Clinical trial NCT03794544
Conditions: Resectable Early-stage NSCLC
Keywords: Neoadjuvant Non-small Cell Lung Cancer Cancer Lung Resectable Early-stage Stage I Stage II Stage IIIA Durvalumab
Sponsor: MedImmune LLC
Start date: 2019-03-08; Completion date: 2021-01-13
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study D9108C00002 (NeoCOAST) is a platform study assessing the effectiveness and safety of neoadjuvant durvalumab alone or in combination with novel agents in participants with resectable, early-stage (Stage I \[\>2cm\] to IIIA) non-small cell lung cancer (NSCLC).

Detailed description:

Arms: arm 1: Participants will receive durvalumab 1500 mg intravenously (IV) every 4 weeks (Q4W; on Week 1 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. Surgical resection will be planned between Day 29 and Day 42. After surgical resection, participants will be followed up to Day 105 (starting from Week 1 Day 1). arm 2: Participants will receive durvalumab 1500 mg IV Q4W (on Week 1 Day 1) and oleclumab 3000 mg IV every 2 weeks (Q2W; on Week 1 Day 1 and Week 3 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. Surgical resection will be planned between Day 29 and Day 42. After surgical resection, participants will be followed up to Day 105 (starting from Week 1 Day 1). arm 3: Participants will receive durvalumab 1500 mg IV Q4W (on Week 1 Day 1) and monalizumab 750 mg IV Q2W (on Week 1 Day 1 and Week 3 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. Surgical resection will be planned between Day 29 and Day 42. After surgical resection, participants will be followed up to Day 105 (starting from Week 1 Day 1). arm 4: Participants will receive danvatirsen 200 mg IV on Days 1, 3, and 5 of Week 0 (7-day danvatirsen lead-in period), followed by durvalumab 1500 mg IV Q4W (on Week 1 Day 1) and danvatirsen 200 mg IV every week (on Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, and Week 4 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. Surgical resection will be planned between Day 29 and Day 42. After surgical resection, participants will be followed up to Day 105 (starting from Week 1 Day 1).
Interventions: intervention 1: Durvalumab intervention 2: Oleclumab intervention 3: Monalizumab intervention 4: Danvatirsen
Intervention descriptions: intervention 1: Durvalumab 1500 mg IV will be administered Q4W (on Week 1 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. intervention 2: Oleclumab 3000 mg IV will be administered Q2W (on Week 1 Day 1 and Week 3 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. intervention 3: Monalizumab 750 mg IV will be administered Q2W (on Week 1 Day 1 and Week 3 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. intervention 4: Danvatirsen 200 mg IV will be administered on Days 1, 3, and 5 of Week 0 (7-day danvatirsen lead-in period) and later every week (on Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, and Week 4 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period.

Protocol documents:
Prot_000.pdf: 
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A Phase 2 Open-label, Multicenter, Randomized, Multidrug 
Platform Study of Neoadjuvant Durvalumab Alone or in 
Combination with Novel Agents in Subjects with Resectable, 
Early-stage (I [> 2 cm] to IIIA) Non-small Cell Lung Cancer 
(NeoCOAST) 
Sponsor Protocol Number: D9108C00002
Application Number:
IND number: 140575
EudraCT number: 2018-002932-26  
Investigational Products:
Durvalumab (MEDI4736) and novel oncology therapies 
(oleclumab [MEDI9447], monalizumab [IPH2201], and 
danvatirsen [AZD9150])
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of 
AstraZeneca PLC
One MedImmune Way
Gaithersburg, Maryland, 20878, USA
Medical Monitor:
Associate Director, Clinical Development Oncology, 
MedImmune,
Phone: 
Fax: 
Contract Research Organization: ICON Clinical Research Ltd
Protocol History, Date:
Original Protocol, 11Oct2018
Amendment 1, 26Nov2018
Amendment 2, 18Jan2019
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 Neoadjuvant Durvalumab
Alone or in Combination with Novel Agents in Subjects with Resectable, Early-stage (I [> 2 cm] to IIIA) 
Non-small Cell Lung Cancer (NeoCOAST)
HYPOTHESES  
Primary Hypothesis: Neoadjuvant durvalumab alone or in combination with novel agents administered over 
a 28-day treatment period to subjects with resectable, early-stage (Stage I [> 2 cm] to IIIA) non-small cell 
lung cancer (NSCLC) will lead to a pathological response within the resected tumor specimen.
Secondary Hypothesis: Neoadjuvant durvalumab alone or in combination with novel agents will demonstrate 
an acceptable safety profile and will not result in a delay in surgery in subjects with resectable, early-stage 
(Stage I [> 2 cm] to IIIA) NSCLC.
OBJECTIVES AND ASSOCIATED ENDPOINTS
Type
Primary Objective
Primary Endpoint
Efficacy
Assess the antitumor activity of durvalumab alone 
and/or in combination with novel agents 
MPR rate 
MPR = major pathological response.
Type
Secondary Objectives
Secondary Endpoints
Safety
Assess the feasibility of receiving the planned 
surgical resection
Feasibility, defined as having 
the planned surgical resection 
within Day 29 to Day 42 after 
Week 1, Day 1 
Safety
Assess the safety and tolerability of durvalumab 
alone and/or in combination with novel agents
Presence of AEs, SAEs, 
laboratory abnormalities, and 
vital signs
Efficacy
Assess the antitumor activity of durvalumab alone 
and/or in combination with novel agents
pCR rate 
Pharmacokinetics
To describe the PK of durvalumab alone and/or in 
combination with novel agents 
Concentration of durvalumab 
or novel agents in plasma or 
serum
Immunogenicity
(a) To assess the immunogenicity of durvalumab 
alone or in combination with novel agents
ADA incidence of 
durvalumab or novel biologic 
agents
(b) To assess the immunogenicity of novel biologic 
agents in combination with durvalumab
ADA = antidrug antibody; AE = adverse event; pCR = pathological complete response; PK = 
pharmacokinetics; SAE = serious adverse event.


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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, individual durvalumab and 
individual study drug concentrations will be tabulated with descriptive statistics. 
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 percentage of subjects who develop detectable 
antidrug antibodies (ADAs) to durvalumab. For treatment arms that include a novel biologic agent, the 
immunogenic potential of the novel biologic agent will be assessed by summarizing the number and 
percentage of subjects who develop detectable ADAs to the novel biological agent.
Interim analyses: Interim analyses will be conducted during the course of the study to evaluate the clinical 
activity and safety of any treatment arm. The first planned interim analysis will be initiated once at least 
1 treatment arm has enrolled 20 efficacy evaluable subjects. Across all treatment arms, subject accrual beyond 
20 subjects will be determined based on interim data. Bayesian predictive probabilities will be used to 
evaluate clinical activity. In addition, for any treatment arm, enrollment will be stopped if more than 2 out of 
the first 20 enrolled subjects failed the feasibility to surgery.


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS...................................................................................................... 2
LIST OF ABBREVIATIONS ............................................................................................. 12
1
INTRODUCTION............................................................................................ 15
1.1
Disease Background ......................................................................................... 15
1.1.1
Immunotherapy................................................................................................. 17
1.1.1.1
Programmed Cell Death Ligand-1..................................................................... 17
1.1.1.2
CD73................................................................................................................ 17
1.1.1.3
NKG2a ............................................................................................................. 17
1.1.1.4
STAT3.............................................................................................................. 18
1.2
Study Drug Background.................................................................................... 18
1.2.1
Durvalumab...................................................................................................... 18
1.2.2
Oleclumab ........................................................................................................ 19
1.2.3
Monalizumab.................................................................................................... 19
1.2.4
Danvatirsen....................................................................................................... 19
1.3
Summary of Nonclinical Experience................................................................. 19
1.3.1
Durvalumab Nonclinical Experience................................................................. 19
1.3.2
Oleclumab Nonclinical Experience ................................................................... 19
1.3.3
Monalizumab Nonclinical Experience............................................................... 20
1.3.4
Danvatirsen Nonclinical Experience ................................................................. 20
1.4
Summary of Clinical Experience....................................................................... 20
1.4.1
Clinical Experience - Durvalumab .................................................................... 21
1.4.2
Clinical Experience – Oleclumab Alone and in Combination with Durvalumab 21
1.4.3
Clinical Experience - Monalizumab Alone and in Combination with 
Durvalumab...................................................................................................... 22
1.4.4
Clinical Experience – Danvatirsen Alone and in Combination with 
Durvalumab...................................................................................................... 23
1.5
Rationale for Conducting the Study .................................................................. 24
1.5.1
Rationale for Inclusion of Durvalumab in Combination with Oleclumab........... 25
1.5.2
Rationale for Inclusion of Durvalumab in Combination with Monalizumab ...... 25
1.5.3
Rationale for Inclusion of Durvalumab in Combination with Danvatirsen......... 25
1.6
Benefit-risk and Ethical Assessment ................................................................. 26
1.6.1
Potential Benefits.............................................................................................. 26
1.6.2
Potential Risks.................................................................................................. 26
1.6.2.1
Durvalumab...................................................................................................... 26
1.6.2.2
Oleclumab Plus Durvalumab............................................................................. 27
1.6.2.3
Monalizumab Plus Durvalumab........................................................................ 27
1.6.2.4
Danvatirsen Plus Durvalumab........................................................................... 28
1.6.3
Overall Benefit-risk .......................................................................................... 28
1.7
Research Hypotheses ........................................................................................ 29
1.7.1
Primary Hypothesis .......................................................................................... 29
1.7.2
Secondary Hypotheses...................................................................................... 29
2
OBJECTIVES AND ENDPOINTS................................................................... 29






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4.8.4.3
Analysis of Vital Signs ..................................................................................... 69
4.8.4.4
Analysis of ECOG Performance Status............................................................. 70
4.8.5
Analysis of Immunogenicity/Pharmacokinetics................................................. 70
4.8.5.1
Immunogenicity Analyses................................................................................. 70
4.8.5.2
Pharmacokinetic Analyses ................................................................................ 70
4.8.6
Analysis of Biomarkers..................................................................................... 70
4.8.7
Interim Analysis ............................................................................................... 70
5
ASSESSMENT OF SAFETY ........................................................................... 71
5.1
Definition of Adverse Events............................................................................ 71
5.2
Definition of Serious Adverse Events ............................................................... 72
5.3
Definition of Adverse Events of Special Interest............................................... 72
5.3.1
Adverse Events of Special Interest for Durvalumab-containing Regimens ........ 72
5.3.2
Adverse Events of Special Interest Associated with Oleclumab ........................ 74
5.3.3
Adverse Events of Special Interest Associated with Monalizumab.................... 74
5.3.4
Adverse Events of Special Interest Associated with Danvatirsen....................... 74
5.4
Recording of Adverse Events............................................................................ 75
5.4.1
Time Period for Collection of Adverse Events .................................................. 75
5.4.2
Follow-up of Unresolved Adverse Events......................................................... 75
5.4.3
Deaths .............................................................................................................. 75
5.4.4
Adverse Events Based on Signs and Symptoms ................................................ 76
5.4.5
Adverse Events Based on Examination and Tests.............................................. 76
5.4.6
Potential Hy’s Law and Hy’s Law..................................................................... 76
5.4.7
Disease Progression.......................................................................................... 76
5.5
Reporting of Serious Adverse Events................................................................ 77
5.6
Other Events Requiring Immediate Reporting................................................... 78
5.6.1
Overdose .......................................................................................................... 78
5.6.2
Pregnancy......................................................................................................... 78
5.6.2.1
Maternal Exposure............................................................................................ 78
5.6.2.2
Paternal Exposure............................................................................................. 79
5.6.3
Medication Error............................................................................................... 79
6
STUDY AND DATA MANAGEMENT........................................................... 80
6.1
Training of Study Site Personnel....................................................................... 80
6.2
Monitoring of the Study.................................................................................... 81
6.2.1
Source Data ...................................................................................................... 81
6.2.2
Study Agreements............................................................................................. 81
6.2.3
Archiving of Study Documents......................................................................... 81
6.3
Study Timetable and End of Study.................................................................... 82
6.4
Data Management............................................................................................. 82
6.5
Medical Monitor Coverage ............................................................................... 82
7
ETHICAL AND REGULATORY REQUIREMENTS...................................... 82
7.1
Subject Data Protection..................................................................................... 82
7.2
Ethics and Regulatory Review .......................................................................... 83


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7.3
Informed Consent ............................................................................................. 83
7.4
Changes to the Protocol and Informed Consent Form........................................ 84
7.5
Audits and Inspections...................................................................................... 84
8
REFERENCES................................................................................................. 86
9
CHANGES TO THE PROTOCOL ................................................................... 93
9.1
Protocol Amendment 2 ..................................................................................... 93
9.2
Protocol Amendment 1 ..................................................................................... 95
LIST OF TABLES
Table 1
Primary Objective and Associated Endpoint ............................................ 30
Table 2
Secondary Objectives and Associated Endpoints...................................... 30
Table 3
30
Table 4
Criteria for Adequate Organ and Marrow Function .................................. 40
Table 5
Schedule of Screening, Treatment, and Follow-up Period Procedures ...... 45
Table 6
Identification of Investigational Product .................................................. 57
Table 7
Estimated Differences in MPR Rate Between Durvalumab Monotherapy 
and Each Durvalumab Combination Therapy Arm (40 Subjects Each)..... 67
Table A1
Highly Effective Methods of Contraception............................................. 97
Table F1
Evaluation of Overall Response Using RECIST v1.1............................. 110
LIST OF FIGURES
Figure 1
Study Flow Diagram................................................................................ 33
Figure 2
Study Period Duration ............................................................................. 34
Figure 3
Treatment Regimen – Durvalumab Monotherapy..................................... 34
Figure 4
Treatment Regimen – Durvalumab Plus Oleclumab................................. 34
Figure 5
Treatment Regimen – Durvalumab Plus Monalizumab ............................ 35
Figure 6
Treatment Regimen – Durvalumab Plus Danvatirsen ............................... 35
Figure 7
Futility Bar for Major Pathological Response........................................... 71
LIST OF APPENDICES
Appendix A
Contraception Guidance........................................................................... 97
Appendix B
Additional Safety Guidance ..................................................................... 98
Appendix C
National Institute of Allergy and Infectious Diseases and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis............ 101
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 102


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Appendix E
106
Appendix F
RECIST v1.1 Response Criteria............................................................. 109


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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
AUC
area under the curve
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATP
adenosine triphosphate
BOR
best overall response
CD
cluster of differentiation
CI
confidence interval
Cmax
maximum serum concentration
CR
complete response
CSR
clinical study report
CT
computed tomography
DCO
data cutoff
DEHP
bis (2-ethylhexyl) phthalate
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
FAAN
Food Allergy and Anaphylaxis Network
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HLA-E
major histocompatibility complex E
IB
Investigator’s Brochure
IBW
ideal body weight
ICH
International Council for Harmonisation


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Abbreviation or 
Specialized Term
Definition
IEC
Independent Ethics Committee
Ig
immunoglobulin
IL
interleukin
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
MedDRA
Medical Dictionary for Regulatory Activities
MPR
major pathological response
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
NCI CTCAE v5.0
National Cancer Institute Common Terminology Criteria for Adverse Events 
version 5.0
NIAID
National Institute of Allergy and Infectious Diseases
NK
natural killer
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
pCR
pathological complete response
PD-1
programmed cell death-1
PD-L1
programmed cell death ligand-1
PD-L2
programmed cell death ligand-2
PET
positron emission tomography
PI
Package Insert
PK
pharmacokinetic(s)
PR
partial response
PT
preferred term
PVC
polyvinyl chloride
QTc
QTc interval
Q2W
every 2 weeks
Q4W
every 4 weeks


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Abbreviation or 
Specialized Term
Definition
QW
every week
RECIST v1.1
Response Evaluation Criteria for Solid Tumors version 1.1
RP2D
recommended Phase 2 dose 
SAE
serious adverse event
SID
subject identification
SOC
system organ class
SRC
Safety Review Committee
STAT3
signal transducer and activator of transcription 3
SUSAR
suspected unexpected serious adverse reaction
SUV
standardized uptake values
TBL
total bilirubin
TV
target value
US
United States
w/v
weight per volume


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1
INTRODUCTION
Study D9108C00002 (NeoCOAST) is a platform study assessing the efficacy and safety of 
neoadjuvant durvalumab alone or in combination with novel agents in subjects with
resectable, early-stage (Stage I [> 2 cm] to IIIA) non-small cell lung cancer (NSCLC). New 
combination treatment arms can be added during the course of the study via a protocol 
amendment, as novel agents of interest become available for testing in this population of 
patients (Section 1.6.3).
1.1
Disease Background
Lung cancer is the second most common cancer in both men and women, with an estimated 
234,030 new cases of lung cancer in the United States (US) in 2018, and remains the main 
cause of cancer-related deaths worldwide. NSCLC represents approximately 85% of all lung 
cancers, and 30% of patients present with resectable NSCLC at diagnosis (American Cancer 
Society, 2018). Resectable, early-stage NSCLC is considered a potentially curable disease, 
and the standard of care is surgery alone or surgery with adjuvant or neoadjuvant 
platinum-based doublet chemotherapy (National Comprehensive Cancer Network, 2018). 
However, up to 55% of patients eventually relapse after surgery and die from NSCLC 
(Uramoto and Tanaka, 2014). 
Based on the National Cancer Data Base dataset, patients had 5-year survival rates ranging 
from approximately 70% for Stage IA1 NSCLC to 20% for Stage IIIA NSCLC (Chansky et 
al, 2017). The use of adjuvant chemotherapy with a platinum-based regimen has been shown 
to provide survival benefit in patients with resected, early-stage NSCLC; a quantitative 
meta-analysis of multiple clinical trials evaluating adjuvant chemotherapy demonstrated a 4% 
to 5% improvement in overall survival (OS) with the use of adjuvant chemotherapy following 
surgery compared to surgery alone (Burdett et al, 2015). In addition, preoperative neoadjuvant 
chemotherapy has also been studied in several trials in patients with resectable NSCLC 
(Burdett et al, 2006). A meta-analysis of 7 trials showed that neoadjuvant chemotherapy 
improved OS versus surgery alone (5-year OS rate of 20% vs 14%, respectively). 
Furthermore, the use of a neoadjuvant approach offers the possibility for assessing clinical and 
molecular biomarkers that may correlate with sensitivity to therapy and possibly, long-term 
outcomes. 
Compared with adjuvant chemotherapy in early-stage NSCLC, the use of neoadjuvant 
chemotherapy resulted in a higher proportion of patients receiving the planned chemotherapy 
regimen, which supports the notion that early-stage NSCLC patients have a more favorable 
clinical condition before compared to after a major surgical lung resection (Felip et al, 2010). 
In addition, patients with resectable NSCLC treated with neoadjuvant chemotherapy have 
higher rates of pathological tumor response (complete response and/or ≤10% residual viable 
tumor cells) within the resected specimen compared to patients who underwent surgery alone, 


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which may predict clinical benefit and correlates with improved outcomes (Cascone et al, 
2018; Felip et al, 2010; Machtay et al, 2004; Pataer et al, 2012). In other tumor types, such as 
early-stage breast cancer, pathological complete response (pCR) after neoadjuvant 
chemotherapy correlates with OS, and is considered a valid and widely used endpoint in 
clinical studies (Bear et al, 2006; Rastogi et al, 2008).
In the subset of patients with Stage IIIA and N2 disease, the role of surgery remains 
controversial. In general, for unselected patients with Stage IIIA-N2 NSCLC, both 
chemotherapy alone or in combination with radiation followed by surgery or concurrent 
chemoradiotherapy have shown to be equivalent, but neither showed an OS benefit with the 
use of surgery (Albain et al, 2009; Eberhardt et al, 2015; van Meerbeeck et al, 2007).
However, a critical appraisal of these studies demonstrates that the Stage IIIA-N2 population 
is heterogeneous and a subset of patients such as those requiring only a 
lobectomy/bilobectomy instead of a total pneumonectomy, or those with a single lymph node 
(N2 single station) smaller than 3 cm can be considered candidates for surgery (Decaluwé et 
al, 2009; Martins et al, 2012; Pless et al, 2015; van Meerbeeck et al, 2007). Furthermore, it is 
recommended that Stage IIIA-N2 (single nodal station, ≤3 cm in size) disease be rigorously 
confirmed (ie, both radiologically and invasively) and the presence of N3 disease be clearly
excluded (Vansteenkiste et al, 2010).
Recently, the role of programmed cell death-1 (PD-1)/programmed cell death ligand-1 
(PD-L1) inhibition has been evaluated for the treatment of resectable, early-stage NSCLC in 
the neoadjuvant setting. In a single-arm pilot study, a total of 21 subjects with resectable, 
early-stage NSCLC received one month of neoadjuvant treatment with nivolumab 
(OPDIVO®). After 1 month of treatment with neoadjuvant nivolumab, radiologic responses
were observed in 2 (9.5%) subjects, and major pathological responses (MPRs) were observed 
in 45% of the resected tumors (Forde et al, 2018). In another small Phase 2, single-arm study 
evaluating neoadjuvant atezolizumab (TECENTRIQ®) alone, MPRs were observed in 10 of 
50 (20%) subjects, including 3 subjects who had pCRs in the primary tumor. Three subjects 
had partial responses (PRs) per Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST v1.1; Rusch et al, 2018). Overall, both studies concluded that neoadjuvant 
nivolumab and atezolizumab were safe and did not delay the planned surgical resection. These 
studies also demonstrated the potential for using pathologic changes within the tumor as an 
objective measure of antitumor activity.
Overall, early-stage NSCLC, despite being potentially curable, has a high risk of relapse and 
death due to disease progression. Thus, new therapies are needed to further improve the 
long-term prognosis for patients with resectable, early-stage NSCLC.


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1.1.1
Immunotherapy
1.1.1.1
Programmed Cell Death Ligand-1
PD-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 (Chen and Mellman, 2013; Juneja et al, 
2017; Keir et al, 2008; 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 (Pardoll, 
2012; Zou and Chen, 2008; Zou et al, 2016). Monoclonal antibodies (mAbs) targeting PD-1 
(nivolumab, pembrolizumab [KEYTRUDA®]) and PD-L1 (atezolizumab, durvalumab) have 
shown evidence of antitumor activity and a manageable safety profile in patients with NSCLC 
and have been granted approvals by the US Food and Drug Administration and/or the 
European Medicines Agency for the treatment of NSCLC (IMFINZI® US Package Insert [PI], 
2018; KEYTRUDA US PI, 2018; OPDIVO US PI, 2018; TECENTRIQ US PI, 2018).
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 
overactivation, 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 OS 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 


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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 be associated with diminished cytotoxic potential (Mamessier et al, 2011; 
Platonova et al, 2011; Sheu et al, 2005) and has been documented in a variety of solid tumors
including NSCLC, colorectal, ovarian, endometrial, pancreatic, and prostate cancers
(Aparicio-Pages et al, 1991; Gooden et al, 2011; Iannone et al, 2015; 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
(Emens et al, 2017; Gooden et al, 2011; Guo et al, 2015; Versluis et al, 2017).
1.1.1.4
STAT3
Interactions between tumor cells, immune cells and other cell types within the tumor 
microenvironment have a significant impact on the progression of cancer. Inflammatory cells, 
fibroblasts and endothelial cells in the microenvironment release cytokines, chemokines and 
growth factors to stimulate tumor growth and to modulate the invasive potential of tumor 
cells. These signals also create immunosuppressive networks that enable immune evasion of 
tumor cells (Yu et al, 2007). Signal transducer and activator of transcription 3 (STAT3) drives 
the production of interleukin (IL)-6, IL-10 and vascular endothelial growth factor from tumor 
cells, and also regulates the production of pro-tumorigenic and anti-tumorigenic cytokines, as 
well as immune suppressive signaling in immune cells. Thus, STAT3 establishes a critical 
crosstalk between tumor cells and tumor-associated immune cells and is a central component 
of a ‘feed-forward loop’ that shifts the tumor microenvironment to a more pro-tumorigenic 
phenotype (Kortylewski et al, 2009; Yu et al, 2007).
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 


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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 
leads to a reduction in CD73 expression through internalization, thus contributing to decreased 
adenosine production (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.
1.2.4
Danvatirsen
Danvatirsen (AZD9150) is a 16-nucleotide antisense oligonucleotide designed to reduce 
expression of STAT3 protein by targeted down-regulation of STAT3 messenger ribonucleic 
acid (mRNA). STAT3 is a promising cancer drug target, because of its pleiotropic 
involvement in tumorigenesis, including roles in immune evasion, angiogenesis, and 
metastasis. Refer to the current danvatirsen IB for details.
1.3
Summary of Nonclinical Experience
1.3.1
Durvalumab Nonclinical Experience
1.3.2
Oleclumab Nonclinical Experience
 
 
 
 
 
 
 


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1.3.3
Monalizumab Nonclinical Experience
 
 
 
 
 
 
 
 
 
 
 
1.3.4
Danvatirsen Nonclinical Experience
 
 
 
 
 
 
 
 
 
 
1.4
Summary of Clinical Experience
 
 


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1.4.1
Clinical Experience - Durvalumab
 
 
 
 
 
 
 
1.4.2
Clinical Experience – Oleclumab Alone and in Combination with 
Durvalumab
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.4.3
Clinical Experience - Monalizumab Alone and in Combination with 
Durvalumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.4.4
Clinical Experience – Danvatirsen Alone and in Combination with 
Durvalumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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1.5
Rationale for Conducting the Study
Five-year survival rates in early-stage NSCLC ranges from approximately 70% for Stage IA1 
disease to 20% for Stage IIIA disease, with the majority of patients experiencing post-surgical 
relapse and disease recurrence (Chansky et al, 2017; Goldstraw et al, 2007). Adjuvant 
platinum-based chemotherapy provides an approximate 5% increase in survival benefit 
compared to surgery alone, with rates of overall Grade 3 to 4 toxicity of 66%. Thus, there is 
an unmet medical need for more effective therapies for patients with early-stage NSCLC. 
Blockade of the PD-1/PD-L1 pathway in the neoadjuvant setting may provide clinical benefit 
by enhancing the antitumor response, and eradicating micrometastases prior to surgery, 
thereby reducing disease recurrence. Two recent clinical studies have shown that blockade of 
PD-l/PD-L1 in the neoadjuvant setting may yield clinically meaningful pathological response 
(MPR and pCR) in subjects with resectable, early-stage NSCLC without delaying planned 
surgical resection (Forde et al, 2018; Rusch et al, 2018). 
In the NeoCOAST study, utilizing a neoadjuvant approach to assess the role of durvalumab 
alone or in combination with novel agents has several advantages. First, durvalumab alone or 
in combination with novel agents may result in pathological response and/or downstaging 
prior to surgery. Second, the resected tumors can be analyzed and provides a unique 
opportunity to perform correlative biomarker studies and investigate changes in the tumor 
microenvironment. Predictive biomarkers or underlying resistance mechanisms may be 
identified, which will help inform future durvalumab-based combination therapy studies. 
Additionally, nonclinical evidence supports that immune response to neoadjuvant 
immunotherapies may be more effective compared to an adjuvant approach because the total 
load of tumor associated antigens is higher during neoadjuvant immunotherapy, which may 
enhance the antitumor immune response  (Liu et al, 2016). Further, in order to maximize the 
benefit-risk assessment, the treatment period duration will be short, which will minimize 
treatment exposure, potential AEs, and avoid delaying the planned surgical tumor resection.
The NeoCOAST study will utilize a platform study design, which will allow for the rapid 
evaluation of neoadjuvant durvalumab alone or in combination with novel agents in patients 
with resectable, early-stage (Stage I [> 2 cm] to IIIA) NSCLC. Combining a platform study 
design with early efficacy endpoints (eg, MPR) will provide a more dynamic approach to 


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identifying the most efficacious durvalumab-based combination regimens. In comparison, 
executing multiple, individual, Phase 2 studies will require more time and a greater number of 
subjects. Combination therapy arms may be closed or opened during the study based on 
emerging nonclinical and clinical data. Potential new candidate study agents 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, monalizumab, and danvatirsen meet these criteria, and will be used in combination 
with durvalumab as the initial combination arms of this platform study.
1.5.1
Rationale for Inclusion of Durvalumab in Combination with Oleclumab
High CD73 expression in NSCLC is associated with poor OS and recurrence free survival in a 
multivariate analysis (Inoue et al, 2017). CD73 is known to contribute to the 
immunosuppressive effects of both cytotoxic T lymphocytes and myeloid-derived suppressor 
cells, among others (Vijayan et al, 2017). Nonclinical experiments have shown increased 
tumor growth inhibition and survival in tumor bearing mice treated with anti-CD73 antibody 
in combination with anti-PD-1/PD-L1 antibodies (Hay et al, 2016). As oleclumab selectively 
binds to CD73 and inhibits adenosine production as well as leads to a reduction in CD73 
expression, the combination with durvalumab is hypothesized to have a synergistic effect on 
reversal of immune suppression in the tumor microenvironment. Oleclumab in combination 
with durvalumab had a manageable safety profile in Study D6070C00001 (see Section 1.4.2),
further supporting exploration of this treatment combination. 
1.5.2
Rationale for Inclusion of Durvalumab in Combination with 
Monalizumab
 
 
 
 
 
1.5.3
Rationale for Inclusion of Durvalumab in Combination with 
Danvatirsen
 
 


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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, 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
Two recent clinical studies have shown that blockade of PD-l/PD-L1 in the neoadjuvant 
setting may yield clinically meaningful MPR and pCR (Forde et al, 2018; Rusch et al, 2018),
which have been shown to be associated with improved survival (Felip et al, 2010; Machtay et
al, 2004; Pataer et al, 2012).
This protocol will allow subjects with resectable, early-stage (Stage I [> 2 cm] to IIIA) 
NSCLC to receive durvalumab alone or in combination with novel therapies, and potentially 
achieve pathological response. Selection of the combination novel agents was 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 


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events including neurotoxicities, infusion-related reactions (IRRs), hypersensitivity reactions, 
and infections/serious infections. 
 
1.6.2.2
Oleclumab Plus Durvalumab
Overall, oleclumab and durvalumab combination therapy has demonstrated an acceptable 
safety profile (Section 1.4.2).
 
 
For oleclumab, important 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 serious 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. Given the mode of action of 
oleclumab, 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. 
 
1.6.2.3
Monalizumab Plus Durvalumab
Overall, durvalumab and monalizumab combination therapy has demonstrated an acceptable 
safety profile (Section 1.4.3).
 
 
 
There is currently no identified risk with monalizumab alone and/or in combination with 
durvalumab therapies. Given the mode of action of monalizumab, however, there are 
theoretical risks that could be related to its administration. These risks include adverse effects 
on the immune system, such as emergence of autoimmune phenomena, 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 


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receptors. The theoretical risk of infections with monalizumab could be the overlapping 
toxicity when treated with durvalumab.
 
1.6.2.4
Danvatirsen Plus Durvalumab
Overall, danvatirsen and durvalumab combination therapy has demonstrated an acceptable 
safety profile (Section 1.4.4). 
 
 
 
 
 
For danvatirsen, important identified risks are thrombocytopenia and liver enzyme elevations 
(ALT/AST). Important potential risks include reduced absolute neutrophil counts and reduced 
hemoglobin. In addition, as danvatirsen is being studied in combination with durvalumab, the 
side effects of danvatirsen and durvalumab are to some degree overlapping (possible 
ALT/AST elevations [danvatirsen] and immune mediated hepatitis [durvalumab]), therefore 
careful consideration is required in the evaluation and monitoring of the liver function in 
subjects receiving both study drugs simultaneously. The combination therapy may have 
overlapping toxicities and different mechanisms leading to increased hepatic events.
1.6.3
Overall Benefit-risk
Clinical and nonclinical data to date have shown acceptable safety profiles and antitumor 
activity for the novel agents proposed in this study. Neoadjuvant durvalumab alone or in 
combination with novel therapies may provide clinical benefit by enhancing the antitumor 
response and reducing disease recurrence after surgery.
The design of the current study aims to minimize potential risks to subjects, including the 
inclusion and exclusion criteria (Section 4.1.2 and Section 4.1.3), restrictions on concomitant 
medications during the study (Section 4.7.2), safety monitoring (including review of all 
relevant data by the Safety Review Committee [SRC, Section 3.1.4]), toxicity management 
guidelines (Section 3.1.3), stopping criteria (Section 4.4), and rules and procedures to add new 
durvalumab combination therapy 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.


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Further design elements aim to specifically minimize the risks to subjects enrolled in a 
durvalumab combination therapy 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 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 adverse events of special interest (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 treatment arm. 
!
Updated informed consent form with relevant information on the new durvalumab 
combination therapy arm.
Thus, the benefit-risk assessment for this Phase 2 platform study is acceptable.
1.7
Research Hypotheses
1.7.1
Primary Hypothesis
Neoadjuvant durvalumab alone or in combination with novel agents administered over a 
28-day treatment period to subjects with resectable, early-stage NSCLC (Stage I [> 2 cm] to 
IIIA) will lead to a pathological response within the resected tumor specimen.
1.7.2
Secondary Hypotheses
Neoadjuvant durvalumab alone or in combination with novel agents will demonstrate an 
acceptable safety profile and will not result in a delay in surgery in subjects with resectable, 
early-stage (Stage I [> 2 cm] to IIIA) NSCLC.
2
OBJECTIVES AND ENDPOINTS
Overall study objectives and endpoints applicable across treatment arms are presented below.
Each combination therapy arm will evaluate these objectives based on the respective novel 
agent. Secondary immunogenicity objective (b) is applicable only to novel biologic agents
(Table 2).






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3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview
Study D9108C00002 (NeoCOAST) is a Phase 2, open-label, multicenter, randomized, 
multidrug platform study of durvalumab alone or in combination with novel agents in subjects 
with resectable, early-stage (Stage I [> 2 cm] to IIIA) NSCLC.
Subjects will be enrolled and randomized into the durvalumab alone or combination treatment 
arms. Information on subject randomization and sample size is provided in Section 4.6.1 and 
Section 4.8.2, respectively. Up to approximately 25 sites globally will participate in this study.
Treatment arms may be opened sequentially or in parallel. Subjects will be treated with 
durvalumab alone or in combination with novel agents for up to 28 days, followed by surgical 
resection. After surgical resection, subjects will be followed up to Day 105 (Figure 1). New 
durvalumab combination therapy arms may be added based on emerging nonclinical and 
clinical data via a protocol amendment (Section 1.6.3). Interim futility analyses will be 
performed using Bayesian predictive probabilities (Section 4.8.7).


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Figure 1
Study Flow Diagram
ECOG PS = Eastern Cooperative Oncology Group Performance Status; NSCLC = non-small cell lung cancer.
NOTE: Enrollment into treatment arms may be stopped if planned interim analyses show safety concerns or lack 
of efficacy (Section 4.8.7). New combination treatment 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 will receive durvalumab alone or in 
combination with novel agents for a period of 28 days prior to surgical resection. Treatment 
arms may be opened sequentially or in parallel. Study treatment will be discontinued upon 
disease progression, unacceptable toxicity, or other reason, eg, subject decision or 
noncompliance with study procedures (Section 4.1.6). After the 28-day treatment period 
(starting from Week 1, Day 1), surgical resection will be planned within ≤14 days (Day 29 to 
Day 42). After surgical resection, subjects will be followed up to Day 105 (starting from 
Week 1, Day 1; Figure 2). If a subject receives adjuvant chemotherapy or radiotherapy as per 
standard clinical practice prior to Day 105, the subject will come off study and the end of 
study visit will be scheduled prior to start of adjuvant therapy.


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Figure 2
Study Period Duration
NOTE: See Figure 6 for details on the danvatirsen lead-in period (Week 0).
3.1.2.1
Durvalumab Monotherapy (Arm A)
Subjects randomized to durvalumab monotherapy will receive treatment as presented in 
Figure 3.
Figure 3
Treatment Regimen – Durvalumab Monotherapy
D = Day; Du = durvalumab; IV = intravenously; Q4W = every 4 weeks; W = Week.
Subjects will receive 
 durvalumab IV Q4W on Week 1, Day 1.
3.1.2.2
Durvalumab Plus Oleclumab (Arm B)
Subjects randomized to durvalumab in combination with oleclumab will receive treatment as 
presented in Figure 4.
Figure 4
Treatment Regimen – Durvalumab Plus Oleclumab
D = Day; Du = durvalumab; IV = intravenously; O = oleclumab; Q2W = every 2 weeks; Q4W = every 4 weeks; 
W = Week.
Subjects will receive 
 durvalumab IV Q4W on Week 1, Day 1 and 
 oleclumab IV Q2W on 
Week 1, Day 1 and Week 3, Day 1.


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3.1.2.3
Durvalumab Plus Monalizumab (Arm C)
Subjects randomized to durvalumab in combination with monalizumab will receive treatment 
as presented in Figure 5.
Figure 5
Treatment Regimen – Durvalumab Plus Monalizumab
D = Day; Du = durvalumab; IV = intravenously; M = monalizumab; Q2W = every 2 weeks; Q4W = every 4 
weeks; W = Week.
Subjects will receive 
 durvalumab IV Q4W on Week 1, Day 1 and 
 monalizumab IV Q2W on 
Week 1, Day 1 and Week 3, Day 1.
3.1.2.4
Durvalumab Plus Danvatirsen (Arm D)
Subjects randomized to durvalumab in combination with danvatirsen will receive treatment as 
presented in Figure 6.
Figure 6
Treatment Regimen – Durvalumab Plus Danvatirsen
D = Day; Da = danvatirsen; Du = durvalumab; IV = intravenously; Q4W = every 4 weeks; QW = every week; W 
= Week.
Subjects will undergo a 7-day danvatirsen lead-in period 
 danvatirsen IV on Days 1, 3, and 5 [Week 0]), 
followed by 
 durvalumab IV Q4W (Week 1, Day 1) and 
 danvatirsen IV QW (Week 1, Day 1, 
Week 2, Day 1, Week 3, Day 1, and Week 4, Day 1).
3.1.3
Management of Study Medication Related Toxicities
The following general guidance should be followed for management of toxicities.
!
Dose administration of the novel agent can be delayed up to 3 days, with the exception of 
the danvatirsen lead-in period as stated below. If delayed > 3 days, subjects will skip the 
planned dose. 
∀
For the danvatirsen lead-in period (Week 0), dose administration on Day 3 and Day 5 
can be delayed up to 1 day. If delayed > 1 day, subjects will skip the planned dose. 


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!
In the absence of clear alternative etiology, all events should be considered potentially 
immune mediated. 
!
In the event that an AE is considered related only to durvalumab or the combination novel 
therapy, both agents must be delayed.
!
For subjects who develop ≥ Grade 2 pulmonary edema or ≥Grade 3 peripheral edema 
after treatment with durvalumab plus oleclumab, doses should be omitted, and therapy 
may be discontinued at the discretion of the investigator.
If unsure how to manage a subject, 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, IRRs, and non-immune-
mediated reactions for durvalumab alone or in combination with the novel 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 are 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. In addition, a version of the current Toxicity Management Guidelines is 
available through the following link: https://tmg.azirae.com. Please contact the clinical study 
associate for information on how to gain access to this website.
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 
treatment 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)  


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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
 
 
 
 
 
 
3.2.1.2
Oleclumab
 
 
 
 
 
 
 
 
3.2.1.3
Monalizumab
 
 


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3.2.1.4
Danvatirsen
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2.2
Rationale for Study Population
Surgery is the preferred and cornerstone treatment approach for patients diagnosed with 
resectable, early-stage (Stage I [> 2 cm] to IIIA) NSCLC. However, the majority of patients 
experience post-surgical relapse and disease recurrence (Section 1.5). Neoadjuvant 
durvalumab alone or in combination with novel agents may result in pathological response 
and/or downstaging prior to surgery. 
3.2.3
Rationale for Endpoints
The primary objective of this platform study is to evaluate the efficacy of durvalumab alone 
and/or in combination with novel agents. The primary study goal is to assess the pathologic 
changes (eg, MPR) within the resected tumors, and identify promising durvalumab-based 
combination regimens for the treatment of patients with resectable, early-stage NSCLC. This 
study will use MPR, pCR, and BOR and ORR per RECIST v1.1 as efficacy endpoints to 
provide an early measure of antitumor activity. The safety and tolerability of each study 
treatment will be assessed by the standard safety endpoints, including AEs, SAEs, laboratory 


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abnormalities, and vital signs. Safety will also be assessed as feasibility to surgery, to capture 
any delays in the planned surgical resection. The development of ADA and its potential effect 
on safety and PK will also be assessed.
 
 
 
 
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
Up to 40 subjects per treatment arm may be enrolled into the study. Across all treatment arms, 
subject accrual beyond 20 subjects will be determined based on interim data (Section 4.8.7). 
At the onset, subjects will be randomized with equal ratios into each treatment arm. 
New durvalumab combination therapy arms may be added over time via a protocol 
amendment (Section 1.6.3). Details regarding the specifics of a new combination arm will be 
included in the protocol amendment. See also Section 4.6.1 for potential changes to the 
randomization scheme.
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1
Written informed consent and any locally required authorization (eg, data privacy) 
obtained from the subject prior to performing any protocol-related procedures, including 
screening evaluation.
2
Age ≥18 years old
3
Body weight ≥ 35 kg
4
Subjects must have cytologically and/or histologically-documented NSCLC
(a) Stage I (> 2 cm) to IIIA (for subjects with N2 disease, only those with 1 single nodal 
station ≤3 cm are eligible) NSCLC according to the 8th edition of American Joint 
Committee on Cancer staging classification 
(b) Considered amenable to complete surgical resection
(c) Subjects have not received any other therapy for this condition (chemotherapy, 
biologic or radiotherapy)
5
Predicted FEV1 ≥50%
6
Predicted DLCO ≥ 50%


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7
Of the initial 20 subjects per treatment arm to be enrolled, a minimum of 10 subjects per 
arm must provide pretreatment biopsy tumor tissue. Archived biopsies (tissue block or 
unstained slides) collected within ≤6 months of study entry or undergoing a pretreatment 
tumor biopsy are both acceptable. Sites need to confirm the nature of archival tumor 
material (biopsy vs others [cytology, fine needle aspiration, unavailable]) before 
randomization. Refer to the Laboratory Manual for details.
8
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
9
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 (1,000 per mm3)
Platelet count a
≥100 × 109/L (100,000 per mm3)
Hepatic
Total bilirubin
≤ 1.5 × ULN in the absence Gilbert’s syndrome
≤ 3 × ULN if the subject 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 formula using actual body weight (Cockcroft and Gault, 1976) or 
creatinine clearance based on 24-hour urine collection.
10 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 (Appendix A).
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1
Participation in another interventional clinical study within 90 days prior to enrollment.
2
Subjects with small-cell lung cancer or mixed small-cell lung cancer. 
3
Subjects who require or may require pneumonectomy, as assessed by their surgeon, to 
obtain potentially curative resection of primary tumor.
4
Prior treatment with PD-L1, PD-L1, or cytotoxic T-lymphocyte antigen 4 (CTLA-4) 
inhibitors. 
5
Current or prior use of immunosuppressive medication within 14 days before the first 
dose of study drug. The following are exceptions to this criterion:


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(a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection).
(b) Systemic corticosteroids ≤12 mg/day of prednisone or its equivalent.
(c) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
6
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:
(a) Subjects with vitiligo or alopecia.
(b) Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement.
(c) Any chronic skin condition that does not require systemic therapy.
(d) Subjects without active disease in the last 5 years may be included but only after 
consultation with the study physician.
(e) Subjects with celiac disease controlled by diet alone
7
Pregnant or breast-feeding female.
8
Major surgical procedure as defined by the Principal Investigator within 30 days prior to 
the scheduled first dose of study treatment. 
9
History of active primary immunodeficiency.
10 Active infection including tuberculosis, hepatitis B, hepatitis C, or human 
immunodeficiency virus.
11 History of allogenic organ transplantation.
12 Known allergy or hypersensitivity to investigational product formulation(s).
13 QTc interval (QTc) ≥470 ms. (NOTE: If prolonged, then 2 additional ECGs should be 
obtained and the average QTcF interval should be used to determine eligibility.)
14 Have moderate or severe cardiovascular disease:
(a) Presence of cardiac disease, including myocardial infarction or any other arterial 
thrombotic event including cerebrovascular accident, transient ischemic attack, or 
unstable angina pectoris within 6 months prior to study entry.
(b) New York Heart Association Class 3 or 4 congestive heart failure, or uncontrolled 
hypertension.
15 Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
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 
subject to give written informed consent.
16 Receipt of live attenuated vaccination within 30 days prior to study entry.
17 History of another primary malignancy except for:
(a) Curative-treated malignancy with no known active disease > 2 years before
enrollment on the study. 


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(b) Curative-treated non-melanoma skin cancer and/or carcinoma in-situ.
18 Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca/MedImmune staff and/or staff at the study site).
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 (eg, 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. Individuals who do not meet the criteria for 
participation in this study (screen failure) may be re-screened, only after discussion with and 
permission from the sponsor or its designee. 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 
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 will not receive any further investigational product if any of the 
following occur in the subject in question:
1
The subject or the subject’s designee requests withdrawal of consent for further dosing.
2
Disease progression and investigator determination that the subject is no longer 
benefitting from treatment.
3
Any toxicity/AE that in the opinion of the investigator and/or the sponsor, warrants 
discontinuation of further dosing.
4
Any AE that meets criteria for discontinuation as defined in the Toxicity Management 
Guidelines (see Section 3.1.3)
5
Initiation of alternative anticancer therapy 


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6
Intercurrent illness or medical condition, in the judgment of the investigator and/or the 
sponsor warrants discontinuation of further dosing.
7
Pregnancy or intent to become pregnant (Section 5.6.2).
8
Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (eg, refusal to adhere to scheduled visits)
9
The treating physician determines it is not in the best interest of the subject to continue 
treatment.
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.
4.1.7
Replacement of Subjects
Subjects who are dosed 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 is an integral part of the study, if a 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.


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4.2
Schedule of Study Procedures
The schedule of study procedures outlined in this section, with the exception of the study drug 
administration which are treatment-arm specific such as danvatirsen, will be followed for all 
treatment arms. The study drug treatment regimens for each treatment arm are presented in 
Section 3.1.2. 


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Table 5
Schedule of Screening, Treatment, and Follow-up Period Procedures
Procedure
Screening
Danvatirsen
Only Arm 
(Lead-in) a
28-day Treatment Period
Surgical 
Resection b
Follow-up
Day -21 to
Day -1
Week 0, 
Day 1 
(±3 days) c
Week 1, 
Day 1 
(±3 days) c
Week 3, 
Day 1 
(±3 days)
EoT
Day 28 
(±3 days)
Day 29 to 
Day 42
Day 105
(±21 days) d
Written informed consent
X
Demographics 
X
Medical history e
X
Verify eligibility criteria 
X
Physical examination f 
X 
X
X
X
X
X
Vital signs
X
X
X
X
X
X
ECG g
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
Tumor specimen h
X
X
Serum chemistry 
X
X i
X i
X
X
X
Thyroid function tests j
X
X i
X i
X
X
X
Hematology 
X
X i
X i
X
X
X
Urinalysis 
X
As clinically indicated
Coagulation parameters
X
X i
X i
X
X
Hepatitis B and C; HIV k
X
Pregnancy test l
X
X
X
Concomitant medications
X
X
X
X
X
X
Assessment of AEs/SAEs
X
X
X
X
X
X
Disease assessments (scans) m
X 
X




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Table 5
Schedule of Screening, Treatment, and Follow-up Period Procedures
Procedure
Screening
Danvatirsen
Only Arm 
(Lead-in) a
28-day Treatment Period
Surgical 
Resection b
Follow-up
Day -21 to
Day -1
Week 0, 
Day 1 
(±3 days) c
Week 1, 
Day 1 
(±3 days) c
Week 3, 
Day 1 
(±3 days)
EoT
Day 28 
(±3 days)
Day 29 to 
Day 42
Day 105
(±21 days) d
c
Subjects will be randomized after completing the screening assessments. Study treatment must be administered within 3 days after the treatment arm is 
assigned; subjects may also be randomized on Week 0, Day 1 (danvatirsen only arm) or Week 1, Day 1 prior to dosing.
d
If a subject receives subsequent anticancer treatment (eg, adjuvant chemotherapy or radiotherapy) prior to Day 105 (± 21 days), the follow-up visit can be 
scheduled earlier, prior to the start of adjuvant therapy. 
e
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. 
f
A complete physical examination will be performed at screening. Abbreviated symptom-directed physical examinations will be conducted at subsequent 
visits post dosing.
g
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. On Week 0, 
Day 1 and Week 3, Day 1, ECGs will be performed predose and immediately after the end of danvatirsen infusion (prior to the start of durvalumab 
infusion). ECGs should also be performed as clinically indicated. 
h
Of the initial 20 subjects per treatment arm to be enrolled, a minimum of 10 subjects per arm must provide pretreatment biopsy tumor tissue. Archived 
biopsies (tissue block or unstained slides) collected within ≤6 months of study entry or undergoing a pretreatment tumor biopsy are both acceptable. 
Sites need to confirm the nature of archival tumor material (biopsy vs others [cytology, fine needle aspiration, unavailable]) before randomization.  
i
If screening laboratory assessments are performed within 3 days prior to Day 1, they do not need to be repeated at Day 1.
j
TSH only. If TSH is abnormal, add T3 and T4 assessments.
k
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.
l
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 positive or equivocal, then serum β-hCG testing should be performed for confirmation. 
m
CT scan of the chest and abdomen; an equivalent MRI scan is acceptable.
n
A brain MRI (preferred) or CT scan is required only during the screening period.
o
Samples will not be collected from subjects enrolled in the danvatirsen + durvalumab treatment arm on Week 1, Day 1. 
p


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Table 5
Schedule of Screening, Treatment, and Follow-up Period Procedures
Procedure
Screening
Danvatirsen
Only Arm 
(Lead-in) a
28-day Treatment Period
Surgical 
Resection b
Follow-up
Day -21 to
Day -1
Week 0, 
Day 1 
(±3 days) c
Week 1, 
Day 1 
(±3 days) c
Week 3, 
Day 1 
(±3 days)
EoT
Day 28 
(±3 days)
Day 29 to 
Day 42
Day 105
(±21 days) d
q
On Week 0, Day 1 (danvatirsen only arm [lead-in period]), Week 1, Day 1, and Week 3, Day 1, plasma or serum samples for PK will be collected 
predose (within 60 minutes prior to the start of infusion), and immediately post EOI (within 10 minutes after the EOI). In combination arms, PK predose 
and 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.
r
In all treatment arms, ADA samples will be collected predose, within 60 minutes 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.
s
Treatment regimens are described in Section 3.1.2.


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4.3
Description of Study Procedures
4.3.1
Efficacy
4.3.1.1
Evaluation of Response
Pathological tumor response will be assessed locally in the resected specimens. Hematoxylin 
and eosin-stained slides of sections of the gross residual tumor will be prepared by 
pathologists. At least 1 section per cm of tumor at its greatest diameter is recommended. The 
percentage of residual tumor will be estimated by comparing the estimated cross-sectional 
area of the viable tumor cells with estimated cross-sectional total tumor (including areas of
necrosis, fibrosis, and/or inflammation). The results from all slides will be averaged together 
to determine the mean values for each subject. MPR is defined by ≤10% viable tumor cells in 
the resected specimen. pCR is defined as no residual viable tumor cells in the resected 
specimen. At the discretion of the sponsor, an independent, central review may be considered 
to evaluate pathological response. 
RECIST v1.1 (Appendix F) will be used to assess subject response to treatment and allow 
calculation of ORR. Disease assessments will be performed according to the schedules in 
Section 4.2. Radiographical confirmation of a response is not feasible due to the length of the 
study (eg, a confirmatory scan will not be performed). Tumor assessments may include the 
following evaluations: cross-sectional imaging using computed tomography (CT) or magnetic 
resonance imaging (MRI) scan of the chest, abdomen, and brain. 
!
MRI (preferred) or CT scans of the brain will be performed at screening for all subjects
!
CT or MRI scan of the chest and abdomen will be performed at screening and with each 
disease assessment for all subjects. 
The preferred method of disease assessment is CT with contrast; if CT with contrast is 
contraindicated, CT without contrast is preferred over MRI. The preferred method for central 
nervous system imaging is MRI; if CT scan is performed, CT with contrast is required. The 
same method is preferred for all subsequent tumor assessments. 
Computed Tomography Scan
!
CT (contrast preferred) scans of the chest and abdomen should be performed with 
contiguous cuts in slice thickness of 5 mm or less. Spiral CT should be performed using a 
5-mm contiguous reconstruction algorithm. The same imaging device should be used for 
serial evaluations.
Magnetic Resonance Imaging Scan
!
MRI scan of the chest and abdomen is acceptable for measurement of lesions provided 
that the same anatomical plane is used for serial assessments. 


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!
In case of MRI, measurements will be preferably performed in the axial (transverse) plane 
on contrast-enhanced T1-weighted images. However, there are no specific sequence 
recommendations.
4.3.1.2
Baseline 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, 2008).
!
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
Lung Cancer Surgery
Feasibility to surgery will be evaluated (Section 4.8.4). General recommendations for the 
surgical therapy of subjects with resectable NSCLC include, where feasible:
!
Anatomical resection consisting of at least a lobectomy
!
Adequate collection of the margins of resection 
!
N1 and N2 node resection and mapping should be routine with a minimum of three N2 
stations sampled or preferentially a complete mediastinal lymph node resection
!
Complete ipsilateral mediastinal lymph node dissection is highly recommended for 
subjects undergoing resection for Stage IIIA-N2 disease
!
A complete resection is the most important prognostic factor and should include free 
resection margins including mediastinal lymph node dissection
!
Subjects who are eligible for an anatomic segmentectomy with formal ligation of the 
segmental artery and bronchus, and node dissection as described above can be considered 
after discussion with the medical monitor


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4.3.3
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, weight to 0.1 kg, and height (screening only). Abbreviated symptom-directed 
physical examinations will be conducted at subsequent visits post dosing. 
Vital Signs
Vital signs (blood pressure, pulse rate, and temperature) 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 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 (eg, for initially prolonged QTcF value, the average QTcF value 
of all 3 manually overread ECGs should be ≥470 ms for the QTcF prolongation to be 
confirmed).
4.3.4
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. 


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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 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
•
GGT
•
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
ULN = upper limit of normal
Note: Tests for AST, ALT, ALP, and TBL must be conducted concurrently and assessed concurrently.
Hematology
•
Absolute lymphocyte count a
•
Platelet count
•
Absolute neutrophil count a
•
White blood cells count a
•
Absolute leukocyte count
•
Hemoglobin
a
Can be recorded as absolute counts or as percentages. Absolute counts will be calculated by Data 
Management if entered as percentage. Total white blood cell count therefore has to be provided.
Urinalysis
•
Protein
•
Blood 
Pregnancy Test (females of childbearing potential only)
•
Urine hCG
•
Serum β -hCG (required if a urine hCG is equivocal or positive)
β -hCG = beta-human chorionic gonadotropin; hCG = human chorionic gonadotropin.
NOTE: A urine or serum pregnancy test is acceptable; if urine test is positive or equivocal, then serum β-hCG 
testing should be performed for confirmation.


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Other Safety Tests
•
Coagulation tests: activated aPTT and INR. If INR is not available, the sites may substitute a prothrombin 
time PT.
•
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 only. If TSH is abnormal, add T3 and T4 assessments.
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; INR = international normalized ration; 
PT = prothrombin time; RNA = ribonucleic acid; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid 
stimulating hormone.
4.3.5
Pharmacokinetic Evaluation and Methods
Blood samples will be collected to evaluate PK in plasma or serum when durvalumab is 
administered alone and/or in combination with novel agents. Additionally, PK of novel agents 
administered in combination with durvalumab will be evaluated; 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 samples are required, PK 
predose (within 60 minutes prior to the start of infusion) and end of infusion (within 10 
minutes post end of infusion) samples will be collected according to the administration time of 
each study drug. For example: PK predose Agent 1 collected →Agent 1 administration → PK 
end of infusion Agent 1 collected → PK predose Agent 2 collected →Agent 2 administration 
→ PK end of infusion Agent 2 collected.
4.3.6
Immunogenicity Evaluation and Methods
Blood samples will be collected to evaluate antidrug antibody (ADA) responses to biological 
agents (durvalumab, oleclumab, monalizumab, and danvatirsen) when durvalumab is 
administered alone or in combination with novel agents; see Section 4.2 for collection time 
points. Evaluations will be performed using a validated immunoassay. Tiered analyses 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 samples. 
Samples may be utilized for further characterization of the ADA response.
In all treatment arms, ADA samples will be collected within 60 minutes 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.


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4.3.7
4.3.7.1
 
 
 
 
 
 
 
 
4.3.7.2
 
 
 
 
4.3.8
Biomarker Evaluation and Methods
The subject’s consent to the use of donated biological samples is mandatory.
Details on sample collection, processing, handling, shipment, and storage are provided in the 
Laboratory Manual.
4.3.8.1
Radiomics
CT or MRI scans will be performed as indicated in Section 4.2. Changes in radiomics 
signatures may be compared in pretreatment vs post-treatment scans, and correlation with 
pathological response may be evaluated.




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4.3.8.7
 
 
4.3.8.8
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 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.
4.3.9
Estimate of Volume of Blood to Be Collected
A total of no more than 35 mL of blood will be required for all screening tests. No more than 
51 mL of blood will be drawn at any visit during the treatment period. During the follow-up 
visit, no more than approximately 36 mL of blood will be collected. 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 or component of the study may include but are not limited to the 
following: 
1
Recommendation by the SRC, or 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 component of the study based on a planned 
futility analysis
6
Regulatory, ethical or other reason consistent with applicable laws, regulations and GCP.
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 


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applicable). 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, 
MedImmune will promptly inform all investigators, heads of the medical institutions (where 
applicable), and/or institutions conducting the study. MedImmune will also promptly inform 
the relevant regulatory authorities of the suspension/termination along with the reasons for 
such action. Where required by applicable regulations, the investigator or head of the medical 
institution must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination. 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 resuming the study.
4.5
Investigational Products
4.5.1
Identity of Investigational Product(s)
For all the treatment arms, MedImmune will provide the investigators with study drug 
(Table 6) using designated distribution centers. 
Table 6
Identification of Investigational Product 
Investigational Product
Supplier
Concentration and Formulation as Supplied
Durvalumab (MEDI4736)
MedImmune
 
 
 
 
 
 
Oleclumab (MEDI9447)
MedImmune
 
 
 
Monalizumab (IPH2201)
MedImmune
 
Danvatirsen (AZD9150)
AstraZeneca
 
 


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Table 6
Identification of Investigational Product 
Investigational Product
Supplier
Concentration and Formulation as Supplied
 
 
 
 
 
 
 
 
 
 
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. 
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. 


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If there are any defects noted with the investigational product, the investigator and site 
monitor should be notified immediately. Refer to the Product Complaint section 
(Section 4.5.1.9) 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 
exceed: 
!
24 hours at 2°C to 8°C (36°F to 46°F)
!
4 hours at room temperature 
A dose of 
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 
 and 
delivered through an IV administration set with a 0.2- or 0.22-μm filter. 
 of 
durvalumab (ie, 
 of durvalumab) to the IV bag. The IV bag size should be selected 
such that the final concentration is within 
 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 treatment 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. For IV flushing instructions, 
refer to Section 4.5.1.7.
If either preparation time or infusion time exceeds the time limits outlined above, a new dose 
must be prepared from new vials. Durvalumab does not contain preservatives, and any unused 
portion must be discarded.
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 
designated 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)


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!
4 hours at room temperature
No incompatibilities between oleclumab and polyvinylchloride or polyolefin IV bags have 
been observed.
A dose of 
 will be administered using an IV bag containing 0.9% (w/v) saline with a 
final oleclumab concentration of 
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 of the
dose in the bag.
Standard infusion time for oleclumab is 1 hour; however, if there are interruptions during 
infusion, 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 the day 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 
durvalumab administration. In the event that on the day 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. For IV flushing instructions, 
refer to Section 4.5.1.7
If preparation time exceeds the time limits outlined above, a new dose must be prepared from 
new vials. Oleclumab does not contain preservatives, and any unused portion must be 
discarded.
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. Visually inspect the solution to ensure that the entire content of the 
lyophilized cake is completely 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:


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!
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 (PVC) IV bags have been observed.
A dose of 
 will be administered using an IV bag containing 0.9% (w/v) saline or 5% 
(w/v) dextrose, with a final monalizumab concentration of 
 and delivered 
through an IV administration set with a 0.2- or 0.22 μm filter. Add 
 of monalizumab 
(ie, 
 of monalizumab) to the IV bag. The IV bag size should be selected such that the 
final concentration is within 
Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag.
Standard monalizumab 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. The 
infusion rate should not be changed unless necessary to manage acute reactions. 
On the day when both durvalumab and monalizumab are administered, durvalumab will be 
administered 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 
infusion. In the event that on the day when both durvalumab and monalizumab are 
administered and there are interruptions during infusion for either durvalumab and/or 
monalizumab, 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. For IV flushing instructions, 
refer to Section 4.5.1.7
If either preparation time or infusion time exceeds the time limits outlined above, a new dose 
must be prepared from new vials. Monalizumab does not contain preservatives, and any 
unused portion must be discarded.
4.5.1.6
Danvatirsen Dose Preparation and Administration
The dose of danvatirsen for administration must be prepared by the investigator’s or site’s 
designated investigational product manager in a validated aseptic suite; it should not be 
prepared on the ward. 
Vials must be used within the individually assigned expiry date on the label.


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Remove two vials from the refrigerator and allow the vials to equilibrate to room temperature 
for 30 minutes prior to dose preparation.
Add 
 of danvatirsen to an IV infusion bag containing 250 mL of 0.9% (w/v) 
sodium chloride (normal saline) using a regular 18G to 22G stainless steel needle and latex-
free syringe made of polypropylene or polycarbonate. Mix the bag by gently inverting to 
ensure homogeneity of the dose in the bag.
Saline IV bags (250 mL) must be latex-free and can be made of PVC or polyolefins, 
manufactured with bis (2-ethylhexyl) phthalate (DEHP) or DEHP-free. IV infusion lines made 
of PVC/DEHP-free or PVC/DEHP-containing are acceptable for use.
Label the IV bag per the institution’s procedures. Record on the label the total volume 
contained in the IV bag. Include the total volume, the overfill (assume 25 mL unless otherwise 
known) and the volume of danvatirsen that was added.
Fully prime the infusion line with normal saline, prior to connecting it to the danvatirsen IV 
bag.
Following preparation of the dose, the entire contents of the IV bag should be administered at 
a constant rate over 1 hour.
Total time from needle puncture of a danvatirsen vial to end of administration should not 
exceed: 
!
24 hours at 2°C to 8°C (36°F to 46°F)
∀
Note: This represents the maximum storage time at 2°C to 8°C and will therefore be 
reduced by any time spent at room temperature.
!
4 hours at room temperature 
The above storage times are based on chemical and physical stability; assignment of microbial 
shelf-life is the responsibility of the clinical center and should be aligned with local 
procedures for managing microbial risk, so long as the above are not exceeded.
Infusion solution must be allowed to equilibrate to room temperature prior to commencement 
of administration, allow approximately 30 minutes for this. 
If in-use time exceeds the stated limits outlined above, a new dose must be prepared from new 
vials. 
Danvatirsen does not contain preservatives, and any unused portion of concentrate in vial 
must be discarded.


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It is not necessary to protect the diluted infusion from light during the period of preparation 
and administration.
Do not co-administer other drugs or solutions through the same infusion line. For IV flushing 
instructions, refer to Section 4.5.1.7.
On the day when both durvalumab and danvatirsen are administered, danvatirsen will be 
administered first. See 4.5.1.3 for durvalumab treatment administration. 
On the day when danvatirsen and durvalumab are infused, durvalumab will start 
approximately 1 hour after the end of the danvatirsen infusion. 
4.5.1.7
Treatment Administration
The first day of dosing with durvalumab alone or in combination with novel agents is 
considered Week 1, Day 1 in all the treatment arms. In the durvalumab + danvatirsen 
treatment arm, the lead-in period for danvatirsen starts on Week 0, Day 1. 
No specific premedication is required for durvalumab, oleclumab, monalizumab, or 
danvatirsen. Details of any premedication or concomitant medication given to manage or 
prevent AEs should be recorded on the electronic case report form (eCRF).
In all treatment arms, 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 according to institutional policy to ensure the full dose is administered.
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.
4.5.1.8
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.
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 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis.
4.5.1.9
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the MedImmune 
Product Complaint Department by the site with further notification to the site monitor. All 
defects will be communicated to MedImmune and investigated further with the Product 


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Complaint Department. During the investigation of the product complaint, all investigational 
product must be stored at labeled conditions unless otherwise instructed.
MedImmune contact information for reporting product complaints:
Email: productcomplaints@medimmune.com
Phone: +1-301-398-2105
+1-877-MEDI-411 (+1-877-633-4411)
Fax:
+1-301-398-8800
Mail:
MedImmune
Attn: Product Complaint Department
One MedImmune Way,
Gaithersburg, MD USA 20878
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 
Manufacturing 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; 
refrigerated) and must not be frozen. Investigational product supplied as oral tablet should be 
stored at 15°C to 30°C (59°F to 86°F). Drug product should be kept in original 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.


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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. The randomization scheme will use an equal ratio to all study treatment arms open 
for enrollment (eg, if treatment arms are opened sequentially, a treatment arm is added/closed, 
or enrollment in a treatment arm is suspended). After 20 subjects have been enrolled into any 
treatment arm, the randomization ratio can be adjusted. Randomization will be stratified by
lymph node involvement (Yes vs No). At the onset, the randomization scheme will use an 
equal ratio in all treatment arms. 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.
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 
provide adequate prophylactic or supportive care except for those medications identified as 
prohibited 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 
prohibited:
!
Any other investigational anticancer therapy
!
Any concurrent chemotherapy, 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.


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!
Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses exceeding 12 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, topical corticosteroids, or local steroid injections (eg, 
intra-articular injection) 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
!
Herbal and natural remedies should be avoided
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 
summarized by descriptive statistics. Additional details of statistical analyses will be 
described in the statistical analysis plan.
The Intent-to-treat (ITT) Population is defined as all subjects who are randomized and receive 
any amount of investigational product. Subjects will be analyzed according to randomized 
treatment assignment. All analyses will be performed on the ITT Population unless otherwise 
specified.
The As-treated Population is defined as all subjects who receive any investigational product. 
Subjects will be analyzed according to the treatment they actually received. All safety 
endpoints will be analyzed on the As-treated Population.
The Efficacy Evaluable Population includes subjects from the As-treated Population who have 
the opportunity to be followed for the planned surgery by the time of the data cutoff, and 
either have pathological tumor response data post-surgery and/or discontinued treatment due 
to death or disease progression. Interim analyses of efficacy will be performed on this 
population.
4.8.2
Sample Size
This study is designed to obtain preliminary clinical efficacy, safety, PK and immunogenicity
data on durvalumab in combination with novel agents compared to durvalumab monotherapy. 
It is not designed to make explicit power and Type I error considerations for a hypothesis test. 






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concerned treatment arm may be paused. The SRC members will be notified and an SRC 
meeting will be planned within the next 14 days. During the SRC meeting all delays to 
surgery in the concerned arm will be reviewed, and the recommendation of the SRC will be 
discussed with the sponsor to make a final decision about stopping enrollment into the 
concerned arm.
Delays to surgery not considered for the feasibility analysis include:
!
Weather or other local emergencies impacting normal hospital activities.
!
Unforeseen causes not related to the disease under study such a car accident, family 
illness or unexpected travel.
!
Withdrawal of consent to further participation on the study not related to AEs or study 
procedures. 
4.8.4.1
Analysis of Adverse Events
AEs will be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events version 5.0 (NCI CTCAE v5.0) using the Medical Dictionary for 
Regulatory Activities (MedDRA) by system organ class (SOC) and preferred term (PT). 
Specific AEs will be counted once for each subject for calculating rates, but will be presented 
in total in subject listings. In addition, if the same AE occurs multiple times within a particular 
subject, the highest severity and level of causality will be reported. All treatment-emergent 
AEs will be summarized overall and by MedDRA SOC and PT, by severity and relationship 
to investigational product. In addition, summaries of deaths, SAEs and treatment 
discontinuations due to AEs will be provided. AEs before and after surgery will be 
summarized separately.
4.8.4.2
Analysis of Clinical Laboratory Parameters
Laboratory parameters will be assessed at baseline as well as throughout the study. 
Frequencies 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 parameters 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 end of treatment visit 
as well as for the maximum and minimum post-baseline values.


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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 
4.8.5.1
Immunogenicity Analyses
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 
percentage of subjects who develop detectable ADAs to durvalumab. For treatment arms that 
include a novel biologic agent, the immunogenic potential of the novel biologic agent will be 
assessed by summarizing the number and percentage of subjects who develop detectable 
ADAs to the novel biologic agent.
4.8.5.2
Pharmacokinetic Analyses
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 and individual combination study drug concentrations will be tabulated 
with descriptive statistics. 
4.8.6
 
 
4.8.7
Interim Analysis
Interim analyses will be conducted during the course of the study to evaluate the clinical 
activity and safety of any treatment arm. The first planned interim analysis will be initiated 
once at least 1 treatment arm has enrolled 20 efficacy evaluable subjects (see Section 4.8.1). 
Across all treatment arms, subject accrual beyond 20 subjects will be determined based on 
interim data. Bayesian predictive probabilities will be used to evaluate clinical activity (Lee 
and Liu, 2008). In this study, a target value (TV) of ΔMPR as 
% is assumed, where ΔMPR 
is the difference in MPR between a combination therapy treatment arm and the durvalumab 
monotherapy arm.
!
A treatment arm will meet the No-Go criteria if the probability that the true ΔMPR are
larger than TV is less than 
%, ie, Prob.(True ΔMPR > 
) < 
 A No-Go decision 
will be made at the interim analysis if the predictive probability of meeting the No-Go 




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associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
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
investigational product(s) 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 association with the use of this investigational product(s).
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 


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interventions such as steroids, immunosuppressants, and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy 
and combination therapy. An immune-mediated adverse event (imAE) is defined as an AE 
that is associated with drug exposure and is consistent with an immune-mediated mechanism 
of action and where there is no clear alternate 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 disease. 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, serum sickness). 
Subjects who experience an AE suspected to be immune-complex related and with 
confirmed presence of ADAs will discontinue treatment. Immune-complex disease will 
be managed in accordance with standard of care.
!
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 
pharmacological etiology are also considered AESIs. Infusion of biological products is 
commonly associated with IRRs. Anaphylaxis and IRRs have some common manifestations 
and may be difficult to distinguish from each other. IRRs are commonly observed 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 event, usually occurring after subsequent exposure to an antigen, and it is most 


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commonly accompanied by severe systemic, skin and/or mucosal reactions. The investigator 
is advised to carefully examine symptoms of adverse reactions observed during or shortly 
after exposure to investigational product, and consider the above-mentioned facts prior to 
making a final diagnosis. For the investigator’s convenience and to facilitate consistency in 
judgments, a copy of the National Institute of Allergy and Infectious Diseases (NIAID) and 
Food Allergy and Anaphylaxis Network (FAAN) guidance for anaphylaxis diagnosis is 
provided in Appendix C.
Further information on these 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 (Section 3.1.3). These guidelines 
have been prepared by the sponsor to assist the investigator in the exercise of his/her clinical 
judgment in treating these types of toxicities. These guidelines apply to AEs considered 
causally related to the study drug/study regimen by the reporting investigator.
5.3.2
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 
interest due to oleclumab potential risks of arterial calcifications, arterial ischemic disorder, 
and thrombosis. Because of this potential risk, potential subjects with a history of myocardial 
infarction or or any other arterial thrombotic event within 6 months before study entry are not 
eligible (see Section 4.1.3). These events require urgent medical management, 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 an AESI due to oleclumab potential risks 
of increased microvascular permeability. For subjects who develop ≥ Grade 2 pulmonary 
edema or ≥Grade 3 peripheral edema after treatment with durvalumab plus oleclumab, doses 
should be omitted (Section 3.1.3), and therapy may be discontinued at the discretion of the 
investigator.
5.3.3
Adverse Events of Special Interest Associated with Monalizumab
There are no specific AESI for monalizumab, outside of the AESIs associated with 
durvalumab, as stated Section 5.3.1. 
5.3.4
Adverse Events of Special Interest Associated with Danvatirsen
There are currently no AESIs associated with danvatirsen.


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5.4
Recording of Adverse Events
AEs will be recorded on the eCRF using a recognized medical term or diagnosis that 
accurately 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 
Section 5.2 for the definition of SAEs and Appendix B for guidelines on assessment of 
severity and relationship. 
If an AE evolves into a condition that meets the regulatory definition of “serious,” it will be 
reported on the SAE Report Form.
5.4.1
Time Period for Collection of Adverse Events
AEs and SAEs will be collected from time of signature of informed consent throughout the 
treatment period and including the follow-up period.
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 withdrawn 
consent for study participation may be followed up by the investigator for as long as medically 
indicated, but without further recording in the eCRF. MedImmune retains the right to request 
additional information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary.
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. 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).


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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 
intervention by the investigator, or a finding judged by the investigator as medically 
significant 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 laboratory 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-
mandated 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 
reported 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 
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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 
progression (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(s) 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.
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 
necessary 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 
representatives 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 
representative(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 are the IBs for the study
drugs.


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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 respective IB, unless otherwise specified in this protocol. For danvatirsen, 
administration in doses significantly exceeding those specified in the protocol (> 10% of 
recommended dose) is considered an overdose; overdose in an amount ≤10% of the specified 
dose and not associated with AEs does not need to be reported.
!
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 investigational product 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.
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.


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If any pregnancy occurs during the course of the study, then the investigator or other site 
personnel 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 
information 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 
pregnancy 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 
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 
potential to cause harm to the subject. 
A medication error is not lack of efficacy of the study drug, but rather a human- or process-
related failure while the study 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 study 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:
!
Study 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
!
Study drug not administered as indicated, eg, wrong route or wrong site of administration
!
Study drug not taken as indicated, eg, tablet dissolved in water when it should be taken as 
a solid tablet 


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!
Study 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 study 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 study 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
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.  
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate 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 
relevant 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. 
Medication 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 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).


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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)
!
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 the location of the source data.
6.2.2
Study Agreements
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this protocol and the Clinical Study Agreement, the terms of this 
protocol shall prevail with respect to the conduct of the study and the treatment of subjects 
and in all other respects, not relating to study conduct or treatment of subjects, the terms of the 
Clinical Study Agreement shall prevail.
Agreements between 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.


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6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed 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 for the last subject in the study. This date will be 1 year 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.
An EDC system will be used for data collection and query handling. The investigator will 
ensure 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 
investigator 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 
addition, 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 situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 
requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the Principal Investigator is not available, the treating physician or 
health care provider 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 trial, eg, demographic


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information, physical or mental health condition, diagnosis, comorbidities, laboratory test 
results, 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 
incorporating) wording that describes how subject data will be collected, used, and distributed 
in compliance with relevant data protection and privacy legislation. Data (clinical and 
biological samples) 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.
Extra precautions will be taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the subject. MedImmune will not provide individual genotype results 
to subjects, any insurance company, any employer, their family members, general physician or 
any other third party, unless required to do so by law.
7.2
Ethics and Regulatory Review
The IRB/IEC responsible for each site must review and approve the final study protocol, 
including the final version of the informed consent form and any other written information 
and/or materials to be provided to the subjects. The IRB/IEC must also approve all advertising 
used to recruit subjects for the study. The investigator is responsible for submitting these 
documents to the applicable IRB/IEC, and distributing them to the study site staff.
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 SUSARs where 
relevant, to regulatory authorities, IRB/IEC, and Principal 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 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 


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informed consent form for use by all investigators in the clinical study. MedImmune must 
approve any modifications to the informed consent form that are needed to meet local 
requirements.
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
7.4
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and MedImmune. 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, 
advertising, and any other written information and/or materials resulting from the change to 
the protocol.
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 


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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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9.2
Protocol Amendment 1
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 1. The principal reason for this amendment is to address feedback provided by
the US Food and Drug Administration (FDA) after the Investigational New Drug filing. 
Substantial changes to the protocol are summarized below.
1
Section 3.1.3 (Management of Study Medication Related Toxicities): Specified that for 
subjects who develop ≥ Grade 2 pulmonary edema or ≥ Grade 3 peripheral edema after 
treatment with durvalumab plus oleclumab, doses should be omitted, and therapy may be 
discontinued at the discretion of the investigator per FDA request.
2
Table 5 (Schedule of Screening, Treatment, and Follow-up Period Procedures): 
(a) Added ECG assessments predose and immediately after the end of danvatirsen 
infusion on Week 0, Day 1 and Week 3, Day 1, respectively, and as clinically 
indicated per FDA request. 
(b) Added PK assessments on Week 3, Day 1 to align with the ECG assessments on 
Week 3, Day 1 to address an FDA request. 
3
Section 4.8.4 (Safety): Clarified that the SRC will assess feasibility to surgery for all 
treatment arms during every meeting and added safety measures in the event that more 
than 1 subject per treatment arm experiences a delay in receiving the planned surgery 
(outside of the prespecified exclusionary reasons) to address an FDA request. 
4
Section 5.3.2 (Adverse Events of Special Interest Associated with Oleclumab): Revised to 
state that for subjects who develop ≥ Grade 2 pulmonary edema or ≥ Grade 3 peripheral 
edema (previously ≥ Grade 3 edema) after treatment with durvalumab and oleclumab, 
doses should be omitted, and therapy may be discontinued at the discretion of the 
investigator per FDA request.
Changes to the protocol considered to be non-substantial are summarized below: 
1
Figure 1 (Study Flow Diagram): Removed Arm E and Arm F from the study design figure 
per FDA request. 
2
Table 5 (Schedule of Screening, Treatment, and Follow-up Period Procedures): 
(a) Footnote a: Added a dosing window of ± 3 days on Week 2, Day 1 and Week 4, 
Day 1 of danvatirsen administration to provide greater scheduling flexibility for the 
subjects.  
(b) Footnote n: Removed text on the timing of performing a brain MRI or CT scan, “This 
must be performed only after study eligibility is confirmed, to detect intracranial 
metastasis” to correct an error, as subjects with brain metastasis have late-stage 
NSCLC and would not be eligible to participate in this study. 
(c) Footnote q: Revised to “treatment” arms (previously “combination” arms) to clarify 
that ADA samples from all treatment arms (including durvalumab monotherapy) will 
be collected within 60 minutes prior to administration of the first study drug only. 




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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 
contraception described in Table A1 from screening to 180 days after the final dose of 
investigational 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 final dose of investigational product.
Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or postmenopausal. The 
definition 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 (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.
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 a 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 intravenous 
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.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a 
nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE.
Assessment of Relationship
A guide to Interpreting the Causality Question
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? 


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!
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?
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?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
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
NIAID and FAAN 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 the following reference:
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 any 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 the 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 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 
authorities 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:
!
Send the updated SAE (report term ‘Hy’s Law’) according to the sponsor’s standard 
processes.


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∀
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply
∀
As there is no alternative explanation for the 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 
necessary 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 is related to the investigational 
product and seriousness criteria are 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
Laboratory Tests
To evaluate the underlying etiology of potential Hy’s Law cases, relevant laboratory tests will 
be performed as outlined in Section 4.3.4. Additional laboratory assessments may be 
performed as clinically indicated.


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Appendix E
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix F
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.
!
Progressive Disease (PD) - At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered PD.)
!
Stable Disease (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 that 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 (Borghaei et al, 2015). 
Evaluation of Overall Response
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.


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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)


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SAP_001.pdf: 
AstraZeneca/MedImmune
Statistical Analysis Plan for Protocol D9108C00002
Neoadjuvant durvalumab and novel oncology therapies
10Aug2021; final version 4.0
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Statistical Analysis Plan
A Phase 2 Open-label, Multicenter, Randomized, Multidrug Platform Study of 
Neoadjuvant Durvalumab Alone or in Combination with Novel Agents in Subjects with 
Resectable, Early-stage (I [>2cm] to IIIA) Non-small Cell Lung Cancer (NeoCOAST)
Protocol Number: D9108C00002


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Statistical Analysis Plan for Protocol D9108C00002
Neoadjuvant durvalumab and novel oncology therapies
10Aug2021; final version 4.0
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TABLE OF CONTENTS
1 
INTRODUCTION...........................................................................................................5 
2 
STUDY OVERVIEW .....................................................................................................5 
2.1 
Study Objectives...................................................................................................5 
2.1.1Primary Study Objective(s) ..........................................................................5 
2.1.2Secondary Study Objectives.........................................................................5 
2.1.3Exploratory Study Objectives.......................................................................6 
2.2 
Study Design.........................................................................................................7 
2.3 
Treatment Assignment and Blinding....................................................................7 
2.4 
Sample Size...........................................................................................................8 
3 
STATISTICAL METHODS ...........................................................................................9 
3.1 
General Considerations.........................................................................................9 
3.2 
Analysis Populations.............................................................................................9 
3.3 
Study Subjects.....................................................................................................10 
3.3.1Subject Disposition and Completion Status................................................10 
3.3.2Demographics and Baseline Characteristics...............................................10 
3.3.3Study Drug Exposure..................................................................................11 
3.3.4Concomitant Medications...........................................................................11 
3.3.5Protocol Deviations.....................................................................................12 
3.4 
Efficacy Analyses ...............................................................................................12 
3.4.1Primary Efficacy Endpoint(s) and Analyses...............................................12 
3.4.1.1 
Primary Efficacy Endpoint(s) and Analysis .............................12 
3.4.1.2 
Additional Analyses of the Primary Efficacy Endpoint(s) .......13 
3.4.2Secondary Efficacy Endpoint(s) and Analyses...........................................13 
3.4.3Exploratory Efficacy Endpoint(s) and Analyses ........................................14 
3.4.3.1 
Best Overall Response..............................................................14 
3.4.3.2 
Objective Response Rate ..........................................................15 
3.4.3.3 
Other Endpoint..........................................................................15 
3.4.4Handling of Dropouts and Missing Data....................................................16 
3.4.5Subgroup Analyses .....................................................................................16 
3.4.6Exploratory Analyses..................................................................................16 
3.4.7Sensitivity Analyses....................................................................................16 
3.5 
Pharmacodynamic Endpoint(s) and Analyses ....................................................16 
3.6 
Safety Analyses...................................................................................................17 
3.6.1Adverse Events and Serious Adverse Events .............................................17 
3.6.2Adverse Events of Special Interest and Adverse Event of Possible 
Interest ......................................................................................17 


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3.6.2.1 
Adverse Events of Special Interest Associated with 
Oleclumab ..................................................................18 
3.6.2.2 
Adverse Events of Special Interest Associated with 
Durvalumab................................................................18 
3.6.3Deaths and Treatment Discontinuations due to Adverse Events................18 
3.6.4Clinical Laboratory Evaluation...................................................................18 
3.6.5Other Safety Evaluations ............................................................................20 
3.6.5.1 
Vital Signs.................................................................................20 
3.6.5.2 
Electrocardiogram.....................................................................20 
3.6.5.3 
Eastern Cooperative Oncology Group Performance Status......20 
3.6.5.4 
Feasibility to Surgery................................................................20 
3.6.6Subgroup Analyses .....................................................................................20 
3.7 
Immunogenicity..................................................................................................21 
3.8 
Pharmacokinetics................................................................................................21 
4 
INTERIM ANALYSIS..................................................................................................21 
5 
DEVIATIONS FROM PLANNED ANALYSES.........................................................23 
6 
REFERENCES..............................................................................................................23 
7 
VERSION HISTORY ...................................................................................................23 
8 
APPENDIX ...................................................................................................................24 
8.1 
Derivation of RECIST 1.1 Disease Assessment Overall Response....................24 
8.1.1Target Lesion Response..............................................................................24 
8.1.2Non-Target Lesion Response......................................................................26 
8.1.3Disease Assessment Overall Response per RECIST1.1.............................27 
8.1.4Locoregional therapy..................................................................................28 
8.1.5Assignment of Dates of Disease Progression or Disease Response...........28 
8.2 
Efficacy Criteria of Making an Internal Go Decision at an Interim Analysis ....29 
LIST OF TABLES
Table 2.4-1 
Estimated Differences in MPR Rate Between Durvalumab 
Monotherapy Arm and Each Durvalumab Combination Therapy Arm 
(40 Subjects Each) .................................................................................9 
Table 3.2-1 
Analysis Populations............................................................................10 
Table 4-1 
Criteria of Early No-Go Decisions Based on MPR .............................22 
Table 4-2 
Operating Characteristics of Continuous Monitoring for No-Go........22 
Table 8.2-1 
Criteria of Early Go Decisions Based on MPR ...................................30 
Table 8.2-2 
Operating Characteristics of Continuous Monitoring for Go ..............30 


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List of Abbreviations
Abbreviation or 
Specialized Term
Definition
AE
adverse event
AEPI
adverse event of possible interest
AESI
adverse event of special interest
BMI
body mass index
CMH test
Cochran–Mantel–Haenszel test
ctDNA
circulating tumor DNA
CR
complete response
DA
disease assessment
DBL
database lock
DCO
data cutoff
DMPK
Clinical Pharmacology & Drug Metabolism and Pharmacokinetics
eCRF
electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
GFR
glomerular filtration rate
imAE
immune-mediated adverse event
IP
investigational product
ITT
intent-to-treat
IxRS
interactive voice/web response system
mRNA
messenger RNA
LRV
lower reference value
MPR
major pathological response
NSCLC
non-small cell lung cancer 
ORR
objective response rate
pCR
pathological complete response
PD
progressive disease
PK
pharmacokinetics
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SD
stable disease
SPP
statistical programming plan
TV
target value


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Statistical Analysis Plan for Protocol D9108C00002
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1
INTRODUCTION
This document describes the statistical analysis methodology for protocol D9108C00002, a
multidrug platform study of neoadjuvant Durvalumab alone or in combination with novel 
agents in subjects with resectable, early-stage (I [>2cm] to IIIA) 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 assess the antitumor activity of durvalumab alone and/or in combination with novel 
agents, in terms of major pathological response (MPR) rate.
2.1.2
Secondary Study Objectives
Safety:
x
To assess the feasibility of receiving the planned surgical resection;
x
To assess the safety and tolerability of durvalumab alone and/or in combination with 
novel agents.
Efficacy:
x
To assess the antitumor activity of durvalumab alone and/or in combination with 
novel agents, in terms of pathological complete response (pCR) rate.
Pharmacokinetics (PK):
x
To describe the PK of durvalumab alone and/or in combination with novel agents.
Immunogenicity:
x
To assess the immunogenicity of durvalumab alone or in combination with novel 
agents;


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x
To assess the immunogenicity of novel biologic agents in combination with 
durvalumab 
2.1.3
Exploratory Study Objectives
x


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x
2.2
Study Design
NeoCOAST is a Phase 2, open-label, multicenter, randomized, multidrug platform study of 
durvalumab alone or in combination with novel agents in subjects with resectable, early-
stage (Stage I [>2cm] to IIIA) NSCLC.
The study will evaluate the clinical activity and safety of neoadjuvant durvalumab alone or in 
combination with novel agents in subjects with resectable, early-stage NSCLC (Stage I [>2
cm] to IIIA).
Treatment arms may be opened sequentially or in parallel. Subjects will be treated with 
durvalumab alone or in combination with novel agents for up to 28 days, followed by 
surgical resection. After surgical resection, subjects will be followed up to Day 105 (Figure 1
in the protocol). Up to approximately 25 sites globally will participate in this study.
New durvalumab combination therapy arms may be added based on emerging nonclinical 
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 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 lymph node involvement (Yes vs. No) and will use an 
equal ratio to all study treatment arms open for enrollment (e.g., if treatment arms are opened 
sequentially, a treatment arm is added/closed, or enrollment in a treatment arm is suspended). 
At the onset, the randomization scheme will use an equal ratio in all treatment arms. After 20 
subjects have been enrolled into any treatment arm, the randomization ratio can be adjusted.


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Blinding
The study is not blinded.
2.4
Sample Size
This study is designed to obtain preliminary clinical efficacy, safety, PK and immunogenicity 
data on durvalumab in combination with novel agents compared to durvalumab 
monotherapy. It is not designed to make explicit power and Type I error considerations for a 
hypothesis test.
At the onset, subjects will be randomized with equal ratios into each treatment arm. The 
initial arms included are: durvalumab monotherapy, durvalumab plus oleclumab, durvalumab 
plus monalizumab, and durvalumab plus danvatirsen. A total of up to 40 subjects per arm
may be enrolled. An interim analysis will be performed in any given arm, once a respective 
arm enrolls at least 20 efficacy evaluable subjects.
Table 2.4-1 shows estimated differences in MPR rate between durvalumab combination
therapy arm compared to the durvalumab monotherapy arm, along with 95% Wald 
confidence intervals (CIs), with different assumptions and a sample size of 40 subjects each 
assuming an asymptotic normality. The assumed 30% MPR rate with the durvalumab 
monotherapy arm is based on a pooled analysis of data from two recently published clinical 
trials evaluating anti-PD-1/PD-L1 monotherapies in a similar patient population. One study
(Forde et al, 2018, see references in the protocol) reported an MPR rate of 45% (9/20) for 
subjects who received nivolumab monotherapy; while another study (Ruschet et al, 2018, see 
references in the protocol) reported an MPR rate of 20% (10/50) for subjects who received 
atezolizumab monotherapy. An arithmetic average of these two MPR rates is rounded to 30% 
as the assumed MPR rate for durvalumab. Forty subjects per treatment arm provides a 95% 
CI with reasonable width (~± 
%) for the estimated difference between a durvalumab 
combination therapy arm and the durvalumab monotherapy arm. When the MPR rate for a 
durvalumab combination therapy arm is 
%, the lower limit of the 95% CI for the 
difference between the durvalumab combination therapy arm and the durvalumab 
monotherapy arm is 
, which is greater than 
 suggesting that 


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Table 2.4-1
Estimated Differences in MPR Rate Between Durvalumab 
Monotherapy Arm and Each Durvalumab Combination 
Therapy Arm (40 Subjects Each)
Number (%) of Responders 
Difference (%) in MPR
(2-sided 95% Wald CI)
Durvalumab Combination 
Therapy Arm
(n  40)
Durvalumab
Monotherapy Arm
(n  40)
16 (40%)
12 (30%)
10% (-11%, 31%)
CI = confidence interval; MPR = major pathological response.
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% confidence 
level. Baseline values will be defined as the last valid assessment prior to the first 
administration of investigational product (IP).
Data analyses will be conducted using the SAS® System (SAS Institute, Inc., Cary, NC, 
USA) Version 9.3 or above, unless otherwise specified. All analysis outputs will be validated 
according to AstraZeneca/MedImmune SAS programming standards and 
AstraZeneca/MedImmune validation procedures.
3.2
Analysis Populations
The analysis populations are defined in Table 3.2-1.


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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 investigational product. 
Subjects will be analyzed according to the treatment they actually receive.
Efficacy Evaluable
Population
The Efficacy Evaluable Population includes subjects from the As-treated Population who 
have the opportunity to be followed for the planned surgery by the time of the data cutoff, 
and either have pathological tumor response data post-surgery, or did not undergo 
surgical resection due to death or disease progression
All baseline and efficacy parameters will be summarized based on the ITT population as
primary analysis. Safety parameters will be summarized based on the As-treated Population
as primary analysis. The efficacy parameters may be summarized based on efficacy 
evaluable population as supportive analysis and interim analyses of efficacy will be 
performed on this population. Interim analysis will be performed on ITT population as 
sensitivity analysis if deemed appropriate.
3.3
Study Subjects
3.3.1
Subject Disposition and Completion Status
Subject disposition and completion status will be summarized for all subjects screened.
Summaries of the number and percentage of subjects entered at each site will be provided. In
addition, disposition of subjects throughout the study with respect to discontinuation of
treatment and end of study status including reasons 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 investigational product or disease under investigation, or 
other).
3.3.2
Demographics and Baseline Characteristics
Demographics and baseline disease characteristics will be summarized for the ITT
population. Demographic information at study entry related to sex, age, race, ethnicity,
ECOG performance status, weight, height, and body mass index (BMI) will be presented by 
treatment group and for all subjects combined.
Tumor history including histology, stage, and pertinent biomarker results (if data is available)
at the time of initial diagnosis and at study entry will be summarized. A summary of smoking 
history will also be included.


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3.3.3
Study Drug Exposure
Treatment exposure will be summarized for the As-treated population. Duration of exposure
to IP(s) in days, except for single-dose IP(s), will be summarized by descriptive statistics and 
by frequency.
The duration of exposure for each IP is defined as below. More details, if necessary, will be 
provided in the Statistical Programming Plan (SPP). 
x
last dose date plus the dosing interval (days) minus first dose date for subjects on 
treatment. 
x
minimum of (date of death plus 1 day, data cutoff date plus 1 day, last dose date plus 
the dosing interval) minus first dose date for subjects who are no longer on treatment.
Dose intensity will be listed, and relative dose intensity to IP(s) will be summarized by 
descriptive statistics. The relative dose intensity is a percentage 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) will be summarized with reasons for deviations for the following 
categories: delays, omissions, and interruptions. Dosing delays will be derived based on the
scheduled dosing dates or the date of the most recent dose. 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.
3.3.4
Concomitant Medications
The number and percentage of subjects who took concomitant medications will be 
summarized by the generic name coded by World Health Organization (WHO) Drug
Dictionary for the ITT Population. Concomitant medications will include all concomitant 
medications taken on or after the date of first dose of any IP or any concomitant medication 
started prior to the first dose of study treatment that continued beyond the date of first dose of 
any IP.


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3.3.5
Protocol Deviations
Incidence of important protocol deviations will be summarized by deviation categories. 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. Disruptions caused by the COVID-19 
pandemic will be listed and tabulated. Tabulation of important protocol deviations will be 
done including and excluding COVID-19 related deviations.
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 MPR rate. MPR rate is defined as the proportion of subjects 
with ≤ 10% residual viable tumor cells by investigator assessment. The primary analysis of 
MPR rate will be based on the ITT population. The MPR rate and the corresponding 95% CI 
will be reported for each arm. In addition, an estimate of the difference in MPR rate as well 
as its 2-sided 95% exact CI between each combination therapy arm and monotherapy arm 
will be reported. The rates between any durvalumab combination therapy arm and the 
durvalumab monotherapy arm will be evaluated and compared from the Cochran–Mantel–
Haenszel (CMH) test stratified by the baseline lymph node involvement (yes or no). In case
the randomization ratio between monotherapy arm and other combination therapy arms
changes during the study, the CMH test may be additionally stratified by the randomization 
ratio of monotherapy arm vs other combination therapy arms according to randomization 
scheme (if allowed by strata size). The Fisher’s exact test will also be conducted. Subjects
that do not have the planned surgery will be considered as failures/non-responders, and will 
therefore be counted in the denominator, but not in the numerator of MPR rate. The primary 
efficacy analysis will only include subjects in monotherapy arm who are concurrently 
enrolled with each combination therapy arm in order to conduct rigorous between-arm 
comparisons. Concurrently enrolled subjects from monotherapy arm (to a respective 
combination therapy arm) are subjects randomized to monotherapy arm who also had 
opportunity to be randomized to that respective combination therapy arm. The number of 
subjects in monotherapy arm who are concurrently enrolled with the respective combination
therapy arm will be tabulated along with the statistical inferences.
MPR assessed by independent central reviewer may be analyzed by the same approach when 
data is available. 


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3.4.1.2
Additional Analyses of the Primary Efficacy Endpoint(s)
The first additional analysis of MPR rate may be based on the efficacy evaluable population.
Additional analysis of MPR may be a Bayesian logistic regression using power prior
(Ibrahim et al, 2015), performed separately for each combination therapy arm to 
monotherapy arm comparison. The logistic regression will include treatment arm and 
baseline lymph node involvement as explanatory variables. In case the randomization ratio 
between monotherapy arm and other combination therapy arms changes during the study, the 
model may be additionally adjusted for the randomization ratio of monotherapy arm vs other
combination therapy arms according to the subject randomization scheme by adding a 
corresponding covariate (if allowed by size of covariate categories).
The power prior is intended to implement informative knowledge into prior distribution
constructed from data of non-concurrent subjects in monotherapy arm. The weight of the
non-concurrent data in monotherapy arm relative to the concurrent data in monotherapy arm
will be optimized by Deviance Information Criterion (DIC). The odds ratio between each 
combination therapy arm and monotherapy arm will be presented, as well as its 95% credible 
interval and the posterior probability of the odds ratio being greater than 1 (i.e. the 
probability that the subjects in combination therapy arm has higher odds to achieve MPR
than those in the monotherapy arm).
Another additional analysis of MPR may also be conducted by including all subjects from
monotherapy arm for treatment comparisons if deemed appropriate, regardless of whether a
monotherapy arm subject was enrolled concurrently or not with the respective experimental 
arms.
3.4.2
Secondary Efficacy Endpoint(s) and Analyses
The secondary efficacy endpoint is pCR rate. pCR rate is defined as the proportion of 
subjects with no viable tumor cells by investigator assessment, and the corresponding 95% 
CI will be reported for each arm. The primary analysis of pCR rate will be based on the ITT 
population and may be based on the efficacy evaluable population as a supportive analysis.
In addition, the difference between any durvalumab combination therapy arm and the 
durvalumab monotherapy arm will be evaluated. Comparison of each of the combination 
arms with the monotherapy arm will be obtained from a stratified Cochran–Mantel–Haenszel
test as described for the primary efficacy endpoint. The Fisher’s exact test will be also 
conducted. Subjects who do not have the planned surgery will be considered as failures/non-
responders, and will therefore be counted in the denominator, but not in the numerator of 
pCR rate. In the foregoing analysis, only subjects in the monotherapy arm who are 


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concurrently enrolled with combination therapy arm will be included. The number of 
subjects in monotherapy arm who are concurrently enrolled with the respective combination 
therapy arm will be tabulated along with the statistical inferences.
pCR assessed by independent central reviewer may be analyzed by the same approach when 
data is available. 
An additional Bayesian logistic regression of the secondary efficacy endpoints using power 
prior and involving non-concurrent subjects data may also be performed, as described for the 
primary efficacy endpoint. Moreover, additional analysis may also be conducted by including 
all subjects from monotherapy arm for treatment comparisons if deemed appropriate,
regardless of whether a monotherapy arm subject was enrolled concurrently or not with the
respective experimental arms.
3.4.3
Exploratory Efficacy Endpoint(s) and Analyses
Efficacy analyses pertaining to objective response will be based on an application of RECIST
1.1 (Eisenhauer et al, 2009) to investigator assessed tumor measurements.
Programmatic derivation guidance used for the application of RECIST 1.1 are provided in 
Appendix 8.1. RECIST 1.1 guidelines will be used to determine disease response.
3.4.3.1
Best Overall Response
Best overall response (BOR) will be based on all post-baseline disease assessments that 
occur prior to surgery. 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). Radiographical confirmation of a 
response is not feasible due to the length of the study (e.g., a confirmatory scan will not be 
performed). The primary analysis of BOR will be based on the ITT population.
In general, subjects not classifiable under the RECIST 1.1 response categories due to 
insufficient data or early death will be classified as non-evaluable (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 


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NE for BOR. If a subject is missing lesion data at a disease assessment and yet progressive 
disease criteria is met despite the missing data, the subject will be classified as PD.
3.4.3.2
Objective Response Rate
Objective response rate (ORR) is defined as the proportion of subjects with a best overall 
response of CR or PR that occur prior to surgery and the corresponding 95% CI will be 
reported for each arm. Radiographical confirmation of a response is not feasible due to the 
length of the study (e.g., a confirmatory scan will not be performed). The primary analysis of 
ORR will be based on the ITT population. In addition, the difference between any 
durvalumab combination therapy arm and the durvalumab monotherapy arm will be 
evaluated. Comparison of each of the combination therapy arms with the monotherapy arm 
will be obtained from a stratified Cochran–Mantel–Haenszel test as described for the primary 
efficacy endpoint. The Fisher’s exact test will be also conducted. 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. In the foregoing analysis, only 
subjects in the monotherapy arm who are concurrently enrolled with combination therapy 
arm will be included. The number of subjects in monotherapy arm who are concurrently 
enrolled with the respective combination therapy arm will be tabulated along with the 
statistical inferences.
An additional Bayesian logistic regression for the ORR using power prior and involving non-
concurrent subjects data may also be performed, as described for the primary efficacy 
endpoint. Moreover, additional analysis may also be conducted by including all subjects from 
monotherapy arm for treatment comparisons if deemed appropriate, regardless of whether a
monotherapy arm subject was enrolled concurrently or not with the respective experimental
arms.
3.4.3.3
Other Endpoint
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 that occurs prior to surgery. The percentage change from baseline in target lesion 
sum of diameters is defined as follows:
ͳͲͲ ൈσ ܦ݅ܽ݉݁ݐ݁ݎݏܽݐܦܣ͓ܺെσ ܦ݅ܽ݉݁ݐ݁ݎݏܽݐܦܣܽݐܾܽݏ݈݁݅݊݁
σ ܦ݅ܽ݉݁ݐ݁ݎݏܽݐܦܣܽݐܾܽݏ݈݁݅݊݁


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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 that 
occur prior to surgery. 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.
3.4.4
Handling of Dropouts and Missing Data
In general, missing data are not imputed for statistical analysis. Guidance regarding the 
handling of dropouts and missing data and censoring will apply uniformly to all efficacy 
analyses resulting from an application of RECIST 1.1 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. 
3.4.5
Subgroup Analyses
No subgroup analyses are planned.
3.4.6
Exploratory Analyses
3.4.7
Sensitivity Analyses
Sensitivity analyses may be performed for selected efficacy analyses where subjects who are 
randomized but violated inclusion criteria #4 or exclusion criteria #2 will be excluded. These
are the subjects with incorrect disease, incorrect staging, prohibited prior therapy, etc. The
same analyses will be conducted except on a smaller patient population due to exclusion of 
aforementioned subjects.
3.5
Pharmacodynamic Endpoint(s) and Analyses
Descriptive statistics will be the primary method for the biomarker analyses. Depending on 
the nature of the data, geometric mean and other appropriate statistical summaries might be 
used as well.


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3.6
Safety Analyses
All safety analyses will be performed based on the As-treated Population, unless otherwise 
specified. AEs before and after surgery will be summarized separately where it is of
scientific interest. In addition, safety data collected after initiation of subsequent anticancer 
therapy will not be summarized in the tables and figures, unless specified otherwise, but will 
be listed.
3.6.1
Adverse Events and Serious Adverse Events
Adverse events will be coded by Medical Dictionary for Regulatory Activities (MedDRA) 
and be graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events version 5.0 (NCI CTCAE v5.0), and the type incidence, severity and 
relationship to study investigational product 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 highest severity 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 event (TEAE) is defined as events present at baseline that 
worsen in intensity after administration of study investigational product or events absent at 
baseline that emerge after administration of study investigational product. All TEAEs that 
occurred on and after first dose to the end of follow-up period 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 the end of follow-up period will be listed.
The AEs occurring from the signing of the informed consent and prior to the initiation of 
study investigational product will be listed. 
3.6.2
Adverse Events of Special Interest and Adverse Event of Possible 
Interest
An adverse event of special interest (AESI) and adverse event of possible interest (AEPI) are
of scientific and medical interest specific to understanding of the investigational product and 
may require close monitoring and rapid communication by the investigator to the sponsor.
Detailed descriptions/terms of AESIs for each IP can be found in protocol Section 5.3. Other 


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categories may be added or existing terms may be modified as necessary. Preferred terms 
used to identify each AESI group will be clarified/confirmed before database lock (DBL).
3.6.2.1
Adverse Events of Special Interest Associated with Oleclumab
The AESIs associated with Oleclumab will be summarized similarly as other AEs described 
in Section 3.6.1.
3.6.2.2
Adverse Events of Special Interest Associated with Durvalumab
AESI, AEPI, immune-mediated AESI, and immune-mediated AEPI will be derived and 
summarized following the latest version of Durvalumab Global imAE Characterization 
Charter.
3.6.3
Deaths and Treatment Discontinuations due to Adverse Events
For those subjects who died due to an AE, the AE contributing to death and the AE’s 
relationship to IP will be listed.
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, urinalysis,
and thyroid function analysis, where applicable. Listings will be provided for all laboratory 
results, including urinalysis. For chemistry and hematology tests, the change from baseline to
each post-baseline visit will be summarized graphically for selected parameters of scientific 
interest. Descriptive statistics may be provided for the clinical laboratory results and changes 
from baseline by scheduled time of evaluation including maximum and minimum 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 in which CTCAE grade can be numerically 
derived. The analysis will present worst grade observed and the rates of subjects with Grade 
3-4 toxicity. 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 from clinical laboratory tests. Also, laboratory parameters will be assessed by 
presenting tables containing information related to at least 1-grade shift and at least 2-grade 


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shift from baseline. Separate summaries indicating hyper- and hypo- directionality of change 
will be produced, where applicable. For those laboratory parameters that cannot be graded by 
the NCI CTCAE, the frequencies of the post-baseline laboratory value categorized as low 
(L), normal (N), or high (H) using laboratory reference range from baseline will be 
summarized.
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. Number and percentage of these subjects will be tabulated.
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.
Individual subject data where elevated ALT or AST plus total bilirubin fall into the 
“Potential Hy’s law” will be listed.
Assessment of Nephrotoxicity 


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Creatinine clearance rate (CCr) will be calculated using serum creatinine and the Cockcroft-
Gault formula to estimate glomerular filtration rate (GFR). Shift tables from baseline to 
“worst-case” among post-baseline CCr values will be provided. Baseline and “worst-case” 
post-baseline CCr value will be categorized for the following categories:
x
Normal: ≥ 90 mL/min 
x
Mild Impairment: ≥ 60 − < 90 mL/min
x
Moderate Impairment: ≥ 30 − < 60 mL/min 
x
Severe Impairment: ≥ 15 − < 30 mL/min 
x
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 may be 
summarized by study visit which may include descriptive statistics for the value of the 
parameters and the changes from baseline by scheduled time of evaluation and by treatment 
arm including end of treatment visit as well as for the maximum and minimum post-baseline 
values.
3.6.5.2
Electrocardiogram
Electrocardiogram analyses may be performed. 
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 by study visit which 
may include descriptive statistics for the value of the parameters and changes from baseline 
by scheduled time of evaluation and by treatment arm.
3.6.5.4
Feasibility to Surgery 
Feasibility to surgery is defined as the proportion of subjects in each arm with no delay in the 
planned surgery (no later than 42 days after Week 1, Day 1). The feasibility to surgery will 
be evaluated/tabulated.
3.6.6
Subgroup Analyses
No subgroup analyses for safety are planned.


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3.7
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
percentage of subjects who develop detectable ADAs to durvalumab. For treatment arms that
include a novel biologic agent, the immunogenic potential of the novel biologic agent will be
assessed by summarizing the number and percentage of subjects who develop detectable
ADAs to the novel biologic agent.
All valid assay results from subjects who receive any study drug will be included in 
immunogenicity summaries. All subjects with titer information will be shown in the data 
listing.
3.8
Pharmacokinetics
Pharmacokinetic data analyses will be performed by Clinical Pharmacology & Drug 
Metabolism and Pharmacokinetics (DMPK) group or its designee.
4
INTERIM ANALYSIS
Interim analyses will be conducted during the course of the study to evaluate the clinical 
activity and safety of any treatment arm. The first planned interim analysis will be initiated
once at least 1 treatment arm has enrolled 20 efficacy evaluable subjects. Across all treatment 
arms, subject accrual beyond 20 subjects will be determined based on interim data. Bayesian 
predictive probabilities will be used to evaluate clinical activity (Lee and Liu, 2008). In this 
study, a target value (TV) of ΔMPR as 
 is set, where ΔMPR is the difference in MPR
rate between a combination therapy treatment arm and the durvalumab monotherapy arm.
x
A treatment arm will meet the No-Go criteria if the probability that the true ΔMPR
being larger than TV is less than 
, i.e., Prob.(True ΔMPR > 
 <
. A No-
Go decision will be made at the interim analysis if the predictive probability of 
meeting the No-Go criteria (after 40 subjects are all enrolled) given observed interim
data are greater than 
, i.e., Predictive Probability(Prob.[ΔMPR > 
] < 
) > 
Table 4-1 illustrates the sample algorithm to make an early No-Go decision based on MPR at
the interim analysis when combination arm and durvalumab monotherapy each have 20
subjects. 


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Table 4-1
Criteria of Early No-Go Decisions Based on MPR
Number of Subjects with MPR in Durvalumab
Monotherapy Arm
Number of Subjects with MPR in Durvalumab
Combination Therapy Arm
2
≤ 2
3
≤ 2
4
≤ 3
5
≤ 4
6
≤ 5
7
≤ 5
8
≤ 6
9
≤ 7
10
≤ 8
11
≤ 9
MPR = major pathological response.
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 MPR
= 30%)
All No-Go
(Interim & 
final)
Early No-Go
(Confirmed 
at final) 
0%
78%
36% (35%)
10%
40%
15% (12%)
15%
23%
8% (6%)
20%
12%
4% (2%)
25%
5%
2% (1%)
30%
2%
1% (0)
Criteria:  Target Value (TV) δ = 
; No-Go: Pr(δ > TV) < 
; Futility:  PP(No-Go) > 
);
BM MPR:  Benchmark Major Pathological Response Rate.
A treatment arm will be considered futile if it meets the futility bar for MPR according to
Figure 7 in the protocol. If at least 1 treatment arm has more than 20 efficacy evaluable 
subjects’ data at the interim analysis, slightly different futility bars compared to Figure 7 in 
the protocol will be provided on a case-by-case basis. In addition, for any treatment arm, 
enrollment will be stopped if more than 2 out of the first 20 enrolled subjects failed the 
feasibility to surgery.




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Statistical Analysis Plan for Protocol D9108C00002
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x
Corrected the typos identified, minor issues, and/or 
administrative items
3.0
24Nov2020
x
x
Added sensitivity analyses of efficacy excluding 
subjects who had incorrect disease or setting or 
prohibited prior therapy at study entry, suggested by
clinical team.
x
For the purpose of data interpretation, excluded safety 
data collected after initiation of subsequent anticancer 
therapy from safety analyses as suggested by clinical
team.
x
Added descriptive reports of disruptions due to 
pandemic per study team suggestions.
x
Indicated the analyses deviated from what is planned in
the protocol, and provided the rationale of deviations.
x
Administrative edits such as correcting typos, spacing,
updating list of signatory due to personnel changes, etc.
Address issues 
pertaining to
upcoming interim 
analysis
4.0
10Aug2021
x
Editorial updates such as correcting typos, table 
numbering, etc.
x
Remove some analyses where data is not collected in 
this study.
x
Remove some analyses not indicated in the protocol and 
deemed unnecessary after team discussions.
x
Clarify or correct some descriptions of the analyses 
done by standard templates.
x
Add some languages for conducting additional analyses 
deemed scientifically appropriate per study team.
Address outstanding 
comments and
issues identified 
during the CSR dry-
run
8
APPENDIX
8.1
Derivation of RECIST 1.1 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 1.1 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. 
8.1.1
Target Lesion Response
Target lesion response will be programmatically derived on the data collection instrument 
once RECIST 1.1 criteria are applied to the site personnel recorded target lesion 
measurements. 
Possible values include:
x
CR – Complete Response
x
PR – Partial Response


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x
SD – Stable Disease
x
PD – Progressive Disease
x
NE – Non-evaluable
x
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):
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 


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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).
8.1.2
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:
x
CR – Complete Response
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)
x
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
x
PD – Progressive Disease
o
Unequivocal progression of existing non-target lesions. 
x
NE – Non-evaluable
x
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 


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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 
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).
8.1.3
Disease Assessment Overall Response per RECIST1.1
Investigator visit disease response will be programmatically derived on the data collection 
instrument using RECIST 1.1 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:
x
CR – Complete Response
x
PR – Partial Response


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x
SD – Stable Disease
x
PD – Progressive Disease
x
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 1.1, “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).
8.1.4
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.
8.1.5
Assignment of Dates of Disease Progression or Disease Response
For all analyses of endpoints resulting from an application of RECIST 1.1 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 


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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 1.1 the date of PD will be the earliest of the 
following 3 evaluation dates:
x
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.
x
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.
x
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 1.1 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. 
8.2
Efficacy Criteria of Making an Internal Go Decision at an Interim 
Analysis


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Table 8.2-1
Criteria of Early Go Decisions Based on MPR
Number of Subjects with MPR in Durvalumab 
Monotherapy
Number of Subjects with MPR in Durvalumab 
Combination Therapy Arm
3
4
5
6
7
8
9
10
11
12
13
MPR = major pathological response.
Operating characteristics of this continuous monitoring method are presented in Table 8.2-2
based on 10000 simulations using the prespecified LRV.
Table 8.2-2
Operating Characteristics of Continuous Monitoring for Go
True δ
(BM MPR
= 30%)
All Go
(Interim & 
final)
Early Go 
(Confirmed 
at final) 




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