexpected safety concern.  The study may be 
adjusted or suspended depending on the IDMC review outcome. 
Details on the IDMC are provided in Section 12.4 and full details of the IDMC procedures and 
processes can be found in the IDMC Charter. 
End of Analysis Portion of Study 
At the time of the final DCO, the analysis portion of the clinical study will have been 
completed and all patients remaining in the study will be considered to have completed the 
analysis portion of the study.   
Patients in OS follow-up (progressed and have completed treatment) will be considered to 
have completed the study.  Patients in progression-free follow up (patients who have 
completed treatment and have not progressed and who are still potentially eligible for 
retreatment) may decide to continue in the study in progression-free follow up.  These patients 
would therefore remain eligible for possible future re-treatment upon progression if they meet 
re-treatment criteria and the investigator judges that the patient will gain clinical 
benefit.  Patients already receiving re-treatment at the time of final DCO for the study may 
continue receiving investigational product if the investigator judges that they are gaining 
clinical benefit. 
Scans will be collected in accordance with local clinical practice.  Patients in progression-free 
follow-up after the final DCO are to undergo sampling for local laboratory assessments in 
such a way that continued per-protocol re-treatment eligibility can be properly 
determined.  For patients receiving re-treatment after final DCO, it is recommended that the 
patients continue the scheduled site visits and investigators monitor the patient’s safety 
laboratory assessments prior to and periodically during treatment in order to manage AEs in 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
68 
accordance with the toxicity management guidelines (Refer to Section 5.5.3).  All data will be 
recorded on patient charts but will not otherwise be reported for the purposes of this study. 
For patients who either continue to receive treatment or begin re-treatment after the time of 
the final DCO, investigators will report all serious adverse events (SAEs) to 
AstraZeneca/MedImmune patient safety until 90 days after investigational product is 
discontinued.  Following the final DCO, SAE reporting applies only to patients who are active 
on the drug and within 90 days post the last dose.  In addition, in patients who are still in 
progression-free follow-up at the final DCO and who are eligible for future re-treatment (ie, 
the patient was randomised to investigational product, completed the initial 12 month 
treatment period and had SD, PR or CR at completion of 12 months of treatment), notification 
must be sent to QuintilesIMS if the patient dies (via the statement of death CRF) or if the 
patient goes onto receive another alternate systemic anti-cancer therapy and thus becomes 
ineligible for re-treatment. 
In the event that a roll-over or safety extension study will become available, patients currently 
receiving treatment with study drug or patients in progression-free follow-up may be 
transitioned to such a study, and the current study would end.  The roll-over or safety 
extension study would ensure treatment continuation with visits assessment per its protocol.  
Any patient that would be proposed to move to such study would be given a new Informed 
Consent. 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
69 
Figure 3 
Study flow chart (for patients randomised to MEDI4736 monotherapy, 
tremelimumab monotherapy or MEDI4736+tremelimumab) 
 
a 
Screening assessments can be performed in a step-wise process.  The baseline tumour assessment should be performed 
within the 28 days prior to randomisation. 
b 
In the monotherapy arms and during the first 4 cycles of the combination arm, disease progression requires 
confirmation and 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.  Administration of study 
treatment will continue between the initial assessment of progression and confirmation for progression.  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.  The patient must continue to 
meet those inclusion and exclusion criteria that are relevant to treatment through disease progression as specified in 
Section 4.3.  Patients with rapid tumour progression or with symptomatic progression that requires urgent medical 
intervention (eg, central nervous system metastasis, respiratory failure due to tumour compression, spinal cord 
compression) will not be eligible to continue to receive study treatment. 
c 
In the monotherapy arms, patients who achieve and maintain disease control (ie, CR, PR or SD) through to the end of 
the 12-month/48-week treatment period may restart study treatment upon evidence of PD (according to RECIST 1.1) 
with or without confirmation during follow-up.  Patients in the MEDI4736+tremelimumab arm who achieve and 
maintain disease control (ie, CR, PR or SD) through to the end of the 4th cycle (Week 16, 4 weeks after the last dose of 
combination treatment) may restart combination treatment upon evidence of PD (according to RECIST 1.1), with or 
without confirmation, during the MEDI4736 monotherapy part of the combination schedule. Before restarting study 
treatment, the investigator should ensure patients do not have any significant, unacceptable or irreversible toxicities that 
indicate continuing treatment will not further benefit the patient.  The patient must continue to meet those inclusion and 
Screening  Assessments
(Day -28 to -1)a
Day 1 Randomisation/Baseline
Continue tumour assessment using RECIST 1.1.  Follow-up assessments per 
Table 6 until confirmed progression of disease.
For those in the MEDI4736+tremelimumab arm start MEDI4736 monotherapy at Week 16
Disease control at the end of 
12 months of treatment or at 16 weeks for those in 
MEDI4736+tremelimumab arm
Treatment Period (assessments per Table 3 [MEDI4736 monotherapy], Table 4 
[tremelimumab monotherapy] or Table 5 [MEDI4736+tremelimumab]):
Tumour assessments using RECIST 1.1 performed at Screening
and then every 8 weeks thereafter (relative to the date of randomisation)b
Discontinuation of
treatment
Follow-up assessments and survival contact
per Table 7e
Confirmed progression of 
diseased
Due to toxicity or other 
reasons
Due to confirmed progression 
of diseased
Potential for retreatment of patients 
who have experienced disease 
control. A patient is only allowed to 
restart treatment ONCEc
Pre-screening for PD-L1 Status
(Day -42 to -1)


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
70 
exclusion criteria that are relevant to treatment through disease progression and retreatment as specified in Section 4.3.  
To restart study treatment the patient must not have received an intervening systemic anti-cancer therapy post-study 
treatment discontinuation.  Patients should have a baseline tumour assessment within 28 days before restarting study 
treatment, all further scans should occur every 8 weeks (relative to the date of restarting study treatment).  Patients who 
continue to receive re-treatment after the final DCO should receive scans/RECIST and other assessments as per local 
practice.  It is recommended that the patients continue the scheduled site visits and investigators monitor the patient’s 
safety laboratory assessments prior to and periodically during treatment in order to manage AEs in accordance with the 
toxicity management guidelines (Refer to Section 5.5.3). 
d 
Patients with confirmed PD that continue to receive study treatment at the discretion of the investigator (following 
consultation with the sponsor) can receive study treatment for a maximum of 12 months during the initial treatment 
period but for as long as the investigator judges they are gaining clinical benefit in the retreatment phase.  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.  The patient 
must continue to meet those inclusion and exclusion criteria that are relevant to treatment through disease progression 
and retreatment as specified in Section 4.3.  The same exceptions as noted in footnote b apply.  Patients will follow the 
assessments in Table 3, Table 4 or Table 5 including tumour assessments every 8 weeks (relative to the date of 
randomisation) until study treatment is stopped. Study drug should be discontinued if there is confirmed PD while on 
treatment following a previous response (PR or CR) to study drug while on treatment (ie, the response and progression 
events both occurred while receiving study drug during the same treatment period).  Patients who continue to receive 
re-treatment after the final DCO should receive scans/RECIST and other assessments per local practice.  It is 
recommended that the patients continue the scheduled site visits and investigators monitor the patient’s safety 
laboratory assessments prior to and periodically during treatment in order to manage AEs in accordance with the 
toxicity management guidelines (Refer to Section 5.5.3). 
e 
Patients with confirmed PD that discontinue study treatment, should have scans conducted according to local standard 
clinical practice (see Section 6.2.2.2)  until the patient commences a new treatment (these scans are optional). 
Note: It is estimated the DCO for the final analysis of overall survival will take place approximately 24 months after the first 
patient is randomised on Sub-study A and 27 months after the first patient is randomised on Sub-study B.  At this time point, 
patients who are receiving study treatment can either choose to discontinue from the study or where the investigator judges 
patients are gaining clinical benefit, patients may continue to receive study treatment.  For patients who do continue to receive 
study treatment beyond the time of the final DCO, investigators will only report SAEs to AstraZeneca Patient Safety until 
90 days after study drug is discontinued.  Any non-serious AEs occurring or ongoing after the time of this final DCO are to be 
followed up at the investigator’s discretion and per local standard of care. 
AE  Adverse event; CR  Complete response; DCO  Data cut-off; PD  Progression of disease; PD-L1  Programmed death 
ligand 1; PR  Partial response; RECIST  Response Evaluation Criteria In Solid Tumours; SAE  Serious adverse event; SD  
Stable disease.   
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
71 
Figure 4 
Study flow chart (for patients randomised to Standard of Care) 
 
a 
Screening assessments can be performed in a step-wise process.  The baseline tumour assessment should be performed 
within the 28 days prior to randomisation. 
b 
A confirmatory scan is required for all patients even if a subsequent treatment is started.  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 through PD in the Standard of Care arm is at the investigator’s 
discretion.  In cases of unequivocal progression the investigator should discontinue treatment, where it is uncertain if 
disease has progressed the investigator should decide whether (if in the absence of clinically significant deterioration) to 
continue the patient on treatment until progression has been confirmed.  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.  The patient must continue to meet those inclusion 
and exclusion criteria that are relevant to treatment through disease progression as specified in Section 4.3.    
c 
Patients with confirmed PD that discontinue study treatment, should have scans conducted according to local standard 
clinical practice (see Section 6.2.2.2)  until the patient commences a new treatment (these scans are optional). 
Screening  Assessments
(Day -28 to -1)a
Day 1 Randomisation/Baseline
Treatment Period (assessments per Table 8 [vinorelbine and gemcitabine] or 
Table 9 [erlotinib]):
Tumour assessments using RECIST 1.1 performed at Screening
and then every 8 weeks for the first 12 months (relative to the date of randomisation) and then every 
12 weeks thereafterb
Discontinuation of treatment
Follow-up assessments and survival 
contact per Table 10c
Continue tumour assessments using 
RECIST 1.1.
Follow-up assessments per Table 10
Due to toxicity or other 
reasons
Due to confirmed 
progression of disease
Pre-screening for PD-L1 Status
(Day -42 to -1)


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
72 
Note:  It is estimated the DCO for the final analysis of overall survival will take place approximately 24 months after the first 
patient is randomised on Sub-study A and 27 months after the first patient is randomised on Sub-study B.  At this time point, 
patients who are receiving study treatment can either choose to discontinue from the study or where the investigator judges 
patients are gaining clinical benefit, patients may continue to receive study treatment.  For patients who do continue to receive 
study treatment beyond the time of the final DCO, investigators will only continue to report all SAEs to 
AstraZeneca/MedImmune Patient Safety until 30 days after Standard of Care treatment is discontinued and any SAE or 
non-serious AE that is ongoing at the time of this DCO must be followed up to resolution unless the event is considered by 
the investigator to be unlikely to resolve, or the patient is lost to follow-up. 
AE  Adverse event; DCO  Data cut-off; PD  Progression of disease; PD-L1  Programmed death ligand 1; RECIST  Response 
Evaluation Criteria In Solid Tumours; SAE  Serious adverse event.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
73 
Table 3 
Schedule of study procedures for the MEDI4736 monotherapy arm in Sub-study A and Sub-study B: 
Screening and Treatment Period (up to 12 months, maximum of 26 doses. Last infusion at Week 50) 
Visit  
(Assessments to be performed at the times stipulated 
and as clinically required in the management of the 
patient.) 
Pre- 
screening 
for PD-L1 
status 
ONLY 
Screening 
All assessments to be performed pre-infusion unless stated otherwise 
Random-
isation 
 
Every  
2 weeks 
Every  
4 weeks 
Every  
8 Weeks 
Day 
-42 to -1 
-28 to -1 
1a 
15 
29 
43 
57 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
2 
4 
6 
8b 
10, 12, 14, 16, 
etc 
12, 16, 20, 24, 
28, etc  
16, 24, 32, 40 and 
48 
 
 
 
 
-------------------------- (±3 daysb) --------------------------- 
--- (±7 days) --- 
Written pre-screening informed consent/assignment 
of patient identification number (Section 6.2) 
X 
 
 
 
 
 
 
 
 
 
Preliminary eligibility fulfilment (investigator’s 
opinion) 
X 
 
 
 
 
 
 
 
 
 
Demography and history of tobacco and alcohol use 
X 
 
 
 
 
 
 
 
 
 
Previous treatments for NSCLC 
X 
 
 
 
 
 
 
 
 
 
Archival (>3 years) FFPE tumour tissue sample for 
PD-L1 assay (optional) (see Section 6.7) 
X 
 
 
 
 
 
 
 
 
 
Newly acquired or archival (≤3 years) formalin-fixed 
tumour biopsy for PD-L1 assay (mandatory) (see 
Section 6.7) 
X 
 
 
 
 
 
 
 
 
 
Written sub-study informed consent (Note: Patients 
are required to re-consent to continue study drug 
when treated through progression and to restart study 
drug following initial disease control [See 
Section 8.4]) 
 
X 
 
 
 
 
 
 
 
 
Formal verification of eligibility criteria 
 
X 
X 
 
 
 
 
 
 
 
Randomisation (see Section 5.2) 
 
 
X 
 
 
 
 
 
 
 
Patient questionnaires (patient reported outcomes) 
(see Section 6.5) 
 
X 
X 
 
X 
 
X 
 
 
X 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
74 
Table 3 
Schedule of study procedures for the MEDI4736 monotherapy arm in Sub-study A and Sub-study B: 
Screening and Treatment Period (up to 12 months, maximum of 26 doses. Last infusion at Week 50) 
Visit  
(Assessments to be performed at the times stipulated 
and as clinically required in the management of the 
patient.) 
Pre- 
screening 
for PD-L1 
status 
ONLY 
Screening 
All assessments to be performed pre-infusion unless stated otherwise 
Random-
isation 
 
Every  
2 weeks 
Every  
4 weeks 
Every  
8 Weeks 
Day 
-42 to -1 
-28 to -1 
1a 
15 
29 
43 
57 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
2 
4 
6 
8b 
10, 12, 14, 16, 
etc 
12, 16, 20, 24, 
28, etc  
16, 24, 32, 40 and 
48 
 
 
 
 
-------------------------- (±3 daysb) --------------------------- 
--- (±7 days) --- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Medical and surgical history 
 
X 
 
 
 
 
 
 
 
 
Hepatitis B and C; HIV 
 
X 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
Urine hCG or serum βhCG  
 
X 
X 
X 
X 
X 
X 
X 
 
 
Kit assignment and MEDI4736 administration 
 
 
X 
X 
X 
X 
X 
X 
 
 
Physical examination  
 
X 
X 
X 
X 
X 
X 
 
X 
 
Vital signs (BP, pulse [pre- and post-infusion], 
respiratory rate, temperature, oxygen saturation; see 
Section 6.4.8) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Weight  
 
X 
X 
 
X 
 
X 
 
X 
 
Electrocardiogram (see Section 6.4.7)d 
 
X 
Xd 
 
 
 
 
 
Xd 
(Week 12 
only) 
 
Adverse event/serious adverse event assessment (see 
Section 6.4.3) 
Xe 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
 
 
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
75 
Table 3 
Schedule of study procedures for the MEDI4736 monotherapy arm in Sub-study A and Sub-study B: 
Screening and Treatment Period (up to 12 months, maximum of 26 doses. Last infusion at Week 50) 
Visit  
(Assessments to be performed at the times stipulated 
and as clinically required in the management of the 
patient.) 
Pre- 
screening 
for PD-L1 
status 
ONLY 
Screening 
All assessments to be performed pre-infusion unless stated otherwise 
Random-
isation 
 
Every  
2 weeks 
Every  
4 weeks 
Every  
8 Weeks 
Day 
-42 to -1 
-28 to -1 
1a 
15 
29 
43 
57 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
2 
4 
6 
8b 
10, 12, 14, 16, 
etc 
12, 16, 20, 24, 
28, etc  
16, 24, 32, 40 and 
48 
 
 
 
 
-------------------------- (±3 daysb) --------------------------- 
--- (±7 days) --- 
Palliative radiotherapy 
 
As clinically indicated (see Section 5.1) 
World Health Organisation performance status 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum chemistryf 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Amylase, lipase (where available)f 
 
X 
X 
 
X 
 
X 
 
X 
 
Thyroid function tests (TSH and T3 and T4) (see 
Section 6.4.9) 
 
X 
X 
 
X 
 
X 
 
X 
 
Haematologyf 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysisg 
 
X 
X 
 
X 
 
X 
 
X 
 
Coagulation parametersh 
 
X 
As clinically indicated 
 
Pharmacokinetic assessment (see Section 6.6.1)i 
 
 
X  
(and EOI) 
 
 
 
X 
 
 
X  
(Weeks 24 [and 
EOI] and 48 only) 
Immunogenicity assessment (ADA sampling 
[including ADA neutralising antibodies] to identify 
ADA responses in patient circulation) (see 
Section 6.6.2)i 
 
 
X 
 
 
 
X 
 
 
X  
(Weeks 24 and 48 
only) 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
76 
Table 3 
Schedule of study procedures for the MEDI4736 monotherapy arm in Sub-study A and Sub-study B: 
Screening and Treatment Period (up to 12 months, maximum of 26 doses. Last infusion at Week 50) 
Visit  
(Assessments to be performed at the times stipulated 
and as clinically required in the management of the 
patient.) 
Pre- 
screening 
for PD-L1 
status 
ONLY 
Screening 
All assessments to be performed pre-infusion unless stated otherwise 
Random-
isation 
 
Every  
2 weeks 
Every  
4 weeks 
Every  
8 Weeks 
Day 
-42 to -1 
-28 to -1 
1a 
15 
29 
43 
57 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
2 
4 
6 
8b 
10, 12, 14, 16, 
etc 
12, 16, 20, 24, 
28, etc  
16, 24, 32, 40 and 
48 
 
 
 
 
-------------------------- (±3 daysb) --------------------------- 
--- (±7 days) --- 
sPD-L1 concentration (to assess target engagement) 
(see Section 6.7)i 
 
 
X 
 
 
 
X 
 
 
X  
(Weeks 24 and 48 
only) 
Circulating soluble factors (to assess cytokines, 
chemokines, growth factors and antibodies against 
tumour and self antigens in circulation) (see 
Section 6.7) 
 
 
X 
 
X 
 
 
 
X  
(Week 12 
only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour assessment (CT or MRI)j,k,l 
 
X 
 
 
 
 
X 
 
 
X 
a 
Every effort should be made to minimise the time between randomisation and starting treatment.  It is recommended that patients commence study treatment as soon as 
possible after randomisation (ie, on the same day after randomisation in the IVRS/IWRS system) and no later than 48 hours after randomisation. 
b 
At Week 8 the allowed window for the tumour assessment is ±7 days. 
c 
 
d 
ECGs: At Screening digital ECGs should be performed in triplicate with a 2- to 5-minute time lag between each measurement.  During treatment, mandatory ECGs are 
performed on Day 1 and at Week 12; only a single digital ECG measurement is required at these visits. On Day 1 and Week 12, ECGs should be taken 30 to 60 minutes 
before study drug infusion and at least 1 time point 0 to 3 hours after infusion. ECGs should be performed at other times if clinically indicated. 
e 
For SAEs that occur in the pre-screening period additional information such as medical history may be requested. 
f 
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 urea and electrolytes, full blood 
count and liver function tests must be available before commencing any infusion with study drug.  Gamma glutamyltransferase tested at Screening, Day 1 (if screening 
laboratory assessments are not performed within 3 days prior to Day 1) and as clinically indicated.  Creatinine clearance, magnesium, amylase, lipase, and uric acid tested 
at Screening, Day 1 (if screening laboratory assessments are not performed within 3 days prior to Day 1) and every 4 weeks thereafter. 
CCI
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
77 
g 
Urinalysis performed at Screening, Day 1, every 4 weeks and as clinically indicated. 
h 
Coagulation tests: Prothrombin time, APTT and INR only performed at Screening and as clinically indicated. 
i 
PK, ADA and sPD-L1 samples to be collected at Day 1, Week 8, Week 24 and Week 48.  PK samples: At each collection, patients will have 1 sample drawn. On Day 1 
and Week 24, samples will be collected before and after infusion.  At other visits, only a pre-dose sample is required.  Pre-dose samples are drawn within 60 minutes 
prior to the start of infusion and EOT samples within 10 minutes after end of infusion.  ADA samples: At each collection, 1 sample will be drawn.  All samples should be 
collected pre-dose (ie, within 60 minutes prior to the start of the infusion).  sPD-L1 samples: At each collection, 1 sample only is drawn from patients.  All samples 
should be collected pre-dose only (ie, within 60 minutes prior to the start of the infusion).   
j 
RECIST assessments will be performed using CT/MRI assessments of the chest and abdomen (including liver and adrenal glands).  Additional anatomy should be imaged 
based on signs and symptoms of individual patients, including new lesions at follow-up.  The baseline assessment should be performed within the 28 days prior to 
randomisation and ideally as close as possible before the start of MEDI4736.  Follow-up assessments will be performed every 8 weeks ± 1 week for the first 48 weeks 
(relative to the date of randomisation) while on treatment until confirmed objective disease progression per RECIST 1.1.  The confirmatory scans should be performed to 
preferably occur at the next scheduled visit (relative to the date of randomisation) and no less than 4 weeks after the prior assessment of PD (in the absence of clinically 
significant deterioration).  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent 
assessments at their scheduled visits (relative to the date of randomisation).  All confirmatory scans should be databased.  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.  The patient must continue to meet those inclusion and exclusion criteria that are relevant to treatment through disease progression as specified in 
Section 4.3.  Patients with rapid tumour progression or with symptomatic progression that requires urgent medical intervention (eg, central nervous system metastasis, 
respiratory failure due to tumour compression, spinal cord compression) will not be eligible to continue to receive study drug.     
k 
Patients who achieve and maintain disease control (ie, CR, PR or SD) through to the end of the 12-month treatment period may restart MEDI4736 upon evidence of PD 
(according to RECIST 1.1), with or without confirmation, during follow-up.  Before restarting MEDI4736, the investigator should ensure patients do not have any 
significant, unacceptable or irreversible toxicities that indicate continuing treatment will not further benefit the patient.  The patient must continue to meet those inclusion 
and exclusion criteria that are relevant to treatment through disease progression and retreatment as specified in Section 4.3.  To restart MEDI4736 the patient must not 
have received an intervening systemic anti-cancer therapy post discontinuation of MEDI4736.  Patients should have a baseline tumour assessment within 28 days prior to 
restarting MEDI4736, all further scans should occur every 8 weeks ± 1 week (relative to the date of restarting MEDI4736), or, if they continue to receive re-treatment 
after the final DCO, patients should receive scans/RECIST per local practice.  It is recommended that the patients continue the scheduled site visits and investigators 
monitor the patient’s safety laboratory assessments prior to and periodically during the treatment with MEDI4736 in order to manage AEs in accordance with the toxicity 
management guidelines (Refer to Section 5.5.3). 
l 
Patients with confirmed PD during the initial treatment period that continue to receive MEDI4736 at the discretion of the investigator (following consultation with the 
sponsor) can receive MEDI4736 for a maximum of 12 months.  Retreatment may continue as long as the investigator judges the patient to be gaining clinical benefit.  
Patients will have scans every 8 weeks ± 1 week (relative to the date of randomisation) until treatment with MEDI4736 is stopped, or, if they continue to receive 
re-treatment after the final DCO, patients should receive scans/RECIST per local practice.  It is recommended that the patients continue the scheduled site visits and 
investigators monitor the patient’s safety laboratory assessments prior to and periodically during the treatment with MEDI4736 in order to manage AEs in accordance 
with the toxicity management guidelines (Refer to Section 5.5.3).  Patients with rapid tumour progression or with symptomatic progression that requires urgent medical 
intervention (eg, central nervous system metastasis, respiratory failure due to tumour compression, spinal cord compression) will not be eligible to continue to receive 
study drug.  Study drug should be discontinued if there is confirmed PD while on treatment following a previous response (PR or CR) to study drug while on treatment 
(ie, the response and progression events both occurred while receiving study drug during the same treatment period). 
Note: If a patient has a delay to an infusion of MEDI4736 all assessments should be conducted relative to the date of randomisation. 
Note: For ‘re-treatment’ patients who go on to have subsequent treatment prior to the final DCO, the same assessments should be done as in the first 12-month treatment period 
with the exception of  the PK, ADA,  sPD-L1, and PGx,  assessments which do not need to be collected a second time.  This includes all assessments listed under ‘screening’ 
and ‘randomisation’ which should be completed again following the decision to re-treat. Additionally, if feasible or clinically indicated, a biopsy at entry to re-treatment may 
optionally be collected. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
78 
ADA  Anti-drug antibody; APTT  Activated partial thromboplastin time; BP  Blood pressure; CR  Complete response;  CT  Computed tomography; ECG  Electrocardiogram; 
EOI  End of infusion; FFPE Formalin-fixed paraffin-embedded; hCG  Human chorionic gonadotropin; HIV  Human immunodeficiency virus; INR  International normalised 
ratio; IVRS/IWRS  Interactive Voice/Web Response System; miRNA  Micro RNA; MRI  Magnetic resonance imaging; mRNA  Messenger RNA; NSCLC  Non-small cell lung 
cancer; PD  Progression of disease; PGx  Pharmacogenetic(s); PK  Pharmacokinetics; PR  Partial response; RECIST  Response Evaluation Criteria In Solid Tumours; SD  
Stable disease; sPD-L1  Soluble programmed death ligand 1; T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid stimulating hormone. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
79 
Table 4 
Schedule of study procedures for the tremelimumab monotherapy arm in Sub-study B: Screening and 
Treatment Period (up to 48 weeks, maximum of 9 doses of tremelimumab. Last infusion at Week 48) 
Visit  
(Assessments to be performed at the times stipulated and as 
clinically required in the management of the patient.) 
Pre- 
screening 
for PD-L1 
status 
ONLY 
All assessments to be performed pre-infusion unless stated otherwise 
Screening 
Randomisation 
 
Every  
4 weeks 
Every 
8 Weeks 
Every 
12 weeks 
Day 
-42 to -1 
-28 to -1 
1a 
29 
57 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4 
8b 
12, 16, 20, 24, 
28, etc  
16, 24, 32, 
40 and 48 
24, 36 
and 48 
 
 
 
 
------------ (±3 daysb) ----------- 
------- (±7 days) ------- 
Written pre-screening informed consent/assignment of patient 
identification number (Section 6.2) 
X 
 
 
 
 
 
 
 
Preliminary eligibility fulfilment (investigator’s opinion) 
X 
 
 
 
 
 
 
 
Demography and history of tobacco and alcohol use 
X 
 
 
 
 
 
 
 
Previous treatments for NSCLC 
X 
 
 
 
 
 
 
 
Archival (>3 years) FFPE tumour tissue sample for PD-L1 assay 
(optional) (see Section 6.7) 
X 
 
 
 
 
 
 
 
Newly acquired or archival (≤3 years) formalin-fixed tumour 
biopsy for PD-L1 assay (mandatory) (see Section 6.7) 
X 
 
 
 
 
 
 
 
Written sub-study informed consent (Note: Patients are required to 
re-consent to continue study drug when treated through 
progression and to restart study drug following initial disease 
control [See Section 8.4]) 
 
X 
 
 
 
 
 
 
Formal verification of eligibility criteria 
 
X 
X 
 
 
 
 
 
Randomisation (see Section 5.2) 
 
 
X 
 
 
 
 
 
Patient questionnaires (patient reported outcomes) (see 
Section 6.5) 
 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
Medical and surgical history  
 
X 
 
 
 
 
 
 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
80 
Table 4 
Schedule of study procedures for the tremelimumab monotherapy arm in Sub-study B: Screening and 
Treatment Period (up to 48 weeks, maximum of 9 doses of tremelimumab. Last infusion at Week 48) 
Visit  
(Assessments to be performed at the times stipulated and as 
clinically required in the management of the patient.) 
Pre- 
screening 
for PD-L1 
status 
ONLY 
All assessments to be performed pre-infusion unless stated otherwise 
Screening 
Randomisation 
 
Every  
4 weeks 
Every 
8 Weeks 
Every 
12 weeks 
Day 
-42 to -1 
-28 to -1 
1a 
29 
57 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4 
8b 
12, 16, 20, 24, 
28, etc  
16, 24, 32, 
40 and 48 
24, 36 
and 48 
 
 
 
 
------------ (±3 daysb) ----------- 
------- (±7 days) ------- 
Hepatitis B and C; HIV  
 
X 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
Urine hCG or serum βhCG  
 
X 
X 
X 
X 
X 
 
 
Kit assignment and tremelimumab administration (4-weekly for 
24 weeks)  
 
 
X 
X 
X 
X 
 
 
Tremelimumab administration (12-weekly for 24 weeks) 
 
 
 
 
 
 
 
X 
Physical examination  
 
X 
X 
X 
X 
X 
 
 
Vital signs (BP, pulse [pre- and post-infusion], respiratory rate, 
temperature, oxygen saturation; see Section 6.4.8) 
 
X 
X 
X 
X 
X 
 
 
Weight  
 
X 
X 
X 
X 
X 
 
 
Electrocardiogram (see Section 6.4.7)c  
 
Xc 
Xc 
 
 
Xc 
(Week 12 
only) 
 
Adverse event/serious adverse event assessment (see Section 6.4.3) 
Xd 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
 
 
Palliative radiotherapy 
As clinically indicated (see Section 5.1) 
World Health Organisation performance status 
 
X 
X 
X 
X 
X 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
81 
Table 4 
Schedule of study procedures for the tremelimumab monotherapy arm in Sub-study B: Screening and 
Treatment Period (up to 48 weeks, maximum of 9 doses of tremelimumab. Last infusion at Week 48) 
Visit  
(Assessments to be performed at the times stipulated and as 
clinically required in the management of the patient.) 
Pre- 
screening 
for PD-L1 
status 
ONLY 
All assessments to be performed pre-infusion unless stated otherwise 
Screening 
Randomisation 
 
Every  
4 weeks 
Every 
8 Weeks 
Every 
12 weeks 
Day 
-42 to -1 
-28 to -1 
1a 
29 
57 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4 
8b 
12, 16, 20, 24, 
28, etc  
16, 24, 32, 
40 and 48 
24, 36 
and 48 
 
 
 
 
------------ (±3 daysb) ----------- 
------- (±7 days) ------- 
Serum chemistrye 
 
X 
X 
X 
X 
X 
 
 
Amylase, lipase (where available)e 
 
X 
X 
X 
X 
X 
 
 
Thyroid function tests (TSH and T3 and T4) (see Section 6.4.9) 
 
X 
X 
X 
X 
X 
 
 
Haematologye 
 
X 
X 
X 
X 
X 
 
 
Urinalysisf 
 
X 
X 
X 
X 
X 
 
 
Coagulation parametersg 
 
X 
As clinically indicated 
 
 
 
 
 
 
 
 
Pharmacokinetic assessment  (see Section 6.6.1)h 
 
 
X (and EOI) 
 
X 
 
X  
(Weeks 24 [and EOI] and 
48 only) 
Immunogenicity assessment  (ADA sampling [including ADA 
neutralising antibodies] to identify ADA responses in patient 
circulation) (see Section 6.6.2)h 
 
 
X 
 
X 
 
X  
(Weeks 24 and 48 only) 
sPD-L1 concentration  (see Section 6.7)h 
 
 
X 
 
X 
 
X  
(Weeks 24 and 48 only) 
Circulating soluble factors (to assess cytokines, chemokines, 
growth factors and antibodies against tumour and self antigens in 
circulation) (see Section 6.7) 
 
 
X 
X 
 
X  
(Week 12 
only) 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
82 
Table 4 
Schedule of study procedures for the tremelimumab monotherapy arm in Sub-study B: Screening and 
Treatment Period (up to 48 weeks, maximum of 9 doses of tremelimumab. Last infusion at Week 48) 
Visit  
(Assessments to be performed at the times stipulated and as 
clinically required in the management of the patient.) 
Pre- 
screening 
for PD-L1 
status 
ONLY 
All assessments to be performed pre-infusion unless stated otherwise 
Screening 
Randomisation 
 
Every  
4 weeks 
Every 
8 Weeks 
Every 
12 weeks 
Day 
-42 to -1 
-28 to -1 
1a 
29 
57 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4 
8b 
12, 16, 20, 24, 
28, etc  
16, 24, 32, 
40 and 48 
24, 36 
and 48 
 
 
 
 
------------ (±3 daysb) ----------- 
------- (±7 days) ------- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour assessment (CT or MRI)i,j,k 
 
X 
 
 
X 
 
X  
 
a 
Every effort should be made to minimise the time between randomisation and starting treatment.  It is recommended that patients commence study treatment as soon as 
possible after randomisation (ie, on the same day after randomisation in the IVRS/IWRS system) and no later than 48 hours after randomisation. 
b 
At Week 8 the allowed window for the tumour assessment is ±7 days. 
c 
ECGs: At Screening, digital ECGs should be performed in triplicate with a 2- to 5-minute time lag between each measurement.  During treatment, mandatory ECGs are 
performed on Day 1 and at Week 12; only a single digital ECG measurement is required at these visits.  On Day 1 and Week 12, ECGs should be taken 30 to 60 minutes 
before study drug infusion and at least 1 time point 0 to 3 hours after infusion.  ECGs should be performed at other times if clinically indicated. 
d 
For SAEs that occur in the pre-screening period additional information such as medical history may be requested.  
e 
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 urea and electrolytes, full blood 
count and liver function tests must be available before commencing any infusion with study drug.  Gamma glutamyltransferase tested at Screening, Day 1 (if screening 
laboratory assessments are not performed within 3 days prior to Day 1) and as clinically indicated.  Creatinine clearance, magnesium, amylase, lipase, and uric acid tested 
at Screening, Day 1 (if screening laboratory assessments are not performed within 3 days prior to Day 1) and every 4 weeks thereafter. 
f 
Urinalysis performed at Screening, Day 1, every 4 weeks and as clinically indicated. 
g 
Coagulation tests: Prothrombin time, APTT and INR only performed at Screening and as clinically indicated. 
h 
PK, ADA and sPD-L1 samples to be collected at Day 1, Week 8, Week 24 and Week 48.  PK samples: At each collection, patients will have 1 sample drawn. On Day 1 
and Week 24, samples will be collected before and after infusion.  At other visits, only a pre-dose sample is required.  Pre-dose samples are drawn within 60 minutes 
prior to the start of infusion and EOT samples within 10 minutes after end of infusion.  ADA samples: At each collection, 1 sample will be drawn.  All samples should be 
collected pre-dose (ie, within 60 minutes prior to the start of the infusion).  sPD-L1 samples: At each collection, 1 sample only is drawn from patients.  All samples 
should be collected pre-dose only (ie, within 60 minutes prior to the start of the infusion). 
i 
RECIST assessments will be performed using CT/MRI assessments of the chest and abdomen (including liver and adrenal glands).  Additional anatomy should be imaged 
based on signs and symptoms of individual patients, including new lesions at follow-up.  The baseline assessment should be performed within the 28 days prior to 
randomisation and ideally as close as possible before the start of study treatment.  Follow-up assessments will be performed every 8 weeks ± 1 week for the first 48 
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
83 
weeks (relative to the date of randomisation) while on treatment until confirmed objective disease progression per RECIST 1.1.  The confirmatory scans should be 
performed to preferably occur at the next scheduled visit (relative to the date of randomisation) and no less than 4 weeks after the prior assessment of PD (in the absence 
of clinically significant deterioration).  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the 
subsequent assessments at their scheduled visits (relative to the date of randomisation).  All confirmatory scans should be databased.  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.  The patient must continue to meet those inclusion and exclusion criteria that are relevant to treatment through disease progression as specified 
in Section 4.3.  Patients with rapid tumour progression or with symptomatic progression that requires urgent medical intervention (eg, central nervous system metastasis, 
respiratory failure due to tumour compression, spinal cord compression) will not be eligible to continue to receive study drug.     
j 
Patients who achieve and maintain disease control (ie, CR, PR or SD) through to the end of the 48-week treatment period may restart study drug upon evidence of PD 
(according to RECIST 1.1), with or without confirmation, during follow-up.  Before restarting study drug, the investigator should ensure patients do not have any 
significant, unacceptable or irreversible toxicities that indicate continuing treatment will not further benefit the patient.  The patient must continue to meet those inclusion 
and exclusion criteria that are relevant to treatment through disease progression and retreatment as specified in Section 4.3.  To restart study drug the patient must not 
have received an intervening systemic anti-cancer therapy post discontinuation of study drug.  Patients should have a baseline tumour assessment within 28 days prior to 
restarting study drug, all further scans should occur every 8 weeks ± 1 week (relative to the date of restarting study drug), or, if they continue to receive re-treatment after 
the final DCO, patients should receive scans/RECIST per local practice.  It is recommended that the patients continue the scheduled site visits and investigators monitor 
the patient’s safety laboratory assessments prior to and periodically during the treatment in order to manage AEs in accordance with the toxicity management guidelines 
(Refer to Section 5.5.3). 
k 
Patients with confirmed PD during the initial treatment period who continue to receive study drug at the discretion of the investigator (following consultation with the 
sponsor) can receive study drug for a maximum of 48 weeks.  Retreatment may continue as long as the investigator judges the patient to be gaining clinical benefit.  
Patients will have scans every 8 weeks ± 1 week (relative to the date of randomisation) until treatment with study drug is stopped, or, if they continue to receive 
re-treatment after the final DCO, patients should receive scans/RECIST per local practice.  It is recommended that the patients continue the scheduled site visits and 
investigators monitor the patient’s safety laboratory assessments prior to and periodically during the treatment in order to manage AEs in accordance with the toxicity 
management guidelines (Refer to Section 5.5.3).  Patients with rapid tumour progression or with symptomatic progression that requires urgent medical intervention (eg, 
central nervous system metastasis, respiratory failure due to tumour compression, spinal cord compression) will not be eligible to continue to receive study drug. Study 
drug should be discontinued if there is confirmed PD while on treatment following a previous response (PR or CR) to study drug while on treatment (ie, the response and 
progression events both occurred while receiving study drug during the same treatment period).   
Note: If a patient has a delay to an infusion of study drug all assessments should be conducted relative to the date of randomisation. 
Note: For ‘retreatment’ patients who go on to have subsequent treatment prior to the final DCO, the same assessments should be done as in the first 12-month treatment period 
with the exception of  the PK, ADA,  sPD-L1, and PGx,  assessments which do not need to be collected a second time.  This includes all assessments listed under ‘screening’ 
and ‘randomisation’ which should be completed again following the decision to re-treat. Additionally, if feasible or clinically indicated, a biopsy at entry to re-treatment may 
optionally be collected. 
ADA  Anti-drug antibody; APTT  Activated partial thromboplastin time; BP Blood pressure; CR  Complete response;  CT  Computed tomography; ECG  Electrocardiogram; 
EOI  End of infusion; FFPE Formalin-fixed paraffin-embedded; hCG  Human chorionic gonadotropin; HIV  Human immunodeficiency virus; INR  International normalised 
ratio; IVRS/IWRS  Interactive Voice/Web Response System; miRNA  Micro RNA; MRI  Magnetic resonance imaging; mRNA  Messenger RNA; NSCLC  Non-small cell lung 
cancer; PD  Progression of disease; PGx  Pharmacogenetic(s); PK  Pharmacokinetics; PR  Partial response; RECIST  Response Evaluation Criteria In Solid Tumours; SD  
Stable disease; sPD-L1  Soluble programmed death ligand 1; T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid stimulating hormone. 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
84 
Table 5 
Schedule of study procedures for the MEDI4736+tremelimumab arm in Sub-study B: Screening and 
Treatment Period (up to 50 weeks, maximum of 22 doses of MEDI4736 and 4 doses of tremelimumab. 
Last infusion at Week 50) 
Visit  
(Assessments to be performed at 
the times stipulated and as 
clinically required in the 
management of the patient.) 
Pre- 
screening 
for PD-L1 
status 
ONLY 
 
All assessments to be performed pre-infusion unless stated otherwise 
Screening 
Randomi
sation 
 
 
Every 2 weeks 
Every 4 weeks 
Every 8 Weeks 
Day 
-42 to -1 
-28 to -1 
1a 
29 
57 
85 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4 
8b 
12 
16, 18, 20,  
22, 24, etc 
16, 20, 24,  
28, 32, etc  
16, 24, 32, 
40 and 48 
 
 
 
 
----------------------------------- (±3 daysb) ---------------------------------- 
----- (±7 days) ----- 
Written pre-screening informed 
consent/assignment of patient 
identification number (Section 6.2) 
X 
 
 
 
 
 
 
 
 
Preliminary eligibility fulfilment 
(investigator’s opinion) 
X 
 
 
 
 
 
 
 
 
Demography and history of 
tobacco and alcohol use 
X 
 
 
 
 
 
 
 
 
Previous treatments for NSCLC 
X 
 
 
 
 
 
 
 
 
Archival (>3 years) FFPE tumour 
tissue sample for PD-L1 assay 
(optional) (see Section 6.7) 
X 
 
 
 
 
 
 
 
 
Newly acquired or archival (≤3 
years) formalin-fixed tumour 
biopsy for PD-L1 assay 
(mandatory) (see Section 6.7) 
X 
 
 
 
 
 
 
 
 
Written sub-study informed 
consent (Note: Patients are required 
to re-consent to continue study 
drug when treated through 
progression and to restart study 
drug following initial disease 
control [See Section 8.4]) 
 
X 
 
 
 
 
 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
85 
Table 5 
Schedule of study procedures for the MEDI4736+tremelimumab arm in Sub-study B: Screening and 
Treatment Period (up to 50 weeks, maximum of 22 doses of MEDI4736 and 4 doses of tremelimumab. 
Last infusion at Week 50) 
Visit  
(Assessments to be performed at 
the times stipulated and as 
clinically required in the 
management of the patient.) 
Pre- 
screening 
for PD-L1 
status 
ONLY 
 
All assessments to be performed pre-infusion unless stated otherwise 
Screening 
Randomi
sation 
 
 
Every 2 weeks 
Every 4 weeks 
Every 8 Weeks 
Day 
-42 to -1 
-28 to -1 
1a 
29 
57 
85 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4 
8b 
12 
16, 18, 20,  
22, 24, etc 
16, 20, 24,  
28, 32, etc  
16, 24, 32, 
40 and 48 
 
 
 
 
----------------------------------- (±3 daysb) ---------------------------------- 
----- (±7 days) ----- 
Formal verification of eligibility 
criteria 
 
X 
X 
 
 
 
 
 
 
Randomisation (see Section 5.2) 
 
 
X 
 
 
 
 
 
 
Patient questionnaires (patient 
reported outcomes) (see Section 6.5) 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history  
 
X 
 
 
 
 
 
 
 
Hepatitis B and C; HIV  
 
X 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
Urine hCG or serum βhCG  
 
X 
X 
X 
X 
X 
X 
 
 
Kit assignment and MEDI4736 
20 mg/kg administration 
(4-weekly to Week 12)d  
 
 
X 
X 
X 
X 
 
 
 
Kit assignment and 
tremelimumab 1 mg/kg 
administration (4-weekly for 
12 weeksd 
 
 
X 
X 
X 
X 
 
 
 
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
86 
Table 5 
Schedule of study procedures for the MEDI4736+tremelimumab arm in Sub-study B: Screening and 
Treatment Period (up to 50 weeks, maximum of 22 doses of MEDI4736 and 4 doses of tremelimumab. 
Last infusion at Week 50) 
Visit  
(Assessments to be performed at 
the times stipulated and as 
clinically required in the 
management of the patient.) 
Pre- 
screening 
for PD-L1 
status 
ONLY 
 
All assessments to be performed pre-infusion unless stated otherwise 
Screening 
Randomi
sation 
 
 
Every 2 weeks 
Every 4 weeks 
Every 8 Weeks 
Day 
-42 to -1 
-28 to -1 
1a 
29 
57 
85 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4 
8b 
12 
16, 18, 20,  
22, 24, etc 
16, 20, 24,  
28, 32, etc  
16, 24, 32, 
40 and 48 
 
 
 
 
----------------------------------- (±3 daysb) ---------------------------------- 
----- (±7 days) ----- 
Kit assignment and MEDI4736 
10 mg/kg administration 
(2-weekly from Week 16)d  
 
 
 
 
 
 
X 
 
 
Physical examination  
 
X 
X 
X 
X 
X 
 
X 
 
Vital signs (BP, pulse [pre- and 
post-infusion], respiratory rate, 
temperature, oxygen saturation; see 
Section 6.4.8) 
 
X 
X 
X 
X 
X 
X 
 
 
Weight  
 
X 
X 
X 
X 
X 
 
X 
 
Electrocardiogram (see 
Section 6.4.7)e  
 
Xe 
Xe 
 
 
Xe 
 
 
 
Adverse event/serious adverse 
event assessment (see 
Section 6.4.3) 
Xf 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
 
 
Palliative radiotherapy 
 
 
As clinically indicated (see Section 5.1) 
World Health Organisation 
performance status 
 
X 
X 
X 
X 
X 
 
X 
 
Serum chemistryg 
 
X 
X 
X 
X 
X 
X 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
87 
Table 5 
Schedule of study procedures for the MEDI4736+tremelimumab arm in Sub-study B: Screening and 
Treatment Period (up to 50 weeks, maximum of 22 doses of MEDI4736 and 4 doses of tremelimumab. 
Last infusion at Week 50) 
Visit  
(Assessments to be performed at 
the times stipulated and as 
clinically required in the 
management of the patient.) 
Pre- 
screening 
for PD-L1 
status 
ONLY 
 
All assessments to be performed pre-infusion unless stated otherwise 
Screening 
Randomi
sation 
 
 
Every 2 weeks 
Every 4 weeks 
Every 8 Weeks 
Day 
-42 to -1 
-28 to -1 
1a 
29 
57 
85 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4 
8b 
12 
16, 18, 20,  
22, 24, etc 
16, 20, 24,  
28, 32, etc  
16, 24, 32, 
40 and 48 
 
 
 
 
----------------------------------- (±3 daysb) ---------------------------------- 
----- (±7 days) ----- 
Amylase, lipase (where available)g 
 
X 
X 
X 
X 
X 
 
X 
 
Thyroid function tests (TSH and T3 
and T4) (see Section 6.4.9) 
 
X 
X 
X 
X 
X 
 
X 
 
Haematologyg 
 
X 
X 
X 
X 
X 
X 
 
 
Urinalysish 
 
X 
X 
X 
X 
X 
 
X 
 
Coagulation parametersi 
 
X 
 
As clinically indicated 
 
Pharmacokinetic MEDI4736 
assessment (see Section 6.6.1)j 
 
 
X (and 
EOI) 
 
X 
 
 
 
X  
(Weeks 24 [and EOI] 
 and 48 only) 
Pharmacokinetic tremelimumab 
assessment (see Section 6.6.1)j 
 
 
X (and 
EOI) 
 
X 
 
 
X  
(Weeks 24  
and 36 only) 
 
Immunogenicity MEDI4736 
assessment (ADA sampling 
[including ADA neutralising 
antibodies] to identify ADA 
responses in patient circulation) 
(see Section 6.6.2)j 
 
 
X 
 
X 
 
 
 
X  
(Weeks 24  
and 48 only) 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
88 
Table 5 
Schedule of study procedures for the MEDI4736+tremelimumab arm in Sub-study B: Screening and 
Treatment Period (up to 50 weeks, maximum of 22 doses of MEDI4736 and 4 doses of tremelimumab. 
Last infusion at Week 50) 
Visit  
(Assessments to be performed at 
the times stipulated and as 
clinically required in the 
management of the patient.) 
Pre- 
screening 
for PD-L1 
status 
ONLY 
 
All assessments to be performed pre-infusion unless stated otherwise 
Screening 
Randomi
sation 
 
 
Every 2 weeks 
Every 4 weeks 
Every 8 Weeks 
Day 
-42 to -1 
-28 to -1 
1a 
29 
57 
85 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4 
8b 
12 
16, 18, 20,  
22, 24, etc 
16, 20, 24,  
28, 32, etc  
16, 24, 32, 
40 and 48 
 
 
 
 
----------------------------------- (±3 daysb) ---------------------------------- 
----- (±7 days) ----- 
Immunogenicity tremelimumab 
assessment (ADA sampling 
[including ADA neutralising 
antibodies] to identify ADA 
responses in patient circulation) 
(see Section 6.6.2)j 
 
 
X 
 
X 
 
 
X  
(Weeks 24 and 
36 only) 
 
sPD-L1 concentration (to assess 
target engagement) (see 
Section 6.7)j 
 
 
X 
 
X 
 
 
X  
(Weeks 24 and 
36 only) 
X 
(Week 48 only) 
Circulating soluble factors (to 
assess cytokines, chemokines, 
growth factors and antibodies 
against tumour and self antigens in 
circulation) (see Section 6.7) 
 
 
X 
X 
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour assessment (CT or MRI)k,l,m 
 
X 
 
 
X 
 
 
 
X 
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
89 
a 
Every effort should be made to minimise the time between randomisation and starting treatment.  It is recommended that patients commence study treatment as soon as 
possible after randomisation (ie, on the same day after randomisation in the IVRS/IWRS system) and no later than 48 hours after randomisation. 
b 
Week 8 the allowed window for the tumour assessment is ±7 days. 
c 
 
d 
MEDI4736 20 mg/kg plus tremelimumab 1 mg/kg administered once every 4 weeks up to 12 weeks (4 doses) then MEDI4736 10 mg/kg alone administered every 
2 weeks for 34 weeks starting at Week 16 (18 doses). 
e 
ECGs: At Screening, digital ECGs should be performed in triplicate with a 2- to 5-minute time lag between each measurement.  During treatment, mandatory ECGs are 
performed on Day 1 and at Week 12; only a single digital ECG measurement is required at these visits.  On Day 1 and Week 12, ECGs should be taken 30 to 60 minutes 
before study drug infusion and at least 1 time point 0 to 3 hours after infusion.  ECGs should be performed at other times if clinically indicated. 
f 
For SAEs that occur in the pre-screening period additional information such as medical history may be requested.  
g 
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 urea and electrolytes, full blood 
count and liver function tests must be available before commencing any infusion with study drug.  Gamma glutamyltransferase tested at Screening, Day 1 (if screening 
laboratory assessments are not performed within 3 days prior to Day 1) and as clinically indicated.  Creatinine clearance, magnesium and uric acid tested at Screening, 
Day 1 (if screening laboratory assessments are not performed within 3 days prior to Day 1), every 4 weeks until Week 12, and every 2 weeks thereafter.  Amylase and 
lipase are tested at Screening, Day 1 (if screening laboratory assessments are not performed within 3 days prior to Day 1), every 4 weeks thereafter. 
h 
Urinalysis performed at Screening, Day 1, every 4 weeks and as clinically indicated. 
i 
Coagulation tests: Prothrombin time, APTT and INR only performed at Screening and as clinically indicated. 
j 
PK, ADA and sPD-L1 samples to be collected at Day 1, Week 8, Week 24, Week 36 and Week 48.  PK samples: At each collection, patients will have samples drawn 
separately for each of the 2 components of the combination.  On Day 1 and Week 24, samples will be collected before and after infusion.  At other visits, only a pre-dose 
sample is required.  Pre-dose samples are drawn within 60 minutes prior to the start of infusion and EOT samples within 10 minutes after end of infusion.  Note: PK 
samples on Day 1 are as follows: 2 samples before infusion of the first drug of the combination (pre-dose); 1 sample at the end of the first drug infusion and 1 sample at 
the end of the second drug infusion (end-of-infusion samples).  At Week 36, a pre-dose sample for tremelimumab and at Week 48 a pre-dose sample for MEDI4736 is 
drawn before infusion.  ADA samples: At each collection, 2 samples will be drawn from patients with the exception of Weeks 36 and 48 when 1 sample will be drawn.  
All samples should be collected pre-dose (ie, within 60 minutes prior to the start of the infusion or the start of infusion of the first drug of combination).  sPD-L1 
samples: At each collection, 1 sample only is drawn from patients.  All samples should be collected pre-dose only (ie, within 60 minutes prior to the start of the infusion 
or the start of infusion of the first drug of combination).  NB: If a patient discontinues study treatment before 50 weeks, PK, ADA and sPD-L1 samples must still be 
collected for tremelimumab at 3 and 6 months after the last dose of tremelimumab (Week 24 and Week 36). . 
k 
RECIST assessments will be performed using CT/MRI assessments of the chest and abdomen (including liver and adrenal glands).  Additional anatomy should be imaged 
based on signs and symptoms of individual patients, including new lesions at follow-up.  The baseline assessment should be performed within the 28 days prior to 
randomisation and ideally as close as possible before the start of study treatment.  Follow-up assessments will be performed every 8 weeks ± 1 week for the first 48 
weeks (relative to the date of randomisation) while on treatment until confirmed objective disease progression per RECIST 1.1.  The confirmatory scans should be 
performed to preferably occur at the next scheduled visit (relative to the date of randomisation) and no less than 4 weeks after the prior assessment of PD (in the absence 
of clinically significant deterioration).  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the 
subsequent assessments at their scheduled visits (relative to the date of randomisation).  All confirmatory scans should be databased.  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.  The patient must continue to meet those inclusion and exclusion criteria that are relevant to treatment through disease progression as specified 
in Section 4.3.  Patients with rapid tumour progression or with symptomatic progression that requires urgent medical intervention (eg, central nervous system metastasis, 
respiratory failure due to tumour compression, spinal cord compression) will not be eligible to continue to receive study drug.   
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
90 
l 
Patients in the MEDI4736+tremelimumab arm who achieve and maintain disease control (ie, CR, PR or SD) through to the end of the 4th cycle (Week 16, 4 weeks after 
the last dose of combination treatment) will continue with the planned treatment for this arm ie, MEDI4736 10 mg/kg Q2W.  If the patient experiences radiological PD 
(according to RECIST 1.1), with or without confirmation, during treatment, retreatment with the combination regimen may begin.  Before restarting study drug, the 
investigator should ensure patients do not have any significant, unacceptable or irreversible toxicities that indicate continuing treatment will not further benefit the 
patient.  The patient must continue to meet those inclusion and exclusion criteria that are relevant to treatment through disease progression and retreatment as specified in 
Section 4.3.  To restart study drug the patient must not have received an intervening systemic anti-cancer therapy post discontinuation of study drug.  Patients should have 
a baseline tumour assessment within 28 days prior to restarting study drug, all further scans should occur every 8 weeks ± 1 week (relative to the date of restarting study 
drug), or, if they continue to receive re-treatment after the final DCO, patients should receive scans/RECIST per local practice.  It is recommended that the patients 
continue the scheduled site visits and investigators monitor the patient’s safety laboratory assessments prior to and periodically during the treatment in order to manage 
AEs in accordance with the toxicity management guidelines (Refer to Section 5.5.3). 
m 
Patients with confirmed PD during the initial treatment period who continue to receive study drug at the discretion of the investigator (following consultation with the 
sponsor) can receive study drug for a maximum of 12 months.  Retreatment may continue as long as the investigator judges the patient to be gaining clinical benefit.  
Patients will have scans every 8 weeks ± 1 week (relative to the date of randomisation) until treatment with study drug is stopped, or, if they continue to receive 
re-treatment after the final DCO, patients should receive scans/RECIST per local practice.  It is recommended that the patients continue the scheduled site visits and 
investigators monitor the patient’s safety laboratory assessments prior to and periodically during the treatment in order to manage AEs in accordance with the toxicity 
management guidelines (Refer to Section 5.5.3).  Patients with rapid tumour progression or with symptomatic progression that requires urgent medical intervention (eg, 
central nervous system metastasis, respiratory failure due to tumour compression, spinal cord compression) will not be eligible to continue to receive study drug.  Study 
drug should be discontinued if there is confirmed PD while on treatment following a previous response (PR or CR) to study drug while on treatment (ie, the response and 
progression events both occurred while receiving study drug during the same treatment period). 
Note: If a patient has a delay to an infusion of study drug all assessments should be conducted relative to the date of randomisation. 
Note: For ‘retreatment’ patients who go on to have subsequent treatment prior to the final DCO, the same assessments should be done as in the first 12-month treatment period 
with the exception of  the PK, ADA,  sPD-L1, and PGx,  assessments which do not need to be collected a second time.  This includes all assessments listed under ‘screening’ 
and ‘randomisation’ which should be completed again following the decision to re-treat. Additionally, if feasible or clinically indicated, a biopsy at entry to re-treatment may 
optionally be collected. 
ADA  Anti-drug antibody; APTT  Activated partial thromboplastin time; BP Blood pressure; CR  Complete response;  CT  Computed tomography; ECG  Electrocardiogram; 
EOI  End of infusion; FFPE Formalin-fixed paraffin-embedded; hCG  Human chorionic gonadotropin; HIV  Human immunodeficiency virus; INR  International normalised 
ratio; IVRS/IWRS  Interactive voice/web response system; miRNA  Micro RNA; MRI  Magnetic resonance imaging; mRNA  Messenger RNA; NSCLC  Non-small cell lung 
cancer; PD  Progression of disease; PGx  Pharmacogenetic(s); PK  Pharmacokinetics; PR  Partial response; RECIST  Response Evaluation Criteria In Solid Tumours; SD  
Stable disease; sPD-L1  Soluble programmed death ligand 1; T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid stimulating hormone. 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
91 
Table 6 
Follow-up for patients who have completed the treatment period for MEDI4736 monotherapy, 
tremelimumab monotherapy and MEDI4736+tremelimumab and achieved disease control and patients 
who have discontinued study drug due to toxicity or a reason other than confirmed progression of disease   
Evaluation  
Time Since Last Dose on MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab arms  
Day (±3) 
Months (±1 week) 
12 Months and  
Every 6 Months Thereafter 
(±2 weeks)f 
30 
2 
3 
4 
6 
8 
10 
Patient questionnaires (patient reported outcomes) and 
health resource use 
For patients who achieve disease control following 12 months/48 weeks of treatment, patient questionnaires 
and information relating to health resource use should be completed every 12 weeks relative to the date of 
randomisation until confirmed PD by RECIST 1.1 by investigational site review.   
For patients who discontinue study drug due to toxicity or a reason other than confirmed PD, patient 
questionnaires and information relating to health resource use should be completed relative to the date of 
randomisation as follows: every 8 weeks for the first 48 weeks (per Table 3, Table 4 or Table 5), then every 
12 weeks until confirmed PD by RECIST 1.1 by investigational site review.   
Physical examination  
X 
 
 
 
 
 
 
 
Vital signs (BP, pulse, respiratory rate, temperature, oxygen 
saturation) 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
Adverse event/serious adverse event assessment (see 
Section 6.4.3) 
X 
X 
X 
 
 
 
 
 
Concomitant medications 
X 
 
 
 
 
 
 
 
Palliative radiotherapy 
 
As clinically indicated (see Section 5.1) 
World Health Organisation performance statusa 
X 
X 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Subsequent anti-cancer therapya 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status: phone contact with patients who refuse to 
return for evaluations and agree to be contacted 
 
X 
X 
X 
X 
X 
X 
X (every 2 months) 
Haematology 
X 
X 
X 
X 
 
 
 
X 
Serum chemistry  
X 
X 
X 
 
 
 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
92 
Table 6 
Follow-up for patients who have completed the treatment period for MEDI4736 monotherapy, 
tremelimumab monotherapy and MEDI4736+tremelimumab and achieved disease control and patients 
who have discontinued study drug due to toxicity or a reason other than confirmed progression of disease   
Evaluation  
Time Since Last Dose on MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab arms  
Day (±3) 
Months (±1 week) 
12 Months and  
Every 6 Months Thereafter 
(±2 weeks)f 
30 
2 
3 
4 
6 
8 
10 
Amylase, lipase (where available) 
X 
X 
X 
 
 
 
 
 
Thyroid function tests (TSH, and T3 and T4)  
X 
 
 
 
 
 
 
 
Coagulation parametersb 
As clinically indicated 
 
Urinalysis 
As clinically indicated 
 
Pharmacokinetic MEDI4736 assessment 
(MEDI4736+tremelimumab and MEDI4736 monotherapy 
arms)c  
 
 
X 
 
 
 
 
 
Pharmacokinetic tremelimumab assessment  
(MEDI4736+tremelimumab and tremelimumab 
monotherapy arms)c 
 
 
X 
 
 
 
 
 
Immunogenicity MEDI4736 assessment (ADA sampling 
[including ADA neutralising antibodies] to identify ADA 
responses in patient circulation) (MEDI4736+tremelimumab 
and MEDI4736 monotherapy arms)c 
 
 
X 
 
X 
 
 
 
Immunogenicity tremelimumab assessment (ADA sampling 
[including ADA neutralising antibodies] to identify ADA 
responses in patient circulation) (MEDI4736+tremelimumab 
and tremelimumab monotherapy arms)c 
 
 
X 
 
X 
 
 
 
sPD-L1 concentration (to assess target engagement)c 
 
 
X 
 
 
 
 
 
Circulating soluble factors (to assess cytokines, chemokines, 
growth factors and antibodies against tumour and self 
antigens in circulation) 
X 
 
 
 
 
 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
93 
Table 6 
Follow-up for patients who have completed the treatment period for MEDI4736 monotherapy, 
tremelimumab monotherapy and MEDI4736+tremelimumab and achieved disease control and patients 
who have discontinued study drug due to toxicity or a reason other than confirmed progression of disease   
Evaluation  
Time Since Last Dose on MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab arms  
Day (±3) 
Months (±1 week) 
12 Months and  
Every 6 Months Thereafter 
(±2 weeks)f 
30 
2 
3 
4 
6 
8 
10 
Tumour assessment (CT or MRI)d,e 
For patients who achieve disease control following 12 months/48 weeks of treatment, tumour assessments 
should be performed every 12 weeks ± 1 week relative to the date of randomisation until confirmed PD by 
RECIST 1.1 by investigational site review.  Please refer to Table 3, Table 4 or Table 5 for timings of 
confirmatory scans.   
For patients who discontinue study drug due to toxicity or a reason other than confirmed PD, tumour 
assessments should be performed relative to the date of randomisation as follows: every 8 weeks ± 1 week 
for the first 48 weeks (per Table 3, Table 4 or Table 5), then every 12 weeks ± 1 week until confirmed PD by 
RECIST 1.1 by investigational site review.  Please refer to Table 3, Table 4 or Table 5 for timings of 
confirmatory scans.   
Upon confirmed radiological PD (by RECIST), scans should be conducted according to local standard clinical 
practice until a new treatment is started (these scans are optional).  
a 
World Health Organisation 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, please provide World Health Organisation performance status when information on subsequent anti-cancer therapy is provided, where possible. 
b 
Coagulation tests: prothrombin time, APTT and INR will be performed if clinically indicated. 
c 
PK and ADA: At 3 months after the last dose of treatment (and again at 6 months for ADA), 2 samples are drawn from those in the MEDI4736+tremelimumab arm and 
1 sample from each of the monotherapy arms. sPD-L1: At 3 months after the last dose of treatment, 1 sample is drawn from those in each of the 3 treatment arms.  NB: If 
a patient discontinues the MEDI4736+tremelimumab arm, PK, ADA and sPD-L1 samples must still be collected for tremelimumab at 3 and 6 months after the last dose 
of tremelimumab (Week 24 and Week 36). 
d 
RECIST assessments will be performed using CT/MRI assessments of the chest and abdomen (including liver and adrenal glands).  Additional anatomy may be imaged 
based on signs and symptoms of individual patients.  Following the final DCO, patients continuing on the study who remain potentially eligible for future re-treatment 
with MEDI4736 and/or tremelimumab should receive scans/RECIST and other assessments as per investigator’s judgment and local standard of care, but in such way that 
will allow confirmation of re-treatment eligibility criteria per Section 4.3. 
e 
If the patient experiences PD (according to RECIST 1.1), with or without confirmation, during the follow-up phase, retreatment with the initial dosing regimen may 
begin.  Patients can only begin retreatment once, and may continue as long as the investigator judges the patient to be gaining clinical benefit.  Before restarting study 
drug, the investigator should ensure that patients do not have any significant, unacceptable or irreversible toxicities that would indicate continuing treatment will not 
further benefit the patient.  The patient must continue to meet those inclusion and exclusion criteria that are relevant to retreatment as specified in Section 4.3.  To restart 
study drug the patient must not have received an intervening systemic anti-cancer therapy post-discontinuation of study drug.  Patients should have a baseline tumour 
assessment within 28 days prior to restarting study drug, all further scans should occur every 8 weeks ± 1 week (relative to the date of restarting study drug), or, if they 
continue to receive re-treatment after the final DCO, patients should receive scans/RECIST per local practice.  It is recommended that the patients continue the scheduled 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
94 
site visits and investigators monitor the patient’s safety laboratory assessments prior to and periodically during treatment in order to manage AEs in accordance with the 
toxicity management guidelines (Refer to Section 5.5.3). 
f 
Patients on survival follow-up at the time of final DCO will be considered completed from the  study and followed per local standard of care.  
ADA  Anti-drug antibody; APTT  Activated partial thromboplastin time; BP  Blood pressure; CT  Computed tomography; INR  International normalised ratio; MRI  Magnetic 
resonance imaging; PD  Progression of disease; RECIST  Response Evaluation Criteria In Solid Tumours; sPD-L1  Soluble programmed death ligand 1; T3  Triiodothyronine; 
T4  Thyroxine; TSH  Thyroid stimulating hormone. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
95 
Table 7 
Follow-up for patients who have discontinued MEDI4736 monotherapy, tremelimumab monotherapy 
and MEDI4736+tremelimumab due to confirmed progression of disease  
Evaluation 
Time Since Last Dose on MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab arms 
Day (±3) 
Months (±1 week) 
12 Months and  
Every 6 Months Thereafter 
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Patient questionnaires (patient reported outcomes) 
 
 
For patients who continue on study drug after confirmed progression at the investigator’s discretion 
(following consultation with the sponsor), patient questionnaires 
 
should be completed relative to the date of randomisation per Table 3, Table 4 or Table 5until treatment with 
study drug is stopped.   
For patients who discontinue study drug following confirmed progression, patient questionnaires 
 
 should be completed at the Day 30 assessment and at Month 3 after 
confirmed progression, in line with clinic assessments. Questionnaires should be administered before any 
clinical assessment at these visits. 
Physical examination 
X 
 
 
 
 
 
 
 
Vital signs (BP, pulse, respiratory rate, temperature, 
oxygen saturation) 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
Adverse event/serious adverse event assessment (see 
Section 6.4.3) 
X 
X 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
 
 
 
 
Palliative radiotherapy 
As clinically indicated (see Section 5.1) 
World Health Organisation performance statusa 
X 
X 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Subsequent anti-cancer therapya 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status: phone contact with patients who refuse 
to return for evaluations and agree to be contacted 
 
X 
X 
X 
X 
X 
X 
X (every 2 months) 
Haematology 
X 
X 
X 
 
 
 
 
 
Serum chemistry  
X 
X 
X 
 
 
 
 
 
Amylase, lipase (where available) 
X 
X 
X 
 
 
 
 
 
C
CI
CCI
C
CI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
96 
Table 7 
Follow-up for patients who have discontinued MEDI4736 monotherapy, tremelimumab monotherapy 
and MEDI4736+tremelimumab due to confirmed progression of disease  
Evaluation 
Time Since Last Dose on MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab arms 
Day (±3) 
Months (±1 week) 
12 Months and  
Every 6 Months Thereafter 
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Thyroid function tests (TSH, and T3 and T4) 
X 
 
 
 
 
 
 
 
Coagulation parametersb 
As clinically indicated 
 
Urinalysis 
As clinically indicated 
 
Pharmacokinetic MEDI4736 assessment 
(MEDI4736+tremelimumab and MEDI4736 
monotherapy arms)c  
 
 
X 
 
 
 
 
 
Pharmacokinetic tremelimumab assessment  
(MEDI4736+tremelimumab and tremelimumab 
monotherapy arms)c 
 
 
X 
 
 
 
 
 
Immunogenicity MEDI4736 assessment (ADA sampling 
[including ADA neutralising antibodies] to identify ADA 
responses in patient circulation) 
(MEDI4736+tremelimumab and MEDI4736 
monotherapy arms)c 
 
 
X 
 
 
 
 
 
Immunogenicity tremelimumab assessment (ADA 
sampling [including ADA neutralising antibodies] to 
identify ADA responses in patient circulation) 
(MEDI4736+tremelimumab and tremelimumab 
monotherapy arms)c 
 
 
X 
 
 
 
 
 
sPD-L1 concentration  (to assess target engagement)c 
 
 
X 
 
 
 
 
 
Circulating soluble factors (to assess cytokines, 
chemokines, growth factors and antibodies against 
tumour and self antigens in circulation) 
X 
 
 
 
 
 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
97 
Table 7 
Follow-up for patients who have discontinued MEDI4736 monotherapy, tremelimumab monotherapy 
and MEDI4736+tremelimumab due to confirmed progression of disease  
Evaluation 
Time Since Last Dose on MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab arms 
Day (±3) 
Months (±1 week) 
12 Months and  
Every 6 Months Thereafter 
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Tumour biopsy  
A tumour biopsy upon evidence of PD should be performed according to institutional practice.  It is accepted 
that the biopsy procedure should be technically feasible and not associated with unacceptable clinical risk 
(see Section 6.7) 
Time to second progression 
For patients who continue on study drug post confirmed progression at the investigator’s discretion 
(following consultation with the sponsor), tumour assessments should be performed relative to the date of 
randomisation per Table 3, Table 4 or Table 5 until study drug is stopped. 
Patients who discontinue study drug following confirmed progression, will be assessed every 12 weeks for a 
second progression (using the patient’s status at first progression as the reference for assessment of second 
progression).  A patient’s progression status is defined according to local standard clinical practice and may 
involve any of: objective radiological, symptomatic progression or death.   
Tumour assessment (CT or MRI) 
For patients who continue on study drug after confirmed progression at the investigator’s discretion 
(following consultation with the sponsor), tumour assessments should be performed relative to the date of 
randomisation per Table 3, Table 4 or Table 5 until study drug is stopped. 
For patients who discontinue study drug following confirmed progression, scans should be conducted 
according to local clinical practice until a new treatment is started (these scans are optional).   
a 
World Health Organisation 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, please provide World Health Organisation performance status when information on subsequent anti-cancer therapy is provided, where possible. 
b 
Coagulation tests: prothrombin time, APPT and INR will be performed if clinically indicated. 
c 
PK and ADA: At 3 months after the last dose of treatment, 2 samples are drawn from those in the MEDI4736+tremelimumab arm and 1 sample from each of the 
monotherapy arms. sPD-L1: At 3 months after the last dose of treatment, 1 sample is drawn from those in each of the 3 treatment arms. NB: If a patient discontinues the 
MEDI4736+tremelimumab arm, PK, ADA and sPD-L1 samples must still be collected for tremelimumab at 3 and 6 months after the last dose of tremelimumab 
(Week 24 and Week 36). 
ADA  Anti-drug antibody; APTT  Activated partial thromboplastin time; BP  Blood pressure; CT  Computed tomography; INR  International normalised ratio; MRI  Magnetic 
resonance imaging; PD  Progression of disease; sPD-L1  Soluble programmed death ligand 1; T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid stimulating hormone. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
98 
Table 8 
Schedule of study procedures for patients treated with vinorelbine or gemcitabine in the Standard of Care 
arm (a cycle=4 weeks): Screening and Treatment Period 
Visit (Assessments to be performed at 
the times stipulated and as clinically 
required in the management of the 
patient.) 
Pre-
screening 
for PD-L1 
status 
ONLY 
Screening 
All assessments to be performed pre-infusion unless stated otherwise 
Randomisation 
Cycle X 
Every 4 weeks 
Every 
8 weeks 
Every 
12 weeks 
Day 
-42 to -1 
-28 to -1 
Day 1a 
Day 1 
Day 8 
Day 15 
Day 22  
(vinorelbine only) 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4, 8, 
etc 
1, 5, 9, etc  
2, 6, 10, 
etc 
3, 7, 11, etc 
8, 16, 24, 
32, 40, 48, 
etc 
16, 28, 
40, 52, 
etc 
 
 
 
 
---------------------- (±3 days) ----------------------- 
------- (±7 days) ------ 
Written pre-screening informed 
consent/assignment of patient 
identification number (Section 6.2) 
X 
 
 
 
 
 
 
 
 
Preliminary eligibility fulfilment 
(investigator’s opinion) 
X 
 
 
 
 
 
 
 
 
Demography and history of tobacco and 
alcohol use 
X 
 
 
 
 
 
 
 
 
Previous treatments for NSCLC 
X 
 
 
 
 
 
 
 
 
Archival (>3 years) FFPE tumour tissue 
sample for PD-L1 assay (optional) (see 
Section 6.7) 
X 
 
 
 
 
 
 
 
 
Newly acquired or archival (≤3 years) 
formalin-fixed tumour biopsy for PD-L1 
assay (mandatory) (see Section 6.7) 
X 
 
 
 
 
 
 
 
 
Written sub-study informed consent 
(Note: Patients are required to re-consent 
to continue study drug when treated 
through progression [See Section 8.4]) 
 
X 
 
 
 
 
 
 
 
Formal verification of eligibility criteria 
 
X 
X 
 
 
 
 
 
 
Randomisation (see Section 5.2) 
 
 
X 
 
 
 
 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
99 
Table 8 
Schedule of study procedures for patients treated with vinorelbine or gemcitabine in the Standard of Care 
arm (a cycle=4 weeks): Screening and Treatment Period 
Visit (Assessments to be performed at 
the times stipulated and as clinically 
required in the management of the 
patient.) 
Pre-
screening 
for PD-L1 
status 
ONLY 
Screening 
All assessments to be performed pre-infusion unless stated otherwise 
Randomisation 
Cycle X 
Every 4 weeks 
Every 
8 weeks 
Every 
12 weeks 
Day 
-42 to -1 
-28 to -1 
Day 1a 
Day 1 
Day 8 
Day 15 
Day 22  
(vinorelbine only) 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4, 8, 
etc 
1, 5, 9, etc  
2, 6, 10, 
etc 
3, 7, 11, etc 
8, 16, 24, 
32, 40, 48, 
etc 
16, 28, 
40, 52, 
etc 
 
 
 
 
---------------------- (±3 days) ----------------------- 
------- (±7 days) ------ 
Patient questionnaires (patient reported 
outcomes) (see Section 6.5)b 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Medical and surgical history 
 
X 
 
 
 
 
 
 
 
Hepatitis B and C; HIV 
 
X 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
Urine hCG or serum βhCG 
 
X 
X 
 
 
 
 
 
 
Kit assignment and chemotherapy 
administration 
 
 
X 
X 
X 
X 
X 
 
 
Physical examination  
 
X 
X 
X 
 
 
 
 
 
Vital signs (at the beginning and end of 
each infusion where possible) 
 
X 
X 
X 
X 
X 
X 
 
 
Weight 
 
X 
X 
X 
 
 
 
 
 
Electrocardiogram (see Section 6.4.7)d 
 
X 
 
 
 
 
 
 
 
AE/SAE assessment (see Section 6.4.3) 
X 
X 
X 
X 
X 
X 
X 
 
 
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
100 
Table 8 
Schedule of study procedures for patients treated with vinorelbine or gemcitabine in the Standard of Care 
arm (a cycle=4 weeks): Screening and Treatment Period 
Visit (Assessments to be performed at 
the times stipulated and as clinically 
required in the management of the 
patient.) 
Pre-
screening 
for PD-L1 
status 
ONLY 
Screening 
All assessments to be performed pre-infusion unless stated otherwise 
Randomisation 
Cycle X 
Every 4 weeks 
Every 
8 weeks 
Every 
12 weeks 
Day 
-42 to -1 
-28 to -1 
Day 1a 
Day 1 
Day 8 
Day 15 
Day 22  
(vinorelbine only) 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4, 8, 
etc 
1, 5, 9, etc  
2, 6, 10, 
etc 
3, 7, 11, etc 
8, 16, 24, 
32, 40, 48, 
etc 
16, 28, 
40, 52, 
etc 
 
 
 
 
---------------------- (±3 days) ----------------------- 
------- (±7 days) ------ 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
 
 
Palliative radiotherapy 
 
 
As clinically indicated (see Section 5.1) 
 
WHO performance status 
X 
X 
X 
 
 
 
 
 
Serum chemistrye 
 
X 
X 
X 
 
X 
 
 
 
Amylase, lipase (where available)e 
 
X 
X 
 
 
 
X 
 
 
Haematologye 
 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
 
X 
X 
X 
 
 
 
 
 
Coagulation parametersf 
 
X 
 
 
 
 
 
 
 
Thyroid function tests (TSH and T3 and 
T4) (see Section 6.4.9) 
 
X 
 
 
 
 
 
 
 
sPD-L1 concentration (see Section 6.7)g 
 
 
X 
X (C3 
only) 
 
 
 
X (Week 
24 only) 
 
Circulating soluble factors (to assess 
cytokines, chemokines, growth factors 
and antibodies against tumour and self 
antigens in circulation) (see Section 6.7)g 
 
 
X 
X (C2 and 
C4 only) 
 
 
 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
101 
Table 8 
Schedule of study procedures for patients treated with vinorelbine or gemcitabine in the Standard of Care 
arm (a cycle=4 weeks): Screening and Treatment Period 
Visit (Assessments to be performed at 
the times stipulated and as clinically 
required in the management of the 
patient.) 
Pre-
screening 
for PD-L1 
status 
ONLY 
Screening 
All assessments to be performed pre-infusion unless stated otherwise 
Randomisation 
Cycle X 
Every 4 weeks 
Every 
8 weeks 
Every 
12 weeks 
Day 
-42 to -1 
-28 to -1 
Day 1a 
Day 1 
Day 8 
Day 15 
Day 22  
(vinorelbine only) 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4, 8, 
etc 
1, 5, 9, etc  
2, 6, 10, 
etc 
3, 7, 11, etc 
8, 16, 24, 
32, 40, 48, 
etc 
16, 28, 
40, 52, 
etc 
 
 
 
 
---------------------- (±3 days) ----------------------- 
------- (±7 days) ------ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour assessment (CT or MRI)h 
 
X 
 
 
 
 
 
X 
 
a 
Every effort should be made to minimise the time between randomisation and starting treatment.  It is recommended that patients commence study treatment as soon as 
possible after randomisation (ie, on the same day after randomisation in the IVRS/IWRS system) and no later than 48 hours after randomisation. 
b 
Patient questionnaires to be completed at Week 1 (Day 1 [Randomisation]), Week 4 (Day 29) and Week 8 (Day 57) and then every 8 weeks for the first 48 weeks then 
every 12 weeks until confirmed objective disease progression per RECIST 1.1.  
 
c 
 
d 
Digital electrocardiograms should be performed at Screening in triplicate with a 2- to 5-minute time lag between each measurement.   
e 
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 urea and electrolytes, full blood 
count and liver function tests must be available before commencing any infusion with vinorelbine or gemcitabine.  Gamma glutamyltransferase tested at Screening, Day 1 
(if screening laboratory assessments are not performed within 3 days prior to Day 1) and as clinically indicated.  Creatinine clearance, magnesium, amylase, lipase, and 
uric acid tested at Screening, Day 1 (if screening laboratory assessments are not performed within 3 days prior to Day 1) and every 4 weeks thereafter. 
f 
Coagulation tests: prothrombin time, APTT and INR – only performed at Screening and as clinically indicated. 
g 
sPD-L1: Blood samples are collected pre-dose on Day 1, Week 8 and Week 24 only.
 
CCI
CCI
CCI
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
102 
h 
RECIST assessments will be performed using CT/MRI assessments of the chest and abdomen (including liver and adrenal glands).  Additional anatomy should be imaged 
based on signs and symptoms of individual patients.  The baseline assessment should be performed within the 28 days prior to randomisation and ideally as close as 
possible before the start of study treatment.  Follow-up assessments will be performed every 8 weeks ± 1 week for the first 48 weeks (relative to the date of 
randomisation) and then every 12 weeks thereafter until confirmed objective disease progression per RECIST 1.1.  A confirmatory scan is required following the initial 
demonstration of PD.  In the Standard of Care arm, it is at the investigator’s discretion if a patient with uncertain PD continues treatment until PD is confirmed; however, 
a confirmatory scan is required for all patients in the Standard of Care arm even if a subsequent treatment is started.  The confirmatory scans should be performed to 
preferably occur at the next scheduled visit (relative to the date of randomisation) and no less than 4 weeks after the prior assessment of PD (in the absence of clinically 
significant deterioration).  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent 
assessments at their scheduled visits (relative to the date of randomisation).  All confirmatory scans should be databased.  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.  The patient must continue to meet those inclusion and exclusion criteria that are relevant to treatment through disease progression as specified in 
Section 4.3.   
Note: If a patient has a delay to an infusion of study treatment all assessments should be conducted relative to the date of randomisation. 
AE  Adverse event; APTT  Activated partial thromboplastin time; C  Cycle; CT  Computed tomography; FFPE Formalin-fixed paraffin-embedded; hCG  Human chorionic 
gonadotropin; HIV  Human immunodeficiency virus; INR  International normalised ratio; IVRS/IWRS  Interactive Voice/Web Response System; miRNA  Micro RNA; MRI  
Magnetic resonance imaging; mRNA  Messenger RNA; NSCLC  Non-small cell lung cancer; PD  Progression of disease; PGx  Pharmacogenetic(s); RECIST  Response 
Evaluation Criteria In Solid Tumours; SAE  Serious adverse event; sPD-L1  Soluble programmed death ligand 1; T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid 
stimulating hormone; WHO  World Health Organisation. 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
103 
Table 9 
Schedule of study procedures for patients treated with erlotinib in the Standard of Care arm (a 
cycle=4 weeks): Screening and Treatment Period 
Visit (Assessments to be performed at the 
times stipulated and as clinically required in 
the management of the patient.) 
Pre-
screening 
for PD-L1 
status 
ONLY 
Screening  
Randomisation 
Cycle X, Day 1 
Every 4 weeks 
Every 8 weeks  
Every 12 weeks  
Day 
-42 to -1 
-28 to -1 
Day 1a 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4, 8, 12, 16, etc 
8, 16, 24, 32, 
40, 48, etc  
16, 28, 40, 52, etc 
 
 
 
 
------- (±2 days) ------ 
--------------------- (±7 days) -------------------- 
Written pre-screening informed 
consent/assignment of patient identification 
number (Section 6.2) 
X 
 
 
 
 
 
Preliminary eligibility fulfilment 
(investigator’s opinion) 
X 
 
 
 
 
 
Demography and history of tobacco and 
alcohol use 
X 
 
 
 
 
 
Previous treatments for NSCLC 
X 
 
 
 
 
 
Archival (>3 years) FFPE tumour tissue 
sample for PD-L1 assay (optional) (see 
Section 6.7) 
X 
 
 
 
 
 
Newly acquired or archival (≤3 years) 
formalin-fixed tumour biopsy for PD-L1 assay 
(mandatory) (see Section 6.7) 
X 
 
 
 
 
 
Written sub-study informed consent (Note: 
Patients are required to re-consent to continue 
study drug when treated through progression 
[See Section 8.4]) 
 
X 
 
 
 
 
Formal verification of eligibility criteria 
 
X 
X 
 
 
 
Randomisation (see Section 5.2) 
 
 
X 
 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
104 
Table 9 
Schedule of study procedures for patients treated with erlotinib in the Standard of Care arm (a 
cycle=4 weeks): Screening and Treatment Period 
Visit (Assessments to be performed at the 
times stipulated and as clinically required in 
the management of the patient.) 
Pre-
screening 
for PD-L1 
status 
ONLY 
Screening  
Randomisation 
Cycle X, Day 1 
Every 4 weeks 
Every 8 weeks  
Every 12 weeks  
Day 
-42 to -1 
-28 to -1 
Day 1a 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4, 8, 12, 16, etc 
8, 16, 24, 32, 
40, 48, etc  
16, 28, 40, 52, etc 
 
 
 
 
------- (±2 days) ------ 
--------------------- (±7 days) -------------------- 
Patient questionnaires (patient reported 
outcomes) (see Section 6.5)b 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history  
 
X 
 
 
 
 
Hepatitis B and C; HIV 
 
X 
 
 
 
 
Height 
 
X 
 
 
 
 
Urine hCG or serum βhCG 
 
X 
X 
 
 
 
Erlotinib dispensing 
 
 
X 
X 
 
 
Physical examination  
 
X 
X 
X 
 
 
Vital signs 
 
X 
X 
X 
 
 
Weight 
 
X 
X 
X 
 
 
Electrocardiogram (see Section 6.4.7)d 
 
X 
 
 
 
 
AE/SAE assessment (see Section 6.4.3) 
X 
X 
X 
X 
 
 
Concomitant medications 
X 
X 
X 
 
 
WHO performance status 
X 
X 
X 
 
 
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
105 
Table 9 
Schedule of study procedures for patients treated with erlotinib in the Standard of Care arm (a 
cycle=4 weeks): Screening and Treatment Period 
Visit (Assessments to be performed at the 
times stipulated and as clinically required in 
the management of the patient.) 
Pre-
screening 
for PD-L1 
status 
ONLY 
Screening  
Randomisation 
Cycle X, Day 1 
Every 4 weeks 
Every 8 weeks  
Every 12 weeks  
Day 
-42 to -1 
-28 to -1 
Day 1a 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4, 8, 12, 16, etc 
8, 16, 24, 32, 
40, 48, etc  
16, 28, 40, 52, etc 
 
 
 
 
------- (±2 days) ------ 
--------------------- (±7 days) -------------------- 
Palliative radiotherapy 
 
As clinically indicated (see Section 5.1) 
Serum chemistrye 
X 
X 
X 
 
 
Amylase, lipase (where available)e 
 
X 
X 
X 
 
 
Haematologye 
 
X 
X 
X 
 
 
Urinalysis 
 
X 
X 
X 
 
 
Coagulation parametersf 
 
X 
 
 
 
 
Thyroid function tests (TSH and T3 and T4) 
(see Section 6.4.9) 
 
X 
 
 
 
 
sPD-L1 concentration  (see Section 6.7)g 
 
 
X 
X (C3 only) 
X (Week 24 only) 
 
Circulating soluble factors (to assess cytokines, 
chemokines, growth factors and antibodies 
against tumour and self antigens in circulation) 
(see Section 6.7)g 
 
 
X 
X (C2 and C4 only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
106 
Table 9 
Schedule of study procedures for patients treated with erlotinib in the Standard of Care arm (a 
cycle=4 weeks): Screening and Treatment Period 
Visit (Assessments to be performed at the 
times stipulated and as clinically required in 
the management of the patient.) 
Pre-
screening 
for PD-L1 
status 
ONLY 
Screening  
Randomisation 
Cycle X, Day 1 
Every 4 weeks 
Every 8 weeks  
Every 12 weeks  
Day 
-42 to -1 
-28 to -1 
Day 1a 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
4, 8, 12, 16, etc 
8, 16, 24, 32, 
40, 48, etc  
16, 28, 40, 52, etc 
 
 
 
 
------- (±2 days) ------ 
--------------------- (±7 days) -------------------- 
Tumour assessment (CT or MRI)h 
 
X 
 
 
X 
 
a 
Every effort should be made to minimise the time between randomisation and starting treatment.  It is recommended that patients commence study treatment as soon as 
possible after randomisation (ie, on the same day after randomisation in the IVRS/IWRS system) and no later than 48 hours after randomisation. 
b 
Patient questionnaires to be completed at Week 1 (Day 1 [Randomisation]), Week 4 (Day 29) and Week 8 (Day 57) and then every 8 weeks for the first 48 weeks then 
every 12 weeks until confirmed objective disease progression per RECIST 1.1.  
 
c 
 
d 
Digital electrocardiograms should be performed at Screening in triplicate with a 2- to 5-minute time lag between each measurement. 
e 
If Screening laboratory assessments are performed within 3 days prior to Day 1 they do not need to be repeated at Day 1.  Gamma glutamyltransferase tested at 
Screening, Day 1 (if screening laboratory assessments are not performed within 3 days prior to Day 1) and as clinically indicated.  Creatinine clearance, magnesium, 
amylase, lipase, and uric acid tested at Screening, Day 1 (if screening laboratory assessments are not performed within 3 days prior to Day 1) and every 4 weeks 
thereafter.   
f 
Coagulation tests: prothrombin time, APTT and INR – only performed at Screening and as clinically indicated. 
g 
sPD-L1: Blood samples are collected pre-dose on Day 1, Week 8 and Week 24 only.  
 
 
h 
RECIST assessments will be performed using CT/MRI assessments of the chest and abdomen (including liver and adrenal glands).  Additional anatomy should be imaged 
based on signs and symptoms of individual patients.  The baseline assessment should be performed within the 28 days prior to randomisation and ideally as close as 
possible before the start of study treatment.  Follow-up assessments will be performed (relative to the date of randomisation) every 8 weeks ± 1 week for the first 48 
weeks and then every 12 weeks thereafter until confirmed objective disease progression per RECIST 1.1.  A confirmatory scan is required following the initial 
demonstration of PD.  In the Standard of Care arm, it is at the investigator’s discretion if a patient with uncertain PD continues treatment until PD is confirmed; however, 
a confirmatory scan is required for all patients in the Standard of Care arm even if a subsequent treatment is started.  The confirmatory scans should be performed to 
preferably occur at the next scheduled visit (relative to the date of randomisation) and no less than 4 weeks after the prior assessment of PD (in the absence of clinically 
significant deterioration).  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent 
assessments at their scheduled visits (relative to the date of randomisation).  All confirmatory scans should be databased.  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 
CCI
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
107 
benefit the patient.  The patient must continue to meet those inclusion and exclusion criteria that are relevant to treatment through disease progression as specified in 
Section 4.3.   
AE  Adverse event; APTT  Activated partial thromboplastin time; C  Cycle; CT  Computed tomography; FFPE  Formalin-fixed paraffin-embedded; hCG  Human chorionic 
gonadotropin; HIV  Human immunodeficiency virus; INR  International normalised ratio; IVRS/IWRS  Interactive Voice/Web Response System; miRNA  Micro RNA; MRI  
Magnetic resonance imaging; mRNA  Messenger RNA; NSCLC  Non-small cell lung cancer; PD  Progression of disease; PGx  Pharmacogenetic(s);  RECIST  Response 
Evaluation Criteria In Solid Tumours; SAE  Serious adverse event; sPD-L1  Soluble programmed death ligand 1; T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid 
stimulating hormone; WHO  World Health Organisation. 
 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
108 
Table 10 
Follow-up for patients in the Standard of Care arm 
Evaluation 
Time since last dose of Standard of Care treatment 
Day (±3) 
Months (±1 week) 
12 Months and Every 6 Months  
Thereafter 
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Patient questionnaires (patient reported 
outcomes) 
For patients who discontinue study drug due to toxicity or a reason other than confirmed PD, patient questionnaires and 
information for health resource use should be completed relative to the date of randomisation as follows: every 8 weeks for the 
first 48 weeks, then every 12 weeks thereafter until confirmed PD by RECIST 1.1 by investigational site review.   
For patients who discontinue study treatment following confirmed progression, patient questionnaires and information on health 
resource use should be completed at the Day 30 assessment and at Month 3 after confirmed progression, in line with clinic 
assessments. Questionnaires should be administered before any clinical assessment at these visits.  
Health resource use instrument  
Physical examination  
X 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
AE/SAE assessment (see Section 6.4.3) 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
 
 
 
 
 
 
 
Palliative radiotherapy 
As clinically indicated (see Section 5.1) 
World Health Organisation performance 
statusa 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Subsequent anti-cancer therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status: phone contact with 
patients who refuse to return for 
evaluations and agree to be contacted 
 
X 
X 
X 
X 
X 
X 
X (every 2 months) 
Haematology 
X 
 
 
 
 
 
 
Xb 
Serum chemistry  
X 
 
 
 
 
 
 
 
Amylase, lipase (where available) 
X 
 
Coagulation parameters 
 
As clinically indicated 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
109 
Table 10 
Follow-up for patients in the Standard of Care arm 
Evaluation 
Time since last dose of Standard of Care treatment 
Day (±3) 
Months (±1 week) 
12 Months and Every 6 Months  
Thereafter 
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Urinalysis 
 
As clinically indicated 
Circulating soluble factors (to assess 
cytokines, chemokines, growth factors and 
antibodies against tumour and self 
antigens in circulation) 
X 
 
 
 
 
 
 
 
Tumour biopsy  
A tumour biopsy upon evidence of PD should be performed according to institutional practice.  It is accepted that the biopsy 
procedure should be technically feasible and not associated with unacceptable clinical risk (see Section 6.7) 
Tumour assessment (CT or MRI) 
For patients who discontinue study treatment due to toxicity or a reason other than confirmed PD, tumour assessments should 
be performed relative to the date of randomisation as follows: every 8 weeks ± 1 week for the first 48 weeks, then every 12 weeks 
thereafter until confirmed PD by RECIST 1.1.  Please refer to Table 8 (gemcitabine and vinorelbine) and Table 9 (erlotinib) for 
timings of confirmatory scans.   
Upon confirmed PD, scans should be conducted according to local standard clinical practice until a new treatment is started (these 
scans are optional). 
Time to second progression 
Patients who discontinue study treatment following confirmed progression, will be assessed every 12 weeks for a second 
progression (using the patient’s status at first progression as the reference for assessment of second progression).  A patient’s 
progression status is defined according to local standard clinical practice and may involve any of: objective radiological, 
symptomatic progression or death.   
a 
World Health Organisation 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, please provide World Health Organisation performance status when information on subsequent anti-cancer therapy is provided, where possible. 
b 
Only for patients who have discontinued treatment due to toxicity or a reason other than confirmed PD. 
AE  Adverse event; CT  Computed tomography; MRI  Magnetic resonance imaging; PD  Progression of disease; RECIST  Response Evaluation Criteria In Solid Tumours; 
SAE  Serious adverse event; sPD-L1  Soluble programmed death ligand 1. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
110 
3.2 
Rationale for study design, doses and control groups 
3.2.1 
Unmet need and potential role of immunotherapies in NSCLC 
Current therapies for advanced NSCLC have poor outcomes and there is still a significant 
unmet medical need for additional treatment options for use in this patient population.  
Patients who fail second-line chemotherapy usually have a poor prognosis with median 
survival of <6 months.  The outlook for refractory advanced NSCLC is extremely poor, with 
response to further systemic therapy of <10% (GLOBOCAN 2008, Hanna et al 2004).   
Single agent chemotherapy is an acceptable option for patients who fail first- or second-line 
systemic treatment.  However, the impact on PFS and OS is generally modest; thus, novel and 
more effective therapeutic strategies are needed.  Erlotinib (TARCEVA®), an EGFR inhibitor, 
also provides a modest improvement in OS in patients who have failed first- or second-line 
chemotherapy (TARCEVA® prescribing information).  In a randomised, placebo-controlled, 
double-blind trial comparing erlotinib with placebo, patients treated with erlotinib showed OS 
of 6.7 months versus 4.7 months for placebo (HR: 0.73; 95% CI: 0.61 to 0.86); PFS was 
2.3 months for the erlotinib group versus 1.8 months for the placebo group (HR: 0.59; 95% 
CI: 0.50 to 0.70).  
3.2.2 
Potential role for MEDI4736 monotherapy (Sub-study A), and 
MEDI4736+tremelimumab, MEDI4736 monotherapy and tremelimumab 
monotherapy (Sub-study B) in the treatment of NSCLC 
Although clinical experience with MEDI4736 is limited, currently available data from the 
MEDI4736 FTIH study (Section 1.4.1 and MEDI4736 IB), indicates encouraging response 
rates and DoR, with a manageable safety profile in patients with a variety of solid 
malignancies, including patients with NSCLC.  These are advanced patients who have failed 
multiple lines of therapy.  These emerging data support the proposed further investigation of 
MEDI4736 in patients with advanced/metastatic NSCLC who have failed 2 prior lines of 
therapy in a controlled Phase III setting.  Furthermore, data on MEDI4736 presented at ESMO 
2014 showed an ORR of 16% in the overall NSCLC patient population and a 25% ORR in the 
PD-L1-positive subset of patients and an ORR of 10% in the PD-L1-negative subset of 
patients (Antonia et al 2014 ESMO), consistent with the principle that the selection of patients 
based on PD-L1 expression within the tumour microenvironment may have merit as a patient 
enrichment tool.  Updated safety and efficacy data from this study was presented at 
international oncology conferences (Rizvi et al 2015 ASCO).  Nonetheless, patients with PD-
L1-negative tumours also received benefit from MEDI4736. 
Although clinical experience with tremelimumab monotherapy in NSCLC is limited, Study 
A3671015 suggested a trend in benefit in PFS at 3 months, and some partial responses to 
treatment, including in a patient who crossed over from the Best Supportive Care arm after 
PD.  The evolved dosing approach of 10 mg/kg Q4W merits further investigation in the 
NSCLC population.  The safety profile using the greater exposure remains manageable. 
Although clinical experience with MEDI4736+tremelimumab is limited, currently available 
data from a Phase Ib study in patients with advanced NSCLC (Section 1.1.5 and 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
111 
MEDI4736 IB) demonstrate an acceptable and manageable safety and tolerability profile for 
the combination.  Additionally, prior studies combining anti-PD-L1 and anti-CTLA-4 
antibodies have suggested that the efficacy of combination blockade is less dependent on 
PD-L1 expression (Wolchok et al 2013).  With the availability of multiple agents targeting the 
subset of NSCLC patients with PD-L1-positive tumours, the subset of NSCLC patients with 
PD-L1-negative tumours become a group with a great unmet need and limited therapeutic 
options.  MEDI4736 monotherapy, tremelimumab monotherapy or the combination of 
MEDI4736+tremelimumab as therapeutic options may fill this gap in NSCLC patients with 
PD-L1-negative tumours.  The totality of evidence supports the proposed investigation of 
either monotherapy or MEDI4736+tremelimumab in patients with PD-L1 negative 
advanced/metastatic NSCLC who have failed 2 prior lines of therapy. 
3.2.3 
Study design rationale 
3.2.3.1 
MEDI4736 monotherapy dose justification 
A MEDI4736 dose of 10 mg/kg Q2W up to a maximum of 12 months is recommended for 
further development.  
The proposed dose of 10 mg/kg Q2W is supported by multiple lines of evidence including: 
in-vitro data, non-clinical activity, clinical PK/PDx, biomarkers and activity data (ongoing 
FTIH study).  Although clinical activity has been observed at lower doses, no DLTs were 
observed up to a dose of 10 mg/kg Q2W or 15 mg/kg every 3 weeks.  The proposed dosing 
regimen of 10 mg/kg Q2W is expected to (a) achieve a target median concentration of 
approximately 100 µg/mL (identified based on pre-clinical and clinical data) (b) account for 
anticipated variability in PK, PD 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 anti-tumour activity in animal model.  
Based on PK/PDx data from the ongoing FTIH study with dose ranging from 0.1 to 10 mg/kg 
Q2W or 15 mg/kg every 3 weeks, MEDI4736 exhibited non-linear (dose-dependent) PK 
consistent with target-mediated drug disposition.  The PK approached linearity at ≥3 mg/kg 
Q2W dose, suggesting near complete target saturation (membrane bound and soluble PD-L1).  
The expected mean trough concentration following 3 mg/kg Q2W is approximately 50 µg/mL. 
The expected half life with doses ≥3 mg/kg Q2W is approximately 21 days.  A 
dose-dependent suppression in peripheral soluble PD-L1 was observed over the dose range 
studied, consistent with engagement of MEDI4736 with PD-L1.  Pharmacokinetic simulations 
indicate that following a 10 mg/kg Q2W dose of MEDI4736, >90% patients are expected to 
maintain PK exposure, yielding full target saturation throughout the dosing interval.    
Data generated during the dose escalation phase of the FTIH study also suggest that higher 
doses (ie, 10 mg/kg Q2W) may be associated with better clinical activity while still providing 
an acceptable safety profile.  Dose-related changes in a variety of peripheral biomarkers have 
been observed over the dose range of 0.1 to 3 mg/kg Q2W.  Thus far, a low level of 
immunogenicity has been observed.  No patients have experienced immune-complex disease 
following exposure to MEDI4736.  Overall, a low incidence of ADA has been observed.  Of 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
112 
the 220 patients who received MEDI4736 monotherapy and for whom PK/ADA data were 
available as of July 2014, 5 were detected to be ADA positive, with an impact on PK/PDx 
reported in 1 patient.  Thus, the clinical activity observed, coupled with the safety profile, 
translational science correlates and non-clinical data, supports further development with a 
dose of 10 mg/kg Q2W. 
3.2.3.2 
Tremelimumab monotherapy dose justification 
Please see Section 1.1.4 for more information regarding safety.  An extensive programme of 
non-clinical and clinical studies has been conducted for tremelimumab both as monotherapy 
and combination therapy with conventional anti-cancer agents to support various cancer 
indications using different dose schedules.  Tremelimumab has been administered as a 
single-agent treatment to patients participating in 11 sponsored clinical studies, 3 of which are 
ongoing.  In total, more than 1400 patients with a variety of tumour types have been treated 
with tremelimumab given alone or in combination with other anti-cancer agents in 
34 sponsored clinical studies. 
Risks with tremelimumab monotherapy are gastrointestinal effects (colitis, diarrhoea, 
enterocolitis and intestinal perforation); endocrine disorders (hypo and hyperthyroidism, 
hypophysitis and adrenal insufficiency); skin effects (rash and pruritus); elevations in lipase 
and amylase; other gastrointestinal events (ulcerative colitis, dehydration, nausea and 
vomiting); hepatic events (hepatitis and liver enzyme elevations); pneumonitis and interstitial 
lung disease; clinical manifestations of pancreatitis; nervous system events (encephalitis, 
peripheral motor and sensory neuropathies, Guillain-Barre and proximal muscle weakness); 
cytopenias (thrombocytopenia, anaemia and neutropenia); infusion-related reactions, 
anaphylaxis and allergic reactions; renal events (renal failure, acute kidney injury, nephritis, 
nephrotic syndrome, autoimmune nephritis and electrolyte abnormalities such as 
hypokalaemia; autoimmune diseases including autoimmune arthritis, Sjogren's syndrome and 
giant cell temporal arteritis); hyperglycaemia and diabetes mellitus; and pyrexia.  The 
mechanism of action for these risks is thought to be immune-mediated and reflective of the 
pharmacology of tremelimumab. 
Complete updated clinical information, including updates on the identified and potential 
safety risks, efficacy and pharmacokinetic data, can be found in the current version of the 
tremelimumab IB. 
Across the clinical development programme for tremelimumab, and that of the related 
anti-CTLA-4 antibody ipilimumab, a pattern of efficacy has emerged that appears to be 
consistent across different tumour types for anti-CTLA-4 agents.  Response rates to 
anti-CTLA-4 antibodies are generally low, approximately 10%; however, in patients who 
respond, the responses are often durable, lasting several months even in patients with 
aggressive tumours such as refractory metastatic melanoma.  In addition, survival benefit was 
reported even in patients without radiographical regression in their tumour burden. 
As discussed in Section 1.3, tremelimumab at a concentration of 30 μg/mL enhanced IL-2 
release (in vitro) and showed anti-tumour activity (in vivo), and was consequently identified 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
113 
as the target concentration.  Pharmacokinetic simulations indicate that following a dose of 
10 mg/kg Q4W for 6 months, approximately 90% of patients are expected to be above this 
target level of 30 μg/mL during the induction phase.  Tremelimumab at a dose of 10 mg/kg 
Q4W for 6 months followed by 10 mg/kg every 90 days is expected to yield PK exposures 
similar to those of the related anti-CTLA-4 mAb ipilimumab, given at a dose of 10 mg/kg 
every 3 weeks followed by 10 mg/kg every 3 months, the dosing regimen that was tested in 
the pivotal first-line melanoma trial (Robert et al 2011).   
In addition, retrospective analyses of the Phase I and II tremelimumab melanoma studies show 
an improvement in OS for patients who were able to achieve a higher tremelimumab 
exposure, as measured by the area under the plasma concentration-time curve.  The median 
OS was significantly longer in the high-AUC group (15.3 months; N=164) versus the 
low-AUC group (6.0 months; N=163) (based on the median value of AUC 
[103570 µg•hr/mL]).  This difference in OS corresponds to a HR of 0.41; p<0.001, and the 
estimated survival rates in the 2 groups were 59% versus 29% at 1 year and 15.9% versus 
1.2% at 2 years. 
A dose schedule of 10 mg/kg Q4W for 6 months followed by 10 mg/kg Q12W is the dose and 
schedule used in tremelimumab studies that have been started since May 2012.  Study 
D4880C00003 is a randomised, double-blind Phase IIb study comparing tremelimumab to 
placebo in second-or third-line treatment of patients with unresectable pleural or peritoneal 
malignant mesothelioma.  The primary objective of this study is to compare OS between the 
2 treatment arms, and secondary objectives include disease control rate, PFS, patient-reported 
outcomes, ORR, duration of ORR, safety and tolerability, immunogenicity, and PK.  In this 
study, tremelimumab is administered iv at 10 mg/kg Q4W for 7 doses, followed by Q12W.  
Results from the primary analysis based on 571 randomised patients can be found in the 
current version of the tremelimumab IB. 
It is anticipated that the proposed dose and schedule, which is based on PK as well as PDx 
measures such as IL-2 release, coupled with the safety profile, and non-clinical data, supports 
a study evaluating a dose of 10 mg/kg Q4W for 24 weeks followed by 10 mg/kg Q12W for an 
additional 24 weeks in third- and fourth-line NSCLC patients. 
3.2.3.3 
Dose justification for the combination of MEDI4736 20 mg/kg IV Q4W with 
tremelimumab 1 mg/kg IV Q4W for 4 cycles  
The dose and schedule of MEDI4736 20 mg/kg and tremelimumab 1 mg/kg Q4W was 
selected based on PK/PDx, safety and efficacy data from Study D4190C0006.  The goal of 
dose selection was to identify an optimal dose of MEDI4736 and tremelimumab that would 
result in pharmacologically active doses of both drugs as measured by sustained target 
suppression (soluble programmed cell death ligand 1 [sPD-L1]) and evidence of increased 
T-cell proliferation and activation, demonstrate promising efficacy and have an acceptable 
safety profile.  
As of 27 January 2015, a total of 74 patients with advanced non-small cell lung cancer have 
been treated in Study D4190C00006.  The 74 patients have received between 1 and 9 doses of 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
114 
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 
every 2 week (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 PDx values. 
In order to reduce the dosing frequency of MEDI4736 to align with the Q4W dosing of 
tremelimumab, while ensuring an acceptable PK/PDx, safety and efficacy cohorts were 
narrowed to 15 and 20 mg/kg MEDI4736 Q4W.   
Safety data from the 15 and 20 mg/kg MEDI4736 cohorts demonstrated a numerical increase 
in the frequency of treatment-related AEs and AEs leading to discontinuation of 
investigational product with increasing doses (>1 mg/kg) of tremelimumab.  
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.  Complete updated clinical 
data on the MEDI4736 and tremelimumab combination can be found in the current 
MEDI4736 IB. 
3.2.3.3.1 
Rationale for tremelimumab 1 mg/kg Q4W in the combination with 
MEDI4736 
Pre-clinical and clinical data indicate that 1 mg/kg tremelimumab delivered Q4W is a 
pharmacologically active dose. 
Pre-clinical studies of tremelimumab showed significant enhancement of in vitro cytokine 
release in the SEA super-antigen assay at concentrations ranging from 10 to 30 µg/mL.  
Pre-clinical models indicate that a trough concentration of approximately 30 µg/mL is 
associated with anti-tumour activity in-vivo.  Available clinical PK data demonstrate that 
1 mg/kg Q4W would result in median Cmax to be approximately 30 µg/mL followed by a 
decrease in median concentration to approximately 6 µg/mL by the end of dosing interval at 
steady state.  
Monotonic increases in PDx activity with the combination (increased activation/proliferation 
markers on CD4 and CD8 T-cells in periphery) were observed with increasing doses of 
tremelimumab (1, 3, 10 mg/kg).  There was evidence of augmented PDx activity, most 
notably CD8 T-cell proliferation as measured by Ki67, relative to MEDI4736 monotherapy 
even with combination doses containing 1 mg/kg tremelimumab. 
Clinical activity of the MEDI4736 and tremelimumab combination did not appear to provide a 
qualitative change with increasing doses of tremelimumab above 1 mg/kg; however, among 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
115 
the 10 PD-L1 negative patients who received combination doses containing tremelimumab at 
1 mg/kg, objective response was noted in 3 (30%) patients. 
3.2.3.3.2 
Dose justification for MEDI4736 20 mg/kg Q4W 
To maximise MEDI4736 exposure with an acceptable safety profile, the highest dose of 
20 mg/kg was selected.  Preclinical and clinical data supports a decreased frequency of 
MEDI4736 dosing at 20 mg/kg IV Q4W. 
Preclinical data  
A population PK model was developed using monotherapy data from a Phase I study 
(doses = 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; Fairman et al 2014).  This population PK 
model adequately described monotherapy PK data and was utilised to predict expected PK 
exposures following 20 mg/kg Q4W dosing regimens (since none of the monotherapy studies 
explored Q4W regimens).  Pharmacokinetic simulations indicate that a similar overall 
exposure as represented by AUC at steady state (AUCss; 4 weeks) is expected following both 
10 mg/kg Q2W and 20 mg/kg Q4W regimens.  However, median Cmax,ss is expected to be 
higher with 20 mg/kg Q4W (approximately 1.5-fold) and median Ctrough,ss is expected to be 
higher with 10 mg/kg Q2W (approximately 1.25-fold).  Based on similarity in overall 
exposure, use of either 20 mg/kg Q4W or 10 mg/kg Q2W is acceptable.  
Clinical data 
In addition, limited PK data from Study D4190C00006 was available from the combination 
cohort: 20 mg/kg Q4W MEDI4736 plus 1 or 3 mg/kg Q4W tremelimumab.  The observed 
MEDI4736 PK data from this combination study were well in line with the predicted 
monotherapy PK data.  This indicates no PK interaction between these 2 agents and supports 
that combination PK data adequately represent the monotherapy data from the 20 mg/kg Q4W 
cohort.  
Furthermore, in Study 1108, as of 02 February 2015, there are 6 patients dosed in the 
monotherapy MEDI4736 cohort of 20 mg/kg IV Q4W.  All patients have received at least 
1 dose.  One patient has reported 2 unrelated AEs (Grade 1 diarrhoea [recovered] and Grade 2 
abdominal pain [ongoing]).  No AEs have been reported for the other 5 patients.  Updated 
safety data for this study is found in the latest MEDI4736 IB.   
In conclusion, MEDI4736 20 mg/kg Q4W demonstrated comparable overall exposure to 
MEDI4736 10 mg/kg Q2W and does not demonstrate PK interactions when dosed with 
tremelimumab, and has manageable toxicity. 
3.2.3.3.3 
Justification for 4 cycles of the combination regimen: 
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), show 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).  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
116 
Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies:  
Nivolumab (anti-PD-1) was dosed every 2 weeks 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 – 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 (Hodi et al 2014, 
Brahmer et al 2014, Drake et al 2013).  Furthermore, responses were maintained 
beyond treatment discontinuation in the majority of patients who stopped nivolumab 
treatment (either due to protocol specified end of treatment, complete response, 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 are dosed for a finite time period and responses maintained beyond 
treatment discontinuation have been reported (Herbst et al 2013, Wolchok et al 2013). 
Similar long term results may be expected with use of other immune mediated cancer 
therapeutics including anti-CTLA-4 antibodies such as tremelimumab or anti PDL1 such as 
MEDI4736 or the combination of the 2.  
Similarly, the combination regimen will be administered for 4 doses.  Once the combination 
cycles end, patients will revert to a MEDI4736 10 mg/kg Q2W schedule.  
Therefore, there is precedent to utilise MEDI4736 20 mg/kg Q4W in combination with 
tremelimumab 1 mg/kg Q4W for 4 cycles, then to proceed with MEDI4736 10 mg/kg Q2W 
monotherapy for the remainder of the 12 month treatment period. 
3.2.3.3.4 
Conclusion: 
In conclusion, the combination of 20 mg/kg MEDI4736 and 1 mg/kg tremelimumab Q4W for 
4 doses was chosen based on PK/PDx data and based on the balance of safety and clinical 
activity.  This is justified based on the following: 
• 
Pharmacokinetic data following treatment with MEDI4736 monotherapy or in 
combination with tremelimumab demonstrate equivalence in exposure of 
MEDI4736 20 mg/kg Q4W and 10 mg/kg Q2W, with no alterations in PK when 
MEDI4736 and tremelimumab are dosed together, 
• 
Following MEDI4736 in combination with tremelimumab, complete sPD-L1 
suppression (surrogate for PD-L1 targeting) was observed in almost all patients 
over the dose range of 3 to 20 mg/kg MEDI4736 Q4W or Q2W. 
• 
Use of tremelimumab 1 mg/kg Q4W provides the optimal balance between safety 
and clinical activity when utilised in combination with MEDI4736 20 mg/kg Q4W.  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
117 
3.2.3.4 
Justification for Standard of Care as a comparator 
Several drugs are used for the treatment third-line treatment for NSCLC, and patients entering 
this study may have received a variety of prior regimens.  Therefore, the comparator has been 
chosen as Standard of Care as this would depend upon treatments the patient has received as 
well as upon availability of drugs per centre.  The Standard of Care used at study sites will be 
in-line with local treatment practices in the relevant country/region.  The choice of Standard of 
Care has been restricted to an EGFR TKI (erlotinib), gemcitabine or vinorelbine.  Patients in 
the comparator arm will receive study treatment until progression per standard practice.  
Patients will continue to receive Standard of Care until confirmed objective disease 
progression if, in the opinion of the investigator, the patient is not experiencing significant 
toxicity and it does not contravene local practice.  Patients will attend scheduled visits until 
discontinuation of the last study treatment. 
An open label design was needed for this study due to the different schedules and methods of 
administration of treatments in the study (iv and oral).   
3.2.3.5 
Rationale for patient selection (based on biomarkers) 
Predictive biomarkers and rationale for assigning patients to either Sub-study A or 
Sub-study B within Study D4191C00004 based on tumoural PD-L1 expression 
Sub-study A (MEDI4736 monotherapy) 
Published experience with the anti-PD-1/PD-L1 class suggests that it might be beneficial to 
enrich the patient population by selecting those patients who are considered to be most likely 
to respond to therapy.  At the time of the initial writing of this protocol, no assay has been 
established/validated and no single approach has proven accurate for patient enrichment for 
immune-mediated therapies.  However, independent data from multiple sources using 
different assays and scoring methods suggest that PD-L1 expression on tumour cells and/or 
tumour-infiltrating cells may be associated with greater clinical benefit.  For example, data 
presented by Roche at the Annual Meeting of the ASCO 2013 (Powderly et al 2013) 
suggested that PD-L1 expression on infiltrating lymphocytes in NSCLC, melanoma, and renal 
cell carcinoma patient cohorts is associated with greater clinical benefit from anti-PD-L1 
treatment.  Using a proprietary assay for PD-L1 immunohistochemistry, they found a 36% 
ORR in patients who had PD-L1-positive tumours with 50% of patients with PD-L1-positive 
tumours having SD and 33% having PRs.  In contrast, in patients with PD-L1-negative 
tumours, they found only a 13% ORR with 28% of patients having SD and 13% having PRs.   
Similarly, in data presented by Grosso and colleagues at the Annual Meeting of ASCO 
(Grosso et al 2013), PD-L1 staining, when assessed using a different method and scoring 
algorithm, appeared to be associated with greater clinical benefit in patients with metastatic 
melanoma treated with nivolumab (anti-PD-1).  They found a 44% ORR in patients with 
PD-L1-positive tumours versus a 17% ORR in patients with PD-L1-negative tumours.  
Additionally, in their studies, patients with tumours that were PD-L1-positive had a higher 
PFS (9.1 versus 2.0 months) and OS than patients with PD-L1-negative tumours (21 versus 
12 months).  Also, in a data set presented by Garon et al at the World Conference on Lung 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
118 
Cancer (Garon et al 2013), analysis of the relationship between PD-L1 expression status and 
response rates in a cohort of patients with NSCLC indicated that tumour samples displaying 
high levels of expression (according to their assay criteria) were associated with response rates 
of 67% (6/9) per irRC and 57% (4/7) per RECIST.  In contrast, tumour samples expressing 
zero/low levels of PD-L1 were associated with response rates of 4% (1/24) per irRC and 9% 
(2/22) per RECIST.  Similarly, data on MEDI4736 presented at ESMO 2014 showed an ORR 
of 16% in the overall NSCLC patient population, a 25% ORR in the PD-L1-positive subset of 
patients and a 10% ORR in the PD-L1-negative subset of patients (Antonia et al 2014 ESMO).  
Updated efficacy data from MEDI4736 was presented at international oncology conferences 
(Rizvi et al 2015 ASCO) and is described in detail in the latest MEDI4736 IB. 
Therefore, it appears that selection of patients based upon tumour PD-L1 expression may 
improve the probability and/or quality of response to PD-1 pathway targeting agents and, 
therefore, may have merit as a patient enrichment tool. 
Sub-study B (MEDI4736+tremelimumab, MEDI4736 monotherapy and tremelimumab 
monotherapy) 
While NSCLC patients with PD-L1-positive tumours may receive greater benefit from 
anti-PD-L1 therapies, a few NSCLC patients with PD-L1-negative tumours have had 
responses on the FTIH study.  Therefore, due to the limited standard of care options available 
to these patients, studying the MEDI4736 monotherapy is warranted 
Although clinical experience with tremelimumab monotherapy in NSCLC is limited, 
Study A3671015 suggested a trend in benefit in PFS at 3 months, and some partial responses 
to treatment, including in a patient who crossed over from the Best Supportive Care arm after 
PD.  The evolved dosing approach of 10 mg/kg Q4W merits further investigation in the 
NSCLC population.  The safety profile using the greater exposure remains manageable. 
Non-clinical and clinical research suggests that combinations of IMT agents may generate 
superior anti-tumour activity, compared to single-agent immunotherapy, which may translate 
into higher and more durable rates of response.  As a result, concurrent targeting of 
immunologic checkpoints with multiple inhibitory/stimulatory molecules may enhance 
efficacy.  
A study investigating the combination of a PD-1 inhibitor (nivolumab) and a CTLA-4 
inhibitor (ipilimumab) in patients with melanoma suggested that the combination of CTLA-4 
and PD-1 blockade may be active regardless of tumoural PD-L1 expression  
(Wolchok et al 2013). 
With the availability of multiple agents targeting the subset of NSCLC patients with 
PD-L1-positive tumours, the subset of NSCLC patients with PD-L1-negative tumours become 
a group with a great unmet need and limited therapeutic options.  MEDI4736 monotherapy, 
tremelimumab monotherapy or the combination of MEDI4736+tremelimumab as therapeutic 
options regardless of tumoural PD-L1 represents opportunities that may fill this gap.  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
119 
Emerging safety data from these early studies exploring the combination of immune 
checkpoint inhibitors indicate an increased frequency and/or severity of some toxicities, such 
as immune-related toxicities, which are manageable based on immune-related toxicity 
management guidelines.  
PD-L1 testing will be completed on either a recent tissue biopsy (preferred) or an archival 
sample prior to sub-study assignment (details will be provided in the Investigator’s Laboratory 
Manual).  The Ventana PD-L1 immunohistochemistry assay will be used to determine PD-L1 
status in this study.  Results from other assays will not be accepted in lieu of results obtained 
from the Ventana test. 
In patients where both archived (≤3 years) and newly acquired samples are available, both 
samples will be analysed to gain understanding about the relationship between these samples, 
co-evolution of a patient’s tumour and immune system, and to help determine which sample 
type may have the greatest utility for predicting response to therapy.  If both samples are 
submitted prior to sub-study assignment, the PD-L1 result from the most recently acquired 
sample will always take precedence in sub-study assignment unless such sample is 
unevaluable or unavailable.  In the event that a sample is unevaluable or unavailable, the other 
sample can be used for sub-study assignment.  Optional, additional archived samples >3 years 
will be used for exploratory analysis only and not for PD-L1 determination and sub-study 
assignment. 
Patient selection based on EGFR TK activating mutations and ALK rearrangements 
Patients with known EGFR TK activating mutations and ALK rearrangements are not eligible 
for this study.  Patients negative for EGFR TK activating mutations and ALK rearrangements 
are likely to have a poorer prognosis and reduced survival than patients with positive EGFR 
TK mutation status or ALK fusion status.  There are clear biological and treatment outcome 
differences between patients with NSCLC with EGFR/ALK positive tumours and those 
patients with EGFR/ALK negative tumours.  It is considered that patients with “actionable 
mutations”, which have subsequently received the appropriate molecularly targeted therapy 
(ie, an EGFR or ALK TKI) as part of their prior courses of treatment, comprise a subgroup of 
NSCLC patients with a different clinical course and prognosis distinct from those with proven 
EGFR/ALK negative tumours.  Therefore, assessing efficacy and safety separately in patients 
with EGFR/ALK negative tumours is a reasonable choice based on the natural history of the 
disease and response to therapy, which ultimately impacts prognosis and OS.   
Investigators should follow their local clinical practice guidelines for the testing of EGFR and 
ALK prior to considering a patient for the study.  It is recommended that an EGFR mutation 
status should be systematically analyzed - with sequencing as a standard - in patients with 
advanced NSCLC with a non-squamous histology.  Any patient with a tumour bearing an 
activating (sensitizing) EGFR mutation should be considered for an EGFR TKI in any line of 
therapy, if not received previously.  ALK activity can be efficiently targeted by the TKI 
crizotinib, and routine testing for ALK rearrangements should be considered where this drug 
is available.  In the presence of an ALK rearrangement, second third-line treatment with 
crizotinib should be considered if not received as part of first-line therapy. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
120 
3.2.3.6 
Rationale for study endpoints (efficacy) 
The primary aim of this study is to determine the efficacy of MEDI4736 (10 mg/kg Q2W via 
iv infusion) or MEDI4736+tremelimumab (MEDI4736 20 mg/kg plus tremelimumab 1 mg/kg 
Q4W iv up to 12 weeks [4 doses] then MEDI4736 10 mg/kg Q2W iv, starting at Week 16, for 
34 weeks [18 doses]) compared with Standard of Care in terms of OS and PFS.  Testing for 
improvements in OS provides a non-biased assessment of direct clinical benefit to a patient 
(FDA Guidance 2011).  Progression free survival may serve as a surrogate endpoint for OS 
when differences between treatment groups are of sufficient magnitude and clinically 
important (FDA Guidance 2011, Pazdur 2008).   
Anti-tumour activity will be assessed according to RECIST v1.1 guidelines.  The co-primary 
analyses of PFS and sensitivity analyses (Sub-study B) will be based on 
programmatically-derived PFS based upon investigator assessment. 
This is because the response to immunotherapy may differ from typical responses observed 
with cytotoxic chemotherapy including the following (Wolchok et al 2009): 
1. 
Response to immunotherapy may be delayed 
2. 
Response to immunotherapy may occur after PD by conventional criteria 
3. 
The appearance of new lesions may not represent PD with immunotherapy 
4. 
SD while on immunotherapy may be durable and represent clinical benefit. 
To account for these differences, RECIST will be modified so that radiological PD must be 
confirmed no earlier than 4 weeks after the prior assessment of PD in the absence of clinically 
significant deterioration.  Treatment will continue between the initial assessment of 
progression and confirmation for progression.  In addition, patients may continue to receive 
study treatment beyond confirmed PD in the absence of clinically significant deterioration and 
if investigators consider that patients continue to receive benefit from treatment.  In the 
absence of clinically significant deterioration, RECIST with such modifications may 
discourage the early discontinuation of study treatment and provide a more complete 
evaluation of its anti-tumour activity than would be seen with conventional response criteria.  
However, the efficacy analysis will be conducted by programmatically deriving each efficacy 
endpoint based on RECIST 1.1 criteria.  
Study drug should be discontinued if there is confirmed PD while on treatment following a 
previous response (PR or CR) to study drug while on treatment (ie, the response and 
progression events both occurred while receiving study drug during the same treatment 
period). 
The co-primary endpoints for each sub-study are OS and PFS using RECIST v1.1 criteria, and 
each sub-study has been sized to characterise the PFS and OS benefit of MEDI4736 10 mg/kg 
Q2W (in the PD-L1-positive population) and MEDI4736 20 mg/kg plus tremelimumab 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
121 
1 mg/kg Q4W up to 12 weeks (4 doses) then MEDI4736 10 mg/kg Q2W, starting at Week 16, 
for 34 weeks (18 doses) (in the PD-L1-negative population).  Alpha will be controlled across 
all hypotheses in each sub-study.   
3.2.3.7 
Rationale for study endpoints (other exploratory endpoints) 
 
 
 
 
 
   
 
 
4. 
PATIENT SELECTION CRITERIA 
The patient population should be selected without bias.  Investigator(s) should keep a record 
(patient screening log) of patients who entered Pre-screening. 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for the 
applicable sub-study within this study.  Under no circumstances can there be exceptions to this 
rule. 
4.1 
Inclusion criteria 
For inclusion in the study patients should fulfil the following criteria: 
1. 
Provision of signed, written and dated informed consent prior to any study specific 
procedures  
2. 
Male or female aged 18 years or older 
3. 
Patients must have EITHER  
• Histologically- or cytologically-documented NSCLC who present with Stage IIIB/ 
Stage IV disease (according to Version 7 of the IASLC Staging Manual in 
Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology]), OR  
• Recurrent or progressive disease following multimodal therapy (radiation therapy, 
surgical resection, or definitive chemoradiation therapy for locally advanced 
disease) 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
122 
4. 
Patients must have received at least 2 prior systemic treatment regimens for NSCLC 
5. 
Patients must have experienced disease progression or recurrence after both a 
platinum-based chemotherapy regimen and at least 1 additional systemic therapy  
• Maintenance therapy following platinum doublet-based chemotherapy is not 
considered a separate regimen of therapy 
• Prior platinum-containing adjuvant, neoadjuvant or definitive chemoradiation 
therapy given for locally advanced disease is considered first-line therapy only if 
recurrent (local or metastatic) disease developed within 6 months of completing 
therapy.  Patients with recurrent disease >6 months must have received a 
subsequent platinum-based therapy regimen, which counts as their first –line of 
therapy. 
6. 
Patient’s tumour sample must be assessed as PD-L1-positive (where positive is 
defined as ≥25% of tumour cells with membrane staining [proprietary PD-L1 
immunohistochemistry assay; Ventana Medical Systems, Inc]) (for Sub-study A) or 
PD-L1-negative (ie, those with <25% of tumour cells with membrane staining) (for 
Sub-study B) (either recent or archival sample) based on central assessment.  
Sample requirements as follows: 
• Patients must be able and willing to give valid written consent to provide newly 
acquired tumour tissue (preferred) or archival tissue (≤3 years old) for the purpose 
of establishing PD-L1 status (for collection and processing procedures, refer to 
Section 6.7.1 and the Laboratory Manual).  Tumour lesions planned for biopsy 
must not be used as index lesions for assessment of disease, unless there are no 
other lesions suitable for biopsy. Fine needle aspirate specimens are not acceptable.  
Specimens from metastatic bone lesions are typically unacceptable unless there is a 
significant soft tissue component.   
• If the patient’s PD-L1 status has already been assessed using the analytically 
validated Ventana assay as a part of the screening process for another 
AstraZeneca/MedImmune study, this test result can be used for the determination 
of eligibility. 
In addition to the samples used for determining PD-L1 status, patients are required 
to provide an archived tumour tissue block (or at least 10 newly cut unstained 
slides) where such samples exist in a quantity sufficient to allow for analysis 
(Refer to Section 6.7.1 and the Laboratory Manual for details). 
7. 
Patients must have measurable disease, at least 1 lesion, not previously irradiated, 
which can be accurately measured at baseline as ≥10 mm in the longest diameter 
(except lymph nodes that must have short axis ≥15 mm) with CT or MRI and which 
is suitable for accurate repeated measurements per RECIST v1.1 guidelines 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
123 
8. 
Life expectancy ≥12 weeks at Day 1 
9. 
WHO Performance Status of 0 or 1 
10. 
Evidence of post-menopausal status, or negative urinary or serum pregnancy test for 
female pre-menopausal patients.  Women will be considered postmenopausal if they 
are amenorrheic for 12 months without an alternative medical cause.  The following 
age-specific requirements apply:  
• Women <50 years old would be considered postmenopausal 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 postmenopausal 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 sterilisation (bilateral oophorectomy or hysterectomy).   
11. 
Adequate organ and marrow function as defined below:  
• Absolute neutrophil count >1.5 × 109/L (1500 per mm3) 
• Platelets >100 × 109/L (100,000 per mm3) 
• Haemoglobin ≥9.0 g/dL (5.59 mmol/L) 
• Serum creatinine clearance (CL) >40 mL/min by the Cockcroft-Gault formula 
(Cockcroft and Gault 1976) or by 24-hour urine collection for determination of 
creatinine clearance: 
•  
Serum bilirubin ≤1.5 x upper limit of normal (ULN).  This will not apply to 
Males: 
 
 
• Creatinine 
CL 
(mL/min) 
• = 
• Weight (kg) × (140 – Age) 
72 x serum creatinine (mg/dL) 
Females: 
 
 
• Creatinine 
CL 
(mL/min) 
• = 
• Weight (kg) x (140 – Age)
 
× 0.85 
72 × serum creatinine (mg/dL) 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
124 
patients with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinaemia that is predominantly unconjugated in the absence of evidence 
of haemolysis or hepatic pathology) who will be allowed in consultation with their 
physician. 
• In patients with no liver metastasis: AST and ALT ≤2.5 × ULN 
• In patients with liver metastasis: AST or ALT ≤5 × ULN. 
• For patients receiving Standard of care, patients should fulfil the relevant 
requirements in the local prescribing information.   
Genetics research study (optional) 
 
 
 
 
 
4.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca/MedImmune staff and/or staff at the study site) 
2. 
Either: 
• Previous drug assignment in the present study 
• Prior treatment in a previous durvalumab (MEDI4736) clinical study 
3. 
Participation in another clinical study with an investigational product during the last 
4 weeks 
4. 
Concurrent enrolment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study 
5. 
Mixed small cell and non-small cell lung cancer histology 
6. 
Patients with known EGFR TK activating mutations or ALK rearrangements.  
Patients with EGFR TK inactivating mutations eg, exon 20, are eligible  
(Yasuda et al 2012).  Note: Prospective testing is not planned within this study. 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
125 
7. 
Receipt of any investigational drug within 4 weeks prior to the first dose of study 
drug. 
8. 
Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumour embolisation, mAbs) 
≤21 days prior to the first dose of study drug (≤14 days prior to the first dose of 
study drug for patients who have received prior TKIs [eg, erlotinib, gefitinib and 
crizotinib] and within 6 weeks for nitrosourea or mitomycin C).  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/MedImmune 
and the investigator.   
9. 
Current or prior use of immunosuppressive medication within 28 days before the 
first dose of study treatment, with the exceptions of intranasal and inhaled 
corticosteroids or systemic corticosteroids at physiological doses, which are not to 
exceed 10 mg/day of prednisone, or an equivalent corticosteroid 
10. 
Prior exposure to any anti-PD-1 or anti-PD-L1 antibody  
11. 
Any unresolved toxicity CTCAE >Grade 2 from previous anti-cancer therapy.  
Patients with irreversible toxicity that is not reasonably expected to be exacerbated 
by study treatment may be included (eg, hearing loss) after consultation with the 
AstraZeneca/MedImmune medical monitor.   
12. 
Any prior Grade ≥3 irAE while receiving any previous immunotherapy agent, or 
any unresolved irAE >Grade 1 
13. 
Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for 
cancer treatment.  Note: Local treatment of isolated lesions, excluding target 
lesions, for palliative intent is acceptable (eg, by local surgery or radiotherapy). 
14. 
Receipt of radiation therapy within 4 weeks prior to starting study treatment.  
Limited field of radiation for palliation within 2 weeks of the first dose of study 
treatment is allowed: 
• Provided the lung is not in the radiation field 
• Provided irradiated lesion(s) cannot be used as target lesions. 
15. 
Recent major surgery within 4 weeks prior to entry into the study (excluding the 
placement of vascular access) that would prevent administration of study treatment  
16. 
Active or prior documented autoimmune disease within the past 2 years.  
Note: Patients with vitiligo, Grave’s disease, or psoriasis not requiring systemic 
treatment (within the past 2 years) are not excluded. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
126 
17. 
Active or prior documented inflammatory bowel disease (eg, Crohn’s disease, 
ulcerative colitis) 
18. 
History of primary immunodeficiency 
19. 
History of allogeneic organ transplant 
20. 
History of hypersensitivity to MEDI4736, or the active comparators (erlotinib 
gemcitabine or vinorelbine), or any excipient of these agents  
21. 
Brain metastases or spinal cord compression unless asymptomatic, treated and 
stable off steroids and anti-convulsants for at least 1 month prior to entry into the 
study 
22. 
History of leptomeningeal carcinomatosis 
23. 
Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 
3 electrocardiograms (ECGs) using Bazett’s Correction 
24. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active 
bleeding diatheses including any patient known to have acute or chronic hepatitis B, 
hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social 
situations that would limit compliance with study requirements or compromise the 
ability of the patient to give written informed consent 
25. 
Active infection of tuberculosis, as determined by clinical signs and symptoms 
26. 
Receipt of live attenuated vaccination within 30 days prior to study entry or within 
30 days of receiving study treatment 
27. 
History of another primary malignancy within 5 years prior to starting study 
treatment, except for adequately treated basal or squamous cell carcinoma of the 
skin or cancer of the cervix in situ, and the disease under study, except for: 
• Malignancy treated with curative intent and with no known active disease ≥5 years 
before the first dose of study drug and of low potential risk for recurrence 
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease 
• Adequately treated carcinoma in situ without evidence of disease eg, cervical 
cancer in situ 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
127 
28. 
Female patients who are pregnant, breast-feeding or male or female patients of 
reproductive potential who are not employing an effective method of birth control 
29. 
Any condition that, in the opinion of the investigator, would interfere with 
evaluation of study treatment or interpretation of patient safety or study results 
30. 
Absence of a tumour sample (archival and recent). 
Genetics research study (optional) 
 
 
 
 
 
 
 
 
Additional exclusion criteria for Sub-study B  
31. 
Receipt of any prior mAb against CTLA-4. 
32. 
History of chronic inflammatory or autoimmune disease (eg, Addison’s 
disease,multiple sclerosis, Grave’s disease, Hashimoto’s thyroiditis, rheumatoid 
arthritis,hypophysitis, uveitis) with symptomatic disease within the last 3 years prior 
to enrolment.  Note: Active vitiligo or alopecia or a history of vitiligo will not be a 
basis for exclusion. 
33. 
Active or history of diverticulitis. Note: Diverticulosis is permitted.Active or history 
of inflammatory bowel disease (eg, colitis, Crohn’s disease), irritable bowel disease, 
celiac disease, or other serious GI chronic conditionsassociated with diarrhoea. 
Active or history of systemic lupus erythematosus or Wegener’s granulomatosis. 
34. 
History of sarcoidosis syndrome. 
35. 
History of hypersensitivity to compounds of similar biologic composition to 
tremelimumab or any constituent of the product 
4.3 
Criteria for Treatment through Progression of Disease and 
Retreatment 
Patients with rapid tumour progression or with symptomatic progression that requires urgent 
medical intervention (eg, central nervous system metastasis, respiratory failure due to tumour 
compression, spinal cord compression) will not be eligible for continuing MEDI4736.   
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
128 
For all patients who completed the first 12 month period of treatment with MEDI4736 and had 
CR, PR or SD at completion, retreatment during follow-up would be offered on the basis of a 
patient having objective RECIST 1.1 disease progression with or without confirmation.   
For all patients who are treated through progression, and patients who achieve disease control 
[ie, CR, PR, or SD] at 12 months and restart treatment upon evidence of PD during follow-
up,the investigator should ensure patients do not have any significant, unacceptable or 
irreversible toxicities that indicate continuing or restarting treatment would not further benefit 
the patient.  In addition the investigator should ensure patients meet the following inclusion 
criteria (criteria number from Section 4.1): 
• 
The patient must provide signed, written and dated retreatment or treatment through 
progression informed consent (criterion 1).  This consent document for retreatment 
will specify that treatment beyond initial evidence of PD or retreatment upon 
progression during follow-up 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.   
• 
Meet serum creatinine CL >40 mL/min by the Cockcroft-Gault formula (or by 
24-hour urine collection as defined by the formula in protocol inclusion 
criterion 11) and the criterion for AST/ALT.   
The patient should not enter retreatment if any of the following exclusion criteria are fulfilled: 
• 
Concurrent enrolment in another clinical study, unless it is an observational (non 
interventional) clinical study or the follow-up period of an interventional study 
(criterion 4) 
• 
Current use of immunosuppressive medication, with the exceptions of intranasal 
and inhaled corticosteroids or systemic corticosteroids at physiological doses, 
which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid 
(criterion 9) 
• 
Any unresolved toxicity CTCAE >Grade 2 from previous anti-cancer therapy.  
Patients with irreversible toxicity that is not reasonably expected to be exacerbated 
by the investigational product may be included (eg, hearing loss) after consultation 
with the AstraZeneca/MedImmune study physician (criterion 11)   
• 
Any prior Grade ≥3 irAE while receiving any previous immunotherapy agent, or 
any unresolved irAE >Grade 1 (criterion 12) 
• 
Be currently receiving, or have received in the interim period after stopping study 
drug, any chemotherapy, immunotherapy, biologic or hormonal therapy for cancer 
treatment.  Note: Local treatment of isolated lesions, excluding target lesions, for 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
129 
palliative intent is acceptable (eg, by local surgery or radiotherapy) (drawn from 
criterion 13)  
• 
Recent major surgery within 4 weeks prior to retreatment (excluding the placement 
of vascular access) that would prevent administration of investigational product 
(criterion 15) 
• 
Active or prior documented autoimmune disease within the past 2 years (patients 
with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment within 
the past 2 years are not excluded) (criterion 16) 
• 
Active or prior documented inflammatory bowel disease (eg, Crohn’s disease, 
ulcerative colitis) (criterion 17) 
• 
History of primary immunodeficiency (criterion 18) 
• 
History of allogeneic organ transplant (criterion 19) 
• 
History of hypersensitivity to MEDI4736 or any excipient (criterion 20) 
• 
Brain metastases or spinal cord compression unless asymptomatic, treated and 
stable off steroids and anti-convulsants for approximately 1 month prior to first 
dose; timing will be at the discretion of the Principal Investigator (criterion 21) 
• 
History of leptomeningeal carcinomatosis (criterion 22) 
• 
Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using Bazett’s Correction (criterion 23) 
• 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active 
bleeding diatheses including any patient known to have evidence of acute or chronic 
hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric 
illness/social situations that would limit compliance with study requirements or 
compromise the ability of the patient to give written informed consent (criterion 24) 
• 
Active infection of tuberculosis, as determined by clinical signs and symptoms 
(criterion 25) 
• 
Receipt of live attenuated vaccination within 30 days prior to retreatment or within 
30 days of receiving MEDI4736 (criterion 26) 
• 
Female patients who are pregnant, breast-feeding or male or female patients of 
reproductive potential who are not employing an effective method of birth control 
(criterion 28) 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
130 
• 
Any condition that, in the opinion of the investigator, would interfere with 
evaluation of the investigational product or interpretation of patient safety or study 
results (criterion 29) 
• 
For sub-study B only: History of hypersensitivity to compounds of similar biologic 
composition to tremelimumab or any constituent of the product (criterion 35) 
In the MEDI4736 and tremelimumab monotherapy arms, study drug should be discontinued if 
there is confirmed PD while on treatment following a previous response (PR or CR) to study 
drug while on treatment (ie, the response and progression events both occurred while 
receiving study drug during the same treatment period). 
At the time of final DCO, study patients who are receiving re-treatment will remain in the 
study.  Patients who are in progression-free follow up at the time of the final DCO will be 
eligible for re-treatment at the time of progression if the investigator feels that re-treatment is 
the best treatment option and the patient meets the above eligibility criteria.  Patients’ 
eligibility should be recorded in their medical records.    
5. 
STUDY CONDUCT 
5.1 
Restrictions during the study 
1. 
MEDI4736 monotherapy, tremelimumab monotherapy and 
MEDI4736+tremelimumab: Females of childbearing potential who are sexually 
active with a nonsterilised male partner must use 2 methods of effective 
contraception from screening, and must agree to continue using such precautions for 
90 days (MEDI4736 monotherapy) after the final dose of MEDI4736 or 180 days 
(MEDI4736+tremelimumab and tremelimumab monotherapy) after the final dose of 
tremelimumab; 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). 
− 
Patients must use 2 acceptable methods of effective contraception as described 
in Table 11. 
2. 
MEDI4736 monotherapy, tremelimumab monotherapy and 
MEDI4736+tremelimumab: Nonsterilised males who are sexually active with a 
female partner of childbearing potential must use 2 acceptable methods of effective 
contraception (see Table 11) from Day 1 and for 90 days (MEDI4736) after the 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
131 
final dose of MEDI4736 or 180 days (MEDI4736+tremelimumab and 
tremelimumab monotherapy) after the final dose of tremelimumab. 
Table 11 
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. 
Standard of Care: Follow the local prescribing information relating to 
contraception and the time limit for such precautions for agents in the Standard of 
Care arm (eg, gemcitabine prescribing information,  
NAVELBINE® prescribing information, TARCEVA® prescribing information). 
4. 
MEDI4736 monotherapy, tremelimumab monotherapy and 
MEDI4736+tremelimumab: Patients should not donate blood whilst participating 
in this study 
5. 
MEDI4736 monotherapy, tremelimumab monotherapy and 
MEDI4736+tremelimumab: During the study patients may receive palliative 
radiotherapy at the site of bone metastases that were present at baseline, providing 
the investigator does not feel that the bone pain is indicative of clinical disease 
progression.  If a patient has further bone pain for which a second course of 
palliative radiation therapy is considered, the patient should be discussed with the 
QuintilesIMS Physician to decide if it is necessary for a patient to be discontinued 
from study treatment.  The need for radiotherapy to any other site should be 
discussed with the QuintilesIMS Physician and any decisions will be made on a 
case-by-case basis. 
6. 
Standard of Care arm: Please refer to the local prescribing information for the 
relevant product for any additional restrictions (eg,  
gemcitabine prescribing information, NAVELBINE® prescribing information,  
TARCEVA® prescribing information). 
Restrictions relating to concomitant medications are described in Section 5.6. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
132 
5.2 
Patient enrolment and randomisation 
At Pre-screening, the Principal Investigator, or suitably trained delegate, will: 
1. 
Obtain signed informed consent (Pre-screening Informed Consent Form) from the 
potential patient before any study specific procedures are performed. 
2. 
Assign the potential patient a unique 7-digit enrolment number, beginning with 
‘E#’.  This is obtained through the Interactive Voice Response System 
(IVRS)/Interactive Web Response System (IWRS) (ECCNNXXX:  CC being the 
country code, NN being the centre number, XXX being the patient enrolment code 
at the centre).  Enrolment codes will start at 001 in each centre and go up 
sequentially (eg, at Centre 01, patients will be assigned E codes E0101001, 
E0101002, etc).  This number is the patient’s unique identifier and is used to 
identify the patient on the electronic case report forms (eCRFs). 
3. 
Determine preliminary patient eligibility (investigator’s opinion). 
4. 
Send patient’s tumour sample for pre-screening PD-L1 status.  
Before Day 1, the Principal Investigator, or suitably trained delegate, will: 
5. 
Obtain signed informed consent for the relevant sub-study, based on PD-L1 status 
(Sub-study A or Sub-study B Informed Consent Form) from the patient before any 
study treatment is given. 
6. 
Assign patients to the respective sub-study based on PDL-1 status: PDL-1-positive 
NSCLC patients will be assigned to Sub-study A and PD-L1-negative NSCLC 
patients will be assigned to Sub-study B.  This assignment step will take place 
within IVRS/IWRS. 
7. 
Determine formal patient eligibility for each sub-study.  See Sections 4.1 and 4.2. 
8. 
Define the Standard of Care treatment (based on the most appropriate option for the 
patient) that the patient would receive if randomised to the Standard of Care arm 
prior to randomisation of the patient. 
At Day 1 (randomisation [Baseline]), once the patient is confirmed to be eligible for either 
Sub-study A or B, the Principal Investigator, or suitably trained delegate, will: 
9. 
Call IVRS/IWRS to assign the eligible patient a unique randomisation code (patient 
number).  Randomisation codes will be assigned strictly sequentially by 
IVRS/IWRS, as patients are eligible for randomisation.  
Patients may be enrolled but not randomised.  If the patient is not randomised, the 
IVRS/IWRS should be contacted to terminate the patient in the system.  The IVRS/IWRS will 
also be used to track drug supply. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
133 
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused and they cannot re-enter into the study.  
Histology will be determined for all patients prior to randomisation (ie, squamous or all 
other). 
The sub-studies may not run concurrently with the start and completion of recruitment 
potentially occurring at different time points. 
Procedures for randomisation 
Patients must not be randomised unless all eligibility criteria have been met.   
Standard of care treatment will be defined prior to randomisation and thus prior to treatment 
allocation.  The Standard of Care treatment that the patient would be administered, should the 
patient be randomised to Standard of Care treatment arm, will be chosen by the investigator 
prior to randomisation.  Patients will be randomised as follows.  
NSCLC patients with PD-L1-positive tumours will be randomised in a 1:1 ratio to either: 
(a) 
MEDI4736 (10 mg/kg Q2W iv) or  
(b) 
Standard of Care (gemcitabine, vinorelbine or erlotinib)  
in Sub-study A (approximately 60 patients in each arm).   
NSCLC patients with PD-L1-negative tumours will be randomised in a 3:2:2:1 ratio 
(MEDI4736+tremelimumab:MEDI4736:Standard of Care:tremelimumab) to either: 
(a) 
MEDI4736+tremelimumab (MEDI4736 20 mg/kg plus tremelimumab 1 mg/kg 
Q4W iv up to 12 weeks [4 doses]) then MEDI4736 alone (10 mg/kg Q2W iv, 
starting at Week 16, for 34 weeks [18 doses]) (180 patients) or 
(b) 
Standard of Care (gemcitabine, vinorelbine or erlotinib) (120 patients) or 
(c) 
MEDI4736 (10 mg/kg Q2W iv) (120 patients) or 
(d) 
Tremelimumab (10 mg/kg Q4W for 24 weeks then Q12W for 24 weeks iv) 
(60 patients) 
in Sub-study B.   
Patients will be stratified at randomisation based on the Standard of Care treatment that they 
would be administered (2 categories: gemcitabine/vinorelbine versus erlotinib) and histology 
(2 categories: squamous versus all other).  
A separate randomisation list will be produced for each of the sub-studies within this protocol. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
134 
The actual treatment given to patients will be determined by the randomisation scheme in the 
IVRS/IWRS.  The randomisation scheme for Sub-study A will be produced by a computer 
software programme called GRand (AstraZeneca Global Randomisation system) that 
incorporates a standard procedure for generating randomisation numbers.  The randomisation 
scheme for Sub-study B will be produced by a computer software programme called 
RANGEN (Parexel randomisation generating system) that incorporates a standard procedure 
for generating randomisation numbers.  A blocked randomisation will be generated and all 
centres will use the same list in order to minimise any imbalance in the number of patients 
assigned to each treatment arm. 
Patients will be identified to the Centralised Randomisation Centre per country regulations.  
Randomisation codes will be assigned strictly sequentially, within each stratum, as patients 
become eligible for randomisation.  The IVRS/IWRS Centralised Randomisation Centre will 
inform the pharmacist of the kit identification number to be allocated to the patient at the 
randomisation visit. 
Every effort should be made to minimise the time between randomisation and starting 
treatment.  It is recommended that patients commence study treatment as soon as possible 
after randomisation (ie, on the same day after randomisation in the IVRS system) and no later 
than 48 hours after randomisation. 
Please note that all ‘Week 0’ study procedures per Table 3, Table 4, Table 5, Table 8 and 
Table 9 (dependent upon treatment arm) should be conducted on the same day and before 
(unless otherwise stated) the first administration of IP. 
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 to which the patient was originally randomised.  
If a patient discontinues participation in the study, then their enrolment/randomisation code 
cannot be reused. 
The IVRS/IWRS may not be available after the final DCO.  In this case a manual process will 
need to be followed. 
5.3 
Procedures for handling patients incorrectly enrolled or 
randomised or initiated on study treatment 
Patients who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be enrolled or receive study treatment.  There can be no exceptions to this rule. 
Where patients that do not meet the inclusion and/or exclusion criteria, are enrolled in error, 
are randomised in error, or are incorrectly started on treatment, or where patients subsequently 
fail to meet the study criteria post initiation, a discussion must occur between the 
QuintilesIMS Physician and the investigator regarding the patient’s safety and well-being and 
whether to continue or discontinue the patient from study treatment.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
135 
The QuintilesIMS Physician is to ensure all such contacts are appropriately documented.  In 
situations where an agreement cannot be reached, the patient should have their study treatment 
stopped, then be followed up where possible as per Section 5.8.1.  Those patients randomised 
in error should remain in the study and be followed for OS and PFS where possible. 
5.4 
Blinding and procedures for unblinding the study  
5.4.1 
Methods for ensuring blinding 
The study centre pharmacist will be unblinded to study treatment and will prepare MEDI4736 
and tremelimumab or the relevant Standard of Care for a patient as specified by the 
randomisation scheme and IVRS (the investigator will call into IVRS to obtain the 
randomisation/treatment allocation details).  Pharmacists will be given specific instructions for 
study drug preparation.  Lot numbers of study drug dispensed will be recorded by the 
pharmacist and monitored by an unblinded monitor.  The patient, the investigator and study 
centre site staff will also be unblinded to study drug allocation.   
However, no member of the extended study team at AstraZeneca/MedImmune will have 
access to the randomisation scheme nor will conduct any aggregate analysis by treatment arm 
until the time of the final data analysis.  Exceptions are relevant persons within the 
Pharmaceutical Development Supply Chain at AstraZeneca/MedImmune or their designee, 
where the information is needed to package study treatment and the drug safety departments at 
AstraZeneca/MedImmune.   
Where possible, site staff should avoid giving information to parties outside the site team in 
case it leads to unblinding.  
5.4.2 
Methods for unblinding the study 
This will be applicable for the AstraZeneca global team only.  In order to provide proper 
oversight of the toxicity management AstraZeneca/MedImmune retains the right for the 
patient safety representative and the study physician to be provided with SAE reports which 
are unblinded.  Treatment codes will not be broken for the planned analyses of data until all 
decisions on the evaluability of the data from each individual patient have been made and 
documented.   
5.5 
Treatments 
5.5.1 
Identity of investigational product(s) 
AstraZeneca will supply MEDI4736 and tremelimumab (Table 12).   
Table 12 
List of investigational products for this study 
Investigational product  
Dosage form and strength  
Manufacturer 
MEDI4736  
500 mg/vial solution after dilution 
MedImmune 
Tremelimumab  
400 mg/vial solution for infusion after dilution  
MedImmune 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
136 
5.5.1.1 
MEDI4736 
The Pharmaceutical Development Supply chain of AstraZeneca/MedImmune will supply 
MEDI4736 to the investigator as a 500-mg vial solution for infusion after dilution in 1 format 
for use throughout the study or sub-study. 
The solution contains 50 mg/mL MEDI4736, 26 mM histidine/histidine-hydrochloride, 
275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; it has a pH of 
6.0.  The nominal fill volume is 10 mL.  Investigational product vials are stored at 2°C to 8°C 
(36°F to 46°F) and must not be frozen. 
Preparation of MEDI4736 doses for administration with an iv bag 
The dose of MEDI4736 for administration must be prepared by the investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
MEDI4736 vial to the start of administration should not exceed:  
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
A dose of either 10 mg/kg or 20 mg/kg will be administered using an iv bag containing 
0.9% (w/v) saline or 5% (w/v) dextrose, with a final MEDI4736 concentration in the bag 
ranging from 1 to 20 mg/mL, delivered through an iv administration set with a 0.2- or 
0.22-μm in-line filter.   
Patient weight at baseline should be used for dosing calculations unless there is a ≥10% 
change in weight.  Dosing day weight can be used for dosing calculations instead of baseline 
weight per institutional standard.  A volume of 0.9% (weight/volume) saline or 5% 
(weight/volume) dextrose equal to the calculated volume of MEDI4736 to be added to the iv 
bag must be removed from the bag prior to 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. 
No incompatibilities between MEDI4736 and polyvinylchloride or polyolefin copolymers 
have been observed.  
All details can be found in the Drug Handling Instructions. 
Dose calculation of MEDI4736  
The volume of MEDI4736 (in mL) to add to the iv bag is calculated as follows: 
Both sub-studies (monotherapy and combination arms) 
10 mg/kg × Patient Weight (kg) ÷ MEDI4736 concentration (nominal: 50 mg/mL) 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
137 
Sub-study B (combination arm) 
20 mg/kg × Patient Weight (kg) ÷ MEDI4736 concentration (nominal 50 mg/mL) 
Example: For a patient weighing 80 kg, dosed at 20 mg/kg, 32 mL [20 mg/kg × 80 kg divided 
by 50 mg/mL] of MEDI4736 is to be diluted in a 250 mL iv bag containing 
0.9% (weight/volume) saline or 5% (weight/volume) dextrose.  First, 32 mL of iv diluent 
(saline or dextrose) is removed from the iv bag, and then 32 mL of MEDI4736 is added to the 
bag.  The bag is mixed by gentle inversion to ensure homogeneity of the dose in the bag and 
the diluted MEDI4736 is administered as described above. 
Standard infusion time is 1 hour; however, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  Table 13 summarises time 
allowances and temperatures. 
Table 13 
MEDI4736 in-use stability and infusion times 
Maximum time from needle puncture to start of 
administration 
4 hours at room temperature, 24 hours at 2°C to 
8°C 
 
Maximum time for iv bag infusion, including 
interruptions 
8 hours at room temperature 
 
 
iv Intravenous. 
 
In the event that either preparation time or infusion time exceeds the time limits outlined in 
Table 13, a new dose must be prepared from new vials.  MEDI4736 does not contain 
preservatives, and any unused portion must be discarded.  All details can be found in the Drug 
Handling Instructions. 
5.5.1.2 
Tremelimumab 
The Pharmaceutical Development Supply chain of AstraZeneca/MedImmune will supply 
tremelimumab to the investigator. 
Tremelimumab is supplied as a sterile iv solution, filled in 20 mL clear glass vials with a 
rubber stopper and aluminum seal.  The solution contains 20 mg/mL tremelimumab, 20 mM 
histidine/histidine HCl, 222 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, 0.27 mM 
disodium edetate dihydrate (EDTA), at pH 5.5.  The standard supply of tremelimumab is 
delivered in a white carton with 16 vials of tremelimumab within foam inserts.  
Tremelimumab vials should be stored at refrigerated temperatures (2°C to 8°C), and should 
not be frozen. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
138 
Preparation of tremelimumab doses for administration with an iv bag 
The dose of tremelimumab for administration must be prepared by the investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
tremelimumab vial to the start of administration should not exceed:  
• 24 hours at 2°C to 8°C (36°F to 46°F) 
• 4 hours at room temperature 
Doses of 1 mg/kg and 10 mg/kg tremelimumab will be administered using an iv bag 
containing 0.9% (w/v) saline, with a final tremelimumab concentration in the iv bag ranging 
from 0.15 mg/mL to 10 mg/mL, and delivered through an iv administration set with a 0.2 μm 
or 0.22 μm in-line filter.  
Patient weight at baseline should be used for dosing calculations unless there is a ≥10% 
change in weight.  Dosing day weight can be used for dosing calculations instead of baseline 
weight per institutional standard.  A volume of 0.9% (weight/volume) saline equal to the 
calculated volume of tremelimumab to be added to the iv bag must be removed from the bag 
prior to 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. 
Intravenous bags must be latex-free and can be made of polyvinyl chloride (PVC) or 
polyolefins (eg, polyethylene), manufactured with bis (2-ethylhexyl) phthalate (DEHP) or 
DEHP free.  Catheters/infusion sets made of polyurethane or fluoropolymer with silicone and 
stainless steel and/or PVC components can be used for tremelimumab administration.  
Syringes should be made of polypropylene and latex-free.  Polycarbonate syringes should not 
be used with tremelimumab.  Stainless steel needles need to be used. 
All details can be found in the Drug Handling Instructions. 
Dose calculation of tremelimumab 
The volume of tremelimumab (in mL) to be added to the iv bag will be calculated using the 
following formula: 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
139 
Either: 
Sub-study B (combination arm) 
1 mg/kg × Patient Weight (kg) ÷ tremelimumab concentration (nominal 20 mg/mL) 
Sub-study B (monotherapy arm) 
10 mg/kg × Patient Weight (kg) ÷ tremelimumab concentration (nominal 20 mg/mL) 
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL 
(0.1 mL).   
Standard infusion time is 1 hour; however, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  Table 14  summarizes time 
allowances and temperatures. 
Table 14 
Tremelimumab in-use stability and infusion times 
Maximum time from needle puncture to start of 
administration 
4 hours at room temperature, 24 hours at 2°C to 8°C 
Maximum time for iv bag infusion, including 
interruptions 
8 hours at room temperature 
 
iv Intravenous. 
 
In the event that either preparation time or infusion time exceeds the time limits outlined in 
Table 14, a new dose must be prepared from new vials.  Tremelimumab does not contain 
preservatives, and any unused portion must be discarded.  All details can be found in the Drug 
Handling Instructions. 
5.5.1.3 
Standard of Care 
The comparator arm of this study is Standard of Care; this is restricted to gemcitabine, 
vinorelbine or erlotinib (Table 15).  These will be sourced centrally. 
Table 15 
Standard of Care 
Standard of Care 
Dosage form and strength 
Manufacturer 
Gemcitabine 
1000 mg vials 
1000 mg/m2 intravenously over 
30-minutes on Days 1, 8, and 15 of a 
28-day cycle 
Eli Lilly and Company or 
relevant manufacturer if a 
generic equivalent is used  
Vinorelbine 
50 mg vials 
30 mg/m2 intravenously on Days 1, 8, 15 
and 22 of a 28 day cycle 
Pierre Fabre Pharmaceuticals, 
Inc.  for GlaxoSmithKline or 
relevant manufacturer if a 
generic equivalent is used 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
140 
Erlotinib 
25 mg and 100 mg as required for dosing 
150 mg once daily as tablets for oral 
administration taken at least 1 hour before 
or 2 hours after the ingestion of food  
Genentech, Roche, or Chugai 
Pharmaceuticals 
 
5.5.2 
Doses and treatment regimens 
It is important to follow the assessment schedule as closely as possible.   
Treatment delays 
All visits should be conducted based on the schedules provided in Table 3 to Table 10, unless 
otherwise indicated. 
For all treatment arms 
• 
Tumour efficacy (RECIST 1.1) assessments dates are not affected by dose delays, 
and remain as originally scheduled, because they are based on the date of 
randomisation (not the date of therapy). 
• 
All other scheduled assessments must be performed relative to the start of the 
dosing cycle such that all laboratory procedures required for dosing should be 
performed within 3 days prior to dosing. 
For MEDI4736 monotherapy, tremelimumab monotherapy or MEDI4736+tremelimumab 
combination arms 
Patients may delay dosing under certain circumstances: 
• 
Dosing may be delayed due to either an immune or a non-irAE as per Toxicity 
Management Guidelines (Refer to Section 5.5.3). 
• 
If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible. 
• 
Dosing intervals of subsequent cycles in the combination arm may be shortened as 
clinically feasible and in line with the treatment windows in order to gradually align 
treatment cycles with the schedule of tumour efficacy (RECIST 1.1) assessments. 
5.5.2.1 
MEDI4736 monotherapy (Sub-study A and Sub-study B)  
Patients randomised to MEDI4736 monotherapy in either sub-study will receive 10 mg/kg via 
iv infusion Q2W ±3 days.  Treatment with MEDI4736 will commence on Day 1 following 
randomisation after confirmation of eligibility and will continue on a Q2W schedule for up to 
12 months (see Table 3).  The final administration of MEDI4736 will be at the Week 50 visit.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
141 
Study treatment should be discontinued prior to 12 months if there is PD (unless the 
investigator considers the patient continues to receive benefit from treatment), initiation of 
alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to 
discontinue treatment occur.  Study drug should be discontinued if there is confirmed PD 
while on treatment following a previous response (PR or CR) to study drug while on treatment 
(ie, the response and progression events both occurred while receiving study drug during the 
same treatment period). 
Disease progression that occurs while on treatment requires confirmation.  In the absence of 
clinically significant deterioration the investigational site is advised to continue the patient on 
study treatment until progression has been confirmed.  If progression is not confirmed, then 
the patient should continue on study treatment and on treatment assessments. 
Patients in the MEDI4736 monotherapy arms who achieve and maintain disease control (ie, 
CR, PR, or SD) through to the end of the 12-month MEDI4736 treatment period will enter 
follow-up (Table 6).  Upon evidence of PD (according to RECIST 1.1), with or without 
confirmation, during follow-up after completion of 12 months of treatment, patients may 
restart treatment with MEDI4736 for as long as the investigator judges they are gaining 
clinical benefit with the same treatment guidelines followed during the initial 12-month 
treatment period (Table 3).  Patients will only be able to restart treatment once.   
Patients who have a dose interruption due to toxicity at any point in the first 12 months of 
treatment may resume and complete the 12-month treatment period. 
Patients who have confirmed PD during the 12-month initial treatment period, or after 
restarting MEDI4736 and cannot continue to receive MEDI4736 will enter follow-up with 
assessments as shown in Table 7.  Patients with confirmed PD that continue to receive 
MEDI4736 at the discretion of the investigator (following consultation with the sponsor) can 
receive study drug for a maximum of 12 months in the initial treatment period but for as long 
as the investigator judges they are gaining clinical benefit in the re-treatment period (and will 
follow the assessments in Table 3 including tumour assessments).   
Administration 
Following preparation of MEDI4736, the entire contents of the iv bag should be administered 
as an iv infusion over approximately 60 minutes (±5 minutes), using a 0.2- or 0.22-μm in-line 
filter.  The iv line will be flushed with a volume of normal saline equal to the priming volume 
of the infusion set used after the contents of the iv bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed.  Since the compatibility of MEDI4736 with other iv medications 
and solutions, other than normal saline (0.9% [weight/volume] sodium chloride for injection), 
or 5% dextrose is not known, the MEDI4736 solution should not be infused through an iv line 
in which other solutions or medications are being administered.  The date, start time, 
interruption and completion time of MEDI4736 administration must be recorded in the source 
documents. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
142 
5.5.2.2 
MEDI4736+tremelimumab and tremelimumab monotherapy (Sub-study B) 
MEDI4736+tremelimumab 
Patients randomised to MEDI4736+tremelimumab will receive MEDI4736 20 mg/kg and 
tremelimumab 1 mg/kg via iv infusion Q4W ±3 days for up to 12 weeks (4 doses) and then 
MEDI4736 10 mg/kg alone via iv infusion Q2W for 34 weeks starting at Week 16 (18 doses).  
Treatment with MEDI4736+tremelimumab will commence on Day 1 following randomisation 
after confirmation of eligibility (see Table 5).  The final administration of the 
MEDI4736+tremelimumab combination will be at the Week 12 visit and the final 
administration of the MEDI4736 10 mg/kg monotherapy portion in the combination arm will 
be at the Week 50 visit.  
In the combination arm, patients who achieve and maintain disease control (ie, CR, PR or SD) 
through to the end of the 4th cycle (Week 16, 4 weeks after the last dose of combination 
treatment) will continue with the planned treatment for this arm, ie, MEDI4736 10 mg/kg 
Q2W.  If patients should experience PD (according to RECIST 1.1), with or without 
confirmation, during the MEDI4736 monotherapy treatment, retreatment with the combination 
regimen may begin. 
Patients who achieve and maintain disease control (ie, CR, PR or SD) through to the end of 
the 12-month study drug treatment period will enter follow-up (Table 6).  Patients may restart 
MEDI4736+tremelimumab upon evidence of PD (according to RECIST 1.1) with or without 
confirmation, during follow-up. 
Any patient who is restarting the combination treatment regimen will adhere to the same 
treatment guidelines followed during the initial treatment period.  Patients would resume 
MEDI4736 20 mg/kg Q4W as during the initial induction period, along with tremelimumab 
1 mg/kg Q4W for 4 doses.  Monotherapy with MEDI4736 10 mg/kg Q2W would then resume 
at Week 16, 4 weeks after the last dose of combination treatment, and treatment will continue 
for as long as the investigator judges they are gaining clinical benefit. 
Patients will only be able to restart treatment once.  Note that restarting of combination 
treatment can occur any time after Week 16. 
Treatment should be discontinued prior to 50 weeks if there is confirmed PD during the initial 
combination regimen (ie, during the first 4 cycles) or if patients have confirmed PD after 
restarting MEDI4736+tremelimumab and cannot continue to receive 
MEDI4736+tremelimumab (or MEDI4736 monotherapy if on or after Week 16); these 
patients will enter follow-up with assessments as shown in Table 7.  If initiation of alternative 
cancer therapy, unacceptable toxicity, withdrawal of consent, or other reason to discontinue 
treatment occurs, these patients will enter follow-up with assessments as shown in Table 6.  
Patients with confirmed PD that continue to receive MEDI4736+tremelimumab at the 
discretion of the investigator (following consultation with the sponsor) can receive study drug 
for a maximum of 12 months in the initial treatment period but for as long as the investigator 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
143 
judges they are gaining clinical benefit in the re-treatment period (and will follow the 
assessments in Table 5 including tumour assessments). 
Patients who have a dose interruption due to toxicity at any point in the first 12 months of 
treatment may resume and complete the 12-months treatment period. 
Tremelimumab monotherapy 
Patients randomised to tremelimumab monotherapy will receive tremelimumab 10 mg/kg via 
iv infusion Q4W ±3 days up to Week 24 and then every 12 weeks up to a further 24 weeks.  
Treatment with tremelimumab will commence on Day 1 following randomisation after 
confirmation of eligibility (see Table 4) and continue until the Week 48 visit. 
Study treatment should be discontinued prior to 48 weeks if there is PD (unless the 
investigator considers the patient continues to receive benefit from treatment), initiation of 
alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to 
discontinue treatment occur.  Study treatment should be discontinued if there is confirmed PD 
while on treatment following a previous response (PR or CR) to study drug while on treatment 
(ie, the response and progression events both occurred while receiving study drug during the 
same treatment period). 
Disease progression that occurs while on treatment requires confirmation.  In the absence of 
clinically significant deterioration the investigational site is advised to continue the patient on 
study treatment until progression has been confirmed.  If progression is not confirmed, then 
the patient should continue on study treatment and on treatment assessments. 
Patients in the tremelimumab monotherapy arm who achieve and maintain disease control (ie, 
CR, PR, or SD) through to the end of the 48-week treatment period will enter follow-up 
(Table 6).  Upon evidence of PD (according to RECIST 1.1), with or without confirmation, 
during follow-up after completion of 48 weeks of treatment, patients may restart treatment 
with tremelimumab monotherapy for as long as the investigator judges they are gaining 
clinical benefit with the same treatment guidelines followed during the initial 48-week 
treatment period (Table 4).  Patients will only be able to restart treatment once.   
Patients who have a dose interruption due to toxicity at any point in the first 48 weeks of 
treatment may resume and complete the 48 weeks treatment period.   
Patients who have confirmed PD during the 48-week initial treatment period, or after 
restarting tremelimumab monotherapy and cannot continue to receive tremelimumab, will 
enter follow-up with assessments as shown in Table 7.  Patients with confirmed PD that 
continue to receive tremelimumab at the discretion of the investigator (following consultation 
with the sponsor) can receive study drug for a maximum of 12 months in the initial treatment 
period but for as long as the investigator judges they are gaining clinical benefit in the re-
treatment period (and will follow the assessments in Table 4 including tumour assessments).   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
144 
Administration of tremelimumab monotherapy 
Following preparation of tremelimumab, the entire contents of the iv bag should be 
administered as an iv infusion over approximately 1 hour.  The date, start time, interruption 
and completion time of tremelimumab administration must be recorded in the source 
documents. 
Administration of MEDI4736+tremelimumab 
Tremelimumab will be administered first.  MEDI4736 infusion will start approximately 1 hour 
after the end of the tremelimumab infusion for the first infusion only.  If there are no clinically 
significant concerns after the first cycle, and at the discretion of the physician, in all other 
cycles the MEDI4736 can be given immediately after the tremelimumab infusion has finished.  
The duration of each infusion will be approximately 60 minutes (±5 minutes).  After 4 doses, 
patients will receive MEDI4736 monotherapy (see Administration in Section 5.5.2.1). 
Figure 5 
Schema for MEDI4736+tremelimumab treatment 
 
 
1
2
3
4
5
6
0
2
4
6
8
10
12
14
16
18
20
22
7
8
9
10
11
12
13
24
26
28
30
32
34
36
38
40
42
44
46
48
50
Cycle
Week
Cycle
Week
Tremelimumab 1 mg/kg Q4W (4 doses)
MEDI4736 20 mg/kg Q4W (4 doses)
MEDI4736 10 mg/kg Q2W (18 doses)
MEDI4736 10 mg/kg Q2W (18 doses)
Cycles 1 to 4
MEDI4736 and tremelimumab:
Q4W for 4 doses
Cycles 5 to 13
MEDI4736:
Q2W for 18 doses
For 12 months or PD
Screening 
Period
Survival Follow up


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
145 
5.5.2.3 
Monitoring of dose administration of MEDI4736 and/or tremelimumab 
Patients will be monitored during and after the infusion with assessment of vital signs at the 
times specified in Section 6.4.8. 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of MEDI4736 and 
tremelimumab may be decreased by 50% or interrupted until resolution of the event (up to 
4 hours) and re-initiated at 50% of the initial rate until completion of the infusion.  If, 
following 4 hours of interruption, there is persistent Grade 2 toxicity despite the use of 
appropriate medications such as antihistamines or acetaminophen, then study treatment should 
be discontinued.  If, following 4 hours of interruption, there is a decrease to Grade 1, then the 
drug may be re-introduced if it does not present an increased risk to the patient.  If the 
infusion-related reaction is ≥Grade 3 or higher in severity, treatment with MEDI4736 and/or 
tremelimumab will be discontinued. 
As with any antibody, allergic reactions to dose administration are possible.  Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognise and treat anaphylaxis.  The study 
site must have immediate access to emergency resuscitation teams and equipment in addition 
to the ability to admit patients to an intensive care unit if necessary. 
5.5.2.4 
Dose and schedule of agents in the Standard of Care arm 
The choice of Standard of Care used at study sites will be determined by the investigator at the 
local study sites.  The Standard of Care treatment will be selected from the following 
restricted list: an EGFR TKI (ie, erlotinib) gemcitabine or vinorelbine.  The investigator at the 
local study site will be responsible for the choice of the Standard of Care arm for an individual 
patient. 
Treatment in the Standard of Care arm will commence on Day 1 following randomisation 
after confirmation of eligibility and will continue on a 4-weekly schedule until PD (unless the 
investigator considers the patient continues to receive benefit from treatment), initiation of 
alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to 
discontinue treatment occur.   
Treatment through PD in the Standard of Care arm is at the investigator’s discretion.  In cases 
of unequivocal progression the investigator should discontinue treatment, where it is uncertain 
if disease has progressed the investigator should decide whether (if in the absence of clinically 
significant deterioration) to continue the patient on treatment until progression has been 
confirmed.   
Gemcitabine 
Gemcitabine should be administered at a dose of 1000 mg/m2 iv over 30 minutes on Days 1, 8, 
and 15 (±3 days) of a 28-day cycle.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
146 
Section 5.5.3.3 details the recommended dose reductions for gemcitabine for 
myelosuppression in NSCLC. 
Vinorelbine 
Vinorelbine should be administered at a dose of 30 mg/m2 iv on Days 1, 8, 15 and 22 
(±3 days) of a 28-day cycle.   
Vinorelbine should be administered either by slow bolus over 6 to 10 minutes after dilution in 
50 mL of a 0.9% sodium chloride solution or by a short infusion over 20 to 30 minutes, after 
dilution in 125 mL of normal saline solution.  Administration should always be followed by at 
least 250 mL normal saline infusion to flush the vein.   
Section 5.5.3.3 details the dose modifications required based on the neutrophil count on the 
day of administration.   
Erlotinib 
Erlotinib should be administered at a dose of 150 mg once daily as a tablet for oral 
administration  taken at least 1 hour before or 2 hours after the ingestion of food.  Please refer 
to the local prescribing information particularly if the patient will receive concomitant 
cytochrome P450 (CYP) 3A4 inducers or is a smoker (as increases in the dose may be 
required) or is receiving concomitant treatment with a drug that may affect gastric pH.  
For all Standard of Care agents, please refer to Section 5.5.3.3 for details of recommended 
dose modifications in the event of toxicities.   
5.5.2.5 
Treatment through progression of disease 
Study drug should be discontinued if there is confirmed PD while on treatment following a 
previous response (PR or CR) to study drug while on treatment (ie, the response and 
progression events both occurred while receiving study drug during the same treatment 
period). 
Patients who achieve and maintain disease control (ie, CR, PR, or SD) through to the end of 
the 12-month treatment period will enter follow-up.  When these patients experience evidence 
of PD, with or without confirmation, during follow-up and meet the criteria for treatment in 
the setting of PD, they will be given the option to restart their assigned immune-mediated 
cancer treatment (ie, MEDI4736 monotherapy, tremelimumab monotherapy or combination 
MEDI4736+tremelimumab) for as long as the investigator judges they are gaining clinical 
benefit with the same treatment guidelines followed during the initial 12-month treatment 
period.  Patients should have a baseline tumour assessment within 28 days before restarting 
their assigned immune-mediated cancer treatment; all further scans should occur every 
8 weeks (relative to the date of restarting treatment) until study treatment is stopped.  Only 
patients who the investigator determines do not have any significant, unacceptable, or 
irreversible toxicities, or would continue to receive benefit from therapy can restart a second 
12 months of retreatment upon PD.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
147 
Patients with confirmed progression in the MEDI4736 monotherapy or tremelimumab 
monotherapy arms cannot continue treatment or obtain retreatment if the progression occurred 
during treatment and after confirmed response (ie, the response and progression events both 
occurred while receiving active immune-mediated cancer treatment during the same treatment 
period).   
Retreatment in the MEDI4736+tremelimumab arm can only occur if PD, with or without 
confirmation, occurs during the monotherapy portion or after completion of 12 months of 
treatment.  During the retreatment period, the patient would resume MEDI4736 20 mg/kg 
Q4W as during the initial induction period, along with tremelimumab 1 mg/kg Q4W for 
4 doses.  Monotherapy with MEDI4736 10 mg/kg Q2W would then resume at Week 16, 
4 weeks after the last dose of combination treatment, and can continue for as long as the 
investigator judges they are gaining clinical benefit. 
For patients who receive study treatment through disease progression and patients who 
achieve disease control (ie, CR, PR or SD) and restart treatment, the investigator should 
ensure patients do not have any significant, unacceptable or irreversible toxicities that indicate 
continuing treatment will not further benefit the patient.  The patient must meet the inclusion 
and exclusion criteria specified in Section 4.3.  The informed consent documents will specify 
that treatment beyond initial evidence of PD or re-treatment for progression during follow-up 
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.  Patients with rapid 
tumour progression or with symptomatic progression that requires urgent medical intervention 
(eg, central nervous system metastasis, respiratory failure due to tumour compression, spinal 
cord compression) will not be eligible to continue to receive treatment.    
5.5.3 
Management of toxicity  
 
The following general guidance should be followed for management of toxicities. 
1. 
Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity where required). 
2. 
If the symptoms promptly resolve with supportive care, consideration should be 
given to continuing the same dose of study treatments along with appropriate 
continuing supportive care.  If medically appropriate, dose modifications are 
permitted (see below). 
3. 
All dose modifications should be documented with clear reasoning and 
documentation of the approach taken. 
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for durvalumab monotherapy are provided in the Dosing 
Modification and Toxicity Management Guidelines (TMGs).  Please see Appendix H.  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
148 
The most current version of the TMGs is also available through the following link: 
https://tmg.azirae.com.  In addition a version of the current TMGs is maintained within the 
Site Master File.  Please contact your clinical trial associate for information on how to gain 
access to this website.  
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the immune-related 
adverse event (irAE).  Serologic, immunologic, and histologic (biopsy) data, as appropriate, 
should be used to support an irAE diagnosis.  In the absence of a clear alternative etiology, 
events should be considered potentially immune related. 
In addition, there are certain circumstances in which study treatment should be permanently 
discontinued (see Section 5.8 of this protocol and the TMGs). 
These guidelines have been prepared by the sponsor to assist the investigator in the exercise of 
his/her clinical judgment in treating these types of toxicities.  These guidelines apply to AEs 
considered causally related to the study drug/study regimen by the reporting Investigator. 
5.5.3.1 
Management of toxicity attributable to MEDI4736 monotherapy, 
tremelimumab monotherapy or MEDI4736+tremelimumab 
The guidance that should be followed for management of toxicities is presented in the Dose 
Modification and Toxicity Management Plan in Section 5.5.3. 
Following the first infusion of MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab (ie, the study drug), subsequent administration of the study drug 
can be modified based on toxicities observed as described in the TMGs.  These guidelines 
have been prepared by the sponsor to assist the investigator in the exercise of his/her clinical 
judgment in treating these types of toxicities.  These guidelines apply to AEs considered 
causally related to the study drug/study regimen by the reporting investigator. 
All toxicities will be graded according to CTCAE Version 4.03.  Dose reductions are not 
permitted. 
Dose modifications will not be required for AEs that are clearly not attributed to the study 
drug (such as an accident) or for laboratory abnormalities that are not deemed to be clinically 
significant.  Dosing may continue despite concurrent vitiligo of any AE grade. 
Based on the mechanism of action of MEDI4736 and tremelimumab leading to T-cell 
activation and proliferation, there is the possibility of observing irAEs during the conduct of 
this study.  Potential irAEs may be similar to those seen with the use of ipilimumab and 
nivolumab including immune-mediated enterocolitis, dermatitis, hepatitis, and 
endocrinopathies (Brahmer et al 2010, Hodi et al 2010).  Patients should be monitored for 
signs and symptoms of irAEs.  In the absence of an alternate aetiology (eg, infection or PD) 
signs or symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy should be 
considered to be immune-related.    


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
149 
5.5.3.2 
Adverse events of special interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor.  An AESI may be serious or non-serious.  
The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this investigational product. 
More specific guidelines for the evaluation and treatment of these adverse events of special 
interest are described in detail in Section 5.5.3.  These guidelines have been prepared by the 
Sponsor to assist the investigator in exercising his/her judgement in treating these toxicities. 
MEDI4736 adverse events of special interest 
The 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 irAE is defined as an adverse event that is associated with drug 
exposure and is consistent with an immune-mediated mechanism of action and where there is 
no clear alternate aetiology.  Serologic, immunologic, and histologic (biopsy) data, as 
appropriate, should be used to support an irAE diagnosis.  Appropriate efforts should be made 
to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE.  
If the investigator has any questions in regards to an AE being an irAE, the investigator should 
promptly contact the Study Physician. 
AESIs observed with MEDI4736 with or without tremelimumab include, but are not limited 
to: 
• Diarrhea/colitis and intestinal perforation 
• Pneumonitis/interstitial lung disease 
• Hepatitis/transaminase increases  
• Endocrinopathy (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypothyroidism and type I diabetes mellitus) 
• Rash/dermatitis 
• Nephritis/blood creatinine increases 
• Pancreatitis /serum lipase and amylase increases 
• Myocarditis 
• Myositis/polymyositis   
• Neuropathy/neuromuscular toxicity (eg, Guillain-Barré, and myasthenia gravis) 
• Other inflammatory responses that are rare/less frequent with a potential 
immune-mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
150 
uveitis and other events involving the eye, skin, haematological and rheumatological 
events. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological aetiology are also considered AESIs.  
 
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the MEDI4736 IB.  More specific guidelines for their evaluation and treatment are 
described in detail in the TMGs (Refer to Section 5.5.3). 
Tremelimumab adverse events of special interest 
Detailed information on the risks (eg, presenting symptoms) associated with tremelimumab 
can be found in the current version of the tremelimumab IB.  
5.5.3.3 
Management of toxicity attributable to agents in the Standard of Care arm 
Information on recommended dose reductions are provided for each Standard of Care agent 
below; however, please refer to the relevant local prescribing information for the relevant 
agent. 
Gemcitabine 
Recommended dose reductions for gemcitabine for myelosuppression in NSCLC are provided 
in Table 16. 
Table 16 
Dose reduction for gemcitabine for myelosuppression in NSCLC 
Absolute granulocyte count 
(x106/L) 
 
Platelet count (x 106/L) 
% of full dose 
≥1000 
AND 
≥100,000 
100 
500-999 
OR 
50,000-99,999 
75 
<500 
OR 
<50,000 
Do not administer 
 
Gemcitabine should be permanently discontinued for any of the following non-haematologic 
adverse reactions: unexplained dyspnoea or other evidence of severe pulmonary toxicity; 
severe hepatic toxicity; haemolytic-uremic syndrome, or capillary leak syndrome. 
Gemcitabine should be withheld or the dose reduced by 50% for other severe (Grade 3 or 4) 
non-haematological toxicity until resolved.  No dose modifications are recommended for 
alopecia, nausea, or vomiting. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
151 
Vinorelbine 
Adjustments in the dosage of vinorelbine should be based on neutrophil counts obtained on 
the day of treatment (Table 17). 
Table 17 
Vinorelbine dosing based on neutrophil counts 
Neutrophils (cells/mm3) on day of 
treatment 
Dose of vinorelbine (mg/m2) 
≥1500 
30 
1000-1499 
15 
<1000 
Do not administer.  Repeat neutrophil count in 1 week. If 
3 consecutive weekly doses are held because neutrophil 
count is <1000 cells/mm 3, vinorelbine should be 
discontinued. 
 
For patients who, during treatment with vinorelbine, experience fever and/or sepsis while 
neutropenic or have 2 consecutive weekly doses withheld due to neutropenia, the subsequent 
doses of vinorelbine should be: 22.5 mg/m2 for neutrophil counts ≥1500 cells/mm3 or 
11.25 mg/m2 for neutrophil counts between 1000 to 1499 cells/mm3. 
For European sites only: 
In accordance with approved prescribing information for Navelbine 10 mg/mL concentrate for 
solution for infusion, if the neutrophil count is below 1500/mm3 and/or the platelet count is 
below 100000/mm3, then the treatment should be delayed until recovery. 
The dose of vinorelbine should be adjusted for total bilirubin for patients who develop 
hyperbilirubinaemia during treatment (Table 18).  
Table 18 
Vinorelbine dosing based on total bilirubin 
Total bilirubin (mg/dL) 
Dose of vinorelbine (mg/m2) 
≤2.0 
30 
2.1-3.0 
15 
>3.0 
7.5 
 
In patients with both haematologic toxicity and hepatic insufficiency, the lower of the doses 
based on the corresponding starting dose of vinorelbine should be used, as determined from 
Table 17 and Table 18. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
152 
If ≤Grade 2 neurotoxicity develops, vinorelbine should be discontinued. 
Erlotinib 
The following dose modification rules for erlotinib should be applied: 
• 
Follow local prescribing guidelines in cases of severe reactions with concomitant 
use of strong CYP3A4 inhibitors or when using concomitantly with an inhibitor of 
both CYP3A4 and CYP1A2 (eg, ciprofloxacin).  Dose reductions may be required.  
Avoid concomitant use if possible. 
• 
Follow local prescribing guidelines when restarting therapy following withholding 
treatment for a DLT that has resolved to baseline or Grade ≤1.  Dose reductions 
may be required.   
Erlotinib should be withheld in the following circumstances: 
• 
During diagnostic evaluation for possible interstitial lung disease 
• 
For severe (CTCAE Grade 3/4) renal toxicity; consider discontinuation of erlotinib 
• 
In patients without pre-existing hepatic impairment for total bilirubin levels 
>3 × ULN or transaminases >5 × ULN; consider discontinuation of erlotinib 
• 
In patients with pre-existing hepatic impairment or biliary obstruction for doubling 
of bilirubin or tripling of transaminases values over baseline; consider 
discontinuation of erlotinib 
• 
For persistent severe diarrhoea not responsive to medical management (eg, 
loperamide) 
• 
For severe rash not responsive to medical management 
• 
For CTC (Version 4.0) Grade 3/4 keratitis or for Grade 2 keratitis lasting more than 
2 weeks 
• 
For acute/worsening of ocular disorders such as eye pain; consider discontinuation 
of erlotinib. 
Erlotinib should be discontinued in the event of: interstitial lung disease, severe hepatic 
toxicity that does not improve significantly or resolve within 3 weeks, gastrointestinal 
perforation, severe bullous, blistering, or exfoliating skin conditions, or corneal perforation or 
severe ulceration. 
5.5.4 
Additional study drug 
No additional study drug is required in this study. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
153 
5.5.5 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory 
guidelines.  The labels will fulfil Good Manufacturing Practice Annex 13 requirements for 
labelling.  Label text will be translated into local language. 
The label will include the following information: 
• 
Name of sponsor (AstraZeneca) 
• 
Study treatment dosage form, route of administration, and quantity of dosage units 
• 
Storage conditions 
• 
Study code 
• 
Enrolment code  
• 
Directions for use 
• 
The period of use eg, expiry date. 
• 
Product Lot Identifier 
• 
Medication Identity Number 
• 
For clinical study use only 
• 
Keep out of reach of children (if the study treatment is to be taken home by the 
patient). 
Labels will be provided as either a single panel label or as multi-language booklet labels. 
5.5.6 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions and may 
only be dispensed by a pharmacist or a qualified designee.  The product label on the kit 
specifies the appropriate storage.   
Standard of Care agents should be stored per the manufacturer’s recommendations. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
154 
5.6 
Concomitant and post-study treatment(s) 
Investigators may prescribe concomitant medications or treatments (eg, acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care 
except for those medications identified as “excluded” as listed below: 
• 
Any investigational anti-cancer therapy 
• 
Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic, or hormonal 
therapy for cancer treatment.  Concurrent use of hormones for non cancer-related 
conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable.  
Note: Local treatment of isolated lesions, excluding target lesions, for palliative 
intent is acceptable (eg, by local surgery or radiotherapy). 
• 
For patients in the immune therapy arms, immunosuppressive medications 
including, but not limited to systemic corticosteroids at doses beyond 10 mg/day of 
prednisone or equivalent, methotrexate, azathioprine, and tumour necrosis factor 
alpha blockers should not be given concomitantly.  Use of immunosuppressive 
medications in patients for the management of study treatment-related AEs or their 
use in patients with contrast allergies is acceptable.  In addition, use of inhaled and 
intranasal corticosteroids is permitted.  A temporary period of steroids will be 
allowed if clinically indicated and considered to be essential for the management of 
the patient (eg, for chronic obstructive pulmonary disease, radiation, nausea, etc). 
• 
Live attenuated vaccines within 30 days of dosing.  Inactivated viruses such as 
those in the influenza vaccine are permitted. 
• 
For agents used in the Standard of Care arm, please also refer to the local 
prescribing information with regards to warnings, precautions and 
contraindications.   
• 
For patients receiving tremelimumab monotherapy (10 mg/kg), drugs with laxative 
properties and herbal or natural remedies for constipation should be avoided for 
90 days after the last dose of study drug. 
• 
For patients on the MEDI4736+tremelimumab combination arm, drugs with 
laxative properties and herbal or natural remedies for constipation should be used 
with caution for 90 days after the last dose of tremelimumab. 
• 
For patients in the tremelimumab monotherapy and MEDI4736+tremelimumab 
combination arms, sunitinib should not be given concomitantly or for 90 days after 
the last dose of tremelimumab (acute renal failure has been reported with 
combination therapy of tremelimumab and sunitinib). 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
155 
Other medication, 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. 
5.7 
Treatment compliance 
Treatment compliance will be assured by site reconciliation of study treatment dispensed. 
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the eCRF.  The investigator or pharmacy must retain records of 
all study drugs administered.  The study monitor will check these records to confirm the 
compliance with the protocol administration schedule.  Administration of study drug as 
re-treatment following final DCO will be recorded in site documents for the purpose of supply 
management but will not otherwise be reported. 
Any dose reductions will be documented, along with reasons for the dose reduction.  
Note: No dose reductions are allowed for MEDI4736 monotherapy, tremelimumab 
monotherapy or MEDI4736+tremelimumab arms. 
Use of study treatment in doses in excess of that specified in the protocol is considered to be 
an overdose.  Refer to Section 13.2 for procedures in case of overdose.   
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 dispensed to and returned from the 
patient.   
Study site personnel will account for all study drugs received at the site, unused study drugs 
and for appropriate destruction.  Certificates of delivery and destruction should be signed. 
5.8 
Discontinuation of study treatment 
Patients may be discontinued from study treatment in the following situations: 
• 
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment 
• 
Adverse event, that in the opinion of the investigator or the sponsor, contraindicates 
further dosing 
• 
Severe non-compliance to study protocol that, in the opinion of the investigator or 
sponsor, warrants withdrawal; eg, refusal to adhere to scheduled visits 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
156 
• 
Patient is determined to have met 1 or more of the exclusion criteria for study 
participation at study entry and continuing study treatment might constitute a safety 
risk 
• 
Any AE that meets criteria for discontinuation, as defined in Section 5.5.3 for 
MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab or as defined in the local prescribing information for 
agents in the Standard of Care arm 
• 
An AE related to study treatment that is ≥Grade 3, with the exception of toxicities 
that do not meet criteria for discontinuation as defined in Section 5.5.3 for 
MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab or as defined in the local prescribing information for 
agents in the Standard of Care arm 
• 
≥Grade 3 infusion reaction (does not apply to patients receiving erlotinib) 
• 
Initiation of alternative anti-cancer therapy including another investigational agent 
• 
Confirmed PD and investigator determination that the patient is no longer 
benefiting from treatment.  Study drug should be discontinued if there is confirmed 
PD while on treatment following a previous response (PR or CR) to study drug 
while on treatment (ie, the response and progression events both occurred while 
receiving study drug during the same treatment period). 
• 
Pregnancy or intent to become pregnant. 
If the patient is discontinued from study treatment, the scheduled study visits, data collection 
and procedures should continue according to this study protocol until study closure.  
Alternatively, if the patient does not agree to this option, a modified follow-up through eg, 
regular telephone contacts or a contact at study closure should be arranged, if agreed to by the 
patient and in compliance with local data privacy laws/practices.  See Section 5.8.1. 
Following final DCO, only SAEs occurring up to 90 days after the last dose of MEDI4736 or 
tremelimumab will be reported directly to AstraZeneca Global Patient Safety as described in 
Section 6.4.4.  Other AEs should be managed according to the toxicity management 
guidelines in Section 5.5.3, and will be followed up per the investigators’ judgment but will 
not be otherwise reported or recorded for the purposes of this study.  Following the final 
DCO, investigators who intend to commence or continue re-treatment with study drug should 
continue to monitor patients’ safety laboratory assessments so as to ensure that no laboratory 
abnormalities or AEs that could potentially result in IP discontinuation are overlooked.  All 
data will be recorded into the patients’ charts but will not be otherwise documented for the 
purposes of this study. 
Withdrawal of consent for PGx and biological sampling is included in Section 7.5. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
157 
5.8.1 
Procedures for discontinuation of a patient from study treatment  
Patients who are permanently discontinued from further receipt of study treatment, regardless 
of the reason (withdrawal of consent, due to an AE, other), will be identified as having 
permanently discontinued treatment.   
A patient that decides to discontinue study treatment will always be asked about the reason(s) 
for discontinuation and the presence of any AEs.  If possible, they will be seen and assessed 
by an investigator(s).  Adverse events will be followed up (see Sections 6.4.3 and 6.4.4), and 
questionnaires and all study drugs should be returned by the patient. 
If a patient is withdrawn from the study, see Section 5.9. 
5.8.2 
Assessments following withdrawal of study treatment 
Patients who are permanently discontinued from receiving study treatment will remain in the 
study and will be followed per the study plans for safety including the collection of any 
protocol-specified blood specimens and completion of questionnaires and eCRFs relating to 
PRO and hospital resource use, unless consent is withdrawn or the patient is lost to follow-up 
or enrolled in another clinical study.  All patients will be followed for survival up to the time 
of final DCO.  Patients who decline to return to the site for evaluations will be offered 
follow-up by phone as specified in the study plans as an alternative (MEDI4736 monotherapy, 
tremelimumab monotherapy and MEDI4736+tremelimumab: Table 6 [for follow-up of 
patients achieving disease control or who are discontinued due to toxicity or a reason other 
than confirmed PD] and Table 7 [for follow-up of patients discontinuing due to confirmed 
PD]; Standard of Care: Table 10 [follow-up for patients treated with Standard of Care]).  
However, patients who discontinue due to an AE will need to attend all protocol-specified 
visits, and all assessments will be conducted as scheduled.   
All patients who have any Grade 3 or 4 laboratory values at the time of discontinuation must 
have further tests performed and the results recorded on the appropriate eCRF until the 
laboratory values have returned to Grade 1 or 2, unless these values are not likely to improve 
because of the underlying disease.   
At discontinuation, all ongoing study-related toxicities and SAEs must be followed until 
resolution, unless in the investigator’s opinion, the condition is unlikely to resolve due to the 
patient’s underlying disease. 
All new AEs occurring for up to 90 days after the last dose of study treatment (30 days after 
last dose of Standard of Care) must be recorded in the eCRF and reported as SAEs, if 
applicable.   
Patients in the MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab arms who have disease control following completion of treatment 
or patients who are withdrawn from study treatment for reasons other than confirmed PD will 
continue to have objective tumour assessments (see MEDI4736 monotherapy, tremelimumab 
monotherapy and MEDI4736+tremelimumab: Table 6 [for follow-up of patients achieving 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
158 
disease control or who are discontinued due to toxicity or a reason other than confirmed PD]).  
Drug or study procedure-related SAEs must be captured until the patient completes the 
follow-up period following discontinuation of study treatment (due to confirmed PD) or is 
permanently withdrawn from the study (see Section 5.9). 
When confirmed PD has been documented, the long-term follow-up information for survival 
should be collected per the study plans (MEDI4736 monotherapy, tremelimumab 
monotherapy and MEDI4736+tremelimumab: Table 7 [for follow-up of patients discontinuing 
due to confirmed PD]; Standard of Care: Table 10) by telephone contact with the patient, 
patient’s family, or by contact with the patient’s current physician.  An exception is any 
patient in the MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab arms with confirmed PD during the initial treatment period that 
continues to receive study treatment at the discretion of the investigator (MEDI4736, 
tremelimumab monotherapy or MEDI4736+tremelimumab patients can receive treatment for a 
maximum of 12 months/48 weeks as applicable).  Retreatment may continue as long as the 
investigator judges the patient to be gaining clinical benefit.  Patients will follow the 
assessments in the study plan [MEDI4736 monotherapy: Table 3, tremelimumab 
monotherapy: Table 4 or MEDI4736+tremelimumab: Table 5] including tumour assessments 
until study treatment is discontinued the patient must re-consent to be treated through disease 
progression [see Section 8.4]).  
Study drug should be discontinued if there is confirmed PD while on treatment following a 
previous response (PR or CR) to study drug while on treatment (ie, the response and 
progression events both occurred while receiving study drug during the same treatment 
period). 
Both the patient and the physician will be asked about the subsequent treatment the patient 
receives during the follow-up period per the study plans (MEDI4736 monotherapy, 
tremelimumab monotherapy and MEDI4736+tremelimumab: Table 6 [for follow-up of 
patients achieving disease control or who are discontinued due to toxicity in or a reason other 
than confirmed PD] and Table 7 [for follow-up of patients discontinuing due to confirmed 
PD]; Standard of Care: Table 10 [follow-up for patients treated with Standard of Care]). 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
159 
5.9 
Withdrawal from study 
Patients may be discontinued from the study in the following situations: 
• 
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment  
• 
Severe non-compliance to study protocol that, in the opinion of the investigator or 
sponsor, warrants withdrawal; eg, refusal to adhere to scheduled visits 
• 
Patient lost to follow-up. 
Patients are at any time free to withdraw from study (study treatment and assessments), 
without prejudice to further treatment (withdrawal of consent).  Such patients will always be 
asked about the reason(s) and the presence of any AEs.  If possible, they will be seen and 
assessed by an investigator.  Adverse events will be followed up (see Section 6.4.3 and 
Section 6.4.4); and questionnaires and all study drugs should be returned by the patient. 
If consent is withdrawn, the patient will not receive any further study treatment or further 
study observation.  The patient will be specifically asked if they are withdrawing consent to:  
• 
Further participation in the study including any further follow-up (eg, survival calls)  
• 
Withdrawal of consent to the use of their study generated data 
• 
Withdrawal to the use of any samples (see Section 7.5). 
Note that the patient may be offered additional tests or tapering of treatment to withdrawal for 
safety, and will be offered follow-up by phone as specified in the study plans as an alternative 
(MEDI4736 monotherapy, tremelimumab monotherapy and MEDI4736+tremelimumab: 
Table 6 [for follow-up of patients achieving disease control or who are discontinued due to 
toxicity or a reason other than confirmed PD] and Table 7 [for follow-up of patients 
discontinuing due to confirmed PD]; Standard of Care: Table 10 [follow-up for patients 
treated with Standard of Care]).  If a patient wishes to withdraw their consent to further 
participation in the study, including survival follow-up (by phone) this should be clearly 
documented in the patient notes and in the clinical study database.    
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed such that there is insufficient information to determine the 
patient’s status at that time. 
Note: Patients who refuse to continue participation in the study, including phone 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 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
160 
should not be considered lost to follow-up and any evaluations should resume according to the 
protocol. 
Withdrawn patients will not be replaced.  
Vital status (ie, whether a patient is dead or alive), based on public available sources, will be 
investigated at the scheduled study end. 
6. 
COLLECTION OF STUDY VARIABLES 
MEDI4736 monotherapy, tremelimumab monotherapy and MEDI4736+tremelimumab: 
The schedule of study procedures at Screening and during the Treatment Period for 
MEDI4736 monotherapy is presented in Table 3, for tremelimumab monotherapy in Table 4 
and for MEDI4736+tremelimumab in Table 5.  The schedule of follow-up procedures for 
patients who have completed MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab and achieved disease control and patients who have discontinued 
MEDI4736 monotherapy, tremelimumab monotherapy or MEDI4736+tremelimumab due to 
toxicity or a reason other than confirmed PD is presented in Table 6.  The schedule of 
follow-up procedures for patients who have discontinued MEDI4736 monotherapy, 
tremelimumab monotherapy or MEDI4736+tremelimumab due to confirmed PD is presented 
in Table 7.  Following final DCO, no further study data will be captured except for SAEs (in 
the AstraZeneca Global Patient Safety database) for patients whilst the patient is either still 
receiving study drug, (ie, re-treatment patients) or is in the 90-day safety follow-up period 
after receiving the last dose of study drug.  Investigators with patients in progression-free 
follow-up who may become eligible for re-treatment are to conduct scans/RECIST per local 
practice and safety laboratory assessments in such a way that alignment with per-protocol 
re-treatment eligibility criteria can be properly determined. 
Standard of Care: The schedule of assessments for patients treated with vinorelbine or 
gemcitabine is presented in Table 8 and for patients treated with erlotinib is presented in 
Table 9.  The schedule of follow-up procedures for patients treated with Standard of Care is 
presented in Table 10. 
6.1 
Recording of data 
The InForm Web Based Data Capture (WBDC) system will be used for data collection and 
query handling until the point of final DCO and database lock for the study.  The investigator 
will ensure that data are recorded on the eCRFs as specified in the study protocol and in 
accordance with the instructions provided.  Data from the paper questionnaires will be 
transcribed at the investigator site onto the eCRF.   
The investigator ensures the accuracy, completeness, legibility and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement.  The investigator will sign the completed eCRFs.  A copy of the completed eCRFs 
will be archived at the study site. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
161 
6.2 
Data collection at enrolment and follow-up 
6.2.1 
Enrolment procedures 
The following assessments and procedures should be performed within the 42 days prior to 
the first dose of MEDI4736 (Table 3), tremelimumab monotherapy (Table 4), 
MEDI4736+tremelimumab (Table 5) or Standard of Care (Table 8 for patients who will 
receive gemcitabine or vinorelbine and Table 9 for patients who will receive erlotinib).  For 
details of the nature of the assessments, see below: 
• 
Signed informed consent for the Pre-screening Period of the study and assignment 
of a patient identification number 
• 
Preliminary eligibility criteria (investigator’s opinion) 
• 
Demographic details including age, sex and ethnicity and also tobacco and alcohol 
consumption history 
• 
Details on previous treatments for NSCLC 
• 
A mandatory provision of a newly acquired tumour tissue (preferred) or archival 
(≤3 years) tumour biopsy (for collection and processing procedures, refer to 
Section 6.7.1 and the Laboratory Manual).  In addition to the samples used for 
determining PD-L1 status, provision of an archived tumour tissue block (or at least 
10 newly cut unstained slides) where such samples exist in a quantity sufficient to 
allow for analysis (Refer to Section 6.7.1 and the Laboratory Manual for details). 
The following assessments and procedures should be performed within 28 days prior to the 
first dose of MEDI4736 monotherapy (Table 3), tremelimumab monotherapy (Table 4), 
MEDI4736+tremelimumab (Table 5) or Standard of Care (Table 8 for patients who will 
receive gemcitabine or vinorelbine and Table 9 for patients who will receive erlotinib).  For 
details of the nature of the assessments, see below. 
• 
Signed sub-study informed consent for the treatment period of the study 
• 
Formal eligibility criteria verification 
• 
Past medical and surgical history  
• 
Details of any palliative radiotherapy 
• 
Physical examination to assess all conditions that are current and ongoing  
• 
Weight, height and vital signs: systolic blood pressure and diastolic blood pressure, 
pulse, respiratory rate, body temperature and oxygen saturation.  
• 
Recording of AEs from the time of pre-screening consent 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
162 
• 
Concomitant medications  
• 
WHO performance status  
• 
Haematology, clinical chemistry and urinalysis   
• 
Coagulation tests: prothrombin time, activated partial thromboplastin time (APTT) 
and international normalised ratio (INR)   
• 
Hepatitis B and C testing as per local practice 
• 
HIV-1 antibody testing as per local practice 
• 
Thyroid function tests: triiodothyronine (T3; free [if available]), total thyroxine (T4 
[or T4 free]), and thyroid stimulating hormone (TSH) 
• 
Pregnancy testing for female patients, as clinically indicated (urine human chorionic 
gonadotropin [hCG] or serum βhCG) 
• 
12-lead ECG recording 
• 
Patient questionnaires (European Organisation for Research and Treatment of 
Cancer 30-item core quality of life questionnaire [EORTC QLQ-C30] with the 
Lung Cancer Module [LC13]  and EuroQoL 5-dimension,
 
 
• 
 
• 
Tumour assessment scans of the chest and abdomen (including liver and adrenal 
glands) for assessment of disease by CT/MRI (see Appendix F).   
Note: If Screening laboratory assessments are performed within 3 days prior to Day 1 they do 
not need to be repeated at Day 1.   
The Principal Investigator/sub-investigator should adhere to the study plan, procedures and 
perform tests/observations in accordance with the protocol. 
6.2.2 
Follow-up procedures 
Patients should be discontinued from study treatment if any discontinuation criteria are 
fulfilled, see Section 5.8.  The assessments to be carried out during follow-up are detailed in 
the study plans (MEDI4736 monotherapy, tremelimumab monotherapy and 
MEDI4736+tremelimumab: Table 6 [for follow-up of patients achieving disease control or 
who are discontinued due to toxicity or a reason other than confirmed PD] and Table 7 [for 
follow-up of patients discontinuing due to confirmed PD]; Standard of Care: Table 10 
[follow-up for patients treated with Standard of Care]).   
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
163 
Any serious and/or non-serious AEs ongoing at the time of treatment discontinuation or which 
have occurred during the follow-up period must be followed-up (in accordance with 
Section 6.4.3 and Section 6.4.4).  Appropriate safety evaluations should be repeated and/or 
additional tests performed at any time when clinically indicated, or at the discretion of the 
investigator, until resolution, unless, in the investigator’s opinion, the condition is unlikely to 
resolve due to the patient’s underlying disease.  If the patient is lost to follow-up, then this 
should be noted in the eCRF. 
Every effort should be made to obtain accurate follow-up information on patients whose PFS 
and OS data were not accurately recorded.  For example, in the case of PFS, the local 
investigator could provide their clinical assessment of progression if care transfers elsewhere, 
and for OS an effort should be made to continue to follow and use death registries where 
necessary. 
6.2.2.1 
Survival follow-up 
Assessments for survival status should be made following confirmed objective disease 
progression (per RECIST v1.1) as presented in the study plans (MEDI4736 monotherapy, 
tremelimumab monotherapy and MEDI4736+tremelimumab: Table 6 [follow-up of patients 
achieving disease control or who are discontinued due to toxicity or a reason other than 
confirmed PD] and Table 7 [follow-up of patients discontinuing due to confirmed PD]; 
Standard of Care: Table 10).  No OS data will be recorded in the study database after final 
DCO for the study, but such information may continue to be collected for operational 
purposes for patients who remain eligible for re-treatment with study drug. 
Survival information may be obtained via telephone contact with the patient, patient’s family 
or by contact with the patient’s current physician.  In addition, patients should be contacted in 
the week following the DCO for the final analysis of OS for each sub-study, to provide 
complete survival data.   
The status of patients ongoing in the study, those withdrawn (from the study) and those lost to 
follow-up at the time of an OS analysis should be obtained by the site personnel, by checking 
the patient 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 (ie, if the patient 
is dead or alive) can be obtained by site personnel from publicly available resources where it 
is possible to do so under applicable local laws.  
6.2.2.2 
Second progression 
Following objective progression, patients will be assessed every 12 weeks for a 
second progression (using the patient’s status at first progression as the reference for 
assessment of second progression).  A patient’s progression status is defined according to 
local standard clinical practice and may involve any of: objective radiological, symptomatic 
progression or death.  RECIST measurements will not be collected for assessment of PFS2.  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
164 
The date of PFS2 assessment and investigator opinion of progression status (progressed or 
non-progressed) at each assessment will be recorded in the eCRF. 
6.3 
Efficacy  
RECIST 1.1 criteria will be used to assess patient response to treatment and allow calculation 
of PFS, ORR, and DoR.  The RECIST 1.1 guidelines for measurable, non-measurable, target 
and non-target lesions and the objective tumour response criteria (CR, PR, SD or PD) are 
presented in Appendix F. 
The same method of assessment of tumour burden used at baseline CT/MRI scans of the chest 
and abdomen (including liver and adrenal glands) must be used at each subsequent follow-up 
assessment. 
The baseline assessment should be performed within the 28 days prior to randomisation and 
ideally as close as possible before the start of study treatment.  Efficacy for all patients will be 
assessed by objective tumour assessments every 8 weeks for the first 48 weeks (relative to the 
date of randomisation per Table 3 for MEDI4736 monotherapy, Table 4 for tremelimumab 
monotherapy, Table 5 for MEDI4736+tremelimumab, Table 8 for gemcitabine and 
vinorelbine and Table 9 for erlotinib), and then every 12 weeks thereafter, until confirmed 
objective disease progression as defined by RECIST 1.1 (irrespective of the reason for 
stopping treatment and/or subsequent therapy).  If an unscheduled assessment is performed, 
and the patient has not progressed, every attempt should be made to perform the subsequent 
assessments at their scheduled visits.  
For patients who discontinue study drug due to toxicity or a reason other than confirmed PD, 
objective tumour assessments should be continued every 8 weeks for 12 months/48 weeks 
(relative to the date of randomisation) then every 12 weeks thereafter until confirmed 
objective disease progression.   
In the monotherapy arms, disease progression that occurs while on treatment requires 
confirmation.  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 with MEDI4736 monotherapy or tremelimumab 
monotherapy will continue between the initial assessment of progression and confirmation for 
progression.  In the Standard of Care arm, it is at the investigator’s discretion if a patient with 
uncertain PD continues treatment until PD is confirmed; however, a confirmatory scan is 
required for all patients in the Standard of Care arm even if a subsequent treatment is started.   
Patients who achieve and maintain disease control (ie, CR, PR, or SD) through to the end of 
the 12-month treatment period will enter follow-up.  When these patients experience evidence 
of PD, with or without confirmation, during follow-up and meet the criteria for treatment in 
the setting of PD, they will be given the option to restart their assigned immune-mediated 
cancer treatment (ie, MEDI4736 monotherapy or tremelimumab monotherapy) for as long as 
the investigator judges they are gaining clinical benefit with the same treatment guidelines 
followed during the initial 12-month treatment period.  Patients should have a baseline tumour 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
165 
assessment within 28 days prior to restarting their assigned immune-mediated cancer 
treatment; all further scans should occur every 8 weeks (relative to the date of restarting 
treatment) until study treatment is stopped.  Only patients who the investigator determines do 
not have any significant, unacceptable, or irreversible toxicities, or would continue to receive 
benefit from therapy can restart treatment upon PD.  Treatment will continue for as long as the 
investigator judges they are gaining clinical benefit.  Only 1 retreatment cycle can occur.   
In the MEDI4736+tremilimumab combination arm, retreatment can only occur if PD, with or 
without confirmation, occurs during the monotherapy portion or during the follow-up phase 
after completion of 12 months of treatment.  During the retreatment period, the patient would 
resume MEDI4736 20 mg/kg Q4W as during the initial induction period, along with 
tremelimumab 1 mg/kg Q4W for 4 doses.  Monotherapy with MEDI4736 10 mg/kg Q2W 
would then resume at Week 16, 4 weeks after the last dose of combination treatment, for as 
long as the investigator judges they are gaining clinical benefit. 
Patients with rapid tumour progression or with symptomatic progression that requires urgent 
medical intervention (eg, central nervous system metastasis, respiratory failure due to tumour 
compression, spinal cord compression) will not be eligible to continue to receive study drug. 
Progression would be considered confirmed if the following criteria are met: 
• 
≥20% increase in the sum diameters of target lesions compared with the nadir at 
2 consecutive visits with an absolute increase of at least 5 mm  
The assessment of progression of ≥20% increase in the sum diameters of target 
lesions compared with the nadir is at the first progression time point relative to the 
nadir (the smallest sum of diameters and this may be at baseline or subsequent 
follow-up visit).  The confirmed scan confirms the persistence of the ≥20% increase 
relative to the nadir.  
• 
and/or significant progression (worsening) of non-target lesions or new lesions at 
the confirmatory PD time point compared with the first time point where 
progression of non-target lesions  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. 
In the absence of clinically significant deterioration the investigator should continue the 
patient on the planned treatment schedule for the MEDI4736 monotherapy, tremelimumab 
monotherapy or MEDI4736+tremelimumab arms until progression is confirmed.  In the 
Standard of Care arm, it is at the investigator’s discretion if a patient with uncertain PD 
continues treatment until PD is confirmed.  In cases of unequivocal progression the 
investigator should discontinue treatment. 
If progression is not confirmed then the patient should continue on study treatment and on 
treatment assessments. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
166 
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. 
Categorisation of objective tumour 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 tumour burden was at a minimum (ie, smallest sum of diameters 
previously recorded on study).  In the absence of progression, tumour response (CR, PR) and 
SD will be calculated in comparison to the baseline tumour measurements obtained before 
starting treatment. 
If the investigator is in doubt as to whether progression has occurred, particularly with 
response to non-target lesion or the appearance of a new lesion, it is advisable to continue 
treatment until the next scheduled assessment or sooner if clinically indicated and reassess the 
patient’s status.  If repeat scans confirm progression, then the date of the initial scan should be 
declared as the date of progression. 
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of 1 or more non-target lesions is 
usually not sufficient to quality for unequivocal progression status. 
Following confirmed progression, patients should continue to be followed up for survival 
every 2 months as outlined in the study plans (MEDI4736 monotherapy, tremelimumab 
monotherapy or MEDI4736+tremelimumab: Table 7 [for follow-up of patients discontinuing 
due to confirmed PD]; Standard of Care: Table 10) until final DCO.  An exception would be 
those patients with confirmed PD during the initial treatment period that continue to receive 
study treatment at the discretion of the investigator (following consultation with the sponsor); 
these patients can receive treatment for a maximum of 12 months/48 weeks as applicable.  
Patients will have scans every 8 weeks (relative to the date of randomisation) until study 
treatment is stopped per Table 3, Table 4 and Table 5 (Screening and Treatment Period).  
Study drug should be discontinued if there is confirmed PD while on treatment following a 
previous response (PR or CR) to study drug while on treatment (ie, the response and 
progression events both occurred while receiving study drug during the same treatment 
period).  Retreatment may continue as long as the investigator judges the patient to be gaining 
clinical benefit.   
Patients with confirmed PD that discontinue study treatment, should have scans conducted 
according to local standard clinical practice (see Section 6.2.2.2) until the patient commences 
a new treatment (these scans are optional; MEDI4736 monotherapy, tremelimumab 
monotherapy or MEDI4736+tremelimumab: Table 7 [for follow-up of patients discontinuing 
due to confirmed PD]; Standard of Care: Table 10). 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
167 
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
study plans and Appendix F (MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab: Table 3, Table 4 or Table 5 [Screening and Treatment Period], 
respectively, and Table 6 [for follow-up of patients achieving disease control or who are 
discontinued due to toxicity or a reason other than confirmed PD] and Table 7 [for follow-up 
of patients discontinuing due to confirmed PD]; Standard of Care: Table 8 [vinorelbine or 
gemcitabine], Table 9 [erlotinib] and Table 10 [follow-up for patients treated with Standard of 
Care]).   
Central reading of scans 
Efficacy evaluation of PFS, ORR and DoR will be derived using investigator assessments 
according to RECIST 1.1.  All radiological scans for all patients (including those at 
unscheduled visits, or outside of visit windows) will be collected on an ongoing basis and sent 
to an AstraZeneca-appointed Contract Research Organisation to be stored and possibly used 
for a central review at a later stage.  The management of patients will be based solely upon the 
results of the RECIST assessment conducted by the investigator.   
6.4 
Safety 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
Safety guidelines around SAE reporting described within the protocol remain in effect after 
the final DCO. 
6.4.1 
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 SAEs and non-serious AEs. 
For cases where it could be suspected that a tissue-derived medicine has been contaminated by 
a pathogen, information about any of the above conditions (including infection) should be 
collected.  Any deterioration of the disease targeted in the study and associated symptoms 
should not be regarded as an AE as far as the deterioration can be anticipated. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
168 
6.4.2 
Definitions of serious adverse event 
An SAE is an AE occurring during any study phase (ie, treatment, follow-up), that fulfils 1 or 
more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalisation or prolongation of existing hospitalisation  
• 
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 jeopardise 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 to the Clinical Study 
Protocol. 
6.4.3 
Recording of adverse events 
Time period for collection of adverse events 
Adverse events will be collected from time of signature of the sub-study informed consent, 
throughout the treatment period and including the follow-up period (90 days after the last dose 
of MEDI4736 and/or tremelimumab and 30 days after the last dose of Standard of Care). 
Adverse events not meeting SAE criteria that occur after the final DCO for the study will be 
followed up as per standard clinical practice but will not be recorded for the purposes of this 
study. 
All SAEs will be recorded from the time of signature of the pre-screening informed consent, 
throughout the treatment period and including the follow-up period (90 days after the last dose 
of MEDI4736 and/or tremelimumab and 30 days after the last dose of Standard of Care).  For 
SAEs that occur in the pre-screening period, additional information such as medical history 
may be requested. 
After the final DCO, any SAEs occurring whilst the patient is either still receiving study drug 
(ie, re-treatment patients) or is in the 90-day safety follow-up period after receiving the last 
dose of study drug should be reported to AstraZeneca following the procedures outlined in 
Section 6.4.4.  If a patient discontinues from treatment for reasons other than disease 
progression, and therefore continues to have tumour assessments using RECIST, drug or 
procedure-related SAEs must be captured until the patient is considered to have confirmed PD 
and will have no further RECIST assessments.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
169 
For screening failures (ie, patients who do not receive study treatment), SAEs will be 
collected from the time of signature of the pre-screening informed consent until the patient is 
withdrawn from the study.  Any SAE related to a mandated study procedure should be 
reported. 
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/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/MedImmune retains the right to request additional information for any patient 
with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Post-study events 
After the patient has been permanently withdrawn from the study, there is no obligation for 
the investigator to actively report information on new AE or SAEs occurring in former study 
patients after the 90-day/30-day safety follow-up period for patients in the MEDI4736 
monotherapy, tremelimumab monotherapy and MEDI4736+tremelimumab, and Standard of 
Care arms, respectively.  However, if an investigator learns of any SAEs, including death, at 
any time after the patient has been permanently withdrawn from study, and he/she considers 
there is a reasonable possibility that the event is related to study treatment, the investigator 
should notify AstraZeneca/MedImmune, Drug Safety or its representative. 
Variables 
The following variables will be collected for each AE on the eCRF: 
• 
AE (verbatim) 
• 
The date and time when the AE started and stopped 
• 
The maximum CTCAE grade reported 
• 
CTC grade changes for events of Grade 3 or above 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the study treatment (yes or no) 
• 
Action taken with regard to study treatment 
• 
Administration of treatment for the AE 
• 
AE caused patient’s withdrawal from study (yes or no) 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
170 
• 
Outcome. 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE 
• 
Date investigator became aware of SAE 
• 
AE is serious due to 
• 
Date of hospitalisation 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to Study procedure(s) 
• 
Causality assessment in relation to Other medication 
• 
Description of AE. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.4.2.  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.  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. 
Causality collection 
The investigator will assess causal relationship between study treatment 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 study treatment?’ 
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 to the Clinical 
Study Protocol. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
171 
Relationship to protocol procedures 
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form.  This includes non-treatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of study treatment) as well as 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/intervention that was 
described in the protocol for which there is no alternative aetiology present in the 
patient’s medical record. 
• 
Not protocol related: The event is related to an aetiology other than the 
procedure/intervention that was described in the protocol (the alternative aetiology 
must be documented in the study patient’s medical record). 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the eCRF.  
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 
Adverse events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
CSR.  Deterioration as compared to baseline in protocol-mandated laboratory values and vital 
signs should therefore only be reported as AEs if they fulfil any of the SAE criteria or are the 
reason for discontinuation of treatment.  An abnormal laboratory finding (including ECG 
findings) that requires an action or intervention by the investigator, or a finding judged by the 
investigator to represent a change beyond the range of normal physiologic fluctuation, should 
also be reported as an AE. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s). 
Asymptomatic Grade 3 or 4 increases in amylase or lipase resulting in interruption of dosing 
(Refer to Section 5.5.3) should be reported as AEs. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
172 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
Note: Cases where a patient shows an AST or ALT ≥3 × ULN or total bilirubin ≥2 × ULN 
may need to be reported as SAEs.  These cases should be reported as SAEs if after evaluation 
they meet the criteria for a Hy’s Law case or if any of the individual liver test parameters fulfil 
any of the SAE criteria.  For potential Hy’s Law to be met, the elevation in transaminases 
must precede or be coincident with (ie, on the same day) the elevation in total bilirubin, but 
there is no specified timeframe within which the elevations in transaminases and total 
bilirubin must occur.  Please refer to Appendix E ‘Actions required in cases of combined 
increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for further instructions in cases 
of combined increases of aminotransferase and total bilirubin. 
Criteria for Hy’s Law (FDA Guidance 2009) 
• 
The drug causes hepatocellular injury, generally shown by a higher incidence of 
3-fold or greater elevations above the ULN of ALT or AST than the 
(non-hepatotoxic) control drug or placebo  
• 
Among trial subjects showing such aminotransferase elevations, often with 
aminotransferases much greater than 3 × ULN, 1 or more also show elevation of 
serum total bilirubin to >2 × ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase)  
• 
No other reason can be found to explain the combination of increased 
aminotransferases and total bilirubin, such as viral hepatitis A, B, or C; pre-existing 
or acute liver disease; or another drug capable of causing the observed injury. 
Guidelines for management of patients with hepatic function abnormality are outlined in the 
TMGs (Refer to Section 5.5.3). 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  The 
development of new, or progression of existing metastasis to the primary cancer under study 
should be considered as disease progression and not an AE.  Events, which are unequivocally 
due to disease progression, should not be reported as an AE during the study. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
173 
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.   
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 the result of disease progression should be reported to the study 
monitor at the next monitoring visit and should be documented in the eCRF but 
should not be reported as a SAE.   
• 
Where death is not due (or not clearly due) to PD under study, the AE causing the 
death must be reported to the study monitor as a 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 a SAE.  A post 
mortem maybe helpful in the assessment of the cause of death, and if performed a 
copy of the post-mortem results should be forwarded to AstraZeneca/MedImmune 
Drug Safety or its representative within the usual timeframes.   
6.4.4 
Reporting of serious adverse events 
All SAEs occurring whilst the patient is either still receiving study drug (ie, treatment or 
re-treatment patients) or is in the 90 day safety follow-up period after receiving the last dose 
of study drug have to be reported, whether or not considered causally related to study 
treatment, or to the study procedure(s).  All SAEs occurring prior to the final DCO will be 
recorded in the eCRF.  If any SAE occurs in the course of the study, then investigators or 
other site personnel inform appropriate AstraZeneca/MedImmune representatives (ie, 
QuintilesIMS) immediately, or no later than 24 hours of when he or she becomes aware of 
it. 
The designated AstraZeneca/MedImmune representative (ie, QuintilesIMS) works with the 
investigator to ensure that all the necessary information is provided to the 
AstraZeneca/MedImmune Patient Safety data entry site within 1 calendar day of initial 
receipt for fatal and life threatening events and within 5 calendar days of initial receipt for 
all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca/MedImmune representatives of any follow-up information on a previously 
reported SAE immediately, or no later than 24 hours of when he or she becomes aware of it. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
174 
Investigators or other site personnel send relevant eCRF modules by fax to QuintilesIMS and 
any other relevant supporting documentation (eg, ECG, laboratory results, autopsy report). 
Please refer to the study specific Safety Handling Plan.  The AstraZeneca/MedImmune 
representative will advise the investigator/study site personnel how to proceed.  
The reference document for definition of expectedness/listedness is the IB for MEDI4736 and 
the European Summary of Product Characteristics for the active Standard of Care products. 
After the final DCO, any SAEs occurring whilst the patient is either still receiving study drug 
(ie, re-treatment patients) or is in the 90 day safety follow-up period after receiving the last 
dose of study drug are to be recorded in a paper CRF and reported directly to the 
AstraZeneca/MedImmune 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. 
6.4.5 
Laboratory safety assessment 
Blood and urine samples for determination of clinical chemistry, haematology, urinalysis, 
thyroid function tests, amylase, and lipase will be taken at the times indicated in the study 
plans (MEDI4736 monotherapy, tremelimumab monotherapy or MEDI4736+tremelimumab: 
Table 3, Table 4 or Table 5 [Screening and Treatment Period], and Table 6 [for follow-up of 
patients achieving disease control or who are discontinued due to toxicity or a reason other 
than confirmed PD] and Table 7 [for follow-up of patients discontinuing due to confirmed 
PD]; Standard of Care: Table 8 [vinorelbine or gemcitabine], Table 9 [erlotinib] and Table 10 
[follow-up for patients treated with Standard of Care]).  Please also refer to the Laboratory 
Manual.   
Patients in progression-free follow-up after the final DCO are to undergo sampling for local 
laboratory assessments in such a way that continued per-protocol re-treatment eligibility can 
be properly determined.  For patients receiving re-treatment after final DCO, it is 
recommended that the patients continue the scheduled site visits and investigators monitor the 
patient’s safety laboratory assessments prior to and periodically during the treatment with 
study drug in order to manage AEs in accordance with the toxicity management guidelines 
(Refer to Section 5.5.3); data will be recorded on patient charts but will not otherwise be 
reported for the purposes of this study. 
The laboratory variables to be measured are presented in Table 19, Table 20 and Table 21. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
175 
Table 19 
Haematology 
Activated partial thromboplastin timea 
Mean corpuscular haemoglobin concentration 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Haematocrit 
Neutrophils 
Haemoglobin 
Platelet count 
International normalised ratio 
Red blood cell count 
Lymphocytes 
Total white cell count 
Mean corpuscular haemoglobin 
 
a 
Activated partial thromboplastin time will be determined at Screening only, unless clinically indicated.  
Haematology assessments (absolute counts, as appropriate) to be performed at each visit and when clinically indicated. 
 
Table 20 
Clinical chemistry (serum or plasma) 
Albumin 
Glucose 
Alkaline phosphatasea 
Lactate dehydrogenase 
Alanine aminotransferasea 
Lipasec 
Amylasec 
Magnesiumc  
Aspartate aminotransferasea 
Potassium 
Bicarbonate 
Sodium 
Calcium  
Total bilirubina 
Chloride 
Total protein 
Creatinine (creatinine clearance)c 
Urea or blood urea nitrogen, depending on local practice 
Gamma glutamyltransferaseb 
Uric acidc 
a 
Tests for aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin must be 
conducted concurrently and assessed concurrently. 
b 
Gamma glutamyltransferase tested at Screening, Day 1 (unless screening laboratory assessments are performed within 
3 days prior to Day 1) and as clinically indicated. 
c 
Creatinine clearance, magnesium, amylase, lipase, and uric acid tested at Screening, Day 1 (unless screening laboratory 
assessments are performed within 3 days prior to Day 1) and every 4 weeks thereafter.  In the 
MEDI4736+tremelimumab combination arm, amylase and lipase are tested at Screening, Day 1 (unless screening 
laboratory assessments are performed within 3 days prior to Day 1) and every 4 weeks thereafter; creatinine clearance, 
magnesium, and uric acid are tested at Screening, Day 1 (unless screening laboratory assessments are performed within 
3 days prior to Day 1) and every 4 weeks until Week 12, and every 2 weeks thereafter.  Amylase and lipase levels that 
do not meet the AE reporting criteria (see TMGs - Section 5.5.3) will not be captured.  
 
Clinical chemistry assessments to be performed at each visit and when clinically indicated. 
 
Note: In case a patient shows an AST or ALT ≥3 × ULN or total bilirubin ≥2 × ULN please 
refer to Appendix E ‘Actions required in cases of combined increase of Aminotransferase and 
Total Bilirubin – Hy’s Law’, 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 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
176 
test parameters fulfil any of the SAE criteria.  All patients with an AST, ALT or bilirubin 
value (the latter ≥1.5 x 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 (±7days) after permanent discontinuation of study treatment. 
Table 21 
Urinalysisa 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Colour and appearance 
a 
Microscopy should be used as appropriate to investigate white blood cells and use the high power field for red blood 
cells. 
Urinalysis to be performed Screening, Day 1, every 4 weeks of study treatment and as clinically indicated. 
 
Haematology, clinical chemistry and urinalysis tests will be performed by the hospital’s local 
laboratory.  Additional analyses may be performed if clinically indicated. 
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF.  See Section 6.4.3 for when abnormal laboratory values 
should be reported as AEs. 
All patients who have any CTC 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 CTC Grade 1 or 2, unless these values are not likely to improve 
because of the underlying disease. 
For blood volumes see Section 7.1. 
6.4.6 
Physical examination 
For timing of individual measurements refer to the study plans (MEDI4736 monotherapy, 
tremelimumab monotherapy or MEDI4736+tremelimumab: Table 3, Table 4 or Table 5 
[Screening and Treatment Period], and Table 6 [for follow-up of patients achieving disease 
control or who are discontinued due to toxicity or a reason other than confirmed PD] and 
Table 7 [for follow-up of patients discontinuing due to confirmed PD]; Standard of Care: 
Table 8 [vinorelbine or gemcitabine], Table 9 [erlotinib] and Table 10 [follow-up for patients 
treated with Standard of Care]).  Patients receiving re-treatment after final DCO are to 
undergo physical examinations as clinically indicated at the discretion of the investigator and 
per local standard of care; data will be recorded on patient charts but will not otherwise be 
reported for the purposes of this study. 
A complete physical examination will be performed and will include an assessment of the 
following (as clinically indicated): general appearance, respiratory, cardiovascular, abdomen, 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
177 
skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, 
musculo-skeletal (including spine and extremities), genital/rectal, and neurological systems. 
Performance status will be assessed using WHO performance status at the times specified in 
the study plans based on the following: 
0 
Fully active, able to carry out all usual activities without restrictions and without the 
aid of analgesia. 
1 
Restricted in strenuous activity, but ambulatory and able to carry out light work or 
pursue a sedentary occupation.  This group also contains patients who are fully active, 
as in Grade 0, but only with the aid of analgesics. 
2 
Ambulatory and capable of all self-care, but unable to work.  Up and about more than 
50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled, unable to carry out any self-care and confined totally to bed or 
chair. 
Note: WHO 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, please 
provide WHO performance status when information on subsequent anti-cancer therapy is 
provided, where possible. 
6.4.7 
ECG 
Electrocardiograms will be analysed locally according to the study plans (MEDI4736 
monotherapy, tremelimumab monotherapy or MEDI4736+tremelimumab: Table 3, Table 4 or 
Table 5 [Screening and Treatment Period], and Table 6 [for follow-up of patients achieving 
disease control or who are discontinued due to toxicity or a reason other than confirmed PD] 
and Table 7 [for follow-up of patients discontinuing due to confirmed PD]; Standard of Care: 
Table 8 [vinorelbine or gemcitabine],Table 9 [erlotinib] and Table 10 [follow-up for patients 
treated with Standard of Care]).  Note for patients in the MEDI4736 monotherapy, 
tremelimumab monotherapy and MEDI4736+tremelimumab arms only: On Day 1 and 
Week 12, mandatory ECGs should be recorded within 30 and 60 minutes before the start of 
the infusion and at least one time point 0 to 3 hours after the infusion (for the combination arm 
this is 0 to 3 hours after the second infusion). 
Patients receiving re-treatment after final DCO are to receive ECGs as clinically indicated at 
the discretion of the investigator and per local standard of care; data will be recorded on 
patient charts but will not otherwise be reported for the purposes of this study. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
178 
Paper tracings will be used for local management, but a digital copy of all ECGs will be held 
centrally by a central ECG provider, and the data from this review will be stored for analysis 
if necessary at the end of the study.  Two paper copies of each ECG should be printed (one 
copy can be provided to the central ECG core laboratory to be digitised and analysed if 
necessary).  The independent review will not replace the local review by the investigator or 
cardiologist.  Clinical interpretation and management of patients for all ECGs will be done 
locally. 
The same method of assessment should be used throughout.   
At Screening, digital ECGs should be performed in triplicate with a 2- to 5-minute time lag 
between each measurement.  During treatment, only a single digital ECG measurement is 
required at each visit assessment.  Additional ECGs will be performed when clinically 
indicated, eg, in the event of a cardiac AE.  Triplicate ECGs should be performed to measure 
ECG intervals (eg, PR, QT, QRS, etc) if ECG abnormalities are being investigated. 
Twelve-lead ECGs will be obtained after the patient has been rested in a supine position for at 
least 5 minutes.  The investigator or designated physician will review the paper copies of each 
of the timed 12-lead ECGs on each of the study days when they are collected.  The 
investigator should record that the ECG has been clinically evaluated, but no interval data 
should be recorded on the eCRF.   
Electrocardiograms will be recorded at 25 mm/sec.  All ECGs should be assessed by the 
investigator as to whether they are clinically significantly abnormal / not clinically 
significantly abnormal.  If there is a clinically significant abnormal finding, the investigator 
will record it as an AE on the eCRF (see Section 6.4.3). 
At Screening, mean QTc with Bazett’s correction (QTc = QT/√R) must be <470 msec.   
6.4.8 
Vital signs 
For timings of assessments refer to the study plans (MEDI4736 monotherapy, tremelimumab 
monotherapy or MEDI4736+tremelimumab: Table 3, Table 4 or Table 5 [Screening and 
Treatment Period], respectively, and Table 6 [for follow-up of patients achieving disease 
control or who are discontinued due to toxicity or a reason other than confirmed PD] and 
Table 7 [for follow-up of patients discontinuing due to confirmed PD]; Standard of Care: 
Table 8 [vinorelbine or gemcitabine], Table 9 [erlotinib] and Table 10 [follow-up for patients 
treated with Standard of Care]).  Patients receiving re-treatment after final DCO are to 
undergo vital signs assessments as clinically indicated at the discretion of the investigator and 
per local standard of care; data will be recorded on patient charts but will not otherwise be 
reported for the purposes of this study. 
Patients in the MEDI4736 monotherapy, tremelimumab monotherapy and 
MEDI4736+tremelimumab arms will be monitored with assessment of vital signs (blood 
pressure, pulse, respiratory rate, temperature and oxygen saturation) at Screening and on the 
day of each infusion and in the follow-up period on Day 30.  On infusion days, vital signs will 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
179 
all be taken before the infusion.  Blood pressure and pulse will also be collected during and 
after the infusion (see Section 6.4.8.1). 
Additional monitoring with assessment of vital signs is at the discretion of the investigator per 
standard clinical practice or as clinically indicated.  
Additional recording of vital signs may be captured on an unscheduled vital signs eCRF and 
on the eCRF for AE/SAE where applicable.  The date and time of collection and measurement 
will be recorded on the appropriate eCRF. 
For patients in the Standard of Care arm, vital signs should be taken in line with local 
practice guidelines.  In addition, for patients receiving gemcitabine and vinorelbine, please 
provide vital signs measurements at the beginning and end of each infusion where possible.   
6.4.8.1 
Pulse and blood pressure  
Patients in the MEDI4736 monotherapy, tremelimumab monotherapy and 
MEDI4736+tremelimumab arms will have their blood pressure and pulse measured before, 
during and after the infusion at the following times (based on a 60-minute infusion): 
• 
At the beginning of the infusion (at 0 minutes) 
• 
Every 15 minutes during the infusion (at 15, 30 and 45 minutes) (all ±5 minutes) 
• 
At the end of the infusion (at 60 minutes ±5 minutes) 
• 
In the 1-hour observation period post-infusion: 30 and 60 minutes after the infusion 
(ie, 90 and 120 minutes from the start of the infusion) (±5 minutes) 
If the infusion takes longer than 60 minutes then blood pressure and pulse measurements 
should follow the principles as described above or more frequently if clinically indicated. 
For the combination arm these assessments should be followed for each of the 2 component 
infusions. 
The date and time of collection and measurement will be recorded on the appropriate eCRF. 
6.4.8.2 
Temperature, respiratory rate and oxygen saturation 
On infusion days, temperature, respiratory rate and oxygen saturation should be collected 
before the infusion. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
180 
6.4.9 
Other safety assessments 
Pregnancy tests on either blood (serum β-hCG) or urine (hCG) samples will be performed for 
pre-menopausal women of childbearing potential at the times specified in Table 3 
(MEDI4736), Table 4 (tremelimumab monotherapy), Table 5 (MEDI4736+tremelimumab), 
Table 8 (vinorelbine or gemcitabine), and Table 9 (erlotinib).  Tests will be performed by the 
hospital’s local laboratory.  If results are positive the patient is ineligible/must be discontinued 
from the study.  In the event of a suspected pregnancy during the study, the test should be 
repeated. 
Other safety tests to be performed at Screening include:  
• 
Coagulation tests: prothrombin time, APTT and INR.  Prothrombin time, APTT and 
INR only performed at Screening unless clinically indicated. 
• 
Hepatitis B and C testing as per local practice  
• 
HIV-1 antibody testing as per local practice 
• 
T3 free (if available), total T4 (or T4 free), and TSH. 
Timings for additional thyroid function tests in the MEDI4736 arm (TSH and T3 free [if 
available] and total T4 [or T4 free]) are shown in the study plans (MEDI4736 monotherapy, 
tremelimumab monotherapy or MEDI4736+tremelimumab: Table 3, Table 4 or Table 5 
[Screening and Treatment Period], Table 6 [for follow-up of patients achieving disease control 
or who are discontinued due to toxicity or a reason other than confirmed PD] and Table 7 [for 
follow-up of patients discontinuing due to confirmed PD]).   
6.5 
Patient reported outcomes  
Timings of the assessments for PRO are presented in the study plans (MEDI4736 
monotherapy, tremelimumab monotherapy or MEDI4736+tremelimumab: Table 3, Table 4 or 
Table 5 [Screening and Treatment Period], and Table 6 [for follow-up of patients achieving 
disease control or who are discontinued due to toxicity or a reason other than confirmed PD] 
and Table 7 [for follow-up of patients discontinuing due to confirmed PD]; Standard of Care: 
Table 8 [vinorelbine or gemcitabine], Table 9 [erlotinib] and Table 10 [follow-up for patients 
treated with Standard of Care]).  There will be no further collection of PRO data after the final 
DCO for the study.   
The EORTC QLQ-C30 and cancer-specific symptom modules are self-administered 
questionnaires and are to be completed by the patient without the assistance of the 
investigational site personnel.  All questionnaires should be completed before any other study 
procedures are conducted at the visit.  Patient reported outcome questionnaires need to be 
administered at the times specified in the study plans before other clinical procedures.  If 
patients have scans at an outside facility or missed a scheduled data collection, PRO 
questionnaires need to be administered at the next visit.  It takes about 20 to 40 minutes for 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
181 
patients to complete all 3 questionnaires and the patients are asked to only fill out 
questionnaires that have been validated to be relevant to their specific type of cancer; hence 
the burden to the patient is moderate.  When the patient completes the questionnaires, study 
coordinators need to review the questionnaires for missing responses and then ask the patient 
to date and sign at places specified in the questionnaires. 
6.5.1 
EORTC QLQ-C30 
The EORTC QLQ-C30 is a 30-item self-administered questionnaire (Appendix G).  There are 
9 multiple item scales: 5 scales that assess aspects of functioning (physical, role, cognitive, 
emotional, and social); 3 symptom scales (fatigue, pain, and nausea and vomiting); and a 
global health status/Quality of Life (QoL) scale.  There are 5 single-item measures assessing 
additional symptoms commonly reported by cancer patients (dyspnoea, loss of appetite, 
insomnia, constipation, and diarrhoea) and a single item concerning perceived financial 
impact of the disease.  All but 2 questions have 4-point scales: “Not at all,” “A little,” “Quite a 
bit,” and “Very much.”  The 2 questions concerning global health status and QoL have 7 point 
scales with ratings ranging from “Very poor” to “Excellent.”  For each of the 15 domains 
(9 multiple-item scales, 6 single item scales), final scores are transformed such that they range 
from 0 to 100 where as higher scores indicate greater functioning, greater QoL, or greater 
level of symptoms (Aaronson et al 1993). 
6.5.2 
Lung Cancer Module 
For NSCLC patients, a disease-specific 13-item self-administered questionnaire for lung 
cancer was developed (LC13; Appendix G) to be used in conjunction with the EORTC 
QLQ-C30 (Bergman et al 1994).  It comprises both multi-item and single-item measures of 
lung cancer-associated symptoms (ie, coughing, haemoptysis, dyspnoea, and pain) and side 
effects from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore 
mouth and dysphagia).  The EORTC QLQ-C30 questionnaire should be completed before the 
LC13 module. 
6.5.3 
EuroQoL 5-dimension,
  
The EuroQoL 5-dimension utility index (EQ-5D; Appendix G) is a standardised 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 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 2013). 
 
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
182 
 
 
  
 
 
 
 
  
 
6.5.4 
Administration of patient reported outcomes questionnaires 
Each centre must allocate the responsibility for the administration of the PRO instruments to a 
specific individual (eg, a research nurse, study coordinator) and if possible, assign a back-up 
person to cover if that individual is absent.  The AstraZeneca/MedImmune Study Delivery 
Team (or delegate) will provide relevant training in the administration of the PRO 
questionnaires.  The PRO questionnaires must be administered and completed at the clinic as 
per the study plan.  The EORTC-QLQC 30, LC13, and EQ-5D will be administered on the 
days specified in the study plans (MEDI4736 monotherapy, tremelimumab monotherapy or 
MEDI4736+tremelimumab: Table 3, Table 4 or Table 5 [Screening and Treatment Period], 
and Table 6 [for follow-up of patients achieving disease control or who are discontinued due 
to toxicity or a reason other than confirmed PD] and Table 7 [for follow-up of patients 
discontinuing due to confirmed PD]; Standard of Care: Table 8 [vinorelbine or gemcitabine], 
Table 9 [erlotinib] and Table 10 [follow-up for patients treated with Standard of Care]). 
It is important that the significance and relevance of the data are explained carefully to 
participating patients so that they are motivated to comply with data collection. 
The instructions for completion of the PRO questionnaires are as follows: 
• 
It must be completed prior to any other study procedures (following informed 
consent) and before discussion of disease progress to avoid biasing the patient’s 
responses to the questions 
• 
It must be completed in private by the patient 
• 
The patient should be given sufficient time to complete the PRO questionnaires at 
their own speed 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
183 
• 
The patient should not receive help from relatives, friends or clinic staff to answer 
the PRO questionnaires.  However, if the patient is unable to read the questionnaire 
(eg, is blind, illiterate, or forgot their reading glasses), the PRO questionnaires may 
be read out by trained clinic staff and responses recorded. 
• 
On completion of the PRO questionnaires, it should be handed back to the person 
responsible for PRO questionnaires, who should check for completeness 
• 
Only 1 answer should be recorded for each question 
• 
Data from the paper questionnaires will be transcribed at the investigator site onto 
the eCRF.   
6.5.5 
Patient interviews (optional) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
184 
 
 
 
 
 
 
6.6 
Pharmacokinetics and ADA (MEDI4736, tremelimumab and 
MEDI4736+tremelimumab arms only) 
6.6.1 
Collection of PK samples and determination of drug concentration 
Blood samples (3.5 mL) for determination of MEDI4736 and tremelimumab in serum will be 
taken at the times presented in the study plans (MEDI4736 monotherapy, tremelimumab 
monotherapy or MEDI4736+tremelimumab: Table 3, Table 4 or Table 5 [Screening and 
Treatment Period], and Table 6 [for follow-up of patients achieving disease control or who are 
discontinued due to toxicity or a reason other than confirmed PD] and Table 7 [for follow-up 
of patients discontinuing due to confirmed PD].  Patients receiving re-treatment after final 
DCO will not undergo drug concentration or anti-drug antibody assessments. 
Measurement of MEDI4736 and tremelimumab concentrations in serum will be performed 
using a validated immunoassay.  Samples for determination of MEDI4736 and tremelimumab 
concentrations in serum will be analysed by a designated third party on behalf of 
AstraZeneca/MedImmune, using an electrochemiluminescence and ELISA assay, 
respectively.  The lower limit of quantification in serum is 50 ng/mL (MEDI4736) and 
156 ng/mL (tremelimumab) and may be modified if needed and justified. 
Samples will be collected, labelled stored and shipped as detailed in Laboratory Manual.  For 
blood volume see Section 7.1. 
6.6.2 
Collection of samples to measure for the presence of ADA and ADA 
neutralising antibodies 
Presence of ADA will be assessed in samples (from patients in the MEDI4736 monotherapy, 
tremelimumab monotherapy and MEDI4736+tremelimumab arms only) taken according to the 
schedule presented in Table 3, Table 4 and Table 5 (Screening and the Treatment Period), 
Table 6 (for follow-up of patients achieving disease control or who are discontinued due to 
toxicity or a reason other than confirmed PD) and Table 7 (for follow-up of patients 
discontinuing due to confirmed PD). 
Samples will be measured for the presence of ADA and ADA neutralising antibodies using 
validated assays.  Tiered analysis will be performed to include screening, confirmatory and 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
185 
titre assay components and positive-negative cut points will be employed that were 
statistically determined from drug naive validation samples.   
6.7 
Biomarker analysis 
 
  
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
6.7.1 
Collection of PD-L1 expression data for sub-study assignment 
At Pre-screening, there is 1 mandatory provision of tissue to be used for determination of 
eligibility: 
Note: If the patient’s PD-L1 status has already been assessed using the analytically validated 
Ventana assay as a part of the screening process for another AstraZeneca/MedImmune study, 
this test result can be used for the determination of eligibility. 
• MANDATORY: Provision of a newly acquired tumour sample (preferred) OR archival 
tissue obtained within 3 years.  ONLY 1 sample (either newly acquired or archival tissue) 
will be used to assess PD-L1 status for purposes of eligibility.  Where multiple samples 
have been submitted for the same patient, results from the most recent evaluable sample 
will inform patient status for eligibility. 
• Samples should be collected via a core needle of 18 gauge or larger or be collected as an 
excisional tumour biopsy sample.  Where institutional practice, in this setting, uses a 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
186 
smaller gauge needle, samples should be submitted in sufficient number to ensure that a 
valid result can be achieved. 
• When tissue is newly obtained using an 18-gauge needle for the purpose of entry into this 
study, 2 cores 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.  
• The tumour specimen submitted to establish eligibility should be of sufficient quantity to 
allow for PD-L1 IHC analysis (see the Pathology Manual).  
• Samples with limited tumour content and fine needle aspirates are inadequate for defining 
tumour PD-L1 status. 
Tumour lesions used for newly acquired biopsies should not be the same lesions used as 
RECIST 1.1 target lesions, unless there are no other lesions suitable for biopsy. 
If a RECIST 1.1 target lesion is used for biopsy, the lesion must be ≥2 cm in the longest 
diameter and must be biopsied outside of the screening period. 
• OPTIONAL: The collection of additional archived tumour tissue block (formalin-fixed 
paraffin-embedded) is highly encouraged, where such samples exist in a quantity 
sufficient to allow for analysis.  This specimen may be supplied at any time during the 
study.  Tumour tissue block is preferred.  If a tissue block is unavailable, 10-15 unstained 
slides with tissue sections of 4 microns thick may be submitted.  Please consult the 
Laboratory Manual for specific instructions and guidelines regarding sections.  
• OPTIONAL: The collection of additional biopsies prior to re-treatment, if feasible, or 
clinically indicated is strongly encouraged.  
Additional tumour biopsies collected as part of clinical care (eg, for mixed responses or upon 
PD) can be submitted for further analysis. 
Please review the Laboratory Manual for additional details. 
The sponsor intends to assign patients to Sub-study A or B according to their PD-L1 
expression status.  Tumour biopsies will be stored at AstraZeneca/MedImmune Research and 
Development (R&D) or an appropriate vendor selected by AstraZeneca/MedImmune.  Core 
biopsies may be used for correlative studies such as immunohistochemistry, tumour mutation 
analysis, RNA analysis, proteomic analysis, and assessment of immunodiversity.  Samples 
will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
Testing will be completed on either a recent tissue biopsy or an archival sample (see Inclusion 
Criterion 6 in Section 4.1) prior to randomisation   using a validated Ventana assay (details 
will be provided in the Investigator’s Laboratory Manual).  The Ventana PD-L1 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
187 
immunohistochemistry assay will be used to determine PD-L1 immunohistochemistry status 
in this study.   
In patients where both archived (≤3 years) and newly acquired samples are available, both 
samples will be analysed to gain understanding about the relationship between these samples, 
co-evolution of a patient’s tumour and immune system, and to help determine which sample 
type may have the greatest utility for predicting response to therapy.  If both samples are 
submitted prior to sub-study assignment, the PD-L1 result from the most recently acquired 
sample will always take precedence in sub-study assignment unless such sample is 
unevaluable or unavailable.  In the event that a sample is unevaluable or unavailable, the other 
sample can be used for sub-study assignment.  Optional, additional archived samples >3 years 
will be used for exploratory analysis only and not for PD-L1 determination and sub-study 
assignment. 
In addition, if it is feasible, tumour biopsies are to be taken upon disease progression after 
randomisation to study treatment.  Based on the number and viability of the samples collected, 
we will assess whether there is any correlation between PD-L1 expression and response to 
treatment. 
6.7.2 
Collection of exploratory biomarker data  
6.7.2.1 
Blood borne biomarkers 
 
 
 
 
 
   
 
 
 
 
6.7.2.2 
Tumour samples 
 
 
 
 
 
 
 
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
188 
6.7.2.3 
Genomic analysis 
 
 
 
6.7.3 
Management of exploratory biomarker data  
 
 
 
  
 
   
6.8 
Pharmacogenetics 
 
 
6.9 
Health economics 
For the purposes of economic evaluation 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 including the type of contact (hospitalisations, outpatient, day 
case), reason, length of stay by ward type (including intensive care unit) and 
concomitant medications and procedures 
• 
Treatment related to AEs (including the method of delivery of the treatment) 
• 
Treatment not related to the study. 
The above resource use data will mainly come from the patient’s medical record and will be 
captured in the eCRF. 
The assessment of health economic resource use data will provide important information for 
payers and will be used within economic evaluations of MEDI4736. 
CCI
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
189 
7. 
BIOLOGICAL SAMPLING PROCEDURES  
7.1 
Volume of blood 
The total volume of blood that will be drawn from each patient in this study depends on the 
length of time that the patient receives study treatment.  Table 22 (MEDI4736), Table 23 
(tremelimumab), Table 24 (MEDI4736+tremelimumab) and Table 25 (Standard of Care) are a 
guide to the approximate volume of blood that will be drawn from each patient, based on the 
assumption that each patient remains in the study on treatment for 3 months and attends all the 
planned visits.  The sample volumes below are intended as a guide, the exact volume will be 
dependent on the collection tube sizes available from the supplier (eg, site, Contract Research 
Organisation).   
Blood samples taken during progression-free follow-up or during re-treatment following the 
final DCO are to be in accordance with the investigator’s judgment and local institutional 
practice. 
Laboratory assessments for patients in progression-free follow-up after final DCO should be 
monitored in such a way that continued per-protocol re-treatment eligibility can be properly 
determined.  For patients receiving re-treatment after final DCO, it is recommended that 
investigators monitor the patient’s safety laboratory assessments prior to and periodically 
during treatment in order to manage AEs in accordance with the toxicity management 
guidelines (Refer to Section 5.5.3). 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
190 
Table 22 
Volume of blood to be drawn from each patient in the MEDI4736 
monotherapy arm (Sub-study A and B) in the first 3 months on 
treatment 
Assessment 
Sample volume (mL) 
No. of 
samples 
Total 
volume (mL) 
Safety 
Clinical chemistry (serum 
chemistry) 
1.0 
8 
8.0 
Haematology 
2.0 
8 
16.0 
Hepatitis/HIV 
3.0 
1 
3.0 
Thyroid 
1.0 
5 
5.0 
Coagulation 
3.0 
1 
3.0 
Pharmacokinetic(s)  
3.5 
3 
10.5 
ADA testing including ADA neutralising 
antibodies (to identify ADA responses in patient 
circulation) 
8.5 (1 x 3.5 mL sample for 
NAb and 1 x 5.0 mL sample 
for ADA)  
2 
17.0 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Pharmacogenetic(s) 
8.5  
1 
8.5 
Total MEDI4736 monotherapy 
46.5 mL 
 
36 
100.5 mL 
ADA  Anti-drug antibody; HIV  Human immunodeficiency virus; miRNA  Micro RNA; mRNA  Messenger RNA; NAb  
Neutralising antibodies; PD-L1  Programmed death ligand 1.   
 
 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
191 
Table 23 
Volume of blood to be drawn from each patient in the tremelimumab 
monotherapy arm (Sub-study B) in the first 3 months on treatment 
Assessment 
Sample volume (mL) 
No. of 
samples 
Total 
volume (mL) 
Safety 
Clinical chemistry (serum 
chemistry) 
1.0 
5 
5.0 
Haematology 
2.0 
5 
10.0 
Hepatitis/HIV 
3.0 
1 
3.0 
Thyroid 
1.0 
5 
5.0 
Coagulation 
3.0 
1 
3.0 
Pharmacokinetic(s) for tremelimumab 
3.5 
3 
10.5 
ADA testing including ADA neutralising 
antibodies (to identify ADA responses in patient 
circulation) for 
tremelimumab 
8.5 (1 x 3.5 mL sample for 
NAb and 1 x 5.0 mL sample 
for ADA)  
2 
17.0 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Pharmacogenetic(s) 
8.5 
1 
8.5 
Total tremelimumab arm 
46.5 mL 
30 
91.5 mL 
ADA  Anti-drug antibody; HIV  Human immunodeficiency virus; miRNA  Micro RNA; mRNA  Messenger RNA; NAb  
Neutralising antibodies; PD-L1  Programmed death ligand 1.   
 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
192 
Table 24 
Volume of blood to be drawn from each patient in the 
MEDI4736+tremelimumab arm (Sub-study B) in the first 3 months 
on treatment 
Assessment 
Sample volume (mL) 
No. of 
samples 
Total 
volume (mL) 
Safety 
Clinical chemistry (serum 
chemistry) 
1.0 
5 
5.0 
Haematology 
2.0 
5 
10.0 
Hepatitis/HIV 
3.0 
1 
3.0 
Thyroid 
1.0 
5 
5.0 
Coagulation 
3.0 
1 
3.0 
Pharmacokinetic(s) for MEDI4736 
3.5 
3  
10.5 
Pharmacokinetic(s) for tremelimumab 
3.5 
3 
10.5 
ADA testing including ADA neutralising 
antibodies (to identify ADA responses in patient 
circulation) for MEDI4736 
8.5 (1 x 3.5 mL sample for 
NAb and 1 x 5.0 mL sample 
for ADA)  
2 
17.0 
ADA testing including ADA neutralising 
antibodies (to identify ADA responses in patient 
circulation) for 
tremelimumab 
8.5 (1 x 3.5 mL sample for 
NAb and 1 x 5.0 mL sample 
for ADA)  
2 
17.0 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Pharmacogenetic(s) 
8.5 
1 
8.5 
Total MEDI4736+tremelimumab arm 
58.5 mL 
35 
119 mL 
ADA  Anti-drug antibody; HIV  Human immunodeficiency virus; miRNA  Micro RNA; mRNA  Messenger RNA; NAb  
Neutralising antibodies; PD-L1  Programmed death ligand 1. 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
193 
Table 25 
Volume of blood to be drawn from each patient in the Standard of 
Care arms in the first 3 months on treatment 
Assessment 
Sample 
volume (mL) 
No. of 
samples 
Total 
volume (mL) 
Safety 
Clinical chemistry (serum chemistry 
[gemcitabine and vinorelbine]) 
1.0 
8 
8.0 
Clinical chemistry (serum chemistry 
[erlotinib]) 
1.0 
5 
5.0 
Haematology (gemcitabine only) 
2.0 
11 
22.0 
Haematology (vinorelbine only) 
2.0 
14 
28.0 
Haematology (erlotinib only) 
2.0 
5 
10.0 
Hepatitis/HIV 
3.0 
1 
3.0 
Coagulation 
3.0 
1 
15.0 
 
Thyroid 
1.0 
1 
1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Pharmacogenetic(s) 
8.5 
1 
8.5 
Total for patients treated with erlotinib 
34.5 mL 
21 
72.0 mL 
Total for patients treated with gemcitabine 
34.5 mL 
30 
87.0 mL 
Total for patients treated with vinorelbine 
34.5 mL 
33 
93.0 mL 
HIV  Human immunodeficiency virus; miRNA  Micro RNA; mRNA  Messenger RNA; PD-L1  Programmed 
death ligand 1.   
 
7.2 
Handling, storage and destruction of biological samples 
 
 
 
 
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
194 
 
AstraZeneca/MedImmune ensures that any biological samples remaining after analysis have 
been performed may be repatriated upon request or kept until the end of the period specified 
in the informed consent.   
7.2.1 
Pharmacokinetic, immunogenicity and/or pharmacodynamic (soluble PD-L1) 
samples 
Samples will be archived for a minimum of 5 years after the Biologic License Application.  
For sample processing, handling and shipment refer to the Investigators Laboratory Manual. 
7.2.2 
Pharmacogenetic samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. 
 
  
 Samples will be stored and 
used until no further analyses are possible or the maximum storage time has been reached. 
 
7.3 
Labelling and shipment of biohazard samples 
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix C ‘IATA 6.2 Guidance Document’. 
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca/MedImmune and 
appropriate labelling, shipment and containment provisions are approved. 
7.4 
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Principal Investigator, at each centre, keeps full traceability of collected biological 
samples from the patients while in storage at the centre until shipment or disposal (where 
appropriate) and keeps documentation of receipt of arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
QuintilesIMS keeps oversight of the entire life cycle through internal procedures, monitoring 
of study sites and auditing of external laboratory providers. 
CCI
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
195 
Samples retained for further use are registered in the AstraZeneca biobank system during the 
entire life cycle. 
7.5 
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/destroyed, and the action documented.  If samples are already analysed, 
AstraZeneca/MedImmune is not obliged to destroy the results of this research. 
As collection of the biological samples is an optional part of the study, then the patient may 
continue in the study. 
The Principal Investigator: 
• 
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca/MedImmune or its representative 
• 
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 
• 
Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed/destroyed, the action 
documented and the signed document returned to the study site 
• 
Ensures that the patient and AstraZeneca/MedImmune or its representative are 
informed about the sample disposal. 
AstraZeneca/MedImmune or its representative 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. 
In the event that analysis/research has already been performed, AstraZeneca/MedImmune will 
retain the results and associated data for regulatory reasons but these will not be used in any 
subsequent analyses.   
AstraZeneca/MedImmune ensures that biological samples are returned to the source or 
destroyed at the end of a specified period as described in the informed consent. 
8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation 
(ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca 
policy on Bioethics and Human Biological Samples. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
196 
8.2 
Patient data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
AstraZeneca/MedImmune 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/MedImmune Physician (or representative or delegate) 
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. 
   
8.3 
Ethics and regulatory review 
An Ethics Committee (Independent Ethics Committee or Institutional Review Board [IRB], as 
applicable) should approve the final study protocol, including the final version of the 
Informed Consent Form 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 
Ethics Committee, and to the study site staff. 
The opinion of the Ethics Committee should be given in writing.  The investigator should 
submit the written approval to AstraZeneca before enrolment of any patient into the study.   
The Ethics Committee should approve all advertising used to recruit patients for the study. 
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements. 
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.   
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations. 
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities. 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
197 
For all countries except the US and Canada, AstraZeneca will provide Regulatory Authorities, 
Ethics Committees and Principal Investigators with safety updates/reports according to local 
requirements, including Suspected Unexpected Serious Adverse Reactions (SUSARs), where 
relevant. 
For the US and Canada, each Principal Investigator is responsible for providing the Ethics 
Committees/IRB with reports of any SUSARs from any other study conducted with the 
investigational product.  AstraZeneca will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements. 
8.4 
Informed consent 
The Principal Investigator(s) at each centre 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 they are free to discontinue from the study at any 
time 
• 
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided 
• 
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study 
• 
Ensure the original, signed Informed Consent Forms is/are stored in the 
Investigator’s Study File 
• 
Ensure a copy of signed Informed Consent Forms are 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 informed consent form that is approved by an Ethics Committee. 
The PGx component of the study (relating to DNA) is optional and will be detailed on a 
separate informed consent form.   
Patients will sign a Pre-screening Informed Consent Form before any study procedure is 
conducted; this form will detail the pre-screening/screening assessments.  Once the patient is 
assigned to either Sub-study A or B (depending on their PD-L1 status), they will be asked to 
sign the relevant Sub-study Informed Consent Form.  
In the MEDI4736 and tremelimumab monotherapy arms, study drug should be discontinued if 
there is confirmed PD while on treatment following a previous response (PR or CR) to study 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
198 
drug while on treatment (ie, the response and progression events both occurred while 
receiving study drug during the same treatment period). 
For patients who receive study treatment through disease progression and patients who 
achieve disease control (ie, CR, PR or SD) and restart treatment, the investigator should 
ensure patients do not have any significant, unacceptable or irreversible toxicities that indicate 
continuing treatment will not further benefit the patient.  The patient must meet the inclusion 
and exclusion criteria specified in Section 4.3.  The informed consent documents will specify 
that treatment beyond initial evidence of PD or re-treatment for progression during follow-up 
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.  Patients with rapid 
tumour progression or with symptomatic progression that requires urgent medical intervention 
(eg, central nervous system metastasis, respiratory failure due to tumour compression, spinal 
cord compression) will not be eligible to continue with treatment.   
Patients who are eligible for re-treatment following final DCO must sign the re-treatment 
informed consent prior to receiving study drug.  Copies of the informed consent must be 
maintained with the patient’s medical records. 
8.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the International 
Co-ordinating Investigator and AstraZeneca. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol). 
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols. 
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to Ethics Committee see Section 8.3. 
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
199 
8.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all 
study-related activities and documents, to determine whether these activities were conducted, 
and data were recorded, analysed, and accurately reported according to the protocol, GCP, 
guidelines of the ICH, and any applicable regulatory requirements.  The investigator will 
contact AstraZeneca immediately if contacted by a regulatory agency about an inspection at 
the centre. 
9. 
STUDY MANAGEMENT BY ASTRAZENECA 
QuintilesIMS is responsible for the management of this study and thus throughout this section 
QuintilesIMS is considered the representative of AstraZeneca.   
9.1 
Pre-study activities 
Before the first patient is entered into the study, it is necessary for a representative of 
AstraZeneca to visit the investigational study site to: 
• 
Determine the adequacy of the facilities 
• 
Determine availability of appropriate patients for the study 
• 
Discuss with the investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence, and the responsibilities of 
AstraZeneca or its representatives.  This will be documented in a Clinical Study 
Agreement between AstraZeneca and the investigator.  
9.2 
Training of study site personnel 
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures (including those 
listed in the Laboratory Manual) and the IVRS and WBDC system(s) utilised.   
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
200 
9.3 
Monitoring of the study 
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to: 
• 
Provide information and support to the investigator(s) 
• 
Confirm that facilities remain acceptable 
• 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed 
• 
Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients.  This 
will require direct access to all original records for each patient (eg, clinic charts). 
• 
Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the patient. 
The AstraZeneca representative will be available between visits if the investigator(s) or other 
staff at the centre needs information and advice about the study conduct. 
Source data 
Refer to the Clinical Study Agreement for location of source data.   
9.4 
Study agreements 
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled. 
Archiving of study documents 
The investigator follows the principles outlined in the Clinical Study Agreement. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
201 
9.5 
Study timetable and end of study 
The study will continue until the last patient completes 90 days of follow-up after re-treatment 
or the last patient discontinues for any reason from the progression-free follow-up (so no 
further patients are eligible for re-treatment). 
In the event that a roll-over or safety extension study will become available, patients currently 
receiving treatment with study drug or patients in progression-free follow-up may be 
transitioned to such a study, and the current study would end.  The roll-over or safety 
extension study would ensure treatment continuation with visits and assessments per its 
protocol.  Any patient that would be proposed to move to such study would be asked to sign a 
new informed consent. 
The study is expected to start in Q1 2015 and to end by Q4 2018. 
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, if recruitment is slow, or when there are no longer any patients 
being treated or followed in progression-free follow-up once the DCO for final OS analysis 
has occurred.  AstraZeneca may also terminate the entire study prematurely if concerns for 
safety arise within this study or in any other study with MEDI4736. 
9.5.1 
Treatment after final Overall Survival data cut-off 
The 2 sub-studies A and B are considered independent and may or may not be reported 
at the same time.  At the time of final analysis, the clinical study database will be closed 
to new data.   
Patients in OS follow-up (progressed and have completed treatment) will be considered to 
have completed the study.  Patients in progression-free follow-up (patients who have 
completed study drug treatment and have not progressed and who are still potentially eligible 
for re-treatment) may decide to continue in the study in progression-free follow-up.  These 
patients would therefore remain eligible for possible future re-treatment upon progression if 
they meet re-treatment criteria and the investigator judges that the patient will gain clinical 
benefit.  
Patients who are receiving treatment at the time of final DCO may continue receiving 
investigational product if the investigator judges that they are gaining clinical benefit.   
All patients will receive scans and follow-up care in accordance with standard local clinical 
practice.  Patients in progression-free follow-up after the final DCO are to undergo sampling 
for local laboratory assessments in such a way that continued per-protocol re-treatment 
eligibility can be properly determined in the event of progression.  For patients receiving 
re-treatment after final DCO, it is recommended that the patients continue the scheduled site 
visits and investigators monitor the patient’s safety laboratory results prior to and periodically 
during treatment in order to manage AEs in accordance with the toxicity management 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
202 
guidelines (Refer to Section 5.5.3).  All data will be recorded on patient charts but will not 
otherwise be reported for the purposes of this study. 
For patients who do continue to receive treatment beyond the time of the final DCO, 
investigators will report SAEs to AstraZeneca/Medimmune Patient Safety via paper CRFs 
until 90 days after the last dose of study treatment (30 days for the Standard of Care arms), in 
accordance with Section 6.4.4 (Reporting of serious adverse events).  Any non-serious AE 
that is ongoing at the time of this DCO is to be followed up at the discretion of the investigator 
and per local practice and in alignment with the toxicity management guidelines in 
Section 5.5.3 of this protocol.  Data will not be captured for the purposes of this study outside 
of being recorded in the patients’ source documents.   
Following the final DCO, SAE reporting applies only to patients who are active on the drug 
and within 90 days post the last dose; in all other cases only a statement of death notification 
is to be sent to QuintilesIMS.  No OS data will be recorded in the study database after final 
DCO for the study, but such information may continue to be collected for operational 
purposes for patients who remain eligible for re-treatment with study drug. 
10. 
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE 
Data management will be performed by QuintilesIMS. 
The data collected through third party sources will be obtained and reconciled against study 
data. 
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 
will be classified according to the AstraZeneca Drug Dictionary.  All coding will be 
performed by QuintilesIMS. 
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail. 
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked. 
Data associated with biological samples will be transferred to laboratories internal or external 
to AstraZeneca/MedImmune. 
Any genotype data generated in this study will be stored in the AstraZeneca genotyping 
Laboratory Information Management System (LIMS) database, or other appropriate secure 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
203 
system within AstraZeneca and/or third party contracted to work with 
AstraZeneca/MedImmune to analyse samples.  The results from this genetic research may be 
reported in the CSR for the main study, or in a separate report as appropriate. 
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.   
11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA, OR DELEGATE 
A comprehensive Statistical Analysis Plan (SAP) will be prepared before the first patient is 
entered. 
11.1 
Calculation or derivation of efficacy variable(s) 
11.1.1 
RECIST 1.1-based endpoints 
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 anti-cancer 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 randomisation.  If a patient 
has had a tumour assessment that cannot be evaluated then the patient will be assigned a visit 
response of NE (unless there is evidence of progression in which case the response will be 
assigned as PD). 
Please refer to Appendix F for the definitions of CR, PR, SD and PD. 
11.1.2 
Co-primary endpoints 
Within Sub-study A and Sub-study B, the co-primary endpoints are OS and PFS. 
11.1.2.1 Overall survival  
Overall survival is defined as the time from the date of randomisation 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 DCO for the analysis, and 
if patients are confirmed to be alive or if the death date is post the DCO date these patients 
will be censored at the date of DCO.  The status of ongoing, withdrawn (from the study) and 
“lost to follow-up” patients at the time of the final OS analysis should be obtained by the site 
personnel by checking the patient’s notes, hospital records, contacting the patient’s general 
practitioner and checking publicly-available death registries.  In the event that the patient has 
actively withdrawn consent to the processing of their personal data, the vital status of the 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
204 
patient can be obtained by site personnel from publicly-available resources where it is possible 
to do so under applicable local laws. 
11.1.2.2 Progression free survival 
Progression free survival (per RECIST 1.1 as assessed by the investigator) will be defined as 
the time from the date of randomisation until the date of objective disease progression or death 
(by any cause in the absence of progression) regardless of whether the patient withdraws from 
randomised therapy or receives another anti-cancer therapy prior to progression.  Patients who 
have not progressed or died at the time of analysis will be censored at the time of the latest 
date of assessment from their last evaluable RECIST 1.1 assessment.  However, if the patient 
progresses or dies after 2 or more missed visits, the patient will be censored at the time of the 
latest evaluable RECIST 1.1 assessment.  If the patient has no evaluable visits or does not 
have baseline data they will be censored at Day 1 unless they die within 2 visits of baseline.   
The PFS time will always be derived based on scan/assessment dates not visit dates. 
RECIST 1.1 assessments/scans contributing towards a particular visit may be performed on 
different dates.  The following rules will be applied: 
• 
The date of progression will be determined based on the earliest of the RECIST 
assessment/scan dates of the component that indicates progression 
• 
When censoring a patient for PFS the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment.  
Note: For target lesions, only the latest scan date is recorded out of all scans performed at that 
assessment for the target lesions and similarly for non-target lesions only the latest scan date is 
recorded out of all scans performed at that assessment for the non-target lesions. 
In the absence of clinically significant deterioration the investigational site is advised to 
continue the patient on study treatment until progression has been confirmed. 
11.1.3 
Proportion of patients alive at 12 months (OS12) 
The proportion of patients alive at 12 months will be defined as the Kaplan-Meier estimate of 
OS at 12 months. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
205 
11.1.4 
Objective response rate 
Objective response rate (per RECIST 1.1 as assessed by the investigator) is defined as the 
number (%) of patients with at least 1 visit response of CR or PR and will be based on a 
subset of all randomised patients with measurable disease at baseline per the site investigator 
(ie, the ITT population).  Data obtained up until progression, or the last evaluable assessment 
in the absence of progression, will be included in the assessment of ORR.  Patients who go off 
treatment without progression, receive a subsequent therapy and then respond will not be 
included as responders in the ORR.   
11.1.5 
Duration of response 
Duration of response (per RECIST 1.1 as assessed by the investigator) 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.   
The time of the initial response will be defined as the latest of the dates contributing towards 
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. 
Duration of response will not be defined for those patients who do not have documented 
response. 
11.1.6 
Proportion of patients alive and progression free at 6 months 
The proportion of patients alive and progression free at 6 months (ie, APF6) will be defined as 
the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by the investigator) at 6 
months. 
11.1.7 
Proportion of patients alive and progression free at 12 months 
The proportion of patients alive and progression free at 12 months (ie, APF12) will be defined 
as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by the investigator) at 
12 months. 
11.1.8 
Time from randomisation to second progression (PFS2) 
PFS2 will be defined as the time from the date of randomisation to the earliest of the 
progression event subsequent to that used for the PFS endpoint or death.  The date of the first 
progression will be programmatically determined from investigator assessed data (see 
Section 11.1.2.2 for details.)  The date of second progression will be recorded by the 
investigator and defined according to local standard clinical practice and may involve any of: 
objective radiological, symptomatic progression or death.  Second progression status will be 
reviewed every 12 weeks following the progression event used for the co-primary variable 
PFS (the first progression) and status recorded.  Patients alive and for whom a second disease 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
206 
progression has not been observed should be censored at the last time known to be alive and 
without a second disease progression, ie, censored at the latest of the PFS or PFS2 assessment 
date if the patient has not had a second progression or death. 
11.2 
Calculation or derivation of safety variable(s) 
11.2.1 
Adverse events 
Data from all cycles of randomised 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 and treatment arm.   
Any AE occurring before treatment with MEDI4736, tremelimumab, 
MEDI4736+tremelimumab or Standard of Care will be included in the data listings but will 
not be included in the summary tables of AEs. 
Adverse events observed up until 90 days following discontinuation of the immunotherapy 
agents (ie, the last dose of MEDI4736, tremelimumab or MEDI4736+tremelimumab)/30 days 
following discontinuation of the Standard of Care agent or until the initiation of the first 
subsequent therapy following discontinuation of treatment (whichever occurs first) will be 
used for the reporting of the AE summary tables.  This will more accurately depict AEs 
attributable to study treatment only as a number of AEs up to 90 days following 
discontinuation of the immunotherapy agents/30 days following discontinuation of the 
Standard of Care agent are likely to be attributable to subsequent therapy.  However, to assess 
the longer term toxicity profile, AE summaries will also be produced containing AEs observed 
up until 90 days following discontinuation of the immunotherapy agents/30 days following 
discontinuation of the Standard of Care agent (ie, without taking subsequent therapy into 
account).  Any events in this period that occur after a patient has received further therapy for 
cancer (following discontinuation of study treatment) will be flagged in the data listings. 
A separate data listing of AEs occurring more than 90 days after discontinuation of the 
immunotherapy agents (MEDI4736, tremelimumab or MEDI4736+tremelimumab) or more 
than 30 days after discontinuation of the Standard of Care agent will be produced.  These 
events will not be included in AE summaries.  
11.2.2 
Other significant adverse events (OAEs) 
During the evaluation of the AE data, an AstraZeneca/MedImmune 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 judgement, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered 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 haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious) or significant 
additional treatment. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
207 
11.2.3 
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.   
Corrected calcium will be derived during creation of the reporting database using the 
following formulas: 
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – albumin (G/L)] × 0.02) 
The denominator used in laboratory summaries will only include evaluable patients, in other 
words those who had sufficient data to have the possibility of an abnormality.   
For example: 
• 
If a CTCAE criterion involves a change from baseline, evaluable patients would 
have both a pre-dose and at least 1 post-dose value recorded 
• 
If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient need only have 1 post dose-value recorded. 
The denominator in vital signs data should include only those patients with recorded data. 
11.3 
Calculation or derivation of patient reported outcome variables 
PRO questionnaires will be assessed using the EORTC QLQ-C30 with the LC13 module 
(HRQoL with lung cancer specific additional concerns) and EQ-5D-5L.  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 ITT study population, unless stated. 
11.3.1.1 EORTC QLQ-C30 
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional 
scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, pain, 
nausea/vomiting), 5 individual items (dyspnoea, insomnia, appetite loss, constipation, 
diarrhoea) and a global measure of health status.  The EORTC QLQ-C30 will be scored 
according to the EORTC QLQ-C30 scoring manual (Fayers et al 1999).  An outcome variable 
consisting of a score from 0 to 100 will be derived for each of the symptom scales/symptom 
items, 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. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
208 
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 (OPDIVO® prescribing information).  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 categorised as 
improvement, no change or deterioration as shown in Table 26. 
Table 26 
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 
EORTC QLQ-C30  European Organisation for Research and Treatment of Cancer 30-item core quality of life 
questionnaire. 
 
For each subscale, if <50% of the subscale items are missing, then the subscale score will be 
divided by the number of non-missing items and multiplied by the total number of items on 
the subscales (Fayers et al 1999).  If at least 50% of the items are missing, then that subscale 
will 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 
minimised. 
Time to symptom deterioration 
For each of the symptoms scales/items in the EORTC QLQ-C30, time to symptom 
deterioration will be defined as the time from randomisation until the date of the 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
209 
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 
anti-cancer 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 they will be censored at Day 1.  The population for the analysis of time 
to symptom deterioration will include a subset of the ITT population who have baseline scores 
of ≤90. 
Time to QoL/Function deterioration 
For QoL, time to deterioration will be defined as the time from the date of randomisation until 
the date of the first clinically meaningful deterioration (a decrease in the function scales or the 
global health status/QoL 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 anti-cancer therapy prior to QoL/function deterioration.  Death 
will be included as an event only if the death occurs within 2 visits of the last PRO assessment 
where the QoL/function change could be evaluated.   
Patients whose QoL (as measured by EORTC QLQ-C30) has 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 QoL/function could be evaluated.  Also, if QoL 
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 QoL/function could be evaluated.  If a patient has no evaluable visits or 
does not have baseline data they will be censored at Day 1.  The population for the analysis of 
time to QoL/function deterioration will include a subset of the ITT population who have 
baseline scores of ≥10. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
210 
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/items) in that symptom from baseline.  The denominator will consist of a subset of the 
ITT population who have a baseline symptom score ≥10. 
QoL/function improvement rate 
The QoL/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/QoL) in that scale from baseline.  The denominator will consist of a 
subset of the ITT population who have a baseline QoL/function score ≤90. 
11.3.1.2 Lung cancer module 13  
The LC13 is a lung cancer specific module from the EORTC comprising 13 questions to 
assess lung cancer symptoms (cough, haemoptysis, dyspnoea and site-specific pain), 
treatment-related side-effects (sore mouth, dysphagia, peripheral neuropathy and alopecia) and 
pain medication.   
The LC13 incorporates symptom scales including: 
• 
Dyspnoea (multi-item scale based on 3 questions: were you short of breath when 
you rested; walked; climbed stairs) 
• 
Cough: 1 item (how much did you cough?) 
• 
Haemoptysis: 1 item (did you cough up blood?) 
• 
Pain: 3 individual items (Have you had pain in your chest; your arm or shoulder; 
other parts of your body?) 
The dyspnoea scale is only used if all 3 items have been scored; otherwise the items are 
treated as single-item measures.  The scoring approach for the LC13 is identical in principle to 
that for the symptom scales/single items of the EORTC QLQ-C30.   
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 LC13 (Osoba et al 1998).  For example, a clinically meaningful 
deterioration or worsening in chest pain (as assessed by LC13) is defined as an increase in the 
score from baseline of ≥10, whereas a clinically meaningful improvement is defined as a 
decrease in the score from baseline of ≥10.  At each post-baseline assessment, the change in 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
211 
symptoms from baseline will be categorised as an improvement, no change or deterioration as 
shown in Table 27. 
Table 27 
Visit Response for HRQoL and disease-related symptoms 
Score 
Change from baseline 
Visit response 
LC13 symptom scales/items 
≥+10 
Deterioration 
≤-10 
Improvement 
Otherwise 
No change 
HRQoL  Health Related Quality of Life; LC13  Lung Cancer Module. 
 
Time to symptom deterioration 
For each of the symptoms scales/items in LC13, time to symptom deterioration will be defined 
as the time from the date of randomisation 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 anti-cancer 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 LC13) 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 they will be censored at Day 1.  The population for the analysis of time to symptom 
deterioration will include a subset of the ITT population who have baseline scores of ≤90. 
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 LC13 symptom scales/items) in that 
symptom from baseline.  The denominator will consist of a subset of the ITT population who 
have a baseline symptom score ≥10. 
11.3.1.3 Calculation or derivation of health state utility (EQ-5D-5L) 
 
 
 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
212 
 
  
 
 
   
11.4 
Calculation or derivation of pharmacokinetic variables 
11.4.1 
PK non-compartmental analysis 
The PK sample analyses will be performed at AstraZeneca/MedImmune R&D.  The actual 
sampling times will be used in the PK calculations.  Pharmacokinetic concentration data and 
summary statistics will be tabulated.  Individual and mean blood concentration-time profiles 
will be generated and included in the report.  Pharmacokinetic parameters will be determined 
using standard non-compartmental methods.  The following PK parameters will be determined 
after the first or steady-state dose: peak and trough concentrations (as data allow).  Samples 
below the lower limit of quantification will be treated as missing in the analyses. 
11.4.2 
Population PK and exposure-response/safety analysis 
A population PK model will be developed using a non-linear mixed-effects modelling 
approach in patients with NSCLC.  The impact of physiologically-relevant patient 
characteristics (covariates) and disease on PK will be evaluated.  The relationship between 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. 
11.4.3 
Immunogenicity analysis 
Immunogenicity results will be reported descriptively by summarizing the number and 
percentage of patients who develop detectable anti-MEDI4736 and/or anti-tremelimumab 
antibodies.  The immunogenicity titre and presence of neutralizing ADA will be reported 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. 
11.5 
Calculation or derivation of biomarker variable(s) 
  
11.6 
Calculation or derivation of pharmacogenetic variables 
In the case of genetic data, only the date 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 LIMS database or other appropriate system.  This database is a secure database, 
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
213 
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). 
11.7 
Calculation or derivation of health economic variables 
Frequency and estimates of resource use, including length of stay and number of hospital 
admissions, will be derived from the health resource use information. 
12. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION BY ASTRAZENECA 
The 2 sub-studies A and B are considered independent and may or may not be reported at the 
same time.  At the time of final analysis, the clinical study database will be closed to new data.   
12.1 
Description of analysis sets 
A comprehensive SAP will be prepared and finalised before first patient in.  The Full Analysis 
Set (FAS) and the Safety Analysis Set described below will be applied to all randomised 
patients in each of Sub-study A and Sub-study B. 
Table 28 gives a summary of outcome variables and analysis populations. 
Table 28 
Summary of outcome variables and analysis populations 
Outcome variable 
Populations 
Efficacy data 
OS, PFS 
ITT (FAS) 
OS12, ORR, DoR, APF6, APF12, PFS2, PRO endpoints 
ITT (FAS) 
Demography 
ITT (FAS) 
PK data 
PK 
Safety data 
Exposure 
Safety 
Adverse events 
Safety 
Laboratory measurements 
Safety 
Vital Signs 
Safety 
APF6  Proportion of patients alive and progression free at 6 months from randomisation; APF12  Proportion of 
patients alive and progression free at 12 months from randomisation; DoR  Duration of response; ITT  
Intent-to-Treat; ORR  Objective response rate; OS Overall survival; OS12  Proportion of patients alive at 
12 months from randomisation; PFS  Progression free survival; PFS2  Time from randomisation to second 
progression;  PK  Pharmacokinetic; PRO  Patient reported outcomes. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
214 
12.1.1 
Full analysis set 
The FAS will include all randomised patients with treatment groups assigned in accordance 
with the randomisation, regardless of the treatment actually received.  Patients who were 
randomised but did not subsequently receive treatment are included in the FAS.  The analysis 
of data using the FAS therefore follows the principles of ITT.  Therefore, all efficacy and 
HRQoL data will be summarised and analysed using the FAS on an ITT basis. 
12.1.2 
Safety analysis set 
All patients who received at least 1 dose of randomised treatment in each of the sub-studies 
will be included in the safety population.  Throughout the safety results sections, erroneously 
treated patients (eg, those randomised to Treatment A but actually given Treatment B) will be 
accounted for in the actual treatment arm.   
When assessing safety and tolerability, summaries will be produced based on the safety 
analysis set. 
12.1.3 
PK analysis set 
All patients who receive at least 1 dose of MEDI4736 (Sub-study A), or either 
MEDI4736+tremelimumab, MEDI4736 monotherapy or tremelimumab monotherapy 
(Sub-study B) per the protocol, for whom any post-dose data are available will be included in 
the PK analysis set.  The population will be defined by the Study Team Physician, 
Pharmacokineticist and Statistician prior to any analyses being performed. 
12.2 
Methods of statistical analyses 
Sub-study A has 1 treatment comparison of interest as follows: 
• 
MEDI4736 10 mg/kg Q2W compared with Standard of Care 
Sub-study B has 1 treatment comparison of interest that is considered primary as follows: 
• 
MEDI4736 20 mg/kg plus tremelimumab 1 mg/kg Q4W for 12 weeks then 
MEDI4736 10 mg/kg Q2W for 34 weeks compared with Standard of Care 
The co-primary endpoints in each of the sub-studies are OS and PFS using RECIST v1.1.  The 
study was sized to assess PFS and OS endpoints in each of the sub-studies A and B for the 
treatment comparisons mentioned above.  No hypothesis testing will be performed on OS and 
PFS in the PD-L1-positive population in Sub-study A. 
The final analyses of OS will take place on Sub-study B on a pre-specified date when 
approximately 205 deaths have occurred from 300 patients (68% maturity) who have been 
randomised to the MEDI4736+tremelimumab and Standard of Care arms in Sub-study B.  An 
interim analysis of OS for the primary treatment comparison (Section 12.2.14) will be 
performed for Sub-study B at the same time as the primary PFS analysis.  However, for 
practical considerations, if it happens that the analysis time points for the final PFS and OS 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
215 
analyses are closely aligned based on the occurrences of the events, then 1 single analysis of 
OS will be conducted along with the PFS analysis.  In this case, the entire 0.04 alpha will be 
utilized for this OS analysis. 
The final analyses of PFS and OS interim analysis will take place for Sub-study B on a 
pre-specified date when it is predicted that approximately 244 PFS events from 300 patients 
(81% maturity) who have been randomised to the MEDI4736+tremelimumab and Standard of 
Care arms.  
Sub-study B has the following treatment comparisons of interest that are considered 
secondary: 
1. 
MEDI4736 20 mg/kg plus tremelimumab 1 mg/kg Q4W for 12 weeks then 
MEDI4736 10 mg/kg Q2W for 34 weeks compared with MEDI4736 10 mg/kg 
Q2W 
2. 
MEDI4736 20 mg/kg plus tremelimumab 1 mg/kg Q4W for 12 weeks then 
MEDI4736 10 mg/kg Q2W for 34 weeks compared with tremelimumab 10 mg/kg 
Q4W for 24 weeks then Q12W 
3. 
MEDI4736 10 mg/kg Q2W compared with Standard of Care 
4. 
Tremelimumab 10 mg/kg Q4W for 24 weeks then Q12W compared with Standard 
of Care 
A contribution of components analysis will be performed for superiority analysing PFS for 
both of the secondary treatment comparisons ‘1’ and ‘2’ above.  This analysis is planned to be 
performed when approximately 158 PFS events are observed in the 
MEDI4736+tremelimumab and tremelimumab monotherapy arms.  However, for practical 
considerations, if this time is close to the time of the final PFS analysis, the contribution of 
components analysis will be conducted at the time of the final PFS analysis.  As these 
treatment comparisons are secondary and serve a different purpose to that of the primary 
comparisons, they are not included in the multiple testing procedure for the primary 
comparisons, and an alpha of 0.05 will be used for either PFS or OS without multiplicity 
adjustment. 
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment arm.  Continuous variables will be summarised by the number of observations, 
mean, standard deviation, median, minimum, and maximum.  Categorical variables will be 
summarised by frequency counts and percentages for each category.  Unless otherwise stated, 
percentages will be calculated out of the population total for the corresponding treatment arm.  
Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of study treatment, except for efficacy variables.  For efficacy variables, baseline 
is defined as the last visit prior to randomisation. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
216 
Efficacy data will be summarised and analysed on the Full (ITT) analysis set.   
PK data will be summarised and analysed on the PK analysis set. 
Safety data will be summarised on the safety analysis set. 
Results of all statistical analysis will be presented using a 95% CI and 2-sided p-value, unless 
otherwise stated. 
Table 29 details which endpoints are to be subject to formal statistical analysis, together with 
pre-planned sensitivity analyses making clear which analysis is regarded as primary for that 
endpoint. 
Table 29 
Formal statistical analyses to be conducted and pre-planned 
sensitivity analyses 
Endpoints Analysed 
Notes 
Overall Survival 
Sub-study A 
PD-L1-positive population – hazard ratio comparing MEDI4736 versus 
Standard of Care 
 
Sub-study B 
PD-L1-negative population – stratified log rank test comparing 
MEDI4736+tremelimumab versus Standard of Care 
 
Sub-study B only 
Sensitivity analysis using a Kaplan-Meier plot of time to censoring 
where the censoring indicator of the primary analysis is reversed – 
attrition bias 
 
Sub-study B  
The following secondary treatment comparisons will be performed 
dependent upon the results of the contribution of components analysis: 
i) 
MEDI4736+tremelimumab versus MEDI4736  
ii) MEDI4736+tremelimumab versus tremelimumab  
iii) MEDI4736 versus Standard of Care 
iv) Tremelimumab versus Standard of Care 
 
Supportive analysis on Sub-study B only 
Subgroup analysis using Cox proportional hazards models 
Secondary analysis using Cox proportional hazards models to determine 
the effect of covariates on the HR estimate 
Secondary analysis using Cox proportional hazards models to determine 
the consistency of treatment effect between subgroups via the approach 
of Gail and Simon 1985. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
217 
Table 29 
Formal statistical analyses to be conducted and pre-planned 
sensitivity analyses 
Endpoints Analysed 
Notes 
Progression Free Survival 
Co-primary analysis 
Sub-study A 
PD-L1-positive population – hazard ratio using site investigator data 
(RECIST 1.1) comparing MEDI4736 versus Standard of Care 
 
Sub-study B 
PD-L1-negative population – stratified log rank test using site 
investigator data (RECIST 1.1) comparing MEDI4736+tremelimumab 
versus Standard of Care 
Sensitivity analyses using site investigator data (RECIST 1.1) 
1) Interval censored analysis – evaluation time bias 
2) Analysis using alternative censoring rules – attrition bias 
 
Sub-study B only 
The following secondary treatment comparisons will be performed 
dependent upon the results of the contribution of components analysis: 
i) 
MEDI4736+tremelimumab versus MEDI4736  
ii) MEDI4736+tremelimumab versus tremelimumab  
iii) MEDI4736 versus Standard of Care 
iv) Tremelimumab versus Standard of Care 
 
Supportive analysis on Sub-study B only 
Subgroup analysis using Cox proportional hazards models 
Secondary analysis using Cox proportional hazards models to determine 
the effect of covariates on the HR estimate 
Secondary analysis using Cox proportional hazards models to determine 
the consistency of treatment effect between subgroups via the approach 
of Gail and Simon 1985. 
The analyses specified below will be performed in each of the Sub-studies A and B: 
Proportion of patients alive at 
12 months 
Hazard ratio using the Kaplan-Meier estimates of survival at 12 months 
(following the method described by Klein et al 2007) 
Objective Response Rate 
Logistic regression using site investigator data (RECIST 1.1); Sub-study 
B only 
Proportion of patients alive and 
progression free at 6 and 
12 months  
Hazard ratio using the Kaplan Meier estimates of progression free 
survival at 6 and 12 months (following method described by  
Klein et al 2007) 
Time from randomisation to 
second progression 
Stratified log-rank test 
Symptom improvement rate 
(EORTC QLQ-C30 and LC13 
endpoints) 
Logistic regression 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
218 
Table 29 
Formal statistical analyses to be conducted and pre-planned 
sensitivity analyses 
Endpoints Analysed 
Notes 
QoL/Function improvement rate 
(EORTC QLQ-C30 endpoints) 
Logistic regression 
Time to QoL/Function 
deterioration (EORTC QLQ-C30 
endpoints) 
Stratified log-rank test in Sub-study B.  Hazard ratios only in 
Sub-study A 
 
Time to symptom deterioration 
(EORTC QLQ-C30 and LC13 
endpoints) 
Stratified log-rank test in Sub-study B.  Hazard ratios only in 
Sub-study A 
 
 
 
 
 
EORTC QLQ-C30  European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire; 
EQ-5D-5L  EuroQoL 5-dimension, 5-level health state utility index; LC13  Lung Cancer Module; PD-L1  Programmed death 
ligand 1; QoL  Quality of Life; RECIST  Response Evaluation Criteria In Solid Tumours; Sub-study A  MEDI4736 
monotherapy v Standard of Care; Sub-study B  MEDI4736+tremelimumab v Standard of Care.  
 
All outputs will be summarised for each sub-study by treatment arm for all randomised 
patients (ITT).   
12.2.1 
Multiple testing strategy 
The multiple testing procedure will define which significance levels should be applied to the 
interpretation of the raw p-values for the 2 primary endpoints of PFS and OS and the key 
secondary endpoints of OS12 and ORR in Sub-study B. 
The overall type I error of 0.05 will be split between the co-primary endpoints OS and PFS.  
To control for type I error, an alpha of 0.04 will be used for the analysis of OS and an alpha of 
0.01 will be used for the analysis of PFS.  The study will be considered positive if the PFS 
analysis results and/or the OS analysis results are statistically significant in Sub-study B.  The 
0.04 alpha level allocated to OS will be controlled at the interim and primary time point by 
using the Lan DeMets (Lan and DeMets 1983) spending function that approximates an 
O’Brien Fleming approach, where the alpha level applied at the interim depends upon the 
proportion of information available. 
In Sub-study B, an interim OS analysis for superiority and the primary PFS analysis will occur 
at the same time and the primary OS analysis will be performed when 205 deaths have 
accumulated from patients who have been randomised to the MEDI4736+tremelimumab and 
Standard of Care arms. For example, if 82% of the deaths required at the time of the primary 
OS analysis are available at the time of the interim (ie, 169/205 deaths have occurred), the 
2-sided alpha level to be applied in the OS interim analysis would be 0.021 and the 2-sided 
alpha level to be applied for the primary OS analysis would be 0.034. 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
219 
At the time of the primary PFS, interim OS and primary OS analyses, the primary and key 
secondary hypotheses will be tested on the primary treatment comparisons only, for 
Sub-study B, using a multiple testing procedure with an alpha-exhaustive recycling strategy 
(Burman et al 2009).  No adjustment will be made for the contribution of components analysis 
on Sub-study B as it is not concerned with testing the primary treatment comparison.  With 
this approach, hypotheses will be tested in a pre-defined order.  At the time of the primary 
PFS analysis, the PFS endpoint will be tested first and at the time of the primary OS analysis, 
the OS endpoint will be tested first.  The other hypotheses corresponding to secondary 
endpoints will then be tested in a pre-specified hierarchy following PFS and OS rejection.  
This testing procedure stops when the entire test mass is allocated to non-rejected hypotheses.  
Implementation of this pre-defined ordered testing procedure, including recycling, will 
strongly control type I error at 0.05 (2-sided), amongst all key hypotheses.  Figure 6 shows the 
multiple testing framework for Sub–study B.  Alpha will be recycled within Sub-study B. 
Figure 6 
Multiple testing procedures for controlling the type 1 error rate for 
Sub-study B 
 
   DCO  Data cut-off 
Upon achieving statistical significance on the PFS endpoint in Sub-study B, the testing of the 
OS endpoint will be performed hierarchically as illustrated in Figure 6. Similarly the testing of 
the PFS endpoint will be done subsequent to achieving statistical significance on the 
PFS
OS
Interim
OS
PFS
OS12
Interim
ORR
OS12
ORR
OS
PFS
OS12
ORR
Interim α = 0.021
Final α = 0.034
α = 0.04
DCO: Sub-study B= 244 PFS Events and 169 Deaths
α = 0.01
DCO: Sub-study B= 205 Deaths


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
220 
interim/primary OS endpoint in Sub-study B.  If both of these endpoints are significant, the 
alpha level can be combined and passed down to lower levels in the hierarchy.  Spending 
alpha between endpoints in this way will strongly control type I error (Glimm et al 2010). 
It is currently anticipated that the cut-off for PFS co-primary analysis will be before the 
cut-off for OS co-primary analysis.  Alpha will be recycled across the PFS and OS hierarchies 
at the time of the final analysis of the respective endpoints.  If the PFS and OS analyses are 
closely aligned and performed at the same time, the same alpha split (0.01vs. 0.04) will be 
applied to the PFS analysis and OS analysis, and the alpha will be recycled between PFS and 
OS if either of them is significant. 
12.2.2 
Co-primary endpoints 
12.2.2.1 Overall survival 
Overall survival will be analysed in Sub-study B using a stratified log-rank test adjusting for 
Standard of Care therapy type (gemcitabine/vinorelbine versus erlotinib) and histology 
(squamous versus all other).  The effect of treatment will be estimated by the HR together 
with its corresponding ([1-adjusted alpha] x 100)% CI and p-value.  Note that the 
alpha-adjusted CI and p-value will only be generated on Sub-study B.  The HR and 95% CI 
will be generated on Sub-study A.  The boundaries (ie, adjusted alpha levels) for the treatment 
comparison at the interim and final analysis for OS for Sub-study B will be derived based 
upon the exact number of OS events using the Lan and DeMets approach that approximates 
the O’Brien Fleming spending function (see Section 12.2.14).  In Sub-study B, any of the 
secondary treatment comparisons at the time of final analysis will display the 95% CI. 
The HR and its CI can be estimated from the Cox proportional hazards model (Cox 1972). 
Kaplan-Meier plots of OS will be presented by treatment arm within each sub-study.  
Summaries of the number and percentage of patients who have died, those still in survival 
follow-up, those lost to follow-up and those who have withdrawn consent will be provided 
along with the median OS for each treatment.  
OS12 will be summarised (using the Kaplan-Meier curve) and presented by treatment arm.  
Each will be compared between treatments by using the Kaplan-Meier estimator of OS at 
12 months for each treatment to obtain the HR.  The HR and CI will be presented using the 
following approach (Klein et al 2007): 
• The HR(group1:group2) is estimated as 
)
(
ˆ
ln
)
(
ˆ
ln
2
1
t
S
t
S
 
• The variance for ln(HR) is estimated as 
)
(
ln
)
(
ˆ
)
(
ln
)
(
ˆ
2
2
2
2
1
2
2
1
t
S
t
t
S
t
σ
σ
+
 
where 
∑
≤
−
=
t
t
i
i
i
i
i
i
d
n
n
d
t
)
(
)
(
ˆ
2
σ
 is the variance for ln{S(t) derived from greenwood’s formula 
for the variance of S(t)and can be estimated from standard software packages, where di and ni 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
221 
refer to the number of deaths and patients at risk for each risk set.  The ln(HR) and its variance 
in each strata will be estimated and combined by weighting inversely proportionately 
according to each within stratum variance (Whitehead and Whitehead 1991). 
For Sub-study B, the assumption of proportionality will be assessed, initially only with 
regards to the primary treatment comparison.  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 as a result of treatment-by-covariate interactions, which may be investigated. 
A sensitivity analysis for OS (Sub-study B only) will examine the censoring patterns to rule 
out attrition bias with regards to the primary treatment comparisons, achieved by a Kaplan-
Meier plot of time to censoring where the censoring indicator of OS is reversed. 
Subgroup analyses will be conducted in Sub-study B comparing OS between the treatments 
concerned in the primary treatment comparison in the following subgroups of the FAS: 
• 
Sex (male versus female) 
• 
Age at randomisation (<65 versus ≥65 years of age) 
• 
Histology (squamous versus all other) 
• 
Smoking (smoker versus non-smoker [never smoked]) 
• 
Standard of Care grouped (gemcitabine/vinorelbine versus erlotinib) 
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. 
No adjustment to the significance level for testing will be made since all these analyses will be 
considered supportive of the primary analysis of OS. 
Cox proportional hazards modelling will be employed to assess the effect of covariates on the 
HR estimate for the primary treatment comparison for Sub-study B.  A model will be 
constructed, containing treatment and the stratification factors, to ensure any output from the 
Cox modelling is likely to be consistent with the results of the stratified log-rank test. 
Interactions between treatment and stratification factors will also be tested to rule out any 
qualitative interaction using the approach of Gail and Simon 1985. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
222 
For each subgroup, the HR (MEDI4736+tremelimumab: Standard of Care in Sub-study B) and 
95% CI will be calculated from an unstratified Cox proportional hazards model with treatment 
as the only covariate.   
These HRs and associated 2-sided 95% CIs will be summarised and presented on a forest plot, 
along with the results of the overall primary analysis. 
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 analysed.  In 
this case, only descriptive summaries will be provided. 
Impact of switching (crossover outside of this study) to immunotherapies (or other 
potentially active investigational agents) on OS analyses 
 
 
 
12.2.2.2 Progression free survival  
Progression free survival based upon the site investigator data will be analysed in each sub-
study using the same methodology as described for the OS analyses. 
The effect of treatment will be estimated by the HR together with its corresponding 99% CI 
and p-value for Sub-study B.  The HR and 95% CI will be generated on Sub-study A.  In 
Sub-study B, if the contribution of components analysis was performed at an earlier time point 
than the final PFS analysis, for the treatment comparisons tested at both the interim and the 
final analyses, a corresponding ([1-adjusted alpha] x 100)% CI will be produced.  
Kaplan-Meier plots of PFS will be presented by treatment arm for each sub-study.  Summaries 
of the number and percentage of patients experiencing a PFS event, and the type of event 
(RECIST 1.1 or death) will be provided along with median PFS for each treatment. 
The following sensitivity analyses will only be performed for the primary treatment 
comparison in Sub-study B.  
The assumption of proportionality will be assessed in the same way as for OS.  The analysis 
will be based on the PFS from the site investigator data.   
Sensitivity analyses will be performed to assess possible evaluation-time bias that may be 
introduced if scans are not performed at the protocol-scheduled time points.  The midpoint 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
223 
between the time of progression and the previous evaluable RECIST assessment will be 
analysed using a log-rank test.  For patients whose death was treated as PFS event, the date of 
death will be used to derive the PFS time used in the analysis.  This approach has been shown 
to be robust to even highly asymmetric assessment schedules (Sun and Chen 2010).  
Attrition bias will be assessed by repeating the PFS analysis except that the actual PFS event 
times, rather than the censored times, of patients who progressed or died in the absence of 
progression immediately following 2, or more, non-evaluable tumour assessments will be 
included.  In addition, patients who take subsequent therapy prior to progression or death will 
be censored at their last evaluable assessment prior to taking the subsequent therapy.  This 
analysis will be supported by a Kaplan-Meier plot of the time to censoring where the 
censoring indicator of the PFS analysis is reversed. 
Subgroup analyses and a forest plot will be generated comparing PFS between treatments in 
the same way as previously specified for OS.   
No adjustment to the significance level for testing will be made since all these subgroup and 
sensitivity analyses will be considered supportive of the primary analysis of PFS. 
12.2.3 
Objective response rate 
Objective response rate will be based on the site investigator assessments and will use all 
scans regardless of whether they were scheduled or not.  The ORR will be compared between 
MEDI4736 versus Standard of Care in Sub-study A and MEDI4736+tremelimumab versus 
Standard of Care in Sub-study B using logistic regression models adjusting for the same 
factors as the co-primary endpoints.  The results of the analysis will be presented in terms of 
an odds ratio together with its associated profile likelihood 95% CI.  A p-value (based on 
twice the change in log-likelihood resulting from the addition of a treatment factor to the 
model) will only be generated in Sub-study B.   
Summaries will be produced that present the number and percentage of patients with a tumour 
response (CR/PR).  Overall visit response data will be listed and summarised over time for all 
patients (ie, the FAS).  For each treatment arm, best objective response (BoR) will be 
summarised by n (%) for each category (CR, PR, SD, PD and NE).  No formal statistical 
analyses are planned for BoR. 
12.2.4 
Duration of response 
For both sub-studies, 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). 
12.2.5 
Proportion of patients alive and progression free at 6 months  
The proportion of patients alive and progression free at 6 months will be summarised (using 
the Kaplan-Meier curve) and presented by treatment arm.  APF6 will be compared between 
treatments by using the Kaplan-Meier estimator of PFS at 6 months for each treatment to 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
224 
obtain the HR.  The HR and CI will be presented using the following approach  
(Klein et al 2007):  
• The HR(group1:group2) is estimated as 
)
(
ˆ
ln
)
(
ˆ
ln
2
1
t
S
t
S
 
• The variance for ln(HR) is estimated as 
)
(
ln
)
(
ˆ
)
(
ln
)
(
ˆ
2
2
2
2
1
2
2
1
t
S
t
t
S
t
σ
σ
+
 
where 
∑
≤
−
=
t
t
i
i
i
i
i
i
d
n
n
d
t
)
(
)
(
ˆ
2
σ
 is the variance for ln{S(t) derived from greenwood’s formula 
for the variance of S(t) and can be estimated from standard software packages, where di and ni 
refer to the number of deaths and patients at risk for each risk set.  
The ln(HR) and its variance in each strata will be estimated and combined by weighting 
inversely proportionately according to each within stratum variance  
(Whitehead and Whitehead 1991). 
12.2.6 
Proportion of patients alive and progression free at 12 months  
The proportion of patients alive and progression free at 12 months will be summarised (using 
the Kaplan-Meier curve) and presented by treatment arm.  Each will be compared between 
treatments by using the Kaplan-Meier estimator of PFS at 12 months for each treatment to 
obtain the HR.  The HR and CI will be presented using the same approach as for APF6 
(Section 12.2.5). 
12.2.7 
Time from randomisation to second progression  
Time from randomisation to second progression will be analysed using identical methods as 
outlined for the analysis of PFS for Sub-study B only and adjusting for the same set of 
covariates, but no subgroup analysis will be performed.  Medians and Kaplan–Meier plots will 
be presented to support the analysis. 
For supportive purposes, the time to the start of subsequent therapy will be analysed using the 
same methodology and model.  The HR for the treatment effect together with its 95% CI will 
be presented.  In addition, a Kaplan-Meier plot of the time to the start of subsequent therapy 
will be presented by treatment arm and the time between progression and starting subsequent 
therapy will be assessed.  No multiplicity adjustment will be applied as these are viewed as 
supportive endpoints. 
A summary table of first subsequent therapies by treatment arm will be provided, as well as 
response to first subsequent therapy by treatment arm. 
12.2.8 
Patient reported outcomes  
The PRO endpoints that have been identified as primary are EORTC QLQ-C30 time to QoL 
deterioration for global health status and LC13 time to symptom deterioration for each of 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
225 
dyspnea, cough, hemoptysis, and pain.  These are not part of the main multiple testing 
procedure and as supportive endpoints will need a Bonferroni adjustment to the significance 
level to aid interpretation.  Therefore, these 5 endpoints will be tested at a 1% significance 
level and 99% CIs will be produced.  
The other time to symptom deterioration endpoints will be tested at a 5% significance level 
and 95% CIs will be produced. 
12.2.8.1 EORTC QLQ-C30 
Time to symptom deterioration will be analysed for each of the 3 symptom scales (fatigue, 
pain, nausea/vomiting) and the 5 individual symptom items (dyspnoea, insomnia, appetite 
loss, constipation, diarrhoea).  Time to QoL/function deterioration will be analysed for the 
5 function scales (physical, role, emotional, cognitive, and social) and global health 
status/QoL.  This will be achieved by comparing between treatment arms using a stratified 
log-rank test as described for the primary analysis of OS.  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 analysed 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.   
For each of the 3 symptom scales (fatigue, pain, nausea/vomiting), 5 individual symptom 
items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea), 5 functional scales 
(physical, role, emotional, cognitive, and social), and global health status/QoL, time to 
deterioration will be presented using a Kaplan-Meier plot.  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 11.3.1.1) will also be produced for each treatment arm.  
12.2.8.2 LC13 
Time to symptom deterioration for each of the 6 individual symptoms (dyspnoea, cough, 
haemoptysis, chest pain, arm/shoulder pain, other pain) will be compared between treatment 
arms using a stratified log-rank test as described for the primary analysis of OS.  The HR and 
95% CI for each scale/item will be presented graphically on a forest plot.  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
226 
For each of the 6 symptoms items in LC13, time to deterioration in symptoms will be 
presented using a Kaplan-Meier plot.  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.   
A summary of the symptom improvement rate for each of the 6 individual symptom items 
will be produced.  The symptom improvement rate will be compared between treatment arms 
using a logistic regression model as described for ORR.  The odds ratio and 95% CI for each 
symptom will be presented graphically on a forest plot.   
Summaries of original and change from baseline values of each symptom (dyspnoea, cough, 
haemoptysis, chest pain, arm/shoulder pain, other pain) and each treatment-related side effect 
(sore mouth, dysphagia, peripheral neuropathy and alopecia) 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 
symptom item (in terms of the proportion of patients in the categories of improvement, no 
change, and deterioration as defined in Section 11.3.1.2) will also be produced for each 
treatment arm.   
12.2.8.3 EuroQol 5-Dimension 5-Level questionnaire 
 
 
 
 
 
 
 
 
 
 
 
12.2.9 
Healthcare resource use 
 
 
 
 
 
CCI
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
227 
12.2.10 
Safety data 
Safety and tolerability data will be presented by treatment arm in each sub-study 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 summarised 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 
monotherapy in Sub-study A or retreatment with MEDI4736+tremelimumab or MEDI4736 
monotherapy or tremelimumab monotherapy in Sub-study B will be produced separately. 
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
haematology, vital signs and ECGs.  Within each sub-study, exposure to MEDI4736 
monotherapy (Sub-studies A and B), MEDI4736+tremelimumab (Sub-study B), 
tremelimumab monotherapy (Sub-study B) and Standard of Care will be summarised.  Time 
on study, MEDI4736/tremelimumab/Standard of Care dose delays/interruptions and dose 
reductions in the Standard of Care arm will also be summarised.  At the end of the study, 
appropriate summaries of all safety data will be produced, as defined in the SAP.  
12.2.11 
PK data (MEDI4736 monotherapy, MEDI4736+tremelimumab and 
tremelimumab monotherapy arms only) 
Pharmacokinetic concentration data will be listed for each patient and each dosing day, and a 
summary provided for all evaluable patients in each sub-study. 
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/or 
anti-tremelimumab antibodies.  The immunogenicity titre 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. 
12.2.12 
PK/PDx relationships (MEDI4736 monotherapy, MEDI4736+tremelimumab 
and tremelimumab monotherapy arms only) 
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. 
12.2.13 
Biomarker data 
 
 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
228 
 
  
 
 
 
12.2.14 
Interim analysis 
An interim analysis will be performed to test OS on the primary treatment comparison on Sub-
study B.  It will be performed at the time of the final PFS analysis when approximately 
244 PFS events have occurred in patients who have been randomised to the 
MEDI4736+tremelimumab and Standard of Care arms.  However, for practical considerations, 
if it happens that the analysis time points for the final PFS and OS analyses are closely 
aligned, based on the occurrences of the events, then one single analysis of OS will be 
conducted along with the PFS analysis In this case, the entire 0.04 alpha will be utilized for 
this OS analysis. 
All interim analyses will be assessed by an IDMC (further details are given in the IDMC 
charter).  It is probable that recruitment will have completed prior to the results of the interim 
analysis being available. 
Overall survival 
No interim analysis will be performed on Sub-study A. 
For Sub-study B, the criterion for superiority is a statistically significant improvement in OS 
at the interim analysis. The Lan and DeMets approach that approximates the O’Brien Fleming 
spending function will be used to account for multiplicity introduced into the treatment 
comparison by including the interim analysis for superiority (Lan and DeMets 1983). 
It is expected that approximately 169 (82% of the target 205) deaths will be observed in the 
study.  If 82% of the deaths required (assuming a HR of 0.63) at the time of the primary OS 
analysis (approximately 56% maturity) are available at the time of the interim (ie, 169/205 
deaths have occurred), the 2-sided alpha level to be applied in the OS interim analysis would 
be 0.021.  This analysis would have 69% power to detect a HR of 0.65.  The minimal 
difference in OS that would be deemed statistically significant is an average HR of 0.70.  
It is estimated that this interim analysis will be performed approximately 18 months after the 
start of randomisation. 
Under the above assumptions the 2-sided alpha level to be applied for the primary OS analysis 
would be 0.034. 
If the PFS and/or OS results indicate superiority, then analyses of all other endpoints would be 
performed and the results of these analyses will form the basis for submissions for regulatory 
CCI


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
229 
approval.  Patients would continue to be followed for survival until the required number of 
patients have died, when an updated analysis would be performed. 
If the PFS result is not statistically significant and the OS interim analysis result does not meet 
the criterion of stopping for superiority, then the extended study team at 
AstraZeneca/MedImmune will remain blinded and the patients will continue to be followed 
for survival. 
12.3 
Determination of sample size 
The sample size for this study was selected to be consistent with the research hypotheses as 
described in Section 1.2. 
The co-primary endpoints in Sub-study B are OS and PFS.  To control for type I error, an 
overall alpha level of 0.04 will be used for analysis of OS (accounting for 1 formal interim 
analysis to assess efficacy) and an overall alpha level of 0.01 will be used for analysis of PFS.  
Sub-study B will be considered positive (a success) if either the PFS analysis results and/or 
the OS analysis results are statistically significant. 
A total of approximately 1300 patients are expected to be recruited in the study to achieve 
approximately 610 evaluable patients in the study (approximately 126 patients in Sub-study A 
and 480 patients in Sub-study B).  The PD-L1-positive population is assumed to be 
approximately 30% of total population (AstraZeneca, unpublished data).  If the prevalence 
assumption does not hold then it is likely that recruitment will need to be extended.  The 
sample sizing for each sub-study assumes a delay in separation of the survival curves between 
each arm hence the use of average HRs. 
OS analysis 
The OS analysis in Sub-study A (PD-L1-positive population) will be performed when 
approximately 82 deaths have occurred from 126 patients (65% maturity).   
The OS analysis in Sub-study B (PD-L1-negative population) will be performed when 
205 deaths have occurred from the 300 patients (68% maturity) who have been randomised to 
the MEDI4736+tremelimumab and Standard of Care arms.  Assuming the true average HR is 
0.63 in PD-L1-negative population for OS (corresponding to a 4.4-month improvement in 
median OS from a control group median of 7 months), this analysis will have 90% power to 
demonstrate a statistically significant difference for OS, assuming an overall alpha level of 
0.04 2-sided.  The minimal difference in OS that could be deemed statistically significant in 
Sub-study B is an average HR of 0.75.  A 15-month recruitment period and a minimum 
follow-up period of 12 months is assumed on Sub-study B for OS.  Therefore it is anticipated 
that this OS analysis could be performed 27 months after the first patient has been recruited.  
Assuming that the survival curves of the two treatment arms do not separate for 2 months then 
the HR after that point would need to be 0.53 to produce an average HR of 0.63 over the 
follow-up period.  This would be associated with 12-month survival rates of 30.5% for 
Standard of Care and 48.5% for MEDI4736+tremelimumab. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
230 
PFS analysis 
The PFS analysis in Sub-study A (PD-L1-positive population) will be performed at the same 
time as the OS analysis on Sub-study A. 
The PFS analysis in Sub-study B (PD-L1-negative population) will be performed when 
approximately 244 PFS events have occurred from 300 patients (81% maturity) who have 
been randomised to the MEDI4736+tremelimumab and Standard of Care arms.  Assuming the 
true average HR is 0.63 in PD-L1-negative population for PFS (corresponding to a 1.3-month 
improvement in median PFS from a control group median of 3 months), this analysis will 
have 84% power to demonstrate a statistically significant difference for PFS, assuming an 
alpha level of 0.01 2-sided.  The minimal difference in PFS that would be deemed statistically 
significant in Sub-study B is an average HR of 0.72.  Sub-study B is expected to have a 
recruitment period of 15 months and a follow-up period of 7 months for the PFS endpoint.  
Therefore it is anticipated that this PFS analysis could be performed at a minimum of 
22 months after the first patient has been recruited.  If the survival curves of the 2 treatment 
arms do not separate for 2 months then the HR after that point would need to be 0.43 to 
produce an average HR of 0.63 over the follow-up period.  This would be associated with 
12-month PFS rates of 6.3% for Standard of Care and 23.3% for MEDI4736+tremelimumab. 
Please refer to Appendix D for information on PGx. 
12.4 
Independent data monitoring committee  
This study will use an external IDMC to assess ongoing safety analyses on both sub-studies as 
well as the interim analyses for superiority.  The committee will meet approximately 6 months 
after the study has started or 20 patients have been randomised to the combination arm 
(whichever comes first) to review the safety data from the study.  The IDMC will meet 
approximately every 6 months thereafter.  Following each meeting, the IDMC will report to 
the sponsor and may recommend changes in the conduct of the study. 
This committee will be composed of therapeutic area experts and biostatisticians, who are not 
employed by AstraZeneca/MedImmune and do not have any major conflict of interest.   
Following the reviews, the IDMC will recommend whether the study should continue 
unchanged, be stopped, or be modified in any way.  Once the IDMC has reached a 
recommendation, a report will be provided to AstraZeneca/MedImmune.  The report will 
include the recommendation and any potential protocol amendments, and will not contain any 
unblinding information.   
The final decision to modify or stop the study will sit with the sponsor.  The sponsor or IDMC 
may call additional meetings if at any time there is concern about the safety of the study. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
231 
In addition: 
• 
If the contribution of components analysis is performed prior to the final PFS 
analysis, the IDMC will review the efficacy data on Sub-study B for the 
MEDI4736+tremelimumab versus tremelimumab monotherapy treatment 
comparison and the MEDI4736+tremelimumab versus MEDI4736 monotherapy 
treatment comparison.  
• 
The IDMC will review the efficacy data on Sub-study B at the time of the final PFS 
analysis when approximately 244 PFS events have occurred from patients 
randomised to the MEDI4736+tremelimumab and Standard of Care arms, at 
approximately 22 months post first randomisation, at the time of the primary 
analysis of PFS and interim analysis of OS. 
Full details of the IDMC procedures and processes can be found in the IDMC Charter. 
The safety of all AstraZeneca/MedImmune clinical studies is closely monitored on an ongoing 
basis by AstraZeneca/MedImmune representatives in consultation with the Patient Safety 
Department.  Issues identified will be addressed; this could involve, for instance, amendments 
to the clinical study protocol and letters to investigators. 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
13.1 
Medical emergencies, AstraZeneca/MedImmune and QuintilesIMS 
contacts 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study.  A medical emergency usually 
constitutes an SAE and is to be reported as such, see Section 6.4.4. 
In the case of a medical emergency the investigator may contact the 24-hour 
QuintilesIMS Medical Emergency Contact Centre 
 or alternative 
number
.  After final DCO, the investigator should contact 
AstraZeneca/MedImmune Patient Safety using the contact information specified below: 
PPD
PPD


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
232 
Name  
Role in the study  
Address & telephone number 
 
 
Study Delivery Team 
Leader  
QuintilesIMS Ltd 
500 Brook Drive 
Green Park 
Reading 
United Kingdom 
Office: 
 
 
 
 
Senior Director Physician 
Mereside 
Alderley Park, Macclesfield 
Cheshire, SK10 4TG 
Tel: 
 
Patient Safety  
AstraZeneca/MedImmune 
Patient Safety  
BUDAPEST: 
c/o 
  
Tata Consultancy Services 
Office Garden 2, 3rd floor 
Aliz utca 2 
Budapest - 1117, Hungary 
MUMBAI: 
c/o 
 
Tata Consultancy Services 
4th Floor, Tiffany, 
Hiranandani Business Estate 
Thane - West, 400607 
 
AEMailbox: 
 
 
13.2 
Overdose  
Use of MEDI4736, tremelimumab or MEDI4736+tremelimumab in doses in excess of that 
specified in the protocol is considered to be an overdose.  There is currently no specific 
treatment in the event of overdose of MEDI4736 or tremelimumab and possible symptoms of 
overdose are not established.   
Please also refer to the local prescribing information for the relevant Standard of Care agent 
(eg, gemcitabine prescribing information, NAVELBINE® prescribing information, 
TARCEVA® prescribing information). 
• 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose case report form module. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
233 
• 
An overdose without associated symptoms is only reported on the Overdose case 
report form module. 
If an overdose on an AstraZeneca/MedImmune study drug occurs in the course of the study, 
then investigators or other site personnel inform appropriate AstraZeneca/MedImmune 
representatives (ie, QuintilesIMS) immediately, or no later than 24 hours of when he or she 
becomes aware of it. 
The designated AstraZeneca/MedImmune representative (ie, QuintilesIMS) works with the 
investigator to ensure that all relevant information is provided to the 
AstraZeneca/MedImmune Patient Safety data entry site. 
For overdoses associated with SAE, standard reporting timelines apply, see Section 6.4.4.  For 
other overdoses, reporting should be done within 30 days. 
If an overdose on an AstraZeneca study drug occurs after the final DCO, then investigators or 
other site personnel shall inform AstraZeneca/MedImmune Patient Safety immediately, or 
no later than 24 hours of when he or she becomes aware of it. 
13.3 
Pregnancy 
All outcomes of pregnancy should be reported to the AstraZeneca/MedImmune representative 
(ie, QuintilesIMS).  Following the final DCO, investigators or other site personnel shall report 
all pregnancy outcomes to AstraZeneca/MedImmune Patient Safety. 
13.3.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study treatment should be discontinued 
immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication.  
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs.  Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented 
even if the patient was discontinued from the study. 
If any pregnancy occurs in the course of the study, investigators or other site personnel must 
inform appropriate AstraZeneca/MedImmune representatives (ie, QuintilesIMS) immediately, 
or no later than 24 hours from when he or she becomes aware of it. 
If any pregnancy occurs after the final DCO, investigators or other site personnel must inform 
AstraZeneca/MedImmune Patient Safety immediately, or no later than 24 hours of when 
he or she becomes aware of it. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
234 
The designated AstraZeneca/MedImmune representative works with the investigator to ensure 
that all relevant information is provided to the AstraZeneca/MedImmune Patient Safety data 
entry site within 1 or 5 days for SAEs, see Section 6.4.4 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.  Paper-based modules will be available to sites 
following the final DCO. 
13.3.2 
Paternal exposure 
Information on the pregnancy of a patient’s partner must be obtained directly from the 
patient’s partner.  Therefore, prior to obtaining information on the pregnancy, the investigator 
must obtain the consent of the patient’s partner. 
Male patients should refrain from fathering a child or donating sperm during the study and for 
90 days (if in the MEDI4736 monotherapy arm) or 180 days (if in the tremelimumab or 
MEDI4736+tremelimumab arm) following the last dose of study drug.  Please follow the local 
prescribing information relating to contraception and the time limit for such precautions for 
agents in the Standard of Care arm (eg, gemcitabine prescribing information, 
NAVELBINE® prescribing information, TARCEVA® prescribing information). 
Pregnancy of the patient’s partners is not considered to be an AE.  However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should, if possible, be followed up and documented.  To 
capture information about a pregnancy from the partner of a male patient, the male patient’s 
partner consent must be obtained to collect information related to the pregnancy and outcome; 
the male patient should not be asked to provide this information.  A consent form specific to 
this situation must be used. 
The outcome of any conception occurring from the date of the first dose until 90 days 
(180 days if on tremelimumab or MEDI4736+tremelimumab treatment) after the last dose of 
study treatment (MEDI4736, tremelimumab, MEDI4736+tremelimumab or Standard of Care) 
should be followed up and documented.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
235 
14. 
LIST OF REFERENCES  
Aaronson et al 1993 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organisation 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 Mar 3;85(5):365-76. 
Antonia et al 2014 ESMO 
Antonia S, Ou S-H, Khleif SN, Brahmer J, Blake-Haskins A, Robbins PB et al. Clinical 
activity and safety of MEDI4736, an anti-programmed cell death ligand-1 (PD-L1) antibody, 
in patients with NSCLC. European Society for Medical Oncology (ESMO) Meeting in 
Madrid, Spain; 2014 Sep 26-30. Poster #1325P (Abstract ID 7629). 
Antonia et al 2014 ASCO 
Antonia SJ, Gettinger SN, Chow LQM , Juergens RA, Borghaei H, Shen Y, et al. Nivolumab 
(anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in first-line NSCLC: Interim phase I 
results. American Society of Clinical Oncology, 2014. Poster. 
Antonia et al 2015 ASCO 
Antonia S, Goldberg A, Balmanoukian A, Sanborn RE, Steele KE, Narwal R, et al. Phase Ib 
study of MEDI4736, a PD-L1 antibody, in combination with tremelimumab, a CTLA-4 
antibody, in patients with advanced NSCLC. J Clin Oncol 33, 2015 (suppl; abstr 3014). 
Azzoli et al 2009 
Azzoli CG, Baker S Jr, Temin S, Pao W, Aliff T, Brahmer J, et al; American Society of 
Clinical Oncology. American Society of Clinical Oncology Clinical Practice Guideline update 
on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2009 
Dec 20;27(36):6251-66. 
Berger et al 2008 
Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I safety 
and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in 
patients with advanced hematologic malignancies. Clin Cancer Res 2008 
May 15;14(10):3044-51. 
Bergman et al 1994 
Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QLQ-LC13: a 
modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in 
lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur J Cancer 
1994;30A(5):635-42. 
Blank et al 2006 
Blank C, Kuball J, Voelkl S, Wiendl H, Becker B, Walter B, et al. Blockade of PD-L1 
(B7-H1) augments human tumour-specific T-cell responses in vitro. Int J Cancer 2006 
Jul 15;119(2):317-27. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
236 
Brahmer et al 2010 
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study 
of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumours: safety, 
clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010 
Jul 1;28(19):3167-75. 
Brahmer et al 2012 
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity 
of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012 
Jun 28;366(26):2455-65. 
Brahmer et al 2013 
Brahmer JR, Horn L, Antonia SJ, Spigel DR, Gandhi L, Sequist LV, et al. Survival and 
longterm follow-up of the phase 1 trial of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) 
in patients (pts) with previously treated advanced non-small cell lung cancer (NSCLC). J Clin 
Oncol. 2013;31(15_Suppl):Abstract 8030. 
Brahmer et al 2014 
Brahmer JR, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA et al. Nivolumab 
(anti-PD-1, BMS-936558, ONO-4538) in patients (pts) with advanced non-small-cell lung 
cancer (NSCLC): Survival and clinical activity by subgroup analysis. Journal of Clinical 
Oncology, 2014 ASCO Annual Meeting Abstracts; 32(15) (2014 May 20 Supplement): 8112. 
Burman et al 2009 
Burman CF, Sonesson C, Guilbaud O. A recycling framework for the construction of 
Bonferroni-based multiple tests. Stat Med 2009 Feb 28;28(5):739-61.  
Campanelli et al 1991 
Campanelli P, Martin E and Rothgeb J.  The use of respondent and interviewer debriefing 
studies as a way to study response error in survey data. The Statistician 1991;40:253–64. 
Cockcroft and Gault 1976 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41. 
Cox 1972 
Cox DR. Regression models and life-tables. J Royal Stat Society 1972;Series B 34(2):187-220 
Curran et al 2010 
Curran MA, Montalvo W, Yagita H et al. PD-1 and CTLA-4 combination blockade expands 
infiltrating T-cells and reduces regulatory T and myeloid cells within B16 melanoma tumours. 
Proc Natl Acad Sci USA 2010; 107: 4275–80.  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
237 
D’Addario et al 2010 
D’Addario G, Früh M, Reck M, Baumann P, Klepetko W, Felip E, et al; ESMO Guidelines 
Working Group. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines 
for diagnosis, treatment and follow-up. Ann Oncol 2010 May;21(Suppl 5):v116-9. 
Decisions Resources 2013 
Decisions Resources 2013. Non-small-Cell Lung Cancer (Event Driven). June 2013. 
Drake 2012 
Drake CG. Combination immunotherapy approaches. Annals of Oncology 2012; 23 
(Supplement 8): 41-46. 
Drake et al 2013 
Drake CG, McDermott DF, Sznol M, Choueiri TK, Kluger HM, Powderly JD et al. Survival, 
safety, and response duration results of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in 
a phase I trial in patients with previously treated metastatic renal cell carcinoma (mRCC): 
Long-term patient follow-up. J Clin Oncol 31, 2013 (suppl; abstr 4514). 
Eisenhauer et al 2009 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45:228-47. 
Ericsson and Simon 1980 
Ericsson K and Simon H. Verbal reports as data. Psychological Review 1980;87:215-51. 
EuroQoL 1990 
EuroQol Group. EuroQol - a new facility for the measurement of health-related quality of life. 
Health Policy 1990 Dec;16(3):199-208. 
EuroQoL 2013 
EuroQol Group. EQ-5D-5L User Guide: Basic information on how to use the EQ-5D-5L 
instrument, Version 2.0, October 2013. Available from: 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/UserGuide_
EQ-5D-5L_v2.0_October_2013.pdf. Accessed 21 November 2013. 
Fairman et al 2014 
Fairman D, Narwal R, Liang M, Robbins P, Schneider A, Chavez C, Lu H, Pak M, 
Blake-Haskins A, Vasselli J, Ibrahim R, and Lorin Roskos.  Pharmacokinetics of MEDI4736, 
a Fully Human Anti-PDL1 Monoclonal Antibody, in Patients with Advanced Solid Tumours. 
Presented at American Society of Clinical Oncology 2014. Poster. 
Fayers et al 1999 
Fayers P, Aaronson NK, Bjordal K, Curran D, Groenvold M on behalf of the EORTC Quality 
of Life Study Group. EORTC QLQ-C30 Scoring Manual: 2nd Edition 1999. Available on 
request. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
238 
FDA Guidance 2009 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from URL: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf. Accessed 10 December 2013. 
FDA Guidance 2011 
FDA Guidance for Industry (issued June 2011) ‘Clinical trial endpoints for the approval of 
non-small cell lung cancer drugs and biologics’. Available from URL: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM259421.pdf. Accessed 
08 January 2014. 
Gail and Simon 1985 
Gail M, Simon R. Tests for qualitative interactions between treatment effects and patient 
subsets. Biometrics 1985 Jun;41(2):361-72. 
Garon et al 2013 
Garon EB, Balmanoukian A, Hamid O, Hui R, Gandhi L, Leighl N et al. Preliminary clinical 
safety and activity of MK-3475 monotherapy for the treatment of previously treated patients 
with non-small cell lung cancer (NSCLC). J Thorac Oncol. 2013;8(suppl 2):S364.4. 
gemcitabine prescribing information 
GEMZAR® [prescribing information]. Indianapolis, US Eli Lilly and Company; 2013 [cited 
2013 May]. Available from: http://pi.lilly.com/us/gemzar.pdf. Accessed 31 October 2013. 
Gemcitabine prescribing information 
Gemcitabine 40 mg/ml concentrate for solution for infusion [prescribing information]. 
Hafnarfjörður, Actavis Group PTC ehf.; 2014 [cited 2015 November]. 
http://www.actavis.ie/NR/rdonlyres/B78DD208-269F-4BE7-B7FD-
4F25E8617516/31836/7SPC_PA1380153_06nov14_C2148728.pdf. Accessed 
12 November 2015. 
Glimm et al 2010 
Glimm E, Maurer W and Bretz F. Hierarchical testing of multiple endpoints in 
group-sequential trials. Statist. Med. 2010;29:219-228. 
GLOBOCAN 2008 
GLOBOCAN 2008: Estimated cancer Incidence, Mortality, Prevalence and 
Disability-adjusted life years (DALYs) Worldwide in 2008. Available from URL: 
http://globocan.iarc.fr/factsheets/cancers/lung.asp. Accessed 29 October 2013. 
Gordon et al 2013 
Gordon MS, Hamid O, Powderly J, Anderson M, Fine G, Mokatrin A, et al. A phase I study of 
MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic 
tumours. American Association for Cancer Research 2013 Annual Meeting; 2013 Apr 06-10; 
Washington, DC. Abstract LB-288. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
239 
Grosso et al 2013 
Grosso J, Horak CE, Inzunza D, Cardona DM, Simon JS, Gupta AK, et al. Association of 
tumour PD-L1 expression and immune biomarkers with clinical activity in patients (pts) with 
advanced solid tumours treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538). J Clin 
Oncol 2013;31(Suppl):Abstract 3016. 
Hamanishi et al 2007 
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed 
cell death 1 ligand 1 and tumour-infiltrating CD8+ T lymphocytes are prognostic factors of 
human ovarian cancer. Proc Natl Acad Sci USA 2007 Feb 27;104(9):3360-5. 
Hamid et al 2013 
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumour 
responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013 Jul 
11;369(2):134-44. 
Hanna et al 2004 
Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. 
Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell 
lung cancer previously treated with chemotherapy. J Clin Oncol 2004 May 1;22(9):1589-97. 
Herbst et al 2013 
Herbst RS, Gordon MS, Fine GD, Sosman JA, Soria JC, Hamid O, et al. A study of 
MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic 
tumours [abstract]. J Clin Oncol 2013;31(Suppl 15):Abstract 3000. 
Herdman et al 2011 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011 
Dec;20(10):1727-36. 
Hirano et al 2005 
Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and 
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 2005 
Feb 1;65(3):1089-96. 
Hodi et al 2010 
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanan JB, et al. Improved 
survival with ipilimumab in patients with metastatic melanoma [published erratum appears in 
N Engl J Med 2010 Sep 23;363(13):1290]. N Engl J Med 2010 Aug 19;363(8):711-23. 
Hodi et al 2014 
Hodi FS, Sznol M, Kluger HM, McDermott DF, Carvajal RD, Lawrence DP et al. Long-term 
survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with 
nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a phase I trial. J Clin Oncol, 2014 ASCO 
Annual Meeting Abstracts; 32(15) (2014 May 20 Supplement): 9002. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
240 
IASLC Staging Manual in Thoracic Oncology 
Staging Manual in Thoracic Oncology. Goldstraw P, Chief Executive Editor. 7th Ed. IASLC 
2010.  Available on request. 
Iwai et al 2002 
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on 
tumour cells in the escape from host immune system and tumour immunotherapy by PD-L1 
blockade. Proc Natl Acad Sci USA 2002 Sep 17;99(19):12293-7. 
Janssen et al 2008a 
Janssen MF, Birnie E, Haagsma JA, Bonsel GJ. Comparing the standard EQ-5D three-level 
system with a five-level version. Value Health 2008 Mar-Apr;11(2):275-84. 
Janssen et al 2008b 
Janssen MF, Birnie E, Bonsel GJ. Quantification of the level descriptors for the standard 
EQ-5D three-level system and a five-level version according to two methods. Qual Life Res 
2008 Apr;17(3):463-73. 
Kalialis et al 2009 
Kalialis LV, Drzewiecki KT, Klyver H. Spontaneous regression of metastases from 
melanoma: review of the literature. Melanoma Res 2009 Oct;19(5):275-82. 
Keir et al 2008 
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol 2008;26:677-704. 
KEYTRUDA® prescribing information  
KEYTRUDA® [prescribing information]. White House Station, NJ, Merck & Co.; 2014 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125514lbl.pdf. 
Kirkwood et al 2010 
Kirkwood JM, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott D, et al. Phase II trial 
of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. 
Clin Cancer Res 2010 Feb 1;16(3):1042-8. 
Klein et al 2007 
Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a fixed point in 
time. Stat Med 2007 Oct 30; 26(24): 4505–19. 
Krambeck et al 2007 
Krambeck AE, Dong H, Thompson RH, Kuntz SM, Lohse CM, Leibovich BC, et al. Survivin 
and B7-H1 are collaborative predictors of survival and represent potential therapeutic targets 
for patients with renal cell carcinoma. Clin Cancer Res 2007 Mar 15;13(6):1749-56. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
241 
Lan and DeMets 1983 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983;70:659-63. 
Lipson and Drake 2011 
Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin 
Cancer Res 2011 Nov 15;17(22):6958-62. 
Loos et al 2008 
Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, et al. Clinical significance 
and regulation of the costimulatory molecule B7-H1 in pancreatic cancer. Cancer Lett 2008 
Sep 8;268(1):98-109. 
Lynch et al 2012 
Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, 
Lu H, Cuillerot J-M, and Martin Reck. Ipilimumab in Combination With Paclitaxel and 
Carboplatin As First-Line Treatment in Stage IIIB/IV Non–Small-Cell Lung Cancer: Results 
From a Randomized, Double-Blind, Multicenter Phase II Study. J Clin Oncol 2012; 30:2046-
54. 
Mangsbo et al 2010 
Mangsbo SM, Sandin LC, Anger K, Korman AJ, Loskog A, Tötterman TH. Enhanced tumour 
eradication by combining CTLA-4 or PD-1 blockade with CpG therapy. J Immunother 
2010;33:225-35. 
Mu et al 2011 
Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer 
may contribute to poor prognosis and tumour cells immune escape through suppressing 
tumour infiltrating dendritic cells maturation. Med Oncol 2011 Sep;28(3):682-8. 
NAVELBINE® prescribing information 
Navelbine® [prescribing information]. Research Triangle Park, US GlaxoSmithKline; 2002 
[cited 2002].  Available from: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20388s014lbl.pdf.  Accessed 
31 October 2013. 
Nokihara H 2013 
Nokihara H. Phase 1 study of ipilimumab in combination with paclitaxel/carboplatin in 
patients with non-small cell lung cancer. International Association for the Study of Lung 
Cancer; 15th World Conference on Lung Cancer in Sydney, Australia; 2013 October. 
Available upon request. 
Nomi et al 2007 
Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
human pancreatic cancer. Clin Cancer Res 2007 Apr 1;13(7):2151-7. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
242 
Oemar and Janseen 2013 
Oemar M, Oppe M. EQ-5D-3L User Guide: Basic information on how to use the EQ-5D-3L 
instrument V5.0 (October 2013). Available from URL: 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/EQ-5D-
3L_UserGuide_2013_v5.0_October_2013.pdf. Accessed 07 January 2014. 
Okudaira et al 2009 
Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, et al. Blockade of 
B7-H1 or B7-DC induces an anti-tumour effect in a mouse pancreatic cancer model. Int J 
Oncol 2009 Oct;35(4):741-9. 
OPDIVO® prescribing information  
OPDIVO® [prescribing information]. Princeton, NJ, Bristol-Myers Squibb Company; 2014 
[cited 2014].  Available from: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125554lbl.pdf.  Accessed 
03 November 2015.  
Osoba et al 1998 
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998 Jan;16(1):139-44.  
Pagès et al 2010 
Pagès F, Galon J, Dieu-Nosjean MC, Tartour E, Sautès-Fridman C, Fridman WH. Immune 
infiltration in human tumours: a prognostic factor that should not be ignored. Oncogene 2010 
Feb 25;29(8):1093-102. 
Park et al 2010 
Park JJ, Omiya R, Matsumura Y, Sakoda Y, Kuramasu A, Augustine MM, et al. B7-H1/CD80 
interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood 
2010 Aug 26;116(8):1291-8. 
Pardoll 2012 
Pardoll D. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews 
Cancer 2012 April; 12:252-264. 
Pazdur 2008 
Pazdur R.  Endpoints for assessing drug activity in clinical trials. Oncologist 
2008;13(Suppl 2):19-21. 
Pickard et al 2007 
Pickard AS, De Leon MC, Kohlmann T, Cella D, Rosenbloom S. Psychometric comparison of 
the standard EQ-5D to a 5 level version in cancer patients. Med Care 2007 Mar;45(3):259-63. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
243 
Pisters and Le Chevalier 2005 
Pisters KM, Le Chevalier T.  Adjuvant chemotherapy in completely resected non-small-cell 
lung cancer [published erratum appears in J Clin Oncol 2008 May 1;26(13):2238]. J Clin 
Oncol 2005 May 10;23(14):3270-8. 
Powderly et al 2013 
Powderly JD, Koeppen H, Hodi FS, Sosman JA, Gettinger SN, Desai R, et al.  Biomarkers 
and associations with the clinical activity of PD-L1 blockade in a MPDL3280A study. J Clin 
Oncol 2013;31(Suppl):abstract 3001. 
Rizvi et al 2015 ASCO 
Rizvi N, Chaft J; Balmanoukian A, Goldberg SB, Sanborn RE, Steele KE, et al.  Safety and 
clinical activity of MEDI4736, an anti-PD-L1 antibody, in patients with NSCLC. J Clin Oncol 
33, 2015 (suppl; abstr 8032). 
Rizvi et al 2015 SITC 
Rizvi N, Chaft J; Balmanoukian A, Goldberg SB, Sanborn RE, Steele KE, et al.  Tumor 
Response From Durvalumab (MEDI4736) + Tremelimumab Treatment in Patients with 
Advanced Non-small Cell Lung Cancer is Observed Regardless of PD-L1 Status. Journal for 
ImmunoTherapy of Cancer 2015, 3(Suppl 2): P193. 
Robert et al 2011 
Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus 
dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011 
Jun 30;364(26):2517-26. 
Robins and Tsiatis 1991 
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Communications in Statistics-Theory and Methods 
1991; 20(8):2609-31. 
Robins 1993 
Robins JM. Information Recovery and Bias Adjustment in Proportional Hazards Regression 
Analysis of Randomized Trials Using Surrogate Markers. Proceedings of the 
Biopharmaceutical Section, American Statistical Association 1993; 24-33. 
Schadendorf et al 2013 
Schadendorf D, Hodi FS, Robert C et al. Pooled analysis of long-term survival data from 
phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable 
melanoma. Presented at: European Cancer Congress 2013 (ECCO-ESMO-ESTRO); 
September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract 24. 
Sun and Chen 2010 
Sun X, Chen C. Comparison of Finkelstein's Method with the Conventional Approach for 
Interval-Censored Data Analysis. Stat Biopharm Res 2010;2(1):97-108. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
244 
Swann and Smyth 2007 
Swann JB, Smyth MJ. Immune surveillance of tumours. J Clin Invest 2007 
May;117(5):1137-46. 
Syrigos et al 2011  
Syrigos KN, Saif MW, Karapanagiotou EM, Oikonomopoulos G, De Marinis F.  The need for 
third-line treatment in non-small cell lung cancer: an overview of new options. Anticancer Res 
2011 Feb;31(2):649-59. 
TARCEVA® prescribing information 
TARCEVA® [prescribing information]. Hertfordshire, UK Roche Products Limited; 2013 
[cited 2013 June]. Available from: 
http://www.medicines.org.uk/EMC/medicine/16781/SPC/Tarceva%2B25mg,%2B100mg%2B
and%2B150mg%2BFilm-Coated%2BTablets/. Accessed 31 October 2013. 
Tarhini and Kirkwood 2008 
Tarhini AA, Kirkwood JM. Tremelimumab (CP-675,206): a fully human anticytotoxic T 
lymphocyte-associated antigen 4 monoclonal antibody for treatment of patients with advanced 
cancers. Expert Opin Biol Ther. 2008;8(10):1583-93. 
Thompson et al 2005 
Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, et al. 
Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. 
Cancer 2005 Nov 15;104(10):2084-91. 
Thompson et al 2006 
Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumour 
B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term 
follow-up. Cancer Res 2006 Apr 1;66(7):3381-5. 
Topalian et al 2012 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012 Jun 28; 
366(26):2443-54. 
Topalian et al 2014 
Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH et al. 
Survival, durable tumor remission, and long-term safety in patients with advanced melanoma 
receiving nivolumab. J Clin Oncol, 2014 Apr 1; 32(10):1020-30. 
Wang et al 2010 
Wang L, Ma Q, Chen X, Guo K, Li J, Zhang M. Clinical significance of B7-H1 and B7-1 
expressions in pancreatic carcinoma. World J Surg 2010 May;34(5):1059-65. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00004 
Edition Number 07.0 
Date 08 January 2018 
 
245 
Whitehead and Whitehead 1991 
Whitehead A, Whitehead J.  A general parametric approach to the meta-analysis of 
randomized clinical trials.  Statistics In Medicine 1991;10:1665-77. 
Wolchok et al 2009 
Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumours: immune-related response criteria. 
Clin Cancer Res 2009 Dec 1;15(23):7412-20. 
Wolchok et al 2013 
Wolchok JD, Kluger H, Callahan MK, Postow MA et al. Nivolumab plus Ipilimumab in 
Advanced Melanoma. N Engl J Med 2013; 369:122-133. 
Yasuda et al 2012 
Yasuda H, Kobayashi S, Costa DB.  EGFR exon 20 insertion mutations in non-small-cell lung 
cancer: preclinical data and clinical implications. Lancet Oncol 2012;13:e23-31. 
YERVOY™ prescribing information 
Yervoy™ [prescribing information]. Princeton, US: Bristol-Myers Squibb Company; 2011 
[cited 2011 March]. Available from: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf. Accessed 
31 October 2013. 
Zhang et al 2008 
Zhang C, Wu S, Xue X, Li M, Qin X, Li W, et al. Anti-tumour immunotherapy by blockade of 
the PD-1/PD-L1 pathway with recombinant human PD-1-IgV. Cytotherapy 2008;10(7):711-9. 
Zou and Chen 2008 
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev 
Immunol 2008 Jun;8(6):467-77. 
 

SAP_000.pdf: 
Statistical Analysis Plan
Study Code
D4191C00004
Edition Number
3
Date
24 January 2018
A Phase III, Open-label, Randomised, Multi-centre, International Study of
MEDI4736, Given as Monotherapy or in Combination with Tremelimumab, 
Determined by PD-L1 Expression, Versus Standard of Care in Patients with 
Locally Advanced or Metastatic Non-Small Cell Lung Cancer (Stage IIIB-
IV) who Have Received at Least Two Prior Systemic Treatment Regimens 
Including One Platinum-based Chemotherapy Regimen and Do Not Have 
Known EGFR TK Activating Mutations or ALK Rearrangements 
(ARCTIC)


PPD


PPD


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
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............................................................................................... 14
1.1
Study objectives................................................................................................... 14
1.1.1
Primary Objective ................................................................................................ 14
1.1.2
Secondary Objectives........................................................................................... 14
1.1.3
Exploratory Objectives......................................................................................... 15
1.2
Study design ........................................................................................................ 16
2.
ANALYSIS SETS ............................................................................................... 22
2.1
Definition of analysis sets .................................................................................... 22
2.2
Violations and deviations ..................................................................................... 24
3.
PRIMARY AND SECONDARY VARIABLES................................................... 25
3.1
Derivation of RECIST Visit Responses................................................................ 25
3.1.1
Site Investigator Assessment Using RECIST 1.1: Target lesions (TLs) ................ 27
3.1.2
Site Investigator Assessment Using RECIST 1.1: Non-target lesions (NTLs) 
and new lesions.................................................................................................... 31
3.1.3
Site Investigator Assessment Using RECIST 1.1: Overall visit response .............. 32
3.2
Outcome Variables............................................................................................... 33
3.2.1
Co-primary endpoints........................................................................................... 33
3.2.1.1
Overall survival.................................................................................................... 33
3.2.1.2
Progression free survival...................................................................................... 34
3.2.2
Proportion of patients alive at 12 months (OS12) ................................................. 35
3.2.3
Objective Response Rate...................................................................................... 35
3.2.4
Duration of Response........................................................................................... 36
3.2.5
Proportion of patients alive and progression free at 6 months ............................... 36
3.2.6
Proportion of patients alive and progression free at 12 months ............................. 36
3.2.7
Time from randomisation to second progression or death (PFS2) (sub-
study B) ............................................................................................................... 36
3.2.8
Best objective response ........................................................................................ 37
3.2.9
Change in tumour size.......................................................................................... 37
3.3
Patient Reported Outcome (PRO) Variables......................................................... 38
3.3.1
EORTC-QLQ-C30............................................................................................... 38
3.3.1.1
Time to symptom deterioration ............................................................................ 39


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
5
3.3.1.2
Time to HRQoL/Function deterioration................................................................ 40
3.3.1.3
Symptom Improvement Rate................................................................................ 41
3.3.1.4
HRQoL/Function Improvement Rate.................................................................... 41
3.3.2
EORTC-QLQ-LC-13 ........................................................................................... 41
3.3.2.1
Time to symptom deterioration ............................................................................ 42
3.3.2.2
Symptom Improvement Rate................................................................................ 43
3.3.3
EQ-5D-5L............................................................................................................ 43
3.3.4
PRO Compliance Rates........................................................................................ 44
3.4
Safety................................................................................................................... 44
3.4.1
Adverse events (AEs)........................................................................................... 45
3.4.2
Treatment exposure.............................................................................................. 46
3.4.3
Dose intensity ...................................................................................................... 49
3.4.4
Laboratory data.................................................................................................... 49
3.4.5
ECGs ................................................................................................................... 50
3.4.6
Vital signs............................................................................................................ 51
3.4.7
General considerations for safety and PRO assessments....................................... 51
3.5
Biomarker Variables ............................................................................................ 53
3.6
Pharmacokinetic and Immunogenicity Variables.................................................. 53
3.6.1
PK non-compartmental analysis........................................................................... 53
3.6.2
Population PK and exposure-response/safety analysis .......................................... 53
3.6.3
Immunogenicity analysis...................................................................................... 53
3.7
Health Resource Use............................................................................................ 54
4.
ANALYSIS METHODS...................................................................................... 54
4.1
General principles................................................................................................ 55
4.2
Analysis methods................................................................................................. 57
4.2.1
Multiplicity (Sub-study B only)............................................................................ 59
4.2.2
Co-primary endpoints........................................................................................... 61
4.2.2.1
Overall survival.................................................................................................... 61
4.2.2.2
Progression free survival...................................................................................... 65
4.2.3
Objective response rate ........................................................................................ 67
4.2.4
Duration of response ............................................................................................ 68
4.2.5
Proportion of patients alive and progression free at 6 months (APF6)................... 68
4.2.6
Proportion of patients alive and progression free at 12 months (APF12)............... 68
4.2.7
Time from randomisation to second progression (Sub-study B only).................... 68
4.2.8
Change in tumour size.......................................................................................... 69
4.2.9
Patient reported outcomes .................................................................................... 69
4.2.9.1
EORTC QLQ-C30 ............................................................................................... 70
4.2.9.2
LC13.................................................................................................................... 70
4.2.9.3
EuroQol 5-Dimension 5-Level questionnaire........................................................ 71
4.2.10
Health Resource Use............................................................................................ 71
4.2.11
Safety data ........................................................................................................... 71
4.2.12
WHO performance status..................................................................................... 77


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
6
4.2.13
PK data (MEDI4736 monotherapy, MEDI4736+tremelimumab and 
tremelimumab monotherapy arms only) ............................................................... 78
4.2.14
PK/PDx relationships (MEDI4736 monotherapy, MEDI4736+tremelimumab 
and tremelimumab monotherapy arms only)......................................................... 78
4.2.15
Biomarker data..................................................................................................... 78
4.2.16
Demographic and baseline characteristics data..................................................... 78
4.2.17
Treatment exposure.............................................................................................. 79
5.
INTERIM ANALYSES ....................................................................................... 80
5.1
Analysis methods................................................................................................. 80
5.1.1
Overall survival.................................................................................................... 80
5.2
Independent Data monitoring committee.............................................................. 81
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................... 82
7.
REFERENCES .................................................................................................... 83
LIST OF TABLES
Table 1
Summary of Outcome Variables and Analysis Populations............................ 23
Table 2
TL Visit Responses ....................................................................................... 27
Table 3
NTL Visit Responses..................................................................................... 31
Table 4
Overall Visit Responses ................................................................................ 32
Table 5
Mean change and visit response in health related quality of life..................... 39
Table 6
Visit Response for HRQoL and disease-related symptoms............................. 42
Table 7
Formal statistical analyses to be conducted and pre-planned sensitivity 
analyses......................................................................................................... 57
LIST OF FIGURES
Figure 1
Study design schema ..................................................................................... 18
Figure 2
Multiple testing procedures for controlling the type 1 error rate for sub-
study B.......................................................................................................... 60


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
7
LIST OF ABBREVIATIONS
The following abbreviations and special terms are used in this study Statistical Analysis Plan.
Abbreviation or 
special term
Explanation
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
APF6
Proportion of patients alive and progression free at 6 months from 
randomisation
APF12
Proportion of patients alive and progression free at 12 months from 
randomisation
AST
Aspartate aminotransferase
AZDD
AZ drug dictionary
Baseline
Refers to the most recent assessment of any variable prior to dosing with study 
treatment/randomisation (as appropriate)
BDRM
Blinded data review meeting
BoR
Best objective response
CI
Confidence interval 
CR
Complete response
CRF / eCRF 
Case Report Form (electronic)
CRO
Contract Research Organisation
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed tomography
CTC / CTCAE
Common Terminology Criteria for Adverse Event
DAE
Discontinuation of investigational product due to adverse event
DBL
Database lock
DBP
Diastolic blood pressure
DCO
Data cut-off
DoR
Duration of response
ECG
Electrocardiogram 
EGFR
Epidermal growth factor receptor
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer 30-item core 
quality of life questionnaire
EQ-5D
EuroQoL 5-dimension utility index
EQ-5D-5L
EuroQoL 5-dimension, 5-level health state utility index 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
8
Abbreviation or 
special term
Explanation
FAS
Full analysis set
HR
Hazard ratio
HRQoL
Health related quality of life
ICU
Intensive care unit
IDMC
Independent data monitoring committee
ITT
Intention to treat
iv
Intraveneous
IVRS
Interactive voice response system
LC13
Lung Cancer Module; 13-item self-administered questionnaire from the EORTC 
for lung cancer 
LD
Lesion diameter
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milli-gram
MRI
Magnetic resonance imaging
NA
Not applicable
NCI
National Cancer Institute
NE
Not evaluable
NED
No evidence of disease
NSCLC
Non-small cell lung cancer
NTL
Non-target lesions
OAE
Other significant adverse event 
ORR
Objective response rate
OS
Overall survival
OS12
Proportion of patients alive at 12 months from randomisation
PD
Progressive disease
PD-L1
Programmed death ligand 1
PDx
Pharmacodynamic(s)
PFS
Progression free survival
PFS2
Time from randomisation to second progression or death
PGx
Pharmacogenetic(s)
PK
Pharmacokinetic(s)
PR
Partial response
PRO
Patient reported outcomes
Q12W
Every 12 weeks
Q2W
Every 2 weeks
Q4W
Every 4 weeks


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
9
Abbreviation or 
special term
Explanation
QTcF
QT interval (corrected for heart rate using Fridericia's correction)
RDI
Relative dose intensity
RECIST
Response Evaluation Criteria In Solid Tumours
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
SSA
SSB
Stable disease
Sub-Study A
Sub-Study B
SBP
Systolic blood pressure
TEAE
Treatment emergent adverse event
TL
Target lesions
ULN
Upper limit of normal
WHO
World Health Organisation


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
10
AMENDMENT HISTORY
Date
Brief description of change
5 Dec 2016
In line with the Clinical Study Protocol (CSP) Amendments: 
Removal of BICR assessments including irRECIST
Clarification the contribution of components analysis and timing. Also, this
will only be performed once so no multiplicity adjustment
Number of recruited and randomised subject updated.
Since Sub-study A is no-longer powered for hypothesis testing, analyses for
Sub-study A are now descriptive.
The interim OS analysis for sub-study A has been removed
The interim OS analysis for sub-study B will be conducted at the same time
as the final analysis of PFS, regardless of the exact number of deaths.
Clarification to the definition of the Full analysis set, Safety analysis set and
PK analysis set
Removal of sensitivity analyses for PRO endpoints
Updated presentation of OS12, PFS6 and PFS12
Study design section updated
Combination arm regimen change
IDMC first meeting change
Sample size section updated and consequently the statistical assumptions
and trigger points for analysis changed accordingly
Change in requirements for re-treatment
Change in clinically meaningful difference for LC13
Interim analysis for Overall Survival added
Multiplicity strategy
Change to CIs for Overall Survival analysis
In line with project wide developments
Changes in definition of important protocol deviations
Removal of RDI2, PID2 and PID. RDI derivation changed
Added further details for definition of baseline
Change to method of subgroup analysis
Definition of TEAE added
Event rate per 100 patients years definition changed
Clarification of death summary
Other Changes
Removal of time to first subsequent therapy or death, time to second
subsequent therapy or death
Removal of sensitivity analysis modified for confirmation of progression for
PFS and ORR 
Removal of analysis of Expected Duration of Response
Added age at randomisation (<65, ≥65) 75, ≥75) as a subgroup, removed


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
11
Date
Brief description of change
Standard of Care (gemcitabine versus vinorelbine versus erlotinib)
Clarified the definition of subsequent therapy for safety follow-up
Additional death summary
Textual edits to Derivation of RECIST Visit Responses to provide greater
clarity
Small edits to overall visit responses table
Clarification of which CRF fields to use for any Overall Survival analysis
where a survival sweep is not performed
Clarify that date of progression from the reviewer who read baseline first
will be used if there is no adjudication
Add two missed visits definition for Time from randomisation to second
progression
Removal of AESI categories as not mandated to include
Definitions of total and actual exposure for each treatment provided and
Dose intensity simplified. Dose delay definition also provided
Health resource derivation, EQ-5D and treatment switching text changed to
be in line with new Therapeutic area guidance
More detail about visit windowing added
Clarify PFS2 as time from randomisation to second progression or death and
that it will only be analysed for sub-study B
Added details of thyrotoxicity tables
Updated details on Hy’s law categories
Clarifications regarding waterfall plots
22 Jan 2018
Throughout: Corrections to minor typos and omitted words.
List of Abbreviations: Added SSA (Sub-Study A) and SSB (Sub-Study B).
Section 1.1.2 Corrected section references in footnote ‘a’ of the table outlining 
the secondary objectives.
Section 1.1.3 Removed language indicating that exploratory analyses will be 
performed when in fact they may or may not be performed
Sections 1.2, 4: Portions parallel to excerpts from CSP Amendment 7.0 or 
IDMC Charter v7.0 updated to reflect parallel changes or updates to those 
documents, mainly with respect to when and for how long re-treatment may 
be administered and timing of final analyses given that no interim analyses 
were performed.
Section 2.2 updated information specifying and describing important protocol 
deviations as per clinicians.
Section 3.1 ‘Example of scaling’ corrected units (cm to mm).
Section 3.2.5 Was corrected to correspond to the endpoint “Proportion of 
patients alive and progression free at 6 months”; previously, this section 
inadvertently repeated the endpoint described in Section 3.2.6, “Proportion of 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
12
Date
Brief description of change
patients alive and progression free at 12 months”.
Section 3.4.7 Deleted “Note that visits up to 13 days after the last dosing date 
will be considered as being on treatment for the purposes of visit windowing 
and may be assigned to an on-treatment visit. Visits after this will be 
considered as follow-up and may be assigned accordingly.” after it was 
confirmed to refer to a specific case depending on treatment assignment and 
not widely applicable as a general rule per se.
Section 3.5 Added details of PD-L1 status clarifying the groups to be <1% and 
≥1% to <25%.
Sections 4, 4.2.1, 5.1, 5.2: Addition of language clarifying that final analyses 
of OS and PFS for SSA will occur at the same time as those for SSB if they 
have not already been conducted and it is reasonable to conclude that the 
required number of events have been reached as to be consistent with portions 
parallel to excerpts from CSP Amendment 7.0 or IDMC Charter v7.0. Also, 
added “…additionally, at this time the final analyses for OS and PFS for sub-
study A will also be conducted if they have not yet been performed and it is 
reasonable to conclude that the required number of events have been reached.” 
as per IDMC request.
Section 4.1: Removed language noting SAS v9.2 or higher is used for all 
analyses.
Section 4.2: Corrected table numbering.
Section 4.2 Table 7: PD-L1 positive / negative designations here described the 
design of the sub-studies rather than the analyses described in the table. These 
could be misinterpreted and were therefore removed. Analyses specific to the 
PD-L1 subgroups are described elsewhere.
Section 4.2.2.1 changed method of handling ties to be Breslow, rather than 
Efron to be consistent with the log-rank test.
Section 4.2.2.1: Replaced subgroup Stage IIIB vs IV and with Metastatic vs 
locally advanced.
Section 4.2.2.1 Clarified that “When used as stratification factors in stratified 
analyses, standard of care therapy type and histology will be based on the 
values entered into IVRS at randomisation, even if it is subsequently 
discovered that these values were incorrect.”
Section 4.2.2.1 Clarified that “When used as a stratification factor in a 
stratified analysis, histology should come from the IVRS; however, when used 
to define a subgroup or as a general covariate in an unstratified analysis, 
histology should come from the PATHGEN module of the eCRF.” As well as:
“Standard of care will come from the IVRS regardless of whether it is used as 
a stratification factor in a stratified analysis, used to define a subgroup, or as a 
general covariate in an unstratified analysis.”
Also, clarified that “Unless otherwise stated above (e.g., standard of care, 
which always comes from IVRS), note that in general data used to construct 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
13
Date
Brief description of change
subgroups or as a general covariate in an unstratified analysis will come from 
the eCRF; however, note that when data are used in a stratified analysis, they 
should come from the IVRS (e.g., histology).”
Section 4.2.2.1 and 4.2.2.2 added PD-L1 status (<1% or ≥1% to <25%) to 
Subgroup Analysis and Effect of Covariates sections, including that it should 
be included along with the other subgrouping covariates.
Section 4.2.2.1 (Treatment Switching): Exploratory analyses described as 
‘will’ be performed changed to ‘may’ be performed.
Section 4.2.10 Health Resource Use: Analyses now noted to ‘may’ be 
performed as opposed to ‘will’ be performed to be consistent with CSP.
Section 4.2.11 Adverse Events: Summaries described as CTCAE Grade 3 or 
Higher now changed to CTCAE Grades 3 or 4.
Section 4.2.1.1 Clarified that “Fluctuations observed in CTCAE grades during 
study will be listed for all AEs.” as to be parallel with PACIFIC and to reflect 
what is already being done.
Section 4.2.3 Clarified that the logistic regression models are unstratified 
models although they adjust for the same stratification factors as in the 
analysis of the co-primary endpoints.
Section 5.1 Added “…However, for practical considerations, if it happens that 
the analysis time points for the final PFS and OS analyses are closely aligned, 
based on the occurrences of the events, then one single analysis of OS will be 
conducted along with the PFS analysis In this case, the entire 0.04 alpha will 
be utilized for this OS analysis.
Section 5.2 Clarified that "If the interim OS analysis is performed, the IDMC 
will review the efficacy data..." to create parallelism with the IDMC charter.
Section 6: Noted the addition of the PD-L1 status grouped by (<1% or ≥1% to 
<25%) to Subgroup Analysis and Effect of Covariates as different from that 
which is described in the protocol.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
14
1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary Objective
Primary Objective:
Outcome Measure:
Sub-study A (PD-L1-positive population)
To assess the efficacy of MEDI4736 monotherapy compared with Standard 
of Care in terms of OS and PFS
Sub-study B (PD-L1-negative population)
To assess the efficacy of MEDI4736+tremelimumab treatment compared 
with Standard of Care in terms of OS and PFS
OS
PFS using investigator site
assessments according to 
RECIST 1.1 a,b
a
In each of the Sub-studies A and B the assessment of PFS and OS will be considered co-primary objectives.
b
The co-primary analysis of PFS will be based on programmatically derived PFS based upon investigator site
assessment. For the analyses to be conducted, see Section 4.2.2.2.
OS Overall survival; PD-L1 Programmed death ligand 1; PFS Progression free survival; RECIST Response Evaluation 
Criteria In Solid Tumours.
1.1.2
Secondary Objectives
The following are the secondary objectives in Sub-study A (MEDI4736 monotherapy versus 
Standard of Care) and Sub-study B (MEDI4736+tremelimumab versus Standard of Care): 
Secondary Objective:
Outcome Measure:
To further assess the efficacy in terms of: OS12, 
ORR, DoR, APF6, APF12 and PFS2
OS12
ORR using investigator site assessments according to 
RECIST 1.1a
DoR using investigator site assessments according to 
RECIST 1.1 a
APF6 and APF12 using investigator site assessments 
according to RECIST 1.1 a
PFS2 as defined by local standard clinical practice
To assess the safety and tolerability profile
Adverse events, physical examinations, vital signs 
including blood pressure, pulse, electrocardiograms, and 
laboratory findings including clinical chemistry, 
haematology and urinalysis
To assess the PK of MEDI4736 and tremelimumab
Concentration of PK in blood and non-compartmental 
PK parameters (such as peak concentration and trough, 
as data allow) (sparse sampling)
To investigate the immunogenicity of MEDI4736 and 
tremelimumab 
ADA (confirmatory results: positive or negative; titres 
[ADA neutralising antibodies will also be assessed]) 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
15
Secondary Objective:
Outcome Measure:
To assess symptoms and health-related QoL using 
EORTC QLQ-C30 v3 and LC13
EORTC QLQ-C30: Time to symptom deterioration 
(fatigue, pain, nausea/vomiting, dyspnoea, loss of 
appetite, insomnia, constipation, and diarrhoea). Time to 
QoL/function deterioration (physical function; role 
function; emotional function; cognitive function; social 
function and global health status/QoL)
LC13: Time to symptom deterioration (dyspnoea, 
cough, haemoptysis, chest pain, arm/shoulder pain, 
other pain)
Changes in World Health Organisation Performance 
Status will also be assessed
Sub-study B (PD-L1-negative population)
To evaluate the efficacy of 
MEDI4736+tremelimumab treatment compared with 
a) MEDI4736 monotherapy and b) tremelimumab
monotherapy 
PFSa, ORRa, DoRa, using investigator site assessments 
according to RECIST 1.1, and OS 
a
Analysis of ORR, DoR, APF6 and APF12 will be based upon investigator assessment. For the analyses to be conducted, 
see Sections 4.2.3, 4.2.4, 4.2.5, and 4.2.6.
ADA Anti-drug antibody; APF6 Proportion of patients alive and progression free at 6 months from randomisation; APF12
Proportion of patients alive and progression free at 12 months from randomisation; DoR Duration of response; EORTC QLQ-
C30 European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire; LC13 Lung 
Cancer Module; ORR Objective response rate; OS12 Proportion of patients alive at 12 months from randomisation; PFS
Progression free survival; PFS2 Time from randomisation to second progression; PK Pharmacokinetic(s); QoL Quality of 
Life; RECIST Response Evaluation Criteria In Solid Tumours.
In Sub-study B, PFS in MEDI4736+tremelimumab arm will be compared to each of the 
MEDI4736 and tremelimumab monotherapy arms as part of the contribution of components
analysis. This analysis is planned to be performed when approximately 158 PFS events are 
observed in the MEDI4736+tremelimumab and tremelimumab monotherapy arms. However, 
for practical considerations, if this time is close to the time of the final PFS analysis, the 
contribution of components analysis will be conducted at the time of the PFS final analyses.
This is considered a secondary objective of the study.
1.1.3
Exploratory Objectives
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
16
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Adverse event; EQ-5D-5L EuroQoL 5-dimension, 5-level health state utility index; IFN Interferon; IL Interleukin; ORR 
Objective response rate; OS Overall survival; PD-L1 Programmed death ligand 1; PDx Pharmacodynamic(s); PFS
Progression free survival; PK Pharmacokinetic(s).
With regards to PD-L1 expression determined by immunohistochemistry, this will be reported 
in the Clinical Study Report (CSR).
1.2
Study design
This study is a Phase III, randomised, open label, multi-centre study assessing the efficacy and 
safety of MEDI4736 versus Standard of Care in NSCLC patients with PD-L1-positive 
tumours (where positive is defined as ≥25% of tumour cells with membrane staining 
[proprietary PD-L1 immunohistochemistry assay; Ventana Medical Systems, Inc]) and the 
combination of MEDI4736 plus tremelimumab (MEDI4736+tremelimumab) versus Standard 
of Care in NSCLC patients with PD-L1-negative tumours (where negative is defined as <25% 
of tumour cells with membrane staining [proprietary PD-L1 immunohistochemistry assay; 
Ventana Medical Systems, Inc]).
CCI
CCI


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
17
The original study design intended to recruit 250 patients to Sub-study A. However, due to 
low patient accrual, the recruitment to Sub-study A was closed in Q1 2016 at which time 
126 patients had been randomised. As a result, the analysis plan for Sub-study A was updated 
and is presented in Protocol Amendment 6.0, dated 31 August 2016. 
Approximately 1300 patients will be recruited, with 610 patients expected to be randomised 
(126 patients in Sub-study A and 480 patients in Sub-study B) at approximately 250 sites 
worldwide in a 1:1 ratio in Sub-study A and a 3:2:2:1 ratio
(MEDI4736+tremelimumab:MEDI4736:Standard of Care:tremelimumab) in Sub-study B.
Sub-study A (patients with PD-L1-positive tumours):

MEDI4736 (10 mg/kg Q2W iv for up to 12 months) (approximately 60 patients)

Standard of Care (restricted to the erlotinib, gemcitabine or vinorelbine)
(approximately 60 patients). For each agent 4 weeks equates to 1 cycle of treatment.

Erlotinib: 150 mg once daily as a tablet for oral administration taken at least
1 hour before or 2 hours after the ingestion of food

Gemcitabine: 1000 mg/m2 iv over 30 minutes on Days 1, 8, and 15 of a 28-day 
cycle

Vinorelbine: 30 mg/m2 iv on Days 1, 8, 15 and 22 of a 28-day cycle.
Sub-study B (patients with PD-L1-negative tumours):

MEDI4736+ tremelimumab (MEDI4736 20 mg/kg plus tremelimumab 1 mg/kg
Q4W iv for up to 12 weeks [4 doses]) then MEDI4736 alone (10 mg/kg Q2W iv,
starting at Week 16, for 34 weeks [18 doses]) (10 mg/kg Q4W iv for 24 weeks then
Q12W for a further 24 weeks) (180 patients)

Standard of Care (see under Sub-study A) (120 patients)

MEDI4736 (10 mg/kg Q2W iv for up to 12 months) (120 patients)

Tremelimumab (10 mg/kg Q4W iv for 24 weeks then Q12W for 24 weeks)
(60 patients).
The sub-studies may not run concurrently with start and completion of recruitment potentially 
occurring at different time points. Assignment to the applicable sub-study will be preceded by 
the Pre-screening Period during which assessment of the patient’s PD-L1 status, based on a 
tumour sample, will take place. After confirmation of PD-L1 status, patients will enter the 
main Screening Period within their assigned sub-study if it remains open for recruitment. The 
study design is shown in diagram form in Figure 1.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
18
Figure 1
Study design schema
Determination
of PD-L1 
status
PD-L1
positive
PD-L1
negative
Sub-study B
Day -42 to -1
Day 1
Randomisation
Pre-screening
Treatment  Period
Follow-up
Screening and 
Assignment to 
Sub-study
All patients will 
enter follow up.
For the 
immunotherapy 
arms re-
treatment  is 
allowed
for those who 
have disease 
control  after 
12 months of 
treatment but
progress during 
follow-up. For 
combination arm, 
re-treatment 
allowed after 
16 weeks but 
progress during 
MEDI4736 
monotherapy 
period
MEDI4736 monotherapy
(Upto 12 months)
Standard of Care
(For as long as getting clinical benefit)
MEDI4736 monotherapy 
(Up to 12 months)
Tremelimumab monotherapy
(Up to 12 months)
Day -28 to -1
PD-L1 = programmed death ligand 1
MEDI4736+tremelimumab
(Up to 12 months   [combination  for 
12 weeks; MEDI4736 monotherapy for 
34 weeks])
Standard of Care
(For as long as getting clinical benefit)
Sub-study A
1:1 ratio
3:2:2:1 ratio
PD-L1 expression will be determined for all patients prior to randomisation. Patients will be 
assigned to Sub-study A and Sub-study B respectively based on PD-L1 tumour expression 
status (PD-L1 positive versus PD-L1 negative [based on an archival tumour sample or a recent 
tumour biopsy]). Patients will be stratified at randomisation based on the Standard of Care 
treatment that they would be administered (2 categories: gemcitabine/vinorelbine versus 
erlotinib) and histology (2 categories: squamous versus all other).
The primary objective of this study is to assess the efficacy of MEDI4736 monotherapy 
(patients with PD-L1-positive tumours) and MEDI4736+tremelimumab (patients with PD-L1-
negative tumours) compared with Standard of Care in terms of OS and PFS (per RECIST 1.1 
based on investigator data.
For Sub-study B a contribution of components analysis will be performed when 
approximately 158 PFS events are observed in the MEDI4736+tremelimumab and 
tremelimumab monotherapy arms. However, for practical considerations, if this time is close 
to the time of the final PFS analysis, the contribution of components analysis will be 
conducted at the time of the final PFS analysis. The purpose of the analysis is to compare the 
monotherapy and combination dosing regimens to determine if the combination therapy (i.e. 
MEDI4736+tremelimumab) is more efficacious than each of the monotherapy arms. As these 
treatment comparisons are secondary and serve a different purpose to that of the primary 
comparisons, they are not included in the multiple testing procedure for the primary 
comparisons, and an alpha of 0.05 will be used for either PFS or OS without multiplicity 
adjustment.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
19
If the contribution of components analysis is performed prior to the final PFS analysis and the 
MEDI4736+tremelimumab arm is superior to either of the monotherapy arms then that 
monotherapy arm may be dropped from the study and all patients on that treatment will be 
discontinued. However, any patients on that treatment will have the opportunity to remain on 
treatment if they are gaining clinical benefit and if, after discussion with their treating 
physician, it is felt that this is the best treatment option for them.
Sub-study A: Treatment with MEDI4736 10 mg/kg will commence on Day 1 following 
randomisation after confirmation of eligibility and will continue on a Q2W schedule for up to 
12 months. Treatment should be discontinued prior to 12 months if there is confirmed PD 
(unless the investigator considers the patient continues to receive benefit from treatment), 
initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other 
reasons to discontinue treatment occur. Patients who have discontinued treatment due to 
toxicity, symptomatic deterioration or who have commenced subsequent anti-cancer therapy 
will be followed up until confirmed disease progression or death (whichever occurs first).
Study drug should be discontinued if there is confirmed PD while on treatment following a 
previous response (PR or CR) to study drug while on treatment (ie, the response and 
progression events both occurred while receiving study drug during the same treatment 
period).
Sub-study B: Treatment with MEDI4736 or tremelimumab monotherapy, or the combination 
of MEDI4736+tremelimumab will commence on Day 1 following randomisation after 
confirmation of eligibility. MEDI4736 will continue on a 10 mg/kg Q2W schedule when 
given as monotherapy for up to 12 months and tremelimumab when given as a monotherapy, 
will continue on a 10 mg/kg Q4W schedule for 24 weeks then Q12W for a further 24 weeks.
MEDI4736+tremelimumab in combination will be administered from Day 1 on a Q4W 
schedule up to 12 weeks (4 doses of MEDI4736 20 mg/kg and tremelimumab 1 mg/kg) after 
which MEDI4736 10 mg/kg alone will be administered on a Q2W schedule for 34 weeks 
starting at Week 16 (18 doses).
In the monotherapy arms in Sub-study B, treatment should be discontinued prior to 12 months 
(MEDI4736 monotherapy) or 48 weeks (tremelimumab monotherapy) if there is confirmed 
PD (unless the investigator considers the patient continues to receive benefit from treatment), 
initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other 
reasons to discontinue treatment occur. Patients who have discontinued treatment due to 
toxicity, symptomatic deterioration or who have commenced subsequent anti-cancer therapy 
will be followed up until confirmed disease progression or death (whichever occurs first).
Study drug should be discontinued if there is confirmed PD while on treatment following a 
previous response (PR or CR) to study drug while on treatment (ie, the response and 
progression events both occurred while receiving study drug during the same treatment 
period).
In the MEDI4736+tremelimumab combination arm, if a patient experiences PD, retreatment 
with the combination regimen (MEDI4736+ tremelimumab) is allowed. Retreatment in the 
combination arm can only occur if PD, with or without confirmation, occurs during the 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
20
MEDI4736 monotherapy portion or after completion of 12 months of therapy. During the 
retreatment period, the patient would resume MEDI4736 dosing at 20 mg/kg Q4W as during 
the initial induction period, along with 1 mg/kg of tremelimumab Q4W for 4 doses.
Monotherapy with MEDI4736 would then resume at 10 mg/kg Q2W 4 weeks after the last 
combination dose is administered. Retreatment will continue as long as the investigator judges 
the patient is deriving clinical benefit.
Both Sub-study A and B: Treatment in the Standard of Care arm will commence on Day 1 
following randomisation after confirmation of eligibility and will continue on a 4-weekly 
schedule until PD (unless the investigator considers the patient continues to receive benefit 
from treatment), initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of 
consent, or other reasons to discontinue treatment occur.
Tumour assessments using computed tomography (CT)/magnetic resonance imaging (MRI) 
will be performed every 8 weeks for 48 weeks then 12-weekly thereafter.
Once a patient has had objective progression recorded and has discontinued study drug, the 
patient will be followed up for survival status every 2 months until death, withdrawal of 
consent or the final DCO. Patients will also be assessed every 12 weeks for a second 
progression defined according to local standard clinical practice and may involve any of: 
objective radiological, symptomatic progression or death.
At the time of the final DCO, the analysis portion of the clinical study will have been 
completed and all patients remaining in the study will be considered to have completed the 
analysis portion of the study.
Independent Data Monitoring Committee (IDMC)
An IDMC will be convened and will meet approximately 6 months after the study has started 
or 20 patients have been randomised to the combination arm on Sub-study B (whichever 
comes first) to review safety assessments and make recommendations to continue, amend, or 
stop the study based on safety findings. The committee will meet approximately every
6 months thereafter. The IDMC will also review:

The interim analysis for OS on Sub-study B (if performed).

The contribution of components analysis for the immunotherapy arms if this
analysis occurs before the primary PFS analysis.
All patients who receive a dose of study treatment will be evaluated for safety and tolerability.
Enrolment will continue unless there is an unexpected safety concern. The study may be 
adjusted or suspended depending on the IDMC review outcome.
Details on the IDMC are provided in Section 5.2 and full details of the IDMC procedures and 
processes can be found in the IDMC Charter.Number of subjects


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
21
The sample size for this study was selected to be consistent with the research hypotheses as 
described in the protocol Section 1.2.
The co-primary endpoints in sub-study are OS and PFS. To control for type I error, an alpha 
level of 0.04 will be used for analysis of OS (accounting for one formal interim analysis to 
assess efficacy) and an alpha level of 0.01 will be used for analysis of PFS. Sub-study B study 
will be considered positive (a success) if either the PFS analysis results and/or the OS analysis 
results are statistically significant. Sub-study A will be descriptive in nature with no statistical 
testing.
A total of approximately 1300 patients are expected to be recruited in the study to achieve 
610 evaluable patients in the study (approximately 126 patients in Sub-study A and 
480 patients in Sub-study B). The PD-L1-positive population is assumed to be approximately 
30% of total population (AstraZeneca, unpublished data). If the prevalence assumption does 
not hold then it is likely that recruitment will need to be extended. The sample sizing for each 
sub-study assumes a delay in separation of the survival curves between each arm hence the 
use of average HRs.
OS analysis
The OS analysis in Sub-study A (PD-L1-positive population) will be performed when 82 
deaths have occurred from 126 patients (65% maturity). 
The OS analysis in Sub-study B (PD-L1-negative population) will be performed when 
approximately 205 deaths have occurred from the 300 patients (68% maturity) who have been 
randomised to the MEDI4736+tremelimumab and Standard of Care arms. Assuming the true 
average HR is 0.63 in PD-L1-negative population for OS (corresponding to a 4.4-month 
improvement in median OS from a control group median of 7 months), this analysis will have 
90% power to demonstrate a statistically significant difference for OS, assuming an overall 
alpha level of 0.04 two-sided. The minimal difference in OS that could be deemed statistically 
significant in Sub-study B is an average HR of 0.75. A 15-month recruitment period and a 
minimum follow-up period of 12 months is assumed on Sub-study B for OS. Therefore it is 
anticipated that this OS analysis could be performed 27 months after the first patient has been 
recruited. Assuming that the survival curves of the two treatment arms do not separate for 2 
months then the HR after that point would need to be 0.53 to produce an average HR of 0.63 
over the follow-up period. This would be associated with 12-month survival rates of 30.5% 
for Standard of Care and 48.5% for MEDI4736+tremelimumab.
PFS analysis
The PFS analysis in Sub-study A (PD-L1-positive population) will be performed at the same 
time as the OS analysis on Sub-study A. 
The PFS analysis in Sub-study B (PD-L1-negative population) will be performed when 
approximately 244 PFS events have occurred from 300 patients (81% maturity) who have 
been randomised to the MEDI4736+tremelimumab and Standard of Care arms. Assuming the 
true average HR is 0.63 in PD-L1-negative population for PFS (corresponding to a 1.3-month


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
22
improvement in median PFS from a control group median of 3 months), this analysis will 
have 84% power to demonstrate a statistically significant difference for PFS, assuming an 
alpha level of 0.01 two-sided. The minimal difference in PFS that would be deemed 
statistically significant in Sub-study B is an average HR of 0.72. Sub-study B is expected to 
have a recruitment period of 15 months and a follow-up period of 7 months for the PFS 
endpoint. Therefore it is anticipated that this PFS analysis could be performed at a minimum 
of 22 months after the first patient has been recruited. If the survival curves of the two 
treatment arms do not separate for 2 months then the HR after that point would need to be 
0.43 to produce an average HR of 0.63 over the follow-up period. This would be associated 
with 12-month PFS rates of 6.3% for Standard of Care and 23.3% for 
MEDI4736+tremelimumab.
The estimates of median PFS (3 months) and median OS (7 months) in the control group used 
for the design of this study have been estimated following a literature review of available data 
in the NSCLC patient population (Hanna et al 2004).
2.
ANALYSIS SETS
2.1
Definition of analysis sets
Three main analysis sets are defined for this study.
Full analysis set (FAS) (Intention to treat (ITT)): 
The FAS will include all randomised patients with treatment groups assigned in accordance 
with the randomisation, regardless of the treatment actually received. Patients who were 
randomised but did not subsequently receive treatment are included in the FAS.
The analysis of data using the FAS therefore follows the principles of ITT. Therefore, all 
efficacy and HRQoL data will be summarised and analysed using the FAS on an ITT basis.
Safety analysis set 
All patients who received at least one dose of randomised treatment (regardless of whether 
that was the randomised therapy intended or indeed whether, in rare cases, they received 
therapy without being randomised) in each of the sub-studies will be included in the safety 
population. Throughout the safety results sections, erroneously treated patients (eg, those 
randomised to Treatment A but actually given Treatment B) will be accounted for in the actual 
treatment arm. If a patient received treatment from more than one treatment arm then they 
would be accounted for based upon their initial treatment started.
When assessing safety and tolerability, summaries will be produced based on the safety 
analysis set.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
23
PK analysis set
All patients who receive at least 1 dose of MEDI4736 (Sub-study A), or either 
MEDI4736+tremelimumab, MEDI4736 monotherapy or tremelimumab monotherapy 
(Sub-study B) per the protocol, for whom any post-dose data are available will be included in 
the PK analysis set. The population will be defined by the Study Team Physician, 
Pharmacokineticist and Statistician prior to any analyses being performed.
Table 1 gives a summary of outcome variables and analysis populations.
Table 1
Summary of Outcome Variables and Analysis Populations
Outcome variable
Populations
Efficacy Data
OS, PFS
FAS(ITT) 
OS12, ORR*, DoR*, APF6, APF12, PFS2, PRO endpoints*, World Health 
Organisation performance status
FAS(ITT) 
Study Population/Demography Data
Demography characteristics (e.g. age, sex etc.)
FAS(ITT)
Baseline and disease characteristics
FAS(ITT)
Important deviations
FAS(ITT)
Medical/Surgical history
FAS(ITT)
Previous anti-cancer therapy 
FAS(ITT)
Concomitant medications/procedures
FAS(ITT)
Subsequent anti-cancer therapy
FAS(ITT)
PK Data
PK data
PK
Immunogenicity
Immunogenicity data
Safety
Safety Data
Exposure
Safety
Adverse events
Safety
Laboratory measurements
Safety
Vital Signs
Safety
ECGs
Safety
APF6 Proportion of patients alive and progression free at 6 months from randomisation; APF12 Proportion of 
patients alive and progression free at 12 months from randomisation; DoR Duration of response; ITT Intent-to-
Treat; ORR Objective response rate; OS Overall survival; OS12 Proportion of patients alive at 12 months from 
randomisation; PFS Progression free survival; PFS2 Time from randomisation to second progression; PK
Pharmacokinetic; PRO Patient reported outcomes.
*Patients who are evaluable for the analysis of ORR are those with measurable disease at baseline. Patients who 
are evaluable for the analysis of DoR are those who responded in the ORR analysis. Patient evaluability for PRO 
endpoints are detailed in Section 3.3.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
24
2.2
Violations and deviations
The important protocol deviations will be listed and summarised by randomised treatment 
group. Deviation 1 below will lead to exclusion from the Safety analysis set. None of the other 
deviations will lead to 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). 
A per-protocol analysis excluding patients with significant protocol deviations is not planned; 
however, a ‘deviation bias’ sensitivity analysis may be performed excluding patients with 
deviations that may affect the efficacy of the trial therapy if > 10% of patients:

did not have the intended disease or indication or

did not receive any randomised therapy.
The need for such a sensitivity analysis will be determined following review of the protocol 
deviations ahead of database lock and will be documented prior to the primary analysis being 
conducted.
Eligibility criteria deviations are deviations from the protocol inclusion and exclusion criteria. 
Post-entry deviations are deviations from the protocol that occurred after the patient was 
assigned to the study.
The following general categories will be considered important deviations and be listed and 
discussed in the CSR as appropriate for the study. If a ‘deviation bias’ sensitivity analysis is 
conducted then patients with these deviations will be excluded from the sensitivity analysis:

Patients randomised but who did not receive study treatment (Deviation 1).

Patients who deviate from key entry criteria per the CSP Amendment 5 (Deviation
2). These are inclusion criteria 3, 4, 7 and exclusion criteria 5, 6, 10, 17 and, for
sub-study B only, 31, 32, 33.

Baseline RECIST scan > 42 days before date of randomisation (Deviation 3). Note
that although the screening period for baseline RECIST assessment was 28 days, an
additional 14-day window should be applied thus only baseline RECIST
assessments of greater than 42 days will be deemed as constituting an important
deviation.

No baseline RECIST 1.1 assessment on or before date of randomisation (Deviation
4).

Received prohibited concomitant systemic anti-cancer agents (Deviation 5). Please
refer to the Clinical Study Protocol (CSP) section 5.6 for the systemic anti-cancer
agents that are detailed as being ‘excluded’ from permitted use during the study.
This will be used as a guiding principle for the physician review of all medications
prior to database lock.

Patients randomised who received treatment other than that to which they were
randomised to (Deviation 6).


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
25

Patients enrolled to the incorrect sub-study (ie patients who are PD-L1 positive who
are enrolled onto sub-study B and patients who are PD-L1 negative who are
enrolled onto sub-study A (Deviation 7).
The categorisation of these as important deviations is not automatic and will depend on 
duration and the perceived effect on efficacy.
In addition to the programmatic determination of the deviations above, monitoring notes or 
summaries will be reviewed to determine any important post entry deviations that are not 
identifiable via programming, and to check that those identified via programming are correctly 
classified. 
Errors in treatment dispensing, in addition to incorrect stratifications, will also be investigated 
more closely. This may occur when a patient is not randomised or treated according to the 
randomisation schedule on at least one occasion. It is envisaged that there will be 3 sub 
categories of this within the important deviations summary:

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 randomisation
code and the treatment differs from the randomised treatment.

The patient receives a treatment pack with a different code to their randomisation
code. However, the actual treatment may still match the randomised treatment. For
example, a patient is given randomisation code 0001, which according to the
randomisation schedule is MEDI4736. However, at the randomisation visit they are
given treatment pack 0003, but this still contains MEDI4736.
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 errors in 
treatment dispensing (with regards to continuation/discontinuation of study treatment or, if 
applicable, analytically) will be made on an individual basis with written instruction from the 
study team leader and/or statistician.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Derivation of RECIST Visit Responses
For all patients, the RECIST version 1.1 (see further Appendix F of the CSP) tumour response 
data will be used to determine each patient’s visit response. It will also be used to determine if 
and when a patient has progressed in accordance with RECIST and also their best objective 
response to study treatment.
The baseline assessment should be performed no more than 28 days before the start of study 
treatment and ideally as close as possible to the start of randomised treatment. Efficacy for all 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
26
patients will be assessed by objective tumour assessments every 8 weeks for the first 48 weeks 
(relative to the date of randomisation per Table 3 in the CSP for MEDI4736 monotherapy,
Table 4 in the CSP for tremelimumab monotherapy, Table 5 in the CSP for
MEDI4736+tremelimumab, Table 8 in the CSP for gemcitabine and vinorelbine and Table 9
in the CSP for erlotinib) and then every 12 weeks thereafter until confirmed objective disease 
progression as defined by RECIST 1.1 (irrespective of the reason for stopping treatment 
and/or subsequent therapy). If an unscheduled assessment is performed, and the patient has 
not progressed, every attempt should be made to perform the subsequent assessments at their 
scheduled visits. This schedule is to be followed in order to minimise any unintentional bias 
caused by some patients being assessed at a different frequency than other patients.
For patients who discontinue study drug due to toxicity or a reason other than confirmed PD, 
objective tumour assessments should be continued every 8 weeks for 48 weeks (relative to the 
date of randomisation) then every 12 weeks thereafter until confirmed progressive disease by 
RECIST 1.1 by investigational site review.
In the monotherapy arms and during the first 4 cycles of the combination arm, disease
progression requires confirmation and 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. Administration of study treatment will continue 
between the initial assessment of progression and confirmation for progression. 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. The patient must continue to meet those inclusion and 
exclusion criteria that are relevant to treatment through disease progression as specified in 
Section 4.3 of the CSP. Patients with rapid tumour progression or with symptomatic 
progression that requires urgent medical intervention (eg, central nervous system metastasis, 
respiratory failure due to tumour compression, spinal cord compression) will not be eligible to 
continue to receive study treatment.
Study drug should be discontinued if there is confirmed PD following a previous response (PR 
or CR) to study drug while on treatment (ie, the response and progression events both 
occurred while receiving study drug during the same treatment period).
From the investigator’s review of the imaging scans, the RECIST tumour response data will 
be used to determine each patient’s visit response according to RECIST version 1.1. At each 
visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, PR, SD 
or PD, using the information from target lesions (TLs), non-target lesions (NTLs) and new 
lesions and depending on the status of their disease compared with baseline and previous 
assessments. If a patient has had a tumour assessment which cannot be evaluated then the 
patient will be assigned a visit response of not evaluable (NE) (unless there is evidence of 
progression in which case the response will be assigned as PD).
Please refer to Section 3.1.3 for the definitions of CR, PR, SD and PD. 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
27
RECIST outcomes (ie PFS, ORR etc.) will be calculated programmatically for the site 
investigator data (see Section 3.2) from the overall visit responses. 
3.1.1
Site Investigator Assessment Using RECIST 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 patient 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 the date of 
randomisation will be used to define the baseline sum of TLs. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion, which can be measured reproducibly, should be selected.
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline. Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.
Measurable disease (ie at least one TL) is one of the entry criteria for the study. However, if a 
patient with non-measurable disease is enrolled in the study, the evaluation of overall visit 
responses will be based on the overall NTL assessment and the absence/presence of new 
lesions (see Section 3.1.2 for further details). If a patient does not have measurable disease at 
baseline then the TL visit response will be not applicable (NA).
Table 2
TL Visit Responses 
Visit Responses
Description
Complete Response (CR)
Disappearance of all target lesions. Any pathological lymph nodes 
selected as target lesions must have a reduction in short axis to <10mm.
Partial Response (PR)
At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum of diameters as long as criteria for PD are 
not met.
Progressive Disease (PD)
A ≥ 20% increase in the sum of diameters of target lesions and an 
absolute increase of ≥5mm, taking as reference the smallest sum of 
diameters since treatment started including the baseline sum of 
diameters.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
28
Table 2
TL Visit Responses 
Visit Responses
Description
Not Evaluable (NE)
Only relevant in certain situations (i.e. if any of the target lesions were 
not assessed or not evaluable or had a lesion intervention at this visit; 
and scaling up could not be performed for lesions with interventions). 
Note: If the sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a target lesion response
Not Applicable (NA)
No target lesions are recorded at baseline
Rounding of TL data
For calculation of PD and PR for TLs, percentage changes from baseline and previous 
minimum should be rounded to 1 decimal place before assigning a TL response. For example 
19.95% should be rounded to 20.0% but 19.94% should be rounded to 19.9%.
Missing TL data 
For a visit to be evaluable, all TL measurements should be recorded. However, a visit 
response of PD should still be assigned if any of the following occurred:

A new lesion is recorded.

A NTL visit response of PD is recorded.

The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute
increase of ≥ 5mm, from nadir even assuming the non-recorded TLs have
disappeared.
Note: the nadir can only be taken from assessments where all the TLs had a lesion diameter 
recorded.
If there is at least one TL measurement missing and a visit response of PD cannot be assigned, 
the visit response is NE.
Lymph nodes
For lymph nodes, if the size reduces to < 10 mm 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 < 10 mm and all other TLs 
are 0 mm then although the sum may be >0 mm the calculation of TL response should be 
over-written as a CR. 
TL visit responses subsequent to CR
A CR can only be followed by CR, PD or NE. If a CR has occurred then the following rules at 
the subsequent visits must be applied:

Step 1: If all lesions meet the CR criteria (i.e. 0 mm or < 10 mm for lymph nodes)
then response will be set to CR irrespective of whether the criteria for PD of TL is


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
29
also met i.e. if a lymph node lesion diameter (LD) increases by 20% but remains 
< 10 mm. 

Step 2: If some lesion measurements are missing but all other lesions meet the CR
criteria (i.e. 0 mm or < 10 mm for lymph nodes) then response will be set to NE
irrespective of whether when referencing the sum of TL diameters the criteria for
PD is 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. It is expected that a visit response of PD will remain 
in the vast majority of cases.
TL too small to measure
If a TL becomes too small to measure a value of 5 mm will be entered into the database and 
used in TL calculations, unless the radiologist has indicated and entered a smaller value that 
can be reliably measured. If a TL response of PD results then this will be reviewed by the 
study team blinded to treatment assignment.
Irradiated lesions/lesion intervention
Previously irradiated lesions (i.e. lesion irradiated prior to entry into the study) and also 
biopsy lesions 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 / embolisation), should be handled in the following way and 
once a lesion has had intervention then it should be treated as having intervention for the 
remainder of the study noting that an intervention will most likely shrink the size of tumours:

Step 1: the diameters of the TLs (including the lesions that have had intervention)
will be summed and the calculation will be performed in the usual manner. If the
visit response is PD this will remain as a valid response category.

Step 2: If there was no evidence of progression after step 1, treat the lesion diameter
(for those lesions with intervention) as missing and scale up as described below, as
long as there remain 1/3 of the TLs with missing measurements. If the scaling
results in a visit response of PD then the patient would be assigned a TL response of
PD.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
30

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 with interventions),
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 has a value of 0
(or <10mm for lymph nodes) recorded. If scaling up is not appropriate due to too
few non-missing measurements then the visit response will be set as NE.
At subsequent visits the above steps will be repeated to determine the TL and overall visit 
response. When calculating the previous minimum, lesions with intervention should be treated 
as missing and scaled up where appropriate (as per step 2 above).
Scaling (applicable only for irradiated lesions/lesion intervention)
If > 1/3 of target lesion measurements are treated as missing (because of intervention) then 
target lesion response will be NE, unless the sum of diameters of non-missing target lesion 
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 target lesions has increased by 
5mm from nadir).
If ≤ 1/3 of the target lesion measurements are treated as missing (because of intervention) then 
the results will be scaled up (based on the sizes at the nadir visit to give an estimated sum of 
diameters and this will be used in calculations; this is equivalent to comparing the visit sum of 
diameters of the non-missing lesions to the nadir sum of diameters excluding the lesions with 
missing measurements).
Example of scaling
Lesion
Longest diameter at nadir visit
Longest diameter at follow-up visit
1
7.2
7.1
2
6.7
6.4
3
4.3
4.0
4
8.6
8.5
5
2.5
Intervention
Sum
29.3
26
Lesion 5 has had an intervention 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 
baseline visit is 26.8 mm.
Scale up as follows to give an estimated TL sum of 28.4 mm:
(26.0 mm / 26.8 mm) × 29.3 mm = 28.4 mm
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.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
31
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 0 mm.
Change in method of assessment of TLs
CT and MRI are the only methods of assessment that can be used within the trial. 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
Site Investigator Assessment Using RECIST 1.1: Non-target lesions (NTLs) 
and new lesions
At each visit an overall assessment of the NTL response should be recorded by the 
investigator. This section provides the definitions of the criteria used to determine and record 
overall response for NTL at the investigational site at each visit.
NTL response will be derived based on the investigator’s overall assessment of NTLs as 
follows:
Table 3
NTL Visit Responses 
Visit Responses
Description
Complete Response (CR)
Disappearance of all NTLs present at baseline with all lymph nodes 
non-pathological in size (<10 mm short axis).
Progressive Disease (PD)
Unequivocal progression of existing non-target lesions. Unequivocal 
progression may be due to an important progression in one lesion only 
or in several lesions. In all cases the progression MUST be clinically 
significant for the physician to consider changing (or stopping) 
therapy.
Non-CR/Non-PD
Persistence of one or more NTLs with no evidence of progression.
Not Evaluable (NE)
Only relevant when one or some of the non-target lesions were not 
assessed and, in the investigator's opinion, they are not able to provide 
an evaluable overall non-target lesion assessment at this visit.
Note: For patients without target lesions at baseline, this is relevant if 
any of the non-target lesions were not assessed at this visit and the 
progression criteria have not been met.
Not Applicable (NA)
Only relevant if there are no NTLs at baseline.
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 tumour burden has increased sufficiently to merit a determination of disease 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
32
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 tumour.
New lesions will be identified via a Yes/No tick box. The absence and presence of new lesions 
at each visit should be listed alongside the TL and NTL visit responses.
A new lesion indicates progression so the overall visit response will be PD irrespective of the 
TL and NTL response.
If the question ‘Any new lesions since baseline’ has not been answered with Yes or No and 
the new lesion details are blank this is not evidence that no new lesions are present, 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 tumour 
assessments where possible until objective disease progression is observed.
3.1.3
Site Investigator Assessment Using RECIST 1.1: 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 Lesions
Non-target lesions
New Lesions
Overall Response
CR
CR or NA
No (or NE)
CR
NA
CR
No (or NE)
CR
CR
Non CR/Non PD or NE
No (or NE)
PR
PR
Non PD or NE or NA
No (or NE)
PR
SD
Non PD or NE or NA
No (or NE)
SD
NA
Non CR/Non PD
No (or NE)
SD 
NE
Non PD or NE or NA
No (or NE)
NE


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
33
Table 4
Overall Visit Responses
Target Lesions
Non-target lesions
New Lesions
Overall Response
NA
NE
No (or NE)
NE
PD
Any
Any
PD
Any
PD
Any
PD
Any
Any
Yes
PD
NA
NA
No (or NE)
NED
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable, NED = no evidence of disease, NA = not applicable (only relevant if there were no TL/NTL at 
baseline).
3.2
Outcome Variables
All RECIST assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a patient discontinues investigational product.
RECIST outcomes (ie PFS, ORR etc.) will be calculated programmatically for the site 
investigator data from the overall visit responses. 
3.2.1
Co-primary endpoints
Within Sub-study A and Sub-study B, the co-primary endpoints are OS and PFS.
3.2.1.1
Overall survival 
Overall survival is defined as the time from the date of randomisation until death due to any 
cause (ie, date of death or censoring - date of randomisation + 1). Any patient not known to 
have died at the time of analysis will be censored based on the last recorded date on which the 
patient was known to be alive (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 
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 if a 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
34
survival sweep is not performed). The last date for each individual subject is defined as the 
latest among the following dates recorded on the CRFs:

AE start and stop dates

Admission and discharge dates of hospitalization

Study treatment date

End of treatment date

Laboratory test dates

Date of vital signs

Disease assessment dates on RECIST CRF

Start and stop dates of alternative anticancer treatment

Date last known alive on survival status CRF

End of study date
3.2.1.2
Progression free survival
PFS (per RECIST 1.1 as assessed by the investigator) will be defined as the time from the date 
of randomisation until the date of objective disease progression or death (by any cause in the 
absence of progression) regardless of whether the patient withdraws from randomised therapy 
or receives another anti-cancer therapy prior to progression (ie, date of event or censoring -
date of randomisation + 1). 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 prior to the 
two missed visits.
Given the scheduled visit assessment scheme (ie eight-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 274 (ie week 39) then two missing visits will 
equate to 18 weeks since the previous RECIST assessment, allowing for early and late visits
(ie, 2 x 8 weeks + 1 week for an early assessment + 1 week for a late assessment = 18 weeks).
If the two missed visits occur over the period when the scheduled frequency of RECIST 
assessments changes from eight-weekly to twelve-weekly this will equate to 22 weeks (ie,
take the average of 8 and 12 weeks which gives 10 weeks and then apply same rationale hence 
2 x 10 weeks + 1 week for an early assessment + 1 week for a late assessment = 22 weeks). 
The time period for the previous RECIST assessment will be from study days 274 to 344 (ie 
week 39 to week 49). From week 49 onwards (when the scheduling changes to twelve-weekly 
assessments), two missing visits will equate to 26 weeks (ie 2 x 12 weeks + 1 week for an 
early assessment + 1 week for a late assessment = 26 weeks). 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
35
If the patient has no evaluable visits or does not have baseline data they will be censored at 
Day 1 unless they die within 2 visits of baseline (16 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 1.1 assessments/scans contributing towards a particular visit may be
performed on different dates. The following rules will be applied:

For investigational assessments, the date of progression will be determined based on
the earliest of the RECIST assessment/scan dates of the component that indicates
progression

When censoring a patient for PFS the patient will be censored at the latest of the
dates contributing to a particular overall visit assessment.
Note: For TLs, only the latest scan date is recorded out of all scans performed at that 
assessment for the target lesions and similarly for NTLs only the latest scan date is recorded 
out of all scans performed at that assessment for the NTLs.
In the absence of clinically significant deterioration the investigational site is advised to 
continue the patient on study treatment until progression has been confirmed.
3.2.2
Proportion of patients alive at 12 months (OS12)
The proportion of patients alive at 12 months will be defined as the Kaplan-Meier estimate of 
OS at 12 months.
3.2.3
Objective Response Rate 
ORR (per RECIST 1.1 as assessed by the investigator) is defined as the number (%) of 
patients with at least 1 visit response of CR or PR and will be based on a subset of all 
randomised patients. If the investigator finds any patients do not have measurable disease at 
baseline then the analysis of ORR for the investigator data will exclude these patients, so that 
the denominator is a subset of the Intent-to-Treat (ITT) population who have measurable 
disease at baseline per investigator (note that although measurable disease per investigator is 
an inclusion criteria it is possible that the investigator may subsequently determine the patient 
did not have measurable disease). 
Data obtained up until progression, or the last evaluable assessment in the absence of 
progression, will be included in the assessment of ORR. Patients who go off treatment without 
progression, receive a subsequent anti-cancer therapy (note that for this analysis radiotherapy 
is not considered a subsequent anti-cancer therapy) and then respond will not be included as 
responders in the ORR.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
36
3.2.4
Duration of Response
DoR (per RECIST 1.1 as assessed by the investigator) 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 (ie, date of PFS event or censoring - date of first response + 
1). The end of response should coincide with the date of progression or death from any cause 
used for the RECIST 1.1 PFS endpoint. The denominator for DoR related analysis will be 
defined as described for ORR. 
The time of the initial response will be defined as the latest of the dates contributing towards 
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.
3.2.5
Proportion of patients alive and progression free at 6 months
The proportion of patients alive and progression free at 6 months (ie, APF6) will be defined as 
the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by the investigator) at 6 
months.
3.2.6
Proportion of patients alive and progression free at 12 months
The proportion of patients alive and progression free at 12 months (ie, APF12) will be defined 
as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by the investigator) at 
12 months.
3.2.7
Time from randomisation to second progression or death (PFS2) (sub-study B)
PFS2 will be defined as the time from the date of randomisation to the earliest of the 
progression event (subsequent to that used for the PFS endpoint) or death (ie date of PFS2 
event or censoring - date of randomisation + 1). The date of the first progression will be 
programmatically determined from investigator assessed data (See Section 3.2.1.2 for details.)
The date of second progression will be recorded by the investigator and defined according to 
local standard clinical practice and may involve any of: objective radiological, symptomatic 
progression or death. RECIST assessments will not be collected for assessment of PFS2. The 
date of the PFS2 assessment and investigator opinion of progression status (progressed or non-
progressed) at each assessment will be recorded in the electronic case report form (eCRF). 
Second progression status will be reviewed every 12 weeks following the progression event 
used for the co-primary variable PFS (the first progression) and status recorded. 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, ie, censored at the latest 
of the PFS or PFS2 assessment date if the patient has not had a second progression or death.
However, if the patient experiences a second progression or dies after two or more missed 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
37
visits, the patient will be censored at the time of the last PFS2 assessment prior to the two 
missed visits.
3.2.8
Best objective response 
Best objective response (BoR) is calculated based on the overall visit responses from each 
RECIST assessment. It is the best response a patient has had following randomisation but 
prior to starting any subsequent cancer therapy and prior to RECIST progression or the last 
evaluable assessment in the absence of RECIST progression and subsequent cancer therapy. 
Categorisation of BoR will be based on RECIST using the following response categories: CR, 
PR, SD, PD and NE.
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 start of 
subsequent cancer therapy or the last evaluable assessment in the absence of 
progression/subsequent cancer therapy.
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 8 weeks minus
1 week, i.e. at least 49 days (to allow for an early assessment within the assessment window), 
after randomisation (ie study day 50). 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.
The denominator will be consistent with that used in the ORR analysis.
For patients whose PFS event is death, BoR will be calculated based upon all evaluable 
RECIST assessments prior to death.
For patients who die with no evaluable RECIST assessments, if the death occurs ≤17 weeks 
(ie, 16 weeks + 1 week to allow for a late assessment within the assessment window) after 
randomisation, then BoR will be assigned to the progression (PD) category. For patients who 
die with no evaluable RECIST assessments, if the death occurs >17 weeks (ie, 16 weeks + 1 
week) after randomisation then BoR will be assigned to the NE category.
A patient will be classified as a responder if the RECIST criteria for a CR or PR are satisfied 
at any time following randomisation, prior to RECIST progression and prior to starting any 
subsequent cancer therapy.
3.2.9
Change in tumour size
For supportive purposes percentage change from baseline in tumour size will be derived at 
each scheduled tumour assessment visit (ie, week 8, week 16 etc hereafter referred to as week 
X for convenience). Best percentage change from baseline in tumour size will also be derived 
as the biggest decrease or the smallest increase in tumour size from baseline.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
38
This is based on RECIST target lesion measurements taken at baseline and at the timepoint of 
interest. Tumour size is defined as the sum of the longest diameters of the target lesions for 
the investigator data based upon RECIST assessments. Target lesions are measurable tumour 
lesions. Baseline for RECIST is defined to be the last evaluable assessment prior to 
randomisation. The change in target lesion tumour 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 tumour size 
at week X the change in target lesion tumour 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.
Apply a window around the week X visit: Whenever tumour 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 ± 1 week of the protocol 
scheduled visit will be used for that visit.
The above derivations will be programmed for the investigator data based upon RECIST 
assessments. 
3.3
Patient Reported Outcome (PRO) Variables
PRO questionnaires will be assessed using the EORTC-QLQ-C30 with the LC-13 module 
(HRQoL with lung cancer specific additional concerns) and EQ-5D-5L. 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 Intent-to-Treat (ITT) study population, unless stated.
3.3.1
EORTC-QLQ-C30
The EORTC-QLQ-C30 consists of 30 questions which can be combined to produce 5 
functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, 
pain, nausea/vomiting), 5 individual items (dyspnoea, insomnia, appetite loss, constipation, 
diarrhoea) and a global measure of health status. The EORTC-QLQ-C30 will be scored 
according to the EORTC scoring manual (Fayers et al 1999). An outcome variable consisting 
of a score from 0 to 100 will be derived for each of the symptom scales/symptom items, 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.
Baseline will be defined as the last non-missing assessment prior to randomisation for 
symptoms and summaries.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
39
The change from baseline in HRQoL will be assessed using the EORTC-QLQ-C30 global 
QoL scale which includes 2 items from the 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 categorised as improvement, no change 
or deterioration as shown in Table 5.
Table 5
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
EORTC-QLQ-C30 European Organization for Research and Treatment of Cancer 30-item core quality of life 
questionnaire.
For each subscale, if <50% of the subscale items are missing, then the subscale score will be 
divided by the number of non-missing items and multiplied by the total number of items on 
the subscales (Fayers et al 1999). If at least 50% of the items are missing, then that subscale 
will 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 minimised.
For the visit level summaries of Improvement/Deterioration/No change then all patients with a 
baseline and post-baseline score will be included thus the denominator may differ from the 
time to deterioration and improvement rate endpoints derived below.
3.3.1.1
Time to symptom deterioration
For each of the symptoms scales/items in the EORTC-QLQ-C30, time to symptom 
deterioration will be defined as the time from randomisation until the date of the first 
clinically meaningful symptom deterioration (an increase in the score from baseline of ≥10) or 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
40
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 (ie date of symptom deterioration event or 
censoring - date of randomisation + 1). 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 (prior to the two missed assessment visits). 
Given the scheduled visit assessment scheme (ie eight-weekly for the first 48 weeks then 
twelve-weekly thereafter) the definition of 2 missed visits will change (ie 2 x 8 weeks + 
1 week for an early assessment + 1 week for a late assessment = 18 weeks). If the previous 
PRO assessment is less than study day 274 (ie week 39) then two missing visits will equate to 
18 weeks since the previous PRO assessment, allowing for early and late visits. If the two 
missed visits occur over the period when the scheduled frequency of PRO assessments 
changes from eight-weekly to twelve-weekly this will equate to 22 weeks (ie, take the average 
of 8 and 12 weeks which gives 10 weeks and then apply same rationale hence 2 x 10 weeks + 
1 week for an early assessment + 1 week for a late assessment = 22 weeks). The time period 
for the previous PRO assessment will be from study days 274 to 344 (ie week 39 to week 49). 
From week 49 onwards (when the scheduling changes to twelve-weekly assessments),, two 
missing visits will equate to 26 weeks (ie 2 x 12 weeks + 1 week for an early assessment + 
1 week for a late assessment = 26 weeks). If the patient has no evaluable visits or does not 
have baseline data they will be censored at Day 1 unless they die within 2 visits of baseline 
(16 weeks plus 1 week allowing for a late assessment within the visit window). 
The population for analysis of time to symptom deterioration will include a subset of the ITT 
population who have baseline scores ≤ 90.
In the analysis, RECIST 1.1 progression will not be considered as symptom deterioration and 
data will not be affected by RECIST progression.
3.3.1.2
Time to HRQoL/Function deterioration
For HRQoL/function, time to deterioration will be defined as the time from the date of 
randomisation 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 (ie date of HRQoL/function deterioration event or censoring -
date of randomisation + 1). 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.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
41
Patients whose HRQoL/function (as measured by EORTC-QLQ-C30) has 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/function deteriorates after 2 or more missed PRO assessment visits 
(using the same definitions for two missed visits as used in the ‘Time to Symptom 
deterioration’ derivation above) 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 the patient has no evaluable visits or does not have baseline data they 
will be censored at Day 1 unless they die within 2 visits of baseline (16 weeks plus 1 week 
allowing for a late assessment within the visit window). 
The population for analysis of time to HRQoL/function deterioration will include a subset of 
the ITT population who have baseline scores ≥10.
In the analysis, RECIST 1.1 progression will not be considered as HRQoL/function 
deterioration and data will not be affected by RECIST progression.
3.3.1.3
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/items) in that symptom from baseline. The denominator will consist of a subset of the 
ITT population who have a baseline symptom score >10.
3.3.1.4
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. The denominator will consist of 
a subset of the ITT population who have a baseline HRQoL/function score ≤90.
3.3.2
EORTC-QLQ-LC-13
The LC-13 is a lung cancer specific module from the EORTC comprising 13 questions to 
assess lung cancer symptoms (cough, haemoptysis, dyspnoea and site-specific pain), treatment 
related side-effects (sore mouth, dysphagia, peripheral neuropathy and alopecia) and pain 
medication. The LC-13 incorporates symptom scales including:

Dyspnoea (multi-item scale based on 3 questions: were you short of breath when 
you rested; walked; climbed stairs)

Cough: 1 item (how much did you cough?)

Haemoptysis: 1 item (did you cough up blood?)

Pain: 3 individual items (Have you had pain in your chest; your arm or shoulder; 
other parts of your body?)


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
42
The dyspnoea scale is only used if all 3 items have been scored; otherwise the items are 
treated as single-item measures. The scoring approach for the LC-13 is identical in principle to 
that for the symptom scales/single items of the EORTC-QLQ-C30.
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 LC-13 (Osoba et al 1998). For example, a clinically meaningful deterioration or 
worsening in chest pain (as assessed by LC-13) is defined as an increase in the score from 
baseline of ≥10, whereas a clinically meaningful improvement is defined as a decrease in the 
score from baseline of ≥10. At each post-baseline assessment, the change in symptoms from 
baseline will be categorised as improvement, no change or deterioration as shown in Table 6. 
Table 6
Visit Response for HRQoL and disease-related symptoms
Score
Change from baseline
Visit response
LC13 symptom scales/items
≥+10
Deterioration
≤-10
Improvement
Otherwise
No change
HRQoL Health Related Quality of Life; LC13 Lung Cancer Module.
For the visit level summaries of Improvement/Deterioration/No change then all patients with a 
baseline and post-baseline score will be included thus the denominator may differ from the 
time to deterioration and improvement rate endpoints derived below.
3.3.2.1
Time to symptom deterioration
For each of the symptoms scales/items in LC-13, time to symptom deterioration will be 
defined as the time from the date of randomisation 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 (ie date of symptom deterioration event or censoring - date of 
randomisation + 1). 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 LC-13) 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 progress after 
2 or more missed PRO assessment visits (using the same definitions for two missed visits as 
used in the ‘Time to symptom deterioration’ derivation in Section 3.3.1) 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 the patient has no evaluable 
visits or does not have baseline data they will be censored at Day 1 unless they die within 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
43
2 visits of baseline (16 weeks plus 1 week allowing for a late assessment within the visit 
window).
The population for analysis of time to symptom deterioration will include a subset of the ITT 
population who have baseline scores ≤ 90.
In the analysis, RECIST progression will not be considered as symptom deterioration and data 
will not be affected by RECIST progression.
3.3.2.2
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 LC-13 symptom scales/items) in that 
symptom from baseline. The denominator will consist of a subset of the ITT population who 
have a baseline symptom score >10.
3.3.3
EQ-5D-5L 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
44
3.3.4
PRO Compliance Rates 
Summary measures of overall compliance and compliance over time will be derived for the 
EORTC-QLQ-C30, LC13 and 
 respectively. These will be based upon:
!
Received questionnaire = a questionnaire that has been received and has a
completion date and at least one individual item completed.
!
Expected questionnaire = a questionnaire that is expected to be completed at a
scheduled assessment time e.g. a questionnaire from a patient who has not
withdrawn from the study at the scheduled assessment time but excluding patients
in countries with no available translation. For patients that have progressed, the
latest of progression and safety follow-up will be used to assess whether the patient
is still under HRQoL follow-up at the specified assessment time. Date of study
discontinuation will be mapped to the nearest visit date to define the number of
expected forms.
!
Evaluable questionnaire = a questionnaire with a completion date and at least one
subscale that is non-missing.
!
Overall PRO compliance rate is defined as: Total number of evaluable
questionnaires across all time points, divided by total number of questionnaires
expected to be received across all time points multiplied by 100.
!
Overall patient compliance rate is defined for each randomised treatment group as:
Total number of patients with an evaluable baseline and at least one evaluable
follow-up questionnaire (as defined above), divided by the total number of patients
expected to have completed at least a baseline questionnaire multiplied by100.
Compliance over time will be calculated separately for each visit, including baseline, as the 
number of patients with an evaluable questionnaire at the time point (as defined above), 
divided by number of patients still expected to complete questionnaires. Similarly the 
evaluability rate over time will be calculated separately for each visit, including baseline, as 
the number of evaluable questionnaires (per definition above), divided by the number of 
received questionnaires.
3.4
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 (ie, the initial 12 months of treatment) on the 
immunotherapy agents (MEDI4736, tremelimumab or MEDI4736+tremelimumab) will be 
compared against SOC in the main presentations of safety data and safety data from the re-
treatment period may also be summarised 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 
immunotherapy agents (ie, the last dose of MEDI4736, tremelimumab or 
CCI


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
45
MEDI4736+tremelimumab) on each period of treatment and between date of start dose and 
30 days following last dose of the Standard of Care agents. Note that for certain safety outputs 
the period of time after the administration of subsequent anti-cancer therapy will not be 
considered ‘on treatment’ (see further Section 4.2.11). 
The Safety analysis set will be used for reporting of safety data.
3.4.1
Adverse events (AEs)
AEs and SAEs will be collected throughout the study, from the date of sub-study informed 
consent (AEs)/pre-screening informed consent (SAEs) and 90 days after the last dose of 
immunotherapy agents (ie, the last dose of MEDI4736, tremelimumab or 
MEDI4736+tremelimumab)/30 days following last dose of the Standard of Care agents. The 
Medical Dictionary for Regulatory Activities (MedDRA) (using the latest or current MedDRA 
version) will be used to code the AEs. AEs will be graded according to the National Cancer 
Institute Common Terminology Criteria for AEs (CTCAE Version 4.03). A treatment 
emergent adverse event (TEAE) is an AE with an onset date or a pre-existing AE worsening 
following the first dose of study treatment through to 90 days after the last dose of 
immunotherapy agents (ie, the last dose of MEDI4736, tremelimumab or 
MEDI4736+tremelimumab)/30 days after the last dose of the Standard of Care agents. For the
MEDI4736+tremelimumab arm, 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.
Adverse events that have missing causality (after data querying) will be assumed to be related 
to study drug. Additionally, for the MEDI4736+tremelimumab arm a causality of related or 
missing for either component will be taken as related to study drug.
Other significant adverse events (OAE)
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 ‘Discontinuation of Investigational Product 
due to Adverse Events’ (DAEs). Based on the expert’s judgement, significant adverse events 
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 haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious) or significant 
additional treatment.
AEs of special interest
Some clinical concepts (including some selected individual preferred terms and higher level 
terms) have been considered “AEs of special interest” (AESI) to the MEDI4736 program. 
AESIs represent pre-specified risks which are considered to be of importance to a clinical 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
46
development program. These AESIs have been identified as a list of categories provided by 
the patient safety team.
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.
3.4.2
Treatment exposure
Exposure will be defined separately for MEDI4736 monotherapy, MEDI4736 on the 
MEDI4736+ tremelimumab combination arm, tremelimumab on the MEDI4736+ 
tremelimumab combination arm, tremelimumab monotherapy for the 12-month initial period 
of treatment and for the retreatment period as follows.
Total (or intended) exposure of MEDI4736 (monotherapy) 

Total (or intended) exposure is defined as the total treatment period from first dose 
date of study drug to the earliest of “last dose date of study drug + 13 days” or death 
date or DCO.
ie Total (or intended) exposure = min(last dose date where dose>0mg +13, date of 
death, date of DCO) - first dose date of study drug +1 
Total (or intended) exposure of tremelimumab (monotherapy) 

Total (or intended) exposure is defined as the total treatment period from first dose 
date of study drug to the earliest of “last dose date of study drug + (13 days or 83 
days)” or death date or DCO. Thirteen days will be added in the above formulae if 
the subject stopped dosing before week 24 and 83 days will be added if the subject 
stopped dosing at week 24 or later.
ie Total (or intended) exposure = min(last dose date where dose>0mg +(13 or 83 days), 
date of death, date of DCO) - first dose date of study drug +1
Total (or intended) exposure of MEDI4736 (combination) 

Total (or intended) exposure is defined as the total treatment period from first dose 
date of study drug to the earliest of “last dose date of study drug + (13 days or 27 
days)” or death date or DCO or start of re-treatment (applies to initial treatment 
period only). Twenty-seven days will be added in the above formulae if the subject 
stopped dosing before week 16 and 13 days will be added if the subject stopped 
dosing at week 16 or later.
ie Total (or intended) exposure = min(last dose date where dose>0mg +(13 or 27 days), 
date of death, date of DCO) - first dose date of study drug +1


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
47
Total (or intended) exposure of tremelimumab (combination) 

Total (or intended) exposure is defined as the total treatment period from first dose 
date of study drug to the earliest of “last dose date of study drug + 27 days” or death 
date or DCO.
ie Total (or intended) exposure = min(last dose date where dose>0mg +27 days, date of 
death, date of DCO) - first dose date of study drug +1
Actual exposure of MEDI4736/tremelimumab

Actual exposure is defined as above, but excluding total duration of dose delays

The total (or intended) exposure for each SOC treatment will be calculated using 
the same principle as above, according to the dose schedule required for each SOC. 
The total (or intended) exposure will also be summarised by combining the SOC 
treatments together. Actual exposure will not be calculated for SOC.
The total (or intended) exposure for each SOC is defined as follows:
Total (or intended) exposure of Erlotinib

Total (or intended) exposure is defined as the total treatment period from first dose 
date of study drug to the earliest of “last dose date of study drug” or DCO.
ie Total (or intended) exposure = min(last dose date where dose>0mg, date of death, 
date of DCO) - first dose date of study drug +1
Total (or intended) exposure of Gemcitabine

Total (or intended) exposure is defined as the total treatment period from first dose 
date of study drug to the earliest of “last dose date of study drug + 6 days” or death 
date or DCO.
ie Total (or intended) exposure = min(last dose date where dose>0mg + 6 days, date of 
death, date of DCO) - first dose date of study drug +1
Total (or intended) exposure of Vinorelbine

Total (or intended) exposure is defined as the total treatment period from first dose 
date of study drug to the earliest of “last dose date of study drug + 6 days” or death 
date or DCO.
ie Total (or intended) exposure = min(last dose date where dose>0mg + 6 days, date of 
death, date of DCO) - first dose date of study drug +1
Dose reductions are not permitted per the CSP for the immunotherapy agents (MEDI4736, 
tremelimumab or MEDI4736+tremelimumab). The actual exposure calculation makes no 
adjustment for any dose reductions that may have occurred. 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
48
Exposure will also be measured by the number of cycles received. For SOC, the number of 
days in a cycle will be study specific, but generally a cycle corresponds to a period of 28 days.
If a cycle is prolonged due to toxicity, this should still be counted as one cycle. A cycle will be 
counted if treatment is started even if the full dose is not delivered. Each immunotherapy 
agent will be measured in terms of number of doses given.
Calculation of duration of dose delays (for actual exposure):
MEDI4736 (monotherapy):

Since patients in the MEDI4736 monotherapy treatment group will receive 10 
mg/kg MEDI4736 via IV infusion q2w for up to 12 months (up to 26 doses), the 
duration of dose delays will be calculated as follows:
For all dosing dates:
Total duration of dose delays= Sum of (Date of the dose - Date of previous dose -
14 days)
Thus, if no delays were encountered, the duration would sum up to 0, since 
infusions were done every two weeks.
MEDI4736 (given in combination):

Since Patients in the MEDI4736 + Treme treatment group will receive 20 mg/kg 
MEDI4736 via IV infusion q4w for 4 months and tremelimumab 1 mg/kg q4w for 4 
doses followed by MEDI4736 monotherapy at a dose of 10 mg/kg q2w initiated 4 
weeks after the last combination dose is administered for up to 18 additional doses, 
the duration of dose delays will be calculated as follows:
For Cycle 1 to Cycle 4 (for Week 0 to Week 12) doses:
Duration1= Sum of (Date of the dose - Date of previous dose - 28 days)
For Cycle 5 to Cycle 13 (for Week 16 to Week 50) doses: 
Duration2= Sum of (Date of the dose - Date of previous dose - 14 days)
Total duration of dose delays = Duration1 + Duration2
Tremelimumab (monotherapy):

Since Patients in the Treme treatment group will receive 10 mg/kg tremelimumab 
via IV infusion q4w for 7 doses then q12w for 2 additional doses for up to 12 
months (up to 9 doses in total), the duration of dose delays will be calculated as 
follows:
For Cycle 1 to Cycle 7 (for Week 0 to Week 24) doses:
Duration1= Sum of (Date of the dose - Date of previous dose - 28 days)
For Cycle 8 to Cycle 9 (for Week 36 to Week 48) doses: 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
49
Duration2= Sum of (Date of the dose - Date of previous dose - 84 days)
Total duration of dose delays = Duration1 + Duration2
Tremelimumab (given in combination):

Since Patients in the MEDI4736 + Treme treatment group will receive
tremelimumab 1 mg/kg q4w for 4 doses only, the duration of dose delays will be
calculated as follows:
For Cycle 1 to Cycle 4 (for Week 0 to Week 12) doses:
Total duration of dose delays= Sum of (Date of the dose - Date of previous dose -
28 days)
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. 
3.4.3
Dose intensity 
Dose intensity will be derived separately for the initial treatment period and the re-treatment 
period for the immunotherapy agents. It will also be derived for the SOC agents. Relative dose 
intensity (RDI) is the percentage of the actual dose delivered relative to the intended dose 
intensity through to treatment discontinuation. 
Relative dose intensity (RDI) will be defined as follows for MEDI4736, tremelimumab and all 
Standard of Care therapy:

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. D is the total dose that would be delivered, if there were no modification to
dose or schedule. When accounting for the calculation of intended cumulative dose
3 days should be added to the date of last dose to reflect the protocol allowed
window for dosing for all treatments apart from erlotinib.
When deriving actual dose administered the volume before and after infusion will also be 
considered.
3.4.4
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 haematology, clinical 
chemistry, and urinalysis will be collected as described in Section 6.4.5 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 3.4.7 below will 
be used.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
50
Change from baseline in haematology 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 project-wide 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: Corrected Calcium will be derived during creation of the reporting 
database using the following formula:
Corrected calcium = 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.
Local reference ranges will be used for the primary interpretation of laboratory data at the 
local laboratory. Project reference ranges will be used throughout for reporting purposes. 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 baseline and at least 1 post-dose value recorded.

If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient needs only to have 1 post dose-value recorded.
3.4.5
ECGs
ECG data obtained up until the 30 days 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 3.4.7 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. This digital copy of all ECGs will be held centrally by a central ECG provider, 
and the data from this review will be stored for analysis if necessary at the end of the study. If 
analysis is necessary then QTcF (Fridericia) and QTcB (Bazzetts) will also be provided by the 
central vendor.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
51
For triplicate ECGs, the mean of the three ECG assessments will be used to determine the 
value at that time point.
3.4.6
Vital signs
Vital signs data obtained up until the 30 days from date of last dose of study treatment will be 
used for reporting. Change from baseline in vital signs variables will be calculated for each 
post-dose visit on treatment. For derivation of post baseline visit values considering visit 
window and to handle multiple records, derivation rules as described in Section 3.4.7 below 
will be used. 
The denominator in vital signs data should include only those patients with recorded data.
3.4.7
General considerations for safety and PRO assessments
Time windows will need defining for any presentations that summarise values by visit. The 
following conventions should also apply:

The time windows should be exhaustive so that data recorded at any time point has
the potential to be summarised. Inclusion within the time window should be based
on the actual date and not the intended date of the visit.

All unscheduled visit data should have the potential to be included in the
summaries.

The window for the visits following baseline will be constructed in such a way that
the upper limit of the interval falls half way between the two visits (the lower limit
of the first post-baseline visit will be Day 2). If an even number of days exists
between two consecutive visits then the upper limit will be taken as the midpoint
value minus 1 day.
For example, the visit windows for vital signs data for MEDI4736 monotherapy
(with 2 weeks between scheduled assessments) are:

Day 15, visit window 2 - 21

Day 29, visit window 22 - 35

Day 43, visit window 36 - 49

Day 57, visit window 50 - 63

Day 71, visit window 64 - 77

Day 85, visit window 78 - 91
Note that due to the differing assessment schedules the visit windows will be
different for the different study treatments.
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).


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
52

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 summarised, or the earlier in the 
event the values are equidistant from the nominal visit date. If there are two 
values recorded on the same day and the parameter is CTCAE gradeable then 
the record with the highest toxicity grade should be used. Alternatively, if there 
are two records recorded on the same day and the toxicity grade is the same (or 
is not calculated for the parameter) then the average of the two records should 
be used. 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 
summarised 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 for immunotherapy agents then 
baseline is similarly defined as the last non-missing measurement prior to the first 
dose on the re-treatment period. For laboratory data, 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 can be taken as a baseline value (in these cases the 
toxicity grade would be based upon this averaged value). For non-numeric 
laboratory tests (ie 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 summarised over time, study 
day will be calculated in relation to date of first treatment.
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of “< x” (i.e., below the lower limit of quantification) or > x (i.e., above the upper limit 
of quantification) will be imputed as “x” in the calculation of summary statistics but displayed 
as “< x” or “> x” in the listings. Additionally, adverse events that have missing causality (after 
data querying) will be assumed to be related to study drug.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
53
3.5
Biomarker Variables
PD-L1 expression status (positive, negative) is defined according to following criteria:

Positive:- ≥ 25% tumour cell membrane positivity for PD-L1 at any intensity above
background staining as noted on the corresponding negative control.

Negative:- < 25% tumour cell membrane positivity for PD-L1 at any intensity
above background staining as noted on the corresponding negative control.
In addition, for SSB (PD-L1 negative patients) PD-L1 will be further categorised as:

PD-L1 <1% tumour cell membrane positivity for PD-L1 at any intensity above
background staining as noted on the corresponding negative control.

PD-L1 ≥1% to < 25% tumour cell membrane positivity for PD-L1 at any intensity
above background staining as noted on the corresponding negative control.
3.6
Pharmacokinetic and Immunogenicity Variables
Analyses to evaluate the pharmacokinetics and immunogenicity of MEDI4736 and 
tremeluminab will be performed by AstraZeneca/MedImmune Clinical Pharmacology group 
or designee.
3.6.1
PK non-compartmental analysis
The actual sampling times will be used in the PK calculations. Pharmacokinetic concentration 
data and summary statistics will be tabulated. Individual and mean blood MEDI4736 
concentration-time profiles will be generated. PK parameters will be determined using 
standard non-compartmental methods. The following PK parameters will be determined after 
the first and steady state doses: peak and trough concentration (as data allow). Samples below 
the lower limit of quantification will be treated as missing in the analyses.
3.6.2
Population PK and exposure-response/safety analysis
A population PK model will be developed using a non-linear mixed-effects modelling 
approach in patients with NSCLC where possible. The impact of physiologically-relevant 
patient characteristics (covariates) and disease on PK will be evaluated. The relationship 
between PK exposure and the effect on safety and efficacy will be evaluated, if appropriate. 
The results of such an analysis will be reported in a separate report.
3.6.3
Immunogenicity analysis
Immunogenicity results will be analysed descriptively by summarizing the number and 
percentage of patients who develop detectable anti-MEDI4736 and/or anti-tremelimumab 
antibodies. The immunogenicity titre will be reported for samples confirmed positive for the 
presence of anti-MEDI4736 antibodies and/or anti-tremelimumab antibodies. Summaries will 
be based upon all patients from the safety population. The effect of immunogenicity on PK, 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
54
PDx, efficacy and safety will be evaluated, but such analyses, if applicable, will be reported in 
a separate report.
3.7
Health Resource Use
 
 
 
 
 
 
4.
ANALYSIS METHODS
All analyses and reporting will be separated by sub-study.
Sub-study A has 1 treatment comparison of interest as follows:
!
MEDI4736 10 mg/kg Q2W compared with Standard of Care
Sub-study B has 1 treatment comparison of interest that is considered primary as follows:
!
MEDI4736 20 mg/kg Q4W plus tremelimumab 1 mg/kg Q4W for 12 weeks then
MEDI4736 10 mg/kg Q2W for 34 weeks compared with Standard of Care
The co-primary endpoints in each of the sub-studies are OS and PFS using RECIST v1.1. The 
study was sized to assess PFS and OS endpoints in sub-study B for the treatment comparisons 
mentioned above. No hypothesis testing will be performed on OS and PFS in Sub-study A; the 
analyses will be descriptive.
The final analyses of OS will take place on sub-study B on a pre-specified date when 
approximately 205 deaths have occurred from 300 patients (68% maturity) who have been 
randomised to the MEDI4736+tremelimumab and Standard of Care arms in Sub-study B.
Interim analyses of OS for the primary treatment comparison (Section 5) will be performed 
sub-study B at the same time as the primary PFS analysis. However, for practical 
CCI


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
55
considerations, if it happens that the analysis time points for the final PFS and OS analyses are 
closely aligned based on the occurrences of the events, then 1 single analysis of OS will be 
conducted along with the PFS analysis. In this case, the entire 0.04 alpha will be utilized for 
this OS analysis; additionally, at this time the final analyses for OS and PFS for sub-study A 
will also be conducted if they have not yet been performed and it is reasonable to conclude 
that the required number of events have been reached.
The final analyses of PFS and OS interim will take place for sub-study B on a pre-specified 
date when it is predicted that approximately 244 PFS events from 300 patients (81% maturity) 
who have been randomised to the MEDI4736+tremelimumab and Standard of Care arms. 
Sub-study B has the following treatment comparisons of interest that are considered 
secondary:
1.
MEDI4736 20 mg/kg plus tremelimumab 1 mg/kg Q4W for 12 weeks then
MEDI4736 10 mg/kg Q2W for 34 weeks compared with MEDI4736 10 mg/kg
Q2W
2.
MEDI4736 20 mg/kg plus tremelimumab 1 mg/kg Q4W for 12 weeks then
MEDI4736 10 mg/kg Q2W for 34 weeks compared with tremelimumab 10 mg/kg
Q4W for 24 weeks then Q12W
3.
MEDI4736 10 mg/kg Q2W compared with Standard of Care
4.
Tremelimumab 10 mg/kg Q4W for 24 weeks then Q12W compared with Standard
of Care
A single contribution of components analysis will be performed for superiority analysing PFS 
and OS for both of the secondary treatment comparisons ‘1’ and ‘2’ above. 
This analysis is planned to be performed when approximately 158 PFS events are observed in 
the MEDI4736+tremelimumab and tremelimumab monotherapy arms. However, for practical 
considerations, if this time is close to the time of the final PFS analysis, the contribution of 
components analysis will be conducted at the time of the final PFS analysis. As these 
treatment comparisons are secondary and serve a different purpose to that of the primary 
comparisons, they are not included in the multiple testing procedure for the primary 
comparisons, and an alpha of 0.05 will be used for either PFS or OS without multiplicity 
adjustment.
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,


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
56
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.
In general, for efficacy and HRQoL endpoints the last observed measurement prior to 
randomisation will be considered the baseline measurement. However, if an evaluable 
assessment is only available after randomisation but before the first dose of randomised 
treatment then this assessment will be used as baseline. For safety endpoints the last 
observation before the first dose of study treatment will be considered the baseline 
measurement unless otherwise specified.
For assessments on the day of first dose where time is not captured, a nominal pre-dose 
indicator, if available, will serve as sufficient evidence that the assessment occurred prior to 
first dose.
Assessments on the day of the first dose where neither time nor a nominal pre-dose indicator 
are captured will be considered prior to the first dose if such procedures are required by the 
protocol to be conducted before the first dose.
In all summaries change from baseline variables will be calculated as the post-treatment value 
minus the value at baseline. The % change from baseline will be calculated as (post-baseline 
value - baseline value) / baseline value x 100.
Efficacy and HRQoL data will be summarised and analysed on the FAS. Safety and treatment 
exposure data will be summarised based upon the safety analysis set. Study population and
demography data will be summarised based upon the FAS. 
Efficacy from the re-treatment period for the immunotherapy agents may be summarised
separately for the site investigator data. For the site investigator data, any derivations relative 
to baseline (eg RECIST derivations) in the re-treatment period will be relative to the baseline 
scan prior to re-treatment. 
Safety data will be summarised from the initial treatment period (ie the initial 12 months of 
treatment) only for the immunotherapy agents alongside the SOC agents. Safety data from the 
re-treatment period may also be summarised 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.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
57
4.2
Analysis methods
Results of all statistical analyses in Sub-study B will be presented using 95% CIs and 2-sided 
p-values, unless otherwise stated. In Sub-study A no p-values will be presented, but 95% CIs 
will be used throughout.
Table 7 details which endpoints are to be subject to formal statistical analysis, together with 
pre-planned sensitivity analyses making clear which analysis is regarded as primary for that 
endpoint.
Table 7
Formal statistical analyses to be conducted and pre-planned sensitivity 
analyses
Endpoints Analysed
Notes
Overall Survival
Sub-study A
Hazard ratio comparing MEDI4736 versus Standard of Care
Sub-study B
Stratified log rank test comparing MEDI4736+tremelimumab versus 
Standard of Care
Sensitivity analysis using a Kaplan-Meier plot of time to censoring where the 
censoring indicator of the primary analysis is reversed - attrition bias
Sub-study B Only
The following secondary treatment comparisons will be performed:
i)
MEDI4736+tremelimumab versus MEDI4736
ii) MEDI4736+tremelimumab versus tremelimumab
iii) MEDI4736 versus Standard of Care
iv) Tremelimumab versus Standard of Care
Supportive Analysis on Sub-study B only Subgroup analysis using Cox 
proportional hazards models
Secondary analysis using Cox proportional hazards models to determine the 
effect of covariates on the HR estimate
Secondary analysis using Cox proportional hazards models to determine the 
consistency of treatment effect between subgroups via the approach of Gail 
and Simon 1985.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
58
Table 7
Formal statistical analyses to be conducted and pre-planned sensitivity 
analyses
Endpoints Analysed
Notes
Progression Free Survival
Sub-study A
Hazard ratio using site investigator data (RECIST 1.1) comparing MEDI4736 
versus Standard of Care
Sub-study B
Stratified log rank test using site investigator data (RECIST 1.1) comparing 
MEDI4736+tremelimumab versus Standard of Care
Sensitivity analyses using site investigator data (RECIST 1.1)
1)
Interval censored analysis - evaluation time bias
2)
Analysis using alternative censoring rules - attrition bias
Sub-study B only
The following secondary treatment comparisons will be performed:
i)
MEDI4736+tremelimumab versus MEDI4736
ii) MEDI4736+tremelimumab versus tremelimumab
iii) MEDI4736 versus Standard of Care
iv) Tremelimumab versus Standard of Care
Supportive analysis on Sub-study B only
Subgroup analysis using Cox proportional hazards models
Secondary analysis using Cox proportional hazards models to determine the 
effect of covariates on the HR estimate
Secondary analysis using Cox proportional hazards models to determine the 
consistency of treatment effect between subgroups via the approach of Gail 
and Simon 1985.
The analyses specified below will be performed in each of the Sub-studies A and B:
Proportion of patients alive at 
12 months
Kaplan-Meier estimates of survival at 12 months and p-value for comparison 
(sub-study B) (following the method described by Klein et al 2007)
Objective Response Rate
Logistic regression using site investigator data (RECIST 1.1)
Proportion of patients alive and 
progression free at 6 and 
12 months 
Kaplan Meier estimates of progression free survival at 6 and 12 months 
Time from randomisation to 
second progression
Stratified log-rank test (sub-study B)
Symptom improvement rate 
(EORTC QLQ-C30 and LC13 
endpoints)
Logistic regression
HRQoL/Function improvement 
rate (EORTC QLQ-C30 endpoints)
Logistic regression
Time to HRQoL/Function 
deterioration (EORTC QLQ-C30 
endpoints)
Stratified log-rank test in Sub-study B. Hazard ratios only in Sub-study A


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
59
Table 7
Formal statistical analyses to be conducted and pre-planned sensitivity 
analyses
Endpoints Analysed
Notes
Time to symptom deterioration 
(EORTC QLQ-C30 and LC13 
endpoints)
Stratified log-rank test in Sub-study B. Hazard ratios only in Sub-study A
EORTC QLQ-C30 European Organisation for Research and Treatment of Cancer 30-item core quality of life 
questionnaire; LC13 Lung Cancer Module; PD-L1 Programmed death ligand 1; HRQoL Health Related Quality 
of Life; RECIST Response Evaluation Criteria In Solid Tumours; Sub-study A MEDI4736 monotherapy v 
Standard of Care; Sub-study B MEDI4736+tremelimumab v Standard of Care. 
All outputs will be summarised for each Sub-study by treatment arm for all randomised 
patients (ITT).
4.2.1
Multiplicity (Sub-study B only)
The multiple testing procedure will define which significance levels should be applied to the 
interpretation of the raw p-values for the 2 primary endpoints of PFS and OS and the key 
secondary endpoints of OS12 and ORR.
The overall type I error of 0.05 will be split between the co-primary endpoints OS and PFS.
To control for type I error, an alpha of 0.04 will be used for the analysis of OS and an alpha of 
0.01 will be used for the analysis of PFS. The study will be considered positive if the PFS 
analysis results and/or the OS analysis results are statistically significant. The 0.04 alpha level 
allocated to OS will be controlled at the interim and primary time point by using the Lan 
DeMets (Lan and DeMets 1983) spending function that approximates an O’Brien Fleming 
approach, where the alpha level applied at the interim depends upon the proportion of 
information available.
An interim OS analysis for superiority and the primary PFS analysis will occur at the same 
time and the primary OS analysis will be performed when it is expected 205 deaths have 
accumulated from patients who have been randomised to the MEDI4736+tremelimumab and 
Standard of Care arms. For example, if 82% of the deaths required at the time of the primary 
OS analysis are available at the time of the interim (ie, 169/205 deaths have occurred), the 
two-sided alpha level to be applied in the OS interim analysis would be 0.021 and the two-
sided alpha level to be applied for the primary OS analysis would be 0.034.
At the time of the primary PFS, interim OS and primary OS analyses, the primary and key 
secondary hypotheses will be tested on the primary treatment comparisons only, using a 
multiple testing procedure with an alpha-exhaustive recycling strategy (Burman et al 2009).
No adjustment will be made for the contribution of components analysis as it is not concerned 
with testing the primary treatment comparison. With this approach, hypotheses will be tested 
in a pre-defined order. At the time of the primary PFS analysis, the PFS endpoint will be 
tested first and at the time of the primary OS analysis, the OS endpoint will be tested first. The 
other hypotheses corresponding to secondary endpoints will then be tested in a pre-specified 
hierarchy following PFS and OS rejection. This testing procedure stops when the entire test 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
60
mass is allocated to non-rejected hypotheses. Implementation of this pre-defined ordered 
testing procedure, including recycling, will strongly control type I error at 0.05 (two-sided), 
amongst all key hypotheses. Figure 2 shows the multiple testing framework. Alpha will be 
recycled within Sub-study B.
Figure 2
Multiple testing procedures for controlling the type 1 error rate for sub-
study B
PFS
OS
Interim
OS
PFS
OS12
Interim
ORR
OS12
ORR
OS
PFS
OS12
ORR
Interim α 
Final α 
α 0.04
DCO: Sub-study B= 244 PFS Events and 169 Deaths
α 1
DCO: Sub-study B= 205 Deaths
DCO: Data cut-off
Upon achieving statistical significance on the PFS endpoint in sub-study B, the testing of the 
OS endpoint will be performed hierarchically as illustrated in Figure 2. Similarly the testing of 
the PFS endpoint will be done subsequent to achieving statistical significance on the 
interim/primary OS endpoint in sub-study B. If both of these endpoints are significant, the 
alpha level can be combined and passed down to lower levels in the hierarchy. Spending alpha 
between endpoints in this way will strongly control type I error (Glimm et al 2010).
It is currently anticipated that the cut-off for PFS co-primary analysis will be before the 
cut-off for OS co-primary analysis on sub-study B. Alpha will be recycled across the PFS and 
OS hierarchies at the time of the final analysis of the respective endpoints. If the PFS and OS 
analyses are closely aligned and performed at the same time, the same alpha split (0.01 vs. 
0.04) will be applied to the PFS analysis and OS analysis, and the alpha will be recycled 
between PFS and OS if either of them is significant.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
61
4.2.2
Co-primary endpoints
4.2.2.1
Overall survival
OS will be analysed in sub-study B using a stratified log-rank test adjusting for Standard of 
Care therapy type (gemcitabine/vinorelbine versus erlotinib) and histology (squamous versus 
all other) for generation of the p-value and using the Breslow approach for handling ties
(Breslow, 1974). The effect of treatment will be estimated by the HR together with its 
corresponding ([1-adjusted alpha] x 100)% CI and p-value. Note that the alpha-adjusted CI p-
value will only be generated on sub-study B. The HR and CI will be generated on sub-study 
A. The boundaries (ie, adjusted alpha levels) for the treatment comparison at the interim and 
final analysis for OS on sub-study B will be derived based upon the exact number of OS 
events using the Lan and DeMets approach that approximates the O’Brien Fleming spending 
function (see Section 5). In sub-study B, any of the secondary treatment comparisons at the 
time of final analysis will display the 95% CI.
When used as stratification factors in stratified analyses, standard of care therapy type and 
histology will be based on the values entered into IVRS at randomisation, even if it is 
subsequently discovered that these values were incorrect.
The HR and its CI will be estimated from a stratified Cox Proportional Hazards model 
(Cox 1972) (with ties = Breslow and the stratification variables included in the strata 
statement) and the CI calculated using a profile likelihood approach. 
Kaplan-Meier plots of OS will be presented by treatment arm within each sub-study.
Summaries of the number and percentage of patients who have died, those still in survival 
follow-up, those lost to follow-up and those who have withdrawn consent will be provided 
along with the median OS for each treatment. 
OS12 will be summarised (using the Kaplan-Meier curve) and presented by treatment arm. 
For each treatment arm, the survival rate at 12 months based on Kaplan-Meier method will be 
presented, along with its 95% confidence interval. The computation of the confidence interval 
will be based on a log(-log(.)) transformation.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
62
For the comparison between treatments (sub-study B only), the test will be based on the 
method described in Klein 2007 and p-value (Klein et al 2007). The test statistic and its 
variance estimate are as follows:

test statistic =
)
(
ˆ
ln
)
(
ˆ
ln
ln
2
1
t
S
t
S

Variance estimate =
)
(
ln
)
(
ˆ
)
(
ln
)
(
ˆ
2
2
2
2
1
2
2
1
t
S
t
t
S
t



where 




t
t
i
i
i
i
i
i
d
n
n
d
t
)
(
)
(
ˆ
2

is the variance derived from Greenwood’s formula S(t )and can 
be estimated from standard software packages, where di and ni refer to the number of deaths 
and patients at risk for each risk set.
The z-statistic is then calculated as:
estimate
variance
statistic
test 
For stratified analysis, the test statistic and its variance estimate in each stratum will be 
combined by weighting inversely proportionately according to each within stratum variance 
(Whitehead and Whitehead 1991). A Z-test will be performed and the p-value from the test 
will be presented.
For sub-study B the assumption of proportionality will be assessed, initially only with regards 
to the primary treatment comparison. 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 a result of treatment-by-covariate interactions, which may be investigated.
Sensitivity Analyses (Sub-study B only)
A sensitivity analysis for OS will examine the censoring patterns to rule out attrition bias with 
regards to the primary treatment comparisons, achieved by a Kaplan-Meier plot of time to 
censoring where the censoring indicator of OS is reversed.
The number of patients prematurely censored will be summarised by treatment arm. A patient 
would be defined as prematurely censored if their survival status was not defined at the DCO.
In addition, duration of follow-up will be summarised using medians:

In censored patients who are alive at DCO only: Time from randomisation to date 
of censoring (date last known to be alive) by treatment arm.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
63

In all patients: Time from randomisation to the date of death (ie overall survival) or
to the date of censoring for censored patients regardless of treatment arm.
Subgroup analyses (Sub-study B only)
Subgroup analyses will be conducted in Sub-study B comparing OS between the treatments 
concerned in the primary treatment comparison in the following subgroups of the FAS:

Sex (male versus female)

Age at randomisation (<65 versus ≥65 years of age)
-
This will be determined from the date of birth (BIRTHDAT in the DEM
module) and date of randomisation (RND_DAT in the CRIT1 module) on the 
eCRF at screening. Patients with a partial date of birth (ie for those countries 
where year of birth only is given) will have an assumed date of birth of 1st Jan 
[given year]). Patients with a missing age value will be included using the mean 
age (overall FAS) and categorised accordingly.

Age at randomisation (<75 versus ≥75 years of age)
-
This will be determined from the date of birth (BIRTHDAT in the DEM
module) and date of randomisation (RND_DAT in the CRIT1 module) on the 
eCRF at screening. Patients with a partial date of birth (ie for those countries 
where year of birth only is given) will have an assumed date of birth of 1st Jan 
[given year]). Patients with a missing age value will be included using the mean 
age (overall FAS) and categorised accordingly.

Histology (squamous versus all other)
-
When used as a stratification factor in a stratified analysis, histology should
come from the IVRS; however, when used to define a subgroup or as a general 
covariate in an unstratified analysis, histology should come from the 
PATHGEN module of the eCRF.

Smoking (smoker [SUTRTNIC=1, 2, 3, 4, 13] versus non-smoker [never smoked])
-
This will be determined from the response to ‘Nicotine Use Occurrence’ (SU
module) on the eCRF at screening. Patients with a missing smoking status will 
be included in the ‘smoker’ category.

Standard of Care grouped (gemcitabine/vinorelbine versus erlotinib)
-
Standard of care will come from the IVRS regardless of whether it is used as a
stratification factor in a stratified analysis, used to define a subgroup, or as a 
general covariate in an unstratified analysis.

WHO performance status at baseline (normal activity [PSTAT=0] versus restricted
activity [PSTAT=1]).
-
This will be determined from the response to “Performance status” (PSTAT
module) on the eCRF at screening. Patients with a missing performance status 
will be included in the ‘restricted activity’ category.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
64

Region (Asia, Europe, South America versus North America).
-
This will be determined from the centre number (CENTRE). If there are less
than 20 events in the “South America” category, these patients will be 
combined with those in North America.

Race (White, Black/African-American, Asian, Other [Native Hawaiian/Pacific
Islander or American Indian/Alaska Native or Others]).
-
This will be determined from the response to “Race” (DEM module) on the
eCRF at screening.

Metastatic versus locally advanced

PD-L1 status <1% versus ≥ 1% to < 25%

Line of therapy (3rd, 4th, >4th)
-
This will be derived from the response to the “Number of Prior Anti-Cancer
Therapy Regimens” (CAPRX module) on the eCRF at pre-screening.

Site of Local/Metastatic Disease at Study Entry (Brain/CNS [DISSITES=1 or 16]
and/or Liver [DISSITES=22 or 8], Other)
-
This will be determined from the response to the “Site of Local/Metastatic
Disease at Study Entry” (DISEXT module) on the eCRF at screening.
Unless otherwise stated above (e.g., standard of care, which always comes from IVRS), note 
that in general data used to construct subgroups or as a general covariate in an unstratified 
analysis will come from the eCRF; however, note that when data are used in a stratified
analysis, they should come from the IVRS (e.g., histology).
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.
No adjustment to the significance level for testing will be made since all these subgroup 
analyses will be considered exploratory and may only be supportive of the primary analysis of 
OS.
For each subgroup, the HR (MEDI4736+tremelimumab: Standard of Care in Sub-study B) and 
95% CI will be calculated from an unstratified Cox proportional hazards with treatment as 
only covariate. The Cox models will be fitted using SAS® PROC PHREG with the Breslow 
method to control for ties, using the by statement to obtain HR and 95% CI for each subgroup 
level separately.
These hazard ratios and associated two-sided 95% CIs will be summarised and presented on a 
forest plot, along with the results of the overall primary analysis.
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 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
65
subgroup), the relationship between that subgroup and OS will not be formally analysed. In 
this case, only descriptive summaries will be provided.
Effect of covariates on the HR estimate
Cox proportional hazards modelling will be employed to assess the effect of covariates on the 
HR estimate for the primary treatment comparison of Sub-study B. A model will be 
constructed, containing treatment and the stratification factors alone, to ensure any output 
from the Cox modelling is likely to be consistent with the results of the stratified log-rank test.
The result from the initial model and the model containing additional covariates will be 
presented.
Additional covariates for this model will be sex, age at randomisation (<65 versus ≥65 years 
of age), smoking, WHO performance at baseline, region, race, stage, line of therapy, site of 
local/metastatic disease at study entry, and PD-L1 status (<1% versus ≥ 1% to < 25%).
The model will include the effect regardless of whether the inclusion of effect significantly 
improves the fit of the model providing there is enough data to make them meaningful.
Consistency of treatment effect between subgroups
Interactions between treatment and stratification factors will also be tested to rule out any 
qualitative interaction using the approach of Gail and Simon 1985.
Treatment switching / exploratory analysis of overall survival
 
 
 
 
 
 
 
 
 
 
 
 
4.2.2.2
Progression free survival 
PFS based upon the programmatically derived RECIST outcome using the site investigator 
assessment data (using all scans regardless of whether they were scheduled or not) will be 
CCI


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
66
analysed using stratified log-rank tests (on Sub-study B, no p-values will be generated for 
Sub-study A) using the same methodology as described for the OS analyses.
The effect of treatment will be estimated by the HR together with its corresponding 99% CI 
and p-value for sub-study B. The HR and 95% CI will be generated on Sub-study A.
Kaplan-Meier plots of PFS will be presented by treatment arm for each sub-study. Summaries 
of the number and percentage of patients experiencing a PFS event, and the type of event 
(RECIST 1.1 or death) will be provided along with median PFS for each treatment.
The assumption of proportionality will be assessed in the same way as for OS on Sub-study B. 
The analysis will be based on the PFS from the site investigator data.
The treatment status at progression of patients at the time of analysis will be summarised. This 
will include the number (%) of patients who were on treatment at the time of progression, the 
number (%) of patients who discontinued study treatment prior to progression, the number 
(%) of patients who have not progressed and were on treatment or discontinued treatment. 
This will also provide distribution of number of days prior to progression for the patients who 
have discontinued treatment. 
Additional supportive summaries/graphs (Sub-study B only)
In addition, the number of patients prematurely censored will be summarised by treatment 
arm. A patient would be defined as prematurely censored if they had not progressed (or died 
in the absence of progression) and the latest scan prior to DCO was more than one scheduled 
tumour assessment interval plus 2 weeks (10 weeks if time period between randomisation and 
DCO for that patient is 48 weeks or less; 14 weeks otherwise) prior to the DCO date.
Additionally, summary statistics will be given for the number of days from censoring to data 
cut-off for all censored patients.
A summary of the duration of follow-up will be summarised using median time from 
randomisation to date of censoring (date last known to be non-progressor) in censored (not 
progressed) patients only, presented by treatment group.
Additionally, summary statistics for the number of weeks between the time of progression and 
the last evaluable RECIST assessment prior to progression will be presented for each 
treatment group.
Summaries of the number and percentage of patients who miss two or more consecutive 
RECIST assessments will be presented for each treatment group.
All of the collected RECIST 1.1 data will be listed for all randomised patients. In addition, a 
summary of new lesions (i.e., sites of new lesions) will be produced.
Sensitivity Analyses (Sub-study B only)
The following sensitivity analyses will only be performed for the primary treatment 
comparison in Sub-study B. 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
67

Evaluation-Time bias
A sensitivity analysis will be performed to assess possible evaluation-time bias that may be 
introduced if scans are not performed at the protocol-scheduled time points. The midpoint 
between the time of progression and the previous evaluable RECIST assessment (using the 
final date of the assessment) will be analysed using a stratified log-rank test, as described for 
the co-primary analysis of PFS. For patients whose death was treated as PFS event, the date of 
death will be used to derive the PFS time used in the analysis. This approach has been shown 
to be robust to even highly asymmetric assessment schedules (Sun and Chen 2010). To 
support this analysis, the mean of subject-level average inter-assessment times will be 
tabulated for each treatment. This approach will use the site investigator RECIST data.

Attrition bias
Attrition bias will be assessed by repeating the co-primary PFS analysis except that the actual 
PFS event times, rather than the censored times, of patients who progressed or died in the 
absence of progression immediately following two, or more, non-evaluable tumour 
assessments will be included. In addition, and within the same sensitivity analysis, patients 
who take subsequent therapy (note that for this analysis radiotherapy is not considered a 
subsequent anti-cancer therapy) prior to their last evaluable RECIST assessment or 
progression or death will be censored at their last evaluable assessment prior to taking the 
subsequent therapy. This analysis will be supported by a Kaplan-Meier plot of the time to 
censoring from the primary analysis where the censoring indicator of the PFS analysis is 
reversed.

Deviation bias
Deviation bias may be assessed by repeating the PFS analysis excluding patients with 
deviations that may affect the efficacy of trial therapy (see Section 2.2).
A forest plot illustrating the hazard ratio and 95% confidence interval will be provided to 
compare the primary and sensitivity analyses of progression free survival on Sub-study B.
Subgroup analyses and a forest plot will be generated comparing PFS between treatments in 
the same way as previously specified for OS.
No adjustment to the significance level for testing will be made since all these subgroup and 
sensitivity analyses will be considered supportive of the primary analysis of PFS.
The effect of covariates upon the HR estimate and the consistency of treatment effect between 
subgroups will be analysed for PFS using the same methods as those described for OS.
4.2.3
Objective response rate
The ORR will be based on the programmatically derived RECIST outcome using the site 
investigator tumour data, and using all scans regardless of whether they were scheduled or 
not. The ORR will be compared between MEDI4736 versus Standard of Care in Sub-study A
and MEDI4736+tremelimumab versus Standard of Care in Sub-study B using unstratified 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
68
logistic regression models adjusting for the same stratification factors as the co-primary 
endpoints. The results of the analysis will be presented in terms of an odds ratio (an odds ratio 
greater than 1 will favour MEDI4736 monotherapy in Sub-study A/ 
MEDI4736+tremelimumab in Sub-study B) together with its associated profile likelihood 
95% CI (e.g. using the option ‘LRCI’ in SAS procedure GENMOD). A p-value (based on 
twice the change in log-likelihood resulting from the addition of a treatment factor to the 
model) will only be generated on Sub-study B.
If there are not enough responses for a meaningful analysis using logistic regression then a 
Fisher’s exact test using mid p-values will be presented. 
The mid-p-value modification of the Fisher exact test amounts to subtracting half of the 
probability of the observed table from Fisher's p-value.
Summaries will be produced that present the number and percentage of patients with a tumour 
response (CR/PR) based upon the number of patients with measurable disease at baseline per 
investigator (see Section 3.2.3). For each treatment arm, best objective response (BoR) will be 
summarised by n (%) for each category (CR, PR, SD, PD and NE). No formal statistical 
analyses are planned for BoR.
4.2.4
Duration of response
For both sub-studies descriptive data will be provided for the DoR in responding patients (ie 
median duration of response and 95% CIs) by treatment arm, including the associated Kaplan-
Meier curves (without any formal comparison of treatment arms or p-value attached).
4.2.5
Proportion of patients alive and progression free at 6 months (APF6)
The proportion of patients alive and progression free at 6 months (ie at study day 184) will be 
summarised (using the Kaplan-Meier curve) and presented by treatment arm on both sub-
studies. For each treatment arm, the APF6 based on Kaplan-Meier method will be presented, 
along with its 95% confidence interval. The computation of the confidence interval will be 
based on a log(-log(.)) transformation. 
4.2.6
Proportion of patients alive and progression free at 12 months (APF12)
The proportion of patients alive and progression free at 12 months (ie at study day 366) along 
with 95% CIs will be summarised (using the Kaplan-Meier curve) and presented by treatment 
arm on both sub-studies. For each treatment arm, the APF12 based on Kaplan-Meier method 
will be presented, along with its 95% confidence interval. The computation of the confidence 
interval will be based on a log(-log(.)) transformation.
4.2.7
Time from randomisation to second progression (Sub-study B only)
Time from randomisation to second progression or death (PFS2) will be analysed using 
identical methods as outlined for the analysis of PFS and adjusting for the same set of 
covariates, but no subgroup analysis will be performed. The HR for the treatment effect 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
69
together with its 95% CI will be presented. Medians and Kaplan-Meier plots will be presented 
to support the analysis.
The number and percentage of subjects experiencing a PFS2 event and the type of progression 
(objective progression by RECIST, symptomatic progression, new or worsening of soft 
tissue/visceral or bone metastases or other) will also be summarised by treatment arm. 
Time from randomisation to second progression will be summarised by treatment arm.
4.2.8
Change in tumour size
The absolute values, change in TL tumour size from baseline and percentage change in TL
tumour size from baseline will be summarized using descriptive statistics and presented at 
each timepoint and by randomized treatment group. The best change in target lesion tumour 
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 
summarised and presented by randomised treatment group.
Tumour size will also be presented graphically using waterfall plots for each treatment arm, to 
present each subject’s best percentage change in tumour size as a separate bar, with the bars 
ordered from the largest increase to the largest decrease. A reference line at the -30% change 
in TL tumour size level will be added to the plots, which corresponds with the definition of 
‘partial’ response. All progressions will be marked with a ‘●’. . The scale in these plots will be 
fixed to be from -100 to 100 to avoid presenting extreme values. Values that are capped as a 
result of this restriction to the scale are marked with ‘#’. Values are ordered in descending 
order with the imputations due to death appearing first followed by a gap followed by all other 
patients. On each of the waterfall plots the histology classification (Squamous versus All 
other) of each patient will be indicated. Additional waterfall plots showing percentage change 
in tumour size at specific timepoints may be produced if it is felt that these are warranted to 
provide greater clarity. 
The above outputs will be programmed on data based upon site investigator RECIST 
assessments. 
4.2.9
Patient reported outcomes 
The PRO endpoints that have been identified as primary are EORTC QLQ-C30 time to 
HRQoL deterioration for global health status and LC13 time to symptom deterioration for 
each of dyspnea, cough, hemoptysis, and chest pain. These are not part of the main multiple 
testing procedure and as supportive endpoints will need a Bonferroni adjustment to the 
significance level to aid interpretation. Therefore, these 5 endpoints will be tested at a 1% 
significance level and 99% CIs will be produced. 
The other time to symptom deterioration endpoints will be tested at a 5% significance level 
and 95% CIs will be produced.
For sub-study A no p-values will be presented.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
70
4.2.9.1
EORTC QLQ-C30
Time to symptom deterioration will be analysed for each of the 3 symptom scales (fatigue, 
pain, nausea/vomiting) and the 5 individual symptom items (dyspnoea, insomnia, appetite 
loss, constipation, diarrhoea). Time to HRQoL/function deterioration will be analysed for the 
5 function scales (physical, role, emotional, cognitive, and social) and global health
status/HRQoL. This will be achieved by comparing between treatment arms using a stratified 
log-rank test as described for the primary analysis of OS.
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 HRQoL/function 
improvement rate for each of the 5 function scales (physical, role, emotional, cognitive, and 
social) and global health status/HRQoL will be produced. Symptom improvement rate and 
HRQoL/function improvement rate will be analysed 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.
For the primary endpoint, global health status/HRQoL, and the endpoints appetite loss, fatigue 
and physical functioning time to deterioration will be presented using a Kaplan-Meier plot.
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 3.3.1) will also be produced for each treatment arm. 
A summary of compliance rate and evaluability rate will be provided for each treatment arm, 
by assessment time point and also for overall.
4.2.9.2
LC13
Time to symptom deterioration for each of the 6 individual symptoms (dyspnoea, cough, 
haemoptysis, chest pain, arm/shoulder pain, other pain) will be compared between treatment 
arms using a stratified log-rank test as described for the primary analysis of OS.
The HR and 95% CI for each scale/item will be presented graphically on a forest plot. 
For the primary endpoints in LC13, time to deterioration in symptoms will be presented using 
a Kaplan-Meier plot. 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.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
71
A summary of the symptom improvement rate for each of the 6 individual symptom items will 
be produced. The symptom improvement rate will be compared between treatment arms using 
a logistic regression model as described for ORR. The odds ratio and 95% CI for each 
symptom will be presented graphically on a forest plot.
Summaries of original and change from baseline values of each symptom (dyspnoea, cough, 
haemoptysis, chest pain, arm/shoulder pain, other pain) and each treatment-related side effect 
(sore mouth, dysphagia, peripheral neuropathy and alopecia) 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 
symptom item (in terms of the proportion of patients in the categories of improvement, no 
change, and deterioration as defined in Section 3.3.2) will also be produced for each treatment 
arm.
4.2.9.3
EuroQol 5-Dimension 5-Level questionnaire
 
 
 
 
 
 
 
 
4.2.10
Health Resource Use 
 
 
 
4.2.11
Safety data
Safety and tolerability data will be presented by actual treatment group in each sub-study 
using the safety population. Safety data will be summarised only. No formal statistical 
analyses will be performed on the safety data. 
Any safety summaries examining retreatment with MEDI4736 monotherapy in Sub-study A
or retreatment with MEDI4736+tremelimumab or MEDI4736 monotherapy or tremelimumab 
CCI
CCI


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
72
monotherapy in Sub-study B will be produced separately. For safety summaries, if a patient 
starts re-treatment then this is considered a subsequent therapy. 
The following sections describe the planned safety summaries for AEs, vital signs, laboratory 
parameters and ECG. However, additional safety tables (not specified in this SAP) may need 
to be produced to aid interpretation of the safety data. For example, if an imbalance is seen in 
AEs or laboratory abnormalities that could be due to the differential follow-up periods 
(showing up more of the background/disease related AEs/abnormalities), additional 
summaries may be produced using a 30 day follow up period for all treatment arms to further 
explore/explain.
Adverse Events
All AEs, both in terms of current MedDRA preferred term and CTCAE grade, will be 
summarised 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 the summary tables.
AEs observed up until 90 days following discontinuation of the immunotherapy agents (ie, the 
last dose of MEDI4736, tremelimumab or MEDI4736+tremelimumab)/30 days following 
discontinuation of the Standard of Care agent or until the initiation of the first subsequent anti-
cancer therapy (including radiotherapy, with the exception of palliative radiotherapy) 
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 the 
immunotherapy agents/30 days following discontinuation of the Standard of Care agent are 
likely to be attributable to subsequent therapy. 
However, to assess the longer term toxicity profile, AE summaries will also be produced 
containing AEs observed up until 90 days following discontinuation of the immunotherapy 
agents/30 days following discontinuation of the Standard of Care agent (ie without taking 
subsequent therapy into account). 
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 on any episode level summaries which 
may be produced ). 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
73
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 4

AEs with CTCAE grade 3 or 4, causally related to study medication (as determined 
by the reporting investigator) (Sub-study B only)

AEs with outcome of death

AEs with outcome of death causally related to study medication (as determined by 
the reporting investigator)

All SAEs

All SAEs causally related to study medication (as determined by the reporting 
investigator)

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 dose delay of study medication

Other significant AEs

Immune mediated AEs (as determined by the reporting investigator) 

Infusion reaction AEs (as determined by the reporting investigator)
An overall summary of the number and percentage of patients in each category will be 
presented, as will an overall summary of the number of episodes in each category. 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 summarised by preferred term, by decreasing frequency. This cut-off may be modified after 
review of the data. When applying a cut-off (ie, 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 summarised by preferred term within 
each system organ class. 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 and then multiplied by 
365.25 x 100 to present in terms of per 100 patient years. 
Summaries of the number and percentage of patients will be provided by maximum reported 
CTCAE grade, system organ class, preferred term and treatment group. 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
74
Fluctuations observed in CTCAE grades during study will be listed for all AEs.
Deaths
A summary of all deaths will be provided with number and percentage of patients by 
treatment group, categorised as:

Total number of deaths (regardless of the date of death)

Death related to disease under investigation ONLY, as determined by investigator 
(regardless of the date of death) 

TEAE with outcome of death ONLY and onset date prior to initiation of subsequent 
anti-cancer therapy 

AE with outcome of death ONLY and onset date falling after 90 days following the 
date of last dose of immunotherapy/30 days following the date of last dose of SOC
or initiation of subsequent anti-cancer therapy (whichever is earlier)

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 

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 following the 
date of last dose of immunotherapy/30 days following the date of last dose of SOC 
or initiation of subsequent anti-cancer therapy (whichever is earlier)

Death occurred over 90 days after the date of last dose of immunotherapy/30 days 
following the date of last dose of SOC or after initiation of subsequent anti-cancer 
therapy (whichever is earlier), and unrelated to AE or disease under investigation 

Patients with unknown reason for death

Other deaths
This summary will be repeated, including all relevant rows, for all deaths within 90 days of 
last dose of study medication.
Adverse events of special interest 
Preferred terms used to identify AESI 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


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
75

At least one AESI causally related to study medication (as determined by the 
reporting investigator) by CTCAE grade

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. Additionally, there will be several summaries of AESIs requiring concomitant treatment, 
and particularly the relationship of AESIs to the use of immunosuppressive agents (ie, 
depicting which AESI triggered immunosuppressive use) and, separately, to the use of 
immunosuppressive agents at high doses.
Laboratory assessments
Data obtained up until the 90 days following discontinuation of immunotherapy agents (ie, the 
last dose of MEDI4736, tremelimumab or MEDI4736+tremelimumab)/30 days following 
discontinuation of the Standard of Care agent or until the initiation of the first subsequent anti-
cancer-therapy (including radiotherapy, with the exception of palliative radiotherapy) 
following discontinuation of treatment (whichever occurs first) will be used for reporting. This 
will more accurately depict laboratory toxicities attributable to study treatment only as a 
number of toxicities up to 90 days following discontinuation of immunotherapy agents/30 
days following discontinuation of the Standard of Care agent are likely to be attributable to 
subsequent therapy. 
However, to assess the longer term toxicity profile, some summaries of laboratory data may
also be produced containing data collected up until 90 days following discontinuation of the 
immunotherapy agents/30 days following discontinuation of the Standard of Care agent (ie, 
without taking subsequent therapy into account). 
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 90 
days following discontinuation of immunotherapy agents/30 days following discontinuation of 
the Standard of Care agent (ie summarising 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 90 
days last dose for immunotherapy agents/30 days last dose for Standard of Care agents will 
not be summarised.
Data summaries will be provided in preferred 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.
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. For continuous laboratory 


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
76
assessments absolute value and change from baseline will be summarised 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:

Haematology: Haemoglobin, 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
Additional summaries will include a shift table for urinalysis (Bilirubin, Blood, Glucose, 
Ketones, Protein) comparing baseline value to maximum on-treatment value.
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, >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

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.
Liver biochemistry test results over time for patients with elevated ALT or AST (ie ≥ 3x 
ULN), and elevated Total bilirubin (ie ≥ 2x ULN) (at any time) will be plotted. Individual 
patient data where ALT or AST (ie ≥ 3x ULN) plus Total bilirubin (ie ≥ 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 3×ULN for ALT, AST, and 2×ULN for Total bilirubin. In each plot, Total 
bilirubin will be in the vertical axis.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
77
Assessment of Thyrotoxicity
After the discontinuation of the study medication, the thyroid function tests, TSH, T3 and T4, 
were evaluated at 30 days after last dose, hence, the analysis of thyroid function tests will be 
based on data up to 30 days after the last dose of study medication or date of initiation of 
subsequent therapy (whichever occurs first), 
Absolute value and change from baseline will be summarised using descriptive statistics at 
each scheduled assessment time by cohort.
Shift tables showing baseline to maximum and baseline to minimum as well a summary of 
abnormal thyroid tests will also be produced for TSH, T3 and T4.
ECGs
ECG data obtained up until the 30 day safety follow-up visit will be included in the summary 
tables.
Overall evaluation of ECG is collected at each visit 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 (SBP), diastolic blood pressure (DBP), pulse rate, 
temperature, respiratory rate and weight) will be summarised over time in terms of absolute 
values and changes from baseline at each scheduled measurement by actual treatment group. 
Physical examination
All individual physical examination data will not be summarised. 
Other Safety Data
Data from positive pregnancy tests will not be summarised. 
4.2.12
WHO performance status
All WHO performance status will be summarised over time for the ITT population.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
78
4.2.13
PK data (MEDI4736 monotherapy, MEDI4736+tremelimumab and 
tremelimumab monotherapy arms only)
Pharmacokinetic concentration data will be listed for each patient and each dosing day, and a 
summary provided for all evaluable patients in each sub-study. These outputs will be 
produced by AstraZeneca/MedImmune Clinical Pharmacology group or designee.
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 titre 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.
These outputs will be produced by AstraZeneca/MedImmune Clinical Pharmacology group or 
designee. 
4.2.14
PK/PDx relationships (MEDI4736 monotherapy, MEDI4736+tremelimumab 
and tremelimumab monotherapy arms only)
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. These 
outputs will be produced by AstraZeneca/MedImmune Clinical Pharmacology group or 
designee. 
4.2.15
Biomarker data
 
 
 
 
 
4.2.16 Demographic and baseline characteristics data
The following will be summarised 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
!
Inclusion in analysis populations
CCI


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
79

Demographics (age, age group [<50, >=50-< 65, ≥ 65 - <75 years, and ≥ 75 years],
sex, race and ethnicity)

Patient characteristics at baseline (height, weight, weight group)

Patient recruitment by country and centre

Previous disease-related treatment modalities

Number of regimens of previous chemotherapy at baseline

Previous lung cancer therapy

Disease characteristics at baseline (WHO performance status, primary tumour
location, histology type, tumour grade and overall disease classification, best
response to previous therapy)

Extent of disease at baseline

TNM classification at baseline

Disease related medical history (past and current)

Relevant surgical history

Time from most recent disease progression to start of study treatment

Disallowed concomitant medications

Allowed concomitant medications

Post-discontinuation cancer therapy

Nicotine use, categorised (never, current, former)

Stratification factors as per IVRS and eCRF data
The AZ drug dictionary (AZDD) will be used for concomitant medication coding.
Patient disposition data will also be summarised at the time of OS analysis.
4.2.17
Treatment exposure
The following summaries related to study treatment will be produced for the safety analysis 
set by randomised treatment group:

Total exposure of each treatment group.

Actual exposure of each treatment group (for immunotherapy agents only).

Total number of cycles received (for SOC treatments only).

Reasons for dose delays and infusion interruptions of MEDI4736 and
tremelimumab and reasons for dose delays/infusion interruptions, dose reductions
and dose modifications for the relevant Standard of Care agents (gemcitabine and


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
80
vinorelbine). Dose delays and infusion interruptions will be based on investigator 
initiated dosing decisions. 

Number of infusions received (for all treatments apart from Erlotinib).

RDI of MEDI4736, tremelimumab and Standard of Care agents. 
For patients on study treatment at the time of the PFS and OS analysis, the DCO date will be 
used to calculate exposure.
5.
INTERIM ANALYSES
5.1
Analysis methods
An interim analysis will be performed to test OS on the primary treatment comparison in Sub-
study B. 
In Sub-study B the OS interim analysis will be performed when approximately 244 PFS 
events have occurred in patients who have been randomised to the MEDI4736+tremelimumab 
and Standard of Care arms. It is expected that approximately 169 (82% of the target 205) 
deaths will be observed at this time. However, for practical considerations, if it happens that 
the analysis time points for the final PFS and OS analyses are closely aligned, based on the 
occurrences of the events, then one single analysis of OS will be conducted along with the 
PFS analysis In this case, the entire 0.04 alpha will be utilized for this OS analysis.
All interim analyses will be assessed by an IDMC (further details are given in the IDMC 
charter). It is probable that recruitment will have completed prior to the results of the interim 
analysis being available.
5.1.1
Overall survival
No interim analysis will be performed on Sub-study A. 
For sub-study B, the criterion for superiority is a statistically significant improvement in OS at 
the interim analysis. The Lan and DeMets approach that approximates the O’Brien Fleming 
spending function will be used to account for multiplicity introduced into the treatment 
comparison by including the interim analysis for superiority (Lan and DeMets 1983).
If 82% of the deaths required (assuming a HR of 0.63) at the time of the primary OS analysis 
(approximately 56% maturity) are available at the time of the interim (ie, 169/205 deaths have 
occurred), the two-sided alpha level to be applied in the OS interim analysis would be 0.021.
This analysis would have 69% power to detect a HR of 0.65. The minimal difference in OS 
that would be deemed statistically significant is an average HR of 0.70. 
It is estimated that this interim analysis will be performed approximately 22 months after the 
start of randomisation.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
81
Under the above assumptions the two-sided alpha level to be applied for the primary OS 
analysis would be 0.034.
The OS interim will be analysed using a stratified log-rank test (see Section 4.2.2.1 for 
details). The hazard ratio will be estimated with corresponding CI and p-value. The size of the 
CI will be determined based on the actual number of events included in the interim analysis.
The survival status of patients at the time of the interim analysis will be summarised. A 
Kaplan-Meier plot of OS will be presented by randomised treatment group, along with median 
OS. The number of OS events will be presented by randomised treatment group.
If the PFS and/or OS results indicate superiority, then analyses of all other endpoints would be 
performed and the results of these analyses will form the basis for submissions for regulatory 
approval. Patients would continue to be followed for survival until the required number of
patients have died on the respective sub-study, when an updated analysis would be performed.
If the PFS result is not statistically significant and the OS interim analysis result does not meet 
the criterion of stopping for superiority, then the extended study team at 
AstraZeneca/MedImmune will remain blinded and the patients will continue to be followed 
for survival.
The recommendations from the IDMC will not reveal the results of the analysis but will take 
the form of “Continue/Modify/Recommend Early Submission/Stop”.
5.2
Independent Data monitoring committee
This study will use an external IDMC to assess ongoing safety analyses on both sub-studies as 
well as the interim analyses for superiority. The committee will meet approximately 6 months 
after the study has started or 20 patients have been randomised to the combination arm 
(whichever comes first) to review the safety data from the study. The IDMC will meet 
approximately every 6 months thereafter. Following each meeting, the IDMC will report to 
the sponsor and may recommend changes in the conduct of the study.
This committee will be composed of therapeutic area experts and biostatisticians, who are not 
employed by AstraZeneca/MedImmune and do not have any major conflict of interest.
Following the reviews, the IDMC will recommend whether the study should continue 
unchanged, be stopped, or be modified in any way. Once the IDMC has reached a 
recommendation, a report will be provided to AstraZeneca/MedImmune. The report will 
include the recommendation and any potential protocol amendments, and will not contain any 
unblinding information.
The final decision to modify or stop the study will sit with the sponsor. The sponsor or IDMC 
may call additional meetings if at any time there is concern about the safety of the study.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
82
In addition:

If the contribution of components analysis is performed prior to the final PFS 
analysis, the IDMC will review the efficacy data on Sub-study B for the 
MEDI4736+tremelimumab versus tremelimumab monotherapy treatment 
comparison and the MEDI4736+tremelimumab versus MEDI4736 monotherapy 
treatment comparison. 

If the interim OS analysis is performed, the IDMC will review the efficacy data on 
Sub-study B when approximately 244 PFS events have occurred from patients 
randomised to the MEDI4736+tremelimumab and Standard of Care arms, at 
approximately 18 months post first randomisation, at the time of the primary 
analysis of PFS and interim analysis of OS.
Full details of the IDMC procedures and processes can be found in the IDMC Charter.
The safety of all AstraZeneca/MedImmune clinical studies is closely monitored on an ongoing 
basis by AstraZeneca/MedImmune representatives in consultation with the Patient Safety 
Department. Issues identified will be addressed; this could involve, for instance, amendments 
to the clinical study protocol and letters to investigators.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
Section of SAP Affected 
(If applicable)
Change
Rationale
4.2.3.1
Remove HR and added p-value to the 
presentation of OS12
p-value required for multiple 
testing procedure
4.2.6/7
Change presentation of proportion of 
patients alive and progression free at 6 
and 12 months
To match TFL standards
4.2.2.1 and 4.2.2.2
Addition of PD-L1 status (with groups of 
<1% vs ≥1% to <25%) as a subgrouping 
factor and covariate to be analysed in a 
manner similar to covariates and 
subgroups previously established in the 
protocol
To align with emergent 
interest in this biomarker since 
the trial started
4.2.3.1 Overall Survival
Treatment Switching analysis references 
and choice of analysis changed 
Changed to be in line with 
proposed Therapeutic area 
guidance
4.2.10.3 Euro-Qol 5-
Dimension 5-Level 
questionnaire
Mixed model removed and more detail of 
descriptive statistics provided
Changed to be in line with 
proposed Therapeutic area 
guidance 
4.2.10 Health Resource 
Use
More accurate description of summaries 
to be produced
Changed to be in line with 
proposed Therapeutic area 
guidance


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
83
7.
REFERENCES
Berry et al 1991
Berry G, Kitchin RM, Mock PA. A comparison of two simple hazard ratio estimators based 
on the logrank test. Stat Med 1991;10(5):749-55.
Breslow, 1974
Breslow, NE. Covariance Analysis of Censored Survival Data. Biometrics 1974;30:89-99.
Burman et al 2009
Burman CF, Sonesson C, Guilbaud O. A recycling framework for the construction of 
Bonferroni-based multiple tests. Stat Med 2009;28(5):739-61. 
Glimm et al 2010
Glimm E, Maurer W and Bretz F. Hierarchical testing of multiple endpoints in 
group-sequential trials. Statist Med 2010;29:219-28.
Collett 2003
Collett D. Modelling survival data in medical research: 2nd ed. Chapman and Hall/CRC. 
2003. Available on request.
Cox 1972
Cox DR. Regression models and life-tables. J Royal Stat Society Series B 1972;34(2):187-220
Ellis et al 2008
Ellis S, Carroll KJ, Pemberton K. Analysis of duration of response in oncology trials. 
Contemp Clin Trials 2008;29(4):456-65.
Fayers et al 1999
Fayers P, Aaronson NK, Bjordal K, Curran D, Groenvold M on behalf of the EORTC Quality 
of Life Study Group. EORTC QLQ-C30 Scoring Manual: 2nd Edition 1999. Available on 
request.
Fleischer et al 2011
Fleischer F, Gaschler-Markefski B, Bluhmki E. How is retrospective independent review 
influenced by investigator-introduced informative censoring: a quantitative approach. 
Stat Med 2011;30(29):3373-86.
Gail and Simon 1985
Gail M, Simon R. Tests for qualitative interactions between treatment effects and patient 
subsets. Biometrics 1985;41(2):361-72.
Hanna et al 2004
Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. 
Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell 
lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22(9):1589-97.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
84
Klein et al 2007
Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a fixed point in 
time. Stat Med 2007; 26(24): 4505-19.
Lan and DeMets 1983
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. 
Biometrika 1983;70:659-63.
Latimer 2014
Latimer NR, Abrams KR, Lambert PC, Crowther MJ, Wailoo AJ, Morden JP, Akehurst RL, 
Campbell MJ. Adjusting survival time estimates to account for treatment switching in 
randomised controlled trials - an economic evaluation context: Methods, limitations and 
recommendations. Med Decis Making 2014;34(3):387-402
Nishino et al 2013
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH and Hodi FS. Developing a 
common language for tumour response to immunotherapy: Immune-related response criteria 
using unidimensional measurements. Clin Cancer Res 2013;19:3936-43
Oemar and Janseen 2013
Oemar M, Oppe M. EQ-5D-3L User Guide: Basic information on how to use the EQ-5D-3L 
instrument V5.0 (October 2013). Available from URL: 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/EQ-5D-
3L_UserGuide_2013_v5.0_October_2013.pdf. Accessed 07 January 2014.
Osoba et al 1998 
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16(1):139-44.
Pintilie M.
Pintilie M. Competing risks: A practical perspective. Wiley.
Robins and Tsiatis 1991
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. 
Communications in Statistics: Theory and Methods 1991;20(8):2609-31.
Robins 1993
Robins JM. Information Recovery and Bias Adjustment in Proportional Hazards Regression 
Analysis of Randomized Trials Using Surrogate Markers. Proceedings of the 
Biopharmaceutical Section, American Statistical Association 1993;24-33.
Sellke and Siegmund 1983
Sellke T, Siegmund D. Sequential analysis of the proportional hazards model. 
Biometrika 1983;70:315-26.


Statistical Analysis Plan 
Study Code D4191C00004
Edition Number 3
Date 24 January 2018
85
Sun and Chen 2010
Sun X, Chen C. Comparison of Finkelstein's Method with the Conventional Approach for 
Interval-Censored Data Analysis. Stat Biopharm Res 2010;2(1):97-108.
Whitehead and Whitehead 1991
Whitehead A, Whitehead J. A general parametric approach to the meta-analysis of 
randomized clinical trials. Statistics In Medicine 1991;10:1665-77.
Wolchok et al 2009
Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. 
Clin Cancer Res 2009;15(23):7412-20.