Clinical trial NCT03968419
Conditions: Non-small Cell Lung Cancer
Keywords: ACZ885 canakinumab pembrolizumab NSCLC non-small cell lung cancer non small cell lung cancer early stage NSCLC squamous non-squamous, MPR major pathological response hs-CRP PD-L1 hsCRP surgery neo-adjuvant neo adjuvant CD8 hs-IL-6 CANOPY
Sponsor: Novartis Pharmaceuticals
Start date: 2019-11-05; Completion date: 2022-08-15
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the major pathological response (MPR) rate of canakinumab given as a neoadjuvant treatment, either as single agent or in combination with pembrolizumab, in addition to evaluate the MPR of pembrolizumab as a single agent and the dynamic of the tumor microenvironment changes on treatment.

Detailed description:
This was a randomized, phase II, open-label study evaluating canakinumab, an anti-IL-1β monoclonal antibody, or pembrolizumab, a monoclonal antibody designed to block the PD-1 receptor, as monotherapy or in combination as neoadjuvant therapy. The study population included adult subjects with resectable non-small cell lung cancer (NSCLC) planned for surgery in approximately 4-6 weeks. Subjects were treated for a maximum duration of 6 weeks (2 cycles) until surgery, progression, unacceptable toxicity or discontinuation from the study treatment for any other reason.

Subjects were randomized in a 2:2:1 ratio to one of the 3 treatment arms (canakinumab alone or canakinumab in combination with pembrolizumab or pembrolizumab alone). Surgery was performed between 4 to 6 weeks after the first dose of study treatment.

All randomized subjects were followed for safety for up to 130 days following the last dose of study treatment (safety follow-up period).

Arms: arm 1: Participants received 200 mg of canakinumab once every 3 weeks for a maximum duration of 6 weeks prior to surgery arm 2: Participants received 200 mg of canakinumab in combination with 200 mg of pembrolizumab once every 3 weeks for a maximum duration of 6 weeks prior to surgery arm 3: Participants received 200 mg of pembrolizumab every 3 weeks for a maximum duration of 6 weeks prior to surgery
Interventions: intervention 1: Canakinumab intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: 200 mg of canakinumab administered via subcutaneous injections once every 3 weeks for a maximum duration of 6 weeks intervention 2: 200 mg of pembrolizumab administered via infusion once every 3 weeks for a maximum duration of 6 weeks

Protocol documents:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................13
Protocol summary..............................................................................................................15
Amendment 1 (07-Apr-2020)............................................................................................20
1
Introduction .......................................................................................................................25
1.1
Background............................................................................................................25
1.1.1
Disease background ..............................................................................25
1.1.2
Immunotherapy in NSCLC ...................................................................25
1.1.3
Neoadjuvant treatment and major pathological response as a 
surrogate endpoint.................................................................................26
1.1.4
The role of inflammation and IL-1β in NSCLC....................................27
1.2
Introduction to investigational treatment(s) and other study treatment(s).............29
1.2.1
Canakinumab in NSCLC.......................................................................29
1.2.2
Pembrolizumab in NSCLC ...................................................................31
1.2.3
Canakinumab and PD-1 combination in NSCLC .................................31
1.3
Purpose ..................................................................................................................32
2
Objectives and endpoints...................................................................................................32
3
Study design ......................................................................................................................33
4
Rationale............................................................................................................................34
4.1
Rationale for study design .....................................................................................34
4.2
Rationale for dose/regimen and duration of treatment ..........................................35
4.2.1
Pharmacokinetics (PK) consideration...................................................36
4.2.2
Efficacy and pharmacodynamics (PD) considerations .........................37
4.2.3
Safety considerations ............................................................................38
4.2.4
Conclusion for dose regimen selection .................................................39
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................40
4.4
Purpose and timing of interim analyses/design adaptations..................................40
4.5
Risks and benefits..................................................................................................40
5
Population..........................................................................................................................42
5.1
Inclusion criteria ....................................................................................................42
5.2
Exclusion criteria...................................................................................................43
6
Treatment...........................................................................................................................46


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6.1
Study treatment......................................................................................................46
6.1.1
Investigational and control drugs..........................................................46
6.1.2
Additional study treatments ..................................................................46
6.1.3
Treatment arms/group ...........................................................................46
6.1.4
Guidelines for continuation of treatment ..............................................46
6.1.5
Treatment duration................................................................................47
6.2
Other treatment(s)..................................................................................................47
6.2.1
Concomitant therapy.............................................................................47
6.2.2
Prohibited medication ...........................................................................48
6.3
Subject numbering, treatment assignment, randomization....................................48
6.3.1
Subject numbering ................................................................................48
6.3.2
Treatment assignment, randomization ..................................................49
6.4
Treatment blinding.................................................................................................49
6.5
Dose escalation and dose modification..................................................................49
6.5.1
Dose modifications................................................................................49
6.5.2
Follow-up for toxicities.........................................................................54
6.6
Additional treatment guidance...............................................................................56
6.6.1
Treatment compliance...........................................................................56
6.6.2
Emergency breaking of assigned treatment code..................................57
6.7
Preparation and dispensation.................................................................................57
6.7.1
Handling of study treatment and additional treatment..........................57
6.7.2
Instruction for prescribing and taking study treatment .........................58
7
Informed consent procedures ............................................................................................58
8
Visit schedule and assessments .........................................................................................59
8.1
Screening ...............................................................................................................66
8.1.1
Eligibility screening ..............................................................................66
8.1.2
Information to be collected on screening failures.................................66
8.2
Subject demographics/other baseline characteristics.............................................66
8.3
Efficacy..................................................................................................................67
8.3.1
Tumor assessments................................................................................67
8.3.2
Appropriateness of efficacy assessments..............................................67
8.4
Safety.....................................................................................................................67
8.4.1
Laboratory evaluations..........................................................................68
8.4.2
Electrocardiogram (ECG) .....................................................................70
8.4.3
Pregnancy and assessments of fertility .................................................70
8.5
Additional assessments..........................................................................................71
8.5.1
Pharmacokinetics ..................................................................................71


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8.5.2
Biomarkers............................................................................................73
8.5.3
Imaging .................................................................................................74
8.5.4
Other Assessments ................................................................................75
9
Study discontinuation and completion ..............................................................................76
9.1
Discontinuation......................................................................................................76
9.1.1
Discontinuation of study treatment .......................................................76
9.1.2
Withdrawal of informed consent...........................................................77
9.1.3
Lost to follow-up...................................................................................77
9.1.4
Early study termination by the sponsor.................................................78
9.2
Study completion and post-study treatment ..........................................................78
10 Safety monitoring and reporting........................................................................................79
10.1
Definition of adverse events and reporting requirements......................................79
10.1.1
Adverse events ......................................................................................79
10.1.2
Serious adverse events ..........................................................................81
10.1.3
SAE reporting........................................................................................82
10.1.4
Pregnancy reporting ..............................................................................83
10.1.5
Reporting of study treatment errors including misuse/abuse................83
10.2
Additional Safety Monitoring................................................................................84
10.2.1
Steering Committee...............................................................................84
11 Data Collection and Database management......................................................................84
11.1
Data collection.......................................................................................................84
11.2
Database management and quality control............................................................84
11.3
Site monitoring ......................................................................................................85
12 Data analysis and statistical methods ................................................................................86
12.1
Analysis sets ..........................................................................................................86
12.1.1
Full analysis set.....................................................................................86
12.1.2
Safety set ...............................................................................................86
12.1.3
Pharmacokinetic analysis set.................................................................86
12.1.4
Other analysis sets.................................................................................86
12.2
Subject demographics and other baseline characteristics......................................86
12.3
Treatments .............................................................................................................87
12.4
Analysis of the primary endpoint(s) ......................................................................87
12.4.1
Definition of primary endpoint(s).........................................................87
12.4.2
Statistical model, hypothesis, and method of analysis..........................87
12.4.3
Handling of missing values/censoring/discontinuations.......................88
12.4.4
Supportive analyses...............................................................................88
12.5
Analysis of secondary endpoints ...........................................................................88


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12.5.1
Efficacy endpoints.................................................................................88
12.5.2
Safety endpoints....................................................................................89
12.5.3
Pharmacokinetics ..................................................................................90
12.5.4
Biomarkers............................................................................................91
.........................................................................91
.......91
.......................................................................91
...........................................................................92
12.7
Interim analyses.....................................................................................................92
12.8
Sample size calculation..........................................................................................92
12.8.1
Primary endpoint(s)...............................................................................92
13 Ethical considerations and administrative procedures ......................................................93
13.1
Regulatory and ethical compliance........................................................................93
13.2
Responsibilities of the investigator and IRB/IEC..................................................93
13.3
Publication of study protocol and results...............................................................93
13.4
Quality Control and Quality Assurance.................................................................94
14 Protocol adherence ............................................................................................................94
14.1
Protocol amendments.............................................................................................94
15 References .........................................................................................................................96
16 Appendices ......................................................................................................................102
16.1
Appendix 1: Pembrolizumab Dose Modification Guidelines..............................102
16.2
Appendix 2: Medications to be used with caution with canakinumab while on 
study.....................................................................................................................107
16.3
Appendix 3: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival, and Overall Survival (based on RECIST 1.1) 108
16.3.1
Introduction.........................................................................................108
16.3.2
Efficacy assessments...........................................................................108
16.3.3
Efficacy definitions .............................................................................117
16.3.4
Data handling and programming rules................................................127
16.3.5
References (available upon request) ...................................................131
16.4
Appendix 4: NSCLC staging according to AJCC 8th edition..............................132


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List of tables
Table 2-1
Objectives and related endpoints ..........................................................32
Table 4-1
Rationale for study design.....................................................................35
Table 6-1
Investigational and control drug............................................................46
Table 6-2
Criteria for mandatory dose interruption and re-initiation for 
canakinumab due to adverse reactions..................................................50
Table 6-3
Specific clinical and diagnostic assessments ........................................55
Table 6-4
Dose and treatment schedule.................................................................58
Table 8-1
Allowable visit windows are specified as follow:.................................60
Table 8-2
Assessment Schedule ............................................................................61
Table 8-3
Assessments & Specifications...............................................................67
Table 8-4
Clinical laboratory parameters collection plan .....................................69
Table 8-5
Blood collection schedule for canakinumab (s.c. injection, 200 mg 
Q3W) PK, IG and PD............................................................................71
Table 8-6
Blood collection for pembrolizumab (30 min i.v. infusion, 200 mg 
Q3W) PK and IG...................................................................................72
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................83
Table 12-1
Operating characteristics with 44 subjects randomized to 
canakinumab treatment arm ..................................................................93
Table 12-2
Operating characteristics with 44 subjects randomized to the 
canakinumab + pembrolizumab combination treatment arm................93
Table 16-1
Dose Modification and Toxicity management Guidelines for 
Immune-related Adverse Events associated with Pembrolizumab.....102
Table 16-2
CYP3A substrates with narrow therapeutic index, or sensitive 
CYP2C9 substrates with therapeutic index**.....................................107
Table 16-3
Response criteria for target lesions .....................................................113
Table 16-4
Response criteria for non-target lesions..............................................115
Table 16-5
Overall lesion response at each assessment ........................................116
Table 16-6
Overall lesion response at each assessment: subjects with non-
target disease only...............................................................................124
Table 16-7
Options for event dates used in PFS, TTP, duration of response........125
List of figures
Figure 1-1
Activity of canakinumab, pembrolizumab and combination in 
H358 NSCLC cell line xenograft model...............................................31
Figure 3-1
Study design..........................................................................................34
Figure 4-1
Simulated PK profiles of canakinumab 200 mg Q3W s.c. and 300 
mg Q4W s.c...........................................................................................37


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Figure 4-2
Proportions of subjects with hs-CRP below 2.3 mg/L by baseline 
hs-CRP declines in all subjects from the CANTOS study....................38
Figure 16-1
NSCLC staging: AJCC 8th edition ......................................................132


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List of abbreviations
ADA
Anti-Drug Antibodies
ADR
Adverse Drug Reaction
AE
adverse event
AESI
adverse event of special interest
AJCC
American Joint Committee on Cancer
ALK
alkaline
ALP
alkaline phosphatase
alpha-FP
alpha fetoprotein
ALT
Alanine transaminase
AST
Aspartate transaminase
ATC
Anatomical Therapeutic Chemical
BOR
Best Overall Response
CAPS
Cryopyrin Associated Periodic Syndromes
CD-
transferrin
Carbohydrate Deficient-transferrin
CDS
Core Data Sheet (for marketed drugs)
CFR
Code of Federal Regulation
CHF
Congestive Heart Failure
Cmax
Maximum concentration
CMO&PS
Chief medical office and patient safety
CMV
Cytomegalovirus
CR
complete response
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-Reactive Protein
CRS
Case Retrieval Strategy
CSR
Clinical Study Report
CT
Computed Tomography
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating tumor deoxyribonucleic acid
CV
coefficient of variation
CVD
Cardiovascular Disease
CYP
Cytochrome P450
DBP
Diastolic Blood Pressure
DDI
Drug-Drug Interactions
DFS
Disease Free Survival
DILI
Drug Induced Liver Injury
DNA
Deoxyribonucleic acid
e.g.
exempli gratia
EBV
Epstein-Barr Virus


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EC
Ethics committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
Electronic Data Capture
EGFR
Epidermal Growth Factor Receptor
EMA
European medicines agency
EOT
End of Treatment
ERCP
Endoscopic Retrograde Cholangiopancreatography
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose Positron Emission Tomography
FFPE
Formalin-fixed paraffin embedded
FMF
Familial Mediterranean Fever
FPFV
First patient first visit
G-CSF
Granulocyte Colony-Stimulating Factor
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl-transferase
HAV
Hepatitis A Virus
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C Virus
HEV
Hepatitis E Virus
Hgb
Hemoglobin
HIDS
Hyperimmunoglobulin D Syndrome
HIV
human immunodeficiency virus
HR
Hazard Ratio
hs-CRP
High-sensitivity C-reactive protein
hs-IL-6
High sensitivity interleukin 6
HSV
Herpes Simplex Virus
i.e.
id est
i.v.
intravenous
IAC
Infection adjudication committee
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use’
IEC
Independent Ethics Committee
IG
Immunogenicity
IgA
Immunoglobulin A


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IgE
Immunoglobulin E
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IHC
Immunohistochemistry
IL-1β
Interleukin-1β
IN
Investigator Notification
INR
International Normalized Ratio
IO
Immuo-Oncology
IQR
Interquartile Range
irAE
Immune-related adverse events
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intention to treat
IUD
Intrauterine Device
IUS
Intrauterine System
LDH
lactate dehydrogenase
LFT
Liver function test
LPLV
Last patient last visit
MACE
Major Adverse Cardiovascular Events
MCA
methylcholanthrene
MCV
Mean Corpuscular Volume
MDSCs
Myeloid Derived Suppressor Cells
MedDRA
Medical Dictionary for Regulatory Activities
Mg
milligram(s)
MKD
Mevalonate Kinase Deficiency
mL
milliliter(s)
MPR
Major Pathological Response
MRI
Magnetic Resonance Imaging
NASH
Nonalcoholic steatohepatitis
NF-κB
Nuclear Factor Kappa Beta
NIMP
Non-investigational medicinal Product
NSCLC
Non-small cell lung cancer
o.d.
once a day
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic Analysis Set
PD
pharmacodynamic(s)
PD-1
Programmed cell death protein 1
PD-L1
Programmed death-ligand 1
PET
Positron Emission Tomography
PFS
Progression Free Survival
PK
pharmacokinetic(s)


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PR
partial response
PS
Performance Status
PT
Prothrombin Time
Q3W
Every 3 weeks
QMS
Quality Management System
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RoW
Rest of World
RP2D
Recommended Phase 2 Dose
s.c.
subcutaneous
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
sCR
serum creatinine
SD
standard deviation
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
T1D
Type 1 Diabetes
T3
triiodothyronine
T4
Thyroxine
TAM
Tumor Associated Macrophages
TB
Tuberculosis
TBIL
Total Bilirubin
TCR
T Cell Receptor
TFQ
Trial Feedback Questionnaire
TNF
Tumor Necrosis Factor
TNFα
Tumor Necrosis Factor alpha
TPS
Tumor Proportion Score
TRAPS
Tumor Necrosis Factor Receptor Associated Periodic Syndrom
TSH
Thyroid-Stimulating Hormone
TTP
Time to progression
ULN
upper limit of normal
UNK
Unknown
US
United States
USPI
US-Package Insert
VATS
Video-Assisted Thoracic Surgery
VEGF
Vascular Endothelial Growth Factor
Vs
versus
WHO
World Health Organization


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WoC
Withdrawal of Consent


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days)
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used 
to capture data transcribed from paper source forms used at the point of care
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained
Estimand
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable 
(or endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable.
Healthy volunteer
A person with no known significant health problems who volunteers to be a 
study participant 
Intercurrent events
Events occurring after treatment initiation that affect either the interpretation 
or the existence of the measurements associated with the clinical question of 
interest.
Investigational drug
The study drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance”
Investigational 
drug/treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Non-investigational 
medicinal Product 
(NIMP)
Products which are not the object of investigation (e.g. any background 
therapy administered to each of the clinical trial subjects, regardless of 
randomization group, rescue medication, active drug run-ins etc.)
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time 
all study drug administration is discontinued and no further assessments are 
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Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Study completion
Point/time at which the subject came in for a final evaluation visit or when 
study drug was discontinued whichever is later.
Study treatment
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-investigational 
medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and 
should be used to identify the subject throughout the study for all data 
collected, sample labels, etc.
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of study 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer, and does not want/allow any 
further visits or assessments, and does not want any further study related 
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Protocol summary
Protocol 
number
CACZ885V2201C
Full Title
A randomized, open-label, phase II study of canakinumab or pembrolizumab as 
monotherapy or in combination as neoadjuvant therapy in subjects with 
resectable non-small cell lung cancer (CANOPY-N)
Brief title
This study will evaluate the effect of canakinumab or pembrolizumab given as 
monotherapy or in combination as neo-adjuvant treatment for subjects with early 
stages NSCLC.
Sponsor and 
Clinical Phase
Novartis, Phase II
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this randomized, open-label, phase II study is to evaluate the 
major pathological response (MPR) rate of canakinumab given as a neoadjuvant 
treatment, either as single agent or in combination with pembrolizumab, in 
addition to evaluate the MPR of pembrolizumab as a single agent. Additionally 
the dynamics of the tumor microenvironment changes on treatment by 
comparing pre-, on- and post-treatment samples will be evaluated.
Primary 
Objective(s) 
To assess the MPR rate (≤ 10% of residual viable tumor cells) on the resected 
specimen at the time of surgery in all subjects randomized to canakinumab 
alone or in combination with pembrolizumab
Secondary 
Objectives

To assess overall response rate (ORR) in randomized subjects treated 
with canakinumab or pembrolizumab as monotherapy or in combination

To assess surgical feasibility rate in each treatment arm based on 
randomized subjects

To assess the MPR rate at the time of surgery in (a) all subjects 
randomized to pembrolizumab monotherapy arm, (b) all randomized 
subjects based on local review in each treatment arm and (c) to estimate 
the difference in MPR and posterior probability of the difference in MPR ≥ 
10% between subjects randomized to canakinumab + pembrolizumab 
combination and pembrolizumab alone

To assess the prevalence and incidence of immunogenicity (IG) anti-drug 
antibodies (ADA) of canakinumab and pembrolizumab

To assess the pharmacokinetics (PK) of canakinumab and 
pembrolizumab as monotherapy and in combination

To evaluate safety and tolerability of canakinumab and pembrolizumab as 
monotherapy and in combination

To assess the relationship between key blood or tissue based biomarkers 
and MPR
Study design
This is a phase II, randomized, open-label study evaluating efficacy and safety of
canakinumab or pembrolizumab monotherapy or in combination as neoadjuvant 
treatment. Approximately 110 subjects will be randomized in a 2:2:1 ratio to one 
of the treatment arms (canakinumab alone or canakinumab in combination with 
pembrolizumab or pembrolizumab alone).
Randomization will be stratified by histology (squamous vs non-squamous)


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Population
110 adult subjects, male and female with resectable non-small cell lung cancer 
(NSCLC)
Key Inclusion 
criteria
Histologically confirmed NSCLC stage IB-IIIA (per American Joint Committee on 
Cancer (AJCC) 8th edition), deemed suitable for primary resection by treating 
surgeon, except for N2 and T4 tumors.
Subject must be eligible for surgery and with a planned surgical resection in 
approximately 4 to 6 weeks (from the first dose of study treatment).
A mandatory newly obtained tissue biopsy from primary site is required for study 
enrollment. An archival biopsy is also acceptable if obtained up to 5 months 
before first day of study treatment and if the subject did not go through 
antineoplastic systemic therapies between biopsy collection date and beginning 
of study treatment.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 
1.
Key Exclusion 
criteria
Subjects with unresectable or metastatic disease. All subjects should have brain 
imaging (either Magnetic Resonance Imaging (MRI) brain or Computed 
Tomography (CT) brain with contrast) prior to enrollment to exclude brain 
metastasis.
History of severe hypersensitivity reactions to monoclonal antibodies, which in 
the opinion of the investigator may pose an increased risk of serious infusion 
reaction.
Presence or history of a malignant disease that has been diagnosed and/or 
required therapy within the past 3 years. Exceptions to this exclusion include the 
following: completely resected basal cell and squamous cell skin cancers, and 
completely resected carcinoma in situ of any type.
Subjects who received prior systemic therapy (including chemotherapy, other 
anti-cancer therapies and any other antibody or drug specifically targeting T-cell 
co-stimulation or immune checkpoint pathways) in the past 3 years before 
screening.
Study 
treatment
In this study, the “study treatment” refers to both canakinumab and 
pembrolizumab study drugs administered either as monotherapy or in 
combination of study drugs: canakinumab plus pembrolizumab
Subjects will receive 2 doses of canakinumab (200 mg s.c. Q3W) alone or in 
combination with pembrolizumab or two doses of pembrolizumab as single agent 
(200 mg i.v. Q3W).
Efficacy 
assessments
MPR: Response will be assessed centrally at the time of surgery (by number of 
subject with ≤ 10% residual viable cancer cells)
Radiology tumor assessments: by investigator (RECIST 1.1) at screening and 
one before surgery.
Key safety 
assessments

Physical examination

ECOG PS

Body weight and vital signs

Laboratory assessments, including hematology, chemistry, coagulation, 
thyroid function, hepatitis testing and urinalysis

Pregnancy tests for women of child-bearing potential (serum pregnancy test 
at screening for all female subjects)

Adverse events (AEs) the severity, the relationship with to study treatment 
and the seriousness
Data analysis
Primary endpoint:


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The primary endpoint is MPR rate, defined as the percentage of subjects with ≤ 
10% residual viable cancer cells. The analysis of primary endpoint is described 
by the following five attributes:
1.
The target population is defined as all randomized patients who are 
histologically confirmed NSCLC stage IB-IIIA (per AJCC 8th edition), 
deemed suitable for primary resection by treating surgeon, except for N2 
and T4 tumors
2.
The primary variable is the percentage of subjects with a major 
pathological response (defined as ≤ 10% residual viable cancer cells per 
central review). Any patient who has >10% residual viable cancer cells, or 
starts new antineoplastic therapy medication prior to surgery, or does not 
have the surgery performed, is considered as a non-responder
3.
The study treatment is canakinumab as monotherapy or in combination 
with pembrolizumab
4.
The intercurrent events of interest in this study are: start of new 
antineoplastic therapy prior to surgery and discontinuation of study treatment 
prior to surgery. These intercurrent events will be addressed by assessing:
a.
Start of new antineoplastic therapy prior to surgery: subject will be 
considered as non-responder (composite strategy)
b.
Discontinuation of study treatment prior to surgery: subject will be 
included in the analysis regardless of this intercurrent event (treatment-
policy strategy)
5.
The summary measure is MPR rate with its corresponding two-sided exact 
binomial 95% confidence interval in canakinumab alone arm and 
canakinumab in combination with pembrolizumab arm
The proof of efficacy in canakinumab alone arm will be declared if both of the 
following conditions are met:

the mean of the posterior distribution of MPR is at least 30% and

the posterior probability that the MPR is ≥ 20% is at least 90%
The proof of efficacy in the combination treatment arm will be declared if both of 
the following conditions are met:

the mean of the posterior distribution of MPR is at least 45% and

the posterior probability that the MPR is ≥ 30% is at least 90%
The posterior distribution of MPR will be derived from the prior distribution and 
all available data from the subjects included in the Full Analysis Set (FAS). A 
minimally informative unimodal Beta prior will be used for MPR in each arm.
Subjects who have an unknown MPR status due to surgery not being performed 
(including lost to follow-up or withdrawal of study consent before surgery) will be 
considered as non-responders when estimating MPR rate.
Secondary endpoints:
MPR rate will be assessed using the same patient population used in the 
primary analysis, including the strategy for handling intercurrent events (1) 
based on local review in all three treatment arms and (2) based on central 
review in pembrolizumab monotherapy arm.
MPR rate for all the above specified analyses will be summarized by treatment 
arm along with the two-sided exact binomial 95% confidence interval.


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The difference in MPR rate between canakinumab in combination with 
pembrolizumab and pembrolizumab single agent arm along with the two-sided 
exact 95% confidence interval based on Chan and Zhang (1999) will be 
summarized based on central review using the same patient population used in 
the primary analysis, including the strategy for handling intercurrent events. The 
posterior probability of the difference 10% or greater in MPR rate will also 
calculated.
Surgical feasibility rate is defined as the percentage of subjects in FAS who 
undergo surgery following study treatment. Surgical feasibility rate and two-sided 
exact binomial 95% confidence interval will be presented by treatment group.
Overall response rate (ORR) is defined as the percentage of subjects in FAS 
with a best overall response of complete response (CR) or partial response 
(PR), as per local review. The best overall response will be the observed 
response at the assessment performed prior to surgery. ORR will be evaluated 
according to RECIST 1.1. ORR and two-sided exact binomial 95% confidence 
interval will be presented by treatment group. Subjects with a best overall 
response (BOR) of ‘Unknown’ per RECIST 1.1 will be considered as non-
responders when estimating ORR.


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Key words
ACZ885, canakinumab, pembrolizumab, NSCLC, squamous, non-squamous, 
MPR, hs-CRP, PD-L1, CD8, hs-IL-6, CANOPY.


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Amendment 1 (07-Apr-2020) 
Amendment rationale 
As of 07-Apr-2020, 27 sites have been initiated, 25 subjects have been screened and 17 have 
been randomized and treated.
The main rationale for amendment 01 is:

To implement the request from the Health Authority to modify the target population for 
both the primary and secondary endpoint Major Pathological Response (MPR) from 
“evaluable subjects” to “randomized subjects”.
In addition, the following modifications have been implemented:

The following inclusion/exclusion criteria have been added or modified in order to allow 
more clarity and more flexibility for the enrollment/randomization:

Inclusion criterion 3 is updated to reference to Appendix 16.4 which is added to clarify 
which stages of NSCLC are allowed according to AJCC 8th edition

Inclusion criterion 5 is updated to clarify that the biopsy should be taken from primary 
site and that the archival biopsy should not be older than 5 months. This change (i.e. 5 
months) is necessary to take into account the shipment, processing of biopsies and that 
biopsies are only evaluable if not older than 6 months. In addition, it is clarified that 
aspirates will not be accepted.

Exclusion criterion 5 is updated to allow subjects with history of auto-immune disease 
or known auto-immune disease who have not required systemic therapy in the past 2 
years before study entry to be enrolled in the study.

Exclusion criterion 7 is updated to reflect the pembrolizumab label concerning 
pneumonitis

Exclusion criterion 8 is updated to allow more flexibility concerning the adjustment of 
blood pressure medication

Exclusion criterion 15 is added to ensure subjects with severe or uncontrolled medical 
conditions are not enrolled in the study

Updated Section 6.3.2 to clarify that subjects with a tumor of adenosquamous histology 
can be stratified as either squamous or non-squamous histology

The EOT visit window has been changed to within 21 days after the permanent 
discontinuation of study treatment but before the surgery to provide more flexibility to the 
site and patient

Surgery details guidance is included
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Section 1.1.2: The reference of the KEYNOTE-042 study has been updated to “Mok et 
al. 2019”.






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
Section 10.1.1.1: To replace the Adverse Event of Special Interest (AESI) name ‛DILI 
(Hepatic transaminases and bilirubin elevations)’ with the new AESI name ‛Abnormal 
Liver Parameters’ so as to reflect MedDRA search more accurately. 

Section 10.1.4: Clarification added that, if pregnancy occurs while on study, the 
newborn will be followed for at least 12 months.

Section 11.2: Change implemented to reflect the new protocol template version 3.0

Section 12.4.1: Changed the patient population from evaluable to randomized subjects 
requested by the health authority.

Section 12.4.2: 
o
The target population was updated to all randomized patients who are 
histologically confirmed NSCLC stage IB-IIIA (per AJCC 8th edition), deemed 
suitable for primary resection by treating surgeon, except for N2 and T4 tumors. 
o
The primary variable is clarified in details and the non-responder is specifically 
defined.
o
Study treatment was added as a new attribute for primary estimand. 
o
Withdrawal of consent prior to surgery and lost to follow-up prior to surgery 
were removed from intercurrent events. 
o
The intercurrent event of discontinuation of study treatment due to other reasons 
was further clarified as discontinuation of study treatment prior to surgery. 
o
The strategy of handling intercurrent event discontinuation of study treatment 
prior to surgery was clarified to be treatment-policy strategy. 
o
The strategy of handling intercurrent event of start of new antineoplastic therapy 
prior to surgery was updated to composite strategy. 
o
The target MPR rate for the combination arm was updated to 45% which is a 
25% absolute improvement to account for the change of analysis population 
from evaluable subjects to randomized subjects. 

Section 12.4.3: Updated to clarify the handling of unknown MPR status due to surgery 
not being performed (including lost to follow-up or withdrawal of study consent before 
surgery).

Section 12.4.4: Updated to align with the changes made in Section 12.4.2. The 
intercurrent event of start of new antineoplastic therapy will be handled by treatment-
policy strategy.

Section 12.5.1: Updated to align with the changes made in Section 12.4.1 and 12.4.2 for 
the secondary objective of MPR including MPR per central review in pembrolizumab 
arm and MPR per local review in all three arms. Clarification was made on handling 
BOR of ‘Unknown’ per RECIST 1.1, and it is clarified that BOR is based on the 
assessment on the EOT visit.

Section 12.6.2: TCR sequencing was deleted.


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
Section 12.8.1: Changed the patient population from evaluable to randomized subjects 
requested by the health authority, and the target MPR rate for the combination arm was 
updated to 45% which is a 25% absolute improvement. Proof of efficacy and operating 
characteristic tables (Table 12-1 and Table 12-2) were updated accordingly, and the 
probability of erroneously declaring proof of efficacy is at most 2.1% while the 
probability of declaring proof of efficacy is at least 92.2% for MPR ≥ 55%.

Section 15: New and missing references have been added.

Section 16.1: Table 16-1 item 2 in General Instruction was updated to clarify that an 
interruption of pembrolizumab for 12 weeks is not allowed due to the length of the trial.

Section 16.3.3.1: Pembrolizumab±canakinumab/matching placebo study treatment was 
deleted, because it was not applicable for the study. 

Section 16.3.4.2: End of treatment visit was changed to within 21 days of permanent 
discontinuation of study treatment but before the surgery.

Section 16.4: Added NSCLC staging table according to AJCC 8th edition for 
clarification.
The protocol summary has been updated to reflect the changes throughout the document as well 
as the list of abbreviations, the glossary of terms, list of abbreviations.
At last, minor editorial changes (e.g. typographical mistakes, grammatical changes, rewording) 
to improve flow and consistency, and correction of spelling errors or typographical errors have 
been made throughout the protocol.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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1
Introduction
1.1
Background
1.1.1
Disease background
Lung cancer is the most common invasive cancer and cause of cancer death worldwide. An 
estimated 1.8 million people were diagnosed globally with lung cancer in 2012 and there were 
1.6 million deaths from this disease (Globocan 2012). NSCLC accounts for 85% of the lung 
cancer diagnoses and about 30% of subjects have surgically resectable disease at diagnosis 
(Molina et al 2008, Maeda et al 2010). Surgery is the treatment of choice for subjects with 
NSCLC stages I through IIIA. Five-year survival rates range from 50% for stage IA disease to 
19% for stage IIIA disease (Goldstraw et al 2007), with most patients having postsurgical tumor 
relapse (Uramoto and Tanaka 2014). Despite apparently curative surgery, approximately 50% 
of stage IB and 70% of stage II NSCLC patients will relapse and eventually die of their disease. 
Given the current limited survival of patients with NSCLC, even in early stages of disease, new 
treatments options are needed. Neoadjuvant and adjuvant treatments are used to eradicate 
micrometastatic disease and minimize the risk of relapse.
1.1.2
Immunotherapy in NSCLC
Immunotherapy has recently shaped the treatment landscape of advanced NSCLC patients, both 
in the pre treated and treatment-naive setting. Monoclonal antibodies targeting PD-1 and 
Programmed death-ligand 1 (PD-L1) (nivolumab, durvalumab, pembrolizumab and 
atezolizumab) have demonstrated significant activity as monotherapy and superiority over 
single agent chemotherapy in pretreated NSCLC either PD-L1 selected or unselected and have 
been recently approved by the health authorities in this setting (Barlesi et al 2016, 
Antonia et al 2017, Langer et al 2016, Gandhi et al 2018, Borghaei et al 2015, Horn et al 2017, 
Rittmeyer et al 2017, Socinski et al 2018).
Nivolumab is approved in many countries for patients who have previously received 
chemotherapy for both squamous and non-squamous lung cancer based on two randomized 
phase 3 trials (Borghaei et al 2015, Brahmer et al 2015) that demonstrated superior overall 
survival (OS) for nivolumab over docetaxel in both squamous and non-squamous NSCLC. In 
the first line setting, nivolumab was not superior to platinum-based doublet chemotherapy in 
patients with PD-L1 ≥ 1% based on the CheckMate 26 study (Carbone et al 2017). A second 
study, CheckMate-227, demonstrated Progression Free Survival (PFS) improvement of the 
combination of nivolumab+ipilimumab over chemotherapy in patients with high tumor 
mutational burden NSCLC (regardless of PD-L1 levels) (Hellmann et al 2018).
Pembrolizumab a monoclonal PD-1 inhibitor, is also approved in many countries for the 
treatment of advanced NSCLC after platinum-based doublet chemotherapy in patients whose 
tumor have PD-L1 expression on ≥ 1% of tumor cells on the basis of KEYNOTE-010 study 
(Herbst et al 2016). In the first-line setting, pembrolizumab was initially approved as 
monotherapy for NSCLC patients whose tumor has a PD-L1 expression ≥ 50% based on the 
results of KEYNOTE-024 (Reck et al 2016). 
In addition, in Japan, pembrolizumab was approved as monotherapy in the first-line treatment 
of PD-L1-positive (Tumor Proportion Score (TPS) ≥ 1%) unresectable, advanced/recurrent 


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NSCLC (KEYNOTE-042), (Mok et al 2019). More recently, pembrolizumab was approved in 
combination with platinum-based doublet chemotherapy and pemetrexed in non-squamous 
NSCLC as first line treatment based on the results of KEYNOTE-189 (Gandhi et al 2018). 
Pembrolizumab was also approved in combination with carboplatin and either paclitaxel or 
nabpaclitaxel, as first-line treatment of patients with metastatic squamous NSCLC in the United 
States (US), based on the results of KEYNOTE-407 (Paz-Ares et al 2018).
Atezolizumab was approved for previously treated NSCLC with progression on or following a 
platinum-containing regimen (Rittmeyer et al 2017) regardless of the PD-L1 expression and of 
the histology and in the first line setting for non-squamous histology (with no Epidermal Growth 
Factor Receptor (EGFR) and ALK genomic tumor aberrations) in combination with 
bevacizumab, paclitaxel and carboplatin.
1.1.3
Neoadjuvant treatment and major pathological response as a 
surrogate endpoint
A meta-analysis based upon seven trials involving 988 patients suggested that neoadjuvant 
chemotherapy (platinum-based chemotherapy-cisplatin or carboplatin, combined with other 
agents) improved OS in patients with NSCLC when given preoperatively (five-year survival 
20% versus 14% without neoadjuvant chemotherapy). This improvement in survival is similar 
to that observed in the meta-analyses of predominantly adjuvant chemotherapy 
(Burdette-Radoux and Muss 2006, Scagliotti et al 2012, Chuang et al 2017). The neoadjuvant 
setting offers the possibility for the identification of surrogate clinical and biological markers 
that may correlate with response to therapy and in some cases long-term outcome. In addition, 
preoperative therapy may be a useful platform for the development of new targeted therapies. 
Efficient strategies to evaluate promising agents in early phase development are essential for 
rapid progress in lung cancer treatment and prevention. Several studies have shown 
preoperative systemic therapy to be safe prior to surgical resection of NSCLC with no difference 
in extent of surgical procedures performed, operative morbidity and mortality 
(Depierre et al 2002, Gilligan et al 2007, Scagliotti et al 2012).
A comprehensive analysis of 192 patients with stage I-IV NSCLCs treated with neoadjuvant 
chemotherapy (mean of 3 treatment cycles; range 2-7 cycles) followed by complete surgical 
resection demonstrated an improved survival in those with 0-10% viable tumor compared to 
other groups. Among patients with NSCLC treated with neo-adjuvant chemotherapy, the 
hazard ratio for survival was 4.78 (95% confidence interval of 2.06–11.11) when comparing 
patients with > 70% viable tumor cells to those with ≤ 10% viable tumor cells (Pataer 2012). 
The correlation between MPR and survival outcomes remained significant when patients were 
stratified by stage supporting the relevance of MPR as an endpoint for clinical trials 
(Pataer 2012, Hellmann et al 2014). MPR, defined as ≤10% residual viable tumor, was 
demonstrated to positively correlate to disease free survival (DFS) and OS in patients treated 
with neo-adjuvant chemotherapy (Pataer 2012, Hellmann et al 2014) and thus used as a 
surrogate efficacy endpoint in some neo-adjuvant studies (Chaft et al 2013, Forde et al 2018, 
Shu et al 2018).
Chaft and colleagues performed a prospective trial investigating pathological response with the 
methods described by Pataer (Pataer 2012) and observed that among 50 patients with stage IB–


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IIIA NSCLCs given neoadjuvant chemotherapy and bevacizumab, 22% patients had 10% or 
less viable tumor (MPR) (Chaft et al 2013).
Recent clinical studies demonstrated promising results of immunotherapy treatment in the 
neoadjuvant setting. PD-1 pathway blockade in patients with early stage lung cancer may have 
enhanced antitumor effects due to the greater fitness of host immunity and reduced tumor clonal 
heterogeneity (McGranahan et al 2016). Neoadjuvant immunotherapy is attractive, since the 
primary tumor may be leveraged as an antigen source for expansion and activation of tumor-
specific T cells and systemic surveillance of micro-metastases.
A single arm study of nivolumab in 21 adults with untreated surgically resectable early (stage 
I, II, or IIIA) NSCLC given approximately for 4 weeks before the surgical resection (two 
preoperative doses of nivolumab Q2W), showed that MPR occurred in nine of the 20 resected 
tumors (45%; 95% CI, 23 to 68). Responses occurred in both PD-L1–positive (TPS ≥ 1%) and 
PD-L1–negative tumors; among 15 patients with evaluable PD-L1 expression, 3 and 2 patients 
had MPR, respectively. There was a significant correlation between the pathological response 
and the pretreatment tumor mutational burden. Patients who had a MPR were found to carry a 
significantly higher number of somatic sequence alterations than those without a MPR, with a 
mean (± SE) number of 311 ± 55 and 74 ± 60, respectively (p = 0.01 by exact Wilcoxon test) 
(Forde et al 2018). The tumor mutational burden was predictive of the pathological response to 
PD-1 blockade as evidenced by the treatment-induced expansion of mutation-associated and 
neoantigen-specific T-cell clones in peripheral blood. In addition, neoadjuvant treatment with 
nivolumab was associated with few side effects and did not delay surgery.
Neoadjuvant single arm study with atezolizumab in combination with carboplatin and nab-
paclitaxel given for ~6 weeks before surgery also showed activity in this setting. Eleven of 14 
patients successfully underwent resection and seven of 14 patients (50%) achieved MPR, 
including three with complete pathological responses (Shu et al 2018). 
Another study in the neo-adjuvant setting is ongoing to evaluate atezolizumab as monotherapy 
in 180 patients with stage IB-IIIB resectable NSCLC. An initial pre-specified safety analysis 
showed that among 21 patients, 19 had MPR assessment and 4/19 (21%) had a MPR 
(Rusch et al 2018).
There are other ongoing studies with other immunotherapy drugs (such as pembrolizumab and 
durvalumab) in the neo-adjuvant setting.
1.1.4
The role of inflammation and IL-1β in NSCLC
Chronic inflammation plays an important role in the development of NSCLC. Key etiological 
risk factors such as smoking (Bracke et al 2006 ), second-hand smoke exposure, chronic 
infections, and exposure to environmental toxins cause a chronic inflammatory milieu that plays 
a critical role in carcinogenesis, particularly, in lung cancer (Krysan et al 2008, 
O'Callaghan 2015).
The cytokine interleukin-1β (IL-1β) is one of the mediators of pulmonary inflammation that 
promotes lung cancer. Genetic evidence also links IL-1β to lung cancer risk (Bhat et al 2014). 
Polymorphisms in the promoter region of the IL-1 gene result in altered levels of IL-1β 
expression and are associated with an increase in lung cancer risk (Li and Wang 2013). 
Extensive pre-clinical data supports the role of IL-1β in several distinct steps in carcinogenesis. 


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These 
steps 
include 
tumor 
initiation, 
promotion, 
angiogenesis, 
and 
metastasis 
(O'Byrne et al 2000, 
O'Byrne and Dalgleish 2001, 
Dalgleish and O'Byrne 2006, 
Mantovani et al 2008). Tumor initiation is the first step in carcinogenesis and involves the 
acquisition of mutations in normal cells that allow a selective growth advantage. IL-1β is 
thought to create a microenvironment that promotes tumor initiation (Wu et al 2016). In a 
mouse model of tumor initiation, the genetic loss of IL-1β resulted in an attenuation of 3-
methylcholanthrene (MCA)-induced tumor formation (Krelin et al 2007, Voronov et al 2007). 
IL-1β promotes tumor initiation by inducing the Nuclear Factor Kappa Beta (NF-κB) 
expression (Kasza 2013). The second step in carcinogenesis is tumor promotion. This step is 
characterized by the growth of a primary tumor from a single transformed cell. This step is 
mediated in part by tumor associated macrophages (TAM) and cytokines that these TAMs 
produce, such as tumor necrosis factor alpha (TNFα), IL-6, and IL-1β (Becker 2006).
Supporting evidence published by Kaplanov and colleagues showed that IL-1β blockade in 
breast cancer models (by using either IL-1β-deficient mice or treatment with an anti-IL-1β 
antibody), resulted in anti-tumor activity which was associated with a decrease in macrophages 
and increase in dendritic cells as well as activated T-cells (Kaplanov et al 2018). 
The third step in carcinogenesis is angiogenesis, in which blood vessel formation is induced to 
generate a vascular network for the primary tumor. In this process, IL-1β may also play a critical 
role, as tumors in mice deficient in IL-1β failed to induce vascular endothelial growth factor 
(VEGF) expression and tumor angiogenesis (Apte et al 2006, Voronov et al 2003). The final 
step in carcinogenesis is metastasis. IL-1β plays an important role in this step as well via the 
induction of genes critical for invasion and cell adhesion. Using a mouse model of lung cancer 
metastasis, Yano and colleagues demonstrated that tumors genetically programmed to express 
high levels of IL-1β developed lung metastasis more rapidly than controls, with treatment with 
an anti-IL-1β antibody inhibited formation of lung metastasis (Yano et al 2003). Taken together, 
these results suggest an important role for IL-1β in multiple steps of carcinogenesis.
Activation of the inflammation and elevated levels of CRP have been shown to negatively affect 
several components of the immune system (Chaturvedi et al 2010). Mature IL-1β can promote 
the infiltration of immunosuppressive cells into the tumor microenvironment, including 
myeloid derived suppressor cells (MDSCs) and TAMs (Guo et al 2014). Elevated CRP levels, 
induced by the expression of IL-1β and IL-6, have also been shown to directly and negatively 
affect the immune cell environment. Both in vitro and transgenic mouse models have 
demonstrated the ability of CRP to suppress the differentiation and proliferation of T-cells, and 
inhibit the maturation, migration and function of dendritic cells (Frenzel et al 2007, 
Zhang et al 2015, Jimenez et al 2018). Moreover, a shift towards increased number of 
suppressive MDSCs was demonstrated in a human CRP expression mouse model 
(Pegues et al 2016). Taken together, these findings indicate a role for CRP/IL-1β towards a 
more immunosuppressive microenvironment, contributing to immune evasion and tumor 
progression. Counteracting these effects through inhibition of the CRP/IL-1β axis may result in 
a microenvironment more susceptible to Immuno-Oncology (IO) agents such as anti-PD-(1) 
inhibitors used in combination.
Recent data confirming this hypothesis demonstrated synergistic anti-tumor activity of anti-IL-
1β and anti-PD-1 combination treatments in a 4T1 breast cancer mouse model. In this model, 
while each of the monotherapy arms resulted in a decrease in tumor volume, the combination 


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of both treatments completely abrogated the tumor growth, which was characterized by a 
significant increase in T-cells (Kaplanov et al 2018). In addition, recently reported results from 
the atezolizumab in second and third line NSCLC studies demonstrated that decreases in CRP 
correlated with RECIST 1.1 responses, prolonged PFS and OS for atezolizumab but not 
docetaxel treated subjects.
Given the evidence for the importance of IL-1β signaling in carcinogenesis, treating cancer with 
IL-1β blockade has been proposed (Wu et al 2016, Jenkins 2017).
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Canakinumab in NSCLC
Canakinumab (ACZ885) is a high affinity human anti-IL-1β monoclonal antibody that belongs 
to the Immunoglobulin G1 (IgG1)/κ isotype subclass. Canakinumab is manufactured in a 
murine SP2/0 cell line. Currently canakinumab is approved and marketed as Ilaris® for the 
treatment of IL-1β driven auto-inflammatory diseases: gouty arthritis, Still's disease, Cryopyrin 
Associated Periodic Syndromes (CAPS), Systemic Juvenile Idiopathic Arthritis (SJIA), Tumor 
Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D 
Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD), Familial Mediterranean Fever 
(FMF). IL-1β, a proinflammatory cytokine, is a key mediator of atherosclerotic plaque
formation and the atherothrombotic process. Novartis has investigated its use in the secondary 
prevention of major adverse cardiovascular events in the CANTOS trial (Canakinumab Anti-
inflammatory Thrombosis Outcomes Study). In this randomized, placebo-controlled study with 
10 061 patients with a history of prior myocardial infarction and inflammatory atherosclerosis 
and elevated hs-CRP at baseline were enrolled and were treated with either placebo or 
canakinumab 50, 150 or 300 mg s.c. every three months for a median follow-up period of 3.8 
years. The administration of canakinumab demonstrated a clinically and statistically significant 
effect in reducing the risk of Major Adverse Cardiovascular Events (MACE). Since treatment 
with immune suppression in transplant medicine and in rheumatic disorders has been found to 
cause cancers (Turesson and Matteson 2013, Geissler 2015), a safety analysis in CANTOS to 
evaluate the development of cancer as an Adverse Event (AE) was included as a pre-specified 
analysis. This analysis showed that canakinumab reduced the occurrence of lung cancer and 
lung cancer mortality compared to placebo in a dose-dependent manner (Ridker et al 2017a). 
The baseline concentrations of hs-CRP (median 6.0 mg/L vs 4.2 mg/L; p<0.0001) and IL-6 ( 3.2 
vs 2.6 ng/L; p<0·0001) were significantly higher for patients who subsequently diagnosed with 
lung cancer than those who were not diagnosed, respectively (Ridker et al 2017a). 
Canakinumab treatment also resulted in dose-dependent decrease in hs-CRP of 26-41% and IL-
6 decrease of 25-43%; lung cancer incidence was less frequent in the treated groups that was 
dose-dependent (Ridker et al 2017a). Lung cancer mortality was significantly less in the 
canakinumab 300 mg treated group than in the placebo group (HR=0.23 [95% CI 0.10-0.54]) 
and in the pooled canakinumab patients (p=0.0002 for trend across all active-treated patients) 
(Ridker et al 2017a). Total cancer mortality was significantly lower in the pooled canakinumab 
groups versus the placebo group (p=0.0007), but only the 300 mg every 12 weeks canakinumab 
group had a statistically significant reduction in risk (HR=0.49, 95% CI: 0.31-0.75, p=0.0009). 


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All-cause mortality did not differ significantly between the canakinumab and placebo groups, 
HR=0.94 (95% CI; 0.83-1.06) (Ridker et al 2017a). 
Circulating tumor deoxyribonucleic acid (ctDNA)
ctDNA was detected at baseline in 66% (44/67) of lung cancer patients from CANTOS, 
suggesting that these patients may have harbored undiagnosed lung cancer at the time of 
enrollment (Baum et al 2018). This included similar lung cancer driver mutations as reported 
in the literature (Chaudhuri et al 2017) and The Cancer Genome Atlas database. Additionally, 
baseline ctDNA positivity, as well as high baseline level of CRP and IL-6, trend with faster 
time to lung cancer occurrence. This trend was only observed with cytokines in the IL-1β/IL-
6/CRP inflammation pathway. Amongst the inflammatory cytokines tested, IL-6 and CRP were 
downregulated by canakinumab, but no change was observed in other cytokines including IL-
18 & TNF-α. These results suggest that the IL-1β/IL-6/CRP inflammation pathway may 
contribute more strongly than other inflammation pathways to lung cancer development, and 
canakinumab’s effect may be mediated by delaying lung cancer progression (Baum et al 2018).
Safety
In the CANTOS study, during a median follow-up time of approximately 3.8 years, there were 
no meaningful differences between canakinumab treatment groups and placebo in the overall 
incidence of AEs, serious adverse events (SAEs), AEs leading to permanent discontinuation or 
to temporary interruption, or of SAEs leading to permanent discontinuation. The most 
frequently reported AEs were viral upper respiratory tract infections (12.5% and 13.9% for 
canakinumab 300mg and 150mg arms and 12.3% for placebo). The majority of infections 
resolved either spontaneously or with standard therapy. A slight increased risk of serious 
infections and of fatal infections/sepsis was observed in canakinumab versus placebo (SAEs of 
infections and infestations reported in 11.7%, 11.3% and 10.2% of subjects in canakinumab 
300 mg, 150 mg and placebo arm, respectively). Rates of all grade AEs of neutropenia (2.0% 
and 1.4% for canakinumab 300 mg and 150 mg and 0.9% for placebo), thrombocytopenia (2.7% 
and 2.0% for canakinumab 300mg and 150mg and 1.6% for placebo) were low, even though 
also numerically higher in the canakinumab group compared with placebo. Decreased 
neutrophil and platelet counts, also reported for canakinumab, were not associated with an 
increased risk of infections or bleeding events. Overall, the safety and tolerability profile of 
canakinumab in the CANTOS study was consistent with the known safety profile in the 
approved indications, for which no specific target organ toxicity has been demonstrated 
(CANTOS CSR, Ridker et al 2017b).
One hypothesis to explain the lower lung cancer incidence and lower lung cancer mortality is 
that canakinumab reduced the rate of progression, invasiveness and metastatic spread of already 
existing tumors, which were too small to be detected at study entry (Ridker et al 2017a). This 
data along with the preclinical information that IL-1β supports tumorigenic inflammation 
provides the rationale to investigate the therapeutic role of canakinumab.
Pre-clinical data
Despite the well-known limitation of mouse models to study the effects of immunotherapy and 
anti-inflammation agents; preliminary mouse data showed that treatment with canakinumab 
single agent or combination with an anti-PD-1 inhibitor could lead to anti-tumor activity. First, 
in an EGFR mutant NSCLC (HCC827 cell line) humanized bone-liver-thymus (BLT) model, 


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anti-tumor activity was observed in 3 out of 5 mice after 3 weeks of treatment with canakinumab 
single agent or combination with pembrolizumab. Furthermore, 3 weeks combination treatment 
of canakinumab and pembrolizumab led to a significant tumor growth inhibition in the KRAS 
H358 NSCLC aggressive model (humanized BLT) compared to vehicle or single agent 
treatment. These treatments were well tolerated with no significant weight loss observed in 
treated mice (both studies were conducted at UCLA, (Jayaraman et al 2019)).
Figure 1-1
Activity of canakinumab, pembrolizumab and combination in H358 
NSCLC cell line xenograft model
Hu-IgG: Humanized Immunoglobulin G
1.2.2
Pembrolizumab in NSCLC
Pembrolizumab (Keytruda®) is a monoclonal humanized antibody designed to identify and 
block the PD-1 receptor. By blocking PD-1, the T-cells can recognize and destroy the cancer 
cells. Pembrolizumab is already approved as first-line treatment of patients with metastatic non-
squamous NSCLC in combination with chemotherapy, as a single agent for the first-line 
treatment of patients whose tumors have high PD-L1 expression (TPS ≥ 50%) and in the second 
line setting. Additionally, pembrolizumab is approved in the US in combination with 
chemotherapy as first-line treatment of patients with metastatic squamous NSCLC 
(Herbst et al 2016, 
Reck et al 2016, 
Langer et al 2016, 
Gandhi et al 2018, 
Paz-Ares et al 2018). See Section 1.1.2.
1.2.3
Canakinumab and PD-1 combination in NSCLC
The combination of canakinumab to a PD-1 inhibitor, such as pembrolizumab, is expected to 
build upon the activity of PD-L1/PD-1 inhibitors blocking the emerging resistance to PD-1 
blockage through inhibition of the CRP/IL-1β axis and thereby resulting in a microenvironment 
more susceptible to anti-PD-(1) inhibitors. Correlation between the IL-1β pathway, CRP levels 
and PD-L1 expression has been observed and provides rationale for combining immune 
checkpoint inhibitors with an IL-1β pathway antagonist (Akamine et al 2018, Guo et al 2017).
No drug-drug interaction (DDI) is expected between pembrolizumab and canakinumab given 
both antibodies are eliminated by non-metabolism dependent pathway. The combination of 


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canakinumab and PDR001, a PD-1 inhibitor under development, has been evaluated in a Phase 
1b dose finding study CPDR001X2103. This study has shown that canakinumab is safe to be 
combined with PDR001. No excess toxicity was observed with the combination canakinumab 
and PDR001, with the AE profile of the combination being representative of the individual AEs 
of each compound. The safety profile of PDR001 is similar to other PD-(L)1 inhibitors, thus 
combination of canakinumab and pembrolizumab is expected to be safe.
In addition, Study CACZ885U2301 (CANOPY-1), a Phase III randomized, double-blind study 
evaluating the combination of platinum-based doublet chemotherapy plus pembrolizumab with 
or without canakinumab in the first line setting in patients with both squamous and non-
squamous (NSCLC) will include a Run-in phase to evaluate the safety of this combination.
Taken together, the role of IL-1β in carcinogenesis, the pre-clinical data, the ctDNA data and 
the reduction in lung cancer incidence and mortality in the CANTOS trial, support the 
hypothesis that canakinumab may provide tumor control/regression as single agent in the neo-
adjuvant setting. In addition, the combination with pembrolizumab, leading to a more 
susceptible tumor micro-environment to PD-L1 inhibition, is expected to further enhance the 
benefit in this setting.
1.3
Purpose
The purpose of this randomized, open-label, phase II study is to evaluate the MPR rate of 
canakinumab given as a neoadjuvant treatment, either as single agent or in combination with 
pembrolizumab, in addition to evaluate the MPR of pembrolizumab as a single agent and the 
dynamic of the tumor microenvironment changes on treatment by comparing pre-, on- and post-
treatment samples. MPR has been shown to positively correlate with OS and DFS in a study 
with patients receiving neo-adjuvant chemotherapy (Hellmann et al 2014)
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the MPR rate (≤10% of residual viable 
tumor cells) at the time of surgery in all subjects  
randomized to canakinumab alone and in 
combination with pembrolizumab arms based on 
central review

MPR rate based on central review
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the prevalence and incidence of IG 
(ADA) of canakinumab and pembrolizumab

ADA prevalence at baseline and ADA 
incidence on-treatment

To assess ORR in randomized subjects treated 
with canakinumab or pembrolizumab as 
monotherapy and in combination (local review)

Overall response rate based on local 
investigator assessment per RECIST 
1.1

To assess the PK of canakinumab and 
pembrolizumab as monotherapy and in 
combination

Concentrations of canakinumab, 
pembrolizumab


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Objective(s)
Endpoint(s)

To assess surgical feasibility rate in each 
treatment arm based on randomized subjects

Surgical feasibility rate

To assess the MPR rate at the time of surgery in
(a) all subjects randomized to pembrolizumab 
monotherapy arm based on central review, (b) all 
randomized subjects based on local review in 
each treatment arm, and (c) to estimate the 
difference in MPR and posterior probability of the 
difference in MPR ≥ 10% between subjects 
randomized to canakinumab + pembrolizumab 
combination and pembrolizumab alone based on 
central review

(a) MPR based on central review
(b) MPR based on local review
(c) Difference in MPR rate based on 
central review

To evaluate safety and tolerability of 
canakinumab and pembrolizumab as 
monotherapy or in combination

Type, frequency and severity of AEs 
(Common Terminology Criteria for 
Adverse Events [CTCAE] v5.0), vital 
signs and laboratory abnormalities

To assess the relationship between key blood or 
tissue based biomarkers and MPR

MPR based on the levels of biomarkers 
(PD-L1, CD8, hs-CRP, hs-IL-6) 
assessed at baseline and on treatment
3
Study design
This is a phase II, randomized, open-label study evaluating efficacy and safety of canakinumab 
or pembrolizumab monotherapy or in combination as neoadjuvant treatment. Approximately 


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110 subjects will be randomized in a 2:2:1 ratio to one of the treatment arms (canakinumab 
alone or canakinumab in combination with pembrolizumab or pembrolizumab alone) and 
receive two doses of canakinumab (200mg s.c. Q3W) alone or in combination with 
pembrolizumab or two doses of pembrolizumab as single agent (200mg i.v. Q3W) (Figure 3-1). 
Randomization will be stratified by histology (squamous vs non-squamous).. Subjects will be 
treated for a maximum duration of 6 weeks (2 cycles) until surgery, progression, unacceptable 
toxicity or discontinuation from the study treatment for any other reason. Surgery must be 
performed between 4 to 6 weeks after the first dose of study treatment. Delay to the surgical 
procedure beyond 6 weeks is acceptable, but should be avoided. The primary endpoint is the 
MPR rate as assessed by the percentage of subjects with ≤ 10% residual viable cancer cells. The 
primary endpoint of MPR will be assessed centrally based on all randomized  subjects, with 
local evaluation being a secondary endpoint. Primary analysis will be performed after all 
subjects have had surgical resection or have discontinued study treatment earlier due to any 
reason. Following the surgical procedure (or early discontinuation) subjects will not receive any 
further dose of study treatment. Subjects will enter in the safety follow-up period up to 130 days 
(i.e. canakinumab and pembrolizumab 5x half-life) after end of treatment visit.
Figure 3-1
Study design
4
Rationale
4.1
Rationale for study design
This randomized study will evaluate the effect of canakinumab and pembrolizumab given as 
monotherapy and in combination as neo-adjuvant treatment for subjects with early stages 
NSCLC. Randomization will be stratified by histology (squamous versus non-squamous). 
Rationale for study design features is described in Table 4-1.


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Table 4-1
Rationale for study design
Study Design Aspect
Rationale
Overall design: three arms, parallel 
randomized design
This will reduce any treatment assignment bias 
and allow an assessment of the three treatment 
arms in the same setting and similar patient 
population.
Randomization stratification factors:

Histology (squamous vs. non-squamous)
Although anti-PD-1/PD-L1 activity is observed in 
both squamous and non-squamous histology, 
the magnitude of benefit and the absolute 
outcomes may differ slightly in the two 
histologies (Brahmer et al 2015, 
Borghaei et al 2015, Herbst et al 2016, 
Reck et al 2016, Herzberg et al 2017, 
Paz-Ares et al 2018, Paesmans 
2012). Therefore randomization is stratified 
based on disease histology.
Open-label study
Treatment blinding was not considered 
necessary since the investigators will have no 
influence on the primary outcome of the study. 
However, the primary endpoint will be evaluated 
based on surgically resected sample by 
independent pathologists who will be blinded to 
the treatment arms.
Duration of study treatment: 4-6 weeks
The duration of treatment will be short and 
flexible (4-6 weeks). The objective is to allow 
sites to have some flexibility to schedule the 
surgical procedure based on their local practice 
and at the same time avoid delays. Additionally, 
it has been shown that checkpoint inhibitors, 
such as nivolumab, led to major pathological 
responses following a 4 week treatment period 
(Forde et al 2018) and canakinumab leads to 
early (~7 days) and sustained reduction of C-
reactive protein (CRP) (Alten et al 2008) in 
addition IL-6 and IL-1RA (Lachmann et al 2007), 
thus 4-6 weeks is considered enough to observe 
the treatment effect
Unbalanced randomization: 2:2:1
The primary endpoint is to assess the MPR rate 
in canakinumab alone and in combination with 
pembrolizumab. The pembrolizumab arm is 
added to estimate the background MPR rate of 
pembrolizumab in order to assess the 
contribution of canakinumab when combined 
with pembrolizumab, thus the randomization 
(2:2:1) will prioritize the two canakinumab arms, 
and less patients will be randomized to the 
pembrolizumab monotherapy arm.
4.2
Rationale for dose/regimen and duration of treatment
In this phase II, randomized, open-label study, canakinumab dose will be 200mg Q3W, which 
is the dosing regimen selected for the development program in NSCLC. This dosing regimen is 
chosen on the basis of the PK and PD properties of canakinumab, the observed safety, 


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biomarker and efficacy data from the CANTOS study, and the safety data from completed and 
ongoing canakinumab studies.
4.2.1
Pharmacokinetics (PK) consideration
Canakinumab displays PK properties typical of an IgG1 antibody, with a mean terminal half-
life of 26 days (Ilaris® USPI). Every 3 weeks dosing schedule of canakinumab is feasible based 
on its half-life of 26 days, and its ability to suppress CRP for at least 1 month as previously 
demonstrated in two single-dose phase II studies with dose ranges of 0.03 to 10 mg/kg i.v. and 
25 to 300 mg s.c. (Study [CACZ885A2213] in diabetes and Study [CACZ885H2251] in gouty 
arthritis). Population PK analysis and simulation were also performed to compare the steady-
state PK of 200 mg Q3W versus 300 mg Q4W s.c. 300 mg Q4W was selected as reference for 
comparison, because it is the highest approved regimen for canakinumab. As shown 
in Figure 4-1, the simulated PK profiles of canakinumab at 200 mg Q3W and 300 mg Q4W are 
comparable, indicating that the safety margin with the 200 mg Q3W regimen is expected to be 
in line with the one from the currently approved regimen of 300 mg Q4W. Specifically, the 
maximum plasma concentration (Cmax) of 200 mg Q3W is not exceeding that of 300 mg Q4W.


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Figure 4-1
Simulated PK profiles of canakinumab 200 mg Q3W s.c. and 300 mg 
Q4W s.c.
4.2.2
Efficacy and pharmacodynamics (PD) considerations
CANTOS study evaluated whether IL-1β inhibition might alter cancer occurrence and mortality 
as there is a strong inflammatory component to certain cancers, especially lung cancer. The 
results show that canakinumab, as compared to placebo, was associated with dose-dependent 
risk reductions in lung cancer and lung cancer mortality. There is a clear differentiation in 
clinical benefits across all three dosing regimens, with the greatest risk reduction in lung cancer 


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mortality achieved with the highest dose, 300 mg s.c. every three months. Hazard ratios (95% 
confidence interval, P-value) were 0.67 (0.37-1.20, P=0.18), 0.64 (0.36-1.14, P=0.13), and 0.23 
(0.10-0.54, P=0.0002) for the 50 mg, 150 mg, and 300 mg s.c. dose groups, respectively as 
reported by (Ridker et al 2017a). The dose-dependent pattern of hs-CRP reduction among 
subjects with lung cancer is also aligned with the clinical results, with the 300 mg group 
demonstrating the largest magnitude of reduction, relative to the other two treatment groups and 
placebo, with no saturating effect at 300 mg s.c. every three months.
The different median baseline hs-CRP levels among canakinumab-treated subjects in CANTOS 
who were subsequently diagnosed with lung cancer compared to those who did not (median 6.0 
mg/L [Interquartile Range (IQR): 3.5-11.5 mg/L] versus 4.2 mg/L [IQR: 2.8-7.1 mg/L], 
P<0.0001) (Ridker et al 2017a) likely reflect the different inflammatory status and risk for 
cancer. Notably, for subjects with higher baseline hs-CRP, the proportion of subjects with hs-
CRP normalized to post-treatment target level (2.3 mg/L) is less, compared to subjects with 
lower baseline hs-CRP (Figure 4-2). This finding suggests that raising the dose and/or 
shortening the dosing interval which will increase canakinumab steady-state PK may lead to 
better control of inflammation in subjects with higher baseline hs-CRP and deliver greater 
efficacy in subjects with higher baseline hs-CRP. Publications examining hs-CRP levels in 
NSCLC subjects show that higher hs-CRP levels is correlated with higher stage and poor 
prognosis (Alifano et al 2011, Hara et al 2010, Vagulienė et al 2011).
Figure 4-2
Proportions of subjects with hs-CRP below 2.3 mg/L by baseline hs-
CRP declines in all subjects from the CANTOS study
4.2.3
Safety considerations
Overall, canakinumab safety and tolerability findings across the three dosing regimens in 
CANTOS showed no new or unexpected signals and are similar to that reported in other 




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wide range of doses and dosing intervals studied in interventional trials, a 200 mg s.c Q3W 
dosing schedule for canakinumab, which has an approximately equivalent total dose amount 
and similar predicted PK range as 300 mg s.c. Q4W (a regimen already used in certain approved 
indications), is selected for the NSCLC development program to ensure a positive benefit/risk 
ratio. The protocol includes appropriate safety assessment to monitor and manage these risks 
(Section 8.4 for further details). The full dose of pembrolizumab (200 mg Q3W) is expected to 
be administered as no additive toxicity is anticipated from this combination.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
This is a proof-of-concept study to evaluate the effect of canakinumab and pembrolizumab 
alone 
and 
in 
combination 
in 
the 
neo-adjuvant 
setting. 
As 
described 
above 
(Section 1.1.3), chemotherapy as neo-adjuvant therapy has shown limited benefit compared to 
surgery alone. There is an unmet medical need in this setting. With the recent approval of 
immunotherapy compounds in advanced/metastatic NSCLC, study results have emerged with 
immunotherapy compounds, such as nivolumab and atezolizumab, in the neo-adjuvant 
treatment. These studies have shown that these compounds can lead to MPR in the neoadjuvant 
setting. Pembrolizumab is also approved in the first line treatment as monotherapy (for patients 
with high PD-L1- TPS > 50%; and with TPS>1% in Japan only) and in combination with 
platinum-based doublet chemotherapy for patients with advanced NSCLC and is being studied 
as neo-adjuvant treatment. Pembrolizumab is expected to provide similar benefit as nivolumab 
in the neo-adjuvant setting. Canakinumab, as monotherapy in CANTOS trial, has led to a 
reduction in hs-CRP, potential reduction in the frequency of allelic mutations of the circulating 
tumor DNA cells and reduction in the incidence and in the mortality due to lung cancer. 
Canakinumab is also being studied in different settings in lung cancer (adjuvant, first and 
second lines) as monotherapy (adjuvant), in combination with pembrolizumab and 
chemotherapy (first line) and in combination with docetaxel (second line). Considering that 
canakinumab is very well-tolerated with low frequency of AEs reported, the benefit of 
pembrolizumab treatment in NSCLC patients, the results showing MPR with PD-L1 blockage 
and the unmet medical need in the neo-adjuvant setting, canakinumab and pembrolizumab were 
selected as treatment options in monotherapy and in combination in this study.
4.4
Purpose and timing of interim analyses/design adaptations
Not applicable
4.5
Risks and benefits
This phase 2 randomized study will evaluate the effect of canakinumab and pembrolizumab 
alone and in combination in patients with NSCLC in the neo-adjuvant setting. Several studies 
have shown preoperative systemic therapy to be safe prior to surgical resection of NSCLC with 
no difference in extent of surgical procedures performed, operative morbidity and mortality 
(Depierre et al 2002, Gilligan et al 2007, Scagliotti et al 2012). However, as described above 
(Section 4.3), chemotherapy in the neo-adjuvant setting has shown limited benefit compared to 
surgery alone. Thus, there is still an unmet medical need in this setting. With the recent approval 
of immunotherapy compounds in advanced/metastatic NSCLC, study results have emerged 
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to MPR, which have been shown to positively correlate to long-term outcome such as DFS and 
OS. Pembrolizumab is expected to provide similar benefit as nivolumab in the neo-adjuvant 
setting, based on the benefits already shown in different settings in patients with NSCLC.
Canakinumab, as monotherapy in CANTOS trial, has led to a reduction in hs-CRP with a 
potential reduction in the frequency of allelic mutations of the ctDNA cells and reduction in the 
incidence and in the mortality due to lung cancer. Canakinumab is also being studied in different 
settings in lung cancer (adjuvant, first and second line) as monotherapy (adjuvant), in 
combination with pembrolizumab and chemotherapy (first line) and in combination with 
docetaxel (second line). Canakinumab combined with pembrolizumab is expected to lead to the 
modulation of the tumor micro environment such that the tumor is rendered more susceptible 
to PD-1 inhibition. 
In this study, the neo-adjuvant treatment with canakinumab and pembrolizumab alone and in 
combination will be of short duration (4-6 weeks) and is expected to be well-tolerated and to 
lead to MPRs. Between NSCLC diagnosis and the date of the surgery, there is usually a window 
of time during which the standard preoperative evaluation is performed. Therefore, no delays 
in the surgical procedure is expected. Please note that this is dependent upon local practice.
In the CANTOS study, with median follow-up of 3.8 years, types and incidence of most 
infections (all grades included) were generally comparable across the treatment groups (51.5% 
all dose combined vs 50.4% placebo).
Based on the CANTOS study (n= 10,066 in the safety set), the proportion of patients with AEs 
of neutropenia (2.0% in the 300 mg arm, 1.4% in the 150 mg arm, 1.1% in the 50 mg arm and 
0.9% in the placebo arm); thrombocytopenia (2.7% in the 300 mg arm, 2.0% in the 150 mg arm, 
2.0% in the 50 mg arm and 1.6% in the placebo arm) and events of sepsis (2.2% in the 300 mg 
arm, 2.1% in the 150 mg arm, 1.8% in the 50 mg arm and 1.3% in the placebo arm) was low.
In addition, a low, but significantly higher risk of fatal events attributed to infection or sepsis 
per 100 person-years was noted in the three canakinumab dose groups combined than in the 
placebo group (incidence rate 0.31 vs 0.18; P=0·023). Time to event analysis on IAC 
confirmed-infection events showed that a considerably low proportion of patients presented 
with the first event of infection within the 3 months of the study treatment across canakinumab 
arms (1.1% in canakinumab 300 mg arm). Even though the frequency of infection with 
canakinumab is low, specifically if considering first 3 months of treatment, complete blood 
counts with differentials will be followed carefully and urinalyses will be routinely performed 
on study visits. Subjects are to notify the investigator and seek medical attention immediately 
if they experience a fever (> 38.0°C) or any signs/symptoms of infection. Refer to the 
[Investigator’s Brochure].
KEYNOTE-024 was a phase III randomized trial of pembrolizumab as first line monotherapy 
vs chemotherapy in patients with NSCLC with PD-L1 expression ≥ 50%. In the pembrolizumab 
group, the most common (> 10%) treatment-related AEs were diarrhea (14.3%), fatigue 
(10.4%) and pyrexia (10.4%). The most common (> 5%) immune-mediated AEs in patients 
receiving 
pembrolizumab 
were 
hypothyroidism 
(9.1%), 
pneumonitis 
(5.8%) 
and 
hyperthyroidism (7.8%) (Reck et al 2016). These toxicities are not expected to overlap with 
canakinumab safety profile, which is also supported by the observations from Study 
CPDR001X2103, described in Section 4.2.


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Even though both canakinumab and pembrolizumab are generally well-tolerated, appropriate 
eligibility criteria, specific dose modification and stopping rules are included in this protocol to 
ensure subjects' safety. Recommended guidelines for prophylactic or supportive management 
of study-drug induced AEs are provided in Section 6. The risk to subjects in this trial may be 
minimized by compliance with the eligibility criteria and study procedures, as well as close 
clinical monitoring. 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the subject will not reliably comply, they should 
not be entered or continue in the study.
Imaging studies (CT, magnetic resonance, PET-scan or X-rays) will be used in this study to 
assess response of tumors to administered treatments. There are two tumor assessments planned 
in the study, one tumor assessment at screening/baseline and one within 7 days prior surgery, 
for more details please refer to Section 8.5.3. Tumor assessments required by the trial allow for 
MRI and CT; the ability to use MRI instead of CT for the brain and abdomen decreases the 
radiation exposure. Only in the chest CT is preferable to MRI. Contrast enhancement is a 
standard tool to evaluate potential metastatic lesions; subjects with contrast allergy are 
exempted from its use. The ordering physician should assure that subjects are well hydrated and 
precautions taken to avoid renal injury due to contrast agents. 
NSCLC is an aggressive disease, even in early stages, with a high chance of recurrence. Given 
that canakinumab and pembrolizumab are expected to lead to MPRs (and potentially lead to a 
prolonged disease-free time), are well-tolerated and subjects will be closely monitored for 
safety, the potential benefits outweights the risks of the short treatment duration with these 
compounds, favoring subjects to participate in the study.
5
Population
The study population will include approximately 110 adult subjects with histologically 
confirmed stage IB-IIIA NSCLC planned for surgery in approximately 4-6 weeks. The 
investigator or designee must ensure that only subjects who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. There will be no 
replacement of subjects who discontinued the study treatment for any reason.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Subjects must provide written informed consent prior to any screening procedures being 
performed.
2. Male and female patients ≥ 18 years of age from the date of birth.
3. Histologically confirmed NSCLC stage IB-IIIA (per AJCC 8th edition), deemed suitable 
for primary resection by treating surgeon, except for N2 and T4 tumors (please refer to 
Appendix 16.4).
4. Subject must be eligible for surgery and with a planned surgical resection in 
approximately 4-6 weeks (after the first dose of study treatment).


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5. A mandatory newly obtained tissue biopsy from primary site is required for study 
enrollment. An archival biopsy is also acceptable if obtained up to 5 months before first 
day of study treatment and if the subject did not go through antineoplastic systemic 
therapies between biopsy collection date and beginning of study treatment.
Note: Aspirates will not be accepted.
6. Subjects must have adequate organ function including the following laboratory values at 
the screening visit:
1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
2. Platelets ≥ 100 x 109/L
3. Hemoglobin (Hgb) > 9 g/dL
4. Creatinine clearance greater than 45 mL/min by calculation using Cockcroft-Gault 
formula
5. Total bilirubin (TBIL) ≤ 1.5 x upper limit of normal (ULN)
6. Aspartate transaminase (AST) ≤ 3 x ULN
7. Alanine transaminase (ALT) ≤ 3 x ULN
8. Serum amylase ≤ 2 x ULN or pancreatic amylase ≤ 1.5 x ULN
7. Subject must have adequate cardiovacular and respiratory function to be submitted to 
surgical procedure as assessed per local clinical practice.
8. ECOG PS of 0 or 1.
9. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Subjects with unresectable or metastatic disease. All patients should have brain imaging 
(either MRI brain or CT brain with contrast) prior to enrollment to exclude brain 
metastasis.
2. History of severe hypersensitivity reactions to monoclonal antibodies, which in the 
opinion of the investigator may pose an increased risk of serious infusion reaction.
3. Presence or history of a malignant disease that has been diagnosed and/or required therapy 
within the past 3 years. Exceptions to this exclusion include the following: completely 
resected basal cell and squamous cell skin cancers, and completely resected carcinoma in 
situ of any type.
4. Subjects who received prior systemic therapy (including chemotherapy, other anti-cancer 
therapies and any other antibody or drug specifically targeting T-cell co-stimulation or 
immune checkpoint pathways) in the past 3 years before screening.
5. Active autoimmune disease that has required systemic treatment in the past 2 years prior 
to randomization (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Control of the disorder with replacement therapy (e.g., 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc) is permitted.
6. Uncontrolled diabetes as defined per the investigator.
7. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.


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8. Clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 
months), such as:
a. Unstable angina or myocardial infarction within 6 months prior to screening
b. History of documented congestive heart failure (CHF) (New York Heart Association 
functional classification III-IV)
c. Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without anti-
hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is 
allowed prior to randomization
d. Ventricular arrhythmias
e. Supraventricular and nodal arrhythmias not controlled with medication
f.
Other cardiac arrhythmia not controlled with medication
9. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior to 
randomization or who have not recovered from side effects of such procedure. Video-
assisted thoracic surgery (VATS) and mediastinoscopy will not be counted as major 
surgery and patients can be enrolled in the study ≥1 week after the procedure.
10. Subject with suspected or proven immunocompromised state or infections, including:

Evidence of active or latent tuberculosis (TB) as determined by locally approved 
screening methods. If presence of TB (active or latent) is established then treatment 
for TB must have been completed according to locally approved country guidelines 
prior to screening for the study.

Chronic or active hepatitis B or C

Known history of testing positive for Human Immunodeficiency Virus (HIV) 
infections. For countries where HIV status is mandatory: testing positive for HIV 
during screening using a local test.

Any other medical condition (such as active infection, treated or untreated), which in 
the opinion of the investigator places the patient at an unacceptable risk for 
participation in immunomodulatory therapy. Subjects with localized condition 
unlikely to lead to a systemic infection e.g. chronic nail fungal infection are eligible.

Allogeneic bone marrow or solid organ transplant

Subject receiving any biologic drugs targeting the immune system (for example, 
TNFα blockers, anakinra, rituximab, abatacept, or tocilizumab).

Current treatment with any immune modulating agent in doses with systemic effects 
e.g.: 

Current systemic glucocorticoid therapy except for daily glucocorticoid-
replacement for conditions such as adrenal or pituitary insufficiency and topical, 
inhaled or local steroid use in doses that are not considered to cause systemic 
effects are permitted

Prednisone > 20 mg (or equivalent) daily for > 14 days;

Prednisone > 5 mg and ≤ 20 mg (or equivalent) daily for > 30 days;

Equivalent dose of methotrexate > 15 mg weekly.
11. Live vaccination within 3 months prior to randomization.


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12. Subjects who have received an investigational drug or device within 5 half-lives prior to 
randomization or those who are expected to participate in any other investigational drug or 
device during the conduct of the study.
13. Pregnant or breast-feeding (lactating) women, or women who plan to become pregnant or 
breast-feed during the study, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory test.
14. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective contraception during the study 
and for 4 months after stopping study treatment.

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception)

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 weeks before 
taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient.

Use of oral (estrogen and progesterone), injected or implanted combined hormonal 
methods of contraception or placement of an intrauterine device (IUD) or intrauterine 
system (IUS), or other forms of hormonal contraception that have comparable 
efficacy (failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception.
In case of use of oral contraception, women should have been stabilized on the same 
pill for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or bilateral tubal ligation at 
least 6 weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child-bearing potential.
15. Subject has any other concurrent severe and/or uncontrolled medical condition that would, 
in the investigator’s judgment, cause unacceptable safety risks, contraindicate subject 
participation in the clinical study, or compromise compliance with the protocol (e.g. 
chronic pancreatitis, uncontrolled diabetes mellitus).


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6
Treatment
6.1
Study treatment
In this study, the “study treatment” refers to both canakinumab and pembrolizumab study drugs 
administered either as monotherapy or in combination of study drugs: canakinumab plus 
pembrolizumab. The term “investigational drug” refers to the Novartis study drug, 
canakinumab (ACZ885).
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Study treatment
Pharmaceutical 
Dosage Form 
and route of 
administration
Strength
Dose
Frequency 
and/or regimen
Canakinumab
(ACZ885)
Solution for s.c. 
injection in 
prefilled syringe
150 mg/1 mL 
AND 50 mg/0.5 
mL
200 mg
Q3W
Pembrolizumaba
Concentrate for 
solution for i.v. 
infusion in vial
Lyophilized 
powder for 
solution for i.v. 
infusion in vial
100 mg/4 mL (25 
mg/mL)
50 mg
200 mg
Q3W
a Either concentrate solution or lyophilized powder formulations of pembrolizumab can be used if 
approved by local country regulations.
For preparation and dispensation please refer to Section 6.7
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
Subjects will be randomized at cycle 1 Day 1 visit to one of the following 3 treatment 
arms/groups (canakinumab alone or canakinumab in combination with pembrolizumab or 
pembrolizumab alone) in a ratio of 2:2:1.
For preparation and dispensation please refer to Section 6.7.
6.1.4
Guidelines for continuation of treatment
Guidelines for management of toxicities and dose modification instructions please refer to 
Section 6.5.
Continuation of treatment beyond the 2 cycles prior and after the surgery is not permitted.


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6.1.5
Treatment duration
Subjects will receive a maximum of two cycles of treatment (Q3 weeks). After the second study 
drug administration (Cycle 2), study treatment will be completed and subject will undergo the 
surgical procedure (4 to ~6 weeks after the first study drug administration). Study treatment can 
discontinue earlier in case of disease progression radiologically documented by investigator 
assessment, unacceptable toxicity that precludes further treatment, at the discretion of the 
investigator, subject withdrawal of consent, pregnancy, lost to follow-up, or death. No crossover 
treatment between the arms is allowed.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
In general, the use of any concomitant medications/non-drug therapies deemed necessary for 
the care of the subject (e.g. Granulocyte Colony-Stimulating Factor [G-CSF], anti-emetics, anti-
diarrhea) is permitted except when specifically prohibited (Section 6.2.2). For pembrolizumab, 
please refer to the locally approved label.
The investigator should instruct the subject to notify the study site about any new medications 
and/or non-drug therapies/procedures he/she takes after signing the informed consent. All 
medications 
including 
herbal/natural 
medications 
and 
significant 
non-drug 
therapies/procedures (including surgeries, physical therapy and blood transfusions) taken 
within 28 days of screening and administered after the subject has signed informed consent 
must be listed on the appropriate electronic case report form (eCRF) pages.
Subjects taking concomitant medication chronically should be maintained on the same dose and 
dose schedule throughout the study period, as medically feasible. The days of PK blood 
sampling should be representative of the other study days with regard to the use of the 
chronically administered concomitant medications. However, if a concomitant medication is 
used intermittently during the study, this medication should be avoided on the days of PK 
sampling, if medically feasible.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medications. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a subject or allowing a new medication to be started. If the subject is already 
randomized, contact Novartis to determine if the subject should continue participation in the 
study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
6.2.1.1.1 Permitted concomitant medications
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and 
supportive care agents, such as pain medications, anti-emetics and anti-diarrheal are 
allowed. Potential drug interactions between study drugs and concomitant medications should 
always be taken into consideration .Note: For Drug-Drug interaction (DDI) potential, please 
refer to Section 1.2.3 .


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Antibodies that modulate cytokines, which may regulate cytochrome P450 (CYP450) enzymes, 
may cause DDI with small molecule drugs because of the potential to alter CYP-mediated 
metabolism (Harvey and Morgan 2014). Anti-cytokine antibodies such as canakinumab that 
target and neutralize these proinflammatory cytokines or their receptors are capable of 
restoration of CYP450 enzymes to normal levels (Ashino et al 2007). This is clinically relevant 
for CYP450 substrates with a narrow therapeutic index. Caution should be exercised when 
administering these agents (see Table 6-2) concomitantly with canakinumab.
Given the potential DDI via cytokine modulation by canakinumab, subjects who are on warfarin 
or warfarin-like treatment with narrow therapeutic index, should have their international 
normalized ratio (INR) measured locally and warfarin or warfarin-like treatment dose adjusted 
accordingly within one month from starting study treatment.
6.2.2
Prohibited medication
6.2.2.1
Prohibited concomitant medications for canakinumab
Use of any treatments below are NOT allowed after the start of study treatment due to potential 
increase in immunosuppressant related concomitant conditions. They are prohibited for the 
duration of the study and for at least 130 days after discontinuation of canakinumab.
Note: steroids are allowed at any dose/duration when necessary to treat immune-related adverse 
events (irAE). Investigators should closely monitor subjects for risk of infections.

Any anti retro-virals and/or any biologic drugs targeting the immune system (e.g., TNFα 
blockers, anakinra, rituximab, abatacept, tocilizumab)

Treatment with any immune modulating agent in doses with systemic effects e.g.: 

Prednisone > 20 mg (or equivalent) oral or intravenous daily for > 14 days;

Prednisone > 5 mg and ≤ 20 mg (or equivalent) daily for > 30 days;

Equivalent dose of methotrexate > 15 mg weekly

Topical, inhaled or local steroid use in doses that are not considered to cause systemic 
effects are permitted

Live vaccines within 90 days of study treatment and after initiation of study treatment. 
Subjects must be discontinued from study treatment if administered any live vaccine 
during the course of the study. Note: Inactivated vaccines are allowed.
The following treatments are NOT allowed after the start of study treatment and until surgery.

Any additional investigational drugs, devices, chemotherapy, or any antineoplastic 
therapies that may be active against cancer.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 


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Upon signing the informed consent form (ICF), the subject is assigned to the next sequential 
Subject No. available to the investigator through the Clinical Data Management System 
interface.
The investigator or designated staff will contact the Interactive Response Technology (IRT) and 
provide the requested identifying information to register the subject. Once assigned, the Subject 
No. must not be reused for any other subject and the Subject No. for that individual must not 
be changed. If the subject fails to be enrolled or randomized or start treatment for any reason, 
the reason will be entered into the appropriate eCRF page.
6.3.2
Treatment assignment, randomization
At visit C1D1, prior to dosing, all eligible subjects will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will contact 
the IRT after confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the subject, which will be used to link the subject to a 
treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the subject.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Global Clinical Supply (GCS) using a validated system that automates the random assignment 
of medication numbers to packs containing the study treatment.
Randomization will be stratified by histology (squamous vs non-squamous). Subjects with 
adenosquamous histology can be stratified as squamous or non-squamous based on the 
predominant histology. 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
Treatment will be open to subjects, investigator staff, persons on site performing the 
assessments, and Novartis global and local trial teams. However, treatment will be blinded to 
the independant pathologists (evaluating the primary endpoint based on surgical resected 
sample) from time to randomization until database lock.
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments are not permitted.
6.5.1
Dose modifications
For subjects who do not tolerate the protocol-specified dosing schedule the following principles 
must be followed:

For both canakinumab and pembrolizumab dose reductions are not permitted.


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
Increase in the canakinumab dosing interval to Q6W is not applicable due to the short 
duration of the study.

Canakinumab dose interuption for a maximum of 1 week is allowed as per Table 6-2.

Pembrolizumab will follow locally approved labels (if pembrolizumab is not yet approved 
in your country, refer to Section 16.1) and local clinical practice.
All dose changes in any study drugs must be recorded on the appropriate eCRF page.
6.5.1.1
Guidelines for mandatory dose modifications for canakinumab
Mandatory dose interruption or discontinuation of canakinumab in the management of adverse 
reactions are summarized in Table 6-2. Clinical judgment of the treating physician should guide 
the management plan of each subject based on individual benefit/risk assessment. Canakinumab 
must be discontinued as listed for events in Table 6-2. If a subject experiences more than one 
toxicity and there are conflicting recommendations between canakinumab and pembrolizumab 
dose modification, the most conservative dose modification should be followed.
In the combination arm, if one of the study drugs (canakinumab or pembrolizumab) is 
permanently discontinued because of unacceptable toxicity, per the investigator discretion, the 
other study drug (canakinumab or pembrolizumab) can continue alone in Cycle 2.
Table 6-2
Criteria for mandatory dose interruption and re-initiation for 
canakinumab due to adverse reactions
Worst toxicity
(CTCAE v5.0) during a cycle of therapy
Mandatory dose schedule interruption and 
re-initiation for canakinumabg
General guidance for adverse events considered to be related to canakinumab (to be followed 
whenever no other specific guidance is described in this table)
Grade 1/ Grade 2
Maintain canakinumab
Grade 3
Interrupt canakinumab until resolved to ≤ Grade 
2, then:

If resolved in ≤ 7 days administer the second 
dose of canakinumab

If resolved in > 7 days discontinue 
canakinumab, due to the short study 
duration
Grade 4
Permanently discontinue canakinumab
Exceptions to the above general guidancee
Neutropenia (ANC)
Grade 2 (ANC < 1500 - 1000/mm3)
Interrupt canakinumab until resolved to ≤ Grade 
1, then:

If resolved in ≤7 days, administer the 
second dose of canakinumab

If resolved in > 7 days discontinue 
canakinumab, due to the short study 
duration.
Grade 3 (ANC < 1000 - 500/mm3)/ Grade 4 
(ANC < 500/mm3)
Permanently discontinue canakinumab


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Worst toxicity
(CTCAE v5.0) during a cycle of therapy
Mandatory dose schedule interruption and 
re-initiation for canakinumabg
Febrile neutropenia 

Grade 4
Permanently discontinue canakinumab
Thrombocytopenia
Grade 3 (PLT < 50,000 - 25,000/mm3)
Interrupt canakinumab until resolved to ≤ Grade 
1, then:

If resolved in ≤ 7 days, administer the 
second dose of canakinumab

If resolved in > 7 days, permanently 
discontinue canakinumab
Serum creatinine
Grade 3 (>3.0 x baseline; >3.0 - 6.0 x ULN)
Interrupt canakinumab until resolved to ≤ Grade 
2 or baseline, then re-start at the same dose.

If resolved within 7 days, administer the 
second dose of canakinumab

If resolved in > 7 days discontinue 
canakinumab, due to the short study 
duration
Isolated total bilirubin elevationa*
Grade 1 (Any elevation) > ULN – 1.5 x ULN
Fractionate bilirubin, evaluate for cholestatic 
liver injury (alkaline phosphatase (ALP)) or 
alternative causes of bilirubin elevation (e.g. 
disease progression [imaging]). Treat alternative 
causes according to local institutional guidelines.
Maintain canakinumab
Grade 2 > 1.5 - 3.0 x ULN
Maintain canakinumab. Repeat Liver function 
tests (LFTs) within 48-72 hours, then monitor 
LFTs weekly until resolution to ≤ Grade 1 or to 
baseline.
Grade 3 > 3.0 - 10.0 x ULNb
Interrupt canakinumab. Repeat LFTs within 48-
72 hours, then monitor LFTs weekly until 
resolution to ≤ Grade 1 or to baseline.
• If resolved in ≤ 7 days, administer the second 
dose of canakinumab
• If resolved in > 7 days, permanently 
discontinue canakinumab 
Grade 4 > 10.0 x ULNb
see footnote* - otherwise discontinue 
canakinumab
Isolated AST or ALT elevationa
With normal baseline AST/ALT:
Grade 1 > ULN - 3.0 x ULN
Maintain canakinumab
Grade 2> 3.0 - 5.0 x ULN
Maintain canakinumab
Repeat LFTs within 48-72 h; if still abnormal 
then monitor LFTs at least weekly, until resolved 
to ≤ 3.0 x ULNc


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Worst toxicity
(CTCAE v5.0) during a cycle of therapy
Mandatory dose schedule interruption and 
re-initiation for canakinumabg
Grade 3: AST or ALT > 5.0 - 10.0 x ULN
Interrupt canakinumab. Repeat LFTs within 48-
72 h; monitor LFTs at least weekly, until 
resolved to ≤ 3.0 x ULN. Then:

If resolved in ≤ 7 days, administer the 
second dose of canakinumab

If resolved in > 7 days, discontinue 
canakinumab, due to the short study 
durationc
Grade 3: AST or ALT > 10.0 - 20.0x ULN
Permanently discontinue canakinumab. Repeat 
LFTs within 48-72 h; monitor LFTs at least 
weekly until resolved to ≤ baseline.
Grade 4: AST or ALT > 20.0 x ULN
Permanently discontinue canakinumab. Repeat 
LFTs within 48-72 h; monitor LFTs at least 
weekly until resolved to ≤ baseline.
With abnormal baseline ALT/AST (up to Grade 
1: ≤ 3.0 ULN):
ALT/AST > 2.0 x baseline AND > 5.0 x ULN
Interrupt canakinumab. Repeat LFTs within 48-
72 hours, then monitor LFTs weekly until 
recovery to baseline.

If resolved in ≤ 7 days, administer the 
second dose of canakinumab

If resolved in > 7 days, discontinue 
canakinumab, due to the short study 
duration
ALT/AST > 3.0 x baseline AND >10 x ULN
Permanently discontinued canakinumab. Repeat 
LFTs within 48-72 hours, then monitor weekly 
until resolved to baseline.
AST/ALT increase associated with concomitant total bilirubin increasea
With normal baseline LFTs:
AST or ALT >3.0 x ULN associated with 
concomitant TBIL >2.0 x ULN without evidence 
of cholestasisc (unless Gilbert syndrome)
Interrupt canakinumab. Assess if case is true 
Drug Induced Liver Injury (DILI).*
If DILI confirmed - Permanently discontinue 
canakinumab
If Not DILI – interrupt canakinumab. Treat the 
identified cause according to institutional 
guidelines. Repeat LFTs within 48-72 hours, 
then monitor weekly, until enzyme levels resolve 
to ≤ Grade 1 or Baselined
Refer to Section 6.5.2.1 for additional follow-up 
of potential DILI cases as applicable
With abnormal baseline LFTs:


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Worst toxicity
(CTCAE v5.0) during a cycle of therapy
Mandatory dose schedule interruption and 
re-initiation for canakinumabg
ALT or AST >3 x baseline OR ALT or AST >8 x 
ULN (whichever is lower) combined with TBIL 
>2.0 x ULN 
After recovery, re-administration of the second 
dose of canakinumab could be considered only 
if Investigator assesses benefit to outweigh the 
risk. Any decision regarding re-administration of 
canakinumab and dose regimen, should be 
discussed with the Novartis medical and 
safety team. Refer to Section 6.5.2.1 for 
additional follow-up evaluations as applicable
Pancreatitisf
Grade 3
Interrupt canakinumab until resolved to ≤ Grade 
1, then:

If resolved in ≤ 7 days, administer the 
second dose of canakinumab

If resolved in > 7 days, discontinue 
canakinumab
Hypertension
Grade 3
Interrupt canakinumab until resolved to ≤ Grade 
1, then:

If resolved in ≤ 7 days, administer the 
second dose of canakinumab

If resolved in > 7 days, discontinue 
canakinumab
Diarrhea - institute appropriate anti-diarrheal treatment and follow general guidelines
Rash/photosensitivity - initiate/institute appropriate skin toxicity therapy (such as antihistamines 
and/or topical corticosteroids) and follow general guidelines
Steven Johnson Syndrome, Toxic epidermal necrolysis

Permanently discontinue canakinumab
Tuberculosis or reactivation of hepatitis

Permanently discontinue canakinumab
Asymptomatic laboratory abnormalities- Provide supportive care and replacement therapy

If clinically significant, follow general guidelines
LFTs – Liver Function Tests
a Refer to protocol Section 6.5.2.1 for monitoring of liver toxicity
b If TBIL > 3.0 x ULN is due to the indirect component only, and hemolysis as the etiology has been 
ruled out as per institutional guidelines continue canakinumab at the discretion of the investigator
c The subject should be monitored biweekly (including LFTs), or more frequently if clinically 
indicated, until TBIL have resolved to baseline or stabilization over 4 weeks
d Repeat within 48 hours then at least weekly until AST, ALT, or bilirubin have resolved to baseline 
or stabilization over 4 weeks
e If relatedness to canakinumab can be excluded with certainty and there is no risk for the patient, 
the dose interruption for canakinumab is not mandatory
fNote: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be 
performed within 1 week of the first occurrence of any ≥ Grade 3 of amylase and/or lipase


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Worst toxicity
(CTCAE v5.0) during a cycle of therapy
Mandatory dose schedule interruption and 
re-initiation for canakinumabg
g If AE is resolved prior to planned C2D1 dose interruption is not applicable. If AE is not resolved 
prior to planned C2D1, please follow dose interruption recommendation. 
* An isolated bilirubin elevation is not typical for drug-induced liver injury. Bilirubin can be elevated 
either as part of a “Hy’s law” constellation with a preceding elevation of ALT/AST, or as part of a 
cholestatic reaction with simultaneous elevation of other cholestatic parameters (ALP, Gamma-
glutamyl-transferase (GGT)). Isolated bilirubin can be seen in conjunction with drugs that inhibit 
bilirubin conjugation or excretion, but both scenarios do not typically represent liver injury. 
Alternative causes of bilirubin elevation should therefore, be ruled out before basing dose 
modification decisions on bilirubin values alone.
6.5.2
Follow-up for toxicities
6.5.2.1
Follow up on potential drug-induced liver injury (DILI) cases
DILI Diagnosis
Subjects with transaminases increase combined with TBIL increase may be indicative of 
potentially severe DILI, and should be considered as clinically important events and should be 
assessed appropriately to establish diagnosis. The required clinical information, as detailed 
below, should be sought to obtain the medical diagnosis of the most likely cause of the observed 
laboratory abnormalities.
The threshold for potential DILI may depend on the subject’s baseline AST/ALT and TBIL 
value (Table 6-2, Section 6.5.1.1); subjects meeting any of the following criteria will require 
further follow-up as outlined below:

For subjects with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For subjects with elevated AST or ALT or TBIL value at baseline: AST or ALT > 3.0 x 
baseline or 8.0 x ULN, whichever is lower combined with (TBIL > 2.0 x baseline AND > 
2.0 x ULN)
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before the diagnosis of DILI is confirmed.
Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, TBIL, direct 
and indirect bilirubin, ALP (fractionated if ALP is grade 2 or higher), creatine kinase, 
prothrombin time (PT) or INR and gamma-glutamyltransferase (GGT). For subjects with 
Gilbert Syndrome: total and direct bilirubin must be monitored, intensified monitoring applies 
to changes in direct bilirubin only.
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion – CT, MRI, 
duplex sonography.
Perform relevant examinations (Ultrasound or MRI, ERCP) as appropriate, to rule out if 
LFTs elevations are caused by cholestasis (defined as: ALP elevation > 2.0 x ULN with R value 
< 2 in subjects without bone metastasis, or elevation of ALP liver fraction in subjects with bone 
metastasis).


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Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to cholestatic 
(R ≤ 2), hepatocellular liver injury (R ≥ 5), or mixed (R > 2 and < 5) liver injury.
Table 6-3 provides guidance on specific clinical and diagnostic assessments to be (OR which 
can be) performed to rule out possible alternative causes of the observed LFT abnormalities.
Table 6-3
Specific clinical and diagnostic assessments
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-Hepatitis A Virus (HAV); HBsAg, 
IgM & IgG anti-HBc, Hepatitis B Virus (HBV) 
DNA; anti-HCV, HCV RNA, IgM & IgG anti-
HEV, HEV RNA
Cytomegalovirus (CMV), Herpes Simplex Virus 
(HSV), Epstein-Barr Virus (EBV) infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; 
IgM & IgG anti-EBV
Autoimmune hepatitis

Antinuclear Antibody (ANA) & Anti-Smooth 
Muscle Antibody (ASMA) titers, total IgM, 
IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, GGT, Mean Corpuscular 
Volume (MCV), Carbohydrate Deficient-
transferrin (CD-transferrin)
Nonalcoholic steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic hepatopathy

Medical history: acute or chronic CHF, 
hypotension, hypoxia, hepatic venous 
occlusion. Ultrasound or MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease (if <40 yrs old)

Caeruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin
Other causes should also be considered based upon patients medical history (Hyperthyroidism 
/ thyrotoxic hepatitis – T3, T4, Thyroid-Stimulating Hormone (TSH); Cardiovascular Disease 
(CVD) / Ischemic hepatitis – Electrocardiogram (ECG), prior hypotensive episodes; T1D / 
glycogenic hepatitis).
Following appropriate causality assessments, as outlined above, the causality of the drug is 
estimated as “probable” i.e. >50% likely, if it appears greater than all other causes combined. 
The term “drug-induced” indicates probably caused by the drug, not by something else, and 
only such a case can be considered DILI case and should be reported as an SAE.
DILI Management
In the absence of cholestasis, these subjects should be immediately discontinued from study 
drug treatment, and repeat LFT within 48 hours. The evaluation should include laboratory tests, 
detailed history, physical assessment, and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring 
dose interruption, which involves:


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
Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency of 
re-testing can decrease to once a week or less if abnormalities stabilize or return to normal 
values.

Obtaining a more detailed history of current symptoms.

Obtaining a more detailed history of prior and/or concurrent diseases, including history of 
any pre-existing liver conditions or risk factors.

Obtaining a history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplements), alcohol use, recreational drug use, and special diets.

Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections 
(CMV, EBV, or HSV); autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic 
hepatopathy; and biliary tract disease.

Obtaining a history of exposure to environmental chemical agents.

Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin).

Considering gastroenterology or hepatology consultations.

Assessing cardiovascular dysfunction or impaired liver oxygenation, including 
hypotension or right heart failure as possible etiologies for liver dysfunction.

Obtaining a PK sample, as close as possible to last dose of study drug to determine 
exposure to study drug.

Considering a liver biopsy, as clinically indicated to assess pathological change and 
degree of potential liver injury.
These assessments should be done in addition to the assessments of immunological markers 
and total bile acids described in Section 8 .
All cases of DILI confirmed on repeat testing meeting the laboratory criteria defined above, 
with no other alternative cause for LFT abnormalities identified, should be considered as 
“medically significant” thus meeting the definition of SAE (Section 10.1.2) and must be 
reported as SAE using the term “potential drug-induced liver injury”. All events must be 
followed up with the outcome clearly documented. Results of tests as well as other clinically 
important information will be recorded in the eCRF.
6.5.2.2
Follow up for infections
Infections are the most common AE observed with canakinumab treatment. Subjects should be 
followed closely for signs or symptoms of infection and receive prompt appropriate treatment 
for suspected infections. Subjects will have a urinalysis performed at screening, on Day 1 of 
every cycle, End of Treatment (EOT) and at safety follow-up visits 1, 3 and 5.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Every time the study treatment is to be administered, IRT must be accessed to assign a 
medication (kit) number (for the investigational drug canakinumab) and/or registration of the 
other study drug (pembrolizumab) dispensed to the subjects.


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The date and time of all study treatment administrations during the study and any deviations 
from the protocol treatment schedule will be captured on the appropriate drug accountability 
log.
Exposure to the study treatment will be based on the number of injections and/or infusions 
administered. Compliance with the study treatment will be assessed by the field monitor at each 
visit using vial counts and information provided by the pharmacist or by the investigator. All 
study treatment dispensed must be recorded in the drug accountability log.
6.6.2
Emergency breaking of assigned treatment code
Not Applicable
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
Canakinumab (investigational drug):
Each study site will be supplied by Novartis with the investigational drug in packaging of 
identical appearance per product volume. Canakinumab is provided in pre-filled syringes, ready 
for use and no preparation is needed. For more details, please refer to Section 6.1. For further 
information on Canakinumab injection, please refer to instruction for use canakinumab manual.
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 
plus tear-off label), immediately before dispensing the medication kit to the subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document.
Pembrolizumab (other study drug):
Pembrolizumab will be supplied locally as commercially available by the site pharmacy or by 
Novartis, if so, the drug will be labeled accordingly to comply with the country legal 
requirements. Preparation and dispensation should follow the locally approved label and local 
practice.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the IB. Clinical supplies are to be dispensed only in 
accordance with the protocol. Technical complaints are to be reported to the respective Novartis 
CO Quality Assurance.


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Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.7.1.2
Handling of additional treatment
Not Applicable
6.7.2
Instruction for prescribing and taking study treatment
Administration of study treatment
Canakinumab (one syringe of 1 mL and one syringe of 0.5mL) will be administered by study 
site personnel via s.c. injections once every 3 weeks.
Pembrolizumab will be administered by study site personnel via i.v. infusion once every 3 
weeks as per locally approved label and local practice.
For combination arm, study drugs should be administered sequentially, on the same day 
(canakinumab 200mg s.c injection then 30 minutes later pembrolizumab 200 mg i.v. infusion 
during 30 minutes)
The infusion time reported for pembrolizumab (30 min: -5 min/+10 min) is suggestion only. 
The locally approved label and local practice is to be followed.
Table 6-4
Dose and treatment schedule
Investigational / Control Drug
(Name and Strength)
Dose
Frequency and/or Regimen
Canakinumab 200mg
200mg (1 X 150mg/1mL syring 
and 1x 50mg/0.5mL syringe)
C1D1 (Day 1) and C2D1 (Day 
22)
Pembrolizumab 200mg
200mg ( refer to Table 6-1)
C1D1 (Day 1) and C2D1 (Day 
22)
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation) Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 


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his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed ICF that complies with 
the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use’ (ICH) Good Clinical Practice (GCP) guidelines and regulatory requirements and 
is considered appropriate for this study. Any changes to the proposed consent form suggested 
by the investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB and/or Core Data Sheet (CDS) for marketed drugs. This information will be 
included in the subject informed consent and should be discussed with the subject during the 
study as needed. Any new information regarding the safety profile of the investigational drug 
that is identified between IB updates will be communicated as appropriate, for example, via an 
investigator notification (IN) or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the subject.
The following informed consents are included in this study:

Main study consent, which also included:

A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study

Pregnancy Outcomes Reporting Consent for female subjects
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
Subjects might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience (please refer to Section 8.5.4.1).
8
Visit schedule and assessments
The assessment schedule Table 8-2 lists all of the assessments and indicates with an “X”, the 
visits when they are performed. Note: when the assessment is indicated with an "S", this will 
be documented in the subject source medical record only. All data obtained from these 
assessments (indicated with an “X” and "S") must be supported in the subject’s source 
documentation.
Treatment cycles are intended to be 3 weeks (21 days), but the treatment can be delayed in order 
to manage toxicities according to the canakinumab dose modification criteria 
in Section 6.5.1 and the locally approved label and local practice for pembrolizumab. During 


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the course of the study visits, test procedures should occur on schedule whenever possible as 
per allowable visit windows specified in Table 8-1 below.
Table 8-1
Allowable visit windows are specified as follow:
Visit name
Window
Screening
-1 to -28 Days before Cycle 1 Day 1
All assessments including C1D1, during the 
treatment period (except tumor assessments)
± 3 Days (-3 days for Cycle 1 Day 1)
Canakinumab injection (if applicable)
± 3 Days
Pembrolizumab infusion (if applicable)
± 3 Days
PK/IG/PD sampling
Refer to tables in Section 8.5.1
26, 52, 78 and 104 day safety follow-up visits
± 7 Days
130-day safety follow-up visit
+ 14 Days
EOT
≤ 21 Days after permanent discontinuation of 
study treatment, but before the surgery
EOT biomarker sampling
At time of surgery if possible, if not within 4 days 
prior to surgery
Subjects should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-2) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Subjects who prematurely discontinue the study 
for any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the final and safety follow-up visits will be performed. At this final visit, 
the AE and concomitant medications should be recorded on the case report form (CRF).


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Table 8-2
Assessment Schedule
Period Screening
Treatment
EOT
Safety Follow-up
EOS
Cycle
Cycle 1
Cycle 2
Visit Name Screening Treatment 
C1D1
Treatment 
C2D1
EOT
Surgery
Safety 
Follow-up 1
Safety 
Follow-up 2
Safety 
Follow-up 3
Safety Follow-
up 4
Safety 
Follow-up 5
EOS
Days
-28 to -1
1
22
When 
applicable6
4 to 6 
weeks
From EOT: 
26
From EOT: 
52
From EOT: 
78
From EOT: 
104
From EOT: 
130
-
Informed consent
X
IRT Screening 
(after ICF 
signature)
X
Demography
X
Inclusion / 
Exclusion criteria
X
Medical 
history/current 
medical 
conditions
X
Smoking history
X
Diagnosis, stage 
and grade of 
cancer
X
Archival or newly 
obtained tumor 
sample1
X
Histopathology 
assessment, 
(squamous or 
non-squamous)
X
Hepatitis screen
X
If clinically indicated
Determination of 
tuberculosis 
status
S


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Period Screening
Treatment
EOT
Safety Follow-up
EOS
Cycle
Cycle 1
Cycle 2
Visit Name Screening Treatment 
C1D1
Treatment 
C2D1
EOT
Surgery
Safety 
Follow-up 1
Safety 
Follow-up 2
Safety 
Follow-up 3
Safety Follow-
up 4
Safety 
Follow-up 5
EOS
Days
-28 to -1
1
22
When 
applicable6
4 to 6 
weeks
From EOT: 
26
From EOT: 
52
From EOT: 
78
From EOT: 
104
From EOT: 
130
-
HIV history (HIV 
testing where 
locally required)
S
Total T3, T4 and 
TSH
X
X
X
X
X
Eligibility 
checklist (Within 
IRT 
randomization)
X
Physical 
Examination
S
S
S
S
S
S
S
ECOG 
Performance 
status
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
Body Weight
X
X
X
X
Body Height
X
Electrocardiogra
m (ECG)
pre-dose
If clinically indicated
Hematology 
blood sample
X
X
X
X
X
X
X
Chemistry blood 
sample
X
X
X
X
X
X
X
Coagulation
X
If clinically indicated
Urinalysis 
(dipstick)
X
X
X
X
X
X
X
Prior/concomitant 
medications
From 28 days prior to day 1 until 130 days after EOT or start of new antineoplastic therapy, whichever is sooner. After start of a new 
antineoplastic therapy, only report concomitant medications for AEs/SAEs suspected to be related to study treatment.


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Period Screening
Treatment
EOT
Safety Follow-up
EOS
Cycle
Cycle 1
Cycle 2
Visit Name Screening Treatment 
C1D1
Treatment 
C2D1
EOT
Surgery
Safety 
Follow-up 1
Safety 
Follow-up 2
Safety 
Follow-up 3
Safety Follow-
up 4
Safety 
Follow-up 5
EOS
Days
-28 to -1
1
22
When 
applicable6
4 to 6 
weeks
From EOT: 
26
From EOT: 
52
From EOT: 
78
From EOT: 
104
From EOT: 
130
-
Non-drug 
therapies and 
procedures
From 28 days prior to day 1 until 130 days after EOT or start of new antineoplastic therapy, whichever is sooner. After start of a new 
antineoplastic therapy, only report non-drug therapies for AEs/SAEs suspected to be related to study treatment.
Adverse Events
Continuous, up to 130 days after last dose of study treatment. After starting a new antineoplastic therapy, only report AEs suspected to be 
related to study treatment.
Serious Adverse 
Events
Continuous, up to 130 days after last dose of study treatment. After starting a new antineoplastic therapy only report SAEs suspected to be 
related to study treatment.
Serum 
Pregnancy Test
X
X
Urine Pregnancy 
Test2
S
S
S
S
S
PET-CT (with 
diagnostic quality 
CT)
X
To be 
performed 
within 7 days 
prior to 
surgery
CT/MRI - Thorax, 
Abdomen, Pelvis 
(if no diagnosis 
PET-CT 
captured)
X
To be 
performed 
within 7 days 
prior to 
surgery
FDG-PET (If no 
diagnosis PET-
CT captured)
X
To be 
performed 
within 7 days 
prior to 
surgery
Brain MRI or CT 
with contrast
X
If clinically 
indicated
Surgery
X


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Period Screening
Treatment
EOT
Safety Follow-up
EOS
Cycle
Cycle 1
Cycle 2
Visit Name Screening Treatment 
C1D1
Treatment 
C2D1
EOT
Surgery
Safety 
Follow-up 1
Safety 
Follow-up 2
Safety 
Follow-up 3
Safety Follow-
up 4
Safety 
Follow-up 5
EOS
Days
-28 to -1
1
22
When 
applicable6
4 to 6 
weeks
From EOT: 
26
From EOT: 
52
From EOT: 
78
From EOT: 
104
From EOT: 
130
-
Tumor sample 
from surgery1
X
MPR
X
Canakinumab PK 
sampling
pre-dose
pre-dose
X
X
X
X
Canakinumab 
Immunogenicity 
sampling
pre-dose
pre-dose
X
X
X
X
Canakinumab 
Pharmacodynami
c / Total IL-1β
pre-dose
pre-dose
X
X
X
X
Pembrolizumab 
PK sampling
pre-dose 
and EOI
pre-dose
X
X
Pembrolizumab 
Immunogenicity 
sampling
pre-dose
pre-dose
X
X
Blood (serum) 
hs-CRP3
pre-dose
pre-dose
X7
X
X
X
Blood (plasma) 
Cytokines panel 
including hsIL-64
pre-dose
pre-dose
X7
X
Only hs-IL-6
Only hs-IL-6


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Period Screening
Treatment
EOT
Safety Follow-up
EOS
Cycle
Cycle 1
Cycle 2
Visit Name Screening Treatment 
C1D1
Treatment 
C2D1
EOT
Surgery
Safety 
Follow-up 1
Safety 
Follow-up 2
Safety 
Follow-up 3
Safety Follow-
up 4
Safety 
Follow-up 5
EOS
Days
-28 to -1
1
22
When 
applicable6
4 to 6 
weeks
From EOT: 
26
From EOT: 
52
From EOT: 
78
From EOT: 
104
From EOT: 
130
-
Drug 
Dispensation 
(Canakinumab)
X
X
Drug 
Dispensation 
(Pembrolizumab)
X
X
Trial Feedback 
Questionnaire
X
X
IRT 
discontinuation
X
Antineoplastic 
therapies since 
discontinuation of 
study treatment
X
X
X
X
X
Safety Follow up 
Call
S
S
Disposition 
Assessment
X
X
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
1 Lymph nodes might be requested if collected
2 For women with child bearing potential status confirmed only
3 (5 ml) of whole blood will be collected for hs-CRP
4 (10 ml) of whole blood will be collected for cytokines, except at Safety Follow Up visits at Day 78 and Day 130, (3ml) will be collected.
6 Latest 21 days after permanently discontinuation of study treatment, but before the surgery
7 Biomarker blood samples should be collected at the end of treatment but more specifically at time of surgery if possible, if not within 4 days prior to surgery


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8.1
Screening
All subjects must provide a signed main ICF prior to performing any study-specific procedures. 
Subjects will be evaluated against all study inclusion and exclusion criteria.
After signing the study ICF, the screening assessments will be done within 28 days prior to 
enrollment/randomization (Table 8-1 and Table 8-2). Laboratory parameters may be retested 
within the 28-day screening period for a subject if such parameters meet an exclusion criterion. 
Histopathology status (squamous vs non-squmous) must be determined prior to 
enrollment/randomization for all subjects. Local testing is allowed and results must be 
documented in the source documents prior to randomization.
Imaging assessments will be completed at screening during the regular work-up of the subject 
within 28 days prior to start of treatment. Imaging done before signing the main study ICF can 
be considered as the baseline images for this study. Any imaging assessments obtained after 
randomization cannot be considered baseline images.
Re-screening is not allowed (subject who was screen-failed cannot sign a new ICF, however, 
laboratory parameters or other screening parameters may be retested within 28-day screening 
period for an individual subject).
Subjects who are randomized and fail to start treatment, e.g. subjects randomized in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate eCRF.
8.1.1
Eligibility screening
Following registering in the IRT for screening, subject eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
8.1.2
Information to be collected on screening failures
Subjects who sign an ICF and subsequently found to be ineligible prior to randomization will 
be considered a screen failure. The reason for screen failure should be recorded on the 
appropriate CRF. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure subjects. No other data will be entered into the 
clinical database for subjects who are screen failures, unless the subject experienced a SAE 
during the screening phase (see SAE section for reporting details). AEs that are not SAEs will 
be followed by the investigator and collected only in the source data. If the subject fails to be 
randomized, the IRT must be notified within 2 days of the screen fail that the subject was not 
randomized.
8.2
Subject demographics/other baseline characteristics
Data to be collected on subject characteristics at screening include:

Demographic information (age, gender, race and ethnicity as allowed by local regulations)

Other background or relevant medical history (including smoking history) and current 
medical condition


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
Cancer characteristics including diagnosis, stage and grade of cancer

Other assessments will be completed for the purpose of determining eligibility for 
inclusion in the study as reported in Table 8-2 (e.g. ECOG PS, complete physical 
examination, vital signs, body weight, hematology, blood chemistry, coagulation, 
urinalysis, serum pregnancy test for all female subjects, tumor imaging assessments).

Prior and current concomitant medications and surgical and medical procedures.

Tumor imaging assessments - Refer to Section 8.5.3.

Tumor sample with histopathology assessment 
Data to be collected on Cycle 1 Day 1 pre-dose include:

12-Lead ECG

PK, IG and PD
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. Participant race and ethnicity are collected to 
identify variations in safety or efficacy due to these factors as well as to assess the diversity of 
the study population as required by Health Authorities.
8.3
Efficacy
8.3.1
Tumor assessments
MPR: Response will be assessed centrally at the time of surgery (by number of subject with 
≤10% residual viable tumor cells). For details please refer to Section 8.5.2.
Radiology tumor assessments: Will be assessed by investigator (RECIST 1.1) at screening 
and before surgery. For details please refer to Section 8.5.4 .
8.3.2
Appropriateness of efficacy assessments
Not Applicable.
8.4
Safety
Safety assessments are specified below and will be monitored by assessing physical 
examination, ECOG PS, vital signs, body weight, ECG, laboratory assessments, pregnancy tests, 
as well as collecting AEs at every visit. For details on AE collection and reporting, refer to 
AE section. All safety assessments should be completed as per Table 8-2.
Table 8-3
Assessments & Specifications
Assessment
Specification
Physical examination
At screening (within 10 days before cycle 1 day 
1), a complete physical examination will include 
the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological. If 
indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and 
pelvic exams will be performed.


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Assessment
Specification
After randomization (at C1D1 and all following 
visits) a short physical exam will include the 
examination of general appearance and vital 
signs (including blood pressure [SBP and DBP] 
and pulse). .
Information for all physical examinations must 
be included in the source documentation at the 
study site. Clinically relevant findings that are 
present prior to signing informed consent must 
be recorded on the appropriate CRF that 
captures medical history. Significant findings 
made after signing informed consent which meet 
the definition of an AE must be recorded as an 
AE.
Vital signs
Vital signs must include at minimum: systolic 
and diastolic blood pressure (supine position 
preferred when ECG is collected), respiratory 
rate, pulse rate and body temperature.
Height and weight
Height in centimeters (cm) or inches (in) and 
body weight (to the nearest 0.1 kilogram (kg) or 
pounds (lb) in indoor clothing, but without shoes) 
will be measured as specified in Table 8-2.
ECG
Local single 12-lead ECGs should be recorded 
at baseline prior to the dose administration, after 
the subject has been resting for 5-10 min.
Post-treatment discontinuation 
All safety assessments (including pregnancy test for female subjects of child bearing potential) 
should be completed as per Table 8-2. However, if the subject begins post-treatment 
antineoplastic medication before the completion of the 130-Day safety follow-up visit, only the 
new SAEs and AEs suspected to be related to study treatment will be collected up to the 130-
Day safety follow-up visit. Data collected should be added to the appropriate eCRF.
8.4.1
Laboratory evaluations
Central laboratories will be used for the analysis of scheduled hematology, chemistry, and other 
blood specimens (Table 8-1 and Table 8-2). The laboratory evaluations should be assessed on 
the actual scheduled day, even if study drug is being withheld. The time windows for laboratory 
evaluations correspond to the visit time windows for each visit (Table 8-1).
More frequent timepoints should be added as deemed necessary per the investigator's judgment 
to make sure toxicity profile is sufficiently characterized and dose interruption performed to 
safeguard the safety of the subject. Additional results from unscheduled laboratory evaluations 
should be recorded on the appropriate eCRF.
Laboratory values obtained during the screening phase from the central laboratory will be used 
to assess eligibility. However, the site does not need to wait for the results of centrally-analyzed 
laboratory assessments when an immediate clinical decision needs to be made (e.g. 
confirmation of eligibility, study drug interruption, re-initiation, and/or termination). In those 
cases, local laboratory testing may be performed. The investigator is responsible for reviewing 


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all laboratory reports for subjects in the study and evaluating any abnormalities for clinical 
significance.
Dipstick urinalysis (macroscopic panel) will be performed at the site (unless local institution 
policies dictate otherwise), and in the case of any out of range parameters, a urine sample will 
be sent to central laboratory for further analysis (microscopic panel).
Details on the collection, sample shipment, and reporting of results by the central laboratory are 
provided in the Central Laboratory Manual and flowchart.
If at any time a subject has laboratory parameters obtained from a local laboratory, Novartis 
must be provided with a copy of the certification and a tabulation of the normal ranges and units 
for this laboratory. The results of the local laboratory will be recorded in the eCRF if any the 
following criteria are met:

A treatment decision was made based on the local results, or

Patient eligibility was confirmed based on the local results or

There are no concomitant central results available, or

Local lab results document an AE not reported by the central lab, or

Local lab results document an AE where the severity is worse than the one reported by the 
central lab.
Table 8-4
Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hemoglobin, Platelets, Red blood cells, White
blood cells, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils (absolute 
value preferred, %s are acceptable))
Chemistry
Albumin, ALP, ALT, AST, GGT, Lactate 
dehydrogenase (LDH), Calcium, Magnesium, 
Phosphorus, Sodium, Potassium, Creatinine, 
Creatinine clearance, Direct Bilirubin, Indirect 
Bilirubin (Only if TBIL is >= grade 2), TBIL, 
Blood Urea Nitrogen (BUN) or Urea, Uric Acid, 
Amylase, pancreatic amylase (as needed), 
Lipase, Glucose (fasting)
Urinalysis
Microscopic Panel (Red Blood Cells, White 
Blood Cells, Casts, Crystals, Bacteria, Epithelial 
cells)
Macroscopic Panel (Dipstick) (Color, Bilirubin, 
Blood, Glucose, Ketones, Leukocytes esterase, 
Nitrite, pH, Protein, Specific Gravity, 
Urobilinogen)
Coagulation
PT, International normalized ratio (INR), 
Activated partial thromboplastin time (APTT)
Thyroid
T3 [free], T4 [free], TSH
Hepatitis markers
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-
PCR (baseline)
Infectious markers
Tuberculosis testing (as defined by country 
guidelines), HIV (where locally required)


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Test Category
Test Name
Pregnancy Test
At screening visit and EOT, serum pregnancy 
test; if local requirements dictate otherwise, local 
regulations should be followed 
Urine pregnancy test (refer to 'Pregnancy and 
assessments of fertility' Section 8.4.3)
Hematology, chemistry, thyroid function tests, coagulation, urinalysis and infectious disease marker 
tests are to be performed according to the visit schedule (Table 8-2). Laboratory assessment done ≤ 3 
days of first dose of study treatment are permitted to be used as Cycle 1 Day 1 labs and do not need 
to be repeated.
8.4.2
Electrocardiogram (ECG)
At cycle 1 Day 1 pre-dose, local single 12-lead ECGs should be recorded after the subject has 
been resting for 5-10 min as indicated in Table 8-2.
An unscheduled ECG may be repeated at the discretion of the investigator at any time during 
the study and as clinically indicated. Interpretation of the tracing must be made by a qualified 
physician and documented in the appropriate eCRF.
Each ECG tracing should be labeled with the study number, subject initials (where regulations 
permit), subject number, date, and kept in the source documents at the study site. Clinically 
significant ECG abnormalities present at screening should be reported on the appropriate eCRF. 
New or worsened clinically significant findings occurring after informed consent must be 
recorded on the appropriate eCRF.
8.4.3
Pregnancy and assessments of fertility
During screening, a serum pregnancy test will be completed for all female subjects. Only for 
women of child bearing potential on Cycle 1 Day 1 prior to dosing and at subsequent cycles, a 
urine pregnancy test (dipstick) will be performed. A serum pregnancy test will also be 
completed at EOT. The time windows granted for pregnancy testing are identical to the 
corresponding visit time windows for each visit (Table 8-2). If local requirements dictate 
otherwise, local regulations should be followed.
Women who are determined not to be of child bearing potential before the study will only 
complete a serum pregnancy test at screening. When non-child bearing potential status is 
determined during the study, further pregnancy testing will not be continued. Women are 
considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea 
with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms), and 
otherwise not of child bearing potential if they have had surgical bilateral oophorectomy (with 
or without hysterectomy), or bilateral tubal ligation at least 6 weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of child bearing potential (such 
testing is not covered as part of the study assessments). If local requirements dictate otherwise, 
local regulations should be followed.
If a positive pregnancy test is obtained in between study visits, the subject must immediately 
notify the investigator. (Section 10.1.4).




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Dose 
Reference 
Identificati
on (ID)
PK sample 
number
IG sample 
numberb
Total IL-1β 
(PD) 
sample 
numberb
Scheduled timepoints (hours)
Cycle
Day
Scheduled 
time 
(hours)
4
14
24
safety 
follow-up 1 
(26 days 
post-EOT)
NA
Anytime
5
15
25
safety 
follow-up 3 
(78 days 
post-EOT)
NA
Anytime
6
16
26
safety 
follow-up 5 
(130 days 
post-EOT)
NA
Anytime
1001+c
2001+ d
3001+ e
NA
NA
Unschedule
d
* The first Dose Reference ID is for last dose received prior to the collection of the PK sample, while 
the second Dose Reference ID is for the current dose
a Sample should be drawn within 24 hours prior to the next dose of canakinumab
b IG and PD samples are to be collected together with PK samples at the same time.
c PK sample numbers for any unscheduled PK collection will start with 1001, 1002, etc.
d IG sample numbers for any unscheduled IG collection will start with 2001, 2002 etc.
e PD sample numbers for any unscheduled PD collection will start with 3001, 3002 etc.
Timepoints of blood sample collection for pembrolizumab PK and IG are outlined in Table 8-6.
Table 8-6
Blood collection for pembrolizumab (30 min i.v. infusion, 200 mg 
Q3W) PK and IG
Dose 
Reference 
Identification 
(ID)
PK sample 
number
IG sample 
numberb
Scheduled timepoints (hours)
Cycle
Day
Scheduled 
time (hours)
201
31
41
1
1
0 hr / pre-
infusiona
201
32
1
1
EOI (within 30 
min)
201/202*
33
42
2
1
504 h post-
dose / 0 hr 
pre-infusiona
34
43
EOT
NA
Anytime
35
44
safety follow-
up 1 (26 days 
post-EOT)
NA
Anytime
4001+c
5001+d
NA
NA
Unscheduled
EOI = end of infusion
* The first Dose Reference ID is for last dose received prior to the collection of the PK sample, while 
the second Dose Reference ID is for the current dose






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Screening/baseline assessment:
Imaging assessments will be performed at screening/baseline within 28 days of start of 
treatment (Day -28 to Day -1 prior to Cycle 1 Day 1).
Any imaging assessments already completed during the regular work-up of the subject within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered the baseline images for this study.
End of treatment assessment:
Imaging assessment will be performed within 7 days prior surgery.
Unscheduled assessment:
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a subject, as necessary. Clinical 
suspicion of disease progression at any time requires a physical examination and tumor 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment.
8.5.4
Other Assessments
8.5.4.1
Trial Feedback Questionnaire (TFQ)
This trial will include an option for patients to complete an anonymized questionnaire, TFQ for 
subjects to provide feedback on their clinical trial experience. Individual subject level responses 
will not be reviewed by investigators. Responses would be used by the sponsor (Novartis) to 
understand where improvements can be made in the clinical trial process. This questionnaire 
does not collect data about the subject's disease, symptoms, treatment effect or AEs and 
therefore would not be trial data.
8.5.4.2
Surgery related information
The surgery should be performed as per local guidelines/clinical practice. The following surgery 
instructions are general recommendations and should only be considered as a guidance.  

Mediastinal lymph node staging by endobronchial ultrasound or mediastinoscopy is 
encouraged.

Resection may be accomplished by open or minimally invasive techniques (i.e. 
clamshell or hemiclamshell incision, robot assisted thoracic surgery, sternotomy, 
thoracotomy, or video assisted thoracic surgery/thoracoscopy).

Pathologic complete resection of the primary tumor (R0 resection) should be performed. 
Anatomic resection by bilobectomy, lobectomy, pneumonectomy, or segmentectomy is 
strongly preferred. Wedge (nonanatomic) resection can be done for very small (2 cm or 
less) tumors located peripherally where at least a 1 cm margin in all directions is possible.

Hilar and mediastinal lymph node dissection or sampling should be performed. For right 
sided resections, lymph nodes for levels 4R, 7, 10R, and 11R, and for left sided 
resections lymph nodes from levels 5/6, 7, 10L, and 11L should be dissected or sampled.


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Surgery related information, including safety-related, will be collected on the appropriate eCRF 
page.
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator.
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances :

Subject/guardian decision

Physician decision

Pregnancy

Any situation in which study participation might result in a safety risk to the subject

Study terminated by sponsor
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information. The investigator must register the subject's discontinuation from 
study treatment in the IRT system.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 7). Where possible, they should return for the assessments as 
indicated in the Assessment Schedule. If they fail to return for these assessments for unknown 
reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the subject/pre-
designated contact as specified in the lost to follow-up section. This contact should preferably 
be done according to the study visit schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
All subjects will have an EOT visit once all drugs of the study treatment are permanently 
discontinued (canakinumab and/or pembrolizumab as applicable). Subjects should be scheduled 
for an EOT visit latest 21 days after permanent discontinuation of study treatment but before 
the surgery, at which time all assessments listed for EOT visit will be performed (Table 8-2). 
Appropriate eCRF page should be completed at this time, giving the date and reason for 
stopping the study treatment. EOT is not considered as end of study.
After study treatment discontinuation, all randomized subjects will be followed for AEs and 
SAEs for at least 130 days following the last dose of study treatment. Subjects will complete a 


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total of five safety follow-up visits every 26 days until 130 days after end of treatment visit, 
during these safety follow-up visits additional assessments and blood samples will be collected 
as indicated in the Visit Evaluation Schedule (VES) (Table 8-2). The information collected is 
kept in source documentation and in eCRF (Table 8-2). All SAEs reported during this time 
period must be reported as described in Section 10.1.3 . Documentation of attempts to contact 
the subject should be recorded in the source documentation.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore,
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Where consent to the use of personal and coded data is not required, the participant  cannot 
withdraw consent but still retains the right to object to the further use of personal data.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table (Table 8-2).
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law.
For US: All biological samples not yet analyzed at the time of withdrawal may still be used for 
further testing/analysis in accordance with the terms of this protocol and of the ICF.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 


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diligence has been completed. Subjects lost to follow up should be recorded as such on the 
appropriate eCRF page.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety.
Should early termination be necessary, subjects must be seen as soon as possible (provide 
instruction for contacting the subject, when the subject should stop taking drug, when the 
subject should come for a final visit) and treated as a prematurely withdrawn subject 
(Section 9.1.1). The investigator may be informed of additional procedures to be followed in 
order to ensure that adequate consideration is given to the protection of the subject’s interests. 
The investigator or sponsor depending on the local regulation will be responsible for informing 
IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their last safety follow-up visit at 
130 days after end of treatment visit and any repeat assessments associated with this visit have 
been documented and followed-up appropriately by the Investigator or, in the event of an early 
study termination decision, the date of that decision (each subject will be required to complete 
the study in its entirety and thereafter no further study treatment will be made available to them).
Novartis will not supply study treatment to subjects after surgery. All randomized subjects 
should have the last safety follow-up visit conducted 130 days after end of treatment visit. The 
information collected is kept as source documentation. All SAEs reported during this time 
period must be reported as described in Section 10.1.3 . Documentation of attempts to contact 
the subject should be recorded in the source documentation.
Primary analysis will be performed after all subjects have had surgical resection or have 
discontinued study treatment earlier due to any reason. The primary analysis data will be 
summarized in the primary clinical study report (CSR). Following the cut-off date for the 
analysis reported in the primary CSR, the study will remain open. Ongoing subjects will 
continue with safety follow-up assessments as per the schedule of assessments (Table 8-2).
The end of study defined as the earliest occurrence of one of the following: all subjects have 
completed or discontinued from the study.
The final analysis will occur at the end of the study. All available data from all subjects up to 
this cut-off date will be analyzed and summarized in a final CSR.


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10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a subject or clinical 
investigation subject after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying AEs.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of AEs must be sought by non-directive questioning of the subject at each visit 
during the study. AEs also may be detected when they are volunteered by the subject during or 
between visits or through physical examination findings, laboratory test findings, or other 
assessments.
AEs must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer 
to Section 10.1.2 ):
1. AEs will be assessed and graded according to the Common Terminology Criteria (CTC) 
for AEs (CTCAE v5.0)
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment
All AEs must be treated appropriately. Treatment may include one or more of the following:

Dose not changed

Drug interrupted/withdrawn
6. its outcome (not recovered/not resolved, recovered/resolved, recovered/resolved with 
sequelae, fatal, unknown)


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If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 AEs only, if improvement to a lower 
grade is determined a new entry for this event should be reported in the CRF noting the start 
date when the event improved from having been Grade 3 or Grade 4.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms.
AE monitoring should be continued for at least 130 days following the last dose of study 
treatmentOnce an adverse event is detected, it must be followed until its resolution or until it is 
judged to be permanent (e.g. Continuing at the end of the study), and assessment must be made 
at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as a SAE, 
except if the investigator considers that progression of malignancy is related to study treatment.
AEs separate from the progression of malignancy (i.e. deep vein thrombosis at the time of 
progression or hemoptysis concurrent with finding of disease progression) will be reported as 
per usual guidelines used for such events with proper attribution regarding relatedness to the 
drug.
Information about adverse drug reactions for the investigational drug can be found in the IB.
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease.
10.1.1.1 Adverse events of special interest
AESI are defined as events (serious or non-serious) which are ones of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor may be appropriate. Such events may require 
further investigation in order to characterize and understand them.
AESI are defined on the basis of an ongoing review of the safety data.
AESI for canakinumab include:

Infections/Opportunistic infections

Neutropenia


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
Abnormal Liver Parameters 

Thrombocytopenia

Immunogenicity/allergenicity

Autoimmunity reactions

Second primary malignancy

Interactions with vaccines

Interactions with drugs eliminated by CYP450 enzymes

Pulmonary complications: pulmonary hypertension and interstitial lung disease

Injection site reactions
Details regarding these AEs are provided in the [canakinumab Investigator’s Brochure]. 
Potential emergent new AEs will be monitored during the course of the study.
10.1.2
Serious adverse events
An SAE is defined as any AE (appearance of [or worsening of any pre-existing]) undesirable 
sign(s), symptom(s), or medical conditions(s) which meets any one of the following criteria:

Fatal

Life-threatening Note:Life-threatening in the context of a SAE refers to a reaction in 
which the subject was at risk of death at the time of the reaction; it does not refer to a 
reaction that hypothetically might have caused death if it were more severe (please refer to 
the ICH-E2D Guidelines).

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

Is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life-threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 


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do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of study 
indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered SAE irrespective 
if a clinical event has occurred.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 130 days after the last administration of study treatment or 
the start of a new post study treatment antineoplastic medication, whichever comes first must 
be reported to Novartis safety within 24 hours of learning of its occurrence. Detailed 
instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site.
Note: Any SAEs experienced after the 130-day safety follow-up period or after the start of a 
new post study treatment antineoplastic medication should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
The following SAE reporting timeframes apply:
1. Screen Failures (e.g. a subject who is screened but is not treated or randomized): SAEs 
occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis.
2. Randomized OR Treated Subjects: SAEs collected between time subject signs ICF until 
130 days after the subject has discontinued or stopped study treatment
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a Novartis Chief Medical Office & Patient Safety 
(CMO&PS) department associate may urgently require further information from the 
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investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees (ECs) in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries.
10.1.4
Pregnancy reporting
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor to ask about her pregnancy. To ensure subject safety, each pregnancy occurring after 
signing the informed consent must be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported.
If a pregnancy occurs while on study, the newborn will be followed for at least 12 months.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (European medicines agency (EMA) definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE


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For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional Safety Monitoring
Not applicable.
10.2.1
Steering Committee
The Steering Committee (SC) will be established comprising investigators participating in the 
trial, i.e. not being members of Novartis representatives from the Clinical Trial Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
Code of Federal Regulation (CFR) Part 11 requirements. Investigator site staff will not be given 
access to the Electronic Data Capture (EDC) system until they have been trained. Automatic 
validation programs check for data discrepancies in the eCRFs, allow modification and/or 
verification of the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
Data collected by third parties (hematology, biochemistry, biomarkers, ECG, MPR and PK) 
will be sent electronically to Novartis.
11.2
Database management and quality control
Novartis personnel (or designated contract research organisation (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data.


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Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive IRT. The system will be supplied by a 
vendor, who will also manage the database. The data will be sent electronically to Novartis (or 
a designated CRO) at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis. Any changes to 
the database after that time can only be made after written agreement by Novartis/development 
management.
After database lock, the investigator will receive copies of the subject data for archiving at the 
investigational site.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e. eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of subject records, the accuracy 
of data capture / data entry, the adherence to the protocol and to GCP, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a 
Novartis/delegated CRO/CRA organization. Additionally, a central analytics organization may 
analyze data & identify risks & trends for site operational parameters, and provide reports to 
Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information on CRFs must be traceable to these source documents in the subject’s file. The 
investigator must also keep the original ICF signed by the subject (a signed copy is given to the 
subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 


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study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
The primary efficacy analysis will be performed after all subjects have had surgical resection 
or have discontinued study treatment earlier due to any reason.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
12.1.1
Full analysis set
The FAS comprises all subjects to whom study treatment has been assigned by randomization. 
According to the intent to treat principle, subjects will be analyzed according to the treatment 
and strata, to which they have been assigned to during the randomization procedure.
12.1.2
Safety set
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received, either canakinumab and/or 
pembrolizumab, where treatment received is defined as the randomized treatment if the subject 
took at least one dose of that treatment or the first treatment received if the randomized 
treatment was never received.
12.1.3
Pharmacokinetic analysis set
The Pharmacokinetic Analysis Set (PAS) consists of all subjects who received at least one dose 
of study drug and have at least one evaluable PK sample. The definition of an evaluable PK 
blood sample will be further specified in the Statistical Analysis Plan (SAP). PAS will be 
defined for canakinumab and pembrolizumab separately.
12.1.4
Other analysis sets
Other analysis sets, if needed, will be specified in the SAP.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS and Safety set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, by treatment group.


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12.3
Treatments
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The duration of exposure for study treatment and for each study drug (canakinumab and 
pembrolizumab) will be presented. The dose intensity and relative dose intensity will be 
summarized for each study drug components by descriptive statistics.
The number of subjects with dose adjustments (interruption, or permanently discontinuation) 
and the reasons will be summarized for each study drug. All dosing data will be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system.
12.4
Analysis of the primary endpoint(s)
The primary objective of the study is to assess the rate of MPR (≤ 10% residual viable tumor) 
per central review at the time of surgery in canakinumab alone and in combination with 
pembrolizumab treatment arms.
12.4.1
Definition of primary endpoint(s)
The primary endpoint is MPR rate, defined as the percentage of subjects with ≤ 10% residual 
viable cancer cells. MPR will be assessed in FAS per central review. 
12.4.2
Statistical model, hypothesis, and method of analysis
The primary endpoint analysis will be described by the following five attributes:
1. The target population is defined as all randomized patients who are histologically 
confirmed NSCLC stage IB-IIIA (per AJCC 8th edition), deemed suitable for primary 
resection by treating surgeon, except for N2 and T4 tumors.
2. The primary variable is the percentage of subjects with a major pathological response 
(defined as ≤ 10% residual viable cancer cells per central review). Any patient who has 
>10% residual viable cancer cells, or starts new antineoplastic therapy medication prior to 
surgery, or does not have the surgery performed, is considered as a non-responder.
3. The study treatment is canakinumab as monotherapy or in combination with 
pembrolizumab.
4. The intercurrent events of interest in this study are: start of new antineoplastic therapy 
prior to surgery and discontinuation of study treatment prior to surgery. These intercurrent 
events will be addressed as follows:
a. Start of new antineoplastic therapy prior to surgery: subject will be considered as 
non-responder (composite strategy)
b. Discontinuation of study treatment prior to surgery: subject will be included in the 
analysis regardless of this intercurrent event (treatment-policy strategy).
5. The summary measure is MPR rate with its corresponding two-sided exact binomial 
95% confidence interval (Clopper and Pearson E. 1934) in canakinumab alone arm and 
canakinumab in combination with pembrolizumab arm.


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A MPR of approximately 20% can be achieved using chemotherapy (Pataer 2012). For 
canakinumab alone arm, a 10% absolute improvement in the MPR to 30% is considered a 
clinically meaningful minimum improvement in this study population. Therefore, proof of 
efficacy in canakinumab alone arm will be declared if both of the following conditions are met:

the mean of the posterior distribution of MPR is at least 30% and

the posterior probability that the MPR is ≥ 20% is at least 90%
For the combination of canakinumab and pembrolizumab treatment arm, a 25% absolute 
improvement in the MPR to 45% is considered a clinically meaningful minimum improvement 
in this study population. Therefore, proof of efficacy in the combination treatment arm will be 
declared if both of the following conditions are met:

the mean of the posterior distribution of MPR is at least 45% and

the posterior probability that the MPR is ≥ 30% is at least 90%
The posterior distribution of MPR will be derived from the prior distribution and all available 
data from the subjects included in the FAS. A minimally informative unimodal Beta prior 
(Neuenschwander et al 2008) will be used for MPR in each arm. Details of prior distribution 
will be specified in the SAP.
12.4.3
Handling of missing values/censoring/discontinuations
Refer to Section 12.4.2 for details on handling of intercurrent events. 
Subjects who have an unknown MPR status due to surgery not being performed (including lost 
to follow-up or withdrawal of study consent before surgery) will be considered as non-
responders when estimating MPR rate.
12.4.4
Supportive analyses
Additional supportive analysis for the primary analysis of MPR rate will be conducted by using 
an alternative strategy in handling of the intercurrent events.
The target population, the primary variable and the summary measure will be the same as for 
the primary endpoint analysis. For the intercurrent event of start of new antineoplastic therapy 
prior to surgery: subjects will be included in the analysis regardless of this intercurrent event 
(treatment-policy strategy).
12.5
Analysis of secondary endpoints
12.5.1
Efficacy endpoints
MPR rate will be assessed using the same patient population used in the primary analysis, 
including the strategy for handling intercurrent events (1) based on local review in all three 
treatment arms and (2) based on central review in pembrolizumab monotherapy arm.
MPR rate for all the above specified analyses will be summarized by treatment arm along with 
the two-sided exact binomial 95% confidence interval (Clopper and Pearson E. 1934).
The difference in MPR rate between canakinumab in combination with pembrolizumab and 
pembrolizumab single agent arm along with the two-sided exact 95% confidence interval based 
on Chan and Zhang (1999) will be summarized based on central review using the same patient 


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population used in the primary analysis, including the strategy for handling intercurrent events. 
The posterior probability of the difference 10% or greater in MPR rate will also calculated.
Surgical feasibility rate is defined as the percentage of subjects in FAS who undergo surgery 
following study treatment. Surgical feasibility rate and two-sided exact binomial 95% 
confidence interval (Clopper and Pearson E. 1934) will be presented by treatment group.
ORR is defined as the percentage of subjects in FAS with a best overall response of CR or PR, 
as per local review. The best overall response will be the observed response at the assessment 
performed on the EOT visit prior to surgery. ORR will be evaluated according to RECIST 1.1 
(see Section 16.3 for details). ORR and two-sided exact binomial 95% confidence interval 
(Clopper and Pearson E. 1934) will be presented by treatment group. Subjects with a best 
overall response (BOR) of ‘Unknown’ per RECIST 1.1 will be considered as non-responders 
when estimating ORR.
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for AEs will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent AEs).
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of subject’s informed consent to the day before first dose 
of study medication
2. On-treatment period: from day of first dose of study medication to 130 days after last dose 
of study medication
3. Post-treatment period: starting at day 131 after last dose of any component of the study 
treatment.
12.5.2.1 Adverse events
Summary tables for AEs will include only AEs that started or worsened during the on-treatment 
period, the treatment-emergent AEs.
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and/or preferred term, severity (based on CTCAE v5.0) and 
relationship to study treatment.
SAE, non-serious AEs and AESI during the on-treatment period will be tabulated. AESIs will 
be defined based on the case retrieval strategy (CRS) available at the time of the analysis.
All deaths (on-treatment and post-treatment) will be summarized overall and separately.
All AEs, deaths and SAEs (including those from the pre and post-treatment periods) will be 
listed and those collected during the pre-treatment and post-treatment period will be flagged.


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12.5.2.2 Clinical laboratory evaluations
Grading of laboratory values will be assigned programmatically as per NCI CTCAE 
version 5.0. The calculation of CTCAE grades will be based on the observed laboratory values 
only, clinical assessments will not be taken into account.
CTCAE v5.0 Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
Grade 5 will not be used.
For laboratory tests where grades are not defined by CTCAE v5.0, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following summaries/listings will be generated separately for hematology, and 
biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding 
CTCAE v5.0 grades if applicable and the classifications relative to the laboratory normal 
ranges
For laboratory tests where grades are defined by CTCAE v5.0:

Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only once for the worst grade observed post-baseline

Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment value
For laboratory tests where grades are not defined by CTCAE v5.0:

Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value.
In addition to the above mentioned tables and listings, other exploratory analyses, for example, 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the analysis plan.
12.5.2.3 Other safety evaluations
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/cycle. Notable values 
will be flagged.
Immunogenicity
Immunogenicity of canakinumab and pembrolizumab will be characterized descriptively by 
tabulating ADA prevalence at baseline and ADA incidence on-treatment.
12.5.3
Pharmacokinetics
PAS will be used in the pharmacokinetic data analysis. Descriptive statistics (n, m (number of 
non-zero concentrations), mean, coefficient of variation in percent (CV%), SD, median, 
geometric mean, geometric CV%, minimum and maximum) for canakinumab and 
pembrolizumab concentrations will be presented at each scheduled timepoint separately.
All concentration data for canakinumab and pembrolizumab vs. time profiles will be displayed 
graphically.


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12.5.3.1 Population pharmacokinetic analysis
If there is adequate amount of data, a mixed-effects model may be applied to the serum 
canakinumab concentration-time data from this study along with other studies to generate 
posthoc estimates of pharmacokinetic parameters using NONMEM to characterize 
canakinumab exposure and to determine the effects of intrinsic (i.e. demographic factors) and 
extrinsic covariates (e.g. combination partners) on canakinumab exposure. If there is sufficient 
data for analysis, the details of the population pharmacokinetic analyses may be provided in a 
separate reporting and analysis plan, and the results may be reported in a separate population 
pharmacokinetic report. Similarly, population PK analysis may also be applied to 
pembrolizumab to determine the effects of canakinumab on pembrolizumab.
12.5.4
Biomarkers
The secondary objective related to biomarker is to assess the relationship between key blood or 
tissue based biomarkers and MPR. FAS will be used for biomarker related analyses.
The relationship between key IHC markers (PD-L1, CD8), key cytokines (hs-CRP and hs-IL-
6) assessed at baseline and post-baseline and MPR will be explored. MPR will be summarized 
by treatment arm and subgroup along with the two-sided exact binomial 95% confidence 
interval (Clopper and Pearson E. 1934). The threshold used for the markers will be specified in 
SAP. In addition, baseline and changes from baseline for the IHC markers and cytokines 
(absolute change, percent change and fold change) at each time point will be summarized in 
tables that include sample size, mean, standard deviation, CV%, median, minimum and 
maximum. For fold change from baseline, geometric mean and geometric CV% will also be 
included.
All biomarker data will also be listed.


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12.7
Interim analyses
Not applicable.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
A MPR of approximately 20% can be achieved using chemotherapy (Pataer 2012). A 10% 
absolute improvement to 30% and a 25% absolute improvement to 45% in MPR rate are 
considered clinically meaningful minimum improvement in canakinumab alone arm and 
canakinumab in combination with pembrolizumab arm, respectively.
Approximately 110 subjects will be randomized in a 2:2:1 ratio to one of the treatment arms 
(canakinumab alone or canakinumab in combination with pembrolizumab or pembrolizumab 
alone). The proof of efficacy in each treatment arm will be determined by Bayesian double 
criteria.
Among the 44 subjects randomized to canakinumab single agent treatment, at least 14 
responders are needed to meet the proof of efficacy criteria. When the true MPR rate is ≤ 20%, 
the probability of erroneously declaring proof of efficacy is at most 4.4%, while the probability 
of declaring proof of efficacy is at least 89.8% for MPR ≥ 40% (Table 12-1).
Among the 44 subjects randomized to the canakinumab and pembrolizumab combination 
treatment, at least 20 responders are required to meet the proof of efficacy criteria. When the 
true MPR rate is ≤ 30%, the probability of erroneously declaring proof of efficacy is at most 
2.1% while the probability of declaring proof of efficacy is at least 92.2% for MPR ≥ 55% 
(Table 12-2). Assuming an enrollment rate of 6 subjects per month, the enrollment will be 
completed at approximately 18 months and MPR assessment for the last patient randomized 
will occur at approximately 20 months from the date of first subject randomized in the study.


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Table 12-1
Operating characteristics with 44 subjects randomized to 
canakinumab treatment arm
True MPR
Probability of declaring proof 
of efficacy (14 or more 
responders)
Probability of missing proof 
of efficacy (13 or less 
responders)
20%
4.4%
95.6%
30%
45.2%
54.8%
40%
89.8%
10.2%
50%
99.5%
0.5%
Table 12-2
Operating characteristics with 44 subjects randomized to the 
canakinumab + pembrolizumab combination treatment arm
True MPR
Probability of declaring proof 
of efficacy (20 or more 
responders)
Probability of missing proof 
of efficacy (19 or less 
responders)
30%
2.1%
97.8%
40%
27.7%
72.3%
45%
53.4%
46.6%
55%
92.2%
7.8%
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations 
(including European Directive 2001/20/EC, US CFR 21), and with the ethical principles laid 
down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written ICF, consent form updates, subject recruitment 
procedures (e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 


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posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal Standard Operating Procedures (SOPs), and are performed according to 
written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 


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study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request
Akamine T, Takada K, Toyokawa G, et al (2018) Association of preoperative serum CRP 
with PD-L1 expression in 508 patients with non-small cell lung cancer: A comprehensive 
analysis of systemic inflammatory markers. Surg. Oncol. p. 88-94.
Alifano M, Falcoz PE, Seegers V, et al (2011) Preresection serum C-reactive protein 
measurement and survival among patients with resectable non-small cell lung cancer. J. 
Thorac. Cardiovasc. Surg. p. 1161-7.
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advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French 
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review, hypothesis and implications. Anticancer Res. p. 1113-34.
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Nonsquamous Non-Small-Cell Lung Cancer. N. Engl. J. Med. p. 1627-39.
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Squamous-Cell Non-Small-Cell Lung Cancer. N. Engl. J. Med. p. 123-35.
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Guo B, Zhang J, Fu S (2017) Inflammasomes/IL-1 pathways in myeloid cells modulate PD-
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chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major 
pathological response as a surrogate endpoint. Lancet Oncol. p. e42-50.
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Cancer with a High Tumor Mutational Burden. N. Engl. J. Med. p. 2093-2104.
Herbst RS, Baas P, Kim DW, et al (2016) Pembrolizumab versus docetaxel for previously 
treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a 
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Development, Maturation, and Function: Implications for Peripheral Tolerance. Front 
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immunosuppression in mouse breast cancer and synergizes with anti-PD-1 for tumor 
abrogation. Proc. Natl. Acad. Sci. U.S.A.
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cancer. Cytokine p. 22-33.
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the development and invasiveness of chemical carcinogen-induced tumors. Cancer Res. p. 
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Paz-Ares L, Luft A, Trafreshi A, et al (2018) Phase 3 study of carboplatin-paclitaxel/nab-
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Canakinumab for Atherosclerotic Disease. N. Engl. J. Med. p. 1119-1131.
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16
Appendices
16.1
Appendix 1: Pembrolizumab Dose Modification Guidelines
Table 16-1
Dose Modification and Toxicity management Guidelines for Immune-related Adverse Events associated with 
Pembrolizumab
General instructions:
1.
Corticosteroids taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive 
treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune related AEs
Toxicity grade or 
conditions (CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies
Monitor and follow-up
Pneumonitis
Grade 2
Withhold

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper

Monitor participants for 
signs and symptoms of 
pneumonitis

Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid treatment

Add prophylactic 
antibiotics for 
opportunistic infections
Grade 3 or 4, or recurrent 
Grade 2
Permanently discontinue
Diarrhea / Colitis
Grade 2 or 3
Withhold

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 

Monitor participants for 
signs and symptoms of 
enterocolitis (ie, 
Grade 4
Permanently discontinue


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General instructions:
1.
Corticosteroids taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive 
treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune related AEs
Toxicity grade or 
conditions (CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies
Monitor and follow-up
prednisone or 
equivalent) followed by 
taper
diarrhea, abdominal 
pain, blood or mucus in 
stool with or without 
fever) and of bowel 
perforation (ie, 
peritoneal signs and 
ileus)

Participants with ≥ 
Grade 2 
diarrhea suspecting 
colitis should consider 
GI consultation and 
performing endoscopy 
to rule out colitis

Participants with 
diarrhea/colitis should 
be 
advised to drink libera
l quantities of clear 
fluids. If sufficient oral 
fluid intake is not 
feasible, fluid and 
electrolytes should be 
substituted via IV 
infusion


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General instructions:
1.
Corticosteroids taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive 
treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune related AEs
Toxicity grade or 
conditions (CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies
Monitor and follow-up
AST /ALT elevation or 
Increased bilirubin
Grade 2
Withhold

Administer 
corticosteroids (initial 
dose of 0.5-1 mg/kg 
prednisone or 
equivalent) followed by 
taper

Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned 
to baseline or is stable).
Grade 3 or 4
Permanently discontinue

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper
Type 1 diabetes mellitus 
(TIDM) or Hyperglycemia
Newly onset T1DM or 
Grade 3 or 4 hyperglycemia 
associated with evidence of 
beta-cell failure
Withhold

Initiate insulin 
replacement therapy for 
participants with T1DM

Administer anti-
hyperglycemic in 
participants with 
hyperglycemia

Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes.
Hypophysitis
Grade 2
Withhold

Administer corticosteroi
ds and initiate hormonal 
replacements as 
clinically indicated.

Monitor for signs 
and symptoms of 
hypophysitis (including 
Grade 3 or 4
Withhold or permanently 
discontinue1


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General instructions:
1.
Corticosteroids taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive 
treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune related AEs
Toxicity grade or 
conditions (CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies
Monitor and follow-up
hypopituitarism and 
adrenal insufficiency)
Hyperthyroidism
Grade 2
Continue

Treat with non-selective 
beta-blockers 
(eg, propranolol) or 
thionamides as 
appropriate

Monitor for signs and 
symptoms of thyroid 
disorders.
Grade 3 or 4
Withhold or permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue

Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyroinine) per 
standard of care

Monitor for signs and 
symptoms of thyroid 
disorders.
Nephritis and Renal 
dysfunction
Grade 2
Withhold

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper

Monitor changes of 
renal function
Grade 3 or 4
Permanently discontinue
Myocarditis
Grade 1 or 2
Withhold

Based on severity of 
AE, administer 
corticosteroids

Ensure adequate eval
uation to confirm 
etiology and/or exclude 
other causes
Grade 3 or 4
Permanently discontinue
All other immune-related 
AEs
Intolerable/persistent Grade 
2
Withhold


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General instructions:
1.
Corticosteroids taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive 
treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune related AEs
Toxicity grade or 
conditions (CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies
Monitor and follow-up
Grade 3
Withhold or discontinue 
based on the type of event. 
Events that require 
discontinuation include and 
not limited to: Gullain-Barre 
Syndrome, encephalitis

Based on type and 
severity of AE, 
administer 
corticosteroids

Ensure adequate eval
uation to confirm 
etiology and/or exclude 
other causes
Grade 4 or recurrent Grade 
3
Permanently discontinue


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16.2
Appendix 2: Medications to be used with caution with 
canakinumab while on study
Table 16-2
CYP3A substrates with narrow therapeutic index, or sensitive CYP2C9 
substrates with therapeutic index**
CYP2C9 substrates with narrow therapeutic index
warfarin
phenytoin
CYP3A4/5 substrates with narrow therapeutic index
astemizole*
diergotamine
pimozide
alfentanil
cisapride*
ergotamine
quinidine*
terfenadine*
cyclosporine
fentanyl
tacrolimus
sirolimus
*Compounds known to increase QTc interval that are also primarily metabolized by CYP3A4/5. 
For an updated list of CYP2C9 substrates, CYP3A substrates, inhibitors and inducers, please 
reference the Novartis Oncology Clinical Pharmacology internal memo: drug-drug interactions (DDI) 
database, October 2010, which is compiled primarily from the FDA’s “Guidance for Industry, Drug 
Interaction Studies”, the Indiana University School of Medicine’s Drug Interactions Database, and 
the University of Washington’s Drug Interaction Database.
**Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-
administered with a known potent inhibitor. Substrates with narrow therapeutic index (NTI): Drugs 
whose exposure-response indicates that increases in their exposure levels by the concomitant use 
of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes).


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16.3
Appendix 3: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival, and Overall 
Survival (based on RECIST 1.1)
16.3.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse 2000) and the revised RECIST 
1.1 guidelines (Eisenhauer 2009).
The efficacy assessments described in Section 16.3.2 and the definition of best response in 
Section 16.3.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 16.3.3.2 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 16.3.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the SAP (Statistical Analysis Plan) to provide further details needed for programming.
16.3.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria by Therasse 2000 and revised RECIST 
guidelines (version 1.1) by Eisenhauer 2009.
16.3.2.1 Definitions
16.3.2.1.1
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. If 
the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For subjects without measurable disease, even if not expected as per eligibility criteria in this
protocol, see Section 16.3.3.2.9
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5 mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes >=15 mm in short axis can be
considered for selection as target lesions. Lymph nodes measuring >=10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 


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baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease.

Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no septations, 
and low CT density [water-like] content) should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same subject, these are preferred for selection as target 
lesions.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 
>=10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.
16.3.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the subject may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that subjects be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how subjects with just non-measurable disease at baseline 
(even if not expected as per eligibility criteria of this protocol) will be evaluated for response 
and also handled in the statistical analyses is given in Section 16.3.3.2.9.
16.3.2.2 Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v.) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of subjects, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a subject is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 


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be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.

A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However, 
another response assessment than the Novartis calculated UNK response may be accepted 
from the investigator or the central blinded reviewer if a definitive response 
assessment can be justified, based on the available information.

FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.

No FDG-PET at baseline with a positive FDG-PET at follow-up:

If new disease is indicated by a positive PET scan but is not confirmed by CT (or some 
other conventional technique such as MRI) at the same assessment, then follow-up 
assessments by CT will be needed to determine if there is truly progression occurring at 
that site. In all cases PD will be the date of confirmation of new disease by CT (or some 
other conventional technique such as MRI) rather than the date of the positive PET scan. 
If there is a positive PET scan without any confirmed progression at that site by CT, then a 
PD cannot be assigned. 

If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD.

Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.

Physical exams: Evaluation of lesions by physical examination is accepted when lesions 
are superficial, with at least 10mm size, and can be assessed using calipers.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions, unless pre-specified by the 
protocol. It is, however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions and thyroid nodules. US might also be useful 
to confirm the complete disappearance of superficial lesions usually assessed by clinical 
examination.

Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained.


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
Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 
PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be 
integrated as non-target disease. If markers are initially above the upper normal limit they 
must normalize for a subject to be considered in complete clinical response when all 
lesions have disappeared.

Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
16.3.2.3 Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the eCRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 16.3.2.1.1

Nodal target: See Section 16.3.2.1.1. A sum of diameters (long axis for non-nodal 
lesions, short axis for nodal) for all target lesions will be calculated and reported as the 
baseline sum of diameters (SOD). The baseline sum of diameters will be used as reference 
by which to characterize the objective tumor response. Each target lesion identified at 
baseline must be followed at each subsequent evaluation and documented on eCRF.
Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not fulfilling 
the criteria for target lesions at baseline. Presence or absence or worsening of on-target lesions 
should be assessed throughout the study; measurements of these lesions are not required. 
Multiple non-target lesions involved in the same organ can be assessed as a group and recorded 
as a single item (i.e. multiple liver metastases). Each non-target lesion identified at baseline 
must be followed at each subsequent evaluation and documented on eCRF.


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16.3.2.4 Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 16-3) and non-target lesions (Table 16-4) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 16-5) as well as the presence or absence of new lesions.
16.3.2.4.1
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore, all such data applicable to a particular visit should be associated with the same 
assessment.
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.


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16.3.2.4.2
Determination of target lesion response
Table 16-3
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all non-nodal target lesions. In 
addition, any pathological lymph nodes assigned 
as target lesions must have a reduction in short 
axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter 
of all target lesions, taking as reference the 
baseline sum of diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameter 
of all measured target lesions, taking as 
reference the smallest sum of diameter of all 
target lesions recorded at or after baseline. In 
addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of 
at least 5 mm 2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or 
CR nor an increase in lesions which would 
qualify for PD.
Unknown (UNK)
Progression has not been documented and one 
or more target lesions have not been assessed 
or have been assessed using a different method 
than baseline.3
1.
SOD for CR may not be zero when nodal lesions are part of target lesions
2.
Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not 
present and all nodal lesions are <10 mm in size. In this case, the target lesion response is CR
3.
In exceptional circumstances an UNK response due to change in method could be over-ruled by 
the investigator or central reviewer using expert judgment based on the available information 
(see Notes on target lesion response and methodology change in Section 16.3.2.2).
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities:

The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease.

The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the eCRF and the tumor assessment will remain 
based on the sum of tumor measurements as presented in Table 16-3 above (i.e., a PD will 
be determined if there is at least 20% increase in the sum of diameters of all measured 
target lesions, taking as reference the smallest sum of diameters of all target lesions 
recorded at or after baseline with at least 5 mm increase in the absolute sum of the 
diameters). Proper documentation should be available to support this decision. This 


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applies to subjects who have not achieved target response of CR. For subjects who have 
achieved CR, please refer to last bullet in this section.

For those subjects who have only one target lesion at baseline, the reappearance of the 
target lesion, which disappeared previously, even if still small, is considered a PD.

Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.

Nodal lesion decrease to normal size: When nodal disease is included in the sum of 
target lesions and the nodes decrease to “normal” size they should still have a 
measurement recorded on scans. This measurement should be reported even when the 
nodes are normal in order not to overstate progression should it be based on increase in the 
size of nodes.

Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) 
of the two split lesions should be added together and the sum recorded in the diameter 
field on the CRF under the original lesion number. This value will be included in the sum 
of diameters when deriving target lesion response. The individual split lesions will not be 
considered as new lesions, and will not automatically trigger a PD designation.

Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs, a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis -
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the CRF, the diameter of the “merged lesion” should be 
recorded for the size of one of the original lesions while a size of “0”mm should be 
entered for the remaining lesion numbers which have coalesced.

The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.

Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all non-
nodal target lesions have disappeared.

Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions.

Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters.


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A change in method for the evaluation of one or more lesions will usually lead to an UNK target 
lesion response unless there is progression indicated by the remaining lesions which have been 
evaluated by the same method. In exceptional circumstances an investigator or central reviewer 
might over-rule this assignment to put a non-UNK response using expert judgment based on 
the available information. E.g. a change to a more sensitive method might indicate some tumor 
shrinkage of target lesions and definitely rule out progression in which case the investigator 
might assign an SD target lesion response; however, this should be done with caution and 
conservatively as the response categories have well defined criteria.
16.3.2.4.3
Determination of non-target lesion response
Table 16-4
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In 
addition, all lymph nodes assigned a non-target 
lesions must be non-pathological in size (< 10 
mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target 
lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one 
or more non-target lesions have not been 
assessed or have been assessed using a 
different method than baseline2.
1.
The assignment of PD solely based on change in non-target lesions in light of target lesion 
response of CR, PR or SD should be exceptional. In such circumstances, the opinion of the 
investigator or central reviewer prevails.
2.
It is recommended that the investigator and/or central reviewer should use expert judgment to 
assign a Non-UNK response wherever possible (see notes Section 16.3.2.4.3 for more details)
Notes on non-target lesion response

The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned.

The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. >=10 mm) the response can only be 
‘Non- CR/Non-PD’ unless there is unequivocal progression of the non-target lesions (in 
which case response is PD) or it is not possible to determine whether there is unequivocal 
progression (in which case response is UNK).
Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such that, 
even in presence of CR, PR or SD in target disease, the overall tumor burden has increased 


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sufficiently to merit discontinuation of therapy. A modest “increase” in the size of one or more 
non-target lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease in the face 
of CR, PR or SD of target disease is therefore expected to be rare. In order for a PD to be 
assigned on the basis of non-target lesions, the increase in the extent of the disease must be 
substantial even in cases where there is no measurable disease at baseline. If there is 
unequivocal progression of non-target lesion(s), then at least one of the non-target lesions must 
be assigned a status of “Worsened”. Where possible, similar rules to those described in 
Section 16.3.2.4.2 for assigning PD following a CR for the non-target lesion response in the 
presence of non-target lesions nodal lesions should be applied.
16.3.2.4.4
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion

If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
subject in which case the response should be UNK, as for any of this subject's assessment 
(Section 16.3.2.5).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to ≥ 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for ‘new’ 
disease). See Section 16.3.2.2.
16.3.2.5 Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in 
Table 16-5.
Table 16-5
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall lesion 
response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD


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Target lesions
Non-target lesions
New Lesions
Overall lesion 
response
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1This overall lesion response also applies when there are no non-target lesions identified at 
baseline.
2Once confirmed PR was achieved, all these assessments are considered PR.
3As defined in Section 16.3.2.4
If there are no baseline scans available at all, then the overall lesion response at each 
assessment should be considered Unknown (UNK).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
16.3.3
Efficacy definitions
The following definitions primarily relate to subjects who have measurable disease at 
baseline. Section 16.3.3.2.9 outlines the special considerations that need to be given to subjects 
with no measurable disease at baseline in order to apply the same concepts.
16.3.3.1 Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the subject's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 130 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

For non-randomized trials where response is the primary endpoint, confirmation is needed.

For trials intended to support accelerated approval, confirmation is needed


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
For all other trials, confirmation of response may be considered optional.
The best overall response for each subject is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required.

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required.

SD = at least one SD assessment (or better) > 5 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression ≤ 13 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 5 weeks or early progression within the first 13 weeks).
The time durations specified in the SD/PD/UNK definitions above are based on a 6 week tumor 
assessment frequency taking into account assessment windows. E.g. if the assessment occurs 
every 6 weeks with a time window of ± 7 days, a BOR of SD would require a SD or better 
response longer than 5 weeks after randomization/start of treatment.
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A subject who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a subject has a single PR (>=30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not >=20% increase from previous smallest sum), the objective 
status at that assessment should be SD. Once a confirmed PR was seen, the overall lesion 
response should be considered PR (or UNK) until progression is documented or the lesions 
totally disappear in which case a CR assignment is applicable. In studies where confirmation 
of response is not required after a single PR the overall lesion response should still be 
considered PR (or UNK) until progression is documented or the lesion totally disappears in 
which case a CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this subject. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments.


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Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a subject is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:

Investigator overall lesion response

Central Blinded Review overall lesion response

Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)
The primary analysis of the best overall response will be based on the sequence of investigator 
overall lesion responses.
Based on the subjects’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of subjects with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of subjects with a best overall response of CR or 
PR or SD. The objective of this endpoint is to summarize subjects with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.
Clinical benefit rate (CBR) is the proportion of subjects with a best overall response of CR or 
PR , or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum time 
duration (with a default of at least 24 weeks in breast cancer studies). This endpoint measures 
signs of activity taking into account duration of disease stabilization.
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of subjects with progressive disease within 7 
weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study-specific. EPR is used for the multinomial designs of Dent et al (2001) and counts 
all subjects who at the specified assessment do not have an overall lesion response of SD, PR 
or CR. subjects with an unknown (UNK) assessment at that time point and no PD before, will 
not be counted as early progressors in the analysis but may be included in the denominator of 
the EPR rate, depending on the analysis population used. Similarly when examining overall 
response and disease control, subjects with a best overall response assessment of unknown 
(UNK) will not be regarded as “responders” but may be included in the denominator for ORR 
and DCR calculation depending on the analysis population (e.g. populations based on an ITT 
approach).


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16.3.3.2 Time to event variables
16.3.3.2.1
Progression free survival
Usually in all Oncology studies, subjects are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
subject has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint.
16.3.3.2.2
Overall survival
All subjects should be followed until death or until subject has had adequate follow-up time as
specified in the protocol whichever comes first. The follow-up data should contain the date the 
subject was last seen alive / last known date subject alive, the date of death and the reason of 
death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a subject is not known to have died, survival will be censored 
at the date of last known date subject alive.
16.3.3.2.3
Time to progression
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a subject has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.
16.3.3.2.4
PFS2
A recent EMA Guidelines, 2012 recommends a substitute end point intermediate to PFS and 
OS called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses the 
impact of the experimental therapy on next-line treatment. The main purpose of this endpoint 
is to assess long term maintenance strategies, particularly of resensitizing agents and where it 
is necessary to examine the overall “field of influence”.
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 


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document, and in addition may involve other considerations which will need to be detailed in 
the protocol.
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments.
It is strongly recommended that the teams consult regulatory agencies for scientific advice given 
the limited experience with the use of this endpoint in regulatory setting in light of 
methodological issues w.r.t. censoring foreseen.
16.3.3.2.5
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment 
failure may be considered as a sensitivity analysis for time to progression. The list of 
discontinuation reasons to be considered or not as treatment failure may be adapted according 
to the specificities of the study or the disease.
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for subjects who did not experience treatment failure will be censored at last adequate 
tumor assessment.
16.3.3.2.6
Duration of response
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of subjects: a good risk group and a poor risk 
group. Good risk subjects tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk subjects tend to be difficult to achieve 
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk subjects. Less potent agents 
induce a response mainly in good risk subjects only. This is described in more detail by Morgan 
1988.
It is recommended that an analysis of all subjects (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates... If an 
inferential comparison between treatments is required this should only be performed on all 
subjects (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis 2008. It should also be stated in the protocol if duration of 
response is to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-subject analysis of these endpoints are not appropriate since the status of 
subjects throughout the study is usually taken into account in the analysis).


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Duration of overall response (CR or PR): For subjects with a CR or PR (which may have to 
be confirmed) the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen.
Duration of overall complete response (CR): For subjects with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For subjects with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression.
16.3.3.2.7
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 16.3.3.2.6. It is recommended that 
an analysis of all subjects (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all subjects should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all subjects, subjects who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options;

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for subjects who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the subject cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)

at last adequate tumor assessment date otherwise. In this case subjects have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
16.3.3.2.8
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT scan) if the overall lesion response at that assessment is 


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CR/PR/SD/UNK. Otherwise, if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number.
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred), the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 16.3.3.2.8).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the EOT visit.

Date of last contact is defined as the last date the subject was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date subject alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.
Date of secondary anti-cancer therapy is defined as the start date of any additional (secondary) 
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16.3.3.2.9
Handling of patients with non-measurable disease only at baseline
It is possible that subjects with only non-measurable disease present at baseline are entered into 
the study, because of a protocol violation . In such cases the handling of the response data 
requires special consideration with respect to inclusion in any analysis of endpoints based on 
the overall response evaluations.
It is recommended that any subjects with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
subjects with measurable disease at baseline, subjects without measurable disease should also 
be incorporated in an appropriate manner. The overall response for subjects with non-
measurable disease is derived slightly differently according to Table 16-6.
Table 16-6
Overall lesion response at each assessment: subjects with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 16.3.2.4
In general, the non-CR/non-PD response for these subjects is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response subjects with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these subjects into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from subjects with only 
non-measurable disease at baseline, handling subjects with a best response of CR as “responders” 
with respect to ORR and all other subjects as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
subjects with only non-measurable disease at baseline, with possible sensitivity analyses 
which exclude these particular subjects. Endpoints such as PFS which are reliant on the 
determination and/or timing of progression can incorporate data from subjects with only non-
measurable disease.
16.3.3.2.10
Sensitivity analysis
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 


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of a subject being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 16.3.3.2.8, and using the FDA guideline on endpoints 
(Section 16.3.5) as a reference, the following analyses can be considered:
Table 16-7
Options for event dates used in PFS, TTP, duration of response
Situation
Options for end-date 
(progression or 
censoring)1
(1) = default unless 
specified differently 
in the protocol or 
RAP
Outcome
A
No baseline 
assessment
(1) Date of 
randomization/start of 
treatment3
Censored
B
Progression at or 
before next scheduled 
assessment
(1) Date of progression 
(2) Date of next 
scheduled 
assessment2
Progressed 
Progressed
C1
Progression or death 
after exactly one 
missing assessment
(1) Date of progression 
(or death)
(2) Date of next 
scheduled 
assessment2
Progressed
Progressed
C2
Progression or death 
after two or more 
missing assessments
(1) Date of last 
adequate assessment2
(2) Date of next 
scheduled 
assessment2
(3) Date of progression 
(or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last 
adequate assessment
Censored
E
Treatment 
discontinuation due to 
‘Disease progression’ 
without documented 
progression, i.e. 
clinical progression 
based on investigator 
claim
(1) Ignore clinical 
progression and follow 
situations above
(2) Date of 
discontinuation (visit 
date at which clinical 
progression was 
determined)
As per above 
situations
Progressed
F
New anticancer 
therapy given
(1) Ignore the new 
anticancer therapy and 
follow situations above 
(ITT approach)
As per above 
situations
Censored
Censored
Event


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Situation
Options for end-date 
(progression or 
censoring)1
(1) = default unless 
specified differently 
in the protocol or 
RAP
Outcome
(2) Date of last 
adequate assessment 
prior to new anticancer 
therapy
(3) Date of secondary 
anti-cancer therapy
(4) Date of secondary 
anti-cancer therapy
G
Deaths due to reason 
other than 
deterioration of ‘Study 
indication’
(1) Date of last 
adequate assessment
Censored (only TTP 
and duration of 
response)
1 =Definitions can be found in Section 16.3.3.2.8
2 =After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 16.3.3.2.8.
3 =The rare exception to this is if the subject dies no later than the time of the second scheduled 
assessment as defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as subjects without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 


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analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy.
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of 
the event or censoring. This should be clearly specified in the analysis plan.
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis.
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the subject is switched to a new 
cancer therapy.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 16-7 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation.
16.3.4
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
16.3.4.1 Study / project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.


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The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
16.3.4.2 End of treatment phase completion
Subjects may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For subjects who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the subject, e.g., dates of telephone calls, registered letters, 
etc.
The EOT visit and its associated assessments should occur within 21 days of the permanent 
discontinuation of study treatment but before the surgery.
Subjects may discontinue study treatment for any of the following reasons:

AE(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
Death is a reason which “must” lead to discontinuation of subject from trial.
16.3.4.3 End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study 
treatment and post-treatment evaluations but prior to collecting survival follow-up.
Subjects may provide study phase completion information for one of the following reasons:

AE

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

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
Death

Progressive disease

Study terminated by the sponsor
16.3.4.4 Medical validation of programmed overall lesion response
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses 
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the investigator or central reader’s 
response assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion 
response at that specific assessment is to be kept in a dataset. This must be clearly documented 
in the RAP documentation and agreed before database lock. This dataset should be created and 
stored as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only subjects with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
16.3.4.5 Programming rules
The following should be used for programming of efficacy results:
16.3.4.5.1
Calculation of 'time to event' variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
16.3.4.5.2
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 


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assessment date is calculated as outlined in Section 16.3.3.2.8). If all measurement dates have 
no day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
16.3.4.5.3
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
16.3.4.5.4
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
16.3.4.5.5
Study / project specific programming
The standard analysis programs need to be adapted for each study/project.
16.3.4.5.6
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 16-7)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
* Adequate assessment is defined in Section 16.3.3.2.8. This reason is applicable when 
adequate evaluations are missing for a specified period prior to data cut-off (or prior to any 
other censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason 
should also be noted:


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
This may be when there has been a definite decision to stop evaluation (e.g. reason 
“Sponsor decision” on study evaluation completion page), when subjects are not followed 
for progression after treatment completion or when only UNK assessments are available 
just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.
16.3.5
References (available upon request)
Dent S, Zee B, Dancey J, et al (2001) application of a new multinomial phase II stopping rule 
using response and early progression; J Clin Oncol: 19:785-91.
Eisenhauer EA, Therasse P, BogaertsJ, et al (2009) New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1); Euro J Cancer; 45:228-47.
Ellis S, Carroll KJ, Pemberton K, et al (2008) Analysis of duration of response in oncology 
trials. Contemp Clin Trials; 29:456-65.
EMA Guidelines: 2012 Guideline on the evaluation of anticancer medicinal products in man.
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007.
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials; Cont Clin 
Trials; 9: 11-18.
Therasse P, Arbuck SG, Eisenhauer EA, et al (2000) New Guidelines to Evaluate the 
Response to Treatment in Solid Tumors; J Natl Cancer Inst; 92; 205-16.


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16.4
Appendix 4: NSCLC staging according to AJCC 8th edition
Figure 16-1
NSCLC staging: AJCC 8th edition
Note: 
Subjects with histological stage within the red box will be eligible. 
N2, T4 and N2+ T4 subjects are not eligible.

SAP_001.pdf: 






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Table of contents
Template Document History – Changes compared to previous version .............................2
Table of contents .................................................................................................................4
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Study objectives, endpoints and estimands .............................................................9
1.2.1
Primary estimands.................................................................................10
2
Statistical methods.............................................................................................................11
2.1
Data analysis general information .........................................................................11
2.1.1
Data included in the analysis.................................................................11
2.1.2
General analysis conventions................................................................11
2.1.3
General definitions................................................................................12
2.2
Analysis sets ..........................................................................................................16
2.2.1
Subgroup of interest ..............................................................................18
2.3
Subject disposition, demographics and other baseline characteristics ..................18
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................20
2.4.1
Study treatment / compliance................................................................20
2.4.2
Prior, concomitant and post therapies...................................................22
2.5
Analysis of the primary objective..........................................................................23
2.5.1
Primary endpoint...................................................................................23
2.5.2
Statistical hypothesis, model, and method of analysis..........................23
2.5.3
Handling of missing values/censoring/discontinuations.......................24
2.5.4
Supportive analyses...............................................................................24
2.6
Analysis of secondary efficacy objective(s)..........................................................25
2.6.1
MPR rate ...............................................................................................25
2.6.2
Overall response rate (ORR).................................................................26
2.6.3
Surgical Feasibility Rate .......................................................................26
2.7
Secondary objective: safety analyses.....................................................................26
2.7.1
Adverse events (AEs)............................................................................26
2.7.2
Deaths....................................................................................................27
2.7.3
Laboratory data .....................................................................................27
2.7.4
Other safety data ...................................................................................29
2.8
Secondary objective: Pharmacokinetic endpoints .................................................31


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2.9
Secondary objective: Immunogenicity ..................................................................32
2.10
Secondary objective: Biomarkers..........................................................................32
.........................34
...............................................................................34
.........34
........................35
......................35
............................35
............................................................................35
2.12
Interim analysis......................................................................................................36
3
Sample size calculation .....................................................................................................36
3.1
Primary analysis.....................................................................................................36
4
Change to protocol specified analyses ..............................................................................37
5
Appendix ...........................................................................................................................37
5.1
Imputation rules.....................................................................................................37
5.1.1
Study drug.............................................................................................37
5.1.2
AE, ConMeds and safety assessment date imputation..........................37
5.2
AEs coding/grading ...............................................................................................38
5.3
Laboratory parameters derivations ........................................................................38
5.4
Statistical models...................................................................................................39
5.4.1
Primary analysis....................................................................................39
6
Reference...........................................................................................................................40


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List of tables
Figure 1-1
Study Design ...........................................................................................9
Table 1-1
Objectives and related endpoints ............................................................9
Table 2-1
Time windows for ECOG performance status......................................15
Table 2-2
Last contact date data sources...............................................................15
Table 2-3
Subject classification based on protocol deviations and non-PD 
criteria ...................................................................................................17
Table 2-4
Clinically notable changes in vital signs...............................................30
Table 2-5
ECOG Performance Scale.....................................................................30
Table 2-6
Scheduled sample biomarker summary table for secondary and 
explorary objectives ..............................................................................33
Table 3-1
Operating characteristics with 44 subjects randomized to 
canakinumab treatment arm ..................................................................36
Table 3-2
Operating characteristics with 44 subjects randomized to the 
canakinumab + pembrolizumab combination treatment arm................37
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) ....37
List of figures
Figure 1-1
Study Design ...........................................................................................9


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List of abbreviations
ADA
Anti-drug antibodies
AE
Adverse event
AESI
Adverse event of special interest
ATC
Anatomical Therapeutic Classification
BMI
Body Mass Index
BOR
Best Overall Response
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dose Administration Record
DI
Dose Intensity
DRL
Drug Reference Listing
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
FAS
Full Analysis Set
i.v.
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MPR
Major Pathological Response
NCI
National Cancer Institute
ORR
Overall Response Rate
PAS
Pharmacokinetic Analysis Set
PDI
Planned Dose Intensity
PK
Pharmacokinetics
Q3W
Every 3 Week
RDI
Relative Dose Intensity
RECIST
Response Evaluation Criteria in Solid Tumors 
SAP
Statistical Analysis Plan
s.c.
Subcutaneous
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization
WHO-DD
World Health Organization-Drug Dictionary


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1
Introduction
This statistical analysis plan (SAP) describes the planned analyses for the primary clinical study 
report (CSR) of study CACZ885V2201C, a randomized, open-label, phase II study of 
canakinumab or pembrolizumab as monotherapy or in combination as neoadjuvant therapy in 
subjects with resectable non-small cell lung cancer. 
As specified in the Section 3 of study protocol, the primary analysis will be performed after all 
subjects have had surgical resection or have discontinued study treatment earlier due to any 
reason. At this time, the CSR for primary analysis will be produced. On Feb. 1, 2022, Novartis 
decided to halt the recruitment into the study given the number of subjects already randomized 
to the study and the challenges with recruitment.
No change was made to the statistical assumptions and the impact on the probability of 
declaring proof of efficacy (power) and the probability of missing proof of efficacy (type I error 
rate) will be limited. The primary analysis will be conducted as planned according to the 
protocol.  
The content of this SAP is based on protocol CACZ885V2201C version 01 (dated 07-Apr-
2020). All decisions regarding the primary analysis, as defined in the SAP document, have been 
made prior to database lock of the study data.
1.1
Study design
This is a phase II, randomized, open-label study evaluating efficacy and safety of canakinumab 
or pembrolizumab monotherapy or in combination as neoadjuvant treatment.
Approximately 110 subjects were planned to be randomized in a 2:2:1 ratio to one of the 
treatment arms (Canakinumab alone, Cankinumab in combination with Pembrolizumab and 
Pembrolizumab alone) . Subjects randomized will receive two doses of canakinumab (200mg 
s.c. Q3W) alone or in combination with pembrolizumab or two doses of pembrolizumab as 
single agent (200mg i.v. Q3W) (Figure 1-1). Randomization will be stratified by histology 
(squamous vs non-squamous). Subjects with adenosquamous histology can be stratified as 
squamous or non-squamous based on the predominant histology.
The primary endpoint is the MPR rate as assessed by the percentage of subjects with ≤ 10% 
residual viable cancer cells based on central review. Primary analysis will be performed after 
all subjects have had surgical resection or have discontinued study treatment earlier due to any 
reason.
No formal interim efficacy analysis is planned in this study.


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Figure 1-1
Study Design
1.2
Study objectives, endpoints and estimands
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the MPR rate (≤10% of residual viable 
tumor cells) at the time of surgery for all subjects 
randomized to canakinumab alone and in 
combination with pembrolizumab based on 
central review

MPR rate based on central review
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the prevalence and incidence of IG 
(ADA) of canakinumab and pembrolizumab

ADA prevalence at baseline and ADA 
incidence on-treatment

To assess ORR in randomized subjects treated 
with canakinumab or pembrolizumab as 
monotherapy and in combination (local review)

Overall response rate based on local 
investigator assessment per RECIST 
1.1

To assess the PK of canakinumab and 
pembrolizumab as monotherapy and in 
combination

Concentrations of canakinumab, 
pembrolizumab

To assess surgical feasibility rate in each 
treatment arm based on randomized subjects

Surgical feasibility rate

To assess the MPR rate at the time of surgery in 
(a) all subjects randomized to pembrolizumab 
monotherapy arm based on central review, (b) all 
randomized subjects based on local review in 
each treatment arm, (c) to estimate the difference 
in MPR and posterior probability of the difference 

(a) MPR based on central review
(b) MPR based on local review
(c) Difference in MPR rate based on 
central review


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Objective(s)
Endpoint(s)
in MPR ≥ 10% between subjects randomized to 
canakinumab + pembrolizumab combination and 
pembrolizumab alone based on central review.

To evaluate safety and tolerability of 
canakinumab and pembrolizumab as 
monotherapy or in combination

Type, frequency and severity of AEs 
(Common Terminology Criteria for 
Adverse Events [CTCAE] v5.0), vital 
signs and laboratory abnormalities

To assess the relationship between key blood or 
tissue based biomarkers and MPR

MPR based on the levels of biomarkers 
(PD-L1, CD8, hs-CRP, hs-IL-6) 
assessed at baseline and on treatment
1.2.1
Primary estimands
The primary estimand will be described by the following five attributes:
1. The target population is defined as all randomized patients who are histologically 
confirmed NSCLC stage IB-IIIA (per AJCC 8th edition), deemed suitable for primary 
resection by treating surgeon, except for N2 and T4 tumors.
2. The primary variable is the percentage of subjects with a major pathological response 
(defined as ≤ 10% residual viable cancer cells per central review). Any patient who 
has >10% residual viable cancer cells, or starts new antineoplastic therapy prior to 
surgery, or does not have the surgery performed, or have the surgery performed but with 
unevaluable MPR results, is considered as a non-responder.
3. The study treatment is canakinumab as monotherapy or in combination with 
pembrolizumab.


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4. The intercurrent events of interest in this study are: start of new antineoplastic therapy 
prior to surgery and discontinuation of study treatment prior to surgery. These intercurrent 
events will be addressed as follows:
a.
Start of new antineoplastic therapy prior to surgery: subject will be 
considered as non-responder (composite strategy)
b. Discontinuation of study treatment prior to surgery: subject will be 
included in the analysis regardless of this intercurrent event (treatment-policy 
strategy).
5. The summary measure is MPR rate with its corresponding two-sided exact binomial 95% 
confidence interval (Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial 
limits illustrated in the case of the binomial.  Biometrical, 26, 404-413.) in canakinumab 
alone arm and canakinumab in combination with pembrolizumab arm.
2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by Novartis statistics and programming team. SAS version 
9.4 or later will be used to perform all data analyses and to generate tables, figures and listings.
2.1.1
Data included in the analysis
Data from all participants who signed main informed consent in centers that participate in this 
study will be used in the analysis. Data collected after patients’ withdrawal of informed consent 
for further participation in the study will not be reported (except for death date, if it is obtained 
from public records).
The analysis cut-off date for the primary analysis of study data will be established after all 
subjects have had surgical resection or have discontinued study treatment earlier due to any 
reason. All statistical analyses will be performed using all data collected in the database up to
the data cutoff date. All data with an assessment date or event start date (e.g. vital sign
assessment date or start date of an adverse event) prior to or on the cut-off date will be included
in the analysis. Any data collected beyond the cut-off date will not be included in the analysis 
and will not be used for any derivations.
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. The same rule will be applied to events starting before or on the cut-off 
date and not having documented end date. This approach applies, in particular, to adverse event 
and concomitant medication reports. For these events, the end date will not be imputed and 
therefore will not appear in the listings.
2.1.2
General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of subjects enrolled at centers, no center effect 
will be assessed.


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Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables
by treatment arm; a missing category will be included as applicable. Percentages will be 
calculated using the number of subjects in the relevant population or subgroup as the
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, percentiles, minimum, and maximum) by 
treatment arm.
2.1.3
General definitions
2.1.3.1
Study drug and study treatment
The study drug refers to canakinumab and pembrolizumab. The study treatment refers to 
canakinumab monotherapy, canakinumab in combination with pembrolizumab, and 
pembrolizumab monotherpay.
2.1.3.2
Date of first administration of study drug
The date of first administration of study drug is defined as the first date when a non-zero dose 
of study drug is administered and recorded on the Dosage Administration Record (DAR) 
(e)CRF. The date of first administration of study drug will also be referred as start date of study
drug.
Note : Dates from “DAR – PK sampling” (e)CRF will not be used for this derivation.
2.1.3.3
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a nonzero dose of 
study drug is administered and recorded on DAR (e)CRF. The date of last administration of 
investigational drug will also be referred as end date of study drug.
Note 1: Dates from “DAR – PK sampling” (e)CRF will not be used for this derivation.
Note 2: Last date of study drug exposure may not be the same as the last date of study drug (See 
Section 2.1.3.6)
2.1.3.4
Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any component of study treatment (canakinumab, pembrolizumab) was administered as 
per the DAR (e)CRF. 
For the sake of simplicity, the date of first administration of study treatment will also be referred 
as start date of study treatment.
For canakinumab monotherapy and pembrolizumab monotherapy arms, the date of first 
administration of study treatment is the same as the date of first administration of study drug. 
For canakinumab and pembrolizumab combination arm, the date of first administration of study 
treatment is derived as the first date when a nonzero dose of any component of study treatment
was administered as per the DAR (e)CRF. For example: if 1st dose of canakinumab is 


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administered on 03-Jan-2019, and 1st dose of pembrolizumab is administered on 05-Jan-2019, 
then the date of first administration of study treatment is on 03-Jan-2019.
2.1.3.5
Date of last administration of study treatment 
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of study treatment (canakinumab, pembrolizumab) was administered as per DAR (e)CRF. 
For canakinumab monotherapy and pembrolizumab monotherapy arms, the date of last 
administration of study treatment is the same as the date of last administration of study drug.
For canakinumab and pembrolizumab combination arm, the date of last administration of study 
treatment is derived as the last date when a nonzero dose of any component of study treatment
was administered as per Dose Administration (e)CRF. For example: if the last canakinumab 
dose is administered on 15-Apr-2019, and the last dose of pembrolizumab is administered on 
17-Apr-2019, then the date of last administration of study treatment is on 17-Apr-2019.
2.1.3.6
Last date of exposure to study drug/treatment
The study treatment schedule is organized in cycles of 21 days. The last date of exposure to 
study drug (canakinumab, pembrolizumab) will be derived as follows: 

Min ((last date of administration of study drug + (length of cycle duration - 1), i.e.
[last date of study drug administration + 20]), date of death, last contact date in 
case subject is lost to follow-up, withdrawal of consent date)
The last date of exposure to canakinumab+pembrolizumab study treatment is derived to be the
latest date among the last date of exposure to canakinumab and pembrolizumab. If the derived 
last date of exposure to study drug/study treatment goes beyond the data cutoff date, it should 
be truncated to the date of data cutoff. ‘Date of last administration of study drug’ and ‘Date
of last contact’ are defined in Section 2.1.3.3 and Section 2.1.3.12 respectively.
2.1.3.7
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date (randomization date or start date of study treatment). 
The study day is defined as:
The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date.
The reference start date for safety assessments (e.g. adverse event onset, laboratory 
abnormality occurrence, vital sign measurement, dose interruption, PK and etc.) is the start
date of study treatment.
The reference start date for all other non-safety assessments (e.g., MPR assessment, tumor
response, and ECOG performance status) is the date of randomization.
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.


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2.1.3.8
Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375.  If duration is reported in 
years, duration in days will be divided by 365.25.
2.1.3.9
Baseline
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the date of randomization is taken as “baseline” value or “baseline” assessment. In 
the context of baseline definition, the efficacy evaluations also include ECOG performance 
status. For biomarker, the last available data collected before the first dose of study treatment 
will be defined as “baseline”.
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken as “baseline” assessment.
If subjects have no value as defined above, the baseline result will be missing.
In rare cases where multiple measurements meet the baseline definition, with no further flag or 
label that can identify the chronological order, then the following rule should be applied: If 
values are from central and local laboratories, the value from central assessment should be
considered as baseline. If multiple values are from the same laboratory (local or central) or
collected, then the worst value should be considered as baseline.
2.1.3.10 On-treatment assessment/event and observation periods
For adverse event reporting the overall observation period will be divided into three mutually 
exclusive segments: 
1. pre-treatment period: from day of subject’s informed consent to the day before first 
administration of study treatment
2. on-treatment period: from date of first administration of study treatment to 130 days 
(approximately five terminal half-lives of canakinumab/pembrolizumab) after the date 
of last administration of study treatment
3. post-treatment period: starting at day 131 after the date of last administration of study 
treatment
Safety summaries (tables, figures) and summaries of on-treatment death include only data from 
the on-treatment period with the exception of baseline data which will also be summarized 
where appropriate (e.g. change from baseline summaries). In addition, a separate summary for 
death including on treatment and post treatment deaths will be provided. In particular, summary 
tables for adverse events (AEs) will summarize only on-treatment events, with a start date 
during the on-treatment period (treatment-emergent AEs).  
An on-treatment assessment is defined as any assessment performed after the date of first
administration of study treatment i.e. assessments performed in the following time interval
(including the lower and upper limits): from date of first administration of study treatment +1 
up to 130 days after the date of last administration of study treatment. 


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In case at time of the analysis, the date of last administration of study treatment is missing, on-
treatment adverse event/assessment include any adverse event/assessment recorded in the 
database which occur after the start date of the study treatment.
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged.
2.1.3.11 Windows for multiple assessments 
Time windows will be defined for descriptive summary of ECOG performace status data by 
visit and longitudinal data analysis. If more than one assessment is available in the same time 
window, the assessment closest to the planned date will be considered. If two assessments are 
obtained with the same time difference compared to the scheduled visit day, the assessment 
obtained prior to visit will be considered. 
Table 2-1
Time windows for ECOG performance status
Time Window
Planned Visit Timing 
Time Window Definition
Treatment phase
Baseline
On or before Study Day 1*
≤ Study Day 1
Week 3
Study Day 22
Study Days 2 to end of treatment 
visit date^ + 7
“Note: EOT visit data will be 
included if obtained within 7 days 
after EOT visit”
Safety follow-up
Safety follow-up 1
26 days from EOT
[end of treatment visit date + 8;
end of treatment visit date + 52]
Safety follow-up 3
78 days from EOT
[end of treatment visit date + 53; 
end of treatment visit + 104]
Safety follow-up 5
130 days from EOT
[end of treatment visit date + 105; 
end of treatment visit + 156]
* Study Day 1 = randomization date
^ Use end of treatment disposition date if EOT visit date is not available
2.1.3.12 Last contact date 
The last contact date will be derived for subjects not known to have died at the analysis cut-off 
using the last complete date among the following:
Table 2-2
Last contact date data sources
Source data
Conditions
Date of Randomization 
No condition
Start/End dates from further antineoplastic 
therapy
Non-missing medication/procedure term.
Start/End dates from drug administration record
Non-missing dose. Doses of 0 are allowed.


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Source data
Conditions
End of treatment date from end of treatment page
No condition
Safety follow-up visit date
If the visit is completed and the patient doesn’t die 
before the visit
Surgery date from surgery page
“Was a Surgery Performed?” marked as ‘Yes’
Laboratory/PK collection dates
Sample collection marked as ‘done’. 
Vital signs date
At least one non-missing parameter value
Performance Status date
Non-missing performance status
Start/End dates of AE 
Non-missing verbatim term
Imaging assessment date
Imaging marked as done
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date. The cut-off date will not be used for last contact date, unless the subject was 
seen or contacted on that date. No date post cut-off date will be used. Imputed dates (e.g.
the analysis cut-off date programmatically imputed to replace the missing end date of a dose
administration record) will not be used to derive the last contact date. 
2.2
Analysis sets
Full Analysis Set (FAS)
The FAS comprises all subjects to whom study treatment has been assigned by randomization. 
According to the intent to treat principle, subjects will be analyzed according to the treatment 
and strata, to which they have been assigned to during the randomization procedure.
Safety Set
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received, either canakinumab and/or 
pembrolizumab, where treatment received is defined as the randomized treatment if the subject 
took at least one dose of that treatment or the first treatment received if the randomized 
treatment was never received.
Pharmacokinetic analysis set (PAS)
The PAS consists of all subjects who received at least one dose of study drug and have at least 
one evaluable PK sample. The PAS will be defined for canakinumab and pembrolizumab 
separately.
The canakinumab pharmacokinetic analysis set (PAS-canakinumab) includes all subjects 
who provide at least one evaluable canakinumab PK concentration. For a concentration to be 
evaluable, subjects are required to:

Receive at least one dose of canakinumab prior to sampling except C1D1 pre-dose sample


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
Have pre-dose samples drawn prior to the 2nd dose of canakinumab

Receive 200 mg of canakinumab prior to post-dose PK sampling

It is collected (except for cycle 1 day 1) between 16 days (384 hours) and 26 days (624 
hours) after the last 200 mg canakinumab dose administration
The pembrolizumab pharmacokinetic analysis set (PAS-pembrolizumab) includes all 
subjects who provide at least one evaluable pembrolizumab PK concentration. For a 
concentration to be evaluable, subjects are required to:
For pre-dose sample:

It is collected before the next dose administration

It is collected (except for cycle 1 day 1) between 16 days (384 hours) and 26 days (624 
hours) after the last 200 mg pembrolizumab dose administration
For post-dose sample:

Received 200 mg of pembrolizumab prior to post-dose PK sampling

For end-of-infusion samples, have the sample collected within 2 hours post end of 
infusion
Subject Classification: 
Subjects may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules defined in Table 
2-3. 
Table 2-3
Subject classification based on protocol deviations and non-PD 
criteria
Analysis set
Protocol deviations leading 
to exclusion
Non protocol deviation leading to 
exclusion
FAS
No written informed consent
Not applicable
Safety Set
No written informed consent
No dose of any component of study 
treatment
PAS-canakinumab
No written informed consent
See definition of PAS-canakinumab
PAS-pembrolizumab
No written informed consent
See definition of PAS-pembrolizumab
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis. The date on which a subject
withdraws full consent is recorded in the eCRF. 
Additional data for which there is a separate informed consent, e.g. PK, biomarker etc., 
collected in the clinical database without having obtained that consent will not be included in 
the analysis. These data will be excluded by the presence of the appropriate protocol deviation 
criterion.




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Diagnosis and extent of cancer 
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will 
include the following: primary site of cancer, predominant histology/cytology, additional 
histology/cytology, stage at initial diagnosis, time since initial diagnosis, stage at time of study 
entry and other relevant information if collected.
Medical history
Relevant medical histories and current medical conditions at baseline will be summarized and 
listed by treatment arm. The summaries will be presented by primary system organ class (SOC), 
preferred term (PT) and treatment arm. Medical history and current medical conditions will be
coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The 
MedDRA version used for reporting will be specified in the CSR and as a footnote in the 
applicable tables/listings.
Other
All data collected at baseline (e.g., other informed consent than main study informed consent) 
will be listed.
Subject disposition
The number (%) of randomized subjects included in the FAS will be presented by treatment 
arm. The number (%) of screened and not-randomized subjects and the reasons for screening 
failure will also be displayed. The number (%) of subjects in the FAS who are still on treatment, 
who discontinued the study phases and the reason for discontinuation will be presented overall 
and by treatment arm.
The following summaries will be provided (with % based on the total number of FAS subjects):

Number (%) of subjects who were randomized (based on data from IRT system)

Number (%) of subjects who were randomized but not treated (based on ‘DAR’ 
eCRF page not completed for any study treatment component)

Primary reason for not being treated (based on “Treatment disposition” eCRF page)

Number (%) of subjects who were treated (based on ‘DAR’ eCRF pages of each 
study treatment component completed with non-zero dose administered)

Number (%) of subjects who are still on-treatment (based on the ‘Treatment 
disposition’ page not completed); 

Number (%) of subjects who discontinued the study treatment phase (based on the 
‘Treatment disposition’ page) 

Primary reason for study treatment phase discontinuation (based on the ‘Treatment 
disposition’ page)

Number (%) of patients who are still in the safety follow-up phase  (based on 
presence of the ‘Treatment disposition’ page and absence of the‘ Study 
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
Number (%) of patients who discontinued from safety follow-up phase (based on 
completion of ‘Study disposition’ page)

Primary reasons for discontinuation from safety follow-up phase (based on 
discontinuation reasons entered under ‘Subject Status’ in the ‘Study 
discontinuation’ page).
Protocol deviations
The number (%) of subjects in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the edit-check specification) overall and by treatment arm
for the FAS. All protocol deviations will be listed.
In addition to the pre-defined standard PD terms, Novartis has also defined 6 new protocol 
deviations and the corresponding relationship (health status related vs. site lockdown, patient 
concerns, etc.) to the COVID-19 pandemic in line with “FDA Guidance on Conduct of Clinical 
Trials of Medical Products during COVID-19 Public Health Emergency” (March 2020) and 
“Guidance on the management of clinical trials during the COVID-19 (coronavirus) pandemic” 
(April 2020) from EMA as listed below. Two additional study specific PDs are also defined to 
capture treatment delay/interruption and MPR Assessment missed due to COVID-19. The 
following deviations related to the COVID-19 pandemic will be summarized. 

Missing visits

Changes in procedures and assessments

Planned visits not done at sites

Changes in drug supply method

Treatment not given

Patient discontinuation due to COVID-19 situation

Treatment delayed/interrupted

MPR Assessment missed due to COVID-19
A cross-tabulation of COVID-19 related PD vs. corresponding relationship will also be 
produced by treatment arm.
Analysis sets
The number (%) of subjects in each analysis set will be summarized by treatment arm and 
randomization stratum. Reasons for exclusion of patients from analysis sets will be tabulated 
separately overall and by treatment arm.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure, cumulative dose, dose intensity (DI) and relative dose intensity (RDI)
will be summarized by treatment arm. The number (%) of subjects with interruptions, 
discontinuation and the corrresponding reasons, will be summarized and listed. 
The safety set will be used for all summaries and listings of study treatment. 


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Duration of exposure to study drug
Duration of exposure to study drug (canakinumab and pembrolizumab) is defined as
Duration of exposure (days) = (last date of exposure to study drug) – (date of first administration 
of study drug) + 1
Duration of exposure to study treatment
Duration of exposure to study treatment is the same as the duration of exposure to study drug 
for 
Canakinumab 
only 
and 
Pembrolizumab 
only 
treatment 
arms. 
For 
Canakinumab+Pembrolizumab arm, duration of exposure to study treatment is derived by 
taking into account the duration of exposure to each study drug:
Duration of exposure (days) = (last date of exposure to study treatment) – (date of first 
administration of study treatment) + 1
The duration includes the periods of temporary interruption except for the last one, a dose 
interruption occurring after the last date of exposure to study drug won’t be considered. ‘Date 
of first administration of study drug/treatment’ and ‘last date of exposure to study 
drug/treatment’ are defined in Section 2.1.3.
Duration of exposure to study drug/treatment will be summarized using descriptive statistics 
(mean, standard deviation etc).
Cumulative dose
Cumulative dose for any component of study treatment is defined as the total dose of the 
medication given during the study treatment exposure.
Cumulative dose will be summarized using descriptive statistics by treatment arm for each 
component of study treatment. For subjects who do not receive any drug the cumulative dose 
will be set to zero.
The cumulative dose is defined according to the type of dosing schedule and is calculated from 
the DAR eCRF. 
The cumulative dose for canakinumab and pembrolizumab is defined based on the days when 
the subject is assumed to have taken a non-zero dose during dosing periods. 
Dose intensity and relative dose intensity
Dose intensity (DI) for subjects with non-zero duration of exposure is defined as follows: 
DI (dosing unit / cycle) = Actual Cumulative dose (dosing unit) / (last dose date-first dose 
date+dose interval) *21 (days/cycle).
For canakinumab, dose interval is 21 days. For pembrolizumab, dose interval is 21 days.
For subjects who did not take any drug the DI is by definition equal to zero. 
Planned dose intensity (PDI) is defined as follows:

for canakinumab, PDI is 200mg/cycle; 


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
for pembrolizumab, PDI is 200mg/cycle.
Relative dose intensity (RDI) is defined as follows:
RDI = DI (dosing unit / cycle)  / PDI (dosing unit / cycle) * 100%.  
For canakinumab and pemborolizumab, the dosing unit is mg. DI and RDI will be summarized 
for each of the study drug (canakinumab and pembrolizumab) by treatment arm using 
descriptive summaries. In addition, categorical summary of RDI for each study drug will be 
presented. The number of administrations of each study drug component of the study treatment 
will be summarized.
Dose interruptions or permanent discontinuations
The number of subjects who have dose interruptions and permanent discontinuations and the
corresponding reasons, will be summarized separately for each of the study treatment
components. The duration of the interruption will also be summarized by descriptive statistics. 
‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the Dosage 
Administration CRF pages (DAR) will be used to determine the dose interruptions, and 
permanent discontinuations, respectively. The corresponding fields ‘Reason for dose 
interrupted’ and ‘Reason for permanent discontinuation’ will be used to summarize the reasons.
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive days, then it will be counted as one interruption. 
2.4.2
Prior, concomitant and post treatment therapies
Post treatment anti-cancer therapy
Given neoadjuvant setting, no prior antineoplastic therapies are allowed.
Antineoplastic medications since discontinuation of study treatment will be summarized by
Anatomical Therapeutic Chemical (ATC) class, preferred term and treatment arm. 
Separate listings will be produced for anti-neoplastic medications, radiotherapy, and surgery 
since discontinuation of study treatment. 
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD). 
Details regarding WHO-DD version will be included in the footnote in the tables/listings. 
The above analyses will be performed using the FAS.
Concomitant therapy
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapy include medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study treatment 
and continuing after the start date of study treatment. 


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Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference  Listing  (DRL)  dictionary  that  employs  the  WHO  ATC classification system and 
summarized by lowest ATC class, preferred term and treatment arm using frequency counts and 
percentages. Surgical and medical procedures will be coded using MedDRA and summarized 
by SOC, preferred term and treatment arm. These summaries will include:
1. Medications starting on or after the start of study treatment but no later than 130 days 
after start of last dose of study treatment and
2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment.
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study treatment or starting more than 130 days after the last date of study 
treatment will be flagged in the listing. The safety set will be used for all concomitant 
medication tables and listings.
2.5
Analysis of the primary objective
The primary objective of the study is to assess the MPR rate (≤ 10% residual viable tumor) per 
central review at the time of surgery in canakinumab alone and in combination with 
pembrolizumab treatment arms.
2.5.1
Primary endpoint
The primary endpoint is MPR rate, defined as the percentage of subjects with ≤ 10% residual 
viable cancer cells. MPR will be assessed in FAS per central review. 
2.5.2
Statistical hypothesis, model, and method of analysis
The primary estimand will be described by the following five attributes:
1. The target population is defined as all randomized patients who are histologically 
confirmed NSCLC stage IB-IIIA (per AJCC 8th edition), deemed suitable for primary 
resection by treating surgeon, except for N2 and T4 tumors.
2. The primary variable is the percentage of subjects with a major pathological response 
(defined as ≤ 10% residual viable cancer cells per central review). Any patient who 
has >10% residual viable cancer cells, or starts new antineoplastic therapy prior to 
surgery, or does not have the surgery performed, or has the surgery performed but with 
unevaluable MPR result, is considered as a non-responder.
3. The study treatment is canakinumab as monotherapy or in combination with 
pembrolizumab.
4. The intercurrent events of interest in this study are: start of new antineoplastic therapy 
prior to surgery and discontinuation of study treatment prior to surgery. These intercurrent 
events will be addressed as follows:
a. Start of new antineoplastic therapy prior to surgery: subject will be considered as 
non-responder (composite strategy)
b. Discontinuation of study treatment prior to surgery: subject will be included in the 
analysis regardless of this intercurrent event (treatment-policy strategy).


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5. The summary measure is MPR rate with its corresponding two-sided exact binomial 
95% confidence interval (Clopper CJ and Pearson ES (1934).  The use of confidence or 
fiducial limits illustrated in the case of the binomial.  Biometrical, 26, 404-413.) in 
canakinumab alone arm and canakinumab in combination with pembrolizumab arm.
A MPR of approximately 20% can be achieved using chemotherapy (Pataer 2012 et al). For 
canakinumab alone arm, a 10% absolute improvement in the MPR to 30% is considered a 
clinically meaningful minimum improvement in this study population. Therefore, proof of 
efficacy in canakinumab alone arm will be declared if both of the following conditions are met:
•
the mean of the posterior distribution of MPR is at least 30% and
•
the posterior probability that the MPR is ≥ 20% is at least 90%
For the combination of canakinumab and pembrolizumab treatment arm, a 25% absolute 
improvement in the MPR to 45% is considered a clinically meaningful minimum improvement 
in this study population. Therefore, proof of efficacy in the combination treatment arm will be 
declared if both of the following conditions are met:
•
the mean of the posterior distribution of MPR is at least 45% and
•
the posterior probability that the MPR is ≥ 30% is at least 90%
The posterior distribution of MPR will be derived from the prior distribution and all available 
data from the subjects in the FAS. A minimally informative unimodal Beta prior 
(Neuenschwander et al 2008) Beta(3/7, 1) and Beta(9/11, 1) will be used for canakinumab 
monotherapy and canakinumab in combination with pembrolizumab, respectively. Please refer 
to Section 5.4.1 for details of prior distribution. The posterior mean of MPR will be calculated
and the MPR rate with its corresponding two-sided exact binomial 95% confidence interval 
(Clopper CJ and Pearson ES (1934)) will be estimated in both the canakinumab monotherapy
arm and canakinumab in combination with pembrolizumab arm. The posterior probability that 
MPR>= 20% and the posterior probability that MPR>= 30% will be calculated for canakinumab 
monotherapy arm and canakinumab in combination with pembrolizumab arm, respectively.
Waterfall plot for percentage of residual viable tumor based on central review in canakinumab 
monotherapy arm and canakinumab in combination with pembrolizumab arm will be generated.
2.5.3
Handling of missing values/censoring/discontinuations
Refer to Section 2.5.2 for details on handling of intercurrent events. Subjects who have an
unknown MPR status due to surgery not being performed (including lost to follow-up or 
withdrawal of study consent before surgery) or due to unevaluable MPR results will be 
considered as non-responders when estimating MPR rate.
2.5.4
Supportive analyses
Additional supportive analysis for the primary analysis of MPR rate will be conducted by using 
an alternative strategy in handling of the intercurrent events.
The target population, study treatment, the primary variable and the summary measure will be 
the same as for the primary estimand except for handling of the intercurrent event of starting 
new antineoplastic therapy prior to surgery. Subjects will be included in the analysis for MPR


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regardless of this intercurrent event (treatment-policy strategy). Same analyses will be done as 
for the primary estimand.
2.6
Analysis of secondary efficacy objective(s)
The secondary efficacy objectives are to:

To assess the MPR rate at the time of surgery
a) in the randomized pembrolizumab monotherapy arm based on central review
b) in all three randomized treatment arms based on local review 
c) to estimate the difference in MPR and posterior probability that the difference 
in MPR is ≥ 10% between the randomized canakinumab + pembrolizumab 
combination arm and randomized pembrolizumab monotherapy arm based on 
central review

To assess overall response rate in randomized subjects treated with canakinumab 
or pembrolizumab as monotherapy and in combination based on local review on 
the EOT visit

To assess surgical feasibility rate in each treatment arm based on randomized 
subjects
2.6.1
MPR rate
MPR rate (1) based on local review in all 3 treatment arms and (2) based on central review in 
pembrolizumab monotherapy arm will be assessed in the same patient population as the primary 
estimand. The intercurrent events and the strategy for handling intercurrent events will be the 
same as primary estimand.
MPR rate for all the above specified analyses will be summarized by treatment arm along with 
the two-sided exact binomial 95% confidence interval (Clopper and Pearson 1934). Waterfall 
plot for percentage of residual viable tumor based on central review in pembrolizumab arm will 
be generated.
The difference in MPR rate between canakinumab in combination with pembrolizumab and 
pembrolizumab single agent arm along with the two-sided exact 95% confidence interval based 
on Chan and Zhang (1999) will be summarized based on central review using the same patient 
population used in the primary analysis, including the strategy for handling intercurrent events.
The posterior probability that the difference is 10% or greater in MPR rate will also calculated 
in the following way: first, sampling from posterior distribution of MPR rate for each arm; then, 
calculating the sampling differences and probability that the difference is 10% or greater 
between the two arms. The minimal informative Beta prior Beta(9/11, 1) and Beta(3/7, 1) will 
be used for canakinumab in combination with pembrolizumab arm and pembrolizumab single 
agent arm, respectively. 


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2.6.2
Overall response rate (ORR)
ORR is defined as the percentage of subjects in FAS with a best overall response of CR or PR, 
as per local review. The best overall response will be the observed response at the assessment 
performed on the EOT visit prior to surgery. ORR will be evaluated according to RECIST 1.1.
Patients with a best overall response (BOR) of ‘Unknown’ per RECIST 1.1 will be considered 
as non-responders when estimating ORR. ORR and two-sided exact binomial 95% confidence 
interval (Clopper and Pearson 1934) will be presented by treatment group.
The BOR will be determined from response assessments undertaken while on treatment. In 
addition, only tumor assessments performed before the start of any further anti-neoplastic 
therapies will be considered in the assessment of BOR. A new anticancer therapy is defined as 
any secondary anticancer therapy (either systemic treatments, radiotherapy or surgery) received 
during or post study treatment. 
2.6.3
Surgical Feasibility Rate
Surgical feasibility rate is defined as the percentage of subjects in FAS who undergo surgery 
following study treatment. Surgical feasibility rate and two-sided exact binomial 95% 
confidence interval (Clopper and Pearson 1934) will be presented by treatment group.
2.7
Secondary objective: safety analyses
All safety analyses will be performed based on the Safety Set and will be presented by treatment
arm unless specified otherwise. 
2.7.1
Adverse events (AEs)
AE summaries will include all AEs occurring during on treatment period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study treatment, AE outcome etc. AEs with start date outside of on-treatment 
period will be flagged in the listings.
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT)
using MedDRA coding by treatment arm. A subject with multiple occurrences of an AE will be 
counted only once in the respective AE category. A subject with multiple CTCAE grades
(version 5.0) for the same preferred term will be summarized under the maximum CTCAE 
grade recorded for the event. AE with missing CTCAE grade will be included in the ‘All grades’ 
column of the summary tables.
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the canakinumab monotherapy arm.
The following adverse event summaries will be produced by treatment arm:
•
Overview of adverse events and deaths
•
AEs by SOC and PT (all AEs and AEs related to at least one study drug component)


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•
AEs by PT (all AEs and AEs related to at least one study drug component) and 
maximum CTC grade
•
AEs leading to permanent discontinuation of one of the study drug component, AEs 
leading to canakinumab permanent discontinuation
•
AEs leading to dose interruption
•
AEs requiring additional therapy
•
SAEs (all SAEs and SAEs related to at least one study drug component) and SAEs 
leading to fatal outcome.
•
Summary of SAEs and non-SAEs with number of occurrences (an occurrence is 
defined as >1 day between start and prior end date of record of same preferred term).
2.7.1.1
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
An adverse event of special interest (AESI) is a grouping of adverse events that are of scientific 
and medical concern specific to compound canakinumab. These groupings are defined using 
MedDRA terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), 
HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA 
queries, NMQ) may also be used. A NMQ is a customized group of search terms which defines 
a medical concept for which there is no official SMQ available or the available SMQ does not 
completely fit the need. It may include a combination of single terms and/or an existing SMQ, 
narrow or broad. The groups are defined according to the MedDRA terms defined in the 
program Case Retrieval Strategy (CRS) document and will be summarized. The latest version 
of the CRS document available at the time of the analyses will be used. For each specified AESI, 
number and percentage of patients with at least one event of the AESI occurring during on 
treatment period will be summarized.
Summaries of these AESIs will be provided by treatment arm, (specifying grade, SAE, 
relationship, leading to treatment discontinuation, leading to dose interruption, hospitalization, 
death etc.).
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated.
AESI groupings are specified in the electronic Case Retrieval Strategy (eCRS). The latest 
version of the eCRS available at the time of the analysis will be used
2.7.2
Deaths
Separate summaries for on-treatment and all deaths will be produced by treatment arm, system 
organ class and preferred term. 
All deaths will be listed, and post treatment deaths will be flagged. A separate listing of deaths 
prior to starting treatment will be provided for all screened subjects.
2.7.3
Laboratory data
When analyzing laboratory related date, all sources (central and local laboratories) will be 
combined. The summaries will include all assessments available for the laboratory parameters
collected no later then 130 days after the last study treatment administration date (see Section 


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2.1.3). Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0.
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment):

Worst post-baseline CTC grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline.

Shift tables using CTC grades to compare baseline to the worst on-treatment value (hypo 
and hyper worst grade will be summarized separately if applicable)

For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-treatment
value.

If there are multiple assessments as baseline candidate, the central lab assessment will be 
defined as “baseline”. If there are multiple assessments from the central lab or the local lab, 
the worst assessment will be defined as “baseline.” 
The following listings will be produced for the laboratory data:

Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.  

Listing of all CTC grade 3 or 4 laboratory toxicities
Liver function parameters
Liver function parameters of interest are total bilirubin (TBL), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of patients with worst post-baseline values as per 
Novartis Liver Toxicity guidelines will be summarized by treatment arm:
The following summaries will be produced:

ALT > 3xULN 

ALT > 5xULN

ALT > 10xULN

ALT > 20xULN

AST > 3xULN 

AST > 5xULN

AST > 10xULN

AST > 20xULN

ALT or AST > 3xULN 

ALT or AST > 5xULN

ALT or AST > 8xULN

ALT or AST > 10xULN


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
ALT or AST > 20xULN

Total bilirubin (BILI) > 2xULN

Total bilirubin (BILI) > 3xULN
AST and ALT =< ULN at baseline

ALT or AST > 3xULN & BILI > 2xULN

ALT or AST > 3xULN & BILI > 2xULN & ALP ≥ 2xULN

ALT or AST > 3xULN & BILI > 2xULN & ALP < 2xULN
AST and ALT > ULN at baseline

Elevated ALT or AST > 3xULN & BILI (>2x Bsl or 2x ULN)

Elevated ALT or AST > 3xULN & BILI (>2x Bsl or 2x ULN) & ALP ≥ 2xULN

Elevated ALT or AST > 3xULN & BILI (>2x Bsl or 2x ULN) & ALP < 2xULN
Elevated AST or ALT defined as: >3x ULN if =< ULN at baseline, or (>3x Bsl or 8x 
ULN) if > ULN at baseline.
In addition, a listing of all BILI, ALT, AST and ALP values for subjects with a post-baseline 
BILI > 2xULN, ALT> 3xULN or AST > 3xULN will be provided.  
2.7.4
Other safety data
2.7.4.1
ECG and cardiac imaging data
A listing of all ECG assessments will be produced by treatment arm.
2.7.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), 
respiratory rate (breaths per minute), pulse rate (beats per minute), supine systolic and diastolic 
blood pressure (mmHg).
Data handling
Vital signs collected on treatment will be summarized. Values measured outside of on treatment 
period will be flagged in the listings.
Data analysis
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-4
below.


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Table 2-4
Clinically notable changes in vital signs
Vital sign 
(unit)
Clinically notable criteria
above normal value 
below normal value
Weight (kg)
increase > 10% from Baseline
decrease  > 10% from Baseline
Systolic blood 
pressure 
(mmHg)
>=180 with increase from baseline 
of >=20
<=90 with decrease from baseline 
of >=20
Diastolic blood 
pressure 
(mmHg)
>=105 with increase from baseline 
of >=15
<=50 with decrease from baseline 
of >=15
Respiratory 
rate (bpm)
< 12
> 25
Pulse rate 
(bpm)
>=100 with increase from baseline 
of >25%
<=50 with decrease from baseline of 
> 25%
Body 
temperature
>= 39.1
-
The number and percentage of subjects with notable vital sign values (high/low) will be 
presented  by treatment arm.         
A listing of all vital sign assessments will be produced by treatment arm and notable values will 
be flagged. In the listing, the assessments collected outside of on-treatment period will be 
flagged. 
2.7.4.3
ECOG performance status
The performance status will be assessed according to the Eastern Cooperative Oncology Group 
(ECOG) performance status scale, ranging from 0 to 5, as specified in Table 2-5 below.
Table 2-5
ECOG Performance Scale
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than  50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
Time window for ECOG PS are defined in Table 2-1 . If the closest assessment to the target 
date has two or more ECOG filled out on the same date, then the worst ECOG PS value will be 
used.
Time windows are applicable for descriptive summary of ECOG data by visit only.


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Frequency counts and percentages of patients in each score category will be provided by 
treatment arm and time point. 
2.7.4.4
Other safety data
Other safety data (e.g. data relating to liver events) will be listed in the safety set.
Data from other tests will be listed, notable values will be flagged, and any other information 
collected will be listed as appropriate.
All assessments collected later than 130 days after the last treatment date will be flagged in the 
listings.
Any statistical tests performed to explore the data will be used only to identify any interesting 
comparisons that may warrant further consideration.
2.8
Secondary objective: Pharmacokinetic endpoints
Pharmacokinetic data analyses will be performed for canakinumab and pembrolizumab 
concentrations. The following analyses are for canakinumab concentrations. They are also 
applicable and will be repeated for pembrolizumab concentrations.
PAS-canakinumab and PAS-pembrolizumab will be used in the pharmacokinetic data analysis 
for canakinumab and pembrolizumab concentrations, respectively.
PK concentrations 
Descriptive statistics (n, m (number of non-zero concentrations), arithmetic mean, CV% mean, 
SD, median, geometric mean, CV% geo-mean, minimum and maximum) for canakinumab 
concentration will be presented at each scheduled time point for the PAS-canakinumab.
Individual concentration-time profiles for canakinumab evaluable concentrations with median 
will be displayed graphically for PAS-canakinumab on the semi-log view. In addition, the mean 
(+/- SD) and geometric mean concentration-time profiles for canakinumab over time will be 
displayed graphically for PAS-canakinumab on the linear and semi-log view.
All individual plasma canakinumab concentration data will be listed by treatment using the FAS.
Handling of PK data below LLOQ or missing
All concentration values below the lower limit of quantitation (LLOQ) are set to zero by the 
Bioanalyst, and will be displayed in the listings as zero and flagged. LLOQ values will be 
treated as zero in any calculations of summary statistics, and treated as missing for the 
calculation of the geometric means and their CV%. The number of non-zero concentrations will 
also be reported in the summary statistics.
Missing values for any PK data will not be imputed and will be treated as missing.
Population pharmacokinetic analysis
If there is adequate amount of data, a mixed-effects model may be applied to the serum 
canakinumab concentration-time data from this study along with other studies to generate post-
hoc estimates of pharmacokinetic parameters using NONMEM to characterize canakinumab 




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Table 2-6
Scheduled sample biomarker summary table for secondary 
 
 objectives
Biomarker
Time point
Sample
Key IHC (e.g., PD-L1, 
CD8) and other tissue 
immune markers
Baseline biopsy and resection
Tissue
hs-CRP
Cycle 1 Day 1 (pre-dose)
Cycle 2 Day 1 (pre-dose)
EOT
Safety follow-up 1
Safety follow-up 3
Safety follow-up 5
Blood (serum)
Cytokine panel testing, 
including hs-IL-6
Cycle 1 Day 1 (pre-dose)
Cycle 2 Day 1 (pre-dose)
EOT
Safety follow-up 1
Safety follow-up 3 (only hs-IL-6)
Safety follow-up 5 (only hs-IL-6)
Blood (plasma)
Relationship between key blood/tissue based biomarker and MPR 
The relationship between key IHC markers (PD-L1, CD8), key cytokines (hs-CRP and hs-IL-
6) assessed at baseline, and MPR will be explored. MPR based on the following pre-defined 
baseline biomarker subgroups will be explored. The estimated and its 95% confidence interval 
of MPR in each subgroup, will be summarized and plotted.

PD-L1 level (<1% vs.  1%-49% vs. ≥50%)

hsCRP level (<2mg/L vs. ≥2mg/L)

hsCRP level (<10mg/L vs. ≥10mg/L)

hsCRP level (<50 mg/L vs. ≥50 mg/L)

hsCRP level (<Q1 vs. ≥Q1 and <Q2 vs. ≥Q2 and<Q3 vs. ≥Q3)

hs-IL-6 level (<Q1 vs. ≥Q1 and <Q2 vs. ≥Q2 and <Q3 vs. ≥Q3)

CD8 level (<median vs. ≥median)

CD8 level (<3% vs. >= 3%)
Quartile of the biomarker concentration is defined as:

<Q1: <25th percentile


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
≥Q1 to <Q2: ≥25th percentile and <50 percentile

≥Q2 to <Q3: ≥50th percentile and <75th percentile

≥Q3: ≥75th percentile
Additional cutoff might be explored if clinically indicated. 
MPR will be summarized by treatment arm and subgroup along with the two-sided exact 
binomial 95% confidence interval (Clopper and Pearson 1934). 
In addition, baseline and changes from baseline for the IHC markers and cytokines (absolute 
change, percent change and fold change) at each time point will be summarized by MPR status 
and for all subjects in tables that include sample size, mean, standard deviation, CV%, median, 
minimum and maximum. For fold change from baseline, geometric mean and geometric CV% 
will also be included.
In addition, association between MPR and time profiles of key IHC markers (PD-L1, CD8) 
and key cytokines (hs-CRP and hs-IL-6) will be displayed graphically by the MPR status and
for all subjects.


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2.12
Interim analysis
Not applicable
3
Sample size calculation
3.1
Primary analysis
A MPR of approximately 20% can be achieved using chemotherapy (Pataer 2012 et al). A 10% 
absolute improvement to 30% and a 25% absolute improvement to 45% in MPR rate are 
considered clinically meaningful minimum improvement in canakinumab alone arm and 
canakinumab in combination with pembrolizumab arm, respectively.
Approximately 110 subjects  will be randomized in a 2:2:1 ratio to one of the treatment arms 
(canakinumab alone or canakinumab in combination with pembrolizumab or pembrolizumab 
alone). The proof of efficacy in each treatment arm will be determined by Bayesian double 
criteria.
Among the 44 subjects randomized to canakinumab single agent treatment, at least 14
responders are needed to meet the proof of efficacy criteria. When the true MPR rate is ≤ 20%, 
the probability of erroneously declaring proof of efficacy is at most 4.4%, while the probability 
of declaring proof of efficacy is at least 89.8% for MPR ≥ 40% (Table 3-1). 
Among the 44 subjects randomized to the canakinumab and pembrolizumab combination 
treatment, at least 20 responders are required to meet the proof of efficacy criteria. When the 
true MPR rate is ≤ 30%, the probability of erroneously declaring proof of efficacy is at most 
2.1% while the probability of declaring proof of efficacy is at least 92.2% for MPR ≥ 55% 
(Table 3-2). Assuming an enrollment rate of 6 subjects per month, the enrollment will be 
completed at approximately 18 months and MPR assessment for the last patient randomized 
will occur at approximately 20 months from the date of first subject randomized in the study.
Table 3-1
Operating characteristics with 44 subjects randomized to
canakinumab treatment arm
True MPR
Probability of declaring proof 
of efficacy (12 or more 
responders)
Probability of missing proof 
of efficacy (11 or less 
responders)
20%
4.4%
95.6%
30%
45.2%
54.8%


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True MPR
Probability of declaring proof 
of efficacy (12 or more 
responders)
Probability of missing proof 
of efficacy (11 or less 
responders)
40%
89.8%
10.2%
50%
99.5%
0.5%
Table 3-2
Operating characteristics with 44 subjects randomized to the 
canakinumab + pembrolizumab combination treatment arm
True MPR
Probability of declaring proof 
of efficacy (20 or more 
responders)
Probability of missing proof 
of efficacy (19 or less 
responders)
30%
2.1%
97.8%
40%
27.7%
72.3%
45%
53.4%
46.6%
55%
92.2%
7.8%
4
Change to protocol specified analyses
Not applicable.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
No imputation of the start date of infusion/injection or end date for infusion will be applied. 
Complete dates are required as per eCRF.
5.1.2
AE, ConMeds and safety assessment date imputation
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS)
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY


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Missing 
Element
Rule
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment start date 
then 15MONYYYY  
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided. 
5.1.2.1
Other imputations
Not applicable
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). 
5.3
Laboratory parameters derivations
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. The criteria to assign CTCAE grades are given in Novartis internal criteria 
for CTCAE grading of laboratory parameters. The latest available version of the document 
based on the underlying CTCAE version 5.0 at the time of analysis will be used. For laboratory 
tests where grades are not defined by CTCAE version 5.0, results will be graded by the 
low/normal/high (or other project-specific ranges, if more suitable) classifications based on 
laboratory normal ranges.
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
For laboratory tests that are graded for both low and high values, summaries will be done 


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separately and labelled by direction, e.g., sodium will be summarized as hyponatremia and 
hypernatremia.
Imputation Rules  
CTC grading for blood differentials is based on absolute values. However,  this data may not 
be reported as absolute counts but rather as percentage of WBC. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula:
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]
In order to apply the above formula, albumin values in g/L will be converted to g/dL by  
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading.
5.4
Statistical models
5.4.1
Primary analysis
The estimate of the response rates (e.g., MPR, ORR, surgical feasibility rate) will be 
summarized in terms of percentage rates with 95% CIs. An exact binomial confidence interval 
(implemented using SAS procedure FREQ with EXACT statement for one-way tables) will be 
calculated (Clopper and Pearson 1934).
SAS procedure FREQ will be used to estimate the proportion of responders, along with the 
associated 95% two-sided exact binomial CI. The difference in MPR rate along with the two-
sided exact 95% confidence interval based on Chan and Zhang (1999) can be obtained by using 
“exact” statement. 
Calculation of posterior probability 
The criteria for proof of efficacy are:
•
the mean of the posterior distribution of MPR is at least 30% and
•
the posterior probability that the MPR is ≥ 20% is at least 90%
for canakinumab single agent arm and
•
the mean of the posterior distribution of MPR is at least 45% and


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•
the posterior probability that the MPR is ≥ 30% is at least 90%
for canakinumab and pembrolizumab combination arm.
Let p1 denote the MPR rate for canakinumab single agent and follow a beta prior distribution 
Beta(a1,b1), where a1>0, b1>0. Let y1 out of n1 patients reach MPR in canakinumab single agent 
arm. Then the posterior distribution of p1 is Beta(a1+ y1, b1+ n1-y1) (Spiegelhalter et al. 2004).
Similarly, for canakinumkab and pembrolizumab combination arm, the posterior distribtuion of 
p2 is Beta(a2+ y2, b2+ n2-y2). 
A minimally informative unimodal Beta prior (Neuenschwander et al. 2008) will be used. For 
canakinumab single agent arm, the parameters will be chosen so that the mean of the prior 
distribution is equal to 0.3, which corresponds to Beta(3/7, 1). For canakinumab in combination 
with pembrolizumab arm, the parameters will be chosen so that the median of the prior 
distribution is equal to 0.45, which corresponds to Beta(9/11, 1).
The efficacy criteria will be assessed based on the actual number of patients enrolled. For 
example, if the total number of patients in canakinumab is 44, the first efficacy criterion requires 
that at least 14 patients who are MPR responders. In that case, the posterior distribution is
Beta(3/7+14, 1+44-14) and the posterior probability P(MPR rate ≥ 0.2) = 96.5%. 
6
Reference
1. Chan IS, Zhang Z. (1999) Test-based exact confidence intervals for the difference of two 
binomial proportions. Biometrics, 55(4), 1202-1209.
2. Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrical, 26, 404-413.
3. Neuenschwander B, Branson M and Gsponer T (2008). Critical aspects of the Bayesian 
approach to Phase I cancer trials. Statistics in Medicine, 27, 2420-2439.
4. Pataer A, Kalhor N, Correa AM, et al (2012) Histopathologic response criteria predict 
survival of patients with resected lung cancer after neoadjuvant chemotherapy. J Thorac 
Oncol p. 825-32.
5. Spiegelhalter DJ, Abrams KR and Myles JP (2004). Bayesian Approaches to Clinical 
Trials and Health-care Evaluation. Chichester, Wiley.