Clinical trial NCT03822351
Conditions: Stage III Non-small Cell Lung Cancer Unresectable
Keywords: Locally Advanced NSCLC Non-small Cell Lung Cancer Cancer Lung Unresectable Stage III
Sponsor: MedImmune LLC
Start date: 2018-12-19; Completion date: 2023-07-18
Enrollment: 189 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the clinical activity of durvalumab alone vs durvalumab in combination with novel agents. The overall study goal is early identification of novel durvalumab combinations that are more active than durvalumab alone in the treatment of patients with unresectable, Stage III NSCLC who have not progressed after cCRT.

Detailed description:
Study D9108C00001 (COAST) is a Phase 2, open-label, multicenter, randomized multidrug platform study assessing the efficacy and safety of durvalumab alone vs durvalumab in combination with novel agents in subjects with locally advanced, unresectable, Stage III non-small cell lung cancer (NSCLC).

Arms: arm 1: durvalumab IV arm 2: durvalumab IV and oleclumab IV arm 3: durvalumab IV and monalizumab IV
Interventions: intervention 1: Durvalumab + Oleclumab intervention 2: Durvalumab intervention 3: Durvalumab + Monalizumab
Intervention descriptions: intervention 1: Durvalumab + Oleclumab intervention 2: Durvalumab intervention 3: Durvalumab + Monalizumab

Protocol documents:
Prot_002.pdf: 
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A Phase 2, Open-label, Multicenter, Randomized, Multidrug 
Platform Study of Durvalumab Alone or in Combination with 
Novel Agents in Subjects with Locally Advanced, Unresectable, 
Stage III Non-small Cell Lung Cancer (COAST)
Sponsor Protocol Number:
D9108C00001
Application Number:
IND number 140603
EudraCT number 2018-002931-35
Investigational Products:
Durvalumab (MEDI4736) and novel oncology 
therapies (oleclumab [MEDI9447], monalizumab
[IPH2201])
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of 
AstraZeneca PLC
One MedImmune Way
Gaithersburg, Maryland, 20878, USA
Medical Monitor:
 
Phone: 
E-mail: 
Contract Research Organization:
ICON Clinical Research Ltd
Protocol History, Date:
Original Protocol, 03Oct2018
Protocol Amendment 1, 19Nov2018
Protocol Amendment 2, 07Jan2019
Protocol Amendment 3, 27Aug2019
Protocol Amendment 4, 27Jul2021
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorization from MedImmune.
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PROTOCOL SYNOPSIS
TITLE
A Phase 2, Open-label, Multicenter, Randomized, Multidrug Platform Study of Durvalumab Alone or in 
Combination with Novel Agents in Subjects with Locally Advanced, Unresectable, Stage III Non-small Cell 
Lung Cancer (COAST)
HYPOTHESES
Durvalumab in combination with novel agents will demonstrate superior antitumor activity than durvalumab 
alone with an acceptable safety profile in subjects with Stage III non-small cell lung cancer (NSCLC) who have 
not progressed following definitive concurrent chemoradiotherapy (cCRT).
OBJECTIVES and ENDPOINTS
Type
Objective
Endpoint
Primary
Clinical activity
To compare the antitumor activity of durvalumab 
alone vs durvalumab in combination with novel 
agents
Objective response (OR) per 
Response Evaluation Criteria 
for Solid Tumors version 1.1 
(RECIST v1.1)
Secondary
Safety
To evaluate the safety and tolerability of 
durvalumab alone and durvalumab in combination 
with novel agents
Presence of adverse events 
(AEs), serious adverse events 
(SAEs), and abnormal 
laboratory parameters and 
vital signs
Clinical activity
To further compare the efficacy of durvalumab 
alone vs durvalumab in combination with novel 
agents
Duration of response (DoR), 
disease control (DC), 
progression-free survival 
(PFS) at 12 months, and PFS 
per RECIST v1.1 and overall 
survival (OS) 
Pharmacokinetics
(a) To describe the pharmacokinetics (PK) of 
durvalumab alone and durvalumab in 
combination with novel agents 
Concentration of durvalumab 
or novel agents in serum 
(b) To describe the PK of novel agents in 
combination with durvalumab
Immunogenicity
(a) To assess the immunogenicity of durvalumab 
alone or in combination with novel agents
Antidrug antibody (ADA) 
incidence of durvalumab or 
novel biologic agents
(b) To assess the immunogenicity of novel 
biologic agents in combination with 
durvalumab


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Type
Objective
Endpoint
Exploratory
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DESIGN
Study D9108C00001 (COAST) is a Phase 2, open-label, multicenter, randomized, multidrug platform study of 
durvalumab alone or in combination with novel agents. Subjects with unresectable, Stage III NSCLC who have 
not progressed following definitive cCRT are eligible. Subjects will be randomized into the study and initiate 
study treatment within 42 days from the last session of cCRT. Subjects may be treated for up to 12 months. 
Study treatment will be discontinued upon disease progression, unacceptable toxicity, or other reason, eg, 
subject decision or noncompliance with study procedures. Experimental arms may be closed based on results of 
planned interim analyses. New durvalumab combination experimental arms may be added based on emerging 
nonclinical and clinical data via protocol amendment. Initially, the study will examine the experimental arms 
comprising durvalumab plus oleclumab (experimental Arm A) and durvalumab plus monalizumab 
(experimental Arm B). Treatment arms may be opened sequentially or in parallel at the discretion of the 
sponsor.
TARGET SUBJECT POPULATION
Unresectable, Stage III NSCLC without progression following definitive cCRT
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TREATMENT GROUPS AND REGIMENS
Control arm (durvalumab monotherapy): durvalumab 1500 mg IV every 4 weeks (Q4W) × 12 months
Experimental Arm A (durvalumab + oleclumab): durvalumab IV 1500 mg Q4W × 12 months plus oleclumab 
3000 mg IV every 2 weeks (Q2W) for 2 months then Q4W starting on Cycle 3, Day 1 × 10 months
Experimental Arm B (durvalumab + monalizumab): durvalumab 1500 mg IV Q4W × 12 months plus 
monalizumab 750 mg IV Q2W × 12 months
STATISTICAL METHODS 
Sample size: Up to approximately 60 subjects per experimental treatment arm will be randomized with equal 
ratios to durvalumab control and each of the open experimental arms. New durvalumab combination 
experimental arms may be added over time and therefore the total number of subjects randomized to the 
durvalumab control arm might be higher than 60 subjects.
Statistical analyses:
Efficacy
The final efficacy analyses of antitumor activity will be based on the Intent-to-treat (ITT) Population (defined as 
all subjects are randomized). The rates of OR based on RECIST v1.1 will be summarized with 95% confidence 
interval based on the exact binomial distribution. Time-to-event endpoints (DoR, PFS, and OS) will be analyzed 
using the Kaplan-Meier method.
Safety
Safety data, including AEs, SAEs, laboratory evaluations, vital signs, and electrocardiogram results will be 
summarized based on the As-treated Population (defined as all subjects who receive any investigational product 
analyzed according to treatment received). Descriptive statistics will be provided for AEs, SAEs, AE grade 
(severity), and relationship to study drug(s). AEs will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events version 5.0. Descriptive statistics will be provided for the 
clinical laboratory results and toxicities.
Pharmacokinetics and Immunogenicity
Only subjects who receive at least 1 dose of durvalumab and/or other combination study drug, and provide at 
least 1 post-treatment sample, will be evaluated. 
For each treatment arm, individual durvalumab concentrations will be tabulated with descriptive statistics. 
Additionally, for each experimental arm, individual novel agent concentrations will be tabulated with 
descriptive statistics. 
For each treatment arm, the immunogenic potential of durvalumab will be assessed by summarizing the number 
and percentage of subjects who develop detectable ADAs to durvalumab. For experimental arms that include a 
biologic agent, the immunogenic potential of the combination study drug will be assessed by summarizing the 
number and percentage of subjects who develop detectable ADAs to the combination study drug.
Interim analyses: Interim analyses will be done for early evaluation of the safety and clinical activity of the 
experimental arms compared to the control arm. The first interim analysis will be performed once the control 
arm has 30 ITT subjects who have reached the data cutoff criteria (defined as the opportunity to be followed for 
at least 16 weeks at the time of data cutoff). Bayesian predictive probabilities will be used to evaluate clinical 
activity. The disease control rate and objective response rate at Week 16 will be used for decision-making. 
Enrollment will not be paused for interim analyses.


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS...................................................................................................... 2
LIST OF ABBREVIATIONS ............................................................................................. 10
1
INTRODUCTION............................................................................................ 13
1.1
Disease Background ......................................................................................... 13
1.1.1
Immunotherapy................................................................................................. 13
1.1.1.1
Programmed Cell Death Ligand-1 (PD-L1)....................................................... 13
1.1.1.2
CD73................................................................................................................ 14
1.1.1.3
NKG2a ............................................................................................................. 14
1.2
Study Drug Background.................................................................................... 15
1.2.1
Durvalumab...................................................................................................... 15
1.2.2
Oleclumab ........................................................................................................ 15
1.2.3
Monalizumab.................................................................................................... 15
1.3
Summary of Nonclinical Experience................................................................. 15
1.3.1
Nonclinical Experience - Durvalumab............................................................... 15
1.3.2
Nonclinical Experience - Oleclumab................................................................. 15
1.3.3
Nonclinical Experience - Monalizumab ............................................................ 16
1.4
Summary of Clinical Experience....................................................................... 16
1.4.1
Clinical Experience - Durvalumab .................................................................... 16
1.4.2
Clinical Experience - Oleclumab Alone and in Combination with Durvalumab. 17
1.4.3
Clinical Experience - Monalizumab Alone and in Combination with Durval-
umab................................................................................................................. 18
1.5
Rationale for Conducting the Study .................................................................. 18
1.5.1
Rationale for Inclusion of Durvalumab in Combination with Oleclumab Arm... 20
1.5.2
Rationale for Inclusion of Durvalumab in Combination with Monalizumab 
Arm.................................................................................................................. 20
1.6
Benefit-risk and Ethical Assessment ................................................................. 20
1.6.1
Potential Benefits.............................................................................................. 20
1.6.2
Potential Risks.................................................................................................. 21
1.6.2.1
Durvalumab...................................................................................................... 21
1.6.2.2
Oleclumab ........................................................................................................ 21
1.6.2.3
Monalizumab.................................................................................................... 22
1.6.3
Overall Benefit-Risk......................................................................................... 23
1.7
Research Hypotheses ........................................................................................ 24
1.7.1
Primary Hypothesis .......................................................................................... 24
1.7.2
Secondary Hypotheses...................................................................................... 24
2
OBJECTIVES AND ENDPOINTS................................................................... 24
2.1
Primary Objective and Associated Endpoint ..................................................... 24
2.1.1
Secondary Objectives and Associated Endpoints............................................... 24
2.1.2
Exploratory Objectives and Associated Endpoints ............................................ 25
3
STUDY DESIGN ............................................................................................. 26
3.1
Description of the Study ................................................................................... 26




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4.3.8
Estimate of Volume of Blood to be Collected ................................................... 49
4.4
Study or Study Component Suspension or Termination..................................... 49
4.5
Investigational Product ..................................................................................... 50
4.5.1
Identity of Investigational Product .................................................................... 50
4.5.1.1
Investigational Product Handling ...................................................................... 51
4.5.1.2
Investigational Product Inspection .................................................................... 52
4.5.1.3
Durvalumab Dose Preparation and Administration............................................ 52
4.5.1.4
Oleclumab Dose Preparation and Administration.............................................. 53
4.5.1.5
Monalizumab Dose Preparation and Administration ......................................... 53
4.5.1.6
Treatment Administration................................................................................. 54
4.5.1.7
Monitoring of Dose Administration .................................................................. 55
4.5.1.8
Reporting Product Complaints .......................................................................... 55
4.5.2
Additional Study Medications........................................................................... 55
4.5.3
Labeling ........................................................................................................... 55
4.5.4
Storage ............................................................................................................. 55
4.5.5
Treatment Compliance...................................................................................... 56
4.5.6
Accountability .................................................................................................. 56
4.6
Treatment Assignment and Blinding ................................................................. 56
4.6.1
Methods for Assigning Treatment Groups......................................................... 56
4.6.2
Methods to Ensure Blinding.............................................................................. 57
4.7
Restrictions During the Study and Concomitant Treatment(s) ........................... 57
4.7.1
Permitted Concomitant Medications ................................................................. 57
4.7.2
Prohibited Concomitant Medications ................................................................ 57
4.8
Statistical Evaluation ........................................................................................ 58
4.8.1
General Considerations..................................................................................... 58
4.8.2
Sample Size...................................................................................................... 58
4.8.3
Efficacy ............................................................................................................ 59
4.8.3.1
Primary Efficacy Analysis ................................................................................ 60
4.8.3.2
Secondary Efficacy Analyses............................................................................ 60
4.8.3.3
Exploratory Analyses........................................................................................ 60
4.8.4
Safety ............................................................................................................... 61
4.8.4.1
Analysis of Adverse Events .............................................................................. 61
4.8.4.2
Analysis of Clinical Laboratory Parameters ...................................................... 61
4.8.4.3
Analysis of Vital Signs ..................................................................................... 61
4.8.4.4
Analysis of ECOG Performance Status............................................................. 61
4.8.5
Analysis of Immunogenicity/Pharmacokinetics................................................. 61
4.8.6
Analyses of Biomarkers.................................................................................... 62
4.8.7
Interim Analysis ............................................................................................... 62
5
ASSESSMENT OF SAFETY ........................................................................... 63
5.1
Definition of Adverse Events............................................................................ 63
5.2
Definition of Serious Adverse Events ............................................................... 64
5.3
Definition of Adverse Events of Special Interest............................................... 64
5.3.1
Adverse Events of Special Interest for Durvalumab-containing Regimens ........ 64
5.3.2
Adverse Events of Special Interest Associated with Oleclumab ........................ 66


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5.3.3
Adverse Events of Special Interest Associated with Monalizumab.................... 66
5.4
Recording of Adverse Events............................................................................ 66
5.4.1
Time Period for Collection of Adverse Events .................................................. 67
5.4.2
Follow-up of Unresolved Adverse Events......................................................... 67
5.4.3
Deaths .............................................................................................................. 67
5.4.4
Adverse Events Based on Signs and Symptoms ................................................ 67
5.4.5
Adverse Events Based on Examination and Tests.............................................. 67
5.4.6
Potential Hy’s Law and Hy’s Law..................................................................... 68
5.4.7
Disease Progression.......................................................................................... 68
5.5
Reporting of Serious Adverse Events................................................................ 69
5.6
Other Events Requiring Immediate Reporting................................................... 69
5.6.1
Overdose………............................................................................................... 69
5.6.2
Pregnancy......................................................................................................... 70
5.6.2.1
Maternal Exposure............................................................................................ 70
5.6.2.2
Paternal Exposure............................................................................................. 70
5.6.3
Medication Error............................................................................................... 71
6
STUDY AND DATA MANAGEMENT........................................................... 72
6.1
Training of Study Site Personnel....................................................................... 72
6.2
Monitoring of the Study.................................................................................... 72
6.2.1
Source Data ...................................................................................................... 73
6.2.2
Study Agreements............................................................................................. 73
6.2.3
Archiving of Study Documents......................................................................... 73
6.3
Study Timetable and End of Study.................................................................... 73
6.4
Data Management............................................................................................. 73
6.5
Medical Monitor Coverage ............................................................................... 74
7
ETHICAL AND REGULATORY REQUIREMENTS...................................... 74
7.1
Subject Data Protection..................................................................................... 74
7.2
Ethics and Regulatory Review .......................................................................... 74
7.3
Informed Consent ............................................................................................. 75
7.4
Changes to the Protocol and Informed Consent Form........................................ 76
7.5
Audits and Inspections...................................................................................... 76
8
REFERENCES................................................................................................. 77
9
CHANGES TO THE PROTOCOL ................................................................... 83
9.1
Protocol Amendment 3 ..................................................................................... 83
9.2
Protocol Amendment 2 ..................................................................................... 85
9.3
Protocol Amendment 1 ..................................................................................... 85


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LIST OF TABLES
Table 1
Primary Objective and Associated Endpoint ............................................ 24
Table 2
Secondary Objectives and Associated Endpoints...................................... 24
Table 3
Exploratory Objectives and Associated Endpoints ................................... 25
Table 4
Criteria for Adequate Organ and Marrow Function .................................. 32
Table 5
Schedule of Screening and Treatment Period Procedures ......................... 37
Table 6
Schedule of Follow-up Procedures: Subjects Who Completed Study 
Treatment and Maintain DC, Subjects Who Discontinued Study Treat-
ment Due to Other Reason Not Related to PD, and Subjects Who Experi-
enced Unconfirmed PD and are Eligible for a Confirmation Scan ............ 40
Table 7
Schedule of Procedures for End of Study Visit......................................... 42
Table 8
Identification of Investigational Product .................................................. 50
Table 9
Estimated Differences in ORR Between Experimental and Control Arm 
of 60 Subjects Each ................................................................................. 59
Table 10
Criteria of No-Go Decisions Based on DCR at 16 Weeks ........................ 63
Table A1
Highly Effective Methods of Contraception............................................. 88
Table F1
Evaluation of Overall Response Using RECIST v1.1............................. 103
............................ 104
LIST OF FIGURES
Figure 1
Study Flow Diagram................................................................................ 27
Figure 2
Treatment Regimen for Control Arm - Durvalumab Monotherapy........... 27
Figure 3
Treatment Regimen for Arm A - Durvalumab Plus Oleclumab ................ 28
Figure 4
Treatment Regimen for Arm B – Durvalumab Plus Monalizumab ........... 28
LIST OF APPENDICES
Appendix A
Contraception Guidance........................................................................... 87
Appendix B
Additional Safety Guidance ..................................................................... 89
Appendix C
National Institute of Allergy and Infectious Diseases and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis.............. 92
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and Eval-
uation of Hy’s Law .................................................................................. 93
Appendix E
Genetic Research..................................................................................... 98
Appendix F
Response Evaluation Criteria in Solid Tumors Version 1.1 .................... 101
......................... 104
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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
ADA
antidrug antibody
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AMP
adenosine monophosphate
AST
aspartate aminotransferase
ATP
adenosine triphosphate
BOR
best overall response
CD
cluster of differentiation
CI
confidence interval
COAST
Study D9108C00001
CR
complete response
cCRT
concurrent chemoradiotherapy
CSR
clinical study report
CT
computed tomography
CTLA-4
cytotoxic T-lymphocyte-associated antigen-4
DC
disease control
DCO
data cutoff
DCR
disease control rate
DLT
dose-limiting toxicity
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOI
end of infusion
GCP
Good Clinical Practice
HBc
hepatitis B core
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus


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Abbreviation or 
Specialized Term
Definition
HIV
human immunodeficiency virus
HLA-E
major histocompatibility complex E
HR
hazard ratio
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
Ig
immunoglobulin
imAE
immune-mediated adverse event
IRB
Institutional Review Board
IRR
infusion-related reaction
ITT
Intent-to-treat
IV
intravenous
IXRS
interactive voice/web response system
mAb
monoclonal antibody
MRI
magnetic resonance imaging
NCI CTCAE v5.0
National Cancer Institute Common Terminology Criteria for Adverse Events 
version 5.0
NK
natural killer
NSCLC
non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PACIFIC
Study D4191C00001 (NCT02125461)
PD
progressive disease
PD-1
programmed cell death-1
PD-L1
programmed cell death ligand-1
PD-L2
programmed cell death ligand-2
PET
positron emission tomography
PFS
progression-free survival
PFS-12
progression-free survival 12-month landmark rate
PI
Package Insert
PK
pharmacokinetic(s)
PP
predictive probability(ies)
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Abbreviation or 
Specialized Term
Definition
PR
partial response
Q2W
every 2 weeks
Q4W
every 4 weeks
RECIST v1.1
Response Evaluation Criteria for Solid Tumors version 1.1
SAE
serious adverse event
SD
stable disease
SID
subject identification
SRC
Safety Review Committee
SUV
standardized uptake value(s)
T3
triiodothyronine
T4
thyroxine
TBL
total bilirubin
TSH
thyroid stimulating hormone
TV
target value
ULN
upper limit of normal
US
United States
w/v
weight per volume


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1
INTRODUCTION
Study D9108C00001 (COAST) is a platform study dynamically assessing the efficacy and 
safety of durvalumab alone vs durvalumab in combination with novel agents in subjects with 
locally advanced, unresectable, Stage III non-small cell lung cancer (NSCLC). Combination 
treatment arms will be added via protocol amendment during the course of the study as novel 
agents of interest become available.
1.1
Disease Background
Lung cancer is the most common and lethal cancer worldwide with an estimated 1.8 million 
new cases annually resulting in approximately 1.6 million deaths (Torre et al, 2015). NSCLC 
represents approximately 85% of all lung cancers and 30% of patients present with Stage III 
disease at diagnosis (American Cancer Society, 2018). For patients with Stage III NSCLC not 
amenable for surgical resection, the standard treatment is platinum-based doublet chemother-
apy given concomitantly with radiotherapy followed by durvalumab consolidation. When ad-
ministered after completion of concurrent chemoradiotherapy (cCRT) in patients with unre-
sectable NSCLC, durvalumab demonstrated a better clinical response than placebo, with pro-
longed progression-free survival (PFS; hazard ratio [HR]: 0.51; 95% confidence interval [CI]: 
0.41, 0.63) and overall survival (OS; HR: 0.68; 99.73% CI: 0.47, 0.997, p = 0.0025; PACIFIC 
[Study D4191C00001]; Antonia et al, 2018; Antonia et al, 2017). Durvalumab showed a me-
dian PFS of 17.2 months compared to 5.6 months in the placebo group. However, despite 
chemoradiotherapy and durvalumab consolidation most patients will relapse and eventually 
die from lung cancer. 
1.1.1
Immunotherapy
1.1.1.1
Programmed Cell Death Ligand-1 (PD-L1)
Programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and programmed 
cell death ligand-2 (PD-L2) are part of a complex system of receptors and ligands that control 
T-cell activation. PD-L1 expression helps tumors evade detection and elimination by the 
immune system (Juneja et al, 2017; Keir et al, 2008; Chen and Mellman, 2013; Ohaegbulam 
et al, 2015). The binding of PD-L1 to PD-1 on activated T cells delivers an inhibitory signal 
preventing T cells from killing target tumor cells (Zou and Chen, 2008; Zou et al, 2016; 
Pardoll, 2012). Monoclonal antibodies (mAbs) targeting PD-1 (nivolumab, pembrolizumab) 
and PD-L1 (durvalumab, atezolizumab) have shown evidence of antitumor activity and a 
manageable safety profile in patients with NSCLC and have been granted approvals by the 
United States (US) Food and Drug Administration and/or the European Medicines Agency for 
the treatment of NSCLC (Opdivo® US PI, 2018; Keytruda® US PI, 2018; Imfinzi® US PI, 
2018; Tecentriq® US PI, 2018). 


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1.1.1.2
CD73
Adenosine is a regulatory autocrine and paracrine factor that accumulates in the tumor 
microenvironment, influencing immune activity, angiogenesis, and metastasis. Upon apoptotic 
or necrotic cell death, tumor cells release adenosine triphosphate (ATP) into the extracellular 
space. ATP has been shown to lead to a pro-inflammatory response. To prevent an immune 
over activation, tissues express cluster of differentiation (CD)39 and CD73 to enzymatically 
convert ATP to adenosine, which induces a localized immunosuppressive response through 
multiple immune cell types. In the extracellular space, CD39 and CD73 in tandem metabolize 
ATP to adenosine monophosphate (AMP), and AMP to adenosine, respectively, and are a 
major source of extracellular adenosine. Extracellular adenosine impairs the proliferation and 
effector function of cytotoxic T lymphocytes while simultaneously contributing to the 
immunosuppressive effects of both regulatory T cells and myeloid-derived suppressor cells, 
among others (Vijayan et al, 2017). The rate limiting step in the generation of extracellular 
adenosine is the dephosphorylation of AMP by CD73. 
One mechanism by which tumors may have evolved to evade the immune system is via 
overexpression of CD73. Overexpression of CD73 has been associated with poor prognosis in 
multiple cancer types (Inoue et al, 2017; Turcotte et al, 2015; Vijayan et al, 2017). Notably, 
high CD73 expression in NSCLC was associated with poor overall survival and recurrence 
free survival in a multivariate analysis (Inoue et al, 2017). It is hypothesized that blocking 
CD73 activity will reduce adenosine production, thus augmenting host and/or immunotherapy 
response to tumor.
1.1.1.3
NKG2a
Major histocompatibility complex E (HLA-E) is a non-classical major histocompatibility 
complex class I molecule, over-expressed by malignant cells in a variety of tumor types. 
HLA-E can present antigens to the CD94/NKG2a receptors on the surface of some types of 
lymphocytes. Activation of CD94/NKG2a receptors induces inhibitory signals that suppress 
cytokine secretion and direct cytotoxicity of cytotoxic T lymphocytes or natural killer (NK) 
cells against stressed, infected, or “transformed” cells. Such activity has been described as a 
possible mechanism in immune escape of cancer cells (Borrego et al, 1998; Braud et al, 1998). 
Conversely, the blockade of CD94/NKG2a by an antagonist mAb restores the response of NK 
cells, enhancing notably their cytotoxicity against tumor cells expressing HLA-E. 
Furthermore, blockade of CD94/NKG2a may enhance NK-mediated antibody-dependent 
cellular cytotoxicity (Denis et al, 2017). NK cells can also decrease metastasis through 
immunosurveillance (López-Soto et al, 2017; Malladi et al, 2016).
Expression of CD94/NKG2a has been documented by subsets of cytotoxic T lymphocytes and 
NK cells infiltrating solid tumors. CD94/NKG2a appeared to be over-expressed in tumor-
infiltrating NK cells as compared to NK cells present in the non-tumoral areas of the same 
tissue or in the blood. Hyper-expression of CD94/NKG2a by infiltrating NK cells appeared to 


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be associated with a diminished cytotoxic potential (Sheu et al, 2005; Mamessier et al, 2011; 
Platonova et al, 2011) and has been documented in a variety of solid tumors including 
NSCLC, colorectal, ovarian, endometrial, pancreatic, and prostate cancers (Aparicio-Pagés et 
al, 1991; Gooden et al, 2011; Iannone et al, 2015; Pardoll, 2012; Pasero et al, 2015; Peng et al, 
2014; Tarle et al, 1993; Zeestraten et al, 2014). In addition, expression of HLA-E has been 
shown to correlate with a poor outcome in colorectal, ovarian, or endometrial carcinoma (Guo 
et al, 2015; Emens et al, 2017; Gooden et al, 2011; Versluis et al, 2017).
1.2
Study Drug Background
1.2.1
Durvalumab
Durvalumab is a human immunoglobulin (Ig) G1 kappa mAb that blocks the interaction of 
PD-L1 (but not PD-L2) with PD-1 on T cells and CD80 (B7.1) on immune cells, and is 
engineered to reduce antibody-dependent cell-mediated cytotoxicity and complement 
activation. Refer to the current durvalumab Investigator’s Brochure (IB) for details. 
1.2.2
Oleclumab
Oleclumab (MEDI9447) is a human IgG1 lambda mAb that selectively binds to CD73 and 
inhibits adenosine production as well as leads to a reduction in CD73 expression through 
internalization (Geoghegan et al, 2016; Hay et al, 2016). It contains a triple mutation in the 
heavy chain constant region for reduced effector function. The enzymatic blockade of CD73 
and decreased expression caused by binding of oleclumab to CD73 may lead to increased 
antitumor immunity. Refer to the current oleclumab IB for details.
1.2.3
Monalizumab
Monalizumab (IPH2201) is a humanized mAb of the IgG-4 subtype produced in Chinese 
hamster ovary cells. It has a non-depleting and purely blocking activity directed with high 
affinity and specificity against the CD94/NKG2a subunit of the heterodimeric inhibitory 
CD94/NKG2a receptor expressed by subsets of NK cells, activated αβ CD8+ T cells and 
γδ-T cells. By suppressing the inhibitory signal transduced by CD94/NKG2a, monalizumab 
enhances the antitumor functions, including cytolytic activity of these immune effector cells. 
Refer to the current monalizumab IB for details.
1.3
Summary of Nonclinical Experience
1.3.1
Nonclinical Experience - Durvalumab
Refer to the current durvalumab IB for a complete summary of nonclinical experience.
1.3.2
Nonclinical Experience - Oleclumab
No oleclumab-related adverse effects were noted in CD-1 mice (5-week, repeat intravenous 
[IV] bolus dose, once every 4 days, total 9 doses) at doses up to 200 mg/kg or in cynomolgus 


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monkeys (5-week, repeat IV 30-minute infusion dose, once weekly, total 5 doses) at doses up 
to 300.7 mg/kg in Good Laboratory Practice toxicity studies. Additionally, no oleclumab-
related effects on electrocardiogram (ECG), blood pressure, or behavioral examinations were 
observed in the 5-week cynomolgus monkey study. The no-observed-adverse-effect-level was 
200 mg/kg/dose in CD-1 mice and 300.7 mg/kg/dose in cynomolgus monkeys. Refer to the 
current oleclumab IB for a complete summary of nonclinical experience.
1.3.3
Nonclinical Experience - Monalizumab
The nonclinical safety profiling of monalizumab has not identified any safety issues. Various 
human in vitro biological assays testing acute pharmacological effects identified no 
non-target-related or potentially target-related safety issues. No toxicities were observed in 
cynomolgus monkeys after 13 weeks of dosing of up to 150 mg/kg weekly. The highest dose 
(150 mg/kg) resulted in approximately 18 weeks of full CD94/NKG2a receptor saturation. In 
humans, monalizumab binds selectively to CD94/NKG2aA receptors. In monkeys, 
monalizumab binds with equal affinity to the activating CD94/NKG2c receptor in addition to 
the inhibitory CD94/NKG2a receptor. This is most likely the reason why it has been 
impossible to observe effects comparable to those seen in humans in functional in vitro assays 
with cynomolgus vs human cells. Further risk assessment of long-term blocking of the 
CD94/NKG2a receptor was therefore performed with a surrogate anti-mouse NKG2a antibody 
that has been used to demonstrate in vitro antitumor efficacy with mouse cells. In toxicology 
studies, mice were dosed subcutaneously every second day for up to 26 weeks at doses up to 
50 mg/kg. As with the cynomolgus monkey studies, the toxicity studies in mice did not 
identify any safety issues. Refer to the current monalizumab IB for a complete summary of 
nonclinical experience.
1.4
Summary of Clinical Experience
A complete summary of clinical experience, including safety, efficacy, and pharmacokinetics 
(PK), for durvalumab, oleclumab, and monalizumab can be found in the current IB of each 
respective agent.
1.4.1
Clinical Experience - Durvalumab
To date, durvalumab has been given to more than 6,000 subjects as part of ongoing studies 
either as monotherapy or in combination with other anticancer agents. In monotherapy clinical 
studies, the most common adverse events (AEs; ≥ 20%) included fatigue (32%), cough (23%), 
decreased appetite, dyspnea (21% each), and nausea (20%). Approximately 9% of subjects 
discontinued durvalumab due to an AE. The majority of treatment-related AEs were 
manageable, with dose delays, symptomatic treatment, and in the case of events suspected to 
have an immune basis, the use of established treatment guidelines for immune-mediated 
toxicity (see Section 3.1.3).


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In the PACIFIC study, 68% (322/475) of subjects with unresectable, Stage III NSCLC without 
progression after cCRT treated with durvalumab reported a treatment-related AE, with 
fatigue (13%), hypothyroidism (11%), diarrhea (10%), pneumonitis (9%), rash (8%), pruritus 
(7%), hyperthyroidism, asthenia, dyspnea, decreased appetite, nausea (6% each), and cough 
(5%) being the most common. Grade 3 or 4 AEs were reported in 30% (142/475) of subjects, 
with pneumonia (4%), pneumonitis or radiation pneumonitis, anemia (3% each), and dyspnea 
(2%) reported in > 1% of subjects (Antonia et al, 2017). 
In PACIFIC, durvalumab treatment for 12 months demonstrated superior PFS and OS in 
comparison to placebo (Section 1.1; Antonia et al, 2018; Antonia et al, 2017).
1.4.2
Clinical Experience - Oleclumab Alone and in Combination with 
Durvalumab
As of the data cutoff (DCO) date of 09Jan2018, 116 adult subjects with advanced solid tumors 
have received oleclumab either as monotherapy (42 subjects) or in combination with 
durvalumab (74 subjects) during the dose-escalation or dose-expansion phases of the 
first-time-in-human Phase 1 Study D6070C00001. 
Following oleclumab monotherapy, 55% (23/42) of subjects reported a treatment-related AE, 
with fatigue (17%), nausea, and anemia (10% each) being the most common. Grade 3 or 4 
AEs were reported in 45% (19/42) of subjects, with ascites (12%), acute kidney injury, 
hyperglycemia, hyponatremia, and hypotension (5% each) reported in more than 1 subject. 
Three deaths occurred in subjects treated with oleclumab monotherapy (1 due to small 
intestinal obstruction and 2 due to disease under treatment); none were considered related to 
oleclumab.
Following oleclumab plus durvalumab combination therapy, 47% (35/74) of subjects reported 
a treatment-related AE, with fatigue (14%), increased aspartate aminotransferase (AST), 
diarrhea, and pyrexia (8% each), increased blood alkaline phosphatase (ALP; 7%), increased 
alanine aminotransferase (ALT), decreased appetite, and vomiting (5% each) being the most 
common. Grade 3 or 4 AEs were reported in 53% (39/74) of subjects, with increased ALP 
(8%), anemia, increased ALT, increased AST, and increased gamma glutamyl transferase 
(5% each) reported in at least 5% of subjects. Six deaths occurred in subjects treated with 
oleclumab plus durvalumab (1 each due to renal failure, vomiting, respiratory failure; 2 due to 
pneumonia; and 1 due to disease under treatment); none of the deaths were considered related 
to study treatment.
Efficacy data from 42 response-evaluable subjects treated with oleclumab plus durvalumab in 
the dose-expansion phase (including subjects with colorectal cancer [n = 21], pancreatic 
adenocarcinoma [n = 20], and NSCLC [n = 1]) showed an objective response rate (ORR; 


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confirmed and unconfirmed) of 7.1% (3/42 subjects; 95% CI: 1.5%, 19.5%) and a disease 
control rate (DCR; 8 weeks) of 16.7% (7/42 subjects; 95% CI: 7.0%, 31.4%).
1.4.3
Clinical Experience - Monalizumab Alone and in Combination with 
Durvalumab
The safety and tolerability as well as single-dose and multiple-dose PK and pharmacodynamic 
properties of monalizumab were initially investigated in subjects with active rheumatoid 
arthritis (Study NN8765-3658). In this first study (completed), 68 subjects received 
monalizumab monotherapy with maximum tested dose levels of 10 mg/kg during IV infusion 
(single dose) and 4.0 mg/kg following subcutaneous administrations (in single and multiples 
doses), with a favorable safety profile. 
Monalizumab is now being developed for the treatment of various hematologic and solid 
malignancies as monotherapy or in combination with other drugs. As of 30Apr2018, a total of 
315 subjects have been treated with monalizumab in 7 hematology/oncology studies with 
multiple doses up to 10 mg/kg or 750 mg IV. Most of the reported AEs were Grade 1 or 2, 
with no obvious dose relationship. The most common (≥ 10%) AEs considered related to 
monalizumab monotherapy were headache (23%), nausea (18%), fatigue (16%), vomiting 
(15%), anorexia (11%), diarrhea, abdominal pain, and sore throat (10% each). There was no 
death related to study treatment. 
In Study D419NC00001, as of 30Apr2018, 154 subjects were exposed to monalizumab and 
durvalumab combination therapy in a dose-escalation (12 subjects) or dose-expansion 
(139 subjects) phase. Overall, 62% (95/154) of subjects reported a treatment-related AE, with 
diarrhea, fatigue (10% each), asthenia, pyrexia (8% each), hypothyroidism, nausea (7% each), 
decreased appetite (6%), and pruritus (5%) being the most common. Grade 3 or 4 AEs were 
reported in 43% (66/154) of subjects, with anemia (7%) reported in at least 5% of subjects. 
Three deaths occurred (2 due to intestinal obstructions and 1 due to bipolar disorder); none of 
the deaths were considered related to study treatment.
Of 39 evaluable subjects with microsatellite-stable colorectal cancer in the dose-expansion 
phase of Study D419NC00001, 3 (8%) subjects had a partial response (PR) and 11 (28%) 
subjects had stable disease (SD; Segal et al, 2018).
1.5
Rationale for Conducting the Study
Current standard of care for patients with unresectable, Stage III NSCLC includes cCRT 
followed by durvalumab maintenance for 12 months. When administered after completion of 
cCRT in patients with unresectable NSCLC, durvalumab demonstrated improved PFS 
(HR: 0.51; 95% CI: 0.41, 0.63) and OS (HR: 0.68; 99.73% CI: 0.47, 0.997, p = 0.0025) vs 


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placebo (PACIFIC study; Antonia et al, 2018). Durvalumab showed a median PFS of 
17.2 months compared to 5.6 months in the placebo group.
Furthermore, ORR might be an appropriate endpoint to assess antitumor activity when sub-
jects are randomized after cCRT. In the PACIFIC study, ORR following cCRT completed 
prior to study drug treatment was 50.5% in the durvalumab group and 49.8% in the placebo 
group (Antonia et al, 2017). Following study drug treatment, ORR was higher in the durval-
umab than the placebo group (28.5% vs 16.0%, respectively). Previous studies assessing the 
role of consolidation or maintenance strategies in subjects with NSCLC treated with CRT 
were consistently negative, and no differences in ORR were seen between the placebo and ex-
perimental arms (Ahn et al, 2015; Kelly et al, 2008). Together, these data suggest that ORR is 
an appropriate endpoint to assess the antitumor activity in a signal finding study where sub-
jects with unresectable Stage III NSCLC are randomized after completing cCRT.
Despite these therapeutic advances, unresectable, Stage III NSCLC remains a condition with a 
high risk of relapse and morbidity. Further improvement in clinical outcomes in this patient 
population with a high unmet medical need may be achieved through combination therapy of 
durvalumab with other immune modulators or anticancer therapies. Several ongoing studies 
are exploring durvalumab and/or other immunotherapies for the treatment of Stage III NSCLC 
(CT03519971, NCT02904954, NCT03217071, and NCT03379441). 
The platform study design permits a dynamic assessment of durvalumab combination 
experimental arms. Experimental arms may be closed based on results of planned interim 
analyses. New experimental arms may be added via protocol amendment (see Section 1.6.3). 
Potential new candidate study drugs to be evaluated in combination with durvalumab in this 
platform study must have a known mechanism of action that could be additive or synergistic 
with durvalumab, an established recommended dose in combination with durvalumab with an 
acceptable safety profile, and preliminary evidence of clinical activity in combination with 
durvalumab in a solid tumor setting. As a starting point, oleclumab and monalizumab meet 
these criteria (see Section 1.5.1 and Section 1.5.2, respectively), and will be used in 
combination with durvalumab in the initial experimental arms of this platform study. Thus, at 
the outset, the study will examine the clinical activity and safety of durvalumab plus 
oleclumab, durvalumab plus monalizumab, and durvalumab alone in subjects with 
unresectable, Stage III NSCLC who have not progressed after cCRT. 
Given this platform study uses randomization and a perpetual control arm, it may require 
adaptions over time as the standard of care in patients with unresectable, Stage III NSCLC 
evolves in order to safeguard the best interests of the patients participating in this study. 
Potential protocol modifications may include changes in the definition of curative intent 
cCRT, inclusion of durvalumab as part of the cCRT treatment plan, or the duration/schedule 


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of durvalumab maintenance. Rationale and supporting evidence for any changes to the current 
protocol design will be addressed via protocol amendment.
1.5.1
Rationale for Inclusion of Durvalumab in Combination with Oleclumab 
Arm
 
 
 
 
 
 
 
 
 
 
1.5.2
Rationale for Inclusion of Durvalumab in Combination with 
Monalizumab Arm
 
 
 
 
1.6
Benefit-risk and Ethical Assessment
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), and applicable regulatory requirements. More detailed 
information about the known and expected benefits and risks and reasonably expected AEs of 
durvalumab and each novel oncology therapy may be found in the respective IB for each 
molecule.
1.6.1
Potential Benefits
Most patients with unresectable, Stage III NSCLC will relapse and die from lung cancer 
despite aggressive cCRT, with a 5-year survival of approximately 15% (Curran et al, 2011, 
CCI
CCI


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Aupérin et al, 2010). Recently, results from the PACIFIC study demonstrated that durvalumab 
maintenance for 12 months improved PFS and OS in comparison to placebo, with a favorable 
safety profile (Antonia et al, 2018; Antonia et al, 2017).
This protocol will allow patients with unresectable, Stage III NSCLC without progression 
after cCRT to receive durvalumab and potentially achieve survival benefit as demonstrated in 
the PACIFIC study (Antonia et al, 2018; Antonia et al, 2017). Further improvement in clinical 
outcomes in this patient population with a high unmet medical need may be achieved through 
combining novel therapies with durvalumab. Selection of the combination novel agents will 
be based on nonclinical and clinical data supporting a potentially favorable interaction with 
durvalumab in this patient population, with a well-tolerated and manageable safety profile.
1.6.2
Potential Risks
1.6.2.1
Durvalumab
Durvalumab may boost endogenous immune responses leading to undesired AEs. Most 
adverse drug reactions seen with durvalumab include, but are not limited to, diarrhea/colitis, 
pneumonitis/interstitial lung disease, endocrinopathies (ie, events of hypophysitis, adrenal 
insufficiency, hyper- and hypo-thyroidism, and type I diabetes mellitus), hepatitis/increases in 
transaminases, nephritis/increases in creatinine, pancreatitis/increases in amylase and lipase, 
rash/dermatitis, myocarditis, myositis/polymyositis, other rare or less frequent inflammatory 
events including neurotoxicities, infusion-related reactions (IRRs), hypersensitivity reactions, 
and infections/serious infections.
For information on all identified and potential risks with durvalumab alone or in combination 
with other anticancer therapies refer to the current version of the durvalumab IB.
1.6.2.2
Oleclumab 
As of 09Jan2018, a total of 42 subjects with advanced solid tumors have received oleclumab 
monotherapy during the dose-escalation phase of the first time-in-human Phase 1 
Study D6070C00001. No dose-limiting toxicities (DLTs), treatment-related SAEs, or 
treatment-related deaths were identified. Following oleclumab monotherapy, 55% (23/42) of 
subjects reported a treatment-related AE, with fatigue, nausea, and anemia being the most 
common (≥ 10%). Additionally, some potential risks for the abrogation of CD73 activity 
caused by oleclumab treatment have been suggested from clinical findings in individuals with 
CD73 deficiency and findings in CD73-deficient mice. Those potential risks include arterial 
calcifications, arterial ischemic disorder, thrombosis, and increased microvascular 
permeability, and potential risks include joint calcifications. Other important potential risks
associated with the administration of mAbs include IRRs, anaphylaxis, hypersensitivity or 
allergic reactions, and immune complex disease. Additional potential risks associated with any 
IV administration are localized infection, redness, swelling, pain, and induration at the 
administration site. 


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Given the mode of action of oleclumab, and the potential risks for durvalumab, the theoretical 
risk associated with removing the inhibition of adenosine on the microenvironment favors 
increased antitumor immunity when combined with durvalumab as well as the risk of 
emergence of autoimmune phenomena. As of 09Jan2018, a total of 74 subjects with advanced 
solid tumors have received oleclumab in combination with durvalumab in 
Study D6070C00001. No DLTs or treatment-related deaths were identified. Following 
oleclumab plus durvalumab combination therapy, 47% (35/74) of subjects reported a 
treatment-related AE, with fatigue, increased AST, diarrhea, pyrexia, increased blood ALP, 
increased ALT, decreased appetite, and vomiting being the most common (≥ 5%). Grade 3 or 
4 AEs were reported in 53% (39/74) of subjects, with increased ALP, anemia, increased ALT, 
increased AST, and increased gamma glutamyl transferase reported in at least 5% of subjects. 
Overall, durvalumab plus oleclumab and oleclumab alone have been well tolerated to date. 
See Section 1.4.2 for a detailed description of AEs reported in Study D6070C00001. 
For information on safety and potential risks with oleclumab, refer to the current oleclumab 
IB. See Section 5.3.2 for adverse events of special interest (AESIs) associated with oleclumab.
1.6.2.3
Monalizumab 
As of 30Apr2018, a total of 315 subjects have been treated with monalizumab in 
hematology/oncology studies. Most of the reported AEs were Grade 1 or 2, with no obvious 
dose relationship. The most frequent (≥ 10%) AEs considered related to monalizumab 
monotherapy were headache, nausea, fatigue, vomiting, anorexia, diarrhea, abdominal pain, 
and sore throat. There were no treatment-related deaths in any of the studies. 
Given the mode of action of monalizumab, and the potential risks for durvalumab, the 
theoretical risk associated when monalizumab is combined with durvalumab may be an 
increased risk of emergence of autoimmune phenomena. However, no such potential risks 
have been identified during the conduct of the development program. As of 30Apr2018, 
154 subjects were exposed to monalizumab and durvalumab combination therapy. Overall, 
62% (95/154) of subjects reported a treatment-related AE, with diarrhea, fatigue, asthenia, 
pyrexia, hypothyroidism, nausea, decreased appetite, and pruritus being the most common 
(≥5%). Grade 3 or 4 AEs were reported in 43% (66/154) of subjects, with anemia reported in 
at least 5% of subjects. No deaths were considered related to study treatment.
Given the mode of action of monalizumab, however, there are theoretical risks that may arise 
when monalizumab is used in combination with durvalumab. The theoretical risk associated 
with inhibiting NKG2a favors increased antitumor immunity when combined with 
durvalumab as well as the risk of emergence of autoimmune phenomena. These risks include 
adverse effects on the immune system, increased risk of infection, acute generalized or 
delayed hypersensitivity reactions, immunogenicity, local injection-site reactions and AEs 
associated with the blocking effect on CD94/NKG2a receptors. 


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Overall, durvalumab plus monalizumab and monalizumab alone have been well tolerated to 
date. See Section 1.4.3 for a description of AEs reported in monalizumab monotherapy and 
durvalumab combination therapy studies. 
For information on safety and potential risks with monalizumab, refer to the current 
monalizumab IB.
1.6.3
Overall Benefit-Risk
While durvalumab administered after completion of cCRT in patients with unresectable 
NSCLC has demonstrated improved clinical benefit over placebo, further improvement in 
clinical outcomes may be achieved through combination therapy of durvalumab with novel 
therapies such as oleclumab or monalizumab. Clinical and nonclinical data to date have shown 
an acceptable safety profile for oleclumab and monalizumab in combination with durvalumab. 
The design of the current study aims to minimize potential risks to subjects and include the 
protocol inclusion and exclusion criteria, restrictions on concomitant medication during the 
study, safety monitoring (including review of all safety, PK, and other relevant data by the 
Safety Review Committee [SRC]), toxicity management guidelines, study stopping criteria, 
and rules and procedures to add new durvalumab combination treatment arms. Specific 
intensive safety monitoring is in place for those risks deemed to be most likely for durvalumab 
alone and for each of the durvalumab combination therapies.
Further design elements aim to specifically minimize the risks for subjects allocated to a 
durvalumab combination experimental arm. Any new combination treatment arm must adhere 
to the following elements: 

A rationale for additive or synergistic activity of the potential new candidate agent in 
combination with durvalumab based on its mechanism of action and/or supported by 
nonclinical or clinical evidence.

An established recommended combination dose for the novel agent in combination with 
durvalumab with an acceptable safety profile for the target population in this study.

Description of the safety profile and AESIs for the novel agent alone and/or in 
combination with durvalumab based on previous Phase 1 expansion cohorts or 
Phase 2 studies. 

Preliminary evidence of clinical activity of the novel agent in combination with 
durvalumab in a solid tumor setting.

Requirement of a protocol amendment and respective health authority and local 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approvals prior to 
implementing any new experimental arm.

Updated informed consent form with relevant information on the new durvalumab 
combination experimental arm.


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Overall, the benefit-risk assessment for this Phase 2 platform study is acceptable.
1.7
Research Hypotheses
1.7.1
Primary Hypothesis
Durvalumab in combination with novel agents will demonstrate superior antitumor activity 
than durvalumab alone in subjects with unresectable, Stage III NSCLC who have not 
progressed following definitive cCRT.
1.7.2
Secondary Hypotheses
Durvalumab alone or in combination with novel agents will demonstrate an acceptable safety 
profile in subjects with Stage III NSCLC who have not progressed following definitive cCRT. 
2
OBJECTIVES AND ENDPOINTS
Overall study objectives and endpoints applicable across treatment arms are presented below.
Each combination experimental arm will evaluate these objectives based on the respective 
novel agent. Secondary immunogenicity objective (b) is applicable only to novel biologic 
agents (Table 2). 
2.1
Primary Objective and Associated Endpoint
Table 1
Primary Objective and Associated Endpoint
Type
Objective
Endpoint
Clinical activity
To compare the antitumor activity of durvalumab 
alone vs durvalumab in combination with novel 
agents  
OR per RECIST v1.1
OR = objective response; RECIST v1.1 = Response Evaluation Criteria for Solid Tumors version 1.1.
2.1.1
Secondary Objectives and Associated Endpoints
Table 2
Secondary Objectives and Associated Endpoints
Type 
Objective
Endpoint
Safety
To evaluate the safety and tolerability of durvalumab 
alone and durvalumab in combination with novel 
agents
Presence of AEs, SAEs, and 
abnormal laboratory parameters 
and vital signs
Clinical activity
To further compare the efficacy of durvalumab alone 
vs durvalumab in combination with novel agents
DoR, DC, PFS-12, and PFS per 
RECIST v1.1 and OS 
Pharmacokinetics
(a) To describe the PK of durvalumab alone and 
durvalumab in combination with novel agents 
Concentration of durvalumab or 
novel agents in serum 
(b) To describe the PK of novel agents in combination 
with durvalumab




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3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview
COAST is a Phase 2, open-label, multicenter, randomized, multidrug platform study of 
durvalumab alone or in combination with novel agents in subjects with locally advanced, 
unresectable, Stage III NSCLC. 
The study will evaluate the clinical activity and safety of durvalumab alone or in combination 
with novel agents in subjects with Stage III NSCLC who have not progressed following 
definitive cCRT (Figure 1). Subjects will be randomized into the study and initiate study 
treatment within 42 days from the last session of cCRT. Information on subject randomization 
and sample size is provided in Section 4.6.1 and Section 4.8.2, respectively. Up to 
approximately 80 sites globally will participate in this study. 
Subjects may be treated for up to 12 months. Study treatment will be discontinued upon dis-
ease progression, unacceptable toxicity, or other reason, eg, subject decision or noncompli-
ance with study procedures. Overall, all subjects continuing in the study must adhere to the 
study procedures for up to 5 years (from randomization) provided they achieve disease control 
(DC) and remain disease free. Subjects who have experienced PD will be followed for sur-
vival. 
All subjects will be followed for survival until the end of the study as per the time points 
shown in Table 6. After completing the 5-year post-randomization study period, all subjects 
included into any treatment arm may be contacted annually for survival until 5 years after the 
final subject is randomized into the study or until the sponsor stops the study, whichever 
occurs first. The platform nature of the study allows an individual experimental arm to be 
permanently closed while the overall COAST study remains open.
New durvalumab combination experimental arms may be added based on emerging 
nonclinical and clinical data via protocol amendment (see Section 1.6.3). Interim futility 
analyses will be performed using Bayesian predictive probability (PP; see Section 4.8.7).


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Figure 1
Study Flow Diagram
cCRT = concurrent chemoradiotherapy; ECOG PS = Eastern Cooperative Oncology Group Performance Status; 
NSCLC = non-small cell lung cancer.
Treatment arms may be opened sequentially or in parallel. Randomization will be stratified by histology 
(adenocarcinoma vs non-adenocarcinoma). 
Enrollment to combination experimental arms may be stopped if planned interim analysis shows safety concerns 
or lack of efficacy. New combination experimental arms may be added based on emerging nonclinical and 
clinical data via a protocol amendment.
3.1.2
Treatment Regimen
Subjects will be randomized to a treatment arm and may remain on study treatment for up to 
12 months. Study treatment will be discontinued upon disease progression, unacceptable 
toxicity, or other reason. See Section 4.1.6 for information on discontinuation of study drug 
for individual subjects.
3.1.2.1
Durvalumab Control Arm
Figure 2 presents the treatment regimen for the durvalumab monotherapy control arm. 
Figure 2
Treatment Regimen for Control Arm - Durvalumab Monotherapy 
D = durvalumab; IV = intravenous; Q4W = every 4 weeks.
a
Subjects in the control arm will receive durvalumab 1500 mg IV Q4W on Day 1 of each cycle.
3.1.2.2
Experimental Arm A – Durvalumab Plus Oleclumab
Subjects randomized to Arm A will receive durvalumab in combination with oleclumab as 
presented in Figure 3. 


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Figure 3
Treatment Regimen for Arm A - Durvalumab Plus Oleclumab 
D = durvalumab; IV = intravenous; O = oleclumab; Q2W = every 2 weeks; Q4W = every 4 weeks.
a
Subjects in Arm A will receive durvalumab 1500 mg IV Q4W on Day 1 of each cycle, and oleclumab 
3000 mg IV Q2W (Day 1 and Day 15) for Cycle 1 and Cycle 2 then Q4W starting on Cycle 3, Day 1. 
On days when both durvalumab and oleclumab are administered, oleclumab will be administered first. 
3.1.2.3
Experimental Arm B – Durvalumab Plus Monalizumab
Subjects randomized to Arm B will receive durvalumab in combination with monalizumab as 
presented in Figure 4. 
Figure 4
Treatment Regimen for Arm B – Durvalumab Plus Monalizumab 
D = durvalumab; IV = intravenous; M = monalizumab; Q2W = every 2 weeks; Q4W = every 4 weeks.
a
Subjects in Arm B will receive durvalumab 1500 mg IV Q4W on Day 1 of each cycle, and monalizumab 
750 mg IV Q2W on Days 1 and 15 of each cycle. 
On days when both durvalumab and monalizumab are administered, durvalumab will be administered first.
3.1.3
Management of Study Medication Related Toxicities 
The following general guidance should be followed for management of toxicities. 
1
Next cycle administration can be delayed or discontinued 
2
In the absence of clear alternative etiology, all events should be considered potentially 
immune mediated 
3
In the event that an AE is considered related only to durvalumab or the combination novel 
therapy, both agents must be delayed 
If unsure how to manage a subject, please contact the study medical monitor to discuss 
individual cases. Treatment for toxicities should be initiated prior to discussion with the study 
medical monitor.
Dose modifications are not allowed.
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for durvalumab alone or in combination with the novel 


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immunotherapies are provided in the Toxicity Management Guidelines. 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. Following the guidelines is expected, but 
changes due to local site procedures are allowed according to the physician’s judgement. 
The most current version of the Toxicity Management Guidelines is to be maintained within 
the Site Master File. 
3.1.4
Safety Review Committee
An SRC will conduct safety reviews of all enrolled subjects at least twice a year. The SRC 
may make recommendations regarding continuation, modification, or termination of any study 
arm for safety concerns. They may request additional data (eg, clinical efficacy) as needed. 
Additional safety reviews may be conducted at the discretion of the SRC.
An SRC will consist of the following:

The sponsor study Medical Monitor, or delegate

Global Safety Physician, or delegate

Study Statistician

Principal Investigators, or delegates, from a subset of active investigational sites. The 
number of sponsor representatives will not exceed the number of Principal Investigators.

External physician not associated with the conduct of the study (SRC Chairperson)
The Clinical Pharmacology Scientist, Patient Safety Scientist, Clinical Operations 
Representative, and other delegates may also be invited as appropriate. Other internal and 
external experts may be consulted by the SRC as necessary. The membership, roles, 
responsibilities, and details on the process flow/communication plan are provided in the SRC 
Charter.
3.2
Rationale for Dose, Population, and Endpoints
3.2.1
Dose Rationale
3.2.1.1
Durvalumab 
Based on available PK and safety data for weight-based doses of durvalumab 10 mg/kg Q2W 
and 20 mg/kg Q4W and simulated PK data for a fixed dose of durvalumab 1500 mg Q4W, the 
fixed-dose regimen was predicted to provide comparable exposure to the body weight-based 
dosing regimens. Durvalumab has a flat exposure-response (efficacy and safety) relationship. 
Based on all the observed and simulated data, a fixed dosing regimen of 1500 mg Q4W was 
predicted to provide similar efficacy and safety profiles as the body weight-based dosing 
regimens. As detailed in the durvalumab IB, a fixed dose of 1500 mg Q4W is being used in 


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numerous ongoing studies. Therefore, a fixed dosing regimen of 1500 mg Q4W was selected 
in this study. 
For additional details on the nonclinical and clinical data that informed durvalumab dose 
selection, see the durvalumab IB.
3.2.1.2
Oleclumab
The oleclumab regimen of 3000 mg Q2W × 4 doses and then Q4W was selected based on data 
from the Phase 1 Study D6070C00001. In that study, oleclumab doses of 5, 10, 20, and 
40 mg/kg Q2W were examined both as a monotherapy and in combination with durvalumab 
10 mg/kg Q2W. Oleclumab was well tolerated and there were no observed DLTs either as 
monotherapy or in combination with durvalumab. Additionally, both oleclumab and 
durvalumab exposures in combination were comparable to monotherapy exposures. The 
oleclumab 40 mg/kg Q2W dose was selected for evaluation with durvalumab 10 mg/kg Q2W 
in the dose-expansion phase of that study. 
A fixed dose of oleclumab 3000 mg Q2W × 4 doses is currently being explored based on 
simulations that oleclumab might achieve similar exposures to those observed with the 
40 mg/kg Q2W dose schedule. The subsequent Q4W schedule at 3000 mg is predicted to 
result in adequate long-term exposures with median trough concentration above the estimated 
CD73 saturating concentration of approximately 40 μg/mL (100-fold of estimated Michaelis-
Menten constant from the population PK model) to maintain optimal CD73 saturation at 
steady state.
3.2.1.3
Monalizumab
The monalizumab dose of 750 mg Q2W was selected based on the available clinical safety, 
tolerability, efficacy, and PK data from the ongoing Phase 1 Study D419NC00001. In that 
study, monalizumab doses of 22.5, 75, 225, and 750 mg Q2W and 750 mg Q4W were 
examined in combination with durvalumab 1500 mg Q4W. Monalizumab was well tolerated 
in all dose-escalation cohorts, and no DLTs were observed. The monalizumab 750 mg Q2W 
dose was identified for evaluation with durvalumab 1500 mg Q4W in the dose-expansion 
phase of the study.
3.2.2
Rationale for Study Population
Patients with unresectable, Stage III NSCLC who have not progressed after cCRT will be 
considered for enrollment into the study. These characteristics defined the patient population 
in the Phase 3 PACIFIC study that showed superiority of durvalumab maintenance over 
placebo (see Section 1.5). Aligning with the PACIFIC target population provides support for 
use of a durvalumab control arm as the comparator for evaluating novel durvalumab 
combinations.


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3.2.3
Rationale for Endpoints
The primary objective of this platform study is to compare the clinical activity of durvalumab 
alone vs durvalumab in combination with novel agents. The overall study goal is early 
identification of novel durvalumab combinations that are more active than durvalumab alone 
in the treatment of patients with unresectable, Stage III NSCLC who have not progressed after 
cCRT. The classical efficacy endpoints of PFS and OS require long evaluation periods, eg, the 
ongoing PACIFIC study showed an interim median PFS of 17.2 months following a 3-year 
follow-up (Antonia et al, 2018). The current study will use objective response (OR) per 
Response Evaluation Criteria for Solid Tumors version 1.1 (RECIST v1.1), which is a 
widespread outcome measure in Phase 1-2 studies, as the primary endpoint to provide an 
earlier measure of antitumor activity. A difference in ORR between the durvalumab 
monotherapy arm and the novel combinations arms is believed to be clinically meaningful as 
responses to immunotherapies can be sustained over time and might relate to the overall PFS 
benefit. Clinical activity will be further assessed by secondary endpoints routinely used in 
oncology studies, including duration of response (DoR), DC, PFS-12, and PFS based on 
RECIST v1.1, and OS.
The safety and tolerability of each study treatment will be assessed by the standard safety 
endpoints, including AEs, SAEs, laboratory parameters, vital signs, and other standard clinical 
parameters.
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
Up to approximately 60 subjects per experimental treatment arm will be randomized with 
equal ratios to durvalumab control and each of the open experimental arms. New durvalumab 
combination experimental arms may be added over time following protocol-specific 
guidelines (see Section 1.6.3) and therefore the total number of subjects randomized to the 
durvalumab control arm might be higher than 60 subjects. Details regarding the specifics of a 
new combination arm will be provided via protocol amendment. See also Section 4.6.1 for 
potential changes to the randomization scheme and changes to overall study enrollment in the 
control arm and the combination experimental arms during the study.
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1
Written informed consent and any locally required authorization obtained from the 
subject prior to performing any protocol-related procedures, including screening 
evaluation
2
Age 18 years or older


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3
Body weight ≥ 35 kg
4
Subjects must have histologically or cytologically documented NSCLC who present with 
locally advanced, unresectable, Stage III disease
5
Subjects must have completed, without progressing, definitive cCRT within 42 days prior 
to being randomized into the study:

Definitive radiotherapy refers to a total dose ≥ 60 Gy at 1.8 Gy per fraction or 
bioequivalent dose

Concurrent chemotherapy refers to a platinum-based doublet

The final chemotherapy administration must end prior to, or concurrently with, the 
final dose of radiation
6
Subjects must have at least one previously irradiated tumor lesion that can be measured 
by RECIST v1.1 (RECIST v1.1 guidelines permit previously irradiated lesions to be 
considered measurable if defined in the protocol [see Section 3.1.3 in Eisenhauer et al, 
2009])
7
Provision of tumor tissue sample, when available, from original diagnosis obtained before 
initiation of chemoradiotherapy (tumor tissue block or unstained slides are acceptable; 
refer to Laboratory Manual for details)
8
Life expectancy ≥ 12 weeks 
9
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
10 Adequate organ and marrow function as defined in Table 4:
Table 4
Criteria for Adequate Organ and Marrow Function
Parameter
Value
Hematological
Hemoglobin a
≥9.0 g/dL (5.59 mmol/L)
Absolute neutrophil count a
≥1.0 × 109/L (1000 per mm3)
Platelet count a
≥100 × 109/L (100,000 per mm3)
Hepatic
Total bilirubin
≤ 1.5 × ULN in the absence of Gilbert’s syndrome
≤ 3 × ULN if the patient has Gilbert’s syndrome
Alanine transaminase and 
aspartate transaminase
≤ 2.5 × ULN
Renal
Calculated creatinine 
clearance b
≥40 mL/minute
ULN = upper limit normal.
a
Hematological criteria cannot be met with ongoing or recent blood transfusions (within 14 days prior to 
the scheduled first dose of study treatment) or require growth factor support (within 21 days prior to the 
scheduled first dose of study treatment).
b
As determined by Cockcroft-Gault (using actual body weight; Cockcroft and Gault, 1976) or 24-hour 
urine creatinine clearance.
11 Females of childbearing potential and non-sterilized male subjects with female partners of 
childbearing potential must use effective methods of contraception from screening to 
180 days after the final dose of study treatment (see Appendix A)


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4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1
Involvement in the planning and/or conduct of the study (applies to both sponsor staff 
and/or staff at the study site)
2
Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or during the follow-up period of an interventional 
study
3
Mixed small cell and non-small cell lung cancer histology 
4
Current or prior use of immunosuppressive medication within 14 days before the first 
dose of study drug. The following are exceptions to this criterion:

Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection)

Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or its equivalent

Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
5
Prior exposure to any anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte-associated 
antigen-4 (CTLA-4) antibody for the treatment of NSCLC
6
Any unresolved toxicity National Cancer Institute Common Terminology Criteria for 
Adverse Events version 5.0 (NCI CTCAE v5.0) > Grade 2 from the prior chemoradiation 
therapy
7
Subjects with history of ≥ Grade 2 pneumonitis from prior chemoradiation therapy
8
Subjects with a history of venous thrombosis within the past 3 months.
9
Subjects with history of myocardial infarction, transient ischemic attack, or stroke in the 
past 6 months.
10 Congestive heart failure ≥ Class 3 based on New York Heart Association Functional 
Classification
11 Major surgical procedure (as defined by the investigator) within 28 days prior to the first 
dose of study drug  
12 Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:

Subjects with vitiligo or alopecia

Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement 

Any chronic skin condition that does not require systemic therapy

Subjects with celiac disease controlled by diet alone
13 History of active primary immunodeficiency 


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14 Active infection including tuberculosis, hepatitis B, hepatitis C, or human 
immunodeficiency virus (HIV)
15 History of allogenic organ transplantation
16 Known allergy or hypersensitivity to study drug formulation(s)
17 QTcF interval ≥ 470 ms
18 Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina 
pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal 
conditions associated with diarrhea, or psychiatric illness/social situations that would
limit compliance with study requirement, substantially increase risk of incurring AEs or 
compromise the ability of the patient to give written informed consent
19 Receipt of live attenuated vaccination within 30 days prior to study entry 
20 History of another primary malignancy except for:

Malignancy treated with curative intent and with no known active disease ≥ 5 years 
before the first dose of study drug and of low potential risk for recurrence

Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease

Adequately treated carcinoma in situ without evidence of disease
21 Females who are pregnant, lactating, or intend to become pregnant during their 
participation in the study
4.1.4
Subject Enrollment and Randomization
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (ie, an interactive voice/web response system [IXRS]), and the 
screening evaluations may begin to assess study eligibility (inclusion/exclusion) criteria. The 
SID number will be used to identify the subject during the screening process and throughout 
study participation, if applicable. 
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria and 
are not randomized), including the reason(s) for screening failure.
Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not be 
randomized or receive study treatment. Further details regarding randomization are detailed in 
Section 4.6.1.
4.1.5
Withdrawal from the Study
Subjects are free to withdraw their consent to participate in the study (study treatment and 
assessments) at any time, without prejudice to further treatment. All study drug(s) should be 


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returned by the subject. If a subject withdraws from further participation in the study, then no 
further study visits or data collection should take place. 
4.1.6
Discontinuation of Investigational Product
An individual subject in any of the treatment arms will not receive any further study drug if 
any of the following occur in the subject in question:
1
Withdrawal of consent 
2
Any toxicity/AE that in the opinion of the investigator and/or the sponsor, warrants 
discontinuation of further dosing
3
Any AE that meets criteria for discontinuation as defined in the Toxicity Management 
Guidelines (see Section 3.1.3)
4
Pregnancy or intent to become pregnant (Section 5.6.2)
5
Delay of more than 56 days from the last administration of study drug to the next planned 
dose
6
Confirmation of disease progression (Section 4.3.1)
7
Unconfirmed disease progression and investigator determination that the subject is not 
eligible for a confirmation scan (Section 4.3.1)
8
Initiation of alternative anticancer therapy 
9
Intercurrent illness or medical condition, in the judgment of the investigator and/or the 
sponsor warrants discontinuation of further dosing 
Subjects who are permanently discontinued from receiving study treatment will be followed 
for protocol-specified assessments, including follow-up of any AEs, unless consent is 
withdrawn from further study participation (Section 4.1.5), disease progression, the subject 
starts alternative treatment/clinical study, or the subject is lost to follow-up. All subjects will 
be followed for survival until the end of the study unless consent is withdrawn from further 
study participation.
4.1.7
Replacement of Subjects
Subjects will not be replaced.
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
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.
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed, 
MedImmune is not obliged to destroy the results of this research. As collection of the 
biological samples (except for the optional tumor biopsy at screening and on-treatment, and 
optional blood sample at screening for germline DNA) is an integral part of the study, if a 


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subject decides to withdraw consent to the use of donated biological samples, then the subject 
will also be withdrawn from further study participation.
The Principal Investigator:

Ensures subject’s withdrawal of informed consent to the use of donated samples is 
notified immediately to MedImmune.

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action documented.

Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site.

Ensures that the subject and MedImmune are informed about the sample disposal.
MedImmune ensures the organizations holding the samples is/are informed about the
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
4.2
Schedule of Study Procedures
The schedule of study procedures outlined in this section, with the exception of study drug 
administration that is treatment-arm specific, will be followed for all treatment arms. 
The study drug treatment regimens for the control arm and each combination experimental 
arm are presented in Section 3.1.2. 
4.2.1
Enrollment/Screening and Treatment Periods
Table 5 shows all procedures to be conducted during the screening and treatment periods.


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Table 5
Schedule of Screening and Treatment Period Procedures
Procedure
Screening
Treatment Period: Up to 12 Months
28-day Cycles
Day -28 to 
Day -1
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 through Cycle 13
Day 1
Day 1 
(± 3 days)
Day 1
(± 3 days)
Day 1 
(± 3 days)
Day 1
(± 3 days)
Written informed consent
X
Demographics 
X
Medical history a
X
Verify eligibility criteria 
X
Physical examination
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
ECG b
X
ECOG performance status
X
X
X
X
X
X
Tumor specimen c
X
X (optional) c
Serum chemistry
X
X d
X
X
X
X
Hematology 
X
X d
X
X
X
X
Urinalysis 
X
As clinically indicated
Thyroid function tests e
X
X d
X
X
X
X
Pregnancy test f
X
X
X
X
X
X
Coagulation parameters 
X
Hepatitis B and C; HIV g
X
Concomitant medications
X
X
X
X
X
X
Assessment of AEs/SAEs
X
X
X
X
X
X
Disease assessment (scans) 
X h
X 
(within 7 days)
Cycle 5 then every 2 cycles
(within 7 days)


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Table 5
Schedule of Screening and Treatment Period Procedures
Procedure
Screening
Treatment Period: Up to 12 Months
28-day Cycles
Day -28 to 
Day -1
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 through Cycle 13
Day 1
Day 1 
(± 3 days)
Day 1
(± 3 days)
Day 1 
(± 3 days)
Day 1
(± 3 days)
Brain MRI (preferred) or CT
X h
PET scan
Cycle 7 only 
(within 7 days of Day 1)
 
 
 
Serum for PK
X (predose & EOI) i
X (predose) j
Cycle 7 and Cycle 11 only 
(predose) j
Serum for ADA
X (predose) k
X (predose) k
Cycle 7 and Cycle 11 only 
(predose) k
Study drug administration l
According to each study drug-specific regimen 
ADA = antidrug antibody; AE = adverse event; β-hCG = beta human chorionic gonadotropin; CT = computed tomography; 
 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; HBc = hepatitis B core; HBs = hepatitis B surface; HBsAg
= hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; MRI = magnetic resonance imaging; 
PET = positron emission tomography; PK = pharmacokinetics; SAE = serious adverse event; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid 
stimulating hormone.
Note: All safety laboratory results must be reviewed by the investigator or physician designee prior to administration of any study treatment.
a
Diagnosis of active tuberculosis is defined by compatible clinical evaluation (medical history and physical examination), radiographic findings, and 
tuberculosis testing in line with local practice.
b
In cases when the first ECG shows clinically significant abnormalities, including a QTcF value ≥ 470 ms, 2 additional ECGs should be obtained over a 
brief period (eg, 30 minutes) to confirm the finding based on the average of all 3 manually overread ECGs by a medically qualified delegate.
CCI
CCI


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Table 5
Schedule of Screening and Treatment Period Procedures
Procedure
Screening
Treatment Period: Up to 12 Months
28-day Cycles
Day -28 to 
Day -1
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 through Cycle 13
Day 1
Day 1 
(± 3 days)
Day 1
(± 3 days)
Day 1 
(± 3 days)
Day 1
(± 3 days)
c
Tumor tissue sample, when available, from the original diagnosis and before initiation of chemoradiotherapy will be collected at screening, per inclusion 
criterion. Optional fresh tumor tissue specimens may be collected after completion of chemoradiotherapy during screening and on treatment at the time of 
the PET/CT (Cycle 7). Additional on-treatment fresh tumor tissue specimens may be collected at the investigator’s discretion as clinically indicated for 
correlative biomarker studies. See Section 4.3.7.4.
d
If screening laboratory assessments are performed within 3 days prior to Day 1, they do not need to be repeated at Day 1.
e
TSH, T3, and T4. If TSH is normal, then T3 or T4 is not required. Free T3/free T4 are preferred over total T3/total T4.
f
Females of childbearing potential are required to have a pregnancy test within 7 days prior to the first dose of study treatment. A urine or serum pregnancy 
test is acceptable; if urine test is equivocal or positive then serum β-hCG testing should be performed for confirmation. 
g
Active hepatitis B, hepatitis C, and HIV infections are defined by positive serologic test. Subjects positive for HBV infection are eligible if findings are 
compatible with past or resolved infection (HBsAg negative, anti-HBc positive and anti-HBs positive) or due to vaccination (HBsAg negative, anti-HBc 
negative and anti-HBs positive). Subjects positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
h
Screening disease assessment and brain MRI or CT must be performed after completion of chemoradiotherapy. 
i
In combination arms, PK predose (within 1 hour prior to dosing) and EOI (within 15 minutes post-EOI) samples will be collected according to the 
administration time of each study drug. For example: PK predose Agent 1 collected →Agent 1 administration →PK EOI Agent 1 collected →PK 
predose Agent 2 collected →Agent 2 administration →PK EOI Agent 2 collected.
j
In combination arms, at visits when predose samples only are required, PK samples will be collected within 1 hour prior to administration of the first 
study drug only. For example: PK predose Agent 1 and Agent 2 collected →Agent 1 administration →Agent 2 administration.
k
In combination arms, ADA samples will be collected within 1 hour prior to administration of the first study drug only. For example: ADA predose 
Agent 1 and Agent 2 collected →Agent 1 administration →Agent 2 administration.
l
Treatment regimens are described in Section 3.1.2.




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Table 6
Schedule of Follow-up Procedures: Subjects Who Completed Study 
Treatment and Maintain DC, Subjects Who Discontinued Study 
Treatment Due to Other Reason Not Related to PD, and Subjects 
Who Experienced Unconfirmed PD and are Eligible for a 
Confirmation Scan
Time since Cycle 1 Day 1
≤ 12 Months
> 12 to ≤ 24 Months
> 24 to 60 Months
Follow-up based on previous 
scheduled visit
Every 8 Weeks
(± 3 days)
Every 12 Weeks
(± 7 days)
Every 6 Months
(± 4 weeks)
Procedure
Serum for ADA
10 months post 
Cycle 1 Day 1 only
Month 15 only
Survival status (if visits are 
discontinued, this may be done 
via telephone contact) c
X
X
X
ADA = antidrug antibody; AE = adverse event; 
; DC = disease control; 
ECOG = Eastern Cooperative Oncology Group; PD = progressive disease; PK = pharmacokinetics; SAE = 
serious adverse event; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone.
a
TSH, T3, and T4. If TSH is normal, then T3 or T4 is not required. Free T3/free T4 are preferred over 
total T3/total T4.
b
Concomitant medications and AEs/SAEs will be collected up to 12 months post Cycle 1 Day 1, 
regardless of whether the subject discontinued treatment. Following the first 12 months, concomitant 
medications and AEs/SAEs will be collected up to 3 months post last dose of study treatment, if 
applicable.
c
Subjects may be contacted for survival status every 12 months beyond 60 months post Cycle 1 Day 1, 
until the end of the entire study, unless the subject withdraws consent from further participation in the 
study.
4.2.3
End of Study
Table 7 presents procedures for the end of study visit for all subjects. End of study visit will 
be performed when a subject discontinues study due to a confirmed PD, or a subject 
experienced an unconfirmed PD but is not eligible for a confirmation scan, or after 60 months 
of follow-up for subjects who achieve DC and remain disease free, or at the last study visit for 
subjects who discontinue study due to reason not related to PD.
Subjects who discontinue treatment due to any reason, including confirmed PD or initiation of 
alternative anticancer therapy, will be followed for survival according to the timepoints in 
Table 6 (every 8 weeks up to 12 months post Cycle 1 Day 1, every 12 weeks from > 12 to 
≤24 months, and every 6 months from > 24 to 60 months post Cycle 1 Day 1) unless the 
subject withdraws consent from further participation in the study. After 60 months, subjects 
may be contacted for survival every 12 months until the end of the entire study.
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4.3.1.2
Disease assessment by PET 
Local changes and the presence of distal metastasis will be assessed by positron emission 
tomography (PET). The methods for assessing metabolic update by PET are summarized 
below (Plathow et al, 2011).

PET requires measurement of the metabolically active lesions and background area. The 
FDG-distribution is rated visually and quantiﬁed as standardized uptake values (SUV).

Any focal tracer uptake in lesions with SUV peak at least 1.5-fold greater than liver 
SUV mean is considered metastatic in absence of any alternative explanation. If liver is 
abnormal, primary tumor lesion should have uptake at least 2.0-fold greater than SUV 
mean of blood pool in descending thoracic aorta.

For each lesion suspicious for malignancy in PET/CT, the site-based localization (lymph 
nodes, lung, liver, adrenal gland, brain, other viscera, and bone) is recorded.

These parameters can be recorded as exploratory data on up to 5 measurable target 
lesions, typically the 5 hottest lesions, which are typically the largest, and no more than 
2 per organ. Tumor size of these lesions can be determined per RECIST v1.1.

Additional SUV measures including SUV mean, SUV peak or volumetric information 
may be measured to assess suspicious lesions.
4.3.2
Medical History, Physical Examination, Electrocardiogram, and Vital 
Signs 
Medical History
Medical history will be collected at screening. Based on findings from medical history, 
ongoing current conditions will be given a baseline grade according to the procedure for AEs. 
Increases in severity of pre-existing conditions during the study will be considered AEs, with 
resolution occurring when the grade returns to the pre-study grade or below.
Physical Examinations
Physical examinations will be performed according to the schedules in Section 4.2. A 
complete physical examination will be performed at screening and should include assessments 
of the head, eyes, ears, nose, and throat, respiratory, cardiovascular, gastrointestinal, 
musculoskeletal, neurological, psychiatric, dermatological, hematologic/lymphatic, endocrine 
systems, and weight to 0.1 kg; and height (at screening only). Abbreviated symptom-directed 
physical examinations will be conducted at subsequent visits post dosing. 
Vital Signs
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Vital signs (blood pressure and pulse rate) will be measured according to the schedules in 
Section 4.2. For all vital sign measurements, subjects should rest for at least 10 minutes in a 
supine or semi-recumbent position, and all vital sign measurements should be taken prior to 
any blood draws or other procedures whenever possible.
ECG
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study as presented in Section 4.2. ECGs should be obtained after the subject has been in a 
supine position for 5 minutes and recorded while the subject remains in that position.
In cases when the first ECG shows clinically significant abnormalities, including a QTcF 
value ≥470 ms, 2 additional 12-lead ECGs should be obtained over a brief period (eg, 
30 minutes) to confirm the finding based on the average of all 3 manually overread ECGs by a 
medically qualified delegate.
4.3.3
Clinical Laboratory Tests
A Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study. 
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a 
licensed clinical laboratory. Urine pregnancy tests may be performed at the site using a 
licensed test (dipstick). Abnormal laboratory results should be repeated using a serum 
pregnancy test as soon as possible (preferably within 24 to 48 hours). 
The following clinical laboratory tests will be performed (see Section 4.2 for the schedule of 
tests): 
Serum Chemistry
•
Albumin
•
Gamma-glutamyl transferase
•
Amylase
•
Glucose
•
ALP
•
Lactate dehydrogenase
•
ALT
•
Lipase
•
AST
•
Magnesium
•
Bicarbonate
•
Potassium
•
Blood urea nitrogen / urea
•
Sodium
•
Calcium
•
Total bilirubin (TBL; direct bilirubin should be obtained 
if TBL is > ULN)
•
Chloride
•
Total protein
•
Creatinine
•
C-reactive protein
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Note: Tests for AST, ALT, ALP, and TBL must be conducted concurrently and assessed concurrently.
Hematology
•
Absolute lymphocyte count
•
Platelet count
•
Absolute neutrophil count
•
White blood cell count
•
Hemoglobin
Urinalysis
•
Blood
•
Protein
Pregnancy Test (females of childbearing potential only)
•
Urine hCG
•
Serum β-hCG (or required if a urine hCG is equivocal or positive)
β-hCG = beta-human chorionic gonadotropin; hCG = human chorionic gonadotropin.
Other Safety Tests
•
Coagulation tests: activated partial thromboplastin time and international normalized ratio. If international 
normalized ratio is not available the sites may substitute a prothrombin time.
•
Tuberculosis: Diagnosis of active tuberculosis is defined by compatible clinical evaluation (medical history 
and physical examination), radiographic findings, and tuberculosis testing in line with local practice.
•
Hepatitis B, hepatitis C, and HIV: Active hepatitis B, hepatitis C, and HIV infections are defined by 
positive serologic test. Subjects positive for HBV infection are eligible if findings are compatible with past 
or resolved infection (HBsAg negative, anti-HBc positive and anti-HBs positive) or due to vaccination 
(HBsAg negative, anti-HBc negative and anti-HBs positive). Subjects positive for HCV antibody are 
eligible only if polymerase chain reaction is negative for HCV RNA.
•
Thyroid function tests: TSH, T3, and T4. If TSH is normal, then T3 or T4 is not required. Free T3/free T4 
are preferred over total T3/total T4.
HBc = hepatitis B core; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C 
virus; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone.
4.3.4
Pharmacokinetic Evaluation and Methods
Blood samples will be collected to evaluate PK in serum of durvalumab when administered 
alone or in combination with novel agents. Additionally, PK in serum of novel agents admin-
istered in combination with durvalumab will be evaluated. Novel agents include oleclumab 
and monalizumab. See Section 4.2 for collection time points. Evaluations will be performed 
using a validated immunoassay.
In combination arms, at visits when predose and end of infusion (EOI) samples are required, 
PK predose (within 1 hour prior to dosing) and EOI (within 15 minutes post-EOI) samples 
will be collected according to the administration time of each study drug. For example: 


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PK predose Agent 1 collected → Agent 1 administration → PK EOI Agent 1 collected → PK 
predose Agent 2 collected → Agent 2 administration → PK EOI Agent 2 collected.
In combination arms, at visits when predose samples only are required, PK samples will be 
collected within 1 hour prior to administration of the first study drug only. For example: PK 
predose Agent 1 and Agent 2 collected → Agent 1 administration → Agent 2 administration.
4.3.5
Immunogenicity Evaluation and Methods
Blood samples will be collected to evaluate antidrug antibody (ADA) responses to durval-
umab when administered alone or in combination with novel agents. Additionally, ADA re-
sponses to novel biologic agents administered in combination with durvalumab will be evalu-
ated. Novel/biologic agents include oleclumab and monalizumab. See Section 4.2 for collec-
tion time points. Evaluations will be performed using a validated immunoassay. Tiered anal-
yses will be performed to include screening, confirmatory, and titer assay components, and the 
positive-negative cut points will be statistically determined from drug-naive validation sam-
ples. Samples may be utilized for further characterization of the ADA response, including pos-
sible assessment of neutralizing antibody.
In combination arms, ADA samples will be collected within 1 hour prior to administration of 
the first study drug only. For example: ADA predose Agent 1 and Agent 2 collected → 
Agent 1 administration → Agent 2 administration.
4.3.6
Genetic Evaluations and Methods
See Appendix E for information regarding genetic research.
4.3.6.1
Collection of Genetic Samples
If the subject agrees to participate in the optional genetic research study, a blood sample will 
be collected. Participation is optional. Subjects who do not wish to participate in the genetic 
research may still participate in the study. 
The blood sample for genetic research will be obtained from the subjects at screening. If for 
any reason the sample is not drawn at screening, it may be taken at any visit until the last 
study visit. Only one sample should be collected per subject for genetics during the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the subject. Signed informed consent will be required to obtain a replacement sample un-
less it was included in the original consent.
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4.3.6.2
Storage and Destruction of Genetic Samples
The processes adopted for the coding and storage of samples for genetic analysis are im-
portant to maintain subject confidentiality. Samples will be stored for a maximum of 15 years 
or as per local regulations from the date of the last subject’s last visit, after which they will be 
destroyed. DNA is a finite resource that may be used up during analyses. The results of any 
further analyses will be reported either in the CSR itself or as an addendum, or separately in a 
scientific report or publication.
No personal details identifying the individual will be available to MedImmune or designated 
organizations working with the DNA.
4.3.7
 
4.3.7.1
4.3.7.2
 
4.3.7.3
 
4.3.7.4
 
 
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screening (Day -28 to Day -1) and on treatment at the time of the PET/CT (Cycle 7). Addi-
 
 
4.3.7.5
Storage, Re-use, and Destruction of Biological Samples
Samples will be stored for a maximum of 15 years or as per local regulations from the date of 
the last subject’s last visit, after which they will be destroyed. The results of this biomarker 
research will be reported either in the clinical study report (CSR) itself or as an addendum, or 
separately in a scientific report or publication. The results of this biomarker research may be 
pooled with biomarker data from other studies with the study drug to generate hypotheses to 
be tested in future research.
4.3.8
Estimate of Volume of Blood to be Collected
A total of no more than 36.8 mL of blood will be required for all screening tests. No more 
than 59.0 mL of blood will be drawn at any visit during the treatment period. During the fol-
low-up period, no more than approximately 34.5 mL of blood will be collected at any visit. 
The total volume to be collected will depend on the treatment arm, central laboratory used, 
and length of a subject’s participation in the study. The Laboratory Manual may be referenced 
for test volume specifics.
4.4
Study or Study Component Suspension or Termination
MedImmune reserves the right to temporarily suspend or permanently terminate this study or 
component of the study at any time. The reasons for temporarily suspending or permanently 
terminating the study may include but are not limited to the following: 
1
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects
2
Subject enrollment is unsatisfactory
3
Non-compliance that might significantly jeopardize the validity or integrity of the study 
4
Sponsor decision to terminate development of durvalumab or any of the combination 
study treatments for this indication
5
Sponsor decision to terminate the study or any treatment arm based on a planned futility 
analysis and/or recommendation from SRC (Section 4.8.7 and Section 3.1.4, respectively)
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If MedImmune determines that temporary suspension or permanent termination of the study 
or component of the study is required, MedImmune will discuss the reasons for taking such 
action with all participating investigators (or head of the medical institution, where applica-
ble). When feasible, MedImmune will provide advance notice to all participating investigators 
(or head of the medical institution, where applicable) of the impending action.
If the study or component of the study is suspended or terminated for safety reasons, MedIm-
mune will promptly inform all investigators, heads of the medical institutions (where applica-
ble), and/or institutions conducting the study. MedImmune will also promptly inform the rele-
vant regulatory authorities of the suspension/termination along with the reasons for such ac-
tion. Where required by applicable regulations, the investigator or head of the medical institu-
tion must inform the IRB/IEC promptly and provide the reason(s) for the suspension/termina-
tion. If the study or component of the study is suspended for safety reasons and it is deemed 
appropriate by MedImmune to resume the study or component of the study, approval from the 
relevant regulatory authorities (and IRBs/IECs when applicable) will be obtained prior to re-
suming the study.
4.5
Investigational Product 
4.5.1
Identity of Investigational Product
For all the treatment arms, control arm and each combination experimental arm, MedImmune 
will provide the investigators with study drug (Table 8) using designated distribution centers. 
Table 8
Identification of Investigational Product 
Investigational Product
Provider
Concentration and Formulation as Supplied
Durvalumab (MEDI4736)
MedImmune
Supplied as a vialed liquid solution containing 
500 mg (nominal) durvalumab per vial. The solution 
contains 50 mg/mL durvalumab, 26 mM 
histidine/histidine HCl, 275 mM trehalose dihydrate, 
and 0.02% (w/v) polysorbate 80, at pH 6.0 and 
density of 1.054 g/mL. The nominal fill volume is 
10.0 mL.
Oleclumab (MEDI9447)
MedImmune
Supplied as a vialed liquid solution containing 
500 mg (nominal) oleclumab. The solution contains 
50 mg/mL oleclumab, 25 mM histidine/histidine HCl, 
240 mM sucrose, 0.03% (w/v) polysorbate 80, at 
pH 6.0. The nominal fill volume is 10.0 mL.


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Table 8
Identification of Investigational Product 
Investigational Product
Provider
Concentration and Formulation as Supplied
Monalizumab (IPH2201)
MedImmune
Supplied as a vialed lyophilized powder containing 
375 mg (nominal) monalizumab per vial. The powder 
is to be reconstituted with 7.4 mL WFI. After 
reconstitution, the vial contains 50 mg/mL
monalizumab, 20 mM histidine/histidine 
hydrochloride, 220 mM sucrose, 0.03% (w/v) 
polysorbate 80, pH 6.0
DP = drug product; DS = drug substance; HCl = hydrochloride; WFI = Water for Injection; w/v = weight per 
volume.
Durvalumab is supplied in 10R vials as a sterile, clear to opalescent, colorless to slightly yel-
low liquid, free from or practically free from visible particles at a concentration of 50 mg/mL.
Oleclumab is supplied in 10R vials as a sterile, clear to opalescent, colorless to yellow liquid, 
that may contain a few white to off-white translucent particles at a concentration of 
50 mg/mL.
Monalizumab is supplied in 20R vials as a vialed lyophilized powder with dried powder visi-
ble on the vial wall. The reconstituted drug product is a clear to opalescent and colorless to
yellow liquid, that may contain some translucent or white to off-white inherent particles at a 
concentration of 50 mg/mL.
Durvalumab, oleclumab, and monalizumab vials are stored at 2°C to 8°C (36°F to 46°F) and 
must not be frozen. Drug products should be kept in original packaging until use to prevent 
prolonged light exposure.
Each investigational product kit has a unique number that is printed on all labels within the kit 
(ie, the outer carton label and the label of each container within the carton). Each carton and 
vial is labeled with the same unique number.
Commercially available 0.9% (weight per volume [w/v]) saline or 5% (w/v) dextrose will be 
supplied by each site.
4.5.1.1
Investigational Product Handling
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records. Upon completion of the study, copies 
of investigational product accountability records will be returned to MedImmune. All unused 
investigational products will be returned to a MedImmune authorized depot or disposed of 
upon authorization by MedImmune according to the investigational site policy. 


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4.5.1.2
Investigational Product Inspection
Each vial selected for dose preparation should be inspected. See Section 4.5.1 for a description 
of investigational product presentation. 
If there are any defects noted with the investigational product, the investigator and site moni-
tor should be notified immediately. Refer to the Product Complaint section (Section 4.5.1.8) 
for further instructions.
4.5.1.3
Durvalumab Dose Preparation and Administration
The dose of durvalumab for administration must be prepared by the investigator’s or site’s 
designated investigational product manager using aseptic technique. 
Total time from needle puncture of a durvalumab vial to start of administration should not ex-
ceed: 

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature 
A dose of 1500 mg will be administered using an IV bag containing 0.9% (w/v) saline or 
5% (w/v) dextrose, with a final durvalumab concentration ranging from 1 to 15 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm filter. Add 30.0 mL of dur-
valumab (ie, 1500 mg of durvalumab) to the IV bag. The IV bag size should be selected such 
that the final concentration is within 1 to 15 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag. 
Standard infusion time is 1 hour, however if there are interruptions during infusion, the total 
allowed infusion time should not exceed 8 hours at room temperature. 
For experimental arms that require administration of durvalumab and the combination study 
drug on the same day, the total infusion time for both study drugs should not exceed 8 hours at 
room temperature. 
Do not co-administer other drugs through the same infusion line. 
Flush the IV line with a volume of IV diluent equal to the priming volume of the infusion set 
used after the contents of the IV bag are fully administered, or complete the infusion accord-
ing to institutional policy to ensure the full dose is administered. 
If either preparation time or infusion time exceeds the time limits, a new dose must be pre-
pared from new vials. Durvalumab does not contain preservatives, and any unused portion 
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4.5.1.4
Oleclumab Dose Preparation and Administration
The dose of oleclumab for administration must be prepared by the investigator’s or site’s des-
ignated investigational product manager using aseptic technique. 
Total time from needle puncture of the oleclumab 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
If preparation time exceeds the time limits a new dose must be prepared from new vials. Ole-
clumab does not contain preservatives, and any unused portion must be discarded.
No incompatibilities between oleclumab and polyvinylchloride or polyolefin IV bags have 
been observed.
A dose of 3000 mg will be administered using an IV bag containing 0.9% (w/v) saline with a 
final oleclumab concentration of 1.5 to 30 mg/mL, and delivered through an IV administration 
set with a 0.2- or 0.22-μm filter. Mix the bag by gently inverting to ensure homogeneity dose 
in the bag.
Standard infusion time for oleclumab is 1 hour; however, if there are interruptions during infu-
sion, the total allowed time should not exceed 4 hours at room temperature. If this duration is 
met, then the remainder of the dose should be abandoned and should not be completed with a 
second prepared dose.
On days when both oleclumab and durvalumab are administered, durvalumab infusion will 
start no less than 15 minutes after the end of oleclumab infusion. See Section 4.5.1.3 for dur-
valumab administration. In the event that on days when both oleclumab and durvalumab are 
administered there are interruptions during infusion for either oleclumab and/or durvalumab, 
the total infusion duration for both study drugs should not exceed 8 hours. Of the total 8-hour 
infusion duration, a maximum of 4 hours may correspond to oleclumab infusion.
Do not co-administer other drugs through the same infusion line.
4.5.1.5
Monalizumab Dose Preparation and Administration
The dose of monalizumab for administration must be prepared by the investigator’s or site’s 
designated investigational product manager using aseptic technique. 
Slowly add 7.4 mL of sterile Water for Injection by tilting the vial to one side such that the 
liquid stream is directed along the vial wall and not directly onto the lyophilized cake. Gently 
swirl the solution until all solids are dissolved. Do not shake or vigorously agitate the vial. 


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Visually inspect the solution to ensure that the entire content of the lyophilized cake is com-
pletely reconstituted. The reconstituted solution should appear clear to opalescent. A thin layer 
of bubbles on the surface of the liquid is normal. 
Monalizumab should be protected from direct sunlight during preparation and handling. Total 
time from start of reconstitution to the start of monalizumab administration should not exceed: 

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
No incompatibilities between monalizumab and polyolefin, polyethylene, polypropylene, or 
polyvinyl chloride IV bags have been observed. 
A dose of 750 mg will be administered using an IV bag containing 0.9% (w/v) saline or 
5% (w/v) dextrose, with a final monalizumab concentration of 1 to 20 mg/mL, and delivered 
through an IV administration set with a 0.2- or 0.22 µm filter. Add 15.0 mL of monalizumab 
(ie, 750 mg of monalizumab) to the IV bag. The IV bag size should be selected such that the 
final concentration is within 1 to 20 mg/mL. Mix the bag by gently inverting to ensure homo-
geneity of the dose in the bag.
Standard monalizumab infusion time is 1 hour, however if there are interruptions during infu-
sion, the total allowed infusion time should not exceed 8 hours at room temperature. The infu-
sion rate should not be changed unless necessary to manage acute reactions. 
On days when both durvalumab and monalizumab are administered, durvalumab will be ad-
ministered first. See Section 4.5.1.3 for durvalumab treatment administration. 
Monalizumab infusion will start no less than 15 minutes after the end of the durvalumab infu-
sion. 
In the event that there are interruptions during infusion for either durvalumab and/or monali-
zumab on days when both durvalumab and monalizumab are administered, the total infusion 
duration for both study drugs should not exceed 8 hours. Of the total 8-hour infusion duration, 
a maximum of 4 hours may correspond to durvalumab infusion. Do not co-administer other 
drugs through the same infusion line.
4.5.1.6
Treatment Administration
The first day of dosing is considered Day 1. 
No specific premedication is required for durvalumab, oleclumab, or monalizumab. Details of 
any premedication or concomitant medication given to manage or prevent AEs should be rec-
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A physician must be present at the site or immediately available to respond to emergencies 
during all administrations of investigational product. Fully functional resuscitation facilities 
should be available.
4.5.1.7
Monitoring of Dose Administration 
Subjects will be monitored during and after infusion(s) of investigational product(s). Vital 
signs will be measured according to the schedules described in Section 4.2.1.
As with any biologic product, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be imme-
diately available, and study personnel must be trained to recognize and treat anaphylaxis.
4.5.1.8
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to AstraZeneca 
Product Quality Complaints by the site with further notification to the site monitor. All defects 
will be communicated to AstraZeneca and investigated further with Product Quality Com-
plaints. During the investigation of the product complaint, all investigational product must be 
stored at labeled conditions unless otherwise instructed.
AstraZeneca contact information for reporting product complaints:
E-mail:
Phone:
Website: 
Mail:
AstraZeneca
Attn: 
,
4.5.2
Additional Study Medications
No other study medications are specified for use in this clinical protocol.
4.5.3
Labeling
Labels for the investigational product will be prepared in accordance with Good Manufactur-
ing Practice and local regulatory guidelines. Label text will be translated into local languages, 
as required.
4.5.4
Storage
All investigational products should be stored in a secure and dry place. Vials of investigational 
product for parenteral administration should be stored at 2°C to 8°C (36°F to 46°F; refriger-
ated) and must not be frozen. Investigational product supplied as oral tablet should be stored 
PPD
PPD
PPD
PPD
PPD
PPD


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at 15°C to 30°C (59°F to 86°F). Drug product should be kept in secondary packaging until use 
to prevent excessive light exposure.
4.5.5
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor compliance.
4.5.6
Accountability
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records. Upon completion of the study, copies 
of investigational product accountability records will be returned to MedImmune. All unused 
investigational product will be returned to a MedImmune-authorized depot or disposed of 
upon authorization by MedImmune.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
Once confirmed that the subject meets eligibility criteria, an IXRS will randomize the subject 
to a treatment arm according to the randomization scheme. 
A randomization method with dynamically changing randomization ratios will be employed to 
account for fluctuation in the number of treatment arms open for enrollment over the course of 
the study. Randomization will be stratified by histology (adenocarcinoma vs non-adenocarci-
noma). The randomization scheme will use an equal ratio to all study treatment arms open for 
enrollment (eg, if experimental arms are opened sequentially, an experimental arm is 
added/closed, or enrollment in an experimental arm is suspended). Additionally, the following 
considerations regarding randomization will apply: 

If there is no experimental arm open for enrollment, then enrollment will be paused. Any 
subject who had consented previously and was in screening when the experimental arm(s) 
was closed due to safety concerns may be allowed to enter into the study but must be 
allocated to the control arm. 

Once the control arm enrolls 60 subjects, a subsequent randomization scheme may be 
initiated to optimize the number of subjects allocated to control arm. 

At any point during the study, the control arm will have no less than a 33% chance to be 
randomized in comparison to the active experimental arm that has the lowest 
randomization ratio in the study. 
Study treatment must be administered within 3 days after the treatment arm is assigned. If 
there is a delay in the administration of study treatment such that it will not be administered 
within the specified timeframe, the study monitor must be notified immediately.


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4.6.2
Methods to Ensure Blinding
This study is not blinded.
4.7
Restrictions During the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the final study visit. Any concomitant medication(s), including herbal 
and natural preparations, taken during the study will be recorded in the eCRF.
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to pro-
vide adequate prophylactic or supportive care except for those medications identified as pro-
hibited in Section 4.7.2.
4.7.2
Prohibited Concomitant Medications
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. The following concomitant medications are pro-
hibited:

Any investigational anticancer therapy

Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of 
hormones for noncancer-related conditions (eg, insulin for diabetes and hormone 
replacement therapy) is acceptable.

Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-alpha blockers. The following are exceptions:

Use of immunosuppressive medications for the management of investigational 
product-related AEs or in subjects with contrast allergies is acceptable. 

Use of inhaled, intranasal, or topical corticosteroids is permitted. 

Temporary courses of corticosteroids for treatment of underlying or concurrent 
illness or in the setting of palliative radiotherapy may be permitted upon discussion 
with the medical monitor.

Live attenuated vaccines during the study through 180 days after the last dose of study 
drug

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4.8
Statistical Evaluation
4.8.1
General Considerations
Tabular summaries will be presented by treatment group. Categorical data will be summarized 
by the number and percentage of subjects in each category. Continuous variables will be sum-
marized by descriptive statistics. Additional details of statistical analyses will be described in 
the statistical analysis plan.
The Intent-to-treat (ITT) Population includes all subjects who are randomized. Subjects will 
be analyzed according to their randomized treatment group.
The As-treated Population includes all subjects who receive any investigational product. Sub-
jects will be analyzed according to the treatment they actually receive.
The Response-evaluable Population includes subjects from the As-treated Population who 
have a baseline disease assessment, have the opportunity to be followed for at least 16 weeks 
at the time of the DCO (ie, dosed at least 16 weeks prior to the time of the DCO), and either 
has at least one post-baseline disease assessment and/or discontinued treatment due to death or 
disease progression.
4.8.2
Sample Size
Subjects will be randomized to the durvalumab monotherapy control arm and combination 
therapy experimental arms. The sample size of 60 subjects per experimental arm is not de-
signed to make explicit power and Type I error considerations for a hypothesis test. It is pri-
marily chosen to obtain a preliminary assessment of antitumor activity with a certain degree of 
precision.
Table 9 shows estimated differences in ORR between an experimental arm and the control 
arm along with 2-sided 95% exact CIs with a sample size of 60 subjects each. Sixty subjects 
per treatment arm provides a 95% CI with reasonable width (approximately ± 18%) for the es-
timated ORR difference between a durvalumab combination experimental arm and the durval-
umab control arm. For a 20% increase in ORR in any durvalumab combination experimental 
arm over durvalumab control arm (50% vs 30%, respectively), the lower limit of the 95% CI 
for the difference between these arms is 1%, which is greater than 0%, suggesting that the dur-
valumab combination experimental arm will have a higher ORR than the durvalumab control 
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Table 9
Estimated Differences in ORR Between Experimental and Control Arm 
of 60 Subjects Each 
Number of Responders (ORR)
Difference (%) in ORR
(2-sided 95% Exact Confidence Interval)
Experimental Arm
(n 60)
Control Arm
(n 60)
24 (40%)
18 (30%)
10% (-9%, 28%)
27 (45%)
18 (30%)
15% (-4%, 33%)
30 (50%)
18 (30%)
20% (1%, 38%)
33 (55%)
18 (30%)
25% (6%, 42%)
ORR = objective response rate.
4.8.3
Efficacy
The final efficacy analyses will be based on the ITT Population defined in Section 4.8.1. Re-
sponse will be summarized and compared between the experimental arm and control arm. 
Time-to-event data will be summarized using the Kaplan-Meier estimates. The following effi-
cacy endpoints will be analyzed. Each experimental arm will be compared to the control arm. 
There will be no formal comparisons between any experimental arms. RECIST v1.1 will be 
used as primary analysis for all endpoints when applicable. Localized post-radiation changes 
which affect lesion sizes may occur and there may be high levels of necrosis/fibrosis with lit-
tle or no active tumor in recently irradiated lesions. However, accepting these limitations in 
this patient population with prior curative radiation, treatment the prior irradiated lesions may 
be considered measurable and selected as target lesions providing they fulfill the other criteria 
for measurability. More details will be provided in the statistical analysis plan.

Best overall response (BOR), defined as the best response (in the order of complete 
response [CR], PR, SD, PD, and not evaluable) among all overall responses recorded 
from randomization until progression, or the last evaluable disease assessment in the 
absence of PD prior to the initiation of subsequent anticancer therapy or discontinuation 
from the study, whichever occurs first. The BOR of CR or PR must be confirmed, which 
means a response of CR/PR is recorded at 1 visit and confirmed by repeat imaging not 
less than 28 days (4 weeks) after the visit when the response was first observed with no 
evidence of progression between the initial and CR/PR confirmation visit.

OR, defined as BOR of confirmed CR or confirmed PR according to RECIST v1.1. 

DC, defined as BOR of confirmed CR, confirmed PR, or SD based on RECIST v1.1. 
Disease control rate (DCR) at 16 weeks is defined as a BOR of confirmed CR, confirmed 
PR or having SD with duration of SD lasting 16 weeks.

DoR, defined as the time from the first documentation of a subsequently confirmed OR to 
the first documentation of a disease progression according to RECIST v1.1 or death due 
to any cause, whichever occurs first. Only subjects who have achieved OR (confirmed CR 
or confirmed PR) will be evaluated for DoR.


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
PFS, defined as the time from randomization until the first documentation of disease 
progression according to RECIST v1.1 or death due to any cause, whichever occurs first, 
regardless of whether the subject receives subsequent anticancer therapy prior to 
progression. Subjects who are alive progression free at the time of DCO will be censored 
on the date of their last evaluable tumor assessment. PFS-12 will be estimated using the 
Kaplan-Meier method. 
4.8.3.1
Primary Efficacy Analysis
The primary efficacy endpoint is OR per RECIST v1.1. ORR is defined as the proportion of 
subjects with OR. The 2-sided 95% CI for ORR will be estimated using the exact binomial 
distribution. In addition, the unconfirmed ORR which is defined as the proportion of subjects 
who achieved a BOR of confirmed/unconfirmed CR or confirmed/unconfirmed PR will be 
presented along with its CI. An estimate of the difference in ORR between the experimental 
arm and the control arm will be reported. Comparison of treatment arms for ORR will be ob-
tained from the Chi-square or Fisher’s exact test.
4.8.3.2
Secondary Efficacy Analyses
Secondary efficacy endpoints include DoR, DC, PFS, and OS. Analyses of secondary end-
points will be performed as follows.

DoR according to RECIST v1.1 will be analyzed using the Kaplan-Meier method for 
those subjects with OR in the corresponding analysis populations. The median of DoR 
with 95% CI will be estimated based on the Kaplan-Meier curves.

The DCR according to RECIST v1.1 is defined as the proportion of subjects with DC. 
The 2-sided 95% CI of DCR will be provided using an exact probability method. DCR at 
16 weeks will be estimated along with the 2-sided 95% CI. 

PFS according to RECIST v1.1 will be analyzed using the Kaplan-Meier method. The 
median PFS with 95% CI will be estimated based on the Kaplan-Meier curves. PFS-12 
will be estimated based on the Kaplan-Meier curves along with their 95% CIs when 
applicable. An estimate of the difference in PFS-12 between an experimental arm and the 
control arm will be reported. Comparison of treatment arms for PFS-12 will be performed 
under complementary log-log transformation of the Kaplan-Meier estimates of PFS-12 
(Klein et al, 2007)

OS will be analyzed using the Kaplan-Meier method. The median OS with 95% CI will 
be estimated based on the Kaplan-Meier curves. The 1-year OS rates will be estimated 
based on the Kaplan-Meier curves along with their 2-sided 95% CI when applicable.
4.8.3.3
Exploratory Analyses
 
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4.8.4
Safety
Safety analyses will be based on the As-treated Population defined in Section 4.8.1.
4.8.4.1
Analysis of Adverse Events
Summary statistics will be provided for AEs, SAEs, and AE grade, severity, and relationship 
to study drug(s). AEs will be graded according to NCI CTCAE v5.0 and coded using system 
organ class and preferred term using the Medical Dictionary for Regulatory Activities pre-
ferred term. Specific AEs will be counted once for each subject when calculating rates, but 
will be all presented in total in subject listings.
4.8.4.2
Analysis of Clinical Laboratory Parameters
Summary statistics will be provided for clinical laboratory parameters, physical examinations, 
vital signs, and ECG. Laboratory abnormalities with toxicity grades according to the 
NCI CTCAE v5.0 will be derived and summarized.
Laboratory parameters will be assessed at baseline as well as throughout the study. Frequen-
cies of maximum observed grade will be presented for each laboratory parameter as well as 
the rates of subjects with Grade 3-4 toxicities. A shift table, presenting the 2-way frequency 
tabulation for baseline and post-baseline grade at scheduled time of evaluation as well as the 
worst post-baseline grade, will be provided for clinical laboratory tests. Also, laboratory pa-
rameters will be assessed by presenting tables containing information related to 2-grade (or 
greater) laboratory shifts.
4.8.4.3
Analysis of Vital Signs
Descriptive statistics will be provided for the vital signs measurements and changes from 
baseline by scheduled time of evaluation and by treatment arm including the maximum and 
minimum post-baseline values. 
4.8.4.4
Analysis of ECOG Performance Status 
Descriptive statistics will be provided for the ECOG Performance Status assessments and 
changes from baseline by scheduled time of evaluation and by treatment arm.
4.8.5
Analysis of Immunogenicity/Pharmacokinetics 
Immunogenicity
Only subjects who receive at least 1 dose of durvalumab and/or other combination study drug, 
and provide at least 1 post-treatment sample, will be evaluated. For each treatment arm, the 
immunogenic potential of durvalumab will be assessed by summarizing the number and per-
centage of subjects who develop detectable ADAs to durvalumab. For experimental arms that 
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include a biologic agent, the immunogenic potential of the combination study drug will be as-
sessed by summarizing the number and percentage of subjects who develop detectable ADAs 
to the combination study drug. 
The impact of ADAs on PK and safety will be assessed if data allow. Samples confirmed posi-
tive for ADAs may also be evaluated for neutralizing antibody activity.
Pharmacokinetics 
Only subjects who receive at least 1 dose of durvalumab and/or other combination study drug, 
and provide at least 1 post-treatment sample, will be evaluated. For each treatment arm, indi-
vidual durvalumab concentrations will be tabulated with descriptive statistics. Additionally, 
for each experimental arm, individual novel agent concentrations will be tabulated with de-
scriptive statistics. 
Non-compartmental PK data analysis will be performed from each treatment arm with sched-
uled PK sample collection where data allow. Relevant descriptive statistics of non-compart-
mental PK parameters will be provided and may include: area under the concentration-time 
curve, observed maximum concentration, clearance, and terminal half-life.
4.8.6
Analyses of Biomarkers
Descriptive statistics will be the primary method for the biomarker analyses (see Section 4.3.7
for a description of the exploratory biomarkers). Depending on the nature of the data, geomet-
ric mean and other appropriate statistical summaries might be used as well.
Summaries and analyses for exploratory biomarkers may be reported outside the CSR in a 
separate report.
4.8.7
Interim Analysis
Interim analyses will be conducted during the course of the study to evaluate the clinical activ-
ity and safety of any experimental arm in comparison with the control arm. The results of the 
interim analyses may be used for internal program decision and/or potential interactions with 
regulatory agencies on future development. The first interim analysis will be performed once 
the control arm has 30 ITT subjects who have reached the data cutoff criteria (defined as the 
opportunity to be followed for at least 16 weeks at the time of data cutoff). The DCR at Week 
16 will be used for No-Go decision, and ORR may be used for early Go decision. Enrollment 
will not be paused for interim analyses. 
Bayesian PP will be used to evaluate clinical activity (Lee and Liu, 2008). Table 10 illustrates 
the sample algorithm to make a No-Go decision based on DCR at 16 weeks at the interim 
analysis when the control arm and an experimental arm each have 30 subjects. If an early No-
Go decision is made, enrollment to the corresponding experimental arm will be stopped. In 


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this study, we assume a target value (TV) of ΔDCR at 16 weeks as 15%, where ΔDCR is the 
difference in DCR between an experimental arm and control arm.

An experimental arm will meet the No-Go criteria if the probability that the true ΔDCR is 
larger than TV is less than 10%, ie, Prob.(True ΔDCR > 0.15) < 0.10. A No-Go decision 
will be made at an interim analysis if the PP of meeting the No-Go criteria given observed 
data is greater than 95%, ie, PP[Prob.(ΔDCR > 0.15) < 0.10)] > 0.95.
Table 10
Criteria of No-Go Decisions Based on DCR at 16 Weeks 
Number of Subjects with DCR at 16 weeks in 
Control Arm
Number of Subjects with DCR at 16 weeks in 
Experimental Arm
10
≤ 7
11
≤ 8
12
≤ 8
13
≤ 9
14
≤ 10
15
≤ 11
16
≤ 12
17
≤ 13
18
≤ 14
19
≤ 15
20
≤ 16
21
≤ 17
22
≤ 19
23
≤ 20
24
≤ 21
25
≤ 23
26
≤ 24
27
≤ 26
28
≤ 28
29
≤ 29
30
≤ 30
DCR = disease control rate.
5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal rela-
tionship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, 
an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease temporally as-
sociated with the use of a medicinal product, whether or not considered related to the medici-
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The term AE is used to include both serious and non-serious AEs and can include a deteriora-
tion of a pre-existing medical occurrence. An AE may occur at any time, including run-in or 
washout periods, even if no study treatment has been administered. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE.
5.2
Definition of Serious Adverse Events
An SAE is any AE that:

Results in death

Is immediately life-threatening

Requires inpatient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability/incapacity 

Is a congenital anomaly/birth defect in offspring of the subject

Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
Medical or scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in this situation. Examples of medically important events are intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalizations; or development of drug dependency or drug abuse.
5.3
Definition of Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the investiga-
tional product and may require close monitoring and rapid communication by the investigator 
to MedImmune. An AESI may be serious or nonserious. The rapid reporting of AESIs allows 
ongoing surveillance of these events in order to characterize and understand them in associa-
tion with the use of this investigational product.
5.3.1
Adverse Events of Special Interest for Durvalumab-containing 
Regimens
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or inter-
ventions such as steroids, immunosuppressants, and/or hormone replacement therapy. These 
AESIs are being closely monitored in clinical studies with durvalumab monotherapy and com-
bination therapy. An imAE is defined as an AE that is associated with drug exposure and is 


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consistent with an immune-mediated mechanism of action and where there is no clear alter-
nate etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be 
used to support an imAE diagnosis. Appropriate efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin, or other etiologic causes of the imAE.
If the investigator has any questions determining whether an AE is an imAE, the investigator 
should promptly contact the Study Physician. 
AESIs observed with durvalumab include:

Diarrhea/colitis and intestinal perforations

Pneumonitis

Hepatitis

Endocrinopathies (ie, events of hypophysitis/hypopituitarism, type 1 diabetes mellitus, 
adrenal insufficiency, and hyper- and hypothyroidism)

Rash/dermatitis

Nephritis

Pancreatitis

Myocarditis

Myositis/polymyositis

Neuropathy/neuromuscular toxicity (eg, Guillain-Barré and myasthenia gravis)

Immune complex mediated diseases

The immune system can respond to foreign mAbs by producing human-anti-human 
antibodies, which may result in formation of immune complexes and their deposition in 
blood vessels, joints, and glomeruli causing symptomatic disease (eg, vasculitis, 
glomerulonephritis, arthritis). Subjects who experience an AE suspected to be immune-
complex related and with confirmed presence of ADAs will discontinue treatment. Other 
inflammatory responses that are rare/less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and other events 
involving the eye, skin, hematological and rheumatological events.
In addition, IRRs and hypersensitivity/anaphylactic reactions with a different underlying phar-
macological etiology are also considered AESIs. Anaphylaxis and IRRs have some common 
manifestations and may be difficult to distinguish from each other. IRRs are commonly ob-
served during or shortly after the first time of exposure to therapeutic mAbs delivered through 
IV infusion. These reactions are less common following subsequent exposures. Unlike IRRs, 
anaphylaxis is a rare allergic mediated event, usually occurring after subsequent exposure to 
an antigen, and it is most commonly accompanied by severe systemic, skin and/or mucosal re-
actions. The investigator is advised to carefully examine adverse reactions observed during or 
shortly after drug infusion, and consider the above-mentioned facts prior to making a final di-
agnosis. For the investigator’s convenience and to facilitate consistency in judgments, a copy 


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of the National Institute of Allergy and Infectious Disease and Food and Allergy Anaphylaxis 
Network guidance for anaphylaxis diagnosis is provided in Appendix C.
Further information on all those risks (eg, presenting symptoms) can be found in the current 
version of the durvalumab IB. More specific guidelines for their evaluation and treatment are 
described in detail in the Toxicity Management Guidelines (see Section 3.1.3). These guide-
lines 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 consid-
ered causally related to the study drug/study regimen by the reporting Investigator.
5.3.2
Adverse Events of Special Interest Associated with Oleclumab
Cardiac Chest Pain, Transient Ischemic Attack, and Thromboembolism
AEs of cardiac chest pain, transient ischemic attack, and thromboembolism are of special in-
terest due to oleclumab potential risks of arterial calcifications, arterial ischemic disorder, and 
thrombosis. Because of this potential risk, potential subjects with a history of venous throm-
bosis in the prior 3 months, or myocardial infarction, stroke, or transient ischemic attack in the 
prior 6 months are not eligible (see Section 4.1.3). These events require urgent medical man-
agement, which should be performed according to consensus guidelines developed by the 
American Heart Association or appropriate local standards of care.
Edema
Edema (eg, pulmonary or peripheral) is regarded as AESI due to oleclumab potential risks of 
increased microvascular permeability. For subjects who develop ≥ Grade 3 edema, doses 
should be omitted (Section 3.1.3), and therapy may be discontinued at the discretion of the in-
vestigator.
5.3.3
Adverse Events of Special Interest Associated with Monalizumab
There are no identified AESIs associated with monalizumab that are not included in the AESIs 
for durvalumab-containing regimens (see Section 5.3.1).
5.4
Recording of Adverse Events
AEs will be recorded on the eCRF using a recognized medical term or diagnosis that accu-
rately reflects the event. AEs will be assessed by the investigator for severity, relationship to 
the investigational product, possible etiologies, and whether the event meets criteria of an 
SAE and therefore requires immediate notification to MedImmune (see Section 5.5). See Sec-
tion 5.2 for the definition of SAEs and 0 for guidelines on assessment of severity and relation-
ship. 
If an AE evolves into a condition that meets the regulatory definition of “serious,” it will be 
reported on the SAE Report Form.


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5.4.1
Time Period for Collection of Adverse Events
AEs and SAEs will be collected from time of signature of informed consent up to 12 months 
post Cycle 1 Day 1, regardless of whether the subject discontinued treatment. Following the 
first 12 months post Cycle 1 Day 1, AEs and SAEs will be collected up to 3 months post last 
dose of study treatment, if applicable.
5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved during the end of study visit or when a subject has consented to 
study participation may be followed up by the investigator for as long as medically indicated, 
but without further recording in the eCRF. The sponsor retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged nec-
essary.
5.4.3
Deaths
All deaths that occur during the study, including the protocol-defined follow-up period must 
be reported as follows:

Death clearly the result of disease progression should be reported and documented in the 
eCRF but should not be reported as an SAE.

Where death is not due (or not clearly due) to disease progression, the AE causing the 
death must be reported as an SAE within 24 hours following investigator awareness of the 
event. The report should contain a comment regarding the co-involvement of disease 
progression, if appropriate, and should assign main and contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE. A post-mortem 
(autopsy) may be helpful in the assessment of the cause of death, and if performed a copy 
of the post-mortem results should be forwarded to MedImmune representative(s) within 
the usual timeframes (refer to Section 5.5 for additional information).
5.4.4
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: ‘Have you 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.
5.4.5
Adverse Events Based on Examination and Tests
The results from the protocol-mandated laboratory tests and vital signs will be summarized in 
the CSR. An abnormal laboratory finding (including ECG finding) that requires medical inter-
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should be reported as an AE. If clinical sequelae are associated with a laboratory abnormality, 
the diagnosis or medical condition should be reported (eg, renal failure, hematuria) not the la-
boratory abnormality (eg, elevated creatinine, urine red blood cell increased).
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 
should use the clinical rather than the laboratory term (eg, anemia vs low hemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-man-
dated parameters should be reported as AE(s).
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.
5.4.6
Potential Hy’s Law and Hy’s Law
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN will need to be re-
ported as SAEs. Please refer to Appendix D for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law.
5.4.7
Disease Progression
Disease progression can be considered as a worsening of a subject’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 devel-
opment of a new metastasis or progression of existing metastasis related to the primary cancer 
under study should not be considered an AE. Death clearly resulting from disease progression 
should not be reported as an SAE (see reporting guidelines in Section 5.4.3).
The term disease progression should not be reported as an AE or SAE, however, medically 
significant individual events and/or laboratory abnormalities associated with disease progres-
sion (see definition of disease progression above) that fulfill the AE or SAE definition should 
be reported.
New Cancers
The development of a new cancer should be regarded as an SAE. New cancers are those that 
are not the primary reason for the administration of the investigational product and have been 
identified after the subject’s inclusion in the study. New metastatic lesion(s) of the subject’s 
known cancer should not be reported as a new cancer.


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5.5
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel must 
inform the appropriate sponsor representative(s) within 1 day, ie, immediately but no later 
than 24 hours after becoming aware of the event.
The designated study representative works with the investigator to ensure that all the neces-
sary information is provided to the sponsor’s 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 sponsor rep-
resentatives of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours after becoming aware of the event.
Once the investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to inform the designated sponsor rep-
resentative(s).
If the EDC system is not available, then the investigator or other study site personnel reports 
an SAE to the appropriate sponsor representative by telephone. The sponsor representative 
will advise the investigator/study site personnel how to proceed. 
The reference document for definition of expectedness/listedness is the IB for the study drug.
5.6
Other Events Requiring Immediate Reporting
5.6.1
Overdose
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in the IB, unless otherwise specified in this protocol.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated AEs is only reported on the Overdose eCRF module.
If an overdose on any study drug occurs during the course of the study, then the investigator 
or other site personnel should inform appropriate sponsor representatives immediately, but no 
later than 24 hours after becoming aware of the event.


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The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply; see Section 5.5. 
For other overdoses (ie, those not associated with an AE or SAE), reporting must occur within 
30 days.
5.6.2
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to the sponsor except if the 
pregnancy is discovered before the subject has received any study drug.
Females of childbearing potential must have a negative pregnancy test result at screening to be 
enrolled in the study and treated with study drug. 
5.6.2.1
Maternal Exposure
If a subject becomes pregnant during the course of the study, investigational product 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 
subject was discontinued from the study.
If any pregnancy occurs during the course of the study, then the investigator or other site per-
sonnel will inform the appropriate sponsor representatives within 1 day, ie, immediately but 
no later than 24 hours after becoming aware of the event.
The designated study representative works with the investigator to ensure that all relevant in-
formation is provided to the sponsor’s patient safety data entry site within 1 or 5 calendar days 
for SAEs (see Section 5.5) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The pregnancy reporting module in the eCRF is used to report the pregnancy and the preg-
nancy outcome module is used to report the outcome of the pregnancy.
5.6.2.2
Paternal Exposure
Pregnancy of the subject’s partners is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 


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birth or congenital abnormality), occurring from the date of the first dose until 90 days after 
the last dose should, if possible, be followed up and documented.
5.6.3
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for a study drug that either causes harm to the subject or has the poten-
tial to cause harm to the subject. 
A medication error is not lack of efficacy of the drug, but rather a human- or process-related 
failure while the drug is in control of the study site staff or subject.
Medication error includes situations where an error: 

Occurred

Was identified and intercepted before the subject received the drug

Did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion (ie, instead of receiving the investigational product, the subject 
received a drug that has a similar-sounding name)

Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the subject

Drug not administered as indicated, eg, wrong route or wrong site of administration

Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature 

Wrong subject received the medication (excluding IXRS errors)

Wrong drug administered to subject (excluding IXRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IXRS - including those which lead to one of the above 
listed events that would otherwise have been a medication error 

Subject accidentally missed drug dose(s), eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Subject failed to return unused medication or empty packaging

Errors related to background and rescue medication 


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Medication errors are not regarded as AEs, but AEs may occur as a consequence of the medi-
cation error. 
If a medication error occurs in the course of the study, then the Investigator or other site per-
sonnel informs the appropriate MedImmune representatives within 1 day, ie, immediately but 
no later than 24 hours of when he or she becomes aware of it.
The designated MedImmune representative works with the Investigator to ensure that all rele-
vant information is completed within 1 or 5 calendar days if there is an SAE associated with 
the medication error (see Section 5.5) and within 30 days for all other medication errors. Med-
ication errors should be reported using a Medication Error Report Form.
6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a MedImmune representative will review and 
discuss the requirements of the protocol and related documents with the investigational staff 
and also train them in any study-specific procedures and system(s) utilized.
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 for-
warded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).
6.2
Monitoring of the Study
During the study, a MedImmune 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 subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require 
direct access to all original records for each subject (eg, clinic charts)


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
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct.
6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.
6.2.2
Study Agreements
The Principal Investigator at each center should comply with all the terms, conditions, and ob-
ligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any in-
consistency between this protocol and the Clinical Study Agreement, the terms of this proto-
col shall prevail with respect to the conduct of the study and the treatment of subjects and in 
all other respects, not relating to study conduct or treatment of subjects, the terms of the Clini-
cal Study Agreement shall prevail.
Agreements between MedImmune and the Principal Investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled.
6.2.3
Archiving of Study Documents
The investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was fol-
lowed through their last protocol-specified visit/assessment, regardless of the number of doses 
of investigational product that was received. 
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Section 4.1.5 and Section 4.1.6).
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study. This date will 
be 5 years after the final subject is entered into the study or when the sponsor stops the study, 
whichever occurs first. 
6.4
Data Management 
Data management will be performed by MedImmune Data Management staff or other party
according to the Data Management Plan.


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An EDC system will be used for data collection and query handling. The investigator will en-
sure that data are recorded in the eCRFs as specified in the study protocol and in accordance 
with the eCRF instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The in-
vestigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived at 
the study site.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the Principal Investigator. In addi-
tion, each subject will receive a toll-free number intended to provide the subject’s physician 
access to a medical monitor 24 hours a day, 7 days a week in the event of an emergent situa-
tion where the subject’s health is deemed to be at risk. In this situation, when a subject pre-
sents to a medical facility where the treating physician or health care provider requires access 
to a physician who has knowledge of the investigational product(s) and the clinical study pro-
tocol and the Principal Investigator is not available, the treating physician or health care pro-
vider can contact a medical monitor through this system, which is managed by a third party 
vendor.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Subject Data Protection
Each subject will be assigned a SID to ensure that personally identifiable information is kept 
separate from the study data. Subject data that are relevant to the study, eg, demographic in-
formation, physical or mental health condition, diagnosis, comorbidities, laboratory test re-
sults, etc will only be collected with the subject’s informed consent. The informed consent 
form will incorporate (or, in some cases, be accompanied by a separate document incorporat-
ing) wording that describes how subject data will be collected, used, and distributed in com-
pliance with relevant data protection and privacy legislation. Data (clinical and biological 
sample) from this study may be used and may be combined with results from other studies for 
additional scientific-related research, based on agreement from the subject as defined in the 
informed consent form.
7.2
Ethics and Regulatory Review
The IRB/IEC responsible for each site must review and approve the final study protocol, in-
cluding the final version of the informed consent form and any other written information 
and/or materials to be provided to the subjects. The IRB/IEC must also approve all advertising 
used to recruit subjects for the study. The investigator is responsible for submitting these doc-
uments to the applicable IRB/IEC and distributing them to the study site staff.


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The opinion of the IRB/IEC must be given in writing. The investigator must provide a copy of 
the written approval to MedImmune before enrollment of any subject into the study. 
MedImmune should approve any substantive modifications to the informed consent form that 
are needed to meet local requirements.
If required by local regulations, the protocol must be re-approved by the IRB/IEC annually.
Before the study is initiated, MedImmune will ensure that the national regulatory authority in
each country has been notified and their approval has been obtained, as required. MedImmune 
will provide safety updates/reports according to local requirements, including suspected unex-
pected serious adverse reactions where relevant, to regulatory authorities, IRB/IEC, and prin-
cipal investigators.
Each Principal Investigator is responsible for providing reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the investigational product(s) to 
the IRB/IEC. MedImmune will provide this information to the Principal Investigator so that 
he/she can meet these reporting requirements.
7.3
Informed Consent
Informed consent of each subject will be obtained through a written and verbal explanation 
process that addresses all elements required by ICH/GCP. MedImmune will develop a core 
informed consent form for use by all investigators in the clinical study. MedImmune must ap-
prove any modifications to the informed consent form that are needed to meet local require-
ments.
The Principal Investigator(s) at each center will:

Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study

Ensure each subject is notified that they are free to discontinue from the study at any time

Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided

Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study

Ensure the original, signed informed consent form(s) is/are stored in the Investigator’s 
Study File

Ensure a copy of the signed informed consent form is given to the subject

Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the informed consent form that is approved by an IRB/IEC


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7.4
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Principal Investi-
gator and the sponsor. Any changes must be documented in a study protocol amendment. 
For a substantial change to the protocol, MedImmune will distribute amended versions of the 
protocol to the Principal Investigator(s). Before implementation, amended protocols must be 
approved by relevant IRB/IEC (see Section 7.2) and reviewed as per local regulatory authority 
requirements. The IRB/IEC must also approve revisions to the informed consent form, adver-
tising, and any other written information and/or materials resulting from the change to the pro-
tocol.
Any non-substantial changes will be communicated to or approved by each IRB/IEC and local 
regulatory authority per local requirements.
7.5
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the center, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines of the 
ICH, and any applicable regulatory requirements. The investigator will contact MedImmune 
immediately if contacted by a regulatory agency about an inspection at the site.


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8
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2012. CA Cancer J Clin. 2015;65(2):87-108.
Turcotte et al, 2015
Turcotte M, Spring K, Pommey S, Chouinard G, Cousineau I, George J, et al. CD73 is 
associated with poor prognosis in high-grade serous ovarian cancer. Cancer Res. 
2015;75(21):4494-503. 
Versluis et al, 2017
Versluis MAC, Marchal S, Plat A, de Bock GH, van Hall, T, de Bruyn M, et al. The 
prognostic benefit of tumour-infiltrating Natural Killer cells in endometrial cancer is 
dependent on concurrent overexpression of human leucocyte antigen-E in the tumour 
microenvironment. Eur J Cancer. 2017;86:285-95.
Vijayan et al, 2017
Vijayan D, Young A, Teng MWL, Smyth MJ. Targeting immunosuppressive adenosine in 
cancer. Nat Rev Cancer. 2017;17(12):709-24.


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Zeestraten et al, 2014
Zeestraten EC, Reimers MS, Saadatmand S, Goossens-Beumer IJ, Dekker JW, Liefers GJ, et 
al. Combined analysis of HLA class I, HLA-E and HLA-G predicts prognosis in colon cancer 
patients. Br J Cancer. 2014;110(2):459-68.
Zou and Chen, 2008
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev
Immunol. 2008;8(6):467-77.
Zou et al, 2016
Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer 
therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med. 
2016;8(328):328rv4. 


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9
CHANGES TO THE PROTOCOL
9.1
Protocol Amendment 4
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 4. All subjects have completed their treatment period as specified by the protocol 
and no subjects are currently receiving any study treatment. The primary reason for this 
amendment is to clarify the frequency and length for collection of overall survival data.
Substantial changes to the protocol are summarized below:
1
Title page: Replaced 
 with 
 as Medical Monitor.
2
Section 3.1.1 (Overview): Clarified that all subjects, including those who have experi-
enced PD, will be followed for survival until the end of the study.
3
Section 4.1.6 (Discontinuation of Investigational Product), Section 4.2.2 (Follow-up Pe-
riod), Table 6 (Schedule of Follow-up Procedures: Subjects Who Completed Study Treat-
ment and Maintain DC, Subjects Who Discontinued Study Treatment Due to Other Rea-
son Not Related to PD, and Subjects Who Experienced Unconfirmed PD and are Eligible 
for a Confirmation Scan), and Section 4.2.3 (End of Study): Clarified that survival status 
will be collected for all subjects until 60 months post Cycle 1 Day 1, at time points de-
tailed in Table 6. Further, subjects may be contacted for survival status every 12 months 
beyond 60 months post Cycle 1 Day 1, until the end of the entire study, unless consent is 
withdrawn.
Non-substantial changes to the protocol are as follows:
1
Protocol Synopsis: Updated to align with the body of the protocol.
2
Section 3.1.3 (Management of Study Medication Related Toxicities): A reference to the 
website hosting the toxicity management guidelines for durvalumab was deleted as the 
website has been decommissioned.
3
Section 4.1.1 (Number of Subjects) and Section 4.8.2 (Sample Size): Clarified that the re-
cruitment estimate of 60 subjects per experimental treatment arm is approximate.
4
Section 4.2.3 (End of Study), Table 7 (Schedule of Procedures for End of Study Visit): 
Added a footnote to clarify that concomitant medications, AEs and SAEs will be col-
lected at this visit only.
5
Section 4.5.1.8 (Reporting Product Complaints): Updated the contact information for re-
porting product complaints.
9.2
Protocol Amendment 3
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 3. The primary reason for the amendment is to increase the window from the sub-
ject’s last cCRT to randomization into the study.
PPD
PPD


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Substantial changes to the protocol are summarized below.
1
Protocol synopsis; Section 3.1.1 (Overview), including Figure 1 (Study Flow Diagram);
and Section 4.1.2 (Inclusion Criteria), Criterion 5: The window from the subject’s last 
cCRT to randomization was increased from 28 days to 42 days to align with the PACIFIC 
study design and to provide sites more flexibility in identifying and enrolling subjects.
2
Section 4.1.3 (Exclusion Criteria): Added criterion (new Criterion 5) excluding subjects 
with prior exposure to any anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody for the 
treatment of NSCLC to avoid confounding factors affecting safety and efficacy 
assessments for this study. 
Non-substantial changes to the protocol are summarized below.
1
Table 5 (Schedule of Screening and Treatment Period Procedures): 
(a) Added assessment for ECOG performance status for Cycle 5 through Cycle 13. This 
assessment was inadvertently omitted in the original protocol. ECOG performance 
status is to be assessed throughout the study, as noted in Table 6 (Schedule of 
Follow-up Procedures) throughout the follow-up period and Table 7 (Schedule of 
Procedures for End of Study Visit).
(b) Footnote “e” revised to align with changes to required TSH tests described in 
Section 4.3.3, Other Safety Tests. 
2
Table 6 (Schedule of Follow-up Procedures: Subjects Who Completed Study Treatment 
and Maintain DC, Subjects Who Discontinued Study Treatment Due to Other Reason Not 
Related to PD, and Subjects Who Experienced Unconfirmed PD and are Eligible for a 
Confirmation Scan): 
(a) Clarified that disease assessments conducted as part of follow-up procedures 
≤12 months from Cycle 1 Day 1 can be conducted within 7 days of the visit, in 
alignment with window for this assessment during the treatment period. 
(b) Footnote “a” revised to align with changes to required TSH tests described in 
Section 4.3.3, Other Safety Tests.
3
Section 4.3.3 (Clinical Laboratory Tests), Other Safety Tests: Thyroid function tests were 
revised permitting sites to only conduct T3 or T4 tests when TSH is abnormal for 
flexibility to accommodate country or institutional guidelines regarding thyroidal 
abnormality screening. Additionally, it was clarified that free T3/free T4 are preferred 
over total T3/total T4 tests.
4
Section 4.5.1.8 (Reporting Product Complaints): Updated the telephone information in 
alignment with current contact.
5
Protocol synopsis and Section 4.8.1 (General Considerations): Modified the definition of 
the ITT Population to align with the Sponsor’s current standard definition.
6
Appendix D (Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law): Removed references as not cited in the protocol.


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9.3
Protocol Amendment 2
The primary reasons for the amendment were alignment of monalizumab information with the 
new manufacturing process (Process C), updating the process for identifying and reporting po-
tential Hy’s Law and Hy’s Law cases, and adding an inclusion criterion to ensure all subjects 
have at least 1 previously irradiated tumor lesion that can be measured by RECIST v1.1. No 
subjects were enrolled in experimental Arm B (durvalumab plus monalizumab) prior to Proto-
col Amendment 2. 
All revisions to the protocol are noted below:
1
Section 1.5 (Rationale for Conducting the Study): Included rationale for use of ORR to 
assess antitumor activity 
2
Section 4.1.2 (Inclusion Criterion): Added criterion to clarify that subjects must have at 
least 1 previously irradiated tumor lesion measurable by RECIST v1.1, consistent with 
the RECIST v1.1 guidelines
3
Section 4.5.1 (Identity of Investigational Product), Table 8 (Identification of 
Investigational Product): Updated with new monalizumab manufacturing process 
information, and added study drug storage information.
4
Section 4.5.1.3 (Durvalumab Dose Preparation and Administration): Revised to align with 
updated preferred durvalumab language, including removal of requirement that 
IV administration filter be in-line. 
5
Section 4.5.1.4 (Oleclumab Dose Preparation and Administration): Revised to align with 
updated preferred oleclumab language, including removal of requirement that 
IV administration filter be in-line.
6
Section 4.5.1.5 (Monalizumab Dose Preparation and Administration): Updated with new 
monalizumab manufacturing process information.
7
Section 5.4.6 (Potential Hy’s Law and Hy’s Law): Revised section heading to include 
potential Hy’s Law and added requirement to report these cases as SAEs.
8
Section 7.1 (Subject Data Protection): Revised to align with preferred MedImmune 
standard language.
9
Appendix D (Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law): Updated to align with revised MedImmune requirements. 
9.4
Protocol Amendment 1
The protocol was revised to incorporate the following US Food and Drug Administration re-
quests:
1
Figure 1 (Study Flow Diagram): Removed placeholders for new combination 
experimental arms (A and X) that could be added via a protocol amendment.
2
Table 5 (Schedule of Screening and Treatment Period Procedures): Additional PK and 
ADA samples will be collected at Cycle 11.


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3
Table 6 (Schedule of Follow-up Procedures: Subjects Who Completed Study Treatment 
and Maintain DC, Subjects Who Discontinued Study Treatment Due to Other Reason Not 
Related to PD, and Subjects Who Experienced Unconfirmed PD and are Eligible for a 
Confirmation Scan): PK and ADA samples will be collected at 10 months post Cycle 1 
Day 1 (for follow-up during the first 12 months) and on Month 15 (for follow-up > 12 to 
≤ 24 months).
4
Section 4.3.4 (Pharmacokinetic Evaluation and Methods): Revised to identify each novel 
agent to be included in the PK evaluation.
5
Section 4.3.5 (Immunogenicity Evaluation and Methods): Revised to identify each 
novel/biologic agent to be included in the ADA evaluation.
6
Section 4.3.8 (Estimate of Volume of Blood to be Collected): Updated to align with 
additional blood samples collected for PK and ADA assessments.
7
Section 4.8.2 (Sample Size): Added detail for sample size determination.


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Appendix A
Contraception Guidance
Females of Childbearing Potential
Females of childbearing potential must use at least one of the highly effective methods of con-
traception described in Table A1 while on study and for 180 days after the final dose of inves-
tigational product. It is strongly recommended for the male partner of a female subject to also 
use male condom plus spermicide throughout this period. In addition, female subjects must 
refrain from egg cell donation and breastfeeding while on study and for 180 days after the fi-
nal dose of investigational product.
Females of childbearing potential are defined as those who are not surgically sterile (ie, bilat-
eral tubal ligation, bilateral oophorectomy, or hysterectomy) or postmenopausal. The defini-
tion of postmenopausal status in this study include:

Women < 50 years of age if they have been amenorrhoeic for ≥ 12 months in the absence 
of any exogenous hormonal treatment, and their levels of luteinizing hormone and 
follicle-stimulating hormone are in the post-menopausal range for the institution or 
underwent surgical sterilization (bilateral oophorectomy or hysterectomy).

Women ≥ 50 years are considered post-menopausal if they have been amenorrhoeic for 
≥12 months in the absence of any exogenous hormonal treatment, or underwent surgical 
sterilization (ie, bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
Non-sterilized Male Subjects
Non-sterilized male subjects must use a male condom with spermicide from screening to 
180 days after the final dose of study treatment as an effective method of contraception. It is 
strongly recommended for the female partner of a male subject to also use a highly effective 
method of contraception throughout this period, as described in Table A1. In addition, male 
subjects must refrain from sperm donation while on study and for 180 days after the final dose 
of investigational product. 


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Table A1
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
•
Intrauterine device
•
Intrauterine hormone-releasing 
system (UIS) a
•
Bilateral tubal occlusion
•
Vasectomized partner b
•
Sexual abstinence c
•
Combined estrogen and progestogen containing 
hormonal contraception: oral (combined pill), injectable 
or transdermal (patch)
•
Progestogen-only hormonal contraception associated 
with inhibition of ovulation d: injectable, implantable or 
intravaginal
a
This is also considered a hormonal method
b
With appropriate post-vasectomy documentation of surgical success (absence of sperm in ejaculate).
c
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of the study and if it is the preferred and usual 
lifestyle of the subject.
d
Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of 
action (eg, minipill), is not accepted as a highly effective method.


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Appendix B
Additional Safety Guidance
Further Guidance on the Definition of a Serious Adverse Event
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the subject was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
Examples of such events are:

Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion) or convulsions 
that do not result in hospitalization

Development of drug dependency or drug abuse
Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the NCI CTCAE v5.0 as provided in 
below. The determination of severity for all other events not listed in the NCI CTCAE v5.0 


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should be made by the investigator based upon medical judgment and the severity categories 
of Grade 1 to 5 as defined below.
Grade 1
An event of mild intensity that is usually transient and may 
require only minimal treatment or therapeutic intervention. The 
event does not generally interfere with usual activities of daily 
living.
Grade 2
An event of moderate intensity that is usually alleviated with 
additional specific therapeutic intervention. The event interferes 
with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject.
Grade 3
A severe event that requires intensive therapeutic intervention. 
The event interrupts usual activities of daily living, or 
significantly affects the clinical status of the subject.
Grade 4
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death.
Grade 5
Death as a result of an event.
Assessment of Relationship
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product. The following factors should be considered when deciding if there is a 
“reasonable possibility” that an AE may have been caused by the investigational product:

Time Course. Exposure to suspect investigational product. Has the subject actually 
received the suspect investigational product? Did the AE occur in a reasonable temporal 
relationship to the administration of the suspect investigational product?

Consistency with known investigational product profile. Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 
or products of the same pharmacological class? OR could the AE be anticipated from its 
pharmacological properties? 

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect investigational product?

No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, or other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected investigational product was 
reintroduced after having been stopped? MedImmune would not normally recommend or 
support a re-challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship?


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In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the investigational product?

Is there a known mechanism?
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 nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) 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, washout of an existing medication). 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 etiology present in the 
subject’s medical record.
Not protocol related: The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record).


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Appendix C
National Institute of Allergy and Infectious Diseases and 
Food Allergy and Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis
National Institute of Allergy and Infectious Diseases and Food Allergy and Anaphylaxis 
Network define anaphylaxis as a serious allergic reaction that is rapid in onset and may cause 
death. They recognize 3 categories of anaphylaxis, with criteria designated to capture from 80% of 
cases (category 1) to > 95% of all cases of anaphylaxis (for all 3 categories).
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING: 
(a) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), hypoxemia)
(b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence)
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
(a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)
(b) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3
Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
(a) Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP
(b) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline
For additional information, please refer to: Sampson HA, Muñoz-Furlong A, Campbell RL, 
Adkinson FN Jr, Bock SA, Branum A, et al. Second symposium on the definition and 
management of anaphylaxis: Summary report. Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin 
Immunol. 2006;117:391-7.


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Appendix D
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
D 1
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report potential Hy’s Law cases and Hy’s Law cases. It is not intended to be a comprehensive 
guide to the management of elevated liver biochemistries. Specific guidance on managing 
liver abnormalities can be found in the Toxicity Management Guidelines (see Section 3.1.3).
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets 
potential Hy’s Law criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of potential Hy’s Law and 
Hy’s Law events; this includes samples taken at scheduled study visits and other visits 
including all local laboratory evaluations even if collected outside of the study visits.
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible potential Hy’s Law events.
The investigator participates, together with MedImmune clinical project representatives, in 
review and assessment of cases meeting potential Hy’s Law criteria to agree whether Hy’s 
Law criteria are met. Hy’s Law criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than drug-induced liver injury (DILI) caused by the 
investigational product. 
The investigator is responsible for recording data pertaining to potential Hy’s Law/Hy’s Law 
cases and for reporting AEs and SAEs according to the outcome of the review and assessment 
in line with standard safety reporting processes.
D 2
Definitions
D 2.1
Potential Hy’s Law
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point during the study 
following the start of investigational product irrespective of an increase in ALP.
D 2.2
Hy’s Law
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than 
the investigational product, can be found to explain the combination of increases; eg, elevated 
ALP indicating cholestasis, viral hepatitis, or another drug.


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For potential Hy’s Law and Hy’s Law, the elevation in transaminases must precede or be 
coincident with (ie, on the same day) the elevation in TBL, but there is no specified timeframe 
within which the elevations in transaminases and TBL must occur.
D 3
Identification of Potential Hy’s Law Cases
In order to identify cases of potential Hy’s Law, it is important to perform a comprehensive
review of laboratory data for any subject who meets any of the following identification criteria 
in isolation or in combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
The investigator will, without delay, review each new laboratory report and if the 
identification criteria are met will:

Notify the sponsor study representative

Determine whether the subject meets potential Hy’s Law criteria (see Section D 2) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory eCRF
D 4
Follow-up
D 4.1
Potential Hy’s Law Criteria Not Met
If the subject does not meet potential Hy’s Law criteria the investigator will:

Inform the study representative that the subject has not met potential Hy’s Law criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the study protocol.
D 4.2
Potential Hy’s Law Criteria Met
If the subject does meet potential Hy’s Law criteria the investigator will:

Notify the sponsor study representative who will then inform the study team

Within 1 day of potential Hy’s Law criteria being met, the investigator will report the 
case as an SAE of Potential Hy’s Law; serious criteria ‘Important medical event’ and 
causality assessment ‘yes/related’ according to clinical study protocol process for SAE 
reporting


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The medical monitor contacts the investigator, to provide guidance, discuss and agree on an 
approach for the study subjects’ follow-up (including further laboratory testing) and the 
continuous review of data. 
Subsequent to this contact the investigator will:

Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated. 
Complete follow-up SAE Form as required.

Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the medical monitor. 

Complete the relevant Case Report Form (CRF) Modules as information becomes 
available
D 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where potential Hy’s Law 
criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the medical 
monitor will contact the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting potential Hy’s Law criteria other than DILI 
caused by the investigational product, to ensure timely analysis and reporting to health author-
ities per local requirements from the date potential Hy’s Law criteria were met. The medical 
monitor and global safety physician will also be involved in this review together with other
subject matter experts as appropriate.
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for an SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE, update the previously submitted potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the sponsor’s standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the investigational product:


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
Send the updated SAE (report term ‘Hy’s Law’) according to the sponsor’s standard 
processes.

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

As there is no alternative explanation for the Hy’s Law case, a causality assessment 
of ‘related’ should be assigned
If, there is an unavoidable delay of over 15 calendar days in obtaining the information neces-
sary to assess whether or not the case meets the criteria for Hy’s Law, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provide any further update to the previously submitted SAE of Potential Hy’s Law (report 
term now ‘Hy’s Law case’), ensuring causality assessment are related to the 
investigational product and seriousness criteria is medically important, according to the 
clinical study protocol process for SAE reporting

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether Hy’s Law criteria are still met. Update the previously submitted potential Hy’s 
Law SAE report following clinical study protocol process for SAE reporting, according to 
the outcome of the review and amend the reported term if an alternative explanation for 
the liver biochemistry elevations is determined
D 6
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a subject meets potential Hy’s Law criteria on study treatment 
and has already met potential Hy’s Law criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
potential Hy’s Law is based on the nature of the alternative cause identified for the previous 
occurrence. 
The investigator should determine the cause for the previous occurrence of potential Hy’s Law 
criteria being met and answer the following question:

Was the alternative cause for the previous occurrence of potential Hy’s Law criteria being 
met found to be the disease under study eg, chronic or progressing malignant disease, 
severe infection, or liver disease?
If No: follow the process described in Section D 4.2, for reporting potential Hy’s Law as an 
SAE.


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If Yes:
Determine if there has been a significant change in the subject’s condition compared with 
when potential Hy’s Law criteria were previously met:

If there is no significant change no action is required

If there is a significant change follow the process described in Section D 4.2, for reporting 
potential Hy’s Law as an SAE
A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in combina-
tion, or a clinically relevant change in associated symptoms. The determination of whether 
there has been a significant change will be at the discretion of the investigator; this may be in 
consultation with the medical monitor if there is any uncertainty.
D 7
Laboratory Tests
To evaluate the underlying etiology of potential Hy’s Law cases, relevant laboratory tests will 
be performed as outlined in Section 4.3.3. Additional laboratory assessments may be per-
formed as clinically indicated.


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Appendix E
Genetic Research
Rationale and Objectives
MedImmune intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, treat-
ments or medications. 
In addition, collection of DNA samples from populations with well described clinical charac-
teristics may lead to improvements in the design and interpretation of clinical trials and, possi-
bly, to genetically guided treatment strategies.
Genetic Research Plan and Procedures
Selection of Genetic Research Population
Study Selection Record
All subjects will be asked to participate in this genetic research. Participation is voluntary and 
if a subject declines to participate there will be no penalty or loss of benefit. The subject will 
not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria described 
in the main body of the Clinical Study Protocol and:

Provide informed consent for the genetic sampling and analyses.
Exclusion Criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection
Discontinuation of Subjects from This Genetic Research
Specific reasons for discontinuing a subject from this genetic research are:
Withdrawal of consent for genetic research: Subjects may withdraw from this genetic research 
at any time, independent of any decision concerning participation in other aspects of the main 
study. Voluntary discontinuation will not prejudice further treatment. Procedures for with-
drawal of informed consent are outlined in Section 4.1.8 of the protocol.


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Collection of Samples for Genetic Research
The blood sample for genetic research will be obtained from the subjects at screening. 
Although DNA is stable, early sample collection is preferred to avoid introducing bias through 
excluding subjects who may withdraw due to an AE, such subjects would be important to 
include in any genetic analysis. If for any reason the sample is not drawn at screening, it may 
be taken at any visit until the last study visit. Only one sample should be collected per subject 
for genetics during the study. Samples will be collected, labelled, stored and shipped as 
detailed in the Laboratory Manual.
Coding and Storage of DNA Samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality. Samples will be stored for a maximum of 
15 years or as per local regulations, from the date of last subject last visit, after which they 
will be destroyed. DNA is a finite resource that is used up during analyses. Samples will be 
stored and used until no further analyses are possible or the maximum storage time has been 
reached.
An additional second code will be assigned to the blood sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable by the second, unique number only. This number is used to identify the sample 
and corresponding data at the MedImmune genetics laboratories, or at the designated 
organization. No personal details identifying the individual will be available to any person 
(MedImmune employee or designated organizations working with the DNA).
The link between the subject enrollment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at MedImmune or 
designated organizations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit 
and to trace samples for destruction in the case of withdrawal of consent.
Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 7 of the protocol.
Informed Consent
The genetic component of this study is optional, and the subject may participate in other 
components of the main study without participating in the genetic component. To participate 
in the genetic component of the study the subject must sign and date both the consent form for 
the main study and the genetic component of the study. Copies of both signed and dated 
consent forms must be given to the subject and the originals filed at the study center. The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 


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subject understands that they may freely discontinue from the genetic aspect of the study at 
any time.
Subject Data Protection
MedImmune will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, or their general physician unless required to do so by 
law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, a MedImmune Physician or an investigator might know a subject’s 
identity and also have access to his or her genetic data. Also, Regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate.
Data Management
Any genotype data generated in this study will be stored at a secure system at MedImmune 
and/or designated organizations to analyze the samples.
The results from this genetic research may be reported in a separate report from the CSR or 
published in scientific journals.
MedImmune and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organizations or health insurance companies. This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease. The researchers can 
only use this information for health-related research purposes. Researchers may see summary 
results, but they will not be able to see individual subject data or any personal identifiers. 
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical Methods and Determination of Sample Size
The number of subjects who will agree to participate in the genetic research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A Statistical 
Analysis Plan will be prepared where appropriate.


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Appendix F
Response Evaluation Criteria in Solid Tumors Version 1.1 
F 1
Measurability of Tumor Lesions
Tumor lesions will be categorized as follows:

Measurable Lesions - Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 

10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the 
slice thickness and a minimum of 10 mm). 

10 mm caliper measurement by clinical examination (when superficial).

Malignant lymph nodes are considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).

Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions (or 
sites of disease), including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis). Lesions considered truly nonmeasurable 
include the following: leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.

Target Lesions - At baseline, all lesions up to a maximum of 5 lesions total (and a 
maximum of 2 lesions per organ) representative of all involved organs should be 
identified as target lesions. 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.

Non-target Lesions - It is possible to record multiple non-target lesions involving the 
same organ as a single item (eg, “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”). 

New Lesions - Though only certain new lesion measurements will be included in the 
tumor burden, all new lesions that can be accurately measured should be recorded. Up to 
5 additional target lesions (maximum of 2 additional lesions per organ) may be added to 
the tumor burden at each postbaseline assessment to facilitate the exploratory iRECIST 
analysis. Other new lesions will be included into the non-tumor burden.


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F 2
RECIST v1.1 Response Criteria
Evaluation of Target Lesions

CR - Disappearance of all target lesions. Any pathological lymph nodes (whether target 
or non-target) must have reduction in short axis to < 10 mm (the sum may not be “0” if 
there are target nodes). 

PR - At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters.

PD - At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on study). 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered PD.)

SD - Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum of diameters while on study.
Evaluation of Non-target Lesions

CR - Disappearance of all non-target lesions and normalization of tumor marker level. 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 

Non-CR/Non-PD - Persistence of 1 or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.

PD - Unequivocal progression of existing non-target lesions will be defined as the overall 
level of substantial worsening in non-target disease such that, even in presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy (see Section 4.1.6). In the absence of measurable disease, 
change in non-measurable disease comparable in magnitude to the increase would be 
required to declare PD for measurable disease. Examples include an increase in a pleural 
effusion from ‘trace’ to ‘large,’ an increase in lymphangitic disease from localized to 
widespread.
Appearance of New Lesions
The appearance of new lesions is considered PD according to RECIST v1.1. Considering the 
unique response kinetics that have been observed with immunotherapy, new lesions can 
nonetheless derive clinical benefit.
Evaluation of Overall Response
For the overall response based on RECIST v1.1, confirmation of CR and PR is required by a 
repeat, consecutive assessment no less than 4 weeks from the date of first documentation. If a 
subject discontinues the study due to PD and begins another treatment, a confirmatory scan is 
not required.


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Table F1 provides overall responses for all possible combinations of tumor responses in target 
and non-target lesions with or without the appearance of new lesions.
Table F1
Evaluation of Overall Response Using RECIST v1.1
Target Lesions
Non-target Lesions
New Lesions
Overall Response
Complete response
Complete response (or no non-
target lesion)
No
Complete response
No target lesion a 
Complete response
No
Complete response
Complete response
Not evaluable b
No
Partial response
Complete response
Non-complete response /
non-progressive disease
No
Partial response
Partial response
Non-progressive disease and
not evaluable (or no non-target 
lesion) b
No
Partial response
Stable disease
Non-progressive disease and
not evaluable (or no non-target 
lesion) b
No
Stable disease
Not all evaluated
Non-progressive disease
No
Not evaluable
No target lesion a
Not all evaluated
No
Not evaluable
No target lesion a
Non-complete response /
non-progressive disease
No
Non-complete response /
non-progressive disease
Progressive disease
Any
Yes/No
Progressive disease
Any
Progressive disease
Yes/No
Progressive disease
Any
Any
Yes
Progressive disease
No target lesion a
Unequivocal progressive disease
Yes/No
Progressive disease
No target lesion a
Any
Yes
Progressive disease
RECIST v1.1 = Response Evaluated Criteria in Solid Tumors version 1.1.
a
Defined as no target lesion at baseline.
b
Not evaluable is defined as either when no or only a subset of lesion measurements are made at an 
assessment.
Reference: Eisenhauer et al, 2009






SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d9108c00001-csp-amendment-4
Document Title:
d9108c00001-csp-amendment-4(COAST)
Document ID:
Doc ID-004111051
Version Label:
2.0 CURRENT LATEST APPROVED
Server Date
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Meaning of Signature
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Content Approval
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Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
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SAP_003.pdf: 
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 Statistical Analysis Plan for Protocol D9108C00001 
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04SEP2023; Final version 5.0 
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Statistical Analysis Plan 
 
A Phase 2, Open-label, Multicenter, Randomized, Multidrug Platform Study of 
Durvalumab (MEDI4736) Alone or in Combination with Novel Agents in Subjects with 
Locally Advanced, Unresectable, Stage III Non-small Cell Lung Cancer (COAST) 
Protocol Number: D9108C00001 
 
 
           


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TABLE OF CONTENTS 
1 
INTRODUCTION .............................................................................................................6 
2 
STUDY OVERVIEW ........................................................................................................6 
2.1 
Study Objectives ...................................................................................................6 
2.1.1Primary Study Objective(s) ..........................................................................6 
2.1.2Secondary Study Objectives .........................................................................6 
2.1.3Exploratory Study Objectives .......................................................................7 
2.2 
Study Design .........................................................................................................7 
2.3 
Treatment Assignment and Blinding ....................................................................8 
2.4 
Sample Size...........................................................................................................9 
3 
STATISTICAL METHODS ............................................................................................10 
3.1 
General Considerations .......................................................................................10 
3.2 
Analysis Populations...........................................................................................10 
3.3 
Study Subjects.....................................................................................................11 
3.3.1Subject Disposition and Completion Status ...............................................11 
3.3.2Demographics and Baseline Characteristics ...............................................11 
3.3.3Study Drug Exposure ..................................................................................12 
3.3.4Concomitant Medications ...........................................................................12 
3.3.5Protocol Deviations.....................................................................................13 
3.4 
Efficacy Analyses ...............................................................................................13 
3.4.1Primary Efficacy Endpoint(s) and Analyses ...............................................13 
3.4.1.1 
Primary Efficacy Endpoint(s) and Analysis ...............13 
3.4.1.2 
Additional Analyses of the Primary Efficacy 
Endpoint(s) .................................................................13 
3.4.2Secondary Efficacy Endpoint(s) and Analyses ...........................................14 
3.4.3Handling of Dropouts and Missing Data ....................................................20 
3.4.4Subgroup Analyses .....................................................................................20 
3.4.5Other Efficacy Analyses .............................................................................20 
3.5 
Pharmacodynamic Endpoint(s) and Analyses ....................................................21 
3.6 
Safety Analyses...................................................................................................21 
3.6.1Adverse Events and Serious Adverse Events .............................................21 
3.6.2Adverse Events of Special/Potential Interest ..............................................22 
3.6.3Deaths and Treatment Discontinuations due to Adverse Events ................22 
3.6.4Clinical Laboratory Evaluation ...................................................................22 
3.6.5Other Safety Evaluations ............................................................................24 
3.6.5.1 
Vital Signs ..................................................................24 
3.6.5.2 
Electrocardiogram ......................................................24 


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3.6.5.3 
Eastern Cooperative Oncology Group Performance 
Status ..........................................................................24 
3.6.5.4 
Physical Examinations ...............................................24 
3.6.6Subgroup Analyses .....................................................................................24 
3.7 
Immunogenicity ..................................................................................................25 
3.8 
Pharmacokinetics ................................................................................................25 
4 
INTERIM ANALYSIS ....................................................................................................25 
5 
REFERENCES ................................................................................................................28 
6 
VERSION HISTORY ......................................................................................................28 
7 
APPENDIX ...................................................................................................................31 
7.1 
Derivation of RECIST v1.1 Disease Assessment Overall Response ..................31 
7.1.1Target Lesion Response ..............................................................................31 
7.1.2Non-Target Lesion Response......................................................................32 
7.1.3Disease Assessment Overall Response per RECIST v1.1 ..........................34 
7.1.4Locoregional therapy ..................................................................................35 
7.1.5Assignment of Dates of Disease Progression or Disease Response ...........36 
7.2 
Efficacy Criteria of Making an Internal Go Decision at an Interim Analysis ....36 
 
LIST OF TABLES 
Table 2.4-1 
Estimated Differences in ORR Between Experimental and Control 
Arm of 60 Subjects Each .......................................................................9 
Table 3.2-1 
Analysis Populations ............................................................................10 
Table 3.4.1     
Summary of Censoring Guidelines for PFS.........................................17 
Table 4.1 
Criteria of Early No-Go Decisions Based on DCR at 16 Weeks .........27 
Table 4.2 
Operating Characteristics of Continuous Monitoring for No-Go ........27 
Table 7.2-1 
Criteria of Early Go Decisions Based on ORR ....................................37 
Table 7.2-2 
Operating Characteristics of Continuous Monitoring for Go ..............38 
 
 




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Abbreviation or 
Specialized Term 
Definition 
ORR 
objective response rate 
OS 
overall survival 
OS-12 (18, 24, 36) 
overall survival at 12 (18, 24, 36) months 
PD 
progressive disease 
PFS 
progression-free survival 
PFS-12 (18, 24, 36) 
progression-free survival at 12 (18, 24, 36) months 
PK 
pharmacokinetics 
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
stable disease 
SPP 
statistical programming plan 
TFL 
Tables, figures, listings  
 
 
TV 
target value 
 
CCI
CCI


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1 
INTRODUCTION 
This document describes the statistical analysis methodology for protocol D9108C00001, a 
multidrug platform study of Durvalumab (MEDI4736) alone or in combination with novel 
agents in subjects with locally advanced, unresectable, stage III non-small cell lung cancer 
(NSCLC). As background information, an overview of the study design is provided. The 
main portion of this document details the statistical summaries relating to each study 
objective and describes the general conventions and definitions that will be used. In addition, 
a set of table templates and specifications will be included in a statistical programming plan 
(SPP) to complement this document. 
2 
STUDY OVERVIEW 
2.1 
Study Objectives 
2.1.1 
Primary Study Objective(s) 
To compare the antitumor activity of durvalumab alone vs. durvalumab in combination with 
novel agents.  
2.1.2 
Secondary Study Objectives 
Safety: 
• To evaluate the safety and tolerability of durvalumab alone and durvalumab in 
combination with novel agents. 
Clinical activity: 
• To further compare the efficacy of durvalumab alone vs durvalumab in combination 
with novel agents. 
Pharmacokinetics (PK): 
• To describe the PK of durvalumab alone and durvalumab in combination with novel 
agents. 
• To describe the PK of novel agents in combination with durvalumab. 
Immunogenicity: 


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• To assess the immunogenicity of durvalumab alone or in combination with novel 
agents. 
• To assess the immunogenicity of novel biologic agents in combination with 
durvalumab. 
2.1.3 
Exploratory Study Objectives 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2 
Study Design 
COAST is a Phase 2, open-label, multicenter, randomized, multidrug platform study of 
durvalumab alone or in combination with novel agents in subjects with locally advanced, 
unresectable, Stage III NSCLC.  
The study will evaluate the clinical activity and safety of durvalumab alone or in combination 
with novel agents in subjects with Stage III NSCLC who have not progressed following 
definitive concurrent chemoradiotherapy (cCRT) (Figure 1 in protocol). Subjects will be 
CCI


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randomized into the study and initiate study treatment within 42 days from the last session of 
cCRT. Up to approximately 80 sites globally will participate in this study. 
Subjects may be treated for up to 12 months. Study treatment will be discontinued upon 
confirmed disease progression, unacceptable toxicity, or other reasons, e.g., subject decision 
or noncompliance with study procedures. Overall, all subjects continuing in the study must 
adhere to the study procedures for up to 5 years (from randomization) provided they achieve 
disease control (DC) and remain disease free.  
After completing the 5-year post-randomization study period, all subjects included into any 
treatment arm may be contacted annually for survival until 5 years after the final subject is 
randomized into the study or until the sponsor stops the study, whichever occurs first. The 
platform nature of the study allows an experimental arm to be permanently closed while the 
overall COAST study remains open. 
New durvalumab combination experimental arms may be added based on emerging non-
clinical and clinical data via protocol amendment. Interim futility analyses will be performed 
using Bayesian predictive probability. 
Details about treatment regimen can be found in Section 3.1.2 of the protocol. 
2.3 
Treatment Assignment and Blinding 
Treatment Assignment 
An interactive voice/web response system (IxRS) will be used to assign investigational 
product (IP) kit numbers to each subject who meets the eligibility criteria. A randomization 
method with dynamically changing randomization ratios will be employed to account for 
fluctuation in the number of treatment arms open for enrollment over the course of the study. 
The randomization will be stratified by histology (adenocarcinoma vs non-adenocarcinoma) 
and will use an equal ratio to all study treatment arms open for enrollment (e.g., if 
experimental arms are opened sequentially, an experimental arm is added/closed, or 
enrollment in an experimental arm is suspended). Additionally, the following considerations 
regarding randomization will apply: 
• If there is no experimental arm open for enrollment, then enrollment will be paused. 
Any subject who had consented previously and was in screening when the 
experimental arm(s) was closed due to safety concerns may be allowed to enter into 
the study but must be allocated to the control arm.  


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• Once the control arm enrolls 60 subjects, a subsequent randomization scheme may be 
initiated to optimize the number of subjects allocated to control arm.  
• At any point during the study, the control arm will have no less than a 33% chance to 
be randomized in comparison to the active experimental arm that has the lowest 
randomization ratio in the study.  
Blinding  
The study is not blinded. 
2.4 
Sample Size 
Sixty subjects will be enrolled in each of the combination therapy experimental arms and 
more than 60 subjects will be enrolled in the durvalumab control arm dependent upon the 
length of the study. The sample size of 60 subjects per experimental arm is not designed to 
make explicit power and Type I error considerations for a hypothesis test. It is primarily 
chosen to obtain a preliminary assessment of antitumor activity with a certain degree of 
precision. 
Table 2.4-1 shows estimated differences in objective response rate (ORR) between an 
experimental arm and control arm along with 2-sided 95% exact CIs with a sample size of 60 
subjects each. Sixty subjects per treatment arm provides a 95% CI with reasonable width 
(approximately ± 18%) for the estimated ORR difference between a durvalumab combination 
experimental arm and the durvalumab control arm. For a 20% increase in ORR in any 
durvalumab combination experimental arm over durvalumab control arm (50% vs 30%, 
respectively), the lower limit of the 95% CI for the difference between these arms is 1%, 
which is greater than 0%, suggesting that the durvalumab combination experimental arm will 
have a higher ORR than the durvalumab control arm with 95% confidence. 
Table 2.4-1 
Estimated Differences in ORR Between Experimental and 
Control Arm of 60 Subjects Each  
Number of Responders (ORR) 
Difference (%) in ORR 
(2-sided 95% Exact Confidence Interval) 
Experimental Arm 
(n = 60) 
Control Arm 
(n = 60) 
24 (40%) 
18 (30%) 
10% (-9%, 28%) 
27 (45%) 
18 (30%) 
15% (-4%, 33%) 
30 (50%) 
18 (30%) 
20% (1%, 38%) 
33 (55%) 
18 (30%) 
25% (6%, 42%) 
ORR = objective response rate. 
 


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3 
STATISTICAL METHODS 
3.1 
General Considerations 
Tabular summaries will be presented by treatment group. Categorical data will be 
summarized by frequency distribution (number and percentage of subjects falling within each 
category). Continuous variables will be summarized by descriptive statistics including N, 
mean, standard deviation, median, and range (minimum and maximum). All available data 
will be used, and thus missing data will not be imputed, unless otherwise specified. In 
general, subjects with missing data for a parameter will be excluded from the summary of 
this parameter. Tables will be supported by data listings showing the original data forming 
the basis for the summaries. Data listings will be sorted by treatment group, subject number 
and date collected where applicable. 
Unless stated otherwise, two-sided confidence intervals will be produced at 95%. Baseline 
values will be defined as the last valid assessment prior to the first administration of IP. 
Assessments on the day of the first dose where neither time nor a nominal pre-dose indicator 
are captured are considered prior to the first dose if such procedures are required by the 
protocol to be conducted before the first dose. 
Data analyses will be conducted using the SAS® System (SAS Institute, Inc., Cary, NC, 
USA) Version 9.4 or above, unless otherwise specified. All analysis outputs will be validated 
according to MedImmune SAS programming standards and MedImmune validation 
procedures. 
3.2 
Analysis Populations 
The analysis populations are defined in Table 3.2-1. 
Table 3.2-1 
Analysis Populations 
Population 
Description 
Intent-to-treat 
(ITT) Population 
The ITT population includes subjects who are randomized. Subjects will be analyzed 
according to their randomized treatment group.  
As-treated 
Population 
The As-treated population includes all subjects who receive any IP. Subjects will be 
analyzed according to the treatment they really receive. 
Response-
evaluable 
Population 
The Response-evaluable population includes subjects from the As-treated population who 
have a baseline disease assessment (DA), have the opportunity to be followed for at least 
16 weeks at the time of the DCO (i.e., dosed at least 16 weeks prior to the time of the 
DCO), and either has at least one post-baseline disease assessment and/or discontinued 
treatment due to death or disease progression. The response-evaluable population will not 
be used for the final analysis. 


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Table 3.2-1 
Analysis Populations 
Population 
Description 
PK-evaluable 
Population 
The PK-evaluable population includes subjects from the As-treated population who have 
a non-missing baseline PK concentration and at least one non-missing post-baseline PK 
concentration. 
IP = investigational product; PK = pharmacokinetic. 
 
All baseline and efficacy parameters will be summarized based on the ITT population as 
primary analysis. The efficacy parameters may be summarized based on response-evaluable 
population as supportive analysis. Safety parameters will be summarized based on the As-
treated population as primary analysis. The analysis of pharmacokinetics will be based on the 
PK-evaluable population.  
3.3 
Study Subjects 
3.3.1 
Subject Disposition and Completion Status 
Subject disposition and completion status will be summarized for all subjects screened, and 
percentages will be based on subjects randomized and treated. In addition, disposition of 
subjects throughout the study with respect to discontinuation of treatment and end of study 
status including reasons will be provided. Summaries of the number and percentage of 
subjects entered at each site will be provided.  
The mortality summary will include subjects with end of study status of death, as well as 
cause of death (toxicity related to IP or disease under investigation, or other). 
Duration of follow-up will also be summarized. 
A listing of global/country study disruptions (impacting visits, concomitant medications 
and/or exposure) will be provided. 
 
3.3.2 
Demographics and Baseline Characteristics 
Demographics and baseline disease characteristics will be summarized for the ITT 
population. Demographic information related to sex, age, race, weight, height, and body mass 
index (BMI) will be presented by treatment group and for all subjects combined. A summary 
of smoking history will also be included.Tumor history including histology, stage, and 
pertinent biomarker results at the time of initial diagnosis and at study entry will be 
summarized. Baseline tumor characteristics including sum of target lesions diameters and 
ECOG performance status will also be summarized. 


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The summary for prior anticancer treatment will include the number and percent of subjects 
by treatment category (systemic therapy, radiation, cancer related surgery, other), number of 
prior systemic regimens and best response (complete response, partial response, stable 
disease, progressive disease, not evaluable, not applicable, per RECIST v1.1) to the most 
recent line of therapy, type of platinum agent (cisplatin, carboplatin, cisplatin and 
carboplatin, derived using the WHO Drug dictionary coded terms), time from last radiation 
to study drug initiation/randomization, and total amount of radiation received.  
3.3.3 
Study Drug Exposure 
• Treatment exposure will be summarized for the As-treated population. Duration of 
exposure to IP(s) in weeks and cycles will be summarized by descriptive statistics and 
by frequency. The duration of exposure for each IP is defined as below. last dose date 
plus the dosing interval (days) minus first dose date for subjects who completed 
treatment.  
• minimum of (date of death plus 1 day, last dose date plus the dosing interval) minus 
first dose date for subjects who discontinued treatment. 
Dose intensity and relative dose intensity of IP(s) will be summarized by descriptive 
statistics. The relative dose intensity is a percent of total actual dose that a subject received 
during corresponding study treatment period versus the total intended dose for the same 
study treatment period according to the study protocol. The details of the dose intensity 
calculation will be provided in the SPP as part of the standard exposure TFL templates. 
Dosing deviations for IP(s), per the CRF, will be summarized with reasons for deviations for 
the following categories: delays, omissions, and interruptions. Duration of dosing delays will 
be derived where a delay is flagged on the CRF, based on the scheduled dosing dates and the 
visit window. The number of subjects with dosing delays and total dose delays will be 
summarized.  
The use of subsequent anticancer treatment after the discontinuation of study treatment will 
be summarized by the type of subsequent anticancer treatment if data allow. 
3.3.4 
Concomitant Medications 
The number and percentage of subjects who took concomitant medications will be 
summarized by the ATC classification and the generic name coded by WHO Drug 
Dictionary Global B3 version March 2022 for the ITT Population. Concomitant medications 
will include all concomitant medications taken on or after the date of first dose of any IP or 


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any concomitant medication started prior to the first dose of study treatment that continued 
beyond the date of first dose of any IP. 
3.3.5 
Protocol Deviations 
The incidence of important protocol deviations will be summarized by deviation categories. 
The COVID-19 related IPDs will also be summarized. A listing will be provided with 
protocol deviation details. None of the deviations will lead to subjects being excluded from 
any analysis populations described in Section 3.2, unless otherwise specified. If a deviation is 
serious enough to have a potential impact on the primary analysis, sensitivity analyses may 
be performed.  
3.4 
Efficacy Analyses 
3.4.1 
Primary Efficacy Endpoint(s) and Analyses 
3.4.1.1 
Primary Efficacy Endpoint(s) and Analysis 
The primary efficacy endpoint is objective response (OR) per Response Evaluation Criteria 
in Solid Tumors version 1.1 (RECIST v1.1). ORR is defined as the proportion of subjects 
with a best overall response of confirmed CR or confirmed PR that occur prior to disease 
progression, and/or prior to the initiation of subsequent anticancer treatment. Confirmation of 
response requirements are defined in Section 3.4.2.1 for best overall response. The primary 
analysis of ORR will be based on the ITT population. An estimate of the difference in ORR 
as well as its 2-sided 95% exact CI between each experimental arm and control arm will be 
reported. The rates between each experimental arm and control arm will be tested for 
significance with a Cochran–Mantel–Haenszel test, stratified by histology (adenocarcinoma 
or non-adenocarcinoma). Subjects that have missing overall response assessments will be 
considered as non-responders, and will therefore be counted in the denominator, but not in 
the numerator of ORR. Primary efficacy analysis will include control subjects that are 
concurrently enrolled with each experimental arm.   
 
3.4.1.2 
Additional Analyses of the Primary Efficacy Endpoint(s) 
The secondary analysis of ORR may be based on the Response-evaluable population, and/or 
Fisher’s exact test. Sensitivity analyses may be provided based on a comparison between 
each experimental arm and all control subjects at the time of analysis.  


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3.4.2 
Secondary Efficacy Endpoint(s) and Analyses 
The secondary efficacy endpoints include disease control (DC); duration of response (DoR); 
progression-free survival (PFS); progression-free survival at 12 months (PFS-12) and overall 
survival (OS). The efficacy endpoints will be summarized based on the ITT population and 
may be based on the Response-evaluable population as a supportive analysis. For analyses 
that involve an arm comparison between an experimental arm and control arm, only control 
subjects that are concurrently enrolled with the experimental arm will be included.  
Efficacy analyses, except for OS, will be based on an application of Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 (Eisenhauer et al, 2009) to investigator assessed 
tumor measurements.  
Programmatic derivation guidance used for the application of RECIST v1.1 is provided in 
Appendix 7.1. RECIST v1.1 guidelines will be used to determine disease response. 
3.4.2.1 
Best Overall Response 
Best overall response (BOR) will be based on all post-baseline disease assessments that 
occur prior to disease progression, and/or prior to the initiation of subsequent anticancer 
treatment. BOR will be summarized with the number and percentage of subjects for the 
following categories: complete response (CR); partial response (PR); stable disease (SD); 
progressive disease (PD); and non-evaluable (NE). At least 7 weeks (8 weeks minus 1 week 
to allow for the protocol-defined disease assessment window) from randomization of IP must 
elapse without a subsequently radiological disease progression to assign a best overall 
response of SD.  
Confirmation of CR and PR is required and must occur at least 4 weeks after initial 
documentation of CR or PR. If CR is pending confirmation and is designated at an 
assessment followed by 1 or more NE assessments, and/or PR assessments such that 1) the 
Target Lesion Response is CR and the Non-Target Lesion Response is NE, or 2) the Target 
Lesion Response is PR due solely to an increase in one or more lymph nodes to a size ≥ 10 
mm and the Non-Target Lesion Response is either CR or NE, CR may be confirmed 
thereafter. Similarly, if a PR is pending confirmation and is designated at an assessment 
followed by 1 or more NE and/or SD assessments, PR may be confirmed thereafter.  
In general, subjects not classifiable under the RECIST v1.1 response categories due to 
insufficient data or early death will be classified as NE for BOR but will be counted in the 
denominator of all response rate calculations. This generalization includes if a subject has 
missing lesion data at baseline. In this scenario, the subject will be classified as NE for BOR. 


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If a subject is missing lesion data at a disease assessment and yet PD criteria is met despite 
the missing data, the subject will be classified as PD. 
3.4.2.2 
Duration of Response 
Duration of response (DoR) is defined as the time from the first documentation of a 
subsequently confirmed OR until the first documentation of a disease progression or death 
due to any cause, whichever occurs first, regardless of whether the subject receives 
subsequent anticancer treatment prior to progression. Only subjects who have achieved OR 
(confirmed CR or confirmed PR) will be evaluated for DoR. DoR is defined in months as 
follows:   
DoR (months) = (Date of PD/death or censoring – Date of first confirmed disease response + 
1) / (365.25/12) 
The date of PD/death or censoring is the same as defined for PFS in Section 3.4.2.4. The 
median DoR and its 95% CI will be estimated using the Kaplan-Meier method.  
3.4.2.3 
Disease Control  
Disease control rate (DCR) is defined as the proportion of subjects with a BOR of confirmed 
CR, confirmed PR, or SD (maintained for ≥ 16 weeks). DCR will be estimated with a 95% 
CI using the exact probability method. An estimate of the difference in DCR between each 
experimental arm and control arm will be reported and tested for significance with the 
Cochran–Mantel–Haenszel test.  
3.4.2.4 
Progression-free Survival  
Progression-free survival (PFS) is defined as the time from randomization until the first 
documentation of a disease progression or death due to any cause, whichever occurs first, 
regardless of whether the subject receives subsequent anticancer treatment prior to 
progression. Subjects who have no documented progression and are still alive at the time of 
analysis will be censored at the time of the latest date of assessment from their last evaluable 
RECIST v1.1 assessment. PFS is defined in months as follows:   
PFS (months) = (Date of PD/death or censoring – Date of randomization + 1) / (365.25/12), 
The censoring guidance and the date of PD/death or censoring are given in the table below. 
The number and percentage of subjects experiencing a PFS event and Kaplan-Meier plots of 
PFS will be presented by treatment group. The median PFS and its 95% CI will be estimated 
using the Kaplan-Meier method. The proportion of subjects progression-free and alive at 12 


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months (PFS-12) and associated 95% CI will be estimated using the Kaplan-Meier method. 
Additional PFS landmarks to be included in the final analysis are PFS-18, PFS-24, and PFS-
36. 
The difference in PFS between each experimental arm and control arm will be tested for 
significance by using a stratified log-rank test on histology (adenocarcinoma vs non-
adenocarcinoma). The log-rank test will be carried out with the Breslow method for handling 
ties. The hazard ratio (HR) (experimental vs. control) with two-sided 95% CI will be 
estimated by stratified Cox regression model on histology with ties handled by the Efron 
method (Efron et al, 1977).  
The comparison of PFS-X (X=12, 18, 24, 36 months) between each experimental arm and 
control arm will be performed by normal approximation under complementary loglog 
(cloglog) transformation (Klein et al, 2007). The test statistic shown below asymptotically 
follows a chi-square distribution with one degree of freedom under the null hypothesis 
𝐻0: 𝑆1(𝑡) = 𝑆2(𝑡). 
𝑋2 =
(log (−log (𝑆̂1(𝑡))) −log (−log (𝑆̂2(𝑡))))
2
𝜎̂1(𝑡)2/ (log (𝑆̂1(𝑡)))
2
+ 𝜎̂2(𝑡)2/ (log (𝑆̂2(𝑡)))
2 
where 
• 
𝑆̂𝑘(𝑡), with 𝑘= 1, 2 is the Kaplan-Meier estimate of the survival function for the kth 
treatment group 
• 𝜎̂𝑘(𝑡)2 = ∑
𝑑𝑘𝑖
𝑛𝑘𝑖(𝑛𝑘𝑖−𝑑𝑘𝑖)
𝑡𝑘𝑖≤𝑡
  (Greenwood’s formula) is from the estimated variance 
𝑉̂(𝑆̂𝑘(𝑡)) = 𝑆̂𝑘(𝑡)2𝜎̂𝑘(𝑡)2 of the KM estimate 𝑆̂𝑘(𝑡) with 𝑘= 1, 2 
•  𝑑𝑘𝑖 refers to the number of events (i.e., deaths or disease progressions) at time 𝑡𝑘𝑖 
• 𝑛𝑘𝑖 refers to the number of subjects at risk at time 𝑡𝑘𝑖 
 
 


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Table 3.4.1     
Summary of Censoring Guidelines for PFS 
Situation 
Date of PD/Death or Censoring 
PFS Outcome 
Documented Progressive Disease (PD) or death  
 
Date of earliest sign of PD or death, 
whichever comes first 
Event (unless the 
censoring rule 
specified below) 
Death or PD immediately after ≥ 2 consecutive 
missed or non-evaluable disease assessments as 
per the protocol specified assessment schedule 
Date of last progression-free disease 
assessment prior to missed or non-
evaluable assessments, or 
randomization, whichever occurred last 
Censored 
No PD or death at time of analysis or lost to 
follow-up 
Date of last evaluable progression-free 
disease assessment 
Censored 
No tumor assessment at baseline and no evidence 
of PD at first post-baseline disease assessment 
OR 
No tumor assessment post-first dose, and no death 
prior to second scheduled post-baseline disease 
assessment 
Date of randomization  
Censored 
PD = progressive disease; PFS = progression-free survival. 
Subjects having missing lesion data at baseline or no disease assessments post-first dose of IP 
will have PFS censored at the date of randomization unless the subject dies prior to the 
second scheduled post-baseline disease assessment in which case the death date will qualify 
as a PFS event.  
If a subject has two or more consecutive completely missed or non-evaluable assessments 
followed immediately by death or an assessment showing radiologic disease progression, 
then the subject will be censored for PFS. PFS will be censored at the date of randomization 
or the last progression-free disease assessment prior to the missed or non-evaluable 
assessments, whichever occurred last.  
If a subject has two or more consecutively missed or non-evaluable assessments followed by 
an assessment showing no radiologic disease progression, then the assumption will be that 
the subject did not progress during the missed or non-evaluable assessments.  
The length of gap (in number of days) to determine two or more consecutive assessments is 
defined as the following: 
• 126 days during the first 12 months (A 8-week disease assessment interval plus a 7-
day window for each assessment). 


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• 182 days from month 12 to month 24 (A 12-week disease assessment interval plus a 
7-day window for each assessment). 
• 422 days after month 24 (A 6-month disease assessment interval plus a 4-week 
window for each assessment). 
Subjects remaining on study without radiologic disease progression or death at the time of 
analysis will be censored for PFS at the date of their last evaluable disease assessment.  
3.4.2.5 
Overall Survival 
Overall survival (OS) is defined as the time from randomization until death due to any cause. 
A subject alive at the end of study or lost to follow-up will be censored for OS at the last date 
when the subject was known to be alive. The last date for each individual subject is defined 
as the latest among the following dates recorded on the case report forms (CRFs): 
• AE start, stop, and change dates 
• Admission and discharge dates of hospitalization 
• Start date of protocol deviations 
• Study treatment date 
• Date of last contact, withdrawal consent, refuse to be followed up, or last known alive 
on end of treatment, end of study, and survival status/follow-up CRFs 
• Laboratory test dates including (but not limited to) hematology, chemistry, urinalysis, 
coagulation, tumor biopsy, immunoglobin, pharmacokinetics, pharmacodynamic 
biomarkers. 
• Disease assessment dates on RECIST CRF 
• Date of visit, vital signs, ECOG, electrocardiogram, and physical examination 
• Start and stop dates of alternative anticancer treatment 
• Start and end date of concomitant medication and surgical/medical procedure 
OS is defined in months as follows:   
OS (months) = (Date of death or censoring – Date of randomization + 1) / (365.25/12). 
The number and percentage of subjects experiencing an OS event and Kaplan-Meier plots of 
OS will be presented by treatment group. The median OS and its 95% CI will be estimated 
using the Kaplan-Meier method. The proportion of subjects alive at 12 months (OS-12) and 


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associated 95% CI will be estimated using the Kaplan-Meier method. Additional OS 
landmarks to be included in the final analysis are OS-18, OS-24, and OS-36. 
The difference in OS between groups will be tested for significance by using a stratified log-
rank test on histology (adenocarcinoma vs non-adenocarcinoma). The log-rank test will be 
carried out with the Breslow method for handling ties. The hazard ratios of each 
experimental arm vs. control arm with two-sided 95% CI will be estimated by a stratified 
Cox regression model on histology with ties handled by the Efron method (Efron et al, 1977).  
The comparison of OS-X (X=12, 18, 24, 36 months) between the 2 treatment arms will be 
performed by normal approximation under cloglog transformation (Klein et al, 2007), where 
the event is death. The test statistic is defined in Section 3.4.2.4. 
3.4.2.6 
Other Endpoints 
Time to Response 
Time to response (TTR) is defined as the time from randomization until the first 
documentation of a subsequently confirmed OR. Only subjects who have achieved OR 
(confirmed CR or confirmed PR) will be evaluated for TTR. TTR is defined in months as 
follows: 
TTR (months) = (Date of first confirmed disease response – Date of randomization + 1) / 
(365.25/12). 
The median TTR and its 95% CI will be assessed using the Kaplan-Meier method. The 
number of subjects with response at different disease assessment timepoints may be 
provided. 
Change from Baseline in Tumor Sizes 
The percent change from baseline in target lesion sum of diameters (longest for non-nodal 
lesions, short axis for nodal lesions) will be calculated at each evaluable post-baseline disease 
assessment (DA) # X (X = 1, 2, 3, etc.). The percent change from baseline in target lesion 
sum of diameters is defined as follows: 
%𝐶ℎ𝑔 𝑎𝑡 𝐷𝐴 #𝑋=  100 ×
∑
𝐷𝑖𝑎𝑚𝑒𝑡𝑒𝑟𝑠 𝑎𝑡 𝐷𝐴 #𝑋−∑
𝐷𝑖𝑎𝑚𝑒𝑡𝑒𝑟𝑠 𝑎𝑡 𝐷𝐴 𝑎𝑡 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
∑
𝐷𝑖𝑎𝑚𝑒𝑡𝑒𝑟𝑠 𝑎𝑡 𝐷𝐴 𝑎𝑡 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
 


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The percent change from baseline in target lesion sum of diameters will be presented by 
subject using spider plots. The best percent change from baseline in target lesion sum of 
diameters is defined as the largest reduction or smallest increase (in the case where a 
reduction does not occur) from baseline observed over all post-baseline disease assessments 
until disease progression. The best percent change from baseline will be presented using 
waterfall plots. Target lesion measurements and sum of diameters will be listed by disease 
assessment and subject. 
3.4.3 
Handling of Dropouts and Missing Data 
In general, missing data are not imputed for statistical analysis. Guidance regarding the 
handling of dropouts, missing data, and censoring will apply uniformly to all efficacy 
analyses resulting from an application of RECIST v1.1 to investigator assessed tumor 
measurements. For investigator reported outcomes, analyses will present outcomes without 
consideration of missing data or censoring rules.  
3.4.4 
Subgroup Analyses 
To assess the consistency of treatment effects, the analyses of ORR and PFS will be 
performed by the following subgroups: 
• Age (< 70, ≥ 70 years) 
• Sex (Female, Male) 
• Race (Asian, non-Asian) 
• Histology (Squamous, non-Squamous) 
• Smoking status (Smoker, never smoker) 
• ECOG performance status at baseline (0, 1) 
• PD-L1 status (Positive, Low/Negative, Unknown) based on 1% and 25% cuts 
separately 
• Platinum agent (Cisplatin, Carboplatin) 
• Time from last radiation to randomization (<14 days, ≥14 days) 
• Disease stage at study entry (IIIA, IIIB/C) 
Forest plots will be provided for difference in ORR (confirmed/unconfirmed response 
and confirmed response, separately) and PFS hazard ratios. 
 
3.4.5 
Other Efficacy Analyses 
Confirmed/unconfirmed ORR will be reported along with the primary analysis of confirmed 
ORR. Analyses will be conducted in the same way as described in Section 3.4.1. 


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Similarly, confirmed/unconfirmed DCR, DoR and TTR will be reported, with analyses 
conducted in the same way as described in Section 3.4.2. 
The proportion of subjects progression-free and alive at 6 months (PFS-6) and 9 months 
(PFS-9) and the associated 95% CIs may be estimated using the Kaplan-Meier method. 
 
 
 
  
The number and percentage of subjects with distal metastasis at 6 months based on PET scan 
may be reported. 
3.5 
Pharmacodynamic Endpoint(s) and Analyses 
Exploratory analysis of pharmacodynamic endpoints may be described separately. 
 
3.6 
Safety Analyses 
All safety analyses will be performed based on the As-treated population, unless otherwise 
specified. Only post-baseline visits up to and including 90 days following the date of last 
dose of study medication will be considered in derivations. 
3.6.1 
Adverse Events and Serious Adverse Events 
Adverse events will be coded by Medical Dictionary for Regulatory Activities (MedDRA) 
version 26.0 and the type, incidence, CTCAE grade and relationship to study IP will be 
summarized. Specific adverse events will be counted once for each subject for calculating 
percentages. In addition, if the same adverse event occurs multiple times within a particular 
subject, the maximum CTCAE grade and level of relationship observed will be reported. If 
any associations of interest between adverse events and baseline characteristics are observed, 
additional stratified results may be presented.  
Treatment-emergent adverse events (TEAEs) are defined as events present at baseline that 
worsen in intensity after administration of study IP or events absent at baseline that emerge 
after administration of study IP. All TEAEs that occurred on and after first dose up to 90 
days after last dose of IP (any) will be summarized overall, as well as categorized by 
MedDRA System Organ Class and Preferred Term. In addition, all TEAEs with an onset date 
no more than 90 days after the last dose of IP (any) will be listed. 
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The AEs occurring from the signing of the informed consent and prior to the initiation of 
study IP will be listed.  
3.6.2 
Adverse Events of Special/Potential Interest 
An adverse event of special/potential interest (AESI/AEPI) is one of scientific and medical 
interest specific to understanding of the IP and may require close monitoring and rapid 
communication by the investigator to the sponsor. The AESI categories for each IP can be 
found in protocol Section 5.3. Other categories may be added, or existing terms may be 
modified, as necessary. The most recent version of the AESI/AEPI preferred terms list at 
clinical data lock will be used to identify and categorize AESI/AEPI. 
The AESIs/AEPIs, as applicable, will be summarized similarly as other AEs described in 
Section 3.6.1. 
Immune-mediated adverse events (imAEs) for durvalumab will be automatically adjudicated 
per the global imAE charter. The imAEs will be summarized, including separate summaries 
of the number and percentage of subjects with imAEs by category, by outcome, by maximum 
CTCAE grade and descriptive statistics of time to onset of imAE by AESI category. 
3.6.3 
Deaths and Treatment Discontinuations due to Adverse Events 
For those subjects who died due to one or multiple AEs, the AE(s) contributing to death will 
be summarized. 
Summaries will be provided for TEAEs resulting in permanent discontinuation of IP. 
Supporting listings will be provided for AEs resulting in death and AEs resulting in 
permanent discontinuation of IP. 
3.6.4 
Clinical Laboratory Evaluation 
Laboratory tests will be grouped according to chemistry, hematology, coagulation, and 
urinalysis. Listings will be provided for all laboratory results, including coagulation. For 
selected chemistry and hematology tests, the change in each laboratory parameter from 
baseline to each post-baseline scheduled visit will be summarized graphically. Descriptive 
statistics will be provided for the clinical laboratory results and changes from baseline by 
scheduled time of evaluation including minimum and maximum post-baseline values.  
Laboratory parameters will be assessed at baseline as well as throughout the study. 
Frequencies of worst observed grade 0-4 toxicity, as defined by the NCI CTCAE v5.0, will 
be presented for each laboratory parameter. The analysis will present the worst grade 


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observed and the rates of subjects with grade 3-4 toxicity. Additionally, 2-grade shifts from 
baseline to worst toxicity grade will be summarized for chemistry and hematology laboratory 
parameters.  Separate summaries indicating hyper- and hypo- directionality of change will be 
produced, where appropriate.  Shifts from baseline relative to the normal range (low, normal, 
high) will also be presented. 
Liver Function Parameters 
Subjects with elevated post-baseline alanine aminotransferase (ALT), aspartate 
aminotransferase (AST) or total bilirubin that fall into the following categories will be 
identified. The number and percentage of these subjects will be summarized. 
Liver Function Parameters 
Category 
ALT 
• 
≥ 3× – ≤ 5× ULN 
• 
> 5× – ≤ 8× ULN 
• 
> 8× – ≤ 10× ULN 
• 
> 10× – ≤ 20× ULN    
• 
> 20× ULN 
AST 
• 
≥ 3× – ≤ 5× ULN 
• 
> 5× – ≤ 8× ULN 
• 
> 8× – ≤ 10× ULN, 
• 
> 10× – ≤ 20× ULN    
• 
> 20× ULN 
Total bilirubin 
• 
≥ 2× – ≤ 3× ULN 
• 
> 3× – ≤ 5× ULN 
• 
> 5× ULN  
ALT or AST 
• 
≥ 3× – ≤ 5× ULN 
• 
> 5× – ≤ 8× ULN 
• 
> 8× – ≤ 10× ULN, 
• 
> 10× – ≤ 20× ULN    
• 
> 20× ULN 
Potential Hy’s law 
• 
(AST ≥ 3 × ULN or ALT ≥ 3 × ULN) and (Total 
Bilirubin ≥ 2×ULN)a 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of 
normal range. 
a: Total bilirubin ≥ 2× ULN is defined as at least one case of post-dose total bilirubin ≥ 2 x 
ULN occurred after ALT or AST ≥ 3 x ULN post treatment. 
 Subjects who meet the potential Hy’s law criteria will be listed. 
Assessment of Nephrotoxicity 


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Creatinine clearance rate (CCr) will be calculated using serum creatinine (SCr) in mg/dL and 
the Cockcroft-Gault formula to estimate glomerular filtration rate (GFR), defined as follows: 
 
CCr (mL/minute) = {((140 – age) × weight)/(72 × SCr)}(× 0.85, if female) 
 
A shift table from baseline to “worst-case” on treatment CCr value will be provided. Baseline 
and “worst-case” on treatment CCr value will be categorized as follows: 
• Normal: ≥ 90 mL/min  
• Mild Impairment: ≥ 60 − < 90 mL/min 
• Moderate Impairment: ≥ 30 − < 60 mL/min  
• Severe Impairment: ≥ 15 − < 30 mL/min  
• Kidney Failure: < 15 mL/min  
 
3.6.5 
Other Safety Evaluations 
3.6.5.1 
Vital Signs 
Vital signs will be assessed at baseline and throughout the study. Vital signs  will be 
summarized by study visit which will include descriptive statistics for the value of the 
parameters and the changes from baseline to post-baseline scheduled visits. Minimum and 
maximum post-baseline values will also be summarized.. 
3.6.5.2 
Electrocardiogram 
No electrocardiogram analyses are planned. ECGs were only collected prior to study 
treatment initiation. 
3.6.5.3 
Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group (ECOG) performance status will be assessed at 
baseline as well as throughout the study. ECOG will be summarized for baseline and the 
“worst” case including descriptive statistics for the value of the parameters and the shift table 
from baseline to the “worst” performance post-baseline. 
3.6.5.4 
Physical Examinations 
No physical examination analyses are planned. 
3.6.6 
Subgroup Analyses 
No subgroup analyses are planned. 


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3.7 
Immunogenicity 
Immunogenicity results will be summarized for the As-treated population. Number and 
percentage of subjects in the following categories will be provided. 
• ADA positive at baseline and/or post-baseline visits. 
• Persistent positive, defined as positive at ≥2 post-baseline assessments (with ≥16 
weeks between first and last positive) or positive at last post-baseline assessment. 
• Transient positive, defined as negative at last post-baseline assessment and positive at 
only one post-baseline assessment or at ≥2 post-baseline assessments (with <16 
weeks between first and last positive). 
• Treatment-boosted, defined as baseline positive ADA titer that was boosted to a 4-
fold or higher-level following drug administration. 
Similarly to safety analyses, only post-baseline visits up to and including 90 days following 
the date of last dose of study medication will be considered when deriving the categories. 
Study discontinuation blood samples will be summarized at the closest nominal time point 
that does not already have a value. All subjects with titer information will be shown in  data 
listings. 
3.8 
Pharmacokinetics 
For each treatment group in the PK-evaluable population, serum concentrations of the study 
drug will be summarized by visit/timepoint with descriptive statistics. Individual novel agent 
concentrations will be summarized similarly. Serum concentrations will be reported in 
ug/mL, and the lower limit of quantification (LLOQ) for each analyte will be defined in the 
SPP. The following statistics are presented: n, n below LLOQ, geometric mean, geometric 
coefficient of variation (%), arithmetic mean, standard deviation, coefficient of variation (%), 
median, minimum, and maximum. 
More details about calculations can be found in the SPP. All serum concentration data will be 
listed for each subject, by analyte.  
4 
INTERIM ANALYSIS 
Interim analyses comparing durvalumab in combination with novel agents to durvalumab 
alone will be performed in a continuous manner using a joint Bayesian predictive probability. 
Bayesian predictive probability has been used in the setting of single-arm trials with tumor 
response endpoints such as OR and allows for continuous assessments for early Go/No-Go 
decision making (Lee and Liu, 2008). A joint Bayesian predictive probability approach 


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allows for continuous assessments of the delta (Δ), or difference, of the DCRs between 
durvalumab/novel agent combinations and durvalumab alone (Pulkstenis et al., 2017).  
Interim analyses will begin after approximately 30 subjects in control arm (durvalumab 
alone) have been randomized and have reached the data cutoff criterion. The data cutoff 
criterion is defined as the opportunity to be followed for at least 16 weeks at the time of the 
data cutoff (i.e., dosed at least 16 weeks prior to the time of the data cutoff). The interim 
analysis will be based on the subset of the ITT Population that have satisfied the data cutoff 
criteria. Enrollment will not pause during the interim analysis before the decision is made. 
Following this initial interim analysis, subsequent interim analyses will be performed for 
each experimental arm regardless of whether it starts enrollment later than control arm. 
Specifically, an interim analysis will be performed once each experimental arm has 
approximately 30 ITT subjects reach the data cutoff criterion. For interim analyses that will 
lead to an early No-Go decision, a response is defined as either a confirmed or unconfirmed 
CR or PR as per RECIST v1.1. Only concurrent control subjects, i.e., enrolled during the 
same period as the experimental arm, will be included in interim analyses. A comparison of 
each experimental arm versus all control subjects may be included as a supportive analysis. 
The Target Value (TV) is set to demonstrate a 15% increase in ΔDCR at 16 weeks, where 
ΔDCR is the difference in DCR between an experimental arm and control arm. At final 
analysis, No-Go criteria will be met if the probability that the true ΔDCR exceeds the 
prespecified TV of 15% is less than 10% (i.e., No-Go: P [ΔDCR > TV] < 10%).  
Given the existing observed data during the continuous monitoring stage, the joint Bayesian 
predictive probability is obtained by calculating the probability of reaching a No-Go decision 
should the treatment groups be randomized and evaluated to the maximum planned final 
sample size of 60. Further randomization into both treatment groups will be terminated if No-
Go criteria are met.  
• Early No-Go is met if it is predicted that there is a high probability of reaching a No-
Go decision upon full randomization of 60 subjects given the existing observed data 
(i.e., predictive probability of a No-Go decision > 95%).  
Table 4.1 illustrates the sample algorithm to make an early No-Go decision based on DCR at 
16 weeks at the interim analysis when control arm and an experimental arm each have 30 
subjects.  


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SAP template version 3.0 
Table 4.1 
Criteria of Early No-Go Decisions Based on DCR at 
16 Weeks  
Number of Subjects with DCR at 16 weeks in 
Control Arm 
Number of Subjects with DCR at 16 weeks in 
Experimental Arm 
10 
≤ 7 
11 
≤ 8 
12 
≤ 8 
13 
≤ 9 
14 
≤ 10 
15 
≤ 11 
16 
≤ 12 
17 
≤ 13 
18 
≤ 14 
19 
≤ 15 
20 
≤ 16 
21 
≤ 17 
22 
≤ 19 
23 
≤ 20 
24 
≤ 21 
25 
≤ 23 
26 
≤ 24 
27 
≤ 26 
28 
≤ 28 
29 
≤ 29 
30 
≤ 30 
DCR = disease control rate. 
 
Operating characteristics of this continuous monitoring method are presented in Table 4.2 
based on 10000 simulations using the prespecified TV. 
Table 4.2 
Operating Characteristics of Continuous Monitoring for No-
Go 
 
 
 
True δ 
 
(BM DCR 
= 60%) 
All No-Go  
(Interim & 
final) 
Early No-Go 
(Confirmed 
at final)  
 
 
0% 
68% 
19% (18%) 
5% 
46% 
11% (10%) 
10% 
25% 
5% (4%) 
15% 
11% 
2% (2%) 
20% 
3% 
1% (0) 
25% 
1% 
0 (0) 




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SAP template version 3.0 
• 
Modified/Added subgroups for 
efficacy analyses. 
• 
Added a missing superscript in 
the formula of PFS-12 testing. 
• 
Updated signature page to 
include new team members. 
• 
Post cCRT window adjusted to 
42 days to match Protocol AM3. 
• 
Added language about 
coagulation and thyroid analyses. 
3.0 
14DEC2020 
• 
Additional summaries added to 
Section 3.3.2. 
• 
New subgroups added to Section 
3.4.4. 
• 
Added PFS-6 and PFS-9 in 
Section 3.4.5. 
• 
Layout update as per review 
comments from IA#1. 
4.0 
07FEB2023 
Updates made for final CSR delivery: 
1. Section 3.3.1 updated to include 
listing of global/country situation 
disruptions. 
2. Section 3.3.2 updated to describe 
categorization of platins. 
3. Section 3.6.2 updated with minor 
clarifications as well as 
description of durvalumab imAE 
analyses. 
4. Additional subgroup added to 
Section 3.4.4 for ORR. 
5. Subgroup analyses included for 
PFS. 
6. Section 3.4.2.4 (PFS) updated to 
include additional landmarks at 
18 and 24 months. 
7. Section 3.4.2.5 (OS) updated to 
include additional landmarks at 
18 and 24 months.  
8. Section 3.4.2.5 (OS) updated to 
include additional field for 
deriving last known alive date. 
9. Section 3.4.4 updated to include 
forest plots for subgroup 
analyses of ORR and PFS. 
10. Section 3.4.5 updated with 
clarification that unconfirmed 
ORR will also be reported. 
11. iRECIST confirmed not to be 
reported in CSR (Section 3.4.5). 
Other minor clarifications were made 
throughout. 
1. Required listing to describe 
impact of COVID-19 on the 
study. 
2. Previously this was not well-
defined and had been subject to 
manual review. The team agrees 
all terms should be coded and 
therefore WHO Drug information 
can be used to derive categories. 
3. Automatic adjudication of 
durvalumab imAEs is a required 
process. Outputs have been 
added to comply with this. 
4. Disease stage at study entry (IIIA 
vs. IIIB/C) is considered a 
clinically important subgroup. 
5. Though confirmed ORR is the 
primary endpoint, PFS is also 
clinically relevant and therefore 
subgroups will be explored. 
6. Data maturity permits further 
landmarks to be presented. 
7. Data maturity permits further 
landmarks to be presented. 
8. Update provides further coverage 
of potential last known alive date 
and increased accuracy. 
9. Forest plots provide a clear way 
to present subgroup results. 
10. This is per the CSP but was not 
previously clarified in the SAP. 
11. Confirmed with clinical team that 
iRECIST is not required for the 
CSR. 


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5.0 
04SEP2023 
1. Added a few terms in the list of 
abbreviations 
2. Section 3.1 clarified for the 
definition of baseline 
3. Updated SAS version to 9.4 
4. Table 3.2-1 Added PK-evaluable 
population 
5. Section 3.3.3 removed data cut-
off from duration of exposure 
definition 
6. Section 3.3.4 add ATC and 
WHO Drug version 
7. Section 3.3.5 Added COVID-19 
related IPDs 
8. Section 3.4.2.4 Added PFS-36 
month landmark 
9. Section 3.4.2.4 Updated and 
clarified the Greenwood’s 
formula, and added more details 
10. Section 3.4.2.5 Added OS-36 
month landmark 
11. Section 3.5 Updated section to 
clarify that no pharmacodynamic 
analyses are planned at this stage 
12. Section 3.6 Added clarification 
regarding any derivation 
timeframe (in Labs, VS, ECOG) 
13. Section 3.6.4 Updated wording 
to increase readiness and match 
what the expectations are, for the 
laboratory tables 
14. Section 3.6.4 Creatinine 
clearance rate formula added 
15. Section 3.6.5.1 Removed 10% 
subjects wording and added 
minimum and maximum post-
baseline summaries of vital signs 
16. Section 3.6.5.2 Added 
information as to why no ECG 
analyses are planned for the CSR 
17. Section 3.6.5.4 Added a section 
for physical examinations (none 
planned) 
18. Section 3.8 Added PK analysis 
plan  
19. Section 3.8 Mentioned that all 
results to be reported in ug/mL 
 
Other minor clarifications were made 
throughout. 
1. Previously missing some 
abbreviations, and new ones 
corresponding to new updates 
2. Lack of information in defining 
baseline when no time indicator 
captured 
3. Latest SAS version available 
4. SAP now includes PK analysis  
5. No DCO defined in final CSR 
6. Clarify that the summary of 
concomitant medications is by 
ATC and PT 
7. COVID-19 related IPDs might be 
required for the CSR 
8. Agreed with the team in prior 
communications to include PFS-
18, PFS-24 and PFS-36 
landmarks for the CSR 
9. Lack of precision in the formula 
details (ni refers to deaths or 
disease progressions in the PFS 
section, difference between i and 
k) 
10. Agreed with the team in prior 
communications to include OS-
18, OS-24, and OS-36 landmarks 
for the CSR 
11. Previous version outdated 
(MedImmune process) - Wording 
confirmed with PK/PD team 
12. Discussed during the Dry Run 
review with the team to consider 
only post-baseline visits up to 
and including 90 days post last 
dose of study drug  
13. Wording was unclear and 
disorganized, clarification was 
needed 
14. Information more complete with 
additional details provided 
15. CSP doesn’t mention a selection 
criterion (10% of subjects) so not 
needed here, but mentions 
min/max summaries of vital 
signs 
16. CSP mentions ECG analyses 
while ECGs were only collected 
at screening 
17. CSP mentions physical 
examination statistical analysis, 


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but none are planned for the CSR 
(data do not allow) 
18. After discussion with the study 
team and the PK/PD team, PK 
analysis plan needed to be 
included in the SAP. Previous 
version outdated (MedImmune 
process). 
19. After discussing with the PK/PD 
team, Durvalumab serum 
concentrations should be 
converted from ng/mL to ug/mL  
 
 
 
 
7 
APPENDIX 
7.1 
Derivation of RECIST v1.1 Disease Assessment Overall Response 
Guidance regarding the handling of dropouts and missing data will apply uniformly to all 
efficacy analyses resulting from an application of RECIST v1.1 to investigator assessed 
tumor measurements. For investigator reported outcomes, analyses will present outcomes 
reported by the investigator without consideration of missing data or censoring rules.  
7.1.1 
Target Lesion Response 
Target lesion response will be programmatically derived on the data collection instrument 
once RECIST v1.1 criteria are applied to the site personnel recorded target lesion 
measurements.  
Possible values include: 
• CR – Complete Response 
• PR – Partial Response 
• SD – Stable Disease 
• PD – Progressive Disease 
• NE – Non-evaluable 
• NA – Not Applicable (set value for all post-baseline disease assessments only if no 
target lesions are identified at baseline) 
The derivation for target lesion response is as follows (please note the order of the algorithm 
below is important): 


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1. If “Any Target Lesions Present” equals “No” on the Target Lesions – Baseline CRF, 
then all post-baseline “Target Lesion Response” equals “NA”.  
2. Else, if “Percent Change from Nadir Sum of Diameters” is greater than or equal to 
20% and the absolute increase from the nadir (defined as the “Total” for each post-
baseline disease assessment minus the “Nadir Sum of Diameters”) is greater than or 
equal to 5 mm, then “Target Lesion Response” equals “PD”. 
3. Else, if “Not Done” is selected, or “Measurement” is left blank, or “Lesion no longer 
Measurable” is selected and equal to “NE”, or “Lesion Intervention” is selected for 
any Target Lesion identified at Baseline, then “Target Lesion Response” equals 
“NE”. 
4. Else, if “Total Non-Lymph Node” equals “0” and all Lymph Node Target Lesion 
“Measurements” are less than “10” individually, then “Target Lesion Response” 
equals “CR”.  
Note: This step requires examining “Measurements” separately for Target Lesions 
with “Lymph Node” equal to “Yes” and “No”. 
5. Else, if “Percent Change from Baseline Sum of Diameters” is less than or equal to -
30%, then “Target Lesion Response” equals “PR”. 
6. Else, “Target Lesion Response” equals “SD”. 
If a subject has a missing tumor measurement at a disease assessment for 1 or more target 
lesions, the sum of diameters (longest for non-nodal lesions, short axis for nodal lesions) will 
be reported for the remaining target lesions. These data will be used to indicate radiologic 
disease progression if the sum of diameters for the observed lesions increases at least 20% 
from the nadir sum of diameters of all target lesions and demonstrates at least a 5 mm 
absolute increase from the nadir sum of diameters of all target lesions, in spite of the missing 
data (or if other criteria for PD are met). 
7.1.2 
Non-Target Lesion Response 
Non-target lesion response will be assigned by site personnel following a qualitative overall 
assessment of all non-target lesions.  
Possible values include: 
• CR – Complete Response 


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o Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (<10mm short axis) 
• Non-CR/Non-PD – Non-Complete Response / Non-Progressive Disease 
o Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits 
• PD – Progressive Disease 
o Unequivocal progression of existing non-target lesions.  
• NE – Non-evaluable 
• NA – Not Applicable (set value for all post-baseline disease assessments only if no 
non-target lesions are identified at baseline) 
Though non-target lesion responses are a subjective decision made by the site personnel, 
certain responses may be limited depending on the non-target lesion statuses recorded. An 
algorithm is provided below highlighting appropriate possible non-target lesion responses 
based on recorded data. Reaching a red box (■) signifies having reached the only allowable 
non-target lesion responses based on non-target lesion statuses. Reaching a green box (■) 
signifies having reached the end of the algorithm and more than one possible non-target 
lesion response is possible from which the Investigator may choose. 
1. a)  If no non-target lesions are identified at baseline, all post-baseline non-target 
lesion responses should equal NA. ■ 
b)  Else, if any non-target lesions are identified at baseline, responses may be limited 
to CR, Non-CR/Non-PD, PD, NE (i.e., responses of NA are not permitted).  
Go to Rule 2. 
2. a)  If all non-target lesions have a status are “Absent”, the responses may be limited 
to CR. ■ 
b)  Else, if at least one non-target lesion status is NOT “Absent”, the responses may 
be limited to Non-CR/Non-PD, PD, NE (i.e., responses of CR, NA are not permitted).  
Go to Rule 3.  
3. a)  If all non-target lesions have a status of “Unequivocal Progression”, responses 
may be limited to PD. ■ 
b)  Else, if no non-target lesions have a status of “Unequivocal Progression”, 
responses may be limited to Non-CR/Non-PD, NE (i.e., responses of CR, PD, NA are 


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not permitted). 
Go to Rule 4. 
c) Else, if at least one (but not all) non-target lesion has a status of “Unequivocal 
Progression”, the responses may be limited to Non-CR/Non-PD, PD, NE (i.e., 
responses of CR, NA are not permitted). (Note: No response has been eliminated as 
an option here.)   
Go to Rule 5.  
4. a)  If all non-target lesions have a status of “Non-evaluable” and/or “Not Done” is 
selected, responses may be limited to NE. ■ 
b)  Else, if no non-target lesions have a status of “Non-evaluable” and “Not Done” is 
not selected, responses may be limited to Non-CR/Non-PD (i.e., responses of CR, 
PD, NE, NA are not permitted). ■  
c) Else, if at least one (but not all) non-target lesion has a status of “Non-evaluable” 
and/or “Not Done” is selected, the responses may be limited to Non-CR/Non-PD, NE 
(i.e., responses of CR, PD, NA are not permitted). ■ 
(Note:  No response has been eliminated as an option here.)  
5. a)  If all non-target lesions have a status of “Non-evaluable” and/or “Not Done” is 
selected, responses may be limited to NE. ■ 
b)  Else, if no non-target lesions have a status of “Non-evaluable” and “Not Done” is 
not selected, responses may be limited to Non-CR/Non-PD, PD (i.e., responses of 
CR, NE, NA are not permitted). ■ 
c) Else, if at least one (but not all) non-target lesion has a status of “Non-evaluable” 
and/or “Not Done” is selected, the responses may be limited to Non-CR/Non-PD, PD, 
NE (i.e., responses of CR, NA are not permitted). ■ 
(Note:  No response has been eliminated as an option here.)  
If a subject has a missing tumor status at a disease assessment for 1 or more non-target 
lesions, radiologic disease progression will be determined if the remaining non-target lesions 
qualitatively demonstrate unequivocal progression (or if other criteria for PD are met). 
7.1.3 
Disease Assessment Overall Response per RECIST v1.1 
Investigator visit disease response will be programmatically derived on the data collection 
instrument using RECIST v1.1 criteria based upon target lesion response, non-target lesion 
response, and new lesion data. Missing values in any of target lesion response, non-target 
lesion response, and new lesion data will result in the disease response not being derived. 
Possible values include: 
• CR – Complete Response 


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• PR – Partial Response 
• SD – Stable Disease 
• PD – Progressive Disease 
• NE – Non-evaluable 
 
Target Lesion 
Response 
Non-Target Lesion Response 
New Lesion 
Derived RECIST Disease 
Response 
CR 
CR or NA 
No 
CR 
CR 
Non-CR/Non-PD or NE 
No (or NE) 
PR 
PR 
CR or Non-CR/Non-PD or NE or NA 
No (or NE) 
PR 
SD 
CR or Non-CR/Non-PD or NE or NA 
No (or NE) 
SD 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Yes 
PD 
NE 
CR or Non-CR/Non-PD or NE or NA 
No 
NE 
NA 
CR 
No 
CR 
NA 
Non-CR/Non-PD 
No 
SD (Non-CR/Non-PD)a 
NA 
NE or NA 
No (or NE) 
NE 
NA 
CR or Non-CR/Non-PD 
NE 
SD (Non-CR/Non-PD)a 
a Per RECIST v1.1, “SD (Non-CR/Non-PD)” is preferred over “SD” for non-target disease since SD is 
increasingly used as endpoint for assessment of efﬁcacy in some trials so to assign this category when no 
lesions can be measured is not advised. 
 
(Note: “(or NE)” values under New Lesion will only be included in confirmation of 
progression or confirmation of new lesions are required per protocol. The last 4 rows may be 
eliminated from any study that requires identification of at least one measurable lesion at 
Baseline. One may choose to allow such cells to remain if an independent central review is 
included in the trial.) 
If a subject has a missing tumor measurement at some assessment(s) for 1 or more target 
lesions and criteria for PD are not otherwise met, an overall response of NE will be assigned 
for the assessment(s). 
7.1.4 
Locoregional therapy 
Any subject receiving locoregional therapy, including surgery, while on study that directly 
affects one or more of the target lesions selected at baseline will be identified. A subject with 
a subsequent response or SD will be considered to be non-evaluable at all disease 
assessments that occur on or after the date of locoregional therapy. Otherwise, the subject 
will be assessed ignoring the locoregional therapy. 


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7.1.5 
Assignment of Dates of Disease Progression or Disease Response 
For all analyses of endpoints resulting from an application of RECIST v1.1 to investigator 
assessed tumor measurements, there may be cases in which disease assessments span a series 
of dates. For establishing the start date of a subsequently confirmed response in which the 
disease assessment spans multiple days, the date of response assigned will be the latest date 
of evaluations corresponding to the disease assessment. The date of latest evaluation will also 
be assigned for a mid-study assessment showing SD as the date assigned for the purposes of 
censoring duration of response, TTP and PFS.  
The date of PD will be the first date at which any objective diagnostic test provides data 
indicating PD. Specifically, for RECIST v1.1 the date of PD will be the earliest of the 
following 3 evaluation dates: 
• Date of PD as indicated by target lesions: If PD is triggered by a change in sum of 
diameters of target lesions, and the dates of evaluation of the target lesions vary for 
the same assessment, assign the first evaluation date among target lesions. 
• Date of PD as indicated by non-target lesions: If the dates of evaluation of the non-
target lesions vary for the same assessment, assign the first evaluation date for which 
any non-target lesion exhibits a status of Unequivocal Progression. 
• Date of PD as indicated by new lesions: If multiple new lesions are identified and the 
dates of evaluation for the new lesions vary for the same assessment, assign the first 
evaluation date for which any new lesion is detected. 
In scenarios where the Investigator disease response is either a response or PD and differs 
from that of the application of RECIST v1.1 to investigator assessed tumor measurements 
separate response and/or progression dates will be required. Determination of the start date of 
a subsequently confirmed response in which the disease assessment spans multiple days 
remains the same as described previously. Specifically, the date of response assigned will be 
the latest date of evaluations corresponding to the disease assessment. The date of PD will be 
the earliest date of evaluations corresponding to the disease assessment.  
  
7.2 
Efficacy Criteria of Making an Internal Go Decision at an Interim 
Analysis 
At an interim analysis, an internal Go decision may be made based on the delta (Δ), or 
difference, of the ORRs between durvalumab/novel agent combinations and durvalumab 


MedImmune 
 Statistical Analysis Plan for Protocol D9108C00001 
Durvalumab and Novel Agents 
 
04SEP2023; Final version 5.0 
CONFIDENTIAL AND PROPRIETARY 
37 of 38 
SAP template version 3.0 
alone. The internal Go decision may initiate further development of the combinations. The 
Go decision will not only be based on meeting the pre-specified efficacy criteria but also the 
totality of data including safety profiles, data from other studies, and internal portfolio 
prioritization. 
For interim analyses that will lead to an internal Go decision, a response is defined as a 
confirmed CR or PR as per RECIST v1.1. The Lower Reference Value (LRV) is set to an 8% 
increase in ΔORR to demonstrate clinically meaningful increase over durvalumab alone. At 
final analysis, Go criteria will be met if the probability that the true ΔORR exceeds the 
prespecified LRV of 8% is more than 80% (i.e., Go: P[ΔORR > LRV] > 80%).  
Early Go criteria are met if it is predicted that there is a high probability of reaching a Go 
decision upon full randomization of 60 subjects given the existing observed data (i.e., 
predictive probability of a Go decision > 95%). If Go criteria are met, randomization may 
continue, and planning activities for further development of the durvalumab/novel agent 
combination may be triggered. 
Table 7.2-1 illustrates the sample algorithm to make an early Go decision based on ORR at 
an interim analysis when control arm and an experimental arm each have 30 subjects. 
Table 7.2-1 
Criteria of Early Go Decisions Based on ORR 
Number of Subjects with OR in Control Arm 
Number of Subjects with OR in Experimental 
Arm 
3 
≥ 12 
4 
≥ 13 
5 
≥ 14 
6 
≥ 16 
7 
≥ 17 
8 
≥ 18 
9 
≥ 19 
10 
≥ 20 
11 
≥ 21 
12 
≥ 22 
13 
≥ 23 
14 
≥ 24 
15 
≥ 25 
16 
≥ 25 
17 
≥ 26 
18 
≥ 27 
19 
≥ 28 
20 
≥ 28 
21 
≥ 29 


MedImmune 
 Statistical Analysis Plan for Protocol D9108C00001 
Durvalumab and Novel Agents 
 
04SEP2023; Final version 5.0 
CONFIDENTIAL AND PROPRIETARY 
38 of 38 
SAP template version 3.0 
Table 7.2-1 
Criteria of Early Go Decisions Based on ORR 
Number of Subjects with OR in Control Arm 
Number of Subjects with OR in Experimental 
Arm 
22 
30 
ORR = objective response rate. 
 
Operating characteristics of this continuous monitoring method are presented in Table 7.2-2 
based on 10000 simulations using the prespecified LRV. 
Table 7.2-2 
Operating Characteristics of Continuous Monitoring for Go 
 
 
 
True δ 
 
(BM ORR 
= 30%) 
All Go  
(Interim & 
final) 
Early Go 
(Confirmed 
at final)  
 
 
0% 
3% 
1% (0) 
8% 
19% 
3% (3%) 
15% 
47% 
10% (10%) 
20% 
69% 
18% (17%) 
25% 
85% 
31% (30%) 
 
Criteria:  Lower Reference Value (LRV) δ = 8%; Go: Pr(δ > LRV) > 80%; Early Go:  PP(Go) > 95%);  
 BM ORR: Benchmark Objective Response Rate.  


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