Conditions: Non-Small-Cell Lung
Keywords: ACZ885 canakinumab docetaxel NSCLC Non Small Cell Lung Cancer Carcinoma IL-1β PD-(L)1 CANOPY CANOPY-2 second or third line therapy PD-(L)1 inhibitors platinum-based chemotherapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 245
Healthy volunteers: no

Brief summary:
This study was designed to evaluate the role of canakinumab in combination with docetaxel in subjects with advanced non-small cell lung cancer (NSCLC) previously treated with PD-(L)1 inhibitors and platinum-based chemotherapy.

Detailed description:
This was a multicenter, Phase III study designed to evaluate the efficacy and safety of canakinumab in combination with docetaxel versus placebo in combination with docetaxel, as second- or third-line treatment. The study included adult subjects with advanced NSCLC whose disease had progressed after prior treatment with a PD-(L)1 inhibitor. Subjects had also been pre-treated with platinum-based chemotherapy, either given together with PD-(L)1 inhibitor or sequentially.

The study consisted of 2 parts:

* Part 1: Safety run-in. This part was conducted to confirm the Recommended Phase 3 Regimen (RP3R) of the canakinumab and docetaxel combination. Participants were treated for at least 2 complete cycles of treatment (21 days per cycle) for safety evaluation (DLT-Dose Limiting Toxicities) to define RP3R. Participants from the safety run-in part were treated until any discontinuation criteria were met. After treatment discontinuation, all participants were followed for safety evaluations during the safety follow up period (up to 130 days). Additionally, subjects who discontinued study treatment without prior documented disease progression continued efficacy assessments in the efficacy follow-up phase irrespective of the start of new antineoplastic therapy and until documented progressive disease as per protocol. After the RP3R was determined, enrollment in this part was closed and additional participants were enrolled in the randomized part (part 2) of the study. Ongoing patients from the safety run-in part continued their treatment at the assigned dose level according to the dose and schedule for the safety run-in part.
* Part 2: Randomized part. The randomized, double-blind, placebo-controlled part of the study opened after confirmation of the RP3R for the combination of canakinumab and docetaxel. Participants from the randomized part were treated until any discontinuation criteria were met as per protocol. After treatment discontinuation, all participants were followed for safety evaluations during the safety follow up period (up to 130 days). Additionally, subjects who discontinued study treatment without prior documented disease progression continued efficacy assessments in the efficacy follow-up phase irrespective of the start of new antineoplastic therapy and until documented progressive disease as per protocol.

Based on the lack of efficacy observed in the primary analysis, Novartis decided to halt canakinumab/placebo treatment. Subjects continued to receive docetaxel if they were deriving clinical benefit as per investigator assessment until discontinuation

Arms:
arm 1: Participants were treated with full doses of docetaxel 75mg/m\^2 intravenous and canakinumab 200 mg subcutaneous on Day 1 of each 21-Day cycle (dose level 1). Subjects were assessed for at least 2 complete cycles of treatment (21 days per cycle; a total of 42 days) for safety evaluation (DLT) to define RP3R. De-escalation to canakinumab 200 mg subcutaneous every 6 weeks + docetaxel 75 mg/m\^2, every 3 weeks could also be considered. arm 2: Participants were treated with canakinumab subcutaneous at RP3R and docetaxel at 75 mg/m\^2 every 3 weeks arm 3: Participants were treated with placebo subcutaneous at RP3R and docetaxel at 75 mg/m\^2 every 3 weeks

Interventions: intervention 1: Canakinumab intervention 2: Docetaxel intervention 3: Placebo
Intervention descriptions: intervention 1: Canakinumab, 200 mg, subcutaneous. The initial dose regimen was once every 3 weeks (on Day 1 of each 21-day cycle) intervention 2: Docetaxel 75mg/m\^2, intravenous, administered on Day 1 of each 21-day cycle intervention 3: Placebo, sub-cutaneous, admnistered at the RP3R defined in Part 1-safety run-in.

Protocol document:
Prot_000.pdf: 


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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................14
Amendment 2 (10-Jun-2020) ............................................................................................16
Amendment 00-CN.01 (08-Jul-2019) ...............................................................................18
Protocol summary..............................................................................................................21
1
Introduction .......................................................................................................................25
1.1
Background............................................................................................................25
1.1.1
Overview of disease pathogenesis, epidemiology and current 
treatment................................................................................................25
1.1.2
Introduction to investigational treatment(s) and other study 
treatment(s) ...........................................................................................26
1.1.3
Potential for drug-drug interactions ......................................................28
1.2
Purpose ..................................................................................................................28
2
Objectives and endpoints...................................................................................................28
3
Study design ......................................................................................................................29
4
Rationale............................................................................................................................34
4.1
Rationale for study design .....................................................................................34
4.1.1
Rationale for choice of background therapy.........................................34
4.2
Rationale for dose/regimen and duration of treatment ..........................................35
4.2.1
PK consideration...................................................................................35
4.2.2
Efficacy and pharmacodynamics (PD) considerations .........................37
4.2.3
Safety consideration..............................................................................37
4.2.4
Consideration for combination with docetaxel .....................................38
4.2.5
Conclusion for dose regimen selection .................................................39
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................39
4.4
Purpose and timing of interim analyses/design adaptations..................................39
4.5
Risks and benefits..................................................................................................39
5
Population..........................................................................................................................40
5.1
Inclusion criteria ....................................................................................................41
5.2
Exclusion criteria...................................................................................................41
6
Treatment...........................................................................................................................45
6.1
Study treatment......................................................................................................45


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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301
6.1.1
Investigational and control drugs..........................................................45
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....................................49
6.3.1
Subject numbering ................................................................................49
6.3.2
Treatment assignment, randomization ..................................................49
6.4
Treatment blinding.................................................................................................50
6.5
Dose escalation and dose modification..................................................................51
6.5.1
Dose confirmation guidelines ...............................................................51
6.5.2
Definitions of dose limiting toxicities (DLTs)......................................53
6.5.3
Dose modifications................................................................................54
6.5.4
Follow-up for toxicities.........................................................................59
6.6
Additional treatment guidance...............................................................................61
6.6.1
Treatment compliance...........................................................................61
6.6.2
Emergency breaking of assigned treatment code..................................61
6.7
Preparation and dispensation.................................................................................62
6.7.1
Handling of study treatment and additional treatment..........................63
6.7.2
Instruction for prescribing and taking study treatment .........................63
7
Informed consent procedures ............................................................................................64
8
Visit schedule and assessments .........................................................................................65
8.1
Screening ...............................................................................................................80
8.1.1
Eligibility screening ..............................................................................80
8.1.2
Information to be collected on screening failures.................................80
8.2
Subject demographics/other baseline characteristics.............................................81
8.3
Efficacy..................................................................................................................81
8.3.1
Survival assessment ..............................................................................81
8.3.2
Tumor assessments................................................................................81
8.3.3
Appropriateness of efficacy assessments..............................................83
8.4
Safety.....................................................................................................................84
8.4.1
Laboratory evaluations..........................................................................84
8.4.2
Determination of tuberculosis status.....................................................86
8.4.3
Performance status ................................................................................86


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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301
8.4.4
Electrocardiogram (ECG) .....................................................................86
8.4.5
Pregnancy and assessments of fertility .................................................87
8.5
Additional assessments..........................................................................................87
8.5.1
Clinical Outcome Assessments (COAs) ...............................................87
8.5.2
Pharmacokinetics ..................................................................................88
90
9
Study discontinuation and completion ..............................................................................91
9.1
Discontinuation......................................................................................................91
9.1.1
Discontinuation of study treatment .......................................................91
9.1.2
Withdrawal of informed consent...........................................................92
9.1.3
Lost to follow-up...................................................................................93
9.1.4
Early study termination by the sponsor.................................................93
9.2
Study completion and post-study treatment ..........................................................93
10 Safety monitoring and reporting........................................................................................94
10.1
Definition of adverse events and reporting requirements......................................94
10.1.1
Adverse events ......................................................................................94
10.1.2
Serious adverse events ..........................................................................96
10.1.3
SAE reporting........................................................................................97
10.1.4
Pregnancy reporting ..............................................................................98
10.1.5
Reporting of study treatment errors including misuse/abuse................98
10.2
Additional Safety Monitoring................................................................................99
10.2.1
Data Monitoring Committee .................................................................99
10.2.2
Steering Committee...............................................................................99
11 Data Collection and Database management....................................................................100
11.1
Data collection.....................................................................................................100
11.2
Database management and quality control..........................................................100
11.3
Site monitoring ....................................................................................................101
12 Data analysis and statistical methods ..............................................................................101
12.1
Analysis sets ........................................................................................................102
12.1.1
Full Analysis Set .................................................................................102
12.1.2
Safety set .............................................................................................102
12.1.3
Dose-determining set ..........................................................................102
12.1.4
Pharmacokinetic analysis set...............................................................103
12.1.5
Other analysis sets...............................................................................103
12.2
Subject demographics and other baseline characteristics....................................103
12.3
Treatments ...........................................................................................................103
12.4
Analysis of the primary endpoint(s) ....................................................................104


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12.4.1
Definition of primary endpoint(s).......................................................104
12.4.2
Statistical model, hypothesis, and method of analysis........................104
12.4.3
Handling of missing values/censoring/discontinuations.....................106
12.4.4
Sensitivity and Supportive analyses....................................................106
12.5
Analysis of secondary endpoints .........................................................................106
12.5.1
Efficacy endpoints...............................................................................107
12.5.2
Safety endpoints..................................................................................108
12.5.3
Pharmacokinetics ................................................................................110
12.5.4
Patient reported outcomes...................................................................111
.112
.112
.112
12.7
Interim analyses...................................................................................................112
12.8
Sample size calculation........................................................................................114
12.8.1
Primary endpoint(s).............................................................................114
13 Ethical considerations and administrative procedures ....................................................115
13.1
Regulatory and ethical compliance......................................................................115
13.2
Responsibilities of the investigator and IRB/IEC................................................115
13.3
Publication of study protocol and results.............................................................115
13.4
Quality Control and Quality Assurance...............................................................115
14 Protocol adherence ..........................................................................................................116
14.1
Protocol Amendments .........................................................................................116
15 References .......................................................................................................................117
16 Appendices ......................................................................................................................120
16.1
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival, and Overall Survival (based on RECIST 1.1) 120
16.1.1
Introduction.........................................................................................121
16.1.2
Efficacy assessments...........................................................................121
16.1.3
Efficacy definitions .............................................................................130
16.1.4
Data handling and programming rules................................................140
16.1.5
References (available upon request) ...................................................143
16.2
Appendix 2: Statistical Details for Safety Run-in Part: Bayesian logistic 
regression model (BLRM): prior and design properties for hypothetical data 
scenarios ..............................................................................................................144
16.2.1
Statistical Models................................................................................144
16.2.2
Summary of prior distributions...........................................................147
16.2.3
Hypothetical on-study scenarios .........................................................148








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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301
List of abbreviations
ADA
Anti-Drug Antibodies
AE
adverse event
AESI
adverse event of special interest
AIC
Akaike information criterion
ALK
Anaplastic Lymphoma Kinase
ALP
alkaline phosphatase
alpha-FP
Alpha-Fetoprotein
ALT
alanine aminotransferase
ANA
Antinuclear Antibody
ANC
Absolute Neutrophil Count
ASMA
Anti-Smooth Muscle Antibody
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area Under the Curve
AUCi
Area Under the Curve with respect to increase
b.i.d.
twice a day
Beta-hCG
Beta-Human Chorionic Gonadotropin
BLRM
Bayesian Logistic Regression Model
BOR
Best Overall Response
BUN
blood urea nitrogen
BVN
Bivariate normal
CANTOS
Canakinumab Anti-inflammatory Thrombosis Outcomes Study
CAPS
Cryopyrin Associated Periodic Syndromes
CD-
transferrin
Carbohydrate Deficient-transferrin
CFR
Code of Federal Regulation
CHF
Congestive Heart Failure
CI
Confidence Interval
Cmax
Concentration maximum
Cmin
Concentration minimum
CMO&PS
Chief Medical Office and Patient Safety
CMV
Cytomegalovirus
CNS
Central Nervous System
CO
Country Organization
COA
Clinical Outcome Assessments
COVID-19
Coronavirus Disease 2019
CR
Complete Response
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-Reactive Protein
CRS
Case Retrieval Strategy


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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301
CSR
Clinical Study Report
CT
Computed Tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating Tumor DNA
CTT
Clinical Trial Team
CV
Coefficient of variation
CVD
Cardiovascular Disease
CYP
Cytochrome P450
DBP
Diastolic Blood Pressure
DCR
Disease Control Rate
DDI
Drug-drug Interaction
DDS
Dose-Determining Set
DILI
Drug-Induced Liver Injury
DL1
Dose Level 1
DLRT
Dose Level Review Team
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DOR
Duration Of Response
EBV
Epstein-Barr Virus
EC
Ethics committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EGFR
Epidermal Growth Factor Receptor
ELISA
Enzyme-linked immunoabsorbent assay
EMA
European Medicines Agency
EOI
End of Infusion
EORTC
European Organization for Research and Treatment of Cancer
EOT
End Of Treatment
ePRO
Electronic Patient Reported Outcome
ERCP
Endoscopic Retrograde Cholangiopancreatography
EU
European Union
EWOC
Escalation With Overdose Control
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDG-PET
Fludeoxyglucose-Positron emission tomography
FFPE
Formalin-Fixed Paraffin Embedded
FMF
Familial Mediterranean Fever
FPFV
First Patient First Visit


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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301
G-CSF
Granulocyte colony-stimulating factor
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyltransferase
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
HSV
Herpes Simplex Virus
i.v.
intravenous
IA
Interim Analysis
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IG
Immunogenicity
IgA
Immunoglobulin A
IgE
Immunoglobulin E
IgG1
Immunoglobulin G 1
IgM
Immunoglobulin M
IHC
Immunohistochemistry
IL
Interleukin
IL-1β
Interleukin-1β
IN
Investigator Notification
INN
International Nonproprietary Names
INR
International Normalized Ratio
IQR
InterQuartile Range
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Insulin Tolerance Tests
IUD
Intrauterine device
IUS
Intrauterine system
LDH
lactate dehydrogenase
LFT
Liver function test


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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301
LLN
lower limit of normal
LLOQ
Lower Limit Of Quantification
LLQ
lower limit of quantification
LPLV
Last Patient Last Visit
MACE
Major Adverse Cardiovascular Events
MAP
Meta-Analytic-Predictive
MCV
Mean Corpuscular Volume
MedDRA
Medical dictionary for regulatory activities
MI
Myocardial Infarction
MKD
Mevalonate Kinase Deficiency
mL
Milliliter(s)
MRI
Magnetic Resonance Imaging
MSD
Meso Scale Discovery
NASH
Nonalcoholic steatohepatitis
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse events
NSCLC
Non-small cell lung cancer
o.d.
once a day
OLE
Open Label Extension
ORR
Overall Response Rate
OS
Overall Survival
p.o.
Oral
PAS
Pharmacokinetic Analysis Set
PD
Pharmacodynamic(s)
Progressive Disease
PD-(L)1
Programmed death-ligand 1
PET
Positron Emission Tomography
PFS
Progression-Free Survival
PK
pharmacokinetic(s)
PR
Partial Response
PRO
Patient Reported Outcome
PS
Performance Status
PT
Prothrombin time
QLQ
Quality of Life Questionnaire
QMS
Quality Management System
QoL
Quality of Life
QxW
Every x weeks
R value
ALT/ALP in multiples of ULN
RBC
Red blood cell(s)
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic Acid
RoW
Rest of the World


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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301
RP3R
Recommended Phase 3 Regimen
s.c.
subcutaneous
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SC
Steering Committee
sCR
serum creatinine
SD
Stable Disease
SOP
Standard Operating Procedure
SUSARs
Suspected Unexpected Serious Adverse Reactions
T1/2
Terminal Half-Life
T1D
Type 1 Diabetes
T3
Triiodothyronine
T4
Thyroxine
TB
Tuberculosis
TBIL
Total Bilirubin
TNF
Tumor Necrosis Factors
TRAPS
Tumor Necrosis Factor Receptor Associated Periodic Syndrome
TSH
Thyroid-Stimulating Hormone
TTP
Time To Progression
TTR
Time To Response
ULN
Upper limit of normal
ULOQ
Upper Limit Of Quantification
UNK
Unknown
US
United States
Ultrasound
USPI
US-Package Insert
VAS
Visual Analogue Scale
VATS
Video-Assisted Thoracic Surgery
vs.
versus
WBC
White blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent


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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301
Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
A study drug 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.
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)
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is associated with 
a purpose (e.g. screening, randomization, treatment, follow-up), which applies 
across all arms of a study.
Healthy volunteer
A person with no known significant health problems who volunteers to be a 
study participant 
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 
treatment
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage.
Medication 
number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system.
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
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Premature 
subject 
withdrawal
Point/time when the subject exits from the study prior to the planned completion 
of all study drug administration and assessments; at this time all study drug 
administration is discontinued and no further assessments are planned.
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
Stage
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
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 drug 
discontinuation
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal.
Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part of the 
required study procedures; includes investigational drug, active drug run-ins or 
background therapy.


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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the defined 
study treatment completion date
Subject
An individual who has consented to participate in this study. The term Subject 
may be used to describe either a healthy volunteer or a patient.
Subject number
A number assigned to each subject who enrolls in the study. When combined 
with the center number, a unique identifier is created for each subject in the 
study.
Treatment 
number
A unique identifier assigned in non-randomized studies to each dosed subject, 
corresponding to a specific treatment arm 
Variable
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints.
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study is defined as when a subject does not 
want to participate in the study any longer, and does not want any further visits 
or assessments, and does not want any further study related contact, and does 
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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301

Table 8-1: allowable time window specific to OLE cycle visits inserted

Table 8-2 and Table 8-3: the start point of safety follow-up period rectified to align with 
the wording used in protocol text

Table 8-3: added possibility for randomized subjects to enter into OLE

Table 8-4: separate Visit Evaluation Schedule created for OLE

Section 8.3.2 and Table 8-5: imaging assessment schedule plan added for OLE; central 
imaging assessments collection and quality check to be discontinued in OLE  

Section 8.4.1, Table 8-6, Section 8.4.4, Section 8.4.5 and Section 8.5.2.1: wording related 
to OLE assessments added 

Section 8.5.1: clarification added on ePRO collection procedure and reduced ePRO
collection in OLE

Section 8.5.3.1: clarifying that tumor block collected at disease progression should be 
submitted as preferred than slides 

Section 8.5.2.2 and Table 16-17: clarification on approximate number of subjects per arm 
in PK docetaxel subset 

Section 9.2: end of study definition revised to more specifically cover the cases of positive 
or negative study readouts

Section 10.1.1.1: AESI DILI name was updated to abnormal liver parameters to reflect 
MedDRA search more accurately 

Section 10.1.2: clarification added on malignant neoplasm not considered as a disease 
progression of the study indication; guidance provided on confirmed COVID-19 infection 
to be considered as medically significant and therefore to be reported as SAE

Section 10.1.4: details inserted on actions to be taken for pregnancy occurring on study 
treatment as well as the duration of follow-up with new born

Section 11.2: revision made on data captured in Interactive Response Technology (IRT) 
system

Section 12: data scope enlarged to include those to be collected post cut-off date for the 
primary OS analysis

Section 12.7: wording revised on the primary intent of the interim analysis
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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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301
Protocol summary
Protocol number
ACZ885V2301
Full Title
A randomized, double-blind, placebo-controlled, phase III study evaluating 
the efficacy and safety of canakinumab in combination with docetaxel 
versus placebo in combination with docetaxel in subjects with non-small 
cell lung cancer (NSCLC) previously treated with PD-(L)1 inhibitors and 
platinum-based chemotherapy (CANOPY-2)
Brief title
Study of efficacy and safety of canakinumab in combination with docetaxel 
in subjects with non-small cell lung cancers as a second or third line 
therapy.
Sponsor and Clinical 
Phase
Novartis, Phase III
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
This phase III study is designed to evaluate the role of IL-1β inhibition in 
combination with docetaxel in subjects with advanced NSCLC previously 
treated with PD-(L)1 inhibitors and platinum-based chemotherapy.
Primary Objective(s) 
Part 1: Safety run-in

To confirm the Recommended Phase 3 Regimen (RP3R) of the 
combination of canakinumab and docetaxel.
Part 2: Double-blind, randomized, placebo-controlled part

To compare the overall survival (OS) in the docetaxel plus 
canakinumab arm versus docetaxel plus placebo arm.
Secondary
Objectives
Part 1: Safety run-in 

To characterize the safety and tolerability of the combination of 
canakinumab and docetaxel.

To assess the preliminary clinical anti-tumor activity of canakinumab 
and docetaxel combination.

To characterize the pharmacokinetics (PK) of canakinumab and 
docetaxel when given in combination.
Part 2: Double-blind, randomized, placebo-controlled part

To evaluate the 2 treatment arms with regards to progression-free 
survival (PFS), overall response rate (ORR), disease control rate 
(DCR), time to response (TTR) and duration of response (DOR) 
based on local investigator assessment per RECIST1.1.

To characterize the safety profile of the combination of docetaxel and 
canakinumab.

To assess the effect of docetaxel plus canakinumab vs docetaxel plus 
placebo on PROs (EORTC QLQ-C30, lung specific module QLQ-
LC13 and EQ-5D-5L) including lung cancer symptoms, health-related 
quality of life and health status.

To characterize the pharmacokinetics of canakinumab when given in 
combination.

To characterize the immunogenicity (anti-drug antibodies (ADA)) of 
canakinumab.

To assess the effect of docetaxel plus placebo vs. docetaxel plus 
canakinumab arms on ECOG performance status.






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The primary efficacy analysis to test this hypothesis and compare the two 
treatment groups will consist of a stratified log-rank test at an overall one-
sided 2.5% level of significance in favor of the docetaxel plus 
canakinumab arm. The stratification factors are line of therapy and 
histology. The primary efficacy variable, OS, will be analyzed at the 
interim analysis and final analysis of a group sequential design, using a 
Lan-DeMets (O’Brien-Fleming) α-spending function. Analyses will be 
based on the Full Analysis Set (FAS) population according to the 
randomized treatment group and strata assigned at randomization. The 
OS distribution will be estimated using the Kaplan-Meier method, and 
Kaplan-Meier curves, median and associated 95% confidence intervals 
will be presented for each treatment group. The Hazard Ratio (HR) for OS 
will be calculated, along with its 95% confidence interval, from a stratified 
Cox model using the same stratification factors as for the log-rank test.
Secondary endpoints:
In Safety run-in part, ORR, DCR, and DOR will be summarized in FAS 
by dose cohort.
In Randomized part, the PFS distribution will be estimated using the 
Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% 
confidence intervals of the medians will be presented for each treatment 
group. The hazard ratio for PFS will be calculated, along with its 95% 
confidence interval, using a stratified Cox model. ORR, DCR and their 
95% confidence interval will be presented by treatment group. The 
distribution functions of TTR and DOR will be estimated using the Kaplan-
Meier method. The median TTR and DOR along with their 95% CIs will be 
presented by treatment arm.
Keywords
ACZ885, canakinumab, docetaxel, NSCLC, IL-1β, PD-(L)1, CANOPY


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1
Introduction
1.1
Background
1.1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1.1
Background on non-small cell lung cancer and use of immunotherapy
An estimated 1.8 million people were diagnosed globally with lung cancer in 2012 and there 
were 1.6 million deaths from this disease. The number of new lung cancer cases is expected to 
grow by about 70% over the next 2 decades (Globocan 2012). Non-small cell lung cancer 
(NSCLC) accounts for 85% of the lung cancer diagnoses (Jemal et al 2011). The majority of 
patients present with advanced disease.
The standard first-line therapy for treatment of patients with stage IIIB to IV NSCLC with no 
targetable oncogenic mutations is platinum-based chemotherapy. The median overall survival 
of advanced NSCLC subjects treated with platinum doublets is 8-10 months, with 
approximately 50-70% of subjects having disease stabilization or shrinkage in response to first-
line chemotherapy (Schiller et al 2002, Scagliotti et al 2002, Scagliotti et al 2008). Following 
the progression on platinum-based chemotherapy, single-agent docetaxel is the standard of care 
based on efficacy and safety data from the randomized studies demonstrating benefits of 
docetaxel 75 mg/m2 over vinorelbine or ifosfamide (Fossella et al 2000) or versus best 
supportive care.
Immunotherapy has further shaped the treatment landscape of advanced NSCLC in patients 
who progressed on platinum-based chemotherapy. Three monoclonal antibodies targeting PD-
1 and PD-L1 (nivolumab, pembrolizumab, and atezolizumab) have each proven superiority over 
single agent docetaxel in pretreated NSCLC patients and have been recently approved by the 
Health Authorities in this setting. The clinical benefit was apparent across squamous and non-
squamous histologies (Herzberg et al 2017).
Table 1-1
Overall survival benefit of immunotherapy for treatment of advanced 
Non-Small Cell Lung Cancer
PD-(L)1 
inhibitor
Reference
NSCLC 
histology
Median OS in 
months in PD-
(L)1 inhibitor 
arm (95% CI)
Median OS in 
months in 
docetaxel arm 
(95% CI)
HR [95% CI] 
and p value
Nivolumab
Borghaei et al
2015
Non-squamous
12.2 [9.7-15.0]
9.4 [8.1-10.7]
HR 0.73 [0.59 -
0.89] p = 0.002
Nivolumab
Brahmer et 
al 2015
Squamous
9.2 [7.3-13.3]
6.0 [5.1-7.3]
HR 0.59 [0.44 -
0.79] p < 0.001
Pembrolizumab
Herbst et al 20
16
Squamous and 
non-squamous
12.7 [10.0-17.3]
8.5 [7.5-9.8]
HR 0.61 [0.49–
0.75] p<0.0001
Atezolizumab
Rittmeyer et al
2017
Squamous and 
non-squamous
13.8 [11.8-15.7]
9.6 [8.6-11.2]
HR 0.73 [0.62–
0.87] p=0.0003
More recently, pembrolizumab was evaluated in combination with platinum-based 
chemotherapy in the randomized Phase 3 studies KEYNOTE-189 in first line patients with non-
squamous NSCLC (Gandhi et al 2018) and KEYNOTE-407 in first line patients with squamous 






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with elevated bilirubin or concomitant elevations of alkaline phosphatase (ALP) with AST/ALT 
(USPI).
Docetaxel is metabolized by the CYP3A4 enzyme: In vivo studies showed that the exposure of 
docetaxel increased 2.2-fold and its clearance diminished by 49% when it was co-administered 
with ketoconazole, a potent inhibitor of CYP3A4.
Docetaxel at the dose of 75mg/m2 is the standard chemotherapy used in NSCLC patients after 
failure to a prior platinum-based chemotherapy regimen and served as the control arms for 
several studies exploring the role of PD-(L)1 inhibitors in this setting (Borghaei et al 2015, 
Brahmer et al 2015, Herbst et al 2016, Rittmeyer et al 2017) described also in the background 
Section 1.1.1.1.
1.1.3
Potential for drug-drug interactions
Canakinumab is not anticipated to be directly eliminated through hepatic/renal metabolism and 
excretion to compete with the elimination of docetaxel. Therefore, the risk of drug-drug 
interaction (DDI) between canakinumab and docetaxel is anticipated to be low. Docetaxel is a 
CYP3A4 substrate. Therefore, concomitant use of docetaxel and drugs that inhibit CYP3A may 
increase the exposure to docetaxel and should be avoided. Similarly, concomitant use of 
docetaxel and drugs that induce CYP3A may reduce the exposure to docetaxel and should be 
used with caution (Section 6.2).
1.2
Purpose
This phase III study is designed to evaluate canakinumab in combination with docetaxel and 
the role of IL-1β inhibition in subjects with advanced NSCLC previously treated with PD-(L)1 
inhibitors and platinum-based chemotherapy. The randomized III part will be preceded by a 
safety run-in part in which the recommended dose of the combination of canakinumab and 
docetaxel will be confirmed.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

Safety run-in part: To confirm the 
Recommended Phase 3 Regimen (RP3R) of 
the combination of canakinumab and 
docetaxel

Incidence rate of dose limiting toxicities (DLTs) in the 
first 42 days associated with the administration of 
canakinumab in combination with docetaxel.

Randomized part: To compare the overall 
survival (OS) in the docetaxel plus 
canakinumab arm versus docetaxel plus 
placebo arm

OS
Secondary objective(s)
Endpoint(s) for secondary objective(s)

Safety run-in part: To assess the preliminary 
clinical anti-tumor activity of canakinumab 
and docetaxel combination

ORR, DOR and DCR by investigator’s assessment 
according to RECIST 1.1


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Objective(s)
Endpoint(s)

Safety run-in part: To characterize the 
safety and tolerability of the combination of 
canakinumab and docetaxel

Type, frequency and severity of adverse events, 
changes in laboratory values, vital signs, ECGs

Safety run-in part: To characterize the 
pharmacokinetics (PK) of canakinumab and 
docetaxel when given in combination

Concentration of canakinumab/docetaxel and PK 
parameters

Randomized part: To evaluate the 2 
treatment arms with regards to progression-
free survival (PFS), overall response rate 
(ORR), disease control rate (DCR), Time to 
response (TTR) and duration of response 
(DOR) based on local investigator 
assessment per RECIST1.1

PFS, ORR, DCR, TTR and DOR based on local 
investigator assessment per RECIST 1.1

Randomized part: To characterize the safety 
profile of the combination of docetaxel and 
canakinumab

AEs (
 ECGs, vital signs and laboratory 
abnormalities

Randomized part: To assess the effect of 
docetaxel plus canakinumab vs. docetaxel 
plus placebo arms on PROs (EORTC QLQ-
C30, lung specific module QLQ-LC13 and 
EQ-5D-5L) including lung cancer symptoms, 
health-related quality of life and health status

Time to definitive 10 point deterioration symptom 
scores of chest pain, cough and dyspnea per QLQ-
LC13 questionnaire are primary PRO variables of 
interest. Time to definitive deterioration in global 
health status/QoL, shortness of breath and pain per 
QLQ-C30 are secondary PRO variables of interest.
Change from baseline in EORTC-QLQ C30 and 
LC13, EQ-5D-5L

Randomized part: To characterize the 
pharmacokinetics of canakinumab when 
given in combination

Concentration of canakinumab/docetaxel and PK 
parameters

Randomized part: To characterize the 
immunogenicity (anti-drug antibodies, ADA) 
of canakinumab

Antidrug antibodies (ADA) prevalence at baseline 
and ADA incidence on-treatment

Randomization part: To assess the effect of 
docetaxel plus placebo vs. docetaxel plus 
canakinumab arms on ECOG performance 
status

Time to definitive deterioration of the 
ECOG performance status of the score from 
baseline.
3
Study design
This is a multicenter phase III study evaluating the efficacy and safety of canakinumab in 
combination with docetaxel versus placebo in combination with docetaxel, as second or third 
line treatment, in adult subjects with advanced NSCLC who have progressed after prior PD-








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4.2
Rationale for dose/regimen and duration of treatment


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4.2.2
Efficacy and pharmacodynamics (PD) considerations
The different median baseline hs-CRP levels among canakinumab-treated subjects in CANTOS 
who were subsequently diagnosed with cancer compared to those who were not (median 6.0 
mg/L [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 2017b) 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. Studies examining hs-CRP levels in Stage I through Stage III 
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 < 2.3 mg/L by baseline hs-CRP 
deciles in all subjects from the CANTOS study
Median hs-CRP at 3 months was 2.3 mg/L based on all subjects in the Full Analysis Set.
4.2.3
Safety consideration
Refer to Section 1.1.2 and the current canakinumab Investigator's Brochure. The canakinumab 
dose and schedule being explored in this phase III study is similar in terms of pharmacokinetics 
to the already approved in non-oncology indications 300mg Q4W regimen (Section 4.2.1). 
Several canakinumab trials are ongoing in oncology: in particular, canakinumab is being 
evaluated in subjects with advanced NSCLC in an ongoing phase 1b study, [CPDR001X2103]. 
This study is examining the safety and tolerability of PDR001, a PD-1 inhibitor from Novartis, 
in combination with various targeted therapies or immunotherapies, including canakinumab. It 
has shown that canakinumab at 600 mg s.c. Q8W is safe to be combined with PDR001 
administered at 400 mg i.v. Q4W (RP2D). Based on preliminary population PK simulation, 600 


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mg s.c. Q8W generates steady-state Cmax greater than that attained at the selected NSCLC dose 
of 200 mg s.c. Q3W. Therefore, no unexpected safety issues are expected with the 
administration of canakinumab at the doses of 200 mg Q3W in NSCLC subjects.
4.2.4
Consideration for combination with docetaxel
There are no data available defining the recommended doses of docetaxel and canakinumab 
when given in combination. These will be confirmed in the first part of this study (safety run 
in). At least 6 subjects will receive the two drugs and be followed for 42 days to confirm the 
starting dose of the combination. Once this dose is confirmed, the randomized part of the study
will begin.
Full dose of docetaxel (75mg/m2 Q3W) and canakinumab (200 mg Q3W) will be given as 
starting dose for the combination in the safety run-in:

The risk of DDI between canakinumab and docetaxel is anticipated to be low as described 
in Section 1.1.3. The PK of docetaxel and canakinumab will be characterized in this study, 
so that DDI, if any, between these two agents, can be explored.

There are two key toxicities overlapping between canakinumab and docetaxel: 

Neutropenia: 

When docetaxel is given at the dose of 75mg/m2 Q3W in pre-treated NSCLC 
subjects (Borghaei et al 2015, Brahmer et al 2015, Rittmeyer et al 2017), 
neutropenia (reported as treatment related adverse event) range between 14-33% 
all grades, and 12-30% grade 3-4; with febrile neutropenia rates between 10 and 
11%.

In the CANTOS study, all-grade neutropenia was reported in 2.0% vs. 0.9% in 
subjects treated with canakinumab 300 mg vs. placebo, respectively. However, 
the rate of severed neutropenia (grade 3) was below 1% and similar to placebo. 
There was no grade 4 neutropenia in subjects treated with any canakinumab dose.

Infections: 

In docetaxel arms of recent clinical studies, no infection was reported at a rate 
above 5% (Brahmer et al 2015, Rittmeyer et al 2017) or 10% 
(Borghaei et al 2015). However, cases of death due to febrile neutropenia (1 
subject out of 268; Borghaei et al 2015); to respiratory infection (1 out of 578 
subjects; Rittmeyer et al 2017) and to sepsis (1 out of 129 subjects; 
Brahmer et al 2015) were reported in these studies.

In the CANTOS study, infections were one of the most frequently reported 
adverse events. In the 300 mg dose, the rate of viral upper respiratory tract 
infection was 12.5-13.9% (range of frequency across 50 to 300 mg doses) of 
canakinumab-treated subjects versus 12.3% in the placebo group.
Elevated bilirubin, AST, ALT and alkaline phosphatase are uncommonly observed with either 
drug. However, during treatment with docetaxel, subjects with elevation of bilirubin or 
abnormalities of transaminases concurrent with alkaline phosphatase are at increased risk of 
developing grade 4 neutropenia, febrile neutropenia, infections and other toxicities. Monitoring 
of bilirubin and liver function tests will be required during the course of this study as per 
assessment schedule in Table 8-2 and Table 8-3.


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4.2.5
Conclusion for dose regimen selection
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 2 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. More 
importantly, given the evidence of the efficacy profile from the CANTOS study in which 
canakinumab shows no plateau effect in lung cancer risk reduction at 300 mg s.c. quarterly 
(Q12W), and the comprehensive and well-established safety profile of canakinumab across a 
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. Lastly there is a high likelihood that the full dose of docetaxel and canakinumab can be 
combined together given the limited risk of overlapping safety profile and low risk of DDI. The 
protocol includes appropriate safety assessment to monitor and manage these risks (please refer 
to Section 6.5 for further details).
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Following progression after platinum based chemotherapy, docetaxel monotherapy is 
considered a standard of care. Given the different mechanism of action of docetaxel and PD-
(L)1 inhibitors, one can assume that docetaxel efficacy outcomes post PD-(L)1 inhibitor therapy 
should remain similar to the one observed with docetaxel in PD-(L)1 inhibitor naive subjects. 
Docetaxel will thus be used as comparator therapy. 
4.4
Purpose and timing of interim analyses/design adaptations
The purpose and timing of the OS interim analysis is detailed in Section 12.7.
4.5
Risks and benefits
The intended study population is non-small cell lung cancer (NSCLC) subjects previously 
treated with platinum-based chemotherapy and PD-(L)1 inhibitors. In this patient population, 
safety and efficacy of docetaxel has been well-established since its approval in 1996. 
Canakinumab or a matching placebo will be administered on the same treatment day as 
docetaxel. The use of placebo is necessary to minimize bias when assessing efficacy and safety 
of the combination treatment.
Because of different mechanisms of action and different metabolism, there is no expected 
significant drug-drug interaction. As a result, adding canakinumab is not likely to change the 
established safety profile of docetaxel with a potential exception of neutropenia and infections 
(overlapping toxicities). Treatment with the combination could potentially result in a higher rate 
and/or grade of neutropenia and infections. The incidence and severity of all adverse events, 
but in particular: neutropenia, infections and pre-defined dose-limiting toxicities will be 
assessed in a safety run-in part before the start of randomization. During the study, the risks 
associated with neutropenia and infections will be minimized by following the monitoring 
procedures prior to each docetaxel and canakinumab/ placebo administration and by modifying 


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the dose as stated in the protocol. Docetaxel has genotoxic effects and may alter male fertility. 
Therefore, men being treated with docetaxel are advised not to father a child during and up to 
6 months after treatment and to seek advice on conservation of sperm prior to treatment.
Canakinumab is approved for pediatric indications in subjects 2 years and older. In animal 
embryo-fetal development studies with canakinumab, there was no evidence of embryotoxicity 
or fetal malformations. However, docetaxel can cause fetal harm when administered to a 
pregnant woman. This study will exclude pediatric subjects, women who are pregnant, could 
become pregnant or are currently nursing. Women of childbearing potential and sexually active 
males will 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 (computed tomography (CT), magnetic resonance or X-rays) will be used in 
this study to assess response of tumors to administered treatments. The frequency is consistent 
with the standard of care assessments every 6 weeks of chemotherapy. Tumor assessments 
required by the trial allow for magnetic resonance imaging (MRI) and CT; the ability to use of 
MRI instead of CT for the brain and abdomen decreases the radiation exposure. Only in the 
chest is CT 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.
In the CANTOS study, the incidence of lung cancer was lower among subjects treated with 
canakinumab vs. placebo (see Section 1.1.2.1 for details about CANTOS study). Through the 
same mechanisms, canakinumab may potentially improve outcomes (overall survival, 
progression-free survival and objective response) while maintaining the overall quality of life 
in the intended population of this study.
Appropriate eligibility criteria and specific dose-limiting toxicity definitions, as well as specific 
dose modification and stopping rules, are included in this protocol. The risk to subjects in this 
study may be minimized by compliance with the eligibility criteria and study procedures, as 
well as close clinical monitoring. Given a potential overall survival benefit and a manageable 
risk of potential infections, canakinumab in combination with docetaxel has a favorable risk-
benefit ratio in the defined study population.
5
Population
The study population will include adult subjects with locally advanced or metastatic (stage IIIB-
IV) non-small cell lung cancer, who have been previously treated with and progressed on 
platinum-based chemotherapy and PD-(L)1-inhibitor (either in combination or sequentially). 
Subjects must be docetaxel naive. Prior neo-adjuvant or adjuvant systemic therapy may be 
allowed if relapse has occurred more than 12 months from the end of the therapy as outlined 
below.
Subjects with targetable oncogenic drivers (EGFR-sensitizing / ALK rearrangement ) will be 
excluded.


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5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained prior to any screening procedures
2. Subject is an adult male/female ≥ 18 years of age at the time of informed consent 
3. Histologically confirmed locally advanced/metastatic (stage IIIB-IV ) NSCLC
4. Subject has received one prior platinum-based chemotherapy and one prior PD-(L)1 
inhibitor therapy for locally advanced or metastatic disease:

Subject may have received the platinum based chemotherapy for advanced or 
metastatic disease and the PD-(L)1 inhibitor either together (in the same line of 
treatment) or sequentially (two different lines of treatment) and then progressed

Subject who received the PD-(L)1-inhibitor as maintenance (no progression on 
platinum-doublet chemotherapy) and progressed on PD-(L)1 are eligible

Subjects who received adjuvant or neoadjuvant platinum-doublet chemotherapy (after 
surgery and/or radiation therapy) and a PD-(L)1 inhibitor and developed recurrent or 
metastatic disease while on or within 12 months of completing therapy are eligible

Subjects with recurrent disease > 12 months after adjuvant or neoadjuvant platinum 
based chemotherapy, who also subsequently progressed during or after a platinum 
doublet regimen and a PD-(L)1 inhibitor (given either together or sequentially to treat 
the recurrence), are eligible
5. Subject with ECOG performance status (PS) of 0 or 1
6. Subject with at least 1 evaluable (measurable or non-measurable) lesion by RECIST 1.1 in 
solid tumors criteria.
7. Subject must have recovered from all toxicities related to prior systemic therapy to grade 
≤ 1 
. Exception to this criterion: subjects with any grade of alopecia
8. Subjects must have adequate organ function including the following laboratory values at 
the screening visit:

Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (without growth factor support)

Platelets ≥ 100 x 109/L (without growth factor support)

Hemoglobin (Hgb) > 9 g/dL (4 weeks without transfusions or erythropoietin)

Aspartate transaminase (AST) ≤ 3 x ULN

Alanine transaminase (ALT) ≤ 3 x ULN

Total bilirubin ≤ ULN

Serum amylase ≤2 x ULN or pancreatic amylase ≤ 1.5 x ULN

Serum lipase ≤ 1.5 x ULN

Creatinine clearance ≥60 mL/min by calculation using Cockcroft-Gault formula
9. Subject must be able to communicate with the investigator and comply with the 
requirements of the study procedures.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.


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1. Patient who previously received docetaxel, canakinumab (or another IL-1β inhibitor), or 
any other systemic therapy for their locally advanced or metastatic NSCLC other than one 
platinum-based chemotherapy and one prior PD-(L)1 inhibitor.
2. Subject with EGFR-sensitizing mutation and/or ALK rearrangement by local laboratory 
testing

Note: Subjects with NSCLC of pure squamous cell histology can initiate treatment 
without EGFR or ALK testing or result, however, subjects with pure squamous cell 
histology that are known to have EGFR/ALK sensitizing mutations are excluded.

Subjects with known BRAF V600 mutation or ROS-1 rearrangement will be 
excluded, if required by local guidelines
3. History of severe hypersensitivity reaction to monoclonal antibodies, taxanes or any 
known excipients of these drugs (i.e. Polysorbate-80-containing infusions, mannitol, 
histidine).
4. Previously untreated or symptomatic central nervous system (CNS) metastases or lepto-
meningeal disease.
Note: subjects with treated CNS metastases with radiotherapy and/or surgery, without 
evidence of CNS disease progression ≥4 weeks after treatment completion and off 
corticosteroid therapy for ≥ 2 weeks prior to treatment start are eligible.
5. Presence or history of a malignant disease, other than the resected NSCLC, 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
6. 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 the screening results require treatment as per local guidelines or 
clinical practice, then the patient is not eligible.

Chronic or active hepatitis B or C.

Known history of testing positive for Human Immunodeficiency Virus (HIV) 
infections. For countries where HIV testing 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. 

Note: 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

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

Subject receiving any biologic drugs targeting the immune system (for example, 
TNFa blockers, anakinra, rituximab, abatacept, or tocilizumab).


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
Note: Daily glucocorticoid-replacement for conditions such as adrenal or 
pituitary insufficiency is allowed.

Note: Topical, inhaled or local steroid use in doses that are not considered to 
cause systemic effects are permitted.

Note: Steroids for pre-medication related to chemotherapy as per local standard 
of care are permitted.
7. Subject has received live vaccination within 3 months prior to first dose of study drug.
8. Subject has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 
4 weeks prior to starting study drug or has not recovered from side effects of such 
procedure. Video-assisted thoracic surgery (VATS) and mediastinoscopy will not be 
counted as major surgery and subject can be enrolled in the study ≥1 week after the 
procedure.
9. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting the study treatment or 
subjects who have not recovered from radiotherapy-related toxicities. For all other 
anatomic sites (including radiotherapy to thoracic vertebrae and ribs) radiotherapy ≤ 2 
weeks prior to starting the study treatment or has not recovered from radiotherapy-related 
toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study 
treatment is allowed.
10. Grade ≥2 motor or sensory neuropathy symptoms 
11. Clinically significant, uncontrolled cardiac disease and/or recent cardiac event (within 6 
months), such as:

Unstable angina or myocardial infarction within 6 month prior to screening

Symptomatic congestive heart failure (defined as New York Heart Association Grade 
II or greater)

Documented cardiomyopathy

Clinical significant cardiac arrhythmias

Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, unless controlled prior to 
screening 
12. History of interstitial lung disease or pneumonitis grade ≥ 2
13. Uncontrolled diabetes as defined by the investigator.
14. Known active or recurrent hepatic disorder including cirrhosis.
15. Subject has any other concurrent severe and/or uncontrolled medical condition that would, 
in the investigator’s judgment cause unacceptable safety risks, contra-indicate patient 
participation in the clinical study or compromise compliance with the protocol (e.g. 
chronic pancreatitis)
16. Subject is currently receiving treatment with drugs known to be strong inhibitors or strong 
inducers of isoenzyme CYP3A. The patient must have discontinued strong inhibitors or 
strong inducers before the treatment is initiated. Switching to a different medication prior 
to randomization is allowed. Please refer to the Table 16-12 for a list of strong inhibitors 
or strong inducers of CYP3A4
17. Patient is concurrently using other anti-cancer therapy


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18. Participation in a prior investigational study within 30 days prior to enrollment or within 5 
half-lives of the investigational product (other than chemotherapy or checkpoint 
inhibitors), whichever is longer or those who are expected to receive any other 
investigational drug or device during the conduct of the study.
19. Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or 
breast-feed during the study. Pregnant or nursing women, where pregnancy is defined as 
the state of a female after conception and until the termination of gestation, confirmed by 
a positive hCG laboratory test
20. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective contraception during the study 
and 6 months after chemotherapy discontinuation. Highly effective contraception methods 
include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
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 subjects 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 childbearing 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 six 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 
childbearing potential.
21. Sexually active males unless they use a condom during intercourse while taking drug and 
during 6 months after chemotherapy discontinuation and should not father a child in this 
period. A condom is required to be used also by vasectomized men in order to prevent 
delivery of the drug via seminal fluid.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects.


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6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
For this study, the term “investigational or study drug” refers to Novartis study drug 
canakinumab.
The other drug to be used in this study is docetaxel. “Study treatment” refers to the combination 
of canakinumab (or matching placebo) and docetaxel.
Canakinumab or matching placebo will be supplied by Novartis in the form of solution for 
injection as ready-to-use pre-filled syringes. Two strengths and respective corresponding 
matching placebos will be supplied (refer to Table 6-1).
Docetaxel will be procured locally as it is commercially available in each participating country .
Table 6-1
Investigational / control drugs / placebo 
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
150mg/1mL AND 
50mg/0.5mL
200 mg
Q3W or Q6Wa
Placebo
0mg/1mL AND 
0mg/0.5mL
0 mg
Docetaxel
Concentrated solution 
for i.v. preparation
strength varies from 
suppliers
75 mg/m2
Q3W
a Depending on RP3R (recommended phase 3 regimen) defined during safety run-in part (Part 1)
The study drug, canakinumab/placebo will be given as subcutaneous injections. All injections 
(one syringe of 1 mL and one syringe of 0.5 mL) will be administered at study sites by trained 
site staff.
Storage conditions are described in the medication label. Medication labels will comply with 
the legal requirements of each country and be printed in the local language.
The Recommended phase 3 Regimen (RP3R) of canakinumab in combination with docetaxel 
will be confirmed during the safety run-in part of the study (please refer to Section 6.5.1 for 
more details).
Docetaxel will be given as an intravenous infusion (75 mg/m2) on Day 1 of each 21 days cycles, 
as per product label and local practice.
All dosages prescribed and dispensed to the subject and all dose changes during the study must 
be recorded on the appropriate eCRF.
6.1.1.1
Supply and administration of study treatment
Supply of study treatment
Canakinumab and canakinumab matching-placebo will be supplied by Novartis or its 
designee in the form of solution for injection as ready-to-use pre-filled syringes.






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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301
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. No PK DDI is expected between 
warfarin and docetaxel as these two drugs are eliminated by different CYP-mediated enzymes 
(warfarin by CYP2C9, docetaxel by CYP3A) and are not inhibitor/inducer of each other’s 
metabolism.
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
in the appropriate eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. 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 
enrolled, 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 Palliative radiotherapy
Palliative radiation is permitted. It should not be delivered to a target lesion and it should not 
encompass more than 25% of irradiated bone marrow (see Section 16.1).
If palliative radiotherapy is initiated after the start of study treatment, the reason for its use must 
be clearly documented and progression as per RECIST 1.1 must be ruled out.
No dose modification of study drug (canakinumab/placebo) is needed during palliative 
radiotherapy.
6.2.2
Prohibited medication
6.2.2.1
Prohibited medications for canakinumab/placebo
Use of any treatments below is 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 study treatment.

Any anti retro-virals and / or any biologic drugs targeting the immune system (e.g., TNFa 
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

Washout period is not mandated, but the steroid half-life and tapering schedule need 
to be considered in patients treated with chronic high dose steroids


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
Steroids for pre-medication related to chemotherapy as per local standard of care are 
permitted

Live and attenuated vaccines within 3 months of study treatment and after initiation of 
study drug. Subjects must be discontinued from the trial if administered any live vaccine 
during the course of the study
Any additional investigational drugs, devices, chemotherapy, or any antineoplastic therapies 
that may be active against cancer are NOT allowed after the start of study treatment and until 
the end of study treatment
6.2.2.2
Prohibited medications for docetaxel
Increased docetaxel toxicity has been observed when concomitant administration of strong 
CYP3A4 inhibitors (antifungals, ritonavir, macrolides). The concomitant use of docetaxel with 
strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) should be 
avoided (see Section 16.3). If the concomitant use of a strong CYP3A4 inhibitor cannot be 
avoided, a close clinical surveillance is warranted and a dose-adjustment of docetaxel may be 
suitable during the treatment with the strong CYP3A4 inhibitor. Please follow local guidelines 
as per standard of care and product labels. In patients treated with strong CYP3A4 inhibitors, 
the washout period is not mandated, but the strong inhibitor's half-life needs to be considered. 
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.
Upon signing the informed consent form, the subject is assigned to the next sequential Subject 
No. available to the investigator through the Clinical Data Management interface.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the subject to register them into the IRT.
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 (safety run-in) or 
randomized or start treatment for any reason, the reason will be entered into the appropriate 
eCRF.
6.3.2
Treatment assignment, randomization
Prior to dosing, for all subjects who fulfill all inclusion/exclusion criteria, the investigator or 
his/her delegate will log on to the IRT system and confirm that the subject fulfills all the 
inclusion/exclusion criteria by completing the key eligibility criteria checklist embedded in the 
system.
Part 1: Safety run-in








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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301
Novartis will communicate the agreed dose decision in writing to the Dose Level Review Team 
(DLRT), data monitoring committee (DMC), steering committee (SC), and all participating 
investigators. Additional communication in a form of teleconference, webcast, or Investigator 
Meeting may be implemented if needed.
6.5.1.4
Implementation of dose escalation decisions
Not applicable
6.5.1.5
Intra-Subject dose escalation
Intra-subject dose escalation is not permitted at any time.
6.5.2
Definitions of dose limiting toxicities (DLTs)
Dose-limiting toxicities will be collected and used in the safety run-in part of the study. A dose-
limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as 
unrelated to the underlying disease, disease progression, inter-current illness, or concomitant 
medications that occurs within the first 42 days of treatment with docetaxel and canakinumab 
and meets any of the criteria included in Table 6-3 . The National Cancer Institute Common 
Terminology Criteria for Adverse events (NCI CTCAE) 
 will be used for all grading. 
In addition to DLTs, the decision about the recommended Phase 3 dose will be based on a 
synthesis of all relevant data available including all CTCAE 
 Grade ≥ 2 and PK data during 
the first 42 days of combination treatment from evaluable subjects.
The investigator must notify the sponsor immediately of any DLT.
Table 6-3
Criteria for defining dose-limiting toxicities
TOXICITY 
DLT CRITERIA (NCI CTCAE v5.0 will be used for grading)
Hematological

Grade 4 neutropenia lasting more than 14 days

Grade 4 febrile neutropenia

Grade 4 anemia

Grade 3 thrombocytopenia with clinically significant bleeding (i.e. life 
threatening and invasive intervention indicated) regardless of duration or 
requirement for transfusion

Grade 4 thrombocytopenia
Infection

Drug-related Grade 4
Cutaneous reactions

≥ Grade 3
Peripheral neuropathy

≥ Grade 3
Hepato-biliary

Grade 4 bilirubin elevation

For subjects with normal baseline AST and ALT values: 

AST or ALT > 8.0 × ULN

For subjects with normal baseline AST and ALT and normal baseline bilirubin 
value: 

AST or ALT > 3.0 × ULN combined with total bilirubin > 2.0 × ULN 
without evidence of cholestasis

For subjects with abnormal baseline AST or ALT or abnormal baseline 
bilirubin value: 

[AST or ALT > 2 × baseline AND > 3.0 × ULN] OR [AST or ALT > 8.0 x 
ULN], combined with [TBIL > 2 × baseline AND > 2.0 × ULN] without 
evidence of cholestasis


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Amended Protocol Version 02 (Clean)                                                       Protocol No. CACZ885V2301
TOXICITY 
DLT CRITERIA (NCI CTCAE 
will be used for grading)
Pneumonitis

Grade 2 pneumonitis if it persists > 7 days despite treatment with 
corticosteroids.

≥ Grade 3 pneumonitis of any duration
Gastrointestinal

Nausea and vomiting ≥ Grade 3 for > 3 days despite optimal anti-emetic 
therapy.

≥ Grade 3 diarrhea for > 5 days despite optimal antidiarrheal treatment (which 
could include steroids).
Pancreas

Symptomatic serum amylase or lipase elevation, medical intervention required 
(Pancreatitis Grade 3 or higher)
Hypertension

≥ Grade 3 hypertension related to the study medication if it persists > 7 days 
despite optimal anti-hypertensive treatment

Grade 4 hypertension of any duration
Cardiac

≥ Grade 3 cardiac event that is symptomatic or requires medical intervention
Other Adverse Events
Other clinically significant adverse events:

≥ Grade 3 adverse event that has not been previously identified for docetaxel 
and/or canakinumab.

≥ Grade 3 AEs that are known to occur with docetaxel and/or canakinumab, 
but cannot be controlled using the recommended product-specific 
management guidelines or leads to ˂50% of planned exposure of study 
medications

Other clinically significant toxicities, including a single event or multiple 
occurrences of the same event that lead to a dosing delay of > 12 weeks 
should be considered to be DLTs by the Investigators and Novartis, even if 
not Grade 3 or higher.
Events which will NOT be considered as DLT for the purpose of this protocol: Clinically insignificant laboratory 
values ≤ Grade 2. For laboratory values ≥ Grade 3, the maximum allowable time limit for correction of 
electrolyte abnormalities to ≤ Grade 1 is 72 hr. Events secondary to disease progression and concomitant 
medications should not be considered DLTs. Decision about RP3R will be made by Dose Level Review Team 
(DLRT) based on a synthesis of all relevant data available from all dose levels evaluated in the ongoing study 
including safety information, DLTs , all CTCAE 
 Grade ≥ 2 toxicity, and PK data during the first 42 days of 
combination treatment from evaluable subjects.
6.5.3
Dose modifications
For subjects who do not tolerate the protocol-specified dosing schedule, dose interruptions are 
permitted as described below, in order to allow the subject to continue the study treatment:

Docetaxel dose modifications will follow the investigator's best judgment, locally 
approved docetaxel label and local clinical practice.

Canakinumab dose reductions are not permitted, only increase in the dosing interval is 
allowed (from Q3W to Q6W; from Q6W to Q9W). The longest dosing interval allowed is 
Q9W. Once the dosing interval is increased (i.e. from Q3W to Q6W; from Q6W to Q9W) 
due to toxicity, the dosing interval cannot be reverted to the previous dosing interval. 
Refer to Table 6-4.
For docetaxel and canakinumab/placebo administered as a combination:

Docetaxel and canakinumab/ placebo should be administered on the same day. If 
docetaxel needs to be interrupted due to toxicity, then canakinumab/ placebo must also be 
interrupted. If canakinumab/ placebo needs to be interrupted due to related toxicity, then 
docetaxel may also be interrupted.


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
Docetaxel and canakinumab/ placebo administration can be delayed up to 42 days until 
criteria to resume treatment are met. If the criteria to resume treatment are not met after 42 
days, consider permanently discontinue docetaxel and continue canakinumab alone. If 
docetaxel is permanently discontinued due to toxicities, the Investigator can continue 
canakinumab/ placebo alone until RECIST 1.1 disease progression ( Section 6.1.5 ).
After permanent docetaxel discontinuation:

If canakinumab/ placebo alone is interrupted for >12 weeks or if the subject misses >2 
doses of canakinumab/ placebo due to canakinumab/ placebo-related toxicities (whichever 
is longer), canakinumab/ placebo must be permanently discontinued.
These changes must be recorded on the appropriate eCRF page.
6.5.3.1
Guidelines for mandatory dose modifications for 
canakinumab/placebo
Mandatory dose interruption or discontinuation of canakinumab/placebo in the management of 
study drug related adverse reactions are summarized in Table 6-4. Clinical judgment of the 
treating physician should guide the management plan of each subject based on individual 
benefit/risk assessment. However, for events requiring discontinuation in Table 6-4, treatment 
must be discontinued.
Unscheduled local laboratory assessments may be performed if medically indicated to 
document a (potential) adverse event or when the treating physician cannot wait for central 
laboratory results for decision making (e.g. dose modifications). In this particular situation, if 
possible, the blood sample obtained at the same time point should be submitted to the central 
laboratory for analysis in parallel with local analysis.
Table 6-4
Criteria for mandatory dose interruption and re-initiation for 
canakinumab/ placebo for adverse drug reactions
Worst toxicity
(CTCAE 
 during a cycle of therapy
Mandatory dose schedule modifications for canakinumab/ 
placebo
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 dose level
Grade 3
Interrupt dose until resolved to ≤ Grade 2, then increase dosing 
intervala
Grade 4
Permanently discontinue investigational drug treatment
Exceptions to the above general guidance
Neutropenia (ANC)
Grade 2 (ANC < 1500 - 1000/mm3)
Interrupt until CTC grade 1 or less then maintain dose.
Grade 3 (ANC < 1000 - 500/mm3)/ Grade 4 
(ANC < 500/mm3) for <7 consecutive days
Interrupt until resolved to ≤ Grade 1, then:

For subjects receiving docetaxel, maintain canakinumab/ 
placebo at the same dosing interval

After permanent discontinuation 
of docetaxel, increase canakinumab/ placebo dosing 
interval.a
Grade 4 (ANC < 500/mm3) for >7 
consecutive days.
Permanently discontinue investigational drug treatment.
Grade 4 Febrile neutropenia 
Permanently discontinue investigational drug treatment


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Worst toxicity
(CTCAE 
) during a cycle of therapy
Mandatory dose schedule modifications for canakinumab/ 
placebo
Thrombocytopenia
Grade 3 (PLT < 50,000 - 25,000/mm3)
Interrupt dose until resolved to ≤ Grade 1, then:

If resolved in ≤ 7 days, then maintain dose level

If resolved in > 7, permanently discontinue investigational 
drug treatment
Serum creatinine
Grade 3
Interrupt dose until resolved to ≤ Grade 2 or baseline, then re-
start at the same dose

If not resolved within 14 days, then permanently 
discontinue subject from investigational drug treatment
Isolated bilirubin elevationb
Any elevation > ULN
Fractionate bilirubin, evaluate for cholestatic liver injury (ALP) 
or alternative causes of bilirubin elevation (e.g. disease 
progression [imaging]). Treat alternative causes according to 
local institutional guidelines
Grade 2 > 1.5 - 3.0 x ULN
Maintain dose. 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 ULNc
Interrupt dose. Repeat LFTs within 48-72 hours, then monitor 
LFTs weekly until resolution to ≤ Grade 1 or to baseline.

If resolved in ≤ 14 days, maintain dosing intervals

If resolved in > 14 days, then increase 
canakinumab/matching-placebo dosing intervalsa. 
Grade 4 > 10.0 x ULNc
See footnotef - otherwise permanently discontinue 
investigational drug treatment
Isolated AST or ALT elevationb
With normal baseline AST/ALT: 
Grade 1 > ULN - 3.0 x ULN
Maintain dose level
Grade 2 > 3.0 - 5.0 x ULN
Maintain dose level.
Repeat LFTs within 48-72 hours; if still abnormal then monitor 
LFTs at least weekly, until resolved to ≤ 3.0 x ULNd, e
Grade 3: AST or ALT > 5.0 - 10.0 x ULN
Interrupt dose. Repeat LFTs within 48-72 hours; monitor LFTs 
at least weekly, until resolved to ≤ 3.0 x ULN or to baseline. 
Then:

If resolved in ≤ 14 days, maintain dose level

If resolved in > 14 days, then increase dosing intervalsa
Grade 3: AST or ALT > 10.0 - 20.0 x ULN
Discontinue subject from investigational drug treatment. 
Repeat LFTs within 48-72 hours; monitor LFTs at least weekly 
until resolved to ≤ baseline, then increase 
canakinumab/matching-placebo dosing intervals a.
Grade 4: AST or ALT > 20.0 x ULN
Permanently discontinue subject from investigational drug.
Repeat LFTs within 48-72 hours; 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 dose. Repeat LFTs within 48-72 hours, then monitor 
LFTs weekly until recovery to baseline. 

If resolved in ≤ 14 days, maintain dose level; 

If resolved in > 14 days, increase the dosing intervala.


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Worst toxicity
(CTCAE 
) during a cycle of therapy
Mandatory dose schedule modifications for canakinumab/ 
placebo
ALT/AST > 3.0 x baseline AND >10 x ULN
Interrupt treatment. Repeat LFTs within 48-72 hours, then 
monitor weekly until resolved to baseline, then increase the 
dosing intervala.
AST or ALT (>20 x ULN)
Permanently discontinue study treatment
AST/ALT increase associated with concomitant total bilirubin increaseb
With normal baseline LFTs
AST or ALT (>3.0xULN) associated with 
concomitant total bilirubin >2.0 x ULN without 
evidence of cholestasisd
(unless Gilbert's syndrome)
Interrupt dose. Assess if case is true DILIf.
If DILI confirmed - Permanently discontinue
If Not DILI – interrupt treatment. Treat the identified cause 
according to institutional guidelines. Repeat LFTs within 48-72 
hours, then monitor weekly, till enzyme levels resolve to 
≤Grade 1 or Baseline.
Refer to  Section 6.5.4.2 for additional follow-up of potential 
drug induced liver injury cases as applicable.


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Worst toxicity
(CTCAE 
) during a cycle of therapy
Mandatory dose schedule modifications for canakinumab/ 
placebo
With abnormal baseline LFTs
ALT or AST > 3 x baseline, OR ALT or AST 
>8 x ULN (whichever is lower) combined with 
total bilirubin >2.0x ULN
After recovery, re-administration of study treatment could be 
considered only if Investigator assesses benefit to outweigh 
the risk. Any decision regarding re-administration of study 
drug/s and dose regimen, should be discussed with the 
Novartis medical and safety team.
Refer to Section 6.5.4.2 for additional follow-up of potential 
drug induced liver injury cases evaluations as applicable
Pancreatitis 
Grade 3
Interrupt canakinumab until resolved to ≤ Grade 1, then:

If resolved in ≤ 7 days, then maintain dose level

If resolved in > 7 days, then discontinue subject from 
investigational drug treatment
Hypertension
Grade 3
Interrupt dose until resolved ≤ Grade 1, then maintain dose 
level
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 investigational drug treatment
Tuberculosis or reactivation of hepatitis 
infection
Permanently discontinue investigational drug treatment
Asymptomatic laboratory abnormalities
Provide supportive care and replacement therapy

If clinically significant, follow general guidelines
LFTs- Liver function Tests
a Canakinumab/ placebo dosing interval can be increased from Q3W to Q6W and from Q6W to Q9W.
b Refer to protocol Section 6.5.4.2 for monitoring of liver toxicity.
c If total bilirubin > 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 treatment at the discretion of the investigator.
d The subject should be monitored biweekly (including LFTs), or more frequently if clinically indicated, until total 
bilirubin have resolved to baseline or stabilization over 4 weeks.
eSubject with liver metastasis and baseline values between 3 and 5 ULN are excluded from repeat assessment
Note: 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.
f 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, 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


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6.5.4
Follow-up for toxicities
6.5.4.1
Follow up for infections
Infections are the most common adverse event observed with canakinumab administration and 
may be related to canakinumab treatment. Subjects should be followed closely for any signs or 
symptoms of infection and receive prompt appropriate treatment for and suspected infection. 
Subjects will have a urinalysis performed at every study visit (screening and throughout the 
study treatment).
6.5.4.2
Follow up on potential drug-induced liver injury (DILI) cases
DILI Diagnosis
Subjects with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potentially severe DILI, 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 (See Table 6-4 in Section 6.5.3.1). Subjects meeting any of the following criteria will 
require further follow-up and assessments 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 x 
baseline] OR [AST or ALT > 8.0 x ULN], whichever is lower, combined with [TBIL > 2 
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, total bilirubin, 
direct and indirect bilirubin, alkaline phosphatase (fractionated if alkaline phosphatase 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, 
Endoscopic 
Retrograde 
Cholangiopancreatography (ERCP)) as appropriate, to rule out if increases in liver parameters 
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).
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), or hepatocellular (R ≥ 5) or mixed (R >2 and < 5) type injury.


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Table 6-5 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 6-5
Guidance on specific clinical and diagnostic assessments
Disease
Assessment
Hepatitis A, B, C, E
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, HCV RNA, 
IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis
ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis
Ethanol history, GGT, MCV, 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)
Ceruloplasmin
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, TSH; CVD / Ischemic hepatitis – 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 possible causes of 
liver injury combined. The term “drug-induced” indicates probably caused by the drug, not by 
something else, and only such a case can be considered a DILI case and should be reported as 
an SAE.
All cases 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” and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential treatment-induced liver injury”. All events should be followed up with the outcome 
clearly documented.
DILI Management
In the absence of cholestasis, these subjects should be immediately discontinued from study 
drug treatment, and repeat Liver Function Tests as soon as possible, preferably within 48 hours 
from the awareness of the abnormal results. 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:

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.


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
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, if PK analysis is performed in the study.

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 
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 Serious Adverse Event (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 appropriate eCRF.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Every time the study treatment is to be administered, IRT needs to be accessed for the 
medication (kit) number. The date and time of all study treatment injections administered during 
the study and any deviations from the protocol treatment schedule will be captured by the 
investigator staff or by field monitor on the appropriate study treatment dispensing form.
Exposure to the study treatment will be based on the number of injections administered. 
Compliance with the study treatment will be assessed by the field monitor at each visit and 
information provided by the pharmacist or by the investigator.
6.6.2
Emergency breaking of assigned treatment code
Part 1: Safety run-in 
Since this part is open-label, there is no need for treatment unblinding instructions.
Part 2: Double-blind, randomized, placebo-controlled 


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Emergency code breaks must only be undertaken when it is required to treat the subject safely. 
Most often, study treatment discontinuation and knowledge of the possible treatment 
assignments are sufficient to treat a study subject who presents with an emergency condition. 
Emergency treatment code breaks are performed using the IRT. When the investigator contacts 
the system to break a treatment code for a subject, he/she must provide the requested subject 
identifying information and confirm the necessity to break the treatment code for the subject. 
The investigator will then receive details of the investigational drug treatment for the specified 
subject and a fax or email confirming this information. The system will automatically inform 
the Novartis monitor for the site and the study team that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

study drug name (if available)

subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
Study treatment must be discontinued once emergency unblinding has occurred.
6.7
Preparation and dispensation
For canakinumab/placebo:
Each study site will be supplied by Novartis with study drug in packaging of identical 
appearance per product volume.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label, which corresponds to one of the four formulations provided (two active and 
two corresponding placebo forms). For more details, please refer to Section 6.1. For further 
information on canakinumab/placebo injection, please refer to the "Instructions for use 
canakinumab/placebo".
Investigator staff will identify the study treatment packages for the subject at each dispensing 
visit by contacting the IRT and obtaining the medication numbers. Immediately before 
administering the study treatment, the investigator staff will detach the outer parts of the labels 
from the packaging and affix them to the source document (Drug Label Form) for that subject’s 
unique subject number.
Appropriate documentation of the subject specific dispensing process must be maintained.
For docetaxel:
Docetaxel will be supplied locally as commercially available and labeled accordingly to comply 
with legal requirements of each country. Preparation and dispensation should follow local 
guidelines as per standard practice and product label.


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6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Investigational drug 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 drug must be stored according to 
the instructions specified on the canakinumab/placebo labels and in the Investigator’s Brochure 
and the docetaxel supplier's label. Clinical supplies are to be dispensed only in accordance with 
the protocol. Technical complaints are to be reported to the respective Novartis Country 
Organization (CO) Quality Assurance.
Medication labels of canakinumab/placebo 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.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return 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.
The study drugs supply can be destroyed at the local Novartis facility or third party, as 
appropriate, or locally at the site only if permitted by local regulations and authorized by 
Novartis.
6.7.1.2
Handling of additional treatment
Not applicable
6.7.2
Instruction for prescribing and taking study treatment
Subjects will receive docetaxel 75mg/m2 and canakinumab/placebo at the RP3R as confirmed 
during the safety run-in part of the study (Please refer to Section 3 for more details on the study 
design, and Section 6.5.1 for more details of confirmation of RP3R). 
Canakinumab injection will be administered first followed by a 30-minute observation. 
Docetaxel infusion will be administered second. 
For canakinumab/placebo:
Study drug will be administered as a subcutaneous injection by appropriately trained study 
center personnel.
All dosages prescribed and dispensed to the subject and all dose interruptions during the study 
must be recorded on the appropriate eCRF.
All injections must be administered by the site staff only.
1. Choose an injection site on the upper arm, upper thigh, abdomen or buttocks. Do not use 
an area that has a rash or broken skin, or is bruised or lumpy. Avoid injecting into scar-
tissue as this may lead to insufficient exposure to canakinumab. Avoid injecting into a 
vein.
2. Clean the injection site with a new alcohol swab. Allow the area to dry. Uncap the 
injection needle.


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3. Gently pinch the skin up at the injection site. Hold the syringe at an approximately
45-degree- angle and in a single, smooth motion, push the needle straight down 
completely into the skin.
4. Keep the needle all the way in the skin while slowly pushing the syringe plunger down 
until the barrel is empty. Release the pinched skin and pull the needle straight out. Dispose 
of the needle and syringe in the sharps container without recapping or removing the 
needle.
5. After the injection: Do not rub the injection area. If bleeding occurs, apply a clean, dry 
cotton swab over the area, and press gently for 1 to 2 minutes, or until bleeding stops. 
Then apply an adhesive bandage.
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
For docetaxel:
Docetaxel administration should follow local guidelines as per standard of care and product 
labels, including steroids pre-medication. See Section 6.1.2.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), 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 
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 informed consent form 
that complies with the ICH 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 adverse effects already known about the investigational drug can 
be found in the [Canakinumab Investigator's Brochure]. 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.
Women of childbearing potential and female partners of male participants must be informed 
that them or their partner 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.




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Table 8-2
Assessment Schedule, Safety run-in part
Period
Screening
Treatment
Follow up
Visit Name
Cycle 1
Cycle 2 
Cycle 3 
etc
EOT
Safety 
follow up 
(130 days 
after last 
study 
treatment)
Efficacy follow up
Survival follow up (every 12 
weeks)
Days
-28 to -1
Da
y 1 Day 2 Day 3
Day 8
Day 15
Day 1
Day 
15
Day 1
-
-
-
-
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
Prior/concomitant 
medications
From 28 days prior to starting study treatment until 130 day after EOT or start of new antineoplastic medications, whichever is sooner. After starting a 
new antineoplastic med., only report concomitant medications for AEs/ SAEs suspected to be related to study treatment.
Non-drug therapies 
and procedures
From 28 days prior to starting study treatment until 130 day after EOT or start of new antineoplastic medications, whichever is sooner. After starting a 
new antineoplastic med., only report non-drug therapies for AEs/ SAEs suspected to be related to study treatment.
Prior anti-neoplastic 
therapies 
(medications, surgery, 
radiotherapy)
X
IRT Enrollment
X
Physical Examination
S
S
S
S
S
S


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Period
Screening
Treatment
Follow up
Visit Name
Cycle 1
Cycle 2 
Cycle 3 
etc
EOT
Safety 
follow up 
(130 days 
after last 
study 
treatment)
Efficacy follow up
Survival follow up (every 12 
weeks)
Days
-28 to -1
Da
y 1 Day 2 Day 3
Day 8
Day 15
Day 1
Day 
15
Day 1
-
-
-
-
ECOG performance 
status
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
Body Height
X
Body Weight
X
X
X
X
X
X
X
Determination of 
tuberculosis status
S
HIV screen where 
locally required
S
Hepatitis screen
X
As clinically indicated
Hematology
X
X
X
X
X
X
X
X
X
Blood Chemistry
X
X
X
X
X
X
X
X
X
Coagulation
X
As clinically indicated
Urinalysis
X
X
X
X
X
X
Serum pregnancy test
X
X
Urine pregnancy test1
S
S
S
S
CT or MRI of chest 
and abdomen
X
Every 6 weeks for the first 12 months and every 12 weeks after the 
first 12 months of treatment until disease progression
X
CT or MRI of brain
X
If clinically indicated or positive at baseline, follow same schedule as 
CT/MRI of chest and abdomen
If clinically indicated 
or positive at 
baseline, follow same 
schedule as CT/MRI 
of chest and 
abdomen


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Period
Screening
Treatment
Follow up
Visit Name
Cycle 1
Cycle 2 
Cycle 3 
etc
EOT
Safety 
follow up 
(130 days 
after last 
study 
treatment)
Efficacy follow up
Survival follow up (every 12 
weeks)
Days
-28 to -1
Da
y 1 Day 2 Day 3
Day 8
Day 15
Day 1
Day 
15
Day 1
-
-
-
-
Whole body bone 
scan
X
If clinically indicated 
If clinically indicated 
CT scan or MRI of 
other metastatic sites
If clinically 
indicated
If clinically indicated or positive at baseline, follow same schedule as 
CT/MRI of chest and abdomen
If clinically indicated 
or positive at 
baseline, follow same 
schedule as CT/MRI 
of chest and 
abdomen
Localized bone CT, 
MRI or X-Ray
If clinically 
indicated
If clinically indicated or positive at baseline, follow same schedule as 
CT/MRI of chest and abdomen
If clinically indicated 
or positive at 
baseline, follow same 
schedule as CT/MRI 
of chest and 
abdomen
Photography (for any 
skin lesions)
If clinically 
indicated
If clinically indicated or positive at baseline, follow same schedule as 
CT/MRI of chest and abdomen
If clinically indicated 
or positive at 
baseline, follow same 
schedule as CT/MRI 
of chest and 
abdomen
Electrocardiogram 
(ECG)2
X3
C6D13
Drug administration 
(docetaxel/
canakinumab)
Day 1 of each cycle
IRT drug 
discontinuation
X


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Period
Screening
Treatment
Follow up
Visit Name
Cycle 1
Cycle 2 
Cycle 3 
etc
EOT
Safety 
follow up 
(130 days 
after last 
study 
treatment)
Efficacy follow up
Survival follow up (every 12 
weeks)
Days
-28 to -1
Da
y 1 Day 2 Day 3
Day 8
Day 15
Day 1
Day 
15
Day 1
-
-
-
-
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.
SAEs related to study 
treatment 
Canakinumab PK 
sampling4
X5
X3
(C4D1, 
C6D1)3
X6
Canakinumab 
Immunogenicity 
sampling4
X3
(C4D1, 
C6D1)3
X6
Docetaxel PK 
sampling4
X3,7
X3,7
(C3D1, 
C4D1)3
Antineoplastic 
therapies since 
discontinuation of 
study treatment
X
X
X
Disposition 
assessment
X
X
X
Survival follow-up
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 For women of childbearing potential only
2 For further details please refer to Section 8.4.4 Electrocardiogram (ECG)
3 Pre-dose
4 Also to be collected as unscheduled as clinically indicated
5 Pre-dose on C1D1 / Post-dose on C1D2, C1D3, C1D8 and C1D15
6 Post-dose
7 EOI (within 5 mins), then 2, 4, 6 and 8 hr post start of infusion on Cycle 1 Day 1 and Cycle 2 Day 1 


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Table 8-3
Assessment Schedule, Randomized part
Period
Screening
Treatment
Follow up
Visit Name
Cycle 1
Cycle 2
Cycle 3 
etc / or 
until 
entering
in OLE16
EOT
Safety 
follow up 
(130 days 
after last 
study 
treatment)
Efficacy follow up
Survival follow 
up (every 12 
weeks)
Days
-28 to -1
Day 1
Day 15
Day 1
Day 15
Day 1
-
-
-
-
Informed consent
X
Optional 
pharmacogenetic 
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
Optional Archival or 
Newly obtained tumor 
sample15
X
Prior/concomitant 
medications
From 28 days prior to starting study treatment until 130 day after EOT or start of new antineoplastic medications, whichever is sooner. After 
starting a new antineoplastic med., only report concomitant medications for AEs/ SAEs suspected to be related to study treatment.
Non-drug therapies and 
procedures
From 28 days prior to starting study treatment until 130 day after EOT or start of new antineoplastic medications, whichever is sooner. After 
starting a new antineoplastic med., only report non-drug therapies for AEs/ SAEs suspected to be related to study treatment.
Prior anti-neoplastic 
therapies (medications, 
surgery, radiotherapy)
X
IRT randomization
X






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Period
Screening
Treatment
Follow up
Visit Name
Cycle 1
Cycle 2
Cycle 3 
etc / or 
until 
entering
in OLE16
EOT
Safety 
follow up 
(130 days 
after last 
study 
treatment)
Efficacy follow up
Survival follow 
up (every 12 
weeks)
Days
-28 to -1
Day 1
Day 15
Day 1
Day 15
Day 1
-
-
-
-
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.
SAEs related to 
study treatment 






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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 the 
enrollment (safety run-in) / randomization (see Table 8-2 and Table 8-3 for list of assessments 
to be performed). Laboratory parameters may be retested within the 28-day screening period 
for an individual subject if such parameters meet an exclusion criterion when initially tested. 
Laboratory assessments performed as part of the screening evaluations will not be required to 
be repeated prior to dosing (except complete blood count if not done within 7 days prior to 
treatment start) unless deemed clinically necessary by investigator and/or required as per local 
institutional policies.
Imaging assessments will be performed at screening between Day -28 and Day -1. 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 as the 
baseline images for this study. Any imaging assessments obtained after randomization cannot 
be considered baseline images.
A new ICF will need to be signed if the investigator chooses to re-screen the subject after a 
subject has screen failed. In case of re-screening, a new subject ID will be generated, however, 
site has to provide original subject ID in respective eCRF to link the two subjects for reporting 
and validation. All required screening activities must be performed when the subject is re-
screened for participation in the study. An individual subject may only be re-screened once for 
the study. Once the number of subjects screened and enrolled is likely to ensure target 
enrollment, the Sponsor may close the study to further screening. In this case, the subjects who 
screen failed will not be permitted to re-screen.
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
When all screening procedures are completed and once the subject’s eligibility has been 
checked and confirmed (i.e., all inclusion/exclusion criteria have been verified), the key 
eligibility criteria checklist will be completed prior to the first dose of study drug in the IRT 
system by the investigator or designee. The eligibility check will be embedded in the IRT 
system. For the randomized part of the study, allocation to one of the two study arms will also 
be registered via IRT. 
Please refer to Section 6.3.2 and comply with detailed guidelines in the IRT manual.
8.1.2
Information to be collected on screening failures
Subjects who sign an informed consent form and are subsequently found to be ineligible prior 
to enrollment/randomization will be considered screen failures. 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 


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will be entered into the clinical database for subjects who are screen failures, unless the subject 
experienced a serious adverse event during the screening phase (see SAE Section 10.1.2 for 
reporting details). Adverse events that are not SAEs will be followed by the investigator and 
collected only in the source data. If the subject fails to be enrolled / randomized, the IRT must 
be notified within 2 days.
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)

Any additional treatment received after the PD-(L)1 inhibitor and enrollment in the 
current study and response to the received additional treatment.

Cancer characteristics including diagnosis, history, extent of cancer, prior antineoplastic 
therapies (medications, radiation, surgeries), date of progression prior to study entry

Other assessments will be completed for the purpose of determining eligibility for 
inclusion in the study (i.e., ECOG Performance Status, complete physical examination, 
vital signs, hematology, blood chemistry, coagulation studies, urinalysis, serum pregnancy 
test for all female subjects).

Prior and current concomitant medications and surgical and medical procedures

Tumor imaging assessments - Refer to Table 8-5 .
Data to be collected on C1D1 pre-dose include:

Patient Reported Outcomes (PROs)

12-Lead ECG

PK
G
8.3
Efficacy
8.3.1
Survival assessment
All subjects will be followed for survival status every 3 months regardless of treatment 
discontinuation reason until death, lost to follow-up, or withdrawal of consent for survival 
follow-up. Additional survival assessments may be performed outside the 3 months follow-up 
schedules if a survival update is required for an interim assessment to meet safety or regulatory 
needs. Survival information can be obtained via phone, and information will be documented in 
the source documents and relevant CRFs. Information on the therapies received for NSCLC, if 
any, after treatment with study medication has been completed will be collected (including start 
date, stop date).
8.3.2
Tumor assessments
Tumor response will be assessed locally based on RECIST 1.1 (Eisenhauer et al 2009). The 
imaging assessment collection plan is presented in Table 8-2, Table 8-3, Table 8-4 and Table 
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All imaging assessments will be centrally collected and checked for quality by an imaging 
Contract Research Organization (CRO) designated by Novartis. Central review of the imaging 
assessments may be performed if deemed necessary. Please refer to the site imaging operations 
manual for additional information on image acquisition and data collection by the imaging CRO.
Central collection and quality check of imaging assessments will be discontinued in OLE.
Imaging assessments should be scheduled using the C1D1 date as the reference and should be 
respected regardless of whether treatment with study treatment is temporarily withheld or 
unscheduled assessments are performed.
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 imaging 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment.
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method or by photography, including a metric ruler) and when possible, the same local 
radiologist/physician throughout the study so that the comparison is consistent.
Combined Positron Emission Tomography (PET)/CT may be used only if the CT is of similar 
diagnostic quality as a CT performed without PET, including the utilization of IV contrast 
media. At the discretion of the Investigators, Fluorodeoxyglucose (FDG)-PET scans may be 
performed to document progressive disease per RECIST 1.1 ( Section 16.1 ).
Table 8-5
Imaging Assessment Collection Plan
Procedure
Screening
/ Baseline
Post baseline (during Treatment)
Efficacy follow up
CT or MRI of Chest 
and Abdomen (with 
intravenous contrast 
enhancement)
Mandated
Mandated every 6 weeks during the first 12 
months, and every 12 weeks thereafter 
until progression of disease (PD) as per 
RECIST 1.1 or subject withdrawal
End of Treatment (EOT): done for all 
subjects without prior documented RECIST 
1.1 PD and who do not enter the efficacy 
follow-up phase provided the last scan was 
not conducted within 30 days prior to the 
end of study treatment
For OLE only: Every 12 weeks until 36 
months since randomization, then every 6 
months thereafter until progressive disease 
(PD) as per RECIST 1.1
Efficacy Follow-up for 
progression: continue 
tumor assessments using 
the same schedule until 
RECIST 1.1 PD 
(regardless of start of new 
anti-neoplastic therapy).
Brain CT or MRI
Mandated
If clinically indicated or positive at baseline, 
follow same schedule as CT/MRI of chest 
and abdomen
If clinically indicated or 
positive at baseline, follow 
same schedule as CT/MRI 
of chest and abdomen
Whole body bone 
scan
Mandated
If clinically indicated
If clinically indicated 
CT scan or MRI of 
other metastatic 
sites (e.g., neck, 
pelvis, etc.)
Only if 
clinically 
indicated
If clinically indicated and/or positive at 
baseline, follow same schedule as CT/MRI 
of chest and abdomen
If clinically indicated and/or 
positive at baseline, follow 
same schedule as CT/MRI 
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Conducting tumor evaluations more than 6 weeks apart may expose a subject to an unnecessary 
treatment if the disease progression event takes place between the infrequent assessments.
8.4
Safety
During treatment 
Safety will be monitored by assessing physical examination, Eastern Cooperative Oncology 
Group (ECOG) Performance Status, vital signs, body weight, ECG, Patient Reported Outcomes, 
laboratory assessments including hematology, chemistry, coagulation, and urinalysis, as well 
as collecting adverse events at every visit. For details on AE collection and reporting, refer to 
Section 10. All safety assessments should be completed as per Table 8-2 Table 8-3 and Table 
8-4.
Post treatment discontinuation 
All safety assessments should be completed as per Table 8-2, Table 8-3 and Table 8-4. However, 
if the subject begins post treatment antineoplastic medication before the completion of the 130-
Day safety follow-up visit, the collection of new SAEs and AEs unrelated to study medication 
will stop and thereafter only suspected AEs and suspected SAEs will continue to be collected 
up to Day 130.
8.4.1
Laboratory evaluations
Central laboratories will be used for the analysis of scheduled hematology, biochemistry and 
other 
blood 
specimens 
collected 
as 
part 
of 
safety 
monitoring 
(as 
detailed 
in Table 8-2, Table 8-3, and Table 8-6). Local laboratories will be used for safety monitoring
(as detailed in Table 8-4 and Table 8-6) in the OLE. Additional timepoints should be added as 
deemed necessary per the investigator's best judgment to make sure toxicity profile is 
sufficiently characterized (e.g. DLT assessment in the safety run-in) and dose adjustments 
performed to safeguard the safety of the patient.
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). Laboratory values 
obtained during the Screening phase from the central laboratory will be used to assess subject’s 
eligibility. The time windows granted for laboratory evaluations are identical to the 
corresponding visit time windows for each visit (refer to Section 8).
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) and in those cases locally unscheduled testing 
may be performed and used for eligibility assessments.
Details on the collection, shipment of samples and reporting of results by the central laboratory 
are provided to investigators in the Central Laboratory Manual/Flowchart.
If at any time a subject has laboratory parameters obtained from a different (outside) laboratory, 
Novartis must be provided with a copy of the certification and a tabulation of the normal ranges 
and units for this laboratory. The investigator is responsible for reviewing all laboratory reports 
for subjects in the study and evaluating any abnormalities for clinical significance.


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The results of the local laboratory will be recorded in the appropriate eCRF if any the following 
criteria are met:

A treatment decision (e.g. treatment delay/interruption) was made 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 8-6
Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hemoglobin, Platelets, White blood cells (WBC) with Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils in percentage or absolute)
Chemistry
Albumin, ALT, AST, calcium (at screening, calcium corrected for albumin will be tested 
in addition to calcium), creatinine, creatinine clearance, total bilirubin, direct bilirubin 
(only if total bilirubin is ≥ grade 2), blood urea nitrogen (BUN) or urea, magnesium, 
potassium, sodium, fasting glucose*, phosphate (inorganic phosphorus), alkaline 
phosphatase, amylase, pancreatic amylase (as needed), lipase, GGT
Note: in OLE calcium, creatinine clearance and fasting glucose are not required to be 
tested.
Urinalysis
Macroscopic panel (Dipstick) (Color, bilirubin, Blood, Glucose, Ketones, Leukocyte 
esterase, nitrite, pH, protein, specific gravity, urobilinogen) Microscopic panel (RBC, 
WBC, casts, crystals, bacteria, epithelial cells)
Pregnancy
At screening visit and EOT, serum pregnancy test
If local requirements dictate otherwise, local regulations should be followed
Coagulation
Pro-thrombin time (PT) and International normalized ratio [INR]) or Quick Test
Hepatitis
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR (baseline)
Infection markers
Tuberculosis testing (as defined by country guidelines), HIV testing (where locally 
required)
*Glucose will be collected with fasting status.
8.4.1.1
Laboratory testings
Hematology, chemistry, coagulation, urinalysis and infectious disease markers tests are to be 
performed according to the Visit Schedules outlined in Table 8-2, Table 8-3 and Table 8-4.
Laboratory assessment done ≤ 7 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.
More frequent laboratory testing may also be performed as medically necessary, and for 
accurate DLT determination in the safety run-in. Additional results from unscheduled 
hematology lab evaluations should be recorded in the appropriate Unscheduled Visit eCRF.
Estimate of Glomerular Filtration Rate (via estimated creatinine clearance rate) will be done 
centrally using Cockcroft-Gault formula:


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8.4.2
Determination of tuberculosis status
Determination of tuberculosis (active or latent) status will be required before administration of 
study drug and should be performed as defined by country guidelines. If presence of 
tuberculosis (active or latent) is established then treatment for tuberculosis must have been 
completed according to locally approved country guidelines prior to screening for the study. In 
case a subject develops tuberculosis during the study, this event must be followed-up and 
recorded in the eCRF.
8.4.3
Performance status
The performance status will be assessed according to the Eastern Cooperative Oncology Group 
(ECOG) Performance Status Scale as specified in Table 8-7 (Oken et al 1982) following the 
schedule given in Table 8-2, Table 8-3 and Table 8-4.
Table 8-7
ECOG Performance Status
Grade
ECOG status
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
8.4.4
Electrocardiogram (ECG)
Local single 12-lead ECGs should be recorded prior to the dose administration, after the subject 
has been resting for 5-10 min prior to the time point indicated in Table 8-2 and Table 8-3. ECGs 
should be performed within 20 minutes prior to the collection of PK sample where applicable.
Local ECGs should be performed as clinically indicated in OLE as recommended in Table 8-4.
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.


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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 C1D1 should be reported on the appropriate eCRF 
page. New or worsened clinically significant findings occurring after informed consent must be 
recorded on the appropriate eCRF page.
8.4.5
Pregnancy and assessments of fertility
During screening, a serum pregnancy test will be completed for all female subjects. On Cycle 
1 Day 1 prior to dosing, at subsequent cycles and during safety follow-up, a urinary pregnancy 
test (dipstick) will be performed. A serum pregnancy test will also be completed at EOT of 
safety run-in part and EOT of double-blind randomized part. The time windows granted for 
pregnancy testing are identical to the corresponding visit time windows for each visit. Refer 
to Table 8-2 and Table 8-3. Urine pregnancy test will be performed at each visit for women 
with childbearing potential in OLE as indicated in Table 8-4. If local requirements dictate 
otherwise, local regulations should be followed.
Women who are determined not to be of childbearing potential before the study will only be 
tested at screening. When non-childbearing 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 childbearing 
potential if they have had surgical bilateral oophorectomy (with or without hysterectomy) or
bilateral tubal ligation at least six 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 childbearing potential (such testing is not covered as part of the study 
assessments). If local requirements dictate otherwise, additional local regulations should be 
followed.
If a positive pregnancy test is performed in between study visits, the subject must immediately 
notify the investigator. Male subjects must notify the investigator in case their partner becomes 
pregnant during the treatment period (Section 10.1.4).
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC-QLQ-C30, and QLQ-LC13), the EuroQoL 5-level instrument (EQ-5D-
5L, tablet version) will be used to evaluate patient-reported outcome measures of health-related 
quality-of-life, functioning, lung cancer symptoms, treatment-related side effects, and global 
health status (Aaronson et al 1993, Rabin and de Charro 2001).
All electronic Patient Reported Outcomes (ePROs) data will only be collected during the 
double-blind, randomized, placebo-controlled part and OLE of the study using an electronic 
tablet device provided by a CRO designated by Novartis. Subjects enrolled in the safety run-in 
part of the study will not complete ePROs questionnaires. All ePRO assessments should be 
administered in the subject’s local language according to the assessment schedule in Table 8-
3 and Table 8-4, prior to any assessments, treatments, or receipt of results from any test to avoid 


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biasing the subject’s perspective. In this study, the completion of the ePRO questionnaires by a
third party is not allowed. If subject belongs to vulnerable populations (i.e. illiterate, blind) and 
is not able to complete ePRO alone, hence no ePRO will be collected, this would not be a 
protocol deviation. 
In the blinded randomized part the ePROs questionnaires must be completed on Day 1 of each 
cycle regardless of study treatment dosing. If study treatment is delayed, ePROs questionnaires 
will not be completed again on the actual dosing day of the same cycle, ePROs questionnaires 
will be completed again at the end of treatment visit and then:

For subjects discontinuing treatment due to RECIST 1.1 progression and entering the 
safety follow up period, PROs will be collected within 7 days of the reported progression 
(potentially at the time of the end of treatment visit) and then again within 28 days of the 
progression.

For subjects discontinuing study treatment without prior documented RECIST 1.1 
progression, PROs will be collected, during the efficacy follow up period, at the same 
timepoints as the imaging collection until progression. Following progression, PROs will 
then be collected within 7 days and 28 days (-7/ +14 days) of the progression.
The ePRO data will only be collected at the C1D1 of OLE and at the disease progression in the 
OLE as indicated in Table 8-4. 
Subjects should be given sufficient space and time to complete all study questionnaires and all 
administered questionnaires should be reviewed for completeness. If missing responses are 
noted, the electronic tablet device will alert subjects of any missing responses, subjects should 
be encouraged to complete any missing responses. Attempts should be made to collect 
responses to all questionnaires for all subjects, including from those who discontinue prior to 
the study evaluation completion visit, however, if subjects refuse to complete questionnaires, 
this should be documented in study source records. Subject’s refusal to complete study 
questionnaires are not protocol deviations.
Please refer to the study ePRO manual for detailed instructions for completion and handling of 
the ePROs.
8.5.2
Pharmacokinetics
8.5.2.1
Blood collection (serum) for canakinumab pharmacokinetics (PK), 
 and immunogenicity (IG) during Safety Run-
in Part and Randomized part
Time points of blood sample collection for canakinumab/placebo PK, IG 
 are outlined 
in Table 16-14 (safety run-in part) and Table 16-15 (randomized part)- Appendix 5. Blood 
samples will be taken by either direct venipuncture or an indwelling cannula inserted in a 
forearm vein.
If dose level -1 (DL-1) of canakinumab/placebo 200 mg Q6W is explored as an alternative 
schedule (see Section 6.5.1.1), the canakinumab PK, 
 and IG sampling schemes in 
Section 16.7 will be followed.
On days and time points where blood IG and PK samples are to be drawn, the PK sample must 
be drawn first. If subjects experience a SAE or an AE leading to the discontinuation of the study 




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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 permanently 
stopped, 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.
An end of treatment visit will be performed when subjects permanently discontinue the study 
treatment. This visit should take place ≤ 7 days after the last dose of study treatment, if possible 
and the disposition 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.
Study treatment must be discontinued under the following circumstances

Subject/guardian decision

Physician decision

Disease progression by RECIST 1.1

Pregnancy

Any situation in which study participation might result in a safety risk to the subject

Subject lost to follow up

Study terminated by the 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 also contact the IRT to register the subject’s 
discontinuation from study treatment. If discontinuation occurs because treatment code has 
been broken, please refer to Emergency breaking of assigned treatment code section 
(Section 6.6.2).
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 (Section 9.1.2). Where possible, they should return for the assessments 
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.


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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.
After study treatment discontinuation, all randomized and/or treated subjects should have a 
safety follow-up visit conducted 130 days after last administration of study treatment. 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.
For subjects who discontinue treatment without prior documented disease progression by 
RECIST 1.1 will continue tumor assessments until documented disease progression by RECIST 
1.1 as per investigator assessment, withdrawal of consent, pregnancy, lost to follow-up or death 
irrespective of start of new anti-neoplastic therapy.
9.1.1.1
Replacement policy
Safety run-in part:
Subjects will not be replaced on study. However, if a subject is considered as non-evaluable for 
the Dose-Determining Set (DDS), enrollment of a new subject to the current cohort will be 
considered if there is less than the required number of evaluable subjects. Enrollment of new 
subjects may be considered until at least the minimum number 6 of evaluable subjects is 
achieved within the cohort. Minimum numbers of evaluable subjects per cohort are defined 
in Section 6.5.1.2.
Randomization part:
During the randomization part, no replacement is needed.
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 allow further collection of personal data
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.
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 8-2, Table 8-3 and Table 8-4.






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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 adverse events must be treated appropriately. Treatment may include one or more of 
the following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
6. its outcome (not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal or unknown).
If the event worsens the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined a new entry for this event should be reported in the appropriate 
eCRF noting the start date when the event improved from having been Grade 3 or Grade 4.
Adverse events that begin or worsen after informed consent should be recorded in the AE eCRF. 
Conditions that were already present at the time of informed consent should be recorded in the 
medical history eCRF. Adverse event monitoring should be continued for at least 130 days 
following the last dose of study treatment. If a new antineoplastic therapy is initiated during the 
130-day safety follow-up period, only AEs suspected to be related to study treatment will be 
collected in Adverse Events eCRF. Adverse events (including lab abnormalities that constitute 
AEs) should be described using a diagnosis whenever possible, rather than individual 
underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign or 
symptom should be reported as a separate Adverse Event.
Once 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, loss of response, progression to accelerated phase or blast crisis), should 
not be reported as a serious adverse event, except if the investigator considers that the 
progression of malignancy is related to study treatment.
Adverse events 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 [Canakinumab Investigator Brochure].
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant


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
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
Adverse events of special interest (AESIs) 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.
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data and include:

Infections/Opportunistic infections

Neutropenia

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 adverse events 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 adverse event [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


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
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 do 
not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). Confirmed COVID-19 infection should be considered as medically 
significant, therefore should be reported as SAE.
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 the 
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 serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of suspected causality, occurring after the 
subject has provided informed consent and until at least 130 days after the subject has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. If a 
new antineoplastic therapy is initiated during the 130-day safety follow-up period, only SAEs 
suspected to be related to study treatment will be collected in Adverse Events eCRF. Note: Any 
SAEs experienced after the 130-day safety follow-up period and prior to start of new post study 
treatment antineoplastic medication should only be reported to Novartis if the investigator 
suspects a causal relationship to the study treatment. Detailed instructions regarding the 
submission process and requirements are to be found in the investigator folder provided to each 
site.
The following SAE reporting timeframes apply:


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
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.

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 Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO&PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
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 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 subject becomes pregnant, the study treatment should be stopped, and the trial 
subject must be asked to read and sign pregnancy consent form to allow the Study Investigator
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. If a pregnancy occurs 
while on study treatment, the new born will be followed for up to 12 months. Pregnancy should 
be recorded and reported by the investigator to the Novartis Chief Medical Office and Patient 
Safety (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. Pregnancy outcomes should be 
collected for the female partners of any males who took study treatment in this study. Consent 
to report information regarding these pregnancy outcomes should be obtained from the mother.
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.


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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 collected in 
the appropriate eCRF 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 Dose 
Administration eCRF 
(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
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections.
10.2
Additional Safety Monitoring
10.2.1
Data Monitoring Committee
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will be constituted prior to the randomization 
of the first subject. The DMC will review at defined intervals the safety data as well as the 
efficacy and safety data from the final OS analysis and interim OS analyses of the double-blind, 
randomized, placebo-controlled part of the study. The DMC meeting will be held 
approximately every six months. Additional DMC reviews may be performed if considered 
appropriate by DMC. DMC will recommend to the sponsor whether to continue, modify or 
terminate a trial. Additional details on the conduct of final OS and interim OS analyses can be 
found in Section 12.7.
Specific details regarding composition, responsibilities, data monitoring and meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate charter that is established between the sponsor and the DMC.
10.2.2
Steering Committee
A steering committee will be established comprising of investigators participating in the trial, 
i.e. not being members of the 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.


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11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 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 eCRFs) (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.
Data collected by third parties (hematology, biochemistry, 
 PK and PROs) will be 
sent electronically to Novartis.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel (or designated 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.
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 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Randomization codes, as well as screening, randomization, and data about all study treatment(s) 
dispensed to the subject will be tracked using an Interactive Response Technology (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 the treatment codes will be unblinded 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.




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Part 2- Randomized phase III part
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
Part 1- Safety run-in part
The full analysis set (FAS) and safety set are defined in the same way and comprise all subjects 
to whom study treatment has been assigned and who received at least one dose of any study 
treatment (i.e. at least one dose of any component of canakinumab or docetaxel (including 
incomplete infusion)). Subjects will be analyzed according to the dose regimen they have been 
assigned to.
Part 2- Randomized phase III part
The FAS comprises of 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 which they have been assigned during the randomization procedure.
12.1.2
Safety set
Part 1- Safety run-in part
See definition of FAS.
Part 2- Randomized phase III part
The Safety Set includes all subjects who received at least one dose of study drug. Subjects will 
be analyzed according to the study treatment they received, either docetaxel plus canakinumab 
or docetaxel plus placebo. The 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
Dose-determining set
Part 1- Safety run-in part
The Dose-Determining Set (DDS) includes all subjects from the Safety Set who meet the 
minimum exposure criterion and have sufficient safety evaluations, or experienced a dose 
limiting toxicity (DLT) during the first 42 days of dosing.


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A subject meets the minimum exposure criterion if the subject receives at least one dose of 
canakinumab and one dose of docetaxel within first 42 days, or if the subject didn’t receive the 
planned number of doses due to dose limiting toxicity. Subjects who do not experience a DLT 
during the first 42 days are considered to have sufficient safety evaluations if they have been 
observed for ≥ 42 days following the first dose.
Subjects will be analyzed according to the study treatment received as defined for the safety set.
Part 2- Randomized phase III part
Not applicable.
12.1.4
Pharmacokinetic analysis set
Part 1- Safety run-in part
The Pharmacokinetic Analysis Set (PAS) consists of all subjects who received at least one dose 
of study drug and have at least one evaluable pharmacokinetic (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 docetaxel separately.
Part 2- Randomized phase III part
The Pharmacokinetic Analysis Set (PAS) consists of all subjects who received at least one dose 
of study drug and have at least one evaluable pharmacokinetic (PK) sample. The definition of 
an evaluable PK blood sample will be further specified in the SAP. PAS will be defined for 
canakinumab and docetaxel separately.
12.1.5
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 dose cohort for the FAS in the safety run-in part and by treatment 
arm for the FAS and safety set in the randomized phase III part. Relevant medical histories and 
current medical condition at baseline will be summarized separately by system organ class and 
preferred term, by dose cohort for the FAS in the safety run-in part and by treatment arm for 
the FAS and safety set in the randomized phase III part.
12.3
Treatments
The Safety set will be used for the analyses below.
The exposure related analyses will be presented by treatment cohort and canakinumab dose 
regimen for the safety run-in part and by treatment group for the randomized Phase III part.
The duration of exposure for study treatment and for each study drug (canakinumab, and 
docetaxel) will be presented. The dose intensity and the relative dose intensity will be 
summarized for each study drug component by descriptive statistics.
The number of subjects with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized for each study drug. All dosing data will 


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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)
Part 1- Safety run-in part
The primary objective is to determine the Recommended Phase 3 Regimen (RP3R) of the 
combination of canakinumab and docetaxel for the randomized part.
Part 2- Randomized phase III part
The primary objective is to compare the overall survival (OS) in the docetaxel plus 
canakinumab arm versus docetaxel plus placebo arm.
12.4.1
Definition of primary endpoint(s)
Part 1- Safety run-in part
The primary endpoint is the incidence of dose limiting toxicities in the first 42 days of dosing 
associated with administration of canakinumab in combination with docetaxel.
Part 2- Randomized phase III part
The primary endpoint is OS, defined as the time from the date of randomization to the date of 
death due to any cause. Censoring conventions are provided below in Section 12.4.3.
12.4.2
Statistical model, hypothesis, and method of analysis
Part 1- Safety run-in part
Identification of recommended regimen
Determination of the RP3R of canakinumab in combination with docetaxel will be based upon 
the estimation of the probability of DLT up to 42 days following first dose for subjects in the 
dose-determining set. A lower recommended regimen may be identified based on other safety 
and PK data from the current study ( Section 6.5.1.2 )
Bayesian adaptive approach
The determination of RP3R will be guided by a Bayesian analysis of DLT data for the first 42 
days during which subjects receive the combination of canakinumab and docetaxel 
(Section 16.2).
The dose-toxicity relationship of canakinumab in combination with docetaxel will be modeled 
by a 5-parameter BLRM for each dose regimen that comprises single agent toxicity parts and 
interaction part. Single agent toxicity is modelled using logistic regression for the probability 
of a subject experiencing a DLT against log-dose. The odds of a DLT for each dose regimen 
are then calculated under no interaction for the two single agent toxicities, and interaction is 
accounted for by adjusting these odds with additional model parameters (odds multipliers).
Dose recommendation


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Dose recommendations will be based on summaries of the posterior distribution of DLT rates 
for each dose level of the respective combination therapy. After each cohort of subjects, the 
posterior distribution for the risk of DLT for new subjects at combination doses of interest will 
be evaluated. The posterior distributions will be summarized to provide the posterior probability 
that the risk of DLT for each dose regimen lies within the following intervals:

Under-dosing: [0, 16%)

Targeted toxicity: [16%, 33%)

Excessive toxicity: [33%, 100%]
Dosing regimen decisions are guided by the escalation with overdose control principle 
(Rogatko et al 2007 ). A dosing regimen may only be used for newly enrolled subjects if the 
risk of excessive toxicity at that dosing regimen is less than 25%.
Starting dose
The starting dosing regimen is 200 mg sc Q3W canakinumab and 75 mg/m2 i.v. Q3W docetaxel 
( Section 6.5.1.1 ). For this starting dose level of canakinumab (i.e. 200 mg Q3W), the prior risk 
of excessive toxicity is 15.7%, which satisfies the EWOC criterion.
Listing of DLTs
DLTs will be listed, and their incidence summarized by primary system organ class and 
preferred term, and worst grade (CTCAE 
). Listings and summaries will be based 
on the DDS.
Part 2- Randomized phase III part
Assuming proportional hazards model for OS, the null hypothesis will be tested at one-sided 
2.5% level of significance:
H01 (null hypotheses): Θ1≥ 0 vs. Ha1 (alternative hypotheses): Θ1 < 0
Where Θ1 is the log hazard ratio of OS in the docetaxel plus canakinumab (investigational) arm 
vs. docetaxel plus placebo (control) arm.
The primary efficacy analysis to test this hypothesis and compare the two treatment groups will 
consist of a stratified log-rank test at an overall one-sided 2.5% level of significance in favor of 
the docetaxel plus canakinumab arm. The stratification will be based on following 
randomization stratification factors (line of therapy: 1 prior line of therapy vs. 2 prior lines of 
therapy; and histology: squamous vs. non-squamous ). The primary efficacy variable, OS, will 
be analyzed at the interim analysis and final analysis of a group sequential design, using a Lan-
DeMets (O’Brien-Fleming) α-spending function.
Analyses will be based on the FAS population according to the randomized treatment group 
and strata assigned at randomization. The OS distribution will be estimated using the Kaplan-
Meier method, and Kaplan-Meier curves, median and associated 95% confidence intervals will 
be presented for each treatment group. The hazard ratio for OS will be calculated, along with 
its 95% confidence interval, from a stratified Cox model using the same stratification factors as 
for the log-rank test.


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12.4.3
Handling of missing values/censoring/discontinuations
Part 1- Safety run-in part
Subjects who are ineligible for the DDS will be excluded from the primary analysis (incidence 
of DLT during first 42 days of canakinumab in combination with docetaxel), although their data 
will be used for all remaining analyses.
Other missing data will simply be noted as missing on appropriate tables/listings.
Part 2- Randomized Phase III part
If a subject is not known to have died, then OS will be censored at the latest date the subject 
was known to be alive (on or before the cut-off date).
12.4.4
Sensitivity and Supportive analyses
Part 1- Safety run-in part
Not applicable.
Part 2- Randomized phase III part Sensitivity analyses will be performed for OS in the FAS. 
Hazard ratio and 95% confidence interval for OS will be obtained from:

an unstratified and covariate unadjusted Cox model.

a stratified and covariate adjusted Cox model including covariates such as gender, age and 
smoking history.
The final list of covariates to be included in the model will be provided in the SAP. Additional 
sensitivity analyses will be detailed in the SAP.
If the primary analysis is statistically significant, subgroup analyses to assess the homogeneity 
of the treatment effect across demographic and baseline disease characteristics will be 
performed for the following subgroups:

Gender (male vs. female)

Age (<65 vs., ≥65 years)

ECOG performance status (0 vs. 1)

Smoking history (Former/Current vs. Never)

Prior line of therapy (1 vs. 2)
Additional subgroup analyses with different thresholds or variables (e.g. hs-CRP on treatment) 
may be conducted for OS. Details will be specified in the SAP.
The number of subjects censored and reasons for OS censoring will be summarized by treatment 
group.
12.5
Analysis of secondary endpoints
Part 1- Safety run-in part


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The secondary objectives in this part of the study are to characterize the safety and tolerability, 
the pharmacokinetics and to assess preliminary anti-tumor activity of canakinumab in 
combination with docetaxel. The incidence and severity of adverse events (AEs) and serious 
adverse events (SAEs), as well as changes in laboratory values, ECOG PS, vital signs, weight, 
physical examination, and cardiac parameters will be summarized. For all safety and tolerability 
descriptive analyses, the safety set will be used. All listings and tables will be presented by dose 
cohort. Refer to Section 12.5.2 for more details.
Refer to Section 12.5.3 for details on the analysis of secondary PK objectives.
Part 2- Randomized phase III part
The secondary objectives in this part of the study are to compare the two treatment groups with 
respect to PFS, tumor related efficacy variables (ORR, DCR, TTR and DOR based on RECIST 
1.1), safety and tolerability, quality of life, pharmacokinetics, and immunogenicity.
12.5.1
Efficacy endpoints
Part 1- Safety run-in part
In order to assess preliminary anti-tumor activity, ORR, DCR and DOR will be summarized in 
FAS by dose cohort, using the local investigator assessment per RECIST1.1. For definitions of 
these endpoints, refer to Section 12.4 and Section 12.5.1 for the randomized part of the study. 
Part 2- Randomized phase III part
The secondary efficacy endpoints will be assessed using the FAS. The following analyses will 
be performed based on local investigator assessment unless otherwise specified.
PFS is defined as the time from the date of randomization to the date of the first documented 
disease progression based on local investigator assessment per RECIST1.1 or death due to any 
cause. PFS will be assessed via local review according to RECIST 1.1. PFS will be censored if 
no PFS event is observed before the analysis cut-off date. The censoring date will be the date 
of the last adequate tumor assessment prior to cut-off. PFS will be analyzed in the FAS 
population according to the randomized treatment group and strata assigned at randomization. 
The PFS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curves, medians and 95% confidence intervals of the medians will be presented for each 
treatment group. The hazard ratio for PFS will be calculated, along with its 95% confidence 
interval, using a stratified Cox model.
Overall response rate (ORR) is defined as the proportion of subjects with a best overall response 
(BOR) of complete response (CR) or partial response (PR) as per local review that is 
subsequently confirmed. ORR will be evaluated according to RECIST 1.1 (see Section 16.1).
ORR based on RECIST1.1 will be calculated based on the FAS and according to the intent-to-
treat (ITT) principle. ORR and its 95% confidence interval will be presented by treatment group. 
BOR 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.

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR).


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
SD = at least one SD assessment (or better) > 5 weeks after randomization (and not 
qualifying for CR or PR).

Non-CR/Non-PD = at least one non-CR/non-PD assessment (or better) > 5 weeks after 
randomization (and not qualifying for CR or PR).

PD = progression ≤ 13 weeks after randomization (and not qualifying for CR, PR or SD).
Complete and partial responses must be confirmed by repeat assessments that should be 
performed not less than 4 weeks after the criteria for response are first met.Disease control rate 
(DCR) is defined as the proportion of subjects with BOR of CR, PR, or SD or Non-CR/Non-
PD. 
DCR will be evaluated according to RECIST 1.1(see Section 16.1 for details).DCR based on 
RECIST1.1 will be calculated based on the FAS and according to the ITT principle. DCR and 
its 95% confidence interval will be presented by treatment group.
Time to response (TTR) is defined as duration of time between the date of randomization and 
the date of first documented response of either CR or PR, which must be subsequently 
confirmed (although date of initial response is used, not date of confirmation).
TTR will be evaluated according to RECIST 1.1(see Section 16.1 for details).
All subjects in the FAS will be included in TTR calculations. Subjects without a confirmed CR 
or PR will be censored at the study-maximum follow-up time (i.e., LPLV-FPFV) for subjects 
with a PFS event (i.e., disease progression or death due to any cause), or at the date of the last 
adequate tumor assessment for subjects without a PFS event. TTR will be listed and 
summarized by treatment group based on RECIST1.1. The distribution function of TTR will be 
estimated using the Kaplan-Meier method. The median TTR along with 95% CIs will be 
presented by treatment arm.
Duration of response (DOR) is defined as the duration of time between the date of first 
documented response (CR or PR) and the date of first documented progression or death due to 
any cause.
Duration of response (DOR) only applies to subjects whose best overall response is complete 
response (CR) or partial response (PR) based on tumor response data per local review. If a 
subject has not had an event, DOR is censored at the date of last adequate tumor assessment. 
Subjects who never achieved a BOR of CR or PR will be excluded from the analysis. The 
distribution function of DOR will be estimated using the Kaplan-Meier method. The median 
DOR along with 95% CIs will be presented by treatment arm.
12.5.2
Safety endpoints
12.5.2.1 Analysis set and grouping for the analyses
For all safety analyses in the randomized part of the study, the safety set will be used. All listings 
and tables will be presented by treatment arm.
For the safety run-in part cohort, summary tables and listings will be presented by dose cohort. 
For the randomized part, summaries and listing will be presented by treatment group.
The overall observation period will be divided into three mutually exclusive segments:






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reported in a separate population pharmacokinetic report. Similarly, population PK analysis 
may also be applied to docetaxel to determine the effects of canakinumab on docetaxel.
12.5.4
Patient reported outcomes
Three patient-reported outcomes (PRO) questionnaires will be assessed: EORTC QLQ-C30 
with QLQ-LC13 incorporated and the EQ-5D-5L. QLQ-C30 and QLQ-LC13 will be considered 
as the primary scale. Scoring of PRO data and methods for handling of missing items or missing 
assessments will be handled according to the scoring manual and user guide for each respective 
subject questionnaire (Fayers et al 2001, Van Reenen et al 2015). No imputation procedures 
will be applied for missing items or missing assessments.
The FAS will be used for analyzing PRO data. Time to definitive 10 point deterioration 
symptom scores of chest pain, cough and dyspnea per QLQ-LC13 questionnaire are primary 
PRO variables of interest.
Utilities derived from EQ-5D-5L together with time to definitive deterioration in global health 
status/QoL, shortness of breath and pain per QLQ-C30 are secondary PRO variables of interest. 
The time to definitive 10 point deterioration is defined as the time from the date of 
randomization to the date of event, which is defined as at least 10 points absolute increase from 
baseline (worsening) of the corresponding scale score, with no later change below this threshold 
i.e. < 10 points was observed or if this increase was observed at the last assessment for the 
subject, or death due to any cause. If a subject has not had an event, time to definitive 
deterioration will be censored at the date of the last adequate assessment. The distribution will 
be presented descriptively using Kaplan-Meier curves. Summary statistics from Kaplan-Meier 
distributions will be determined, including the median time to definitive 10 point deterioration 
along with two-sided 95% confidence interval. Additionally, time to definitive deterioration 
with different definition for deterioration may be specified in the SAP as deemed appropriate. 
A stratified Cox regression will be used to estimate the hazard ratio (HR), along with two-sided 
95% confidence interval.
Descriptive statistics will be used to summarize the original scores, as well as change from 
baseline, of the QLQC30/ QLQ-LC13 and EQ-5D-5L at each scheduled assessment time point 
for each treatment group. Additionally, change from baseline in the scale and subscale values 
at the time of each assessment will be summarized. Subjects with an evaluable baseline score 
and at least one evaluable post baseline score during the treatment period will be included in 
the change from baseline analyses.
The number of subjects completing each questionnaire and the number of missing or incomplete 
assessments will be summarized by treatment group for each scheduled assessment time point. 
No formal statistical tests will be performed for PRO data and hence no multiplicity adjustment 
will be applied.
In addition, a repeated measures model for longitudinal data will be used to estimate differences 
in EORTC QLQ-C30/QLQ-LC13 domains as well as the visual analogue scale (VAS) and 
utility scores of the EQ-5D-5L between treatment arms. The differences in least square means 
between the treatment arms and corresponding 95% confidence interval at selected time points 
will be presented. Details, including handling of missing data, will be specified in the SAP.
ECOG Performance Status 


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ECOG performance status as described in Section 8.4.3 will be used to assess physical health 
of subjects. An analysis of the time to definitive deterioration of the ECOG PS by one category 
of the score from baseline will be performed using Kaplan-Meier and Cox regression method. 
A deterioration is considered definitive if no improvements in the ECOG PS status is observed 
at a subsequent time of measurement during the treatment period following the time point where 
the deterioration is observed.
12.7
Interim analyses
Part 1- Safety run-in part
The decision for RP3R in the safety run-in will be based on analyses performed after 
each cohort. More precisely, after each cohort of subjects the next dose will be chosen 
depending on the observed data (based on safety, PK, tolerability data, guided by the 
recommendations from the BLRM of DLT using EWOC, and recommendations from 


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participating investigators). Details of this procedure and the process for communication with 
Investigators are provided in Section 6.5.2.
Part 2- Randomized phase III part
One interim analysis is planned after approximately 96 of the approximately 137 targeted OS 
events (i.e., at approximately 70% information fraction) have been observed. This interim 
analysis is expected to occur around 20 months from the date of first subject randomized in the 
study. The primary intent of this interim analysis is to claim superior efficacy. There is no intent 
to assess futility at this interim analysis. The interim analysis will only be carried out after all 
subjects have been randomized and (if not withdrawn early) should have at least one post 
baseline assessment.
An α-spending function according to a two-look (Lan-DeMets) group sequential design with 
(O’Brien-Fleming) type stopping boundary (as implemented in East 6.4) will be used to 
construct the efficacy stopping boundaries (Lan and DeMets 1983). Based on the choice of α-
spending function described above and if the interim analysis is performed exactly after 96 OS 
events, the efficacy boundary in terms of p-value scale (or equivalently Z-statistic scale) at the 
interim is calculated as p = 0.0074 (or Z = 2.436). The observed (i.e. nominal) p-value has to 
be smaller than 0.0074 (or equivalently the observed Z-statistic has to be > Z-statistic scale 
boundary = 2.436) to conclude superior efficacy at the interim analysis.
Since the observed number of events at the interim analysis may not be exactly equal to the 
planned 96 OS events, the efficacy boundary will need to be recalculated using the pre-specified 
α-spending function and based on the actual number of observed events at interim and the total 
number of targeted events to calculate the exact information fraction. The observed p-value (or 
Z-test statistic) at the interim analysis will then be compared against the re-calculated efficacy 
boundary.
If the study continues to the final OS analysis, the final OS analysis will be performed when 
approximately 137 OS events have been observed. In practice, the final analysis will be based 
on the actual number of OS events observed at the cut-off date for the final OS analysis and α 
already spent at the interim analyses. The boundary for the final analysis will be derived 
accordingly from the pre-specified α-spending function such that the overall significance level 
across all analyses is maintained at 0.025.
The statistical properties of the group sequential design are summarized for OS in Table 12-1
below.
Table 12-1
Simulated probabilities to stop for efficacy at the interim or final OS 
analysis
Scenario
Look
# OS events
Simulated cumulative 
probabilities (%)
Simulated incremental 
probabilities (%)
Under H0 (HR=1)
Interim
96
0.8
0.8
Final
137
2.4
1.6
Under Ha
(HR=0.57)
Interim
96
61.2
61.2
Final
137
89.7
28.5
Under HR=0.67
Interim
96
32.6
32.6
Final
137
65.0
32.4


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Note: Simulation is performed in East 6.4 with number of simulations = 10,000 and 
randomization seed =1234.
Any unblinding that can occur following interim/final OS analyses are described in Section 6.4.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Safety run-in part
No formal statistical power calculations to determine sample size were performed for this part 
of the study. In the case that the starting dose (canakinumab 200 mg sc Q3W with the fixed 
dose combination of docetaxel 75 mg/m2 i.v. Q3W) is confirmed to be safe and tolerated, the 
safety run-in part is expected to enroll approximately 9 subjects in a cohort in order to have at 
least 6 evaluable subjects (i.e. who met the minimum exposure criterion and had sufficient 
safety evaluations during the first 6 weeks of canakinumab in combination with docetaxel 
dosing). Otherwise, up to 18 additional subjects are foreseen to be enrolled to assess additional 
cohorts.
Randomized phase III part
The sample size calculation is based on the primary variable OS. The hypotheses to be tested 
and details of the testing strategy are described in Section 12.4.2.
Based on available data (Herbst et al 2016, Rittmeyer et al 2017), the median OS in the 
docetaxel plus placebo arm is expected to be around 8 months. It is expected that treatment with 
docetaxel plus canakinumab will result in a 43% reduction in the hazard rate for OS, i.e., an 
expected hazard ratio of 0.57 (which corresponds to an increase in median OS to 14 months 
under the exponential model assumption).
Then in order to ensure 90% power to test the null hypothesis: OS hazard ratio = 1, versus the 
specific alternative hypothesis: OS hazard ratio = 0.57, it is calculated that a total of 137 deaths 
need to be observed. This calculation assumes analysis by a one-sided log-rank test at the overall 
2.5% level of significance, subjects randomized to the two treatment arms in a 1:1 ratio, and a 
2-look group sequential design with a Lan-DeMets (O’Brien-Fleming) alpha spending function 
using an information fraction of 70%. If the final analysis is performed when the targeted 137 
OS events are observed after exactly 96 OS events have been observed at IA, the observed 
hazard ratio will have to be < 0.711 to declare statistical significance. Assuming that enrolment 
will continue for 18 months with an accrual rate of approximately 5 subjects/month in the first 
3 months, and approximately 10 subjects/month for the next 3 months, and approximately 15 
subjects/months till the completion of enrollment, along with an assumed 5% dropout rate/year 
for OS, a total of 226 subjects will need to be randomized to observe the targeted 137 death 
events at about 8 months after the randomization date of the last subject, i.e., 26 months after 
the randomization date of the first subject. These calculations were made using the software 
package East 6.4.


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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 Good Clinical Practice, 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 Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, 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 
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.).
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


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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 
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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References
References are available upon request
Aaronson NK, Ahmedzai S, Bergman B, et al (1993) The European Organization for 
Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
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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.
Ashino T, Arima Y, Shioda S, et al (2007) Effect of interleukin-6 neutralization on CYP3A11 
and metallothionein-1/2 expressions in arthritic mouse liver. Eur. J. Pharmacol. p. 199-207.
Borghaei H, Paz-Ares L, Horn L, et al (2015) Nivolumab versus Docetaxel in Advanced 
Nonsquamous Non-Small-Cell Lung Cancer. N. Engl. J. Med. p. 1627-39.
Brahmer J, Reckamp KL, Baas P, et al (2015) Nivolumab versus Docetaxel in Advanced 
Squamous-Cell Non-Small-Cell Lung Cancer. N. Engl. J. Med. p. 123-35.
Brustugun OT, Sprauten M, Helland Å (2017) Real-world data on nivolumab treatment of 
non-small cell lung cancer. Acta Oncol p. 438-440.
Dalgleish AG, O'Byrne K (2006) Inflammation and cancer: the role of the immune response 
and angiogenesis. Cancer Treat. Res. p. 1-38.
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. p. 785-91.
EMA Guidance (2012) Guideline on the evaluation of anticancer medicinal products in man.
Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer p. 228-47.
Ellis S, Carroll KJ, Pemberton K (2008) Analysis of duration of response in oncology trials. 
Contemp Clin Trials p. 456-65.
FDA Guidelines (2007) Guidance for Industry Clinical Trial Endpoints the Approval of 
Cancer Drugs and Biologics.
Fayers PM, Aaronson NK, Bjordal K, et al (2001) The EORTC QLQ-C30 Scoring Manual.
Fossella FV, DeVore R, Kerr RN, et al (2000) Randomized phase III trial of docetaxel versus 
vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously 
treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell 
Lung Cancer Study Group. J. Clin. Oncol. p. 2354-62.
Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al (2018) Pembrolizumab plus Chemotherapy in 
Metastatic Non-Small-Cell Lung Cancer. N. Engl. J. Med. p. 2078-2092.
Geissler EK (2015) Post-transplantation malignancies: here today, gone tomorrow? Nat Rev 
Clin Oncol p. 705-17.
Globocan (2012) http://globocan.iarc.fr/Default.aspx.


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Hara M, Yonei A, Ayabe T, et al (2010) Postoperative serum C-reactive protein levels in non-
small cell lung cancer patients. Ann Thorac Cardiovasc Surg p. 85-90.
Harvey RD, Morgan ET (2014) Cancer, inflammation, and therapy: effects on cytochrome 
p450-mediated drug metabolism and implications for novel immunotherapeutic agents. Clin. 
Pharmacol. Ther. p. 449-57.
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 
randomised controlled trial. Lancet p. 1540-50.
Herzberg B, Campo MJ, Gainor JF (2017) Immune Checkpoint Inhibitors in Non-Small Cell 
Lung Cancer p. 81-88.
Jemal A, Bray F, Center MM, et al (2011) Global cancer statistics. CA Cancer J Clin p. 69-90.
Krysan K, Lee JM, Dohadwala M, et al (2008) Inflammation, epithelial to mesenchymal 
transition, and epidermal growth factor receptor tyrosine kinase inhibitor resistance. J Thorac 
Oncol p. 107-10.
Lan, K., and DeMets, DL (1983) Discrete sequential boundaries for clinical trials. Biometrika
p. 70:659–663.
Li C, Wang C (2013) Current evidences on IL1B polymorphisms and lung cancer 
susceptibility: a meta-analysis. Tumour Biol. p. 3477-82.
Mantovani A, Allavena P, Sica A, et al (2008) Cancer-related inflammation. Nature p. 436-
44.
Martini DJ, Lalani AA, Bossé D, et al (2017) Response to single agent PD-1 inhibitor after 
progression on previous PD-1/PD-L1 inhibitors: a case series. J Immunother Cancer p. 66.
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Control 
Clin Trials p. 11-8.
Naqash et al (2017) Predictive Utility of c-reactive Protein (CRP) in Advanced Stage Lung 
Cancer Treated with Anti-Programmed Cell Death-1 (PD-1) Therapy .
O'Byrne KJ, Dalgleish AG, Browning MJ, et al (2000) The relationship between angiogenesis 
and the immune response in carcinogenesis and the progression of malignant disease. Eur. J. 
Cancer p. 151-69.
O'Callaghan DS, O'Donnell D, O'Connell F, et al (2010) The role of inflammation in the 
pathogenesis of non-small cell lung cancer. J Thorac Oncol p. 2024-36.
Oken MM, Creech RH, Tormey DC, et al (1982) Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am. J. Clin. Oncol. p. 649-55.
Park SE, Lee SH, Ahn JS, et al (2018) Increased Response Rates to Salvage Chemotherapy 
Administered after PD-1/PD-L1 Inhibitors in Patients with Non-Small Cell Lung Cancer. J 
Thorac Oncol p. 106-111.


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Paz-Ares L, Luft A, Trafreshi A et al (2018) KEYNOTE 407 Phase 3 study of carboplatin-
paclitaxel or nab-paclitaxel with or without pembrolizumab for metastatic NSCLC.
Rabin R, de Charro F (2001) EQ-5D: a measure of health status from the EuroQol Group. 
Ann. Med. p. 337-43.
Ridker PM, Everett BM, Thuren T, et al (2017a) Antiinflammatory Therapy with 
Canakinumab for Atherosclerotic Disease. N. Engl. J. Med. p. 1119-1131.
Ridker PM, MacFadyen JG, Thuren T, et al (2017b) Effect of interleukin-1β inhibition with 
canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from 
a randomised, double-blind, placebo-controlled trial. Lancet p. 1833-1842.
Rittmeyer A, Barlesi F, Waterkamp D, et al (2017) Atezolizumab versus docetaxel in patients 
with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre 
randomised controlled trial. Lancet p. 255-265.
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Cancer Phase I Clinical Trials.
Scagliotti GV, De Marinis F, Rinaldi M, et al (2002) Phase III randomized trial comparing 
three platinum-based doublets in advanced non-small-cell lung cancer. J. Clin. Oncol. p. 
4285-91.
Scagliotti GV, Parikh P, von Pawel J, et al (2008) Phase III study comparing cisplatin plus 
gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-
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Schiller JH, Harrington D, Belani CP, et al (2002) Comparison of four chemotherapy 
regimens for advanced non-small-cell lung cancer. N. Engl. J. Med. p. 92-8.
Schvartsman G, Peng SA, Bis G, et al (2017) Response rates to single-agent chemotherapy 
after exposure to immune checkpoint inhibitors in advanced non-small cell lung cancer. Lung 
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Therasse P, Arbuck SG, Eisenhauer EA, et al (2000) New guidelines to evaluate the response
to treatment in solid tumors. European Organization for Research and Treatment of Cancer, 
National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl. 
Cancer Inst. p. 205-16.
Turesson C, Matteson EL (2013) Malignancy as a comorbidity in rheumatic diseases. 
Rheumatology (Oxford) p. 5-14.
Vagulienė N, Žemaitis M, Miliauskas S, et al (2011) Comparison of C-reactive protein levels 
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5D-5L instrument.


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Appendices
16.1
Appendix 1: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival, and Overall 
Survival (based on RECIST 1.1)
Document type:
TA Specific Guideline
Document status:
Version 3.2: February 11, 2016
Version 3.1: November 29, 2011
Version 3: October 19, 2009 Version 2: January 
18, 2007 Version 1: December 13, 2002
Release date:
11-Feb-2016
Authors (Version 3.2):
Authors (Version 3.1):
Authors (Version 3):
Authors (Version 2):
Authors (Version 1):
Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
GBM
Glioblastoma multiforme
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure


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TTP
Time to progression
UNK
Unknown
16.1.1
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 et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 16.1.2 and the definition of best response in 
Section 16.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 16.1.3.2 is summarizing the “time to event” 
variables, rules, which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 16.1.4 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.
16.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.
16.1.2.1 Definitions
16.1.2.1.1
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 patients without measurable disease see Section 16.1.3.2.8.
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 5mm 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 patient, 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.
16.1.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient 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 patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Information on how patients with non-measurable disease at baseline 
will be evaluated for response and how this data will be handled in the statistical analyses is 
described in Section 16.1.3.2.8.
16.1.2.2 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 patients, 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 patient 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 patient 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.
16.1.2.3 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 CRF 
(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 16.1.2.1.1.

Nodal target: See Section 16.1.2.1.1. 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 
non-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 


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lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
16.1.2.4 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 16-1) and non-target lesions (Table 16-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 16-3) as well as the presence or absence of new lesions.
16.1.2.4.1
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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16.1.2.4.2
Determination of target lesion response
Table 16-1
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 16.1.2.2).
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 CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 16-1 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 applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section.

For those patients 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 


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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 case report form 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 case report form, 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.

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.


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16.1.2.4.3
Determination of non-target lesion response
Table 16-2
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 does prevail..
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 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 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 16.1.2.4.2for assigning PD following a 
CR for the non-target lesion response in the presence of non-target lesions nodal lesions 
should be applied.


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16.1.2.4.4
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 CRF 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 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 16.1.2.5).

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 16.1.2.2.
16.1.2.5 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 16-3.
Table 16-3
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
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1 This overall lesion response also applies when there are no non-target lesions identified at baseline.
2 Once confirmed PR was achieved, all these assessments are considered PR.
3 As defined in Section 16.1.2.4.
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.


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16.1.3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 16.1.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
16.1.3.1 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 patient'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

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient 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).


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
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 patient 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 patient 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 patient. 
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.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
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 patient 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/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses.


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Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients 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 patients with a best overall response of CR or 
PR or SD. The objective of this endpoint is to summarize patients 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 patients 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 patients with progressive disease within 8 
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 and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients 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, 
patients 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).
16.1.3.2 Time to event variables
16.1.3.2.1
Progression-free survival
Usually in all Oncology studies, patients 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 
patient 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.


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16.1.3.2.2
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient 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 patient is not known to have died, survival will be censored 
at the date of last known date patient alive.
16.1.3.2.3
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 patient has not had an event, time to progression is censored at the date of last adequate 
tumor assessment.
16.1.3.2.4
PFS2
A recent EMA guidance (EMA 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 
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 with regards to censoring foreseen.
16.1.3.2.5
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.


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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 patients who did not experience treatment failure will be censored at last adequate 
tumor assessment.
16.1.3.2.6
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 patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients 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 patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by Morgan 
(1988)
It is recommended that an analysis of all patients (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 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis, et al (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-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients 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 patients 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 patients 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.


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16.1.3.2.7
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 16.1.3.2.6. It is 
recommended that an analysis of all patients (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 patients should definitely be included in 
the analysis to ensure the statistical test is valid. For analysis including all patients, patients 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 patients 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 patient 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 patients 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.
16.1.3.2.8
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 
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.


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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 backdating is 
considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 16.1.3.2.8).
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 end of treatment visit.

Date of last contact is defined as the last date the patient 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 patient 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) antineoplastic therapy or surgery.
16.1.3.2.9
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). 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 patients 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 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with non-
measurable disease is derived slightly differently according to Table 16-4.


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Table 16-4
Overall lesion response at each assessment: patients 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 16.1.2.4.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients 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 patients 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 patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses 
which exclude these particular patients. Endpoints such as PFS which are reliant on the 
determination and/or timing of progression can incorporate data from patients with only non-
measurable disease.
16.1.3.2.10
Sensitivity analyses
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 progress 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient 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 16.1.3.2.7, and using the (FDA Guidelines 2007) on 
endpoints as a reference, the following analyses can be considered:


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Table 16-5
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
Ignore the new anticancer therapy and 
follow situations above (ITT approach)
Date of last adequate assessment prior to 
new anticancer therapy
(3) Date of secondary anti-cancer therapy
(4) Date of secondary anti-cancer therapy
As per above situations
Censored
Censored
Event
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 16.1.3.2.7.
2 After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 16.1.3.2.7.
3 The rare exception to this is if the patient 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.


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Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients 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 
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 patient 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 16-5 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.


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16.1.4
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).
16.1.4.1 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.
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).
16.1.4.2 End of treatment phase completion
Patients 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 patients 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 patient, e.g., dates of telephone calls, registered letters, etc.
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment.
Patients may discontinue study treatment for any of the following reasons:

Adverse event(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 patient from trial.
16.1.4.3 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.
Patients may provide study phase completion information for one of the following reasons:

Adverse event


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
Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor
16.1.4.4 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 patients with documented deterioration 
of symptoms indicative of progression of disease should have this reason for discontinuation 
of treatment or study evaluation.
16.1.4.5 Programming rules
The following should be used for programming of efficacy results:
16.1.4.5.1
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)


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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.
16.1.4.5.2
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 
assessment date is calculated as outlined in Section 16.1.3.2.7). 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.
16.1.4.5.3
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.
16.1.4.5.4
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)’.
16.1.4.5.5
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
16.1.4.5.6
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 16-5)


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
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 16.1.3.2.7. 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:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients 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.
16.1.5
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response and 
early progression, J Clin Oncol; 19: 785-791
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465
EMA Guidance: 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 S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16


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16.2
Appendix 2: Statistical Details for Safety Run-in Part: Bayesian 
logistic regression model (BLRM): prior and design properties 
for hypothetical data scenarios
This appendix provides details of the statistical model, the derivation of prior distributions from 
historical and pre-clinical data, the results of the Bayesian analyses and respective dosing 
decisions for some hypothetical data scenarios.
16.2.1
Statistical Models
The statistical model comprises single-agent toxicity parts, which allow the incorporation of 
single-agent toxicity data, and an interaction part.
16.2.1.1 Single agent part
Let π1(d1) be the risk of DLT for Docetaxel given as a single agent at dose d1; π2(d2) be the risk 
of DLT for Canakinumab given as a single agent at dose d2. These single agent dose-DLT 
models are logistic:
Docetaxel: logit(π1(d1))=log(α1)+β1log(d1/d1*)
Canakinumab: logit(π2(d2))=log(α2)+β2log(d2/d2*)
where d1*= 75 mg/m2 Q3W and d2*= 200 mg Q3W (reference doses) are used to scale the doses 
of Docetaxel and Canakinumab, respectively. Hence, α1 and α2 (>0) are the single-agent odds 
of a DLT at d1* and d2*, respectively; and β1 and β2 (>0) are the increase in the log-odds of a 
DLT by a unit increase in log-dose.
16.2.1.2 Interaction
Under the situation of no interaction, the risk of a DLT at dose d1 of Docetaxel and dose d2 of 
Canakinumab is:
π012(d1, d2) = 1- (1 - π1 (d1))(1-π2 (d2))
To allow for interaction between Docetaxel and Canakinumab, an odds multiplier is introduced. 
The risk of DLT for combination dose (d1, d2 ) is then given by:
odds(π12 (d1, d2 ))=exp(η12×d1⁄(d1* )×d2⁄(d2* ))×odds(π120 (d1, d2 ))
where odds (π) =π⁄((1-π) ); and η12 is the log-odds ratio between the interaction and no 
interaction model at reference doses. Here η12=0 corresponds to no interaction, with η12>0 and 
η12<0 representing synergistic and antagonistic toxicity respectively.
16.2.1.3 Prior specifications
The Bayesian approach requires the specification of prior distributions for all model parameters, 
which include the single agent parameters log(α1 ), log(β1) for Docetaxel and log(α2 ), log(β2) 
for Canakinumab, and the interaction parameter η12, A meta-analytic-predictive (MAP) 
approach was used to derive the prior distribution for the single-agent model parameters for 
Canakinumab.A weakly informative prior is derived for the single-agent model parameters for 
docetaxel.


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Prior distribution for the logistic parameters
A MAP approach was used to incorporate the dose-DLT data from historical studies for 
Canakinumab. To make the prior more robust, an additional mixture component corresponding 
to high toxicity was introduced.
Description of the meta-analytic-predictive (MAP) approach
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
(log(α* ),log(β* )) of the new trial using DLT data from historical studies.
Let rds and nds be the number of patients with a DLT, and the total number of patients at dose d 
in historical trial s (s=1,…,S). The corresponding probability of a DLT is πds. αs is the single-
agent odd of a DLT at d* and βs is the increase in the log-odds of a DLT by a unit increase in 
log-dose.
The model specifications for the derivation of the MAP prior are as follows:
rds|πds ~ Bin (πds,nds )
logit (πds )=log(αs ) + βs log(d/d* )
(log(αs ),log(βs ))| μ,ψ ~ BVN(μ,ψ), s=1,…,S
(log(α* ),log(β* )) | μ,ψ ~ BVN(μ,ψ)
The parameters μ =(μ1,μ2) and ψ are the mean and between-trial covariance matrix for the 
logistic parameters, the latter with standard deviations τ1, τ2, and correlation ρ. The parameters 
τ1 and τ2 quantify the degree of between trial heterogeneity. The following priors will be used 
for these parameters:
normal priors for μ1 and μ2,
log-normal priors for τ1 and τ2, and
a uniform prior for ρ.
The MAP prior for single-agent model parameters in the new trial, (log(α* ),log(β* )), is the 
predictive distribution
(log(α* ), log(β* )) | (rds, nds s=1,…,S)
Since the predictive distribution is not available analytically, Markov chain Monte 
Carlo (MCMC) is used to simulate values from this distribution. This is implemented using 
JAGS version 3.12. The sample from this distribution is then approximated by a mixture of 
bivariate normal (BVN) distributions. BVN mixtures with increasing numbers of mixture 
components are fitted to the sample using the expectation-maximization (EM) algorithm 
(Dempster 1977). The optimal number of components of the mixture is then identified using 
the Akaike information criterion (AIC) (Akaike 1974).
Single agent Docetaxel
Single dose 75 mg/m2 Q3W is studied in this study. A weakly prior will be assumed according 
to a DLT rate of 13%. The median for the prior distribution of log(β1) is set to 0 to correspond 
to a doubling of dose leading to a doubling of the odds of DLT. The standard deviation for 
log( α1 ) is derived assuming that there is 90% probability that the DLT rate is lower than 25%


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for the model.The standard deviation for log(β1) is 1. The correlation between the two standard 
deviations is 0.
Single agent Canakinumab
For Canakinumab, this study uses a mixture prior consisting of four components. Component 
1, 2 and 3 are derived based on dose-DLT data from Canakinumab oncology study 
[CACZ885I2202] by MAP approach. The assigned total weight for Component 1, 2 and 3 is 
90%. Component 4 allows for a higher toxicity case. The assigned weight for Component 4 is 
10%.
Component 1, 2 and 3
For the MAP model for Canakinumab, reference dose d2*=200 mg Q3W is used, and data from 
S=1 historical study is available.
Canakinumab dose levels in Q3W and Q6W dosing schedule are converted to Q4W by finding 
out the dose level in Q4W which provides equivalent area under the curve (AUC0-6 weeks) for 
dose levels in Q3W and Q6W. The simulated PK profiles of canakinumab at 200 mg Q3W and 
300 mg Q4W are comparable PK for Canakinumab. Hence, 200 mg on Q3W regimen is 
equivalent to 300 mg on Q4W regimen and 200 mg on Q6W is equivalent to 150 mg on Q4W 
regimen.
After the dose conversion is performed as described above, Canakinumab single agent data is 
then used to derive MAP prior. Firstly, weakly informative priors are assumed for μ1 and μ2, 
with means corresponding to a risk of DLT at the reference dose of 10%, and a doubling in dose 
leading to a doubling in the odds of the risk of a DLT, respectively. Priors for τ1 and τ2 are 
assigned such that (1) their medians correspond to moderate between trial heterogeneity, and 
(2) their uncertainty (95% prior interval) cover plausible between-trial standard deviations 
(Neuenschwander 2014). Canakinumab data was then used to update the prior described above.
The prior distributions for the model used for deriving the MAP priors are specified 
in Table 16-6
Table 16-6
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single-agent Canakinumab model parameters
Parameter
Prior distribution
μ1
N(mean = logit(0.10), sd = 2)
μ2
N(mean = 0, sd=1)
τ1
log-normal(mean = 0.250, sd = log(2)/1.96)
τ2
log-normal(mean = 0.125, sd = log(2)/1.96)
ρ
uniform(-1,1)
Historical data is presented in Table 16-7


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Table 16-7
Historical data from [CACZ885I2202]
Canakinumab 
Q4W dose level 
(mg)
Converted to 
dose level in 
Q8W (mg)
Number of 
patients 
completed 4 
months
Number of patients with 
AEs leading to permanent 
treatment discontinuation 
in first 4 months
Number of 
patients in 
total
5
10
87
0
87
15
30
93
1
94
50
100
84
0
84
150
300
90
1
91
Component 4:
This weakly informative bivariate normal prior allows for a case with higher toxicity.

For the intercept parameter log(α2), the prior mean of -1.099 is derived based on the a-
priori median of an assumed 25% DLT rate at the reference dose d2*= 200 mg Q3W. By 
setting the standard deviation =2, the respective 95% a-priori interval for probability of 
DLT at dose 200 mg Q3W is wide (0.7%, 94.4%), which represents weak prior 
information.

For the log-slope parameter log(β2), the prior mean of 0 and prior standard deviation of 1 
allow for very flat to very steep slopes. Therefore, it is a weakly informative prior. The 
interpretation is as follows: when tripling the dose, the odds of having a DLT are 
multiplied by a factor of 3β2.

The Component 4 is set to be (-1.099, 0, 2, 1, 0)
Interaction parameter: weakly prior distribution 
Based on the available information, the interaction is centered at a 0% increase in odds of DLT 
docetaxel and under each canakinumab dosing regimen. However, in all cases, considerable 
uncertainty remains as to the true interaction, and normal priors are used that allow for both 
synergistic and antagonistic toxicity. The following assumptions will be used for interaction 
parameter for the model:

η12 is normally distributed and centered at 0, i.e. 0% increase in odds of DLT over 
independence at the combination starting dose

97.5th percentile is log(3), i.e. 3-fold increase in odds of DLT over independence at the 
combination starting dose
All the information to derive the prior distributions for the model parameters is provided 
in Table 16-8 .
16.2.2
Summary of prior distributions
The prior distributions of the model parameters are summarized in Table 16-8.
The prior summaries for DLT rates for are summarized in Table 16-9.


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Table 16-8
Prior distribution for the model parameters
Parameter
Mean
Standard 
deviations
correlation
weight
Single agent Docetaxel prior
BVN Mixture (log(α1), β1)
Weakly informative 
prior 
(-1.901 , 0)
(0.626, 1.000)
0
1.000
Single agent Canakinumab prior
BVN Mixture (log(α2), β2)
Component 1 (MAP 
prior)
(-3.847 , -0.475)
(0.651, 0.493)
0.176
0.427
Component 2 (MAP 
prior)
(-3.128 , 0.018)
(0.732, 0.425)
0.463
0.246
Component 3 (MAP 
prior)
(-4.736 , -1.105)
(0.737, 0.696)
0.004
0.227
Component 4 (high 
toxicity)
(-1.099 , 0)
(2, 1)
0
0.100
Interaction parameter
Normal
η12
0
0.561
N/A
N/A
Table 16-9
Summary of prior distribution of DLT rates
Docetax
el dose 
(mg 
Q3W)
Prior probabilities that P(DLT) is 
in the interval :
Mean
SD
Quantiles
[0, 0.16)
[0.16, 
0.33)
[0.33,1]
2.5%
50%
97.5%
In combination with Canakinumab 100 mg Q3W
75
0.535
0.380
0.085
0.181
0.187
0.048
0.152
0.502
In combination with Canakinumab 200 mg Q3W
75
0.475
0.368
0.157
0.183
0.209
0.039
0.167
0.668
Note: The P(DLT) on the excessive toxicity interval is highlighted bold.
16.2.3
Hypothetical on-study scenarios
To illustrate the performance of the Bayesian model used to guide dose de-escalation, 
hypothetical dose de-escalations scenarios following the provisional dose levels specified: 
Docetaxel 75mg/m2, i.v., Q3W+ Canakinumab 200 mg, s.c., Q3W or Docetaxel 75mg/m2, i.v., 
Q3W+ Canakinumab 200 mg, s.c., Q6W. In each case, the dose that can be used in the next 
cohort of patients is shown. This dose is determined using the model based assessment of the 
risk of DLT in future patients and the dose de-escalation rules.
Table 16-10 shows on-study dosing recommendations for some hypothetical data scenarios.
Note that the next dose combination is selected in concordance with the provisional dose levels 
specified in the protocol wherever it is allowed, to mimic possible on-study de-escalation steps.


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Table 16-10
Dose decisions recommended by BLRM under EWOC
Scenario
Docetaxel 75 
mg/m2 + 
Canakinumab
Number of
Next dose level
patients
DLTs
Docetaxel 75 
mg/m2 + 
Canakinumab
P(Target 
toxicity)
P(excessive 
toxicity)
Median 
P(DLT)
1
200 mg Q3W
6
0
200 mg Q3W
0.233
0.016
0.108
2
200 mg Q3W
6
1
200 mg Q3W
0.426
0.068
0.159
3
200 mg Q3W
6
2
200 mg Q3W
0.537
0.200
0.223
4
200 mg Q3W
6
3
200 mg Q6W
0.471
0.431
0.305
5
200 mg Q3W
6
3
200 mg Q6W
6
0
200 mg Q6W
0.584
0.050
0.183
6
200 mg Q3W
6
3
200 mg Q6W
6
1
200 mg Q6W
0.68
0.119
0.220
7
200 mg Q3W
6
3
200 mg Q6W
6
2
200 mg Q6W
0.661
0.248
0.263
8
200 mg Q3W
6
3
200 mg Q6W
6
3
Stop
0.537
0.429
0.311
Note that the overdose criterion is defined as P(excessive toxicity) < 0.25. *Additional dose levels may be 
added if allowed by the BLRM.


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16.3
Appendix 3: List of prohibited concomitant medications and 
concomitant medications requiring caution
Table 16-11
List of medications to be used with caution for docetaxel
Moderate CYP3A4/5 inhibitors
netupitant
darunavir
grapefruit juice
crizotinib
atazanavir/ritonavir
darunavir/ritonavir
aprepitant
tofisopam
amprenavir
diltiazem
casopitant
lomitapide
atazanavir
verapamil
cimetidine
imatinib
nilotinib
Moderate CYP3A4/5 inducers
bosentan
efavirenz
etravirine
modafinil
nafcillin
lersivirine
talviraline
tipranavir
lopinavir
Source: Adapted from Oncology Clinical Pharmacology Drug-Drug Interaction Database (release date: April 
2015) which was compiled from the Indiana University School of Medicine’s “Clinically Relevant” Table and 
supplemented with the FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data 
Analysis, and Implications for Dosing and Labeling (February 2012), and the University of Washington’s Drug 
Interaction Database. The lists provided may not be exhaustive.
Table 16-12
Drugs to be avoided while on study
Strong CYP3A4/5 inhibitors
Macrolide antibiotics:
Antivirals:
Antifungals:
Others:
clarithromycin
indinavir
itraconazole
conivaptan
telithromycin
lopinavir
ketoconazole
elvitegravir
troleandomycin
nelfinavir
posaconazole
mibefradil
ritonavir
voriconazole
nefazodone
saquinavir
tipranavir
Strong CYP3A4/5 inducers
avasimibe
carbamazepine
phenobarbital
phenytoin
rifabutin
rifampin
st. John’s wort
Source: Adapted from Oncology Clinical Pharmacology Drug-Drug Interaction Database (release date: April 
2015) which was compiled from the Indiana University School of Medicine’s “Clinically Relevant” Table and 
supplemented with the FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data 
Analysis, and Implications for Dosing and Labeling (February 2012), and the University of Washington’s Drug 
Interaction Database. The lists provided may not be exhaustive.
Table 16-13
CYP3A substrates with narrow therapeutic index, or sensitive CYP2C9 
substrates with narrow therapeutic index** to be used with caution 
when administering concomitantly with canakinumab
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


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* Compounds known to increase the corrected QT (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, Oct 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).
16.4
Appendix 4: Eligibility algorithm


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16.5
Appendix 5: Schedule of blood collection (serum) for 
canakinumab pharmacokinetics (PK) and immunogenicity (IG) 
during Safety Run-in Part and Randomized part for dose level 1 
with canakinumab/placebo 200mg s.c. Q3W regimen
Table 16-14
Blood collection (serum) for canakinumab pharmacokinetics (PK) and 
immunogenicity (IG) during Safety Run-in part
Dose Reference Identification 
(ID)
PK 
sample 
number
IG 
sample 
numberb
Scheduled time points 
Dose ID 
following 
sampling
Dose ID prior 
to sampling*
Cycle
Day
Scheduled time 
(hours)
Description
1
101
201
1
1
0 hra
Pre-dose
1
102
1
2
24 hr (±2h)
Post-dose
1
103
1
3
48 hr (±8h)
Post-dose
104
1
8
168 hr (±12h)
Post-dose
1
105
1
15
336 hr (±24h)
Post-dose
2
1
106
2
1
0 hra
Pre-dose
3
20
107
202
4
1
0 hra 
Pre-dose
4
21
108
203
6
1
0 hra 
Pre-dose
109
204
EOT
NA
Anytime
Post-dose
NA
NA
1001+c
2001+ d
NA
NA
Unscheduled
* These dose reference IDs refer to the dose administered and dosing time of the last dose prior to collection of 
the corresponding PK and IG samples.
a Sample should be drawn within 24 hours prior to the next dose of canakinumab
b IG 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.
d IG sample numbers for any unscheduled IG collection will start with 2001.
Table 16-15
Blood collection (serum) for canakinumab pharmacokinetics (PK), 
immunogenicity (IG) 
 during Randomized 
part
Dose Reference 
Identification (ID)
PK 
sample 
number
IG 
sample 
numberb
Scheduled time points (hours)
Dose ID 
following 
sampling
Dose ID 
prior to 
sampling*
Cycle
Day
Scheduled 
time 
(hours)
Description
11
301
401
1
1
0 hra
Pre-dose
11
302
1
15
336 hr 
(±24h)
Post-dose
12
31
303
402
4
1
0 hra
Pre-dose
13
32
304
403
6
1
0 hra
Pre-dose
14
33
305
404
12
1
0 hra
Pre-dose
15
34
306
18
1
0 hra
Pre-dose
307
405
EOT
NA
Anytime
Post-dose
308
406
safety 
follow-up
NA
130 days 
after EOT


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NA
NA
3001+c
4001+ d
NA
NA
Unschedul
ed and at 
the time of 
progressio
n or AE
* These dose reference IDs refer to the dose administered and dosing time of the last dose prior to collection of 
the corresponding PK, IG 
 samples.
a Sample should be drawn within 24 hours prior to the next dose of canakinumab
b IG 
 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 3001.
d IG sample numbers for any unscheduled IG collection will start with 4001.
16.6
Appendix 6: Schedule of blood collection (plasma) for docetaxel 
pharmacokinetic during the Safety Run-in part and Randomized 
part
Table 16-16
Blood collection (plasma) for docetaxel (1 hr IV infusion) 
pharmacokinetics (PK) during Safety Run-in part
Dose Reference Identification (ID)
PK sample 
number
Scheduled time points for PK sampling
Dose ID following 
sampling
Dose ID prior 
to sampling
Cycle
Day
Scheduled time 
(hours)
51
601
1
1
Pre-infusiona
51
602
1
1
EOI (within 5 mins)
51
603
1
1
2 hr (±10 minutes)b
51
604
1
1
4 hr (±15 minutes)b
51
605
1
1
6 hr (±30 minutes)b
51
606
1
1
8 hr (±30 minutes)b
52
51
607
2
1
Pre-infusiona
52
608
2
1
EOI (within 5 mins)
52
609
2
1
2 hr (±10 minutes)b
52
610
2
1
4 hr (±15 minutes)b
52
611
2
1
6 hr (±30 minutes)b
612
2
1
8 hr (±30 minutes)b
53
52
613
3
1
Pre-infusiona
54
53
614
4
1
Pre-infusiona
NA
NA
6001+c
NA
NA
Unscheduled
EOI = end of infusion
* These dose reference IDs refer to the dose administered and dosing time of the last dose prior to collection of 
the corresponding PK sample
a Take PK samples within 30 min before the infusion begins
b Time relative to beginning of infusion
c Sample numbers for any unscheduled blood collection will start with 6001.
Note:

PK blood samples are collected from the arm opposite from infusion site.

Plasma samples are collected for PK assessment


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Table 16-17
Blood collection (plasma) for docetaxel (1 hr infusion) 
pharmacokinetics (PK) during Randomized part (subset of 50 
subjects, i.e. approximately 25 subjects per arm)
Dose Reference Identification (ID)
PK sample 
number
Scheduled time points for PK sampling
Dose ID following 
sampling
Dose ID prior 
to sampling
Cycle
Day
Scheduled 
time (hours)
61
701
1
1
Pre-infusiona
61
702
1
1
EOI (within 5 
mins)
61
703
1
1
2 hr (±10 
minutes)b
61
704
1
1
4 hr (±15 
minutes)b
61
705
1
1
6 hr (±30 
minutes)b
62
61
706
2
1
Pre-infusiona
63
621
707
4
1
Pre-infusiona
63
708
4
1
EOI (within 5 
mins)
63
709
4
1
2 hr (±10 
minutes)b
63
710
4
1
4 hr (±15 
minutes)b
63
711
4
1
6 hr (±30 
minutes)b
NA
NA
7001+ c
NA
NA
Unscheduled
EOI = end of infusion
* These dose reference IDs refer to the dose administered and dosing time of the last dose prior to collection of 
the corresponding PK sample
a Take PK samples within 30 min before the infusion begins
b Time relative to beginning of infusion
c Sample numbers for any unscheduled blood collection will start with 7001.
Note:

PK blood samples are collected from the arm opposite from infusion site.

Plasma samples are collected for PK assessment


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16.7
Appendix 7: Schedule of blood collection for canakinumab 
pharmacokinetics (PK) and immunogenicity (IG) for dose level -1 
with canakinumab/placebo 200 mg s.c. Q6W regimen
Table 16-18
Blood collection (serum) for canakinumab pharmacokinetics (PK) and 
immunogenicity (IG) during the safety run-in part for dose level-1 (DL-
1)
Dose Reference 
Identification (ID)
PK 
sample 
number
IG 
sample 
numberb
Scheduled time points (hours)
Dose ID 
following 
sampling
Dose ID 
prior to 
sampling*
Cycle
Day
Scheduled time 
(hours)
Description
41
651
751
1
1
0 hra
Pre-dose
41
652
1
2
24 hr (±2h)
Post-dose
41
653
1
3
48 hr (±8h)
Post-dose
41
654
1
8
168 hr (±12h)
Post-dose
41
655
1
15
336 hr (±24h)
Post-dose
41
656
2
1
504 hr (±48h) post-
C1D1 dose)
Post-dose
42
41
657
752
3
1
0 hra (or 1008 hr 
post-C1D1 dose)
Pre-dose
42
658
753
4
1
504 hr (±48h) post-
C3D1 dose)
Post-dose
43
42
659
754
5
1
0 hra (or 1008 hr 
post-C3D1 dose)
Pre-dose
660
755
EOT, Post-
dose
6501+c
7501+ d
Unscheduled
* These dose reference IDs refer to the dose administered and dosing time of the last dose prior to collection of 
the corresponding PK and IG samples.
a Sample should be drawn within 24 hours prior to the next dose of canakinumab.
b IG 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 6501.
d IG sample numbers for any unscheduled IG collection will start with 7501.
Table 16-19
Blood collection (serum) for canakinumab pharmacokinetics (PK) and 
immunogenicity (IG) 
 during the 
randomized part for dose level-1 (DL-1)
Dose Reference 
Identification (ID)
PK 
sample 
number
IG 
sample 
numberb
Scheduled time points
Dose ID 
following 
sampling
Dose ID 
prior to 
sampling*
Cycle
Day
Scheduled 
time 
(hours)
Description
81
801
901
1
1
0 hra
Pre-dose
81
802
1
15
336 hr 
(±24h)
Post-dose
82
81
803
902
3
1
0 hra (or 
1008 hr 
post-C1D1 
dose)
Pre-dose


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Dose Reference 
Identification (ID)
PK 
sample 
number
IG 
sample 
numberb
Scheduled time points
Dose ID 
following 
sampling
Dose ID 
prior to 
sampling*
Cycle
Day
Scheduled 
time 
(hours)
Description
82
804
903
4
1
504 hr 
(±48h) 
post-C3D1 
dose)
Post-dose
83
82
805
904
5
1
0 hra (or 
1008 hr 
post-C3D1 
dose)
Pre-dose
84
91
806
11
1
0 hra (or 
1008 hr 
post-C9D1 
dose)
Pre-dose
85
92
807
905
17
1
0 hra (or 
1008 hr 
post-
C15D1 
dose)
Pre-dose
808
906
EOT, Post-
dose
809
907
safety 
follow-up, 
130 days 
after EOT
8001+c
9001+ d
Unschedule
d and at the 
time of 
progression 
or AE
* These dose reference IDs refer to the dose administered and dosing time of the last dose prior to collection of 
the corresponding PK, IG 
 samples.
a Sample should be drawn within 24 hours prior to the next dose of canakinumab.
b IG 
 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 8001.
d IG sample numbers for any unscheduled IG collection will start with 9001.

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Date/Version
Section
Changes
Section 6
Two new references were added.


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Table of contents
Table of contents .................................................................................................................5
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
1
Introduction .......................................................................................................................10
1.1
Study design...........................................................................................................10
1.2
Study objectives and endpoints .............................................................................13
2
Statistical methods.............................................................................................................15
2.1
Data analysis general information .........................................................................15
2.1.1
Data included in the analysis.................................................................15
2.1.2
General definitions................................................................................16
2.2
Analysis sets ..........................................................................................................21
2.2.1
Safety run-in part...................................................................................21
2.2.2
Randomization Part...............................................................................23
2.2.3
Subgroup of interest ..............................................................................24
2.3
Subject disposition, demographics and other baseline characteristics ..................25
2.3.1
Randomized part ...................................................................................25
2.3.2
Safety run-in part...................................................................................28
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................28
2.4.1
Randomization part...............................................................................28
2.4.2
Safety run-in part...................................................................................31
2.5
Analysis of the primary objective..........................................................................31
2.5.1
Safety run-in Part ..................................................................................31
2.5.2
Randomization part...............................................................................33
2.6
Secondary objective: Efficacy Analysis ................................................................37
2.6.1
Randomization part...............................................................................37
2.6.2
Safety run-in Part ..................................................................................46
2.7
Secondary objective: Safety analyses....................................................................46
2.7.1
Randomization part...............................................................................46
2.7.2
Safety run-in part...................................................................................52
2.8
Secondary objective: Pharmacokinetic endpoints .................................................52
2.8.1
PK analysis in Randomization part.......................................................52
2.8.2
PK analysis in Safety run-in part ..........................................................54
2.9
Secondary objective: Immunogenicity ..................................................................54
2.10
Secondary objective: ECOG performance status ..................................................54




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List of tables
Table 2-1
Time windows for PRO and ECOG PS assessments............................19
Table 2-2
Last contact date data sources...............................................................20
Table 2-3
Subject classification based on protocol deviations and non-PD 
criteria ...................................................................................................22
Table 2-4
Options for event dates used in PFS, duration of response...................39
Table 2-5
Assessments considered for calculation of best percentage change 
for waterfall graphs ...............................................................................44
Table 2-6
AESI groupings.....................................................................................47
Table 2-7
Time windows for lab assessments.......................................................49
Table 2-8
Clinically notable changes in vital signs...............................................51
Table 2-9
Noncompartmental pharmacokinetic parameters..................................53
Table 2-10
ECOG Performance Scale.....................................................................55
60
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) ....65
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data 
listings. ..................................................................................................66
List of figures
11
Figure 1-2
Study Design: Randomization Part (including the option to 
transition to the Open Label Extension)................................................11


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List of abbreviations
ADA
Anti-drug antibodies
AE
AESI
Adverse event
Adverse events of special interest
ATC
Anatomical Therapeutic Classification
BLRM
Bayesian Logistic Regression Model
BMI
Body Mass Index
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dose Administration Record
DDS
Dose-Determining Set
DI
Dose Intensity
DL
Dose Level
DLT
Dose Limiting Toxicity
DLRT
Dose Level Review Team
DMC
Data Monitoring Committee 
DRL
Drug Reference Listing
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
FAS
Full Analysis Set
DCR
Disease control rate 
DOR
Duration of response
eCRF
Electronic Case Report Form
IA
Interim Analysis
i.v
intravenous
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NSCLC
Non-Small Cell Lung Cancer
ORR
Overall response rate 
OS
PAS
Overall Survival
Pharmacokinetic analysis set
PDI
Planned Dose Intensity
PFS
Progression free survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
PT
Patient-reported Outcomes
Preferred Term
qd
Qua’que di’e / once a day
QoL
Quality of Life
RDI
Relative Dose Intensity
RP3R
Recommended Phase 3 dose Regimen
SAP
Statistical Analysis Plan


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SC
Steering committee
SOC
System Organ Class
TA
Tumor assessment
TFLs
Tables, Figures, Listings
TTR
Time to response
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 CACZ885V2301, a randomized, double-blind, placebo-controlled, 
Phase III study evaluating the efficacy and safety of canakinumab in combination with 
docetaxel versus placebo in combination with docetaxel in patients with non-small cell lung 
cancer (NSCLC) previously treated with PD(L)1 inhibitors and platinum-based chemotherapy.
As specified in Section 12.7 of the study protocol (original version dated 17-July-2018), the 
primary analysis of overall survival (OS) will occur when approximately 137 deaths are 
observed, unless OS is declared statistically significant at the interim OS analysis, in which case 
the  interim OS analysis will be called the primary analysis of OS (approximately 96 deaths are 
expected at the interim OS analysis). At this time, the primary CSR will be produced. In the 
primary CSR, the safety run-in data will also be reported.
The content of this SAP is based on protocol CACZ885V2301 amendment 02 (dated 10-Jun-
2020). All decisions regarding analysis, as defined in the SAP document, have been made prior 
to database lock and unblinding of the study data.
1.1
Study design
This multicenter Phase III study evaluates the efficacy and safety of canakinumab in 
combination with docetaxel versus placebo in combination with docetaxel, as second or third 
line treatment, in adult subjects with advanced NSCLC who have one prior platinum-based 
chemotherapy and one prior PD-(L)1 inhibitor therapy (either given together with the PD-(L)1 
inhibitor or sequentially) and have progressed in at least one prior therapy.
This study has two parts: Safety run-in part and randomized part, which are defined below
Safety run-in part
The objective of the safety run-in part is to confirm the Recommended Phase 3 dose Regimen 
(RP3R) of the combination of canakinumab and docetaxel.
A minimum of 6 subjects will be treated with full doses of docetaxel and canakinumab dose 
level 1 (DL1): docetaxel 75mg/m2 i.v. + canakinumab 200 mg s.c., on Day 1 of each 21-day 
cycle. Subjects will be assessed for at least 2 complete cycles of treatment (21 days per cycle; 
a total of 42 days) for safety evaluation (DLT-Dose Limiting Toxicities) to define RP3R. Once 
this dose is confirmed, the randomized part of the study will begin.
The determination of RP3R will be guided by a Bayesian analysis of dose limiting toxicities 
(DLT), which occurred in the first 42 days during which subjects will receive the combination 
of canakinumab and docetaxel. The dose-toxicity relationship of canakinumab in combination 
with docetaxel will be modeled by a 5-parameter Bayesian logistic regression model (BLRM) 
for each dose regimen. In addition to the recommendations from the BLRM, toxicity 
information (including adverse events and laboratory abnormalities that are not DLTs) and PK 
information will be evaluated by the Dose Level Review Team (DLRT), comprising of study
Investigators and Novartis study personnel: the study physician and statistician.






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to Novartis and the results will be provided to the DMC by the independent statistician. The 
final OS analysis will be performed by the sponsor’s clinical team.
A separate DMC SAP specifies the analyses to be performed for the DMC safety/efficacy 
reviews.
1.2
Study objectives and endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

Safety run-in part: To confirm the 
Recommended Phase 3 Regimen (RP3R) of 
the combination of canakinumab and docetaxel

Incidence rate of dose limiting toxicities (DLTs) in 
the first 42 days associated with the administration 
of canakinumab in combination with docetaxel.

Randomized part: To compare the overall 
survival (OS) in the docetaxel plus 
canakinumab arm versus docetaxel plus 
placebo arm

OS


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Objective(s)
Endpoint(s)
Secondary objective(s)
Endpoint(s) for secondary objective(s)
Safety run-in part: 

To assess the preliminary clinical anti-tumor 
activity of canakinumab and docetaxel 
combination

ORR, DOR and DCR by investigator’s assessment 
according to RECIST 1.1

To characterize the safety and tolerability of the 
combination of canakinumab and docetaxel

Type, frequency and severity of adverse events, 
changes in laboratory values, vital signs, ECGs

To characterize the pharmacokinetics (PK) of 
canakinumab and docetaxel when given in 
combination

Concentration of canakinumab/docetaxel and PK 
parameters
Randomized part: 

To evaluate the 2 treatment arms with regards 
to progression-free survival (PFS), overall 
response rate (ORR), disease control rate 
(DCR), Time to response (TTR) and duration of 
response (DOR) based on local investigator 
assessment per RECIST1.1

PFS, ORR, DCR, TTR and DOR based on local 
investigator assessment per RECIST 1.1

To characterize the safety profile of the 
combination of docetaxel and canakinumab

AEs (CTCAE
), ECGs, vital signs and 
laboratory abnormalities

To assess the effect of docetaxel plus 
canakinumab vs docetaxel plus placebo arms 
on PROs (EORTC QLQ-C30 , lung specific 
module QLQ-LC13 and EQ-5D-5L) including 
lung cancer symptoms, health-related quality of 
life and health status

Time to definitive 10 point deterioration symptom 
scores of chest pain, cough and dyspnea per QLQ-
LC13 questionnaire are primary PRO variables of 
interest. Time to definitive deterioration in global 
health status/QoL, shortness of breath and pain per 
QLQ-C30 are secondary PRO variables of interest.
Change from baseline in EORTC-QLQ C30 and 
LC13, EQ-5D-5L

To characterize the pharmacokinetics of 
canakinumab when given in combination

Concentration of canakinumab/docetaxel and PK 
parameters

To characterize the immunogenicity (anti-drug 
antibodies, ADA) of canakinumab

Antidrug antibodies (ADA) prevalence at baseline 
and ADA incidence on-treatment

To assess the effect of docetaxel plus placebo 
vs docetaxel plus canakinumab arms on ECOG 
performance status.

Time to definitive deterioration of the 
ECOG performance status of the score from 
baseline.


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2
Statistical methods
2.1
Data analysis general information
The interim OS analyses will be performed by an independent statistician external to Novartis. 
If the DMC determined that study met the OS endpoint at the interim analysis, these results will 
be the basis of primary CSR. Otherwise, the final OS analysis will be the basis of primary CSR. 
Novartis will perform the analysis specified in this SAP for the primary CSR. SAS version 9.4
or later will be used to perform all data analyses and to generate tables, figures and listings. R -
2.3.2 will be used to perform the BLRM analysis.
2.1.1
Data included in the analysis
Data from all patients 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).
2.1.1.1
Safety Run-in Part
The analysis cut-off date for the primary analysis of study data for safety run-in part will be 
established after all enrolled subjects who have completed two cycles of treatment with 
canakinumab in combination with docetaxel (between 3 and 6 weeks of treatment, dependent 
on selected dosing regimens) or have discontinued the study. The primary analysis will 
comprise the DLT data to determine the RP3R using the BLRM.  No CSR will be written based 
on the primary analysis of safety run-in part  alone and will be presented in a CSR only at the 
final analysis of safety run-in part.
The analysis cut-off date for the final analysis of study data for safety run-in part will be 
established at the time of the primary analysis for the randomized part, when approximately 
137 OS events are expected to have occurred or when OS is declared statistically significant at 
the interim OS analysis (approximately 96 deaths are expected at the interim OS analysis). At 
this time, data for all subjects from safety run-in part collected until the data cut-off date will 
be included and will be analyzed for Dose Level 1 (DL1) cohort..
The final analysis of the safety run-in part will be included in the primary CSR along with 
BLRM and DLT results from the primary analysis.
2.1.1.2
Randomization Part
There is one interim efficacy analysis and a final analysis planned for the primary efficacy 
endpoint of OS.  A unique cut-off date will be established after the approximately targeted 
number of events for the planned interim and final analyses has been documented. For each 
of the analyses, all statistical analyses will be performed using all data collected in the 
database up to the data cut-off 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.


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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 cases, the end date will not be imputed and 
therefore will not appear in the listings. In case, there are subjects ongoing at the time of the 
primary analysis of the randomized part, a separate TFL shells will detail the planned outputs 
for any planned close-out CSR.
2.1.1.3
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. 
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 (e.g. mean, standard deviation, median, percentiles, minimum, and maximum) by 
treatment arm.
2.1.2
General definitions
2.1.2.1
Study drug and study treatment 
In the safety run-in part, Study drug refers to canakinumab and docetaxel. In the randomized 
part, study drug refers to canakinumab, canakinumab matching placebo and docetaxel. 
In the safety run-in part, study treatment refers to canakinumab in combination with docetaxel. 
In the randomized part, study treatment refers to canakinumab in combination with docetaxel 
or canakinumab matching placebo in combination with docetaxel.
Canakinumab matching placebo will be referred to as “placebo” in the remainder of this 
document.
2.1.2.2
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 (canakinumab/placebo or docetaxel) 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 of study drug.
Note : Dates from “DAR –PK sampling” eCRF will not be used for this derivation.
2.1.2.3
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug (canakinumab/placebo or docetaxel) is administered and recorded on DAR eCRF.
The date of last administration of study drug will also be referred as end of study drug.


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Note 1: Dates from “DAR –PK sampling” eCRF 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
2.1.2.4
Date of first administration of study treatment
The date of first administration of study treatment is derived as the first date when a non-zero 
dose of any component of study treatment (canakinumab/placebo or docetaxel) was 
administered as per the Dosage Administration (e)CRF. The date of first administration of study 
treatment will also be referred as start of study treatment.
For example: if the first dose of canakinumab/placebo is taken on 05JAN2019, and first dose 
of docetaxel is taken on 03JAN2019, then the date of first administration of study treatment is 
03JAN2019.
2.1.2.5
Date of last administration of study treatment 
The date of last administration of study treatment is derived as the last date when a non-zero 
dose of any component of study treatment (canakinumab/placebo or docetaxel) was 
administered as per Dose Administration (e)CRF.
For example: if the last dose of canakinumab/placebo is taken on 15APR2019, and the last dose
of docetaxel is taken on 17APR2019, then the date of last administration of study treatment is 
on 17APR2019.
2.1.2.6
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
treatment is derived to be the latest date of the last date of exposure to canakinumab/placebo
and docetaxel. The last date of exposure to study drug (canakinumab/placebo or docetaxel)
will be derived as follows: 

The last date of exposure to study drug is calculated as (last date of administration
of study drug) + (length of time interval - 1) i.e. [last date of study drug
administration+ (21-1)].
o
If the dose frequency for canakinumab shifts from Q3W to Q6W or from 
Q6W to Q9W, the last date of exposure to canakinumab will be derived 
using the same definition specified above by replacing 20 days with 41 
days (if the subject is on Q6 dose schedule) and 62 days (if the subject is 
on Q9 dose schedule). 

If the subject died or was lost to follow-up within last date of administration of
study drug + 21 days, the last date of exposure to study drug is the date of death or
the date of last contact, respectively.


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o
If the dose frequency for canakinumab shifts from Q3W to Q6W or from 
Q6W to Q9W, the last date of exposure to canakinumab needs to take into 
account whether the subject dies or was lost to follow-up within last date 
of administration of study drug + 42 days (if the subject is on Q6 dose 
schedule) or within last date of administration of study drug + 63 days (if 
the subject is on Q9 dose schedule). 
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 sections Section 2.1.2.3 and Section 2.1.2.12
respectively.
2.1.2.7
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
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.
In Safety run-in part, the reference start date for all assessments is the start of study treatment.
In Randomization part, the reference start date for safety assessments (e.g. adverse event onset,
laboratory abnormality occurrence, vital sign measurement, dose interruption, PK etc.) is
the start of study treatment; and the reference start date for all other, non-safety assessments
(i.e., survival, ECOG performance status, and patient reported outcomes (PRO)) 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.
2.1.2.8
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.
2.1.2.9
Baseline
In the Safety run-in part, the last available assessment on or before the date of start of study 
treatment is defined as “baseline” assessment for both safety and efficacy.
In the Randomization part, the last non-missing assessment, including unscheduled 
assessments on or before the date of randomization is taken as “baseline” assessment for 
efficacy. In the context of baseline definition, the efficacy evaluations also include PRO and
ECOG performance status. For PRO, if the randomization date is not Cycle 1 Day 1, PRO 
assessment on Cycle 1 Day 1 will be defined as “baseline”. For safety evaluations, the last 


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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.
For cases where time of assessment and time of treatment start is captured (e.g. pre-dose ECG, 
laboratory assessments), the last available assessment before the treatment start date/time is 
used for baseline. 
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 for ECGs or vital signs, then the last value should be considered as baseline.
2.1.2.10
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) after date of last administration 
of study treatment (including start and stop date)
3. post-treatment period: starting at day 131 after date of last administration of study 
treatment.
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 adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).  
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.
2.1.2.11
Windows for multiple assessments 
Time windows will be defined for descriptive summary of PRO and ECOG performance 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. Data obtained at the end of treatment will be classified 
as other assessment in the corresponding time window.  
Table 2-1
Time windows for PRO and ECOG PS assessments
Time Window
Planned Visit Timing 
Time Window Definition


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Treatment phase
Baseline 
On or before Study Day 1[a]
≤ Study Day 1
Week 3
Study Day 22
Study Days 2 to 32
Week 6
Study Day 43
Study Days 33 to 53
....... 
......
......
Week k
(with k = 9, 12…)
Study Day 21*(k/3)+1
Study Day 
21*(k/3)-9 to 21*(k/3)+11 
If last dose date is in the 
window, upper bound of this
time window will be EOT visit 
date +7
“Note: EOT will be included if 
EOT is performed within 7 
days of permanent 
discontinuation of study 
treatment”
Safety follow-up
(ECOG PS only)
Post treatment study day 130
Assessment taken at the 
safety follow-up
[EOT visit date+8; EOT date
+130]
Post treatment efficacy 
follow-up
Post treatment follow-up  
(Efficacy follow up) 
Every 6 or 12 weeks depending 
the study stage
First time window:  [upper 
bound of the last previous time 
windows with assessment + 1; 
TA date + TA interval at next 
visit/2]
Otherwise : [TA date - TA 
interval at this visit/2; TA
date+TA interval at next visit/2] 
7 days post disease 
progression (PRO only)
Within 7 days post disease 
progression
[disease progression date+1;
disease progression date +21 ]
28 days post disease 
progression (PRO only)
28 days post disease 
progression
[disease progression date+22; 
disease progression date +42]
[a] Study Day 1 = randomization date and PRO assessment on Cycle 1 Day1 will be baseline for 
PRO if randomization date is not Cycle 1 Day1.
2.1.2.12
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


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Source data
Conditions
Last date subject was known to be alive from 
Survival Follow-up page 
Subject status is reported to be alive, lost to 
follow-up or unknown.
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.
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. Completely 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. Partial date 
imputation is allowed for event (death)/censoring from ‘Survival information’ eCRF (Section 
5.1.2.1). 
The last contact date will be used for censoring of subjects in the analysis of overall survival.
2.2
Analysis sets
2.2.1
Safety run-in part
The full analysis set (FAS) and safety set are defined in the same way and comprise all subjects 
to whom study treatment has been assigned and who received at least one dose of study 
treatment. Subjects will be analyzed according to the dose regimen they have been assigned.
All efficacy data will be analyzed using the FAS. 
All safety data will be analyzed using the Safety Set.
The Dose-Determining Set (DDS) includes all subjects from the Safety Set who meet the
minimum exposure criterion and have sufficient safety evaluations, or experienced a dose 
limiting toxicity (DLT) during the first 42 days of dosing.
A subject meets the minimum exposure criterion if the subject receives at least one dose of 
canakinumab and one dose of docetaxel within first 42 days, or if the subject didn’t receive the 
planned number of doses due to dose limiting toxicity. Subjects who do not experience a DLT 
during the first 42 days are considered to have sufficient safety evaluations if they have been 
observed for ≥ 42 days following the first dose.


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Subjects will be analyzed according to the study treatment received as defined for the safety 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 pharmacokinetic (PK) sample. The following analysis sets will be 
derived.
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

Have pre-dose samples drawn prior to the next 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) (37 days for Q6W) 
and 26 days (624 hours) (47 days for Q6W) after the last 200 mg canakinumab dose 
administration
The docetaxel pharmacokinetic analysis set (PAS-docetaxel) includes all subjects who 
provide at least one evaluable docetaxel PK concentration. For a concentration to be evaluable, 
subjects are required to:

Receive at least one dose of docetaxel prior to sampling except C1D1 predose sample.

Have the pre-dose samples collected within 2 hour before the infusion begins 

Receive 75 mg of docetaxel prior to post-dose PK sampling
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
No dose of any component of 
study treatment
Safety Set
No written informed consent
No dose of any component of 
study treatment
DDS 
No written informed consent
See definition of DDS
PAS-canakinumab
No written informed consent
See definition of PAS-
canakinumab
PAS-docetaxel
No written informed consent
See definition of PAS-docetaxel


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2.2.2
Randomization Part
Full Analysis Set
The Full Analysis Set (FAS) comprises of 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 (Line of therapy: 1 line of prior therapy versus 2 lines of prior therapy; Histology: 
squamous versus non-squamous) to which they have been assigned 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 they received, either canakinumab+docetaxel
or placebo+docetaxel. The 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)
Please see Safety run-in part for the canakinumab pharmacokinetic analysis set (PAS-
canakinumab) and the docetaxel pharmacokinetic analysis set (PAS-docetaxel).
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.
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. 
Death events may be used in the analysis if they are captured from public records (registries), 
local law and subject informed consent permitting.
Additional data for which there is a separate informed consent, e.g. PK, 
 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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regression model stratified by randomization stratification factors. The objective of the efficacy 
subgroup analysis is to demonstrate homogeneity of treatment effect in the above subgroups.
2.2.3.2
Safety
Key safety analyses, including AEs and AESIs will be repeated on safety set in the following 
subgroups:

Gender (Male vs. Female)

Race (White vs. Black vs. Asian vs. Others (includes “Native Hawaiian or Other 
Pacific Islander” and “American Indian or Alaska Native”))

Age (<65 vs., ≥65 years)

ECOG PS status (0 vs. ≥1)

Smoking history (Former/Current vs. Never)
The objective for carrying out these subgroup analyses is to identify potential safety issues 
that may be limited to a subgroup of subjects, or safety issues that are more commonly observed 
in a subgroup of subjects.
The following safety summaries will be performed by subgroups specified above:
   AEs, regardless of study treatment, by  preferred term and maximum CTC grade
   AEs with suspected relationship to study treatment by preferred term and 
maximum CTC grade
   Adverse Event of Special Interest, irrespective of causality, by grouping, 
preferred term, maximum CTC grade 
2.2.3.3
Japan-specific subgroup analyses
Key efficacy and safety outputs, including baseline characteristics, will be repeated for the 
subjects randomized in sites from Japan. An un-stratified Cox model will be used for analysis.
These will be specified in the TFL shells. 
2.3
Subject disposition, demographics and other baseline 
characteristics
2.3.1
Randomized part
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified. Summaries will be reported by treatment arm and for all 
subjects. In addition, listings will be reported by treatment arm.  No inferential statistics will be 
provided.
2.3.1.1
Enrollment status
The following summaries will be provided in each cohort separately for the FAS overall, and 
for both treatment groups:
1. Number (%) of subjects who were randomized


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2. Number (%) of subjects who received at least one dose of study treatment after 
randomization
Number (%) of subjects screened will be summarized by country and center.  In addition, the 
number (%) of subjects randomized will be summarized by country, center and treatment group. 
For subjects who are screen failures, the reasons for not completing screening will be 
summarized based on “Screening Phase Disposition” eCRF.
2.3.1.2
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment arm using the FAS and safety set. Categorical data (e.g. gender, age groups: <65 years 
vs. vs. ≥65 years, race, WHO performance status, smoking history) will be summarized by 
frequency counts and percentages; the number and percentage of subjects with missing data 
will be provided. Continuous data (e.g. age, weight, height, body mass index (BMI)) will be 
summarized by descriptive statistics (e.g. N, mean, median, and standard deviation, percentiles,
minimum and maximum). 
BMI (kg/m2) will be calculated as weight[kg] / (height[m]2) using weight and height at Baseline.  
2.3.1.3
Baseline stratification factors
The number (%) of subjects in each randomization stratum based on data obtained from the IRT 
system will be summarized overall and by treatment arm for the FAS. Discordances between 
the stratum recorded in IRT at the time of randomization and the actual stratum recorded in the 
clinical database through the data collected on eCRF will be cross-tabulated and listed.
2.3.1.4
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, details of tumor histology/cytology and stage.   
2.3.1.5
Medical history
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on (e) CRF 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.
2.3.1.6
Other
All data collected at baseline, including source of subject referral and other informed consents 
than main study informed consent, will be listed.
2.3.1.7
Subject disposition
Enrollment by country and center will be summarized for all screened subjects and also by 
treatment arm using the FAS. The number (%) of randomized subjects included in the FAS will 
be presented overall and by treatment arm. The number (%) of screened and not-randomized 


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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 subjects who have discontinued from the post-treatment follow-up 
(based on the ‘post-treatment follow-up disposition’  page);

Reasons for discontinuation from the post-treatment follow-up (based on ‘post-
treatment follow-up’ page)
2.3.1.8
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. Protocol deviations leading to exclusion from analysis sets will be tabulated 
separately overall and by treatment arm as specified in Section 2.2. 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. One additional study specific PD is also defined to 
capture treatment delay/interruption 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


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
Treatment not given

Patient discontinuation due to COVID-19 situation

Treatment delayed/interrupted (CANOPY-2 study specific)
A cross-tabulation of COVID-19 related PD vs. corresponding relationship will also be 
produced by treatment arm. In addition, COVID-19 related outcomes (e.g., COVID-19 AEs, 
discontinuation due to COVID-19, death due to COVID-19) will be descriptively summarized 
by country, site and treatment arm.
2.3.1.9
Analysis sets
The number (%) of subjects in each analysis set will be summarized by treatment arm and 
randomization stratum.
2.3.2
Safety run-in part
Summaries will be reported by dose cohort and for all subjects; and listings will be reported by 
dose cohort. The following analyses will be repeated for Safety run-in part using the analysis 
details specified for the randomized part in Section 2.3.1. 

Number (%) of subjects treated will be summarized by country, center and dose cohort

Basic demographic and background data

Diagnosis and extent of cancer

Medical history will be listed

Subject disposition and screening disposition

Protocol deviations

Analysis sets
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Randomization part
2.4.1.1
Study treatment / compliance
Duration of study treatment exposure, cumulative dose, dose intensity (DI) and relative dose 
intensity (RDI) will be summarized by treatment. The number of subjects with dose change, 
interruptions, discontinuation and the corresponding reasons, will be summarized and listed. 
Details of the derivations and summaries are provided in the following sections.
The safety set will be used for all summaries and listings of study treatment. 
For the missing date of last administration, use the data handling rule in Section 5.1.2.2
2.4.1.1.1
Duration of study treatment exposure
Duration of exposure to study drug (for canakinumab/placebo and docetaxel) is defined 
according to dosing regimen for each study drug as outlined in Section 2.1.2.1.


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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 is considered 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. ‘Date of first administration of 
study drug/treatment’ and ‘last date of exposure to study drug/treatment’ are defined in Sections 
2.1.2.2 to 2.1.2.6.
Duration of exposure to study drug/treatment will be categorized into time intervals (<1 month, 
at least 1 month, at least 2 months etc.). In addition, summary statistics will be displayed.
Note: If the last record in DAR CRF is a zero dose, this record will not be used in the analyses. 
For subjects who have ongoing treatment, see Section 5.1.2.2.
2.4.1.1.2 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/placebo and docetaxel is defined based on the days when 
the subject is assumed to have taken a non-zero dose during dosing periods. 
2.4.1.1.3 Dose intensity and relative dose intensity
Actual dose intensity (DI) for subjects with non-zero duration of exposure is defined as follows: 
For canakinumab (/placebo)

DI (mg/cycle) = Actual Cumulative dose (mg) / (last date of administration of study 
drug - first date of administration of study drug + length of dose frequency)*21 
(days/cycle)
Where length of dose frequency = 21 if last dose is given on Q3W, and 42 if last dose is given 
on Q6W and 63 if last dose is given on Q9W

PDI (planned dose intensity) is the planned dose as per protocol in mg (i.e. 200 mg Q3W)

RDI (%) = DI (mg/cycle) / PDI (mg/cycle)
For docetaxel 

DI (mg/m2 /cycle) = Actual Cumulative dose (mg) / (last date of administration of study 
drug - first date of administration of study drug + 21)*21 (days/cycle)


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
PDI is the planned dose as per protocol in mg (i.e. 75 mg/m2 Q3W)

RDI (%) = DI (mg/m2 /cycle) / PDI (mg/m2 /cycle)
2.4.1.1.4 Dose changes, interruptions or permanent discontinuations
The number of subjects who have dose changes, dose interruptions and dose permanent 
discontinuations and the corresponding reasons, will be summarized separately for each of the 
study treatment components. 
The duration of the interruption will be summarized for each observed interruption by time 
intervals in weeks : <1week, [1-2 weeks), [2-3 weeks), …  as well as by descriptive statistics. 
The time intervals may be adjusted depending on the observed data.
Of note, a dose interruption reported in the eCRF after the last dose of study drug, won’t be 
considered in the analysis as a dose interruption. 
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive cycles with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive cycles, then it will be counted as one interruption.
For docetaxel, dose change is defined as a reduction of dose from the protocol planned starting 
dose or a decrease from the previous non-zero dose, even if this decrease has been directly 
preceded by an interruption. For canakinumab/placebo, dose change is defined as any dosing 
interval increase from Q3W to Q6W, or from Q6W to Q9W.
2.4.1.2
Prior, concomitant and post therapies
2.4.1.2.1 Prior anti-cancer therapy
The number and percentage of subjects who received any prior anti-neoplastic medications, 
prior anti-neoplastic radiotherapy or prior anti-neoplastic surgery will be summarized by 
treatment arm. Prior anti-neoplastic medications will be summarized by therapy type (e.g. 
chemotherapy, etc.), setting (e.g. adjuvant, etc.) and also by ATC class, preferred term and 
treatment arm. Summaries will include total number of regimens. The medication therapy type 
of any combination therapy will be counted in each therapy. For example, a combination 
therapy of chemotherapy and immunotherapy will be counted under chemotherapy and 
immunotherapy. In addition, the number of lines of prior therapy and the type of regimen within 
each line of therapy (i.e. platinum-based chemotherapy, PD-(L) 1 inhibitor therapy or platinum-
based chemotherapy+PD-(L) 1 inhibitor therapy) will be summarized.
For radiotherapy, time since last radiotherapy, locations and setting of last therapy will be 
summarized by treatment arm. For prior surgery, time since last surgery, procedure and residual 
disease of last therapy will be summarized by treatment arm.
Separate listings will be produced for prior anti-neoplastic medications, radiotherapy, and 
surgery. 
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD); anti-
neoplastic surgery will be coded using MedDRA. Details regarding MedDRA and WHO-DD 
version will be included in the footnote in the tables/listings. 


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The above analyses will be performed using the FAS.
2.4.1.2.2 Post treatment anti-cancer therapy
Anti-neoplastic therapies since discontinuation of study treatment will be listed and summarized 
by ATC class, preferred term, overall and by treatment arm by means of frequency counts and 
percentages using FAS. In addition a summary of the first anti-neoplastic therapy received after 
treatment discontinuation will be summarized by treatment regimen (i.e. in case of combined 
treatments) overall and by treatment arm.
2.4.1.2.3 Concomitant medications
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a subject coinciding with the study treatment 
period. Concomitant therapy include medications (other than study treatment) 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. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference  Listing  (DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical 
(ATC) classification system and summarized by lowest ATC class and preferred term using 
frequency counts and percentages. These summaries will include:
1. Medications starting on or after the start of study treatment but no later than 130 days 
after  last date of administration 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. In addition, Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC, preferred term and treatment arm in the safety set.
2.4.2
Safety run-in part
The analyses for study treatment / compliance in Section 2.4.1.1will be repeated for safety run-
in part but by dose cohort. All prior, concomitant and post therapies in safety run-in part will 
be listed by dose cohort.
2.5
Analysis of the primary objective
2.5.1
Safety run-in Part
The primary objective is to determine the RP3R of the combination of canakinumab and 
docetaxel for the randomized part.


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2.5.1.1
Primary endpoint
The primary endpoint is the incidence of dose limiting toxicities in the first 42 days of dosing 
associated with administration of canakinumab in combination with docetaxel.
2.5.1.2
Statistical model, hypothesis, and method of analysis
Identification of recommended regimen
Determination of the RP3R of canakinumab in combination with docetaxel will be based upon 
the estimation of the probability of DLT up to 42 days following first dose for subjects in the 
dose-determining set. A lower recommended regimen may be identified based on other safety 
and PK data from the current study. For the purposes of confirming the recommended dosing 
regimen for canakinumab in combination with docetaxel to be used in the randomized part of 
the study, each cohort will consist of a minimum of 6 newly enrolled subjects who will be 
treated at the specified dose level.
The recommended dose regimen is confirmed when the following conditions are met:
1.
At least 6 subjects at this dose from DDS
2.
This dose satisfies the EWOC criteria
3.
The selected regimen is recommended either per the model or by review of all clinical 
data by the members of the Dose Level Review Team (DLRT).
If the DLRT cannot confirm the DL1 (docetaxel 75mg/m2 i.v. Q3W+ canakinumab 200 mg 
s.c.Q3W) based on the available data, the team will make a recommendation to either expand 
the cohort for additional subjects in Dose Level 1 or enroll a minimum of 6 subjects in DL-1
(docetaxel 75mg/m2 i.v. Q3W+ canakinumab 200 mg s.c.Q6W) .
Bayesian adaptive approach
The determination of RP3R will be guided by a Bayesian analysis of DLT data for the first 42 
days during which subjects receive the combination of canakinumab and docetaxel.
The dose-toxicity relationship of canakinumab in combination with docetaxel will be modeled 
by a 5-parameter BLRM for each dose regimen that comprises single agent toxicity parts and 
interaction part. Single agent toxicity is modelled using logistic regression for the probability 
of a subject experiencing a DLT against log-dose. The odds of a DLT for each dose regimen 
are then calculated under no interaction for the two single agent toxicities, and interaction is 
accounted for by adjusting these odds with additional model parameters (odds multipliers).
BLRM details are specified in the appendix of the protocol.
Dose recommendation
Dose recommendations will be based on summaries of the posterior distribution of DLT rates 
for each dose level of the respective combination therapy. After each cohort of subjects, the 
posterior distribution for the risk of DLT for new subjects at combination doses of interest will 
be evaluated. The posterior distributions will be summarized to provide the posterior probability 
that the risk of DLT for each dose regimen lies within the following intervals:

Under-dosing: [0, 16%)




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B. The primary variable is OS, defined as the time from the date of randomization to the 
date of death due to any cause.
C. The treatment of interest is the randomized treatment (canakinumab+docetaxel arm or 
the matching placebo+docetaxel arm) with or without any new anti-neoplastic therapy 
post randomization as needed. 
D. The remaining intercurrent event describes how events that may occur after 
randomization are considered when assessing the treatment effect.  
•
Discontinuation of study treatment: OS will take into account all deaths 
irrespective of the study treatment discontinuation reasons 
•
Any unforeseen intercurrent events due to COVID-19 pandemic will be 
handled by treatment policy strategy.
E. The summary measure is the hazard ratio (HR) for OS between two treatment arms. It 
will be estimated using Cox proportional hazard model stratified by randomization 
stratification factors. The primary comparison will be performed using log-rank test
stratified by randomization stratification factors.
2.5.2.2
Statistical hypothesis, model, and method of analysis
Assuming proportional hazards model for OS, the null hypothesis will be tested at one-sided 
2.5% level of significance:
H01 (null hypotheses): Θ1≥ 0 vs. Ha1 (alternative hypotheses): Θ1 < 0
Where Θ1 is the log hazard ratio of OS in the docetaxel plus canakinumab (investigational) arm 
vs. docetaxel plus placebo (control) arm.
The primary analysis to test this hypothesis and compare the two treatment groups will consist 
of a stratified log-rank test at an overall one-sided 2.5% level of significance in favor of the 
docetaxel plus canakinumab arm. The stratification will be based on following randomization 
stratification factors (line of therapy: 1 prior line of therapy vs. 2 prior lines of therapy; and 
histology: squamous vs. non-squamous). The primary efficacy variable, OS, will be analyzed 
at the interim analysis and final analysis of a group sequential design, using a Lan-DeMets 
(O’Brien-Fleming) α-spending function (Section 2.15).
Analyses will be based on the FAS population according to the randomized treatment group 
and strata assigned at randomization. The OS distribution will be estimated using the Kaplan-
Meier method, and Kaplan-Meier curves, median and associated 95% confidence intervals will 
be presented for each treatment group. The OS Kaplan-Meier estimate along with 95% 
confidence intervals will be presented at different time points (e.g. 6 months, 1 year) for each 
of the two treatment arms. The hazard ratio for OS will be calculated, along with its 95% 
confidence interval, from a stratified Cox model using the same stratification factors as for the 
log-rank test.
2.5.2.3
Handling of missing values/censoring/discontinuations
If a subject is not known to have died, then OS will be censored at the last contact date (on or 
before the cut-off date). Subjects not known to have died will be censored for ‘Lost to follow-
up’ if the time between their last contact date and the analysis cut-off date is longer than the 


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protocol specified interval between the survival follow-up assessments plus 2 weeks, i.e., 14 
weeks for this study. Otherwise subjects will be censored as ‘Alive’.
2.5.2.4
Checking proportional hazard assumption
Visual checks of the proportional hazard assumption will be performed based on the Plots 
(SURVIVAL LOGSURV LOGLOGS) generated by LIFETEST procedure in SAS (Section 
5.4.1.)  No formal analysis will be generated. 
If proportion hazard assumption doesn’t hold good, additional methods may be explored to 
assess the treatment effect. Further details will be provided in a separate post-hoc analysis plan.
2.5.2.5
Supportive analyses
For all sensitivity and supplementary estimand analysis, nominal p-values will be presented 
without any statistical inference. The following summaries will be provided: Kaplan-Meier 
estimates, estimate of the median OS along with 95% confidence interval, and hazard ratio 
obtained using the stratified Cox proportional hazards model. 
2.5.2.5.1 Sensitivity estimand analysis related to primary endpoint:
First Sensitivity analysis estimand: the target population, the primary variable, treatment 
attribute, handling of intercurrent events and the summary measure of this endpoint are the same 
as for the primary estimand. The two treatment arms will be compared using the unstratified 
log-rank test. The HR together with the associated 95% confidence interval obtained using the 
unstratified Cox regression model will also be presented. In the summary tables, this approach 
is referred as ‘unstratified OS sensitivity analysis’.
Second sensitivity analysis estimand: the target population, the primary variable, treatment 
attribute, handling of intercurrent events and the summary measure of this endpoint are the same 
as for the primary estimand. The two treatment arms will be compared using the stratified log-
rank test with stratification factors derived from the clinical database. The HR together with the 
associated 95% confidence interval obtained using the unstratified Cox regression model will 
also be presented. In the summary tables, this approach is referred as ‘OS sensitivity analyses
with stratification factors from eCRF’.
2.5.2.5.2 Supplementary estimand analysis related to primary endpoint:
First supplementary analysis estimand: the target population, the primary variable, the treatment 
of interest and intercurrent events are the same as for the primary estimand. A Cox regression 
model stratified by randomization stratification factors will be fitted to evaluate the effect of 
other baseline demographic and disease characteristics on the estimated hazard ratio. The fitted 
model adjusting the treatment difference for key baseline and prognostic factors will include as 
covariates the following: age category (<65 years vs. ≥65 years), gender (male vs. female), 
ECOG status (0 vs. 1), smoking history (former/current vs. never). In the summary tables, this 
approach is referred as ‘OS supplementary analysis adjusted for baseline covariates’.
In addition, analysis to assess the treatment effect based on OS had COVID-19 pandemic not 
occurred will be conducted. The target population, treatment of interest and the summary 
measure of this endpoint are the same as for the primary estimand. The primary variable is 


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defined as defined as the time from the date of randomization to the date of death due to non-
COVID-19 pandemic reasons. The remaining intercurrent events will be handled as follows: 
o
Discontinuation of study treatment due to any non-COVID-19 pandemic 
reasons: OS will take into account all deaths irrespective of the study treatment 
discontinuation reasons (treatment policy)
o
Discontinuation of study treatment due to COVID-19 pandemic reasons: OS 
will be censored on the date of discontinuation of treatment due to COVID-19 
pandemic (hypothetical strategy). The discontinuation reason due to COVID-19 
pandemic will be identified from the defined COVID-19 protocol deviations.
o
Medications used for treating suspected or confirmed COVID-19 cases: OS will 
be censored on the date of administration of COVID-19 medication (hypothetical 
strategy). Details to identify medications in Section 2.5.2.5.3.
o
Death due to COVID-19: OS will be censored on the date of death due to COVID-
19 reason (hypothetical strategy)
In the summary tables, this approach is referred as ‘COVID-19 OS supplementary analysis’.
2.5.2.5.3 Medications treating suspected or confirmed COVID-19
The identification of the drug used to treat COVID-19  depends on whether COVID-19 is 
confirmed or suspected.
For confirmed COVID-19, the drug treating COVID-19 is selected based on 
1. Drug indication that contains key word "COVID" or "SARS-COV" ; 
2. Drug class (CM ATC level 4) is aminoquinolines, protease inhibitors, glucocorticoids, 
macrolides, antiviral or antiretroviral; or drug name (CM standard medicine name) 
contains key word “hydroxychloroquine” or “chloroquine”. 
For suspected  COVID-19,  the drug treating COVID-19 is selected based on drug and AE 
condition
1. AE with preferred term of “SARS-CoV-2 test negative” or “suspected COVID-19”;
2. Drug class (CM ATC level 4) is aminoquinolines, protease inhibitors, glucocorticoids, 
macrolides, antiviral or antiretroviral; or drug name (CM standard medicine name) 
contains key word “hydroxychloroquine” or “chloroquine”; or drug class (CM ATC 
level 4) is glucocorticoids and drug indication contains key word "PNEUM" or equals 
to "DYSPNEA"; 
3. Select the first drug with start date within a time window of +/- 7 days selected AE 
start date. 
2.5.2.5.4 Subgroup analyses for the primary endpoint
If the primary efficacy analysis is statistically significant, the primary endpoint of OS will be 
summarized for the subgroups, which are specified in Section 2.2.3.1 and China subgroup, 
defined as subjects randomized in sites from China using the same conventions as for the 
primary analysis. If sample size of China subgroup is small, then an un-stratified Cox model 
will be used.


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2.5.2.5.5 Censoring pattern of OS
Number of subjects with an OS event and number of subjects censored for the OS analysis will 
be summarized. In addition, a summary of reasons for OS censoring will be provided by 
treatment arm.
The pattern of censored data will be examined between the treatment arms: reasons for 
censoring (‘Alive’ or ‘Lost to follow-up’) will be summarized by treatment arm, details in 
Section 2.5.2.3.
2.6
Secondary objective: Efficacy Analysis 
2.6.1
Randomization part
The secondary efficacy endpoints will be assessed using the FAS. The following analyses will 
be performed based on local investigator assessment unless otherwise specified.
2.6.1.1
Progression survival free (PFS)
PFS based on local investigator assessment as per RECIST 1.1 will be one of the secondary 
efficacy endpoints. The analysis will be based on the FAS and will include all data observed 
up-to the cut-off date. 
The scientific objective guiding the secondary estimand is to estimate the treatment effect based 
on the secondary endpoint of PFS for the combination of canakinumab with docetaxel compared 
to the combination of placebo with docetaxel, for the target population irrespective of any post-
treatment anti-neoplastic therapy received. The secondary estimand will be described by the 
following five attributes:

The target population is defined by all subjects randomized in the study (FAS) )-- adult 
subjects with locally advanced (stage IIIB) or metastatic (stage IV) non-small cell lung 
cancer, who have been previously treated and progressed on platinum-based 
chemotherapy and PD-(L)1-inhibitor (either in combination or sequentially). 

The secondary variable is PFS defined as the time from the date of randomization to 
the date of the first documented disease progression based on local investigator 
assessment as per RECIST 1.1 or date of death due to any cause, whichever occurs first.

The treatment of interest is the randomized treatment (canakinumab arm or the 
matching placebo arm) with or without any new anti-neoplastic therapy post 
randomization as needed.

The remaining intercurrent event describes how events that may occur after 
randomization are considered when assessing the treatment effect.  
o
Discontinuation of study treatment: PFS will take into account all PFS events 
irrespective of the study treatment discontinuation reasons (treatment policy)
o
Any unforeseen intercurrent events due to COVID-19 pandemic will be handled by 
treatment policy strategy.

The summary measure is the hazard ratio (HR) for PFS between the two treatment 
arms. It will be estimated using Cox proportional hazard model stratified by the 
randomization stratification factors. 


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PFS will be censored if no PFS event is observed before the analysis cut-off date. The censoring 
date will be the date of the last adequate tumor assessment prior to cut-off. PFS will be analyzed 
in the FAS population according to the randomized treatment group and strata assigned at 
randomization. The PFS distribution will be estimated using the Kaplan-Meier method, and the 
Kaplan-Meier curves, medians and 95% confidence intervals of the medians will be presented 
for each treatment group. The PFS Kaplan-Meier estimate along with 95% confidence intervals
will be presented at different time points (e.g. 2 months, 4 months and 6 months) for each of 
the two treatment arms. The hazard ratio for PFS will be calculated, along with its 95% 
confidence interval, using a stratified Cox model.
2.6.1.1.1 PFS censoring
The analysis of PFS will be based on the local radiological assessments up until the cut-off date 
defined in Section 2.1.1. The analysis will be performed on the FAS and will use the default 
censoring and event date options from Table 2-4 based on options A(1), B(1), C1(1), C2(1), 
D(1), E(1), and F(1). In particular, PFS will be censored at the last adequate tumor assessment 
if a subject didn’t have an event or if the event occurred after two or more missing tumor 
assessments. PFS will not be censored if a new antineoplastic therapy is started; instead, an 
Intent-To-Treat approach will be used and this new antineoplastic therapy will be ignored for 
the purposes of PFS derivation (and tumor assessments will continue), i.e. option F(1) in Table 
2-4 will be used. Discontinuation of study treatment (for any reason) will not be considered as 
a reason for censoring. A new anticancer therapy is defined in Section 2.6.1.1.2.


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Table 2-4
Options for event dates used in PFS, duration of response
2.6.1.1.2 Supplementary analysis for PFS
Supplementary analysis secondary estimand : the target population, the variable, intercurrent 
events and the summary measure of this endpoint are the same as for the secondary estimand. 
The treatment of interest is the randomized treatment (canakinumab arm or the matching 
placebo arm without any antineoplastic therapy post randomization). An additional intercurrent 
event of antineoplastic therapy post randomization prior to PFS event will be included and 
handled using hypothetical estimand strategy i.e., PFS will be censored at the date of the last 
adequate assessment prior to the start of new anticancer therapy if no PFS event is observed 
prior to the start of new antineoplastic therapy). In the summary table, this approach is referred 
as ‘new anticancer therapy leading to censoring PFS supplementary analysis’.
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 assessment
2
Progressed
Progressed
C1
Progression or death after exactly one
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment
2
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)
(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 
As per 
above 
situations 
Censored 
Censored 
Event 
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 the  Protocol Appendix.Section 16.1..3.25
2.=After the last adequate tumor 
assessment. “Date of next scheduled assessment” is defined in Protocol Appendix 3 Section 16.1..3.25.
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


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In the supplementary analysis second estimand, a new anticancer therapy is defined as any 
systemic anticancer therapy or any radiotherapy other than palliative for bone pain received 
during or post study treatment. Definitive cancer related surgery to either debulk tumor or 
remove an isolated metastasis would be considered as a new anticancer therapy. Surgery that is 
not related to the underlying NSCLC or done for alleviation of symptoms or adverse clinical 
consequences from the tumor such as, but not limited, to relieving an impending spinal cord 
compression, fracture from a lytic lesion or pain relief will not be considered as a new anticancer 
therapy. Continuation of docetaxel monotherapy as 1st new anti-neoplastic therapy after end of 
treatment without prior PD and collected in the “Post antineoplastic therapy –medications” 
eCRF, will not be considered as a new anticancer therapy.
2.6.1.1.3 Determination of missing adequate assessments
The term ‘missing adequate tumor assessment’ is defined as a tumor assessment not done or 
tumor assessment with overall lesion response ‘NE’. For the sake of simplicity, a ‘missing 
adequate tumor assessment’ will also be referred to as a ‘missing assessment’. 
As described in Table 16-5 in the Appendix of the study protocol, the PFS censoring and event 
date options depend on the presence and the number of missing tumor assessments (TAs). In 
the analysis of PFS, an event occurring after two or more missing assessments or non-adequate 
tumor assessments is censored at the last adequate tumor assessment. 
An exact rule to determine whether there is no, one or two missing TAs is therefore needed. 
This rule is based on the time interval between the last adequate tumor assessment (LATA) date 
and the event date. The scheduled date of tumor assessments (in weeks from randomization), 
protocol specified windows for tumor assessments, and the thresholds for LATA to belong to a 
visit can be found in the following table.
Schedule for tumor assessment and time windows
Assessment 
schedule
Scheduled date 
– 1 week
Scheduled 
date 
(weeks 
from 
randomization)
Scheduled 
date 
+1 week
Threshold 
(weeks)*
Every 6 
weeks 
for 
the 
first 12
months
Baseline
0
0^
1
n/a
C3D1
5
6
7
9
C5D1
11
12
13
15
C7D1
17
18
19
21
C9D1
23
24
25
27
C11D1
29
30
31
33
C13D1
35
36
37
39
C15D1
41
42
43
45
C17D1
47
48
49
54
Every 
12 
C21D1
59
60
61
66
C25D1
71
72
73
78


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weeks 
after 12
months
C29D1
83
84
85
90
C33D1
95
96
97
102
* The mid-point between current and next visit (except for baseline) and the upper limit for LATA to 
be matched to a certain scheduled assessment, e.g. if LATA is at week 10, this is after threshold for 
C3D1 and before that for C5D1, so the matching scheduled assessment is C5D1.
^ Day of randomization is taken as 0.
To calculate the number of missing tumor assessments, the LATA before an event is matched 
with a scheduled tumor assessment using the time window in the table above (essentially 
whichever scheduled assessment it is closest to).
Two additional thresholds, D1 and D2 are calculated for that scheduled assessment based on 
the protocol-specified schedule and windows.

The threshold D1 is defined as the protocol-specified time interval between the TAs plus 
2x the protocol-allowed time window around the assessments.

The threshold D2 is defined as twice the protocol-specified time interval between the 
TAs plus 2x the protocol-allowed time window around the assessments (except when 
the matched scheduled tumor assessment is C15D1, in which case D2 is defined in Rule 
2 below).
Since there is a change of schedule for tumor assessments after 12 months, D1 and D2 are 
defined differently depending on when LATA occurs.  
Rule 1: if LATA happens within 39 weeks from randomization (the matched scheduled tumor 
assessment is C13D1 or before). For example, D1=6+2=8 weeks and D2=2*6+2=14 weeks.
Rule 2: if LATA happens after 39 weeks but within 45 weeks from randomization (the matched 
scheduled tumor assessment is C15D1). For example, D1=6+2=8 weeks and D2=6+12+2=20
weeks.
Rule 3: if LATA happens after 45 weeks from randomization (the matched scheduled tumor 
assessment is C17D1 or later). For example, D1=12+2=14 weeks and D2=2*12+2=26 weeks.
The number of missing events is defined as:

An event after LATA+D1 weeks will be considered as having >=1 missing assessment

An event after LATA+D2 weeks will be considered as having >=2 missing assessments
The same definition of D2 will be used to determine the PFS censoring reason.  If there is no 
post-baseline adequate tumor assessment available (before an event or a censoring reason 
occurred), the randomization date will be used to compute the interval. 
If the time interval between the last adequate TA date and the earliest of the following dates is 
smaller or equal to D2 days:
Analysis cut-off date 
Date of consent withdrawal


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Visit date of study treatment discontinuation due to lost to follow-up or end of post-treatment 
follow-up discontinuation due to lost to follow-up.
Then the PFS censoring reason will be respectively:

‘Ongoing’

‘Withdrew consent’

‘Lost to follow-up’
However if the time interval is larger than D2 days with no event then the PFS censoring reason 
will always default to ‘Adequate assessment no longer available’.  If the time interval between 
the last adequate tumor assessment date and the PFS event date is larger than D2 then the subject
will be censored and the censoring reason will be 'Event documented after two or more missing 
tumor assessments'.
2.6.1.1.4 No baseline tumor assessments
As described in Table 16-5 in the Appendix of the study protocol, since the timing of disease 
progression cannot be determined for subjects with missing baseline tumor assessment, these 
subjects are censored in the PFS analysis at the date of randomization. This rule, however, only 
applies to the ‘progressive disease’ component of the PFS assessment.
Subjects without any baseline tumor assessment who die within D2 time interval from date of 
randomization will be counted as having an event in the analysis of PFS at the date of death. 
All deaths will be counted in the overall survival analysis regardless of presence or absence of 
the baseline tumor assessment.
2.6.1.2
Overall response rate
Overall response rate (ORR) is defined as the proportion of subjects with a best overall response 
(BOR) of complete response (CR) or partial response (PR) as per local review. ORR will be 
evaluated according to RECIST 1.1. ORR based on RECIST1.1 will be calculated based on the 
FAS and according to the intent-to-treat (ITT) principle. ORR and its 95% exact confidence 
interval (Clopper 1934) will be presented by treatment group. In addition, ORR in the subset of 
subject with measurable disease at baseline will be presented. Waterfall plot will also be 
generated (Section 2.6.1.3).
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 (i.e. any additional secondary anti-neoplastic therapy with the exception of palliative 
radiotherapy) will be considered in the assessment of BOR. A new anticancer therapy is defined 
in Section 2.6.1.1.2.
BOR 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.

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR).


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
SD = at least one SD assessment (or better) > 5 weeks after randomization (and not 
qualifying for CR or PR).

Non-CR/Non-PD = at least one non-CR/non-PD assessment (or better) > 5 weeks after 
randomization (and not qualifying for CR).

PD = progression ≤ 13 weeks after randomization (and not qualifying for CR, PR or SD).

NE = 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)
Complete and partial responses must be confirmed by repeat assessments that should be 
performed not less than 4 weeks after the criteria for response are first met. 
Subjects with ‘NE’ BOR will be summarized by reason for having unknown status. The 
following reasons will be used:
a. No valid post-baseline assessment
b. All post-baseline assessments have overall lesion response UNK
c. New anti-neoplastic therapy started before first post-baseline assessment
d. SD or non-CR/non-PD too early  
e. PD too late 
Note 1: A SD or Non-CR/Non-PD is considered as “SD too early”’ if the SD or Non-CR/Non-
PD is documented within first 5 weeks after randomization date. 
Note 2: A PD is considered as “PD too late” if the first documentation of PD is recorded more 
than 13 weeks after randomization date with no qualifying CR, PR or SD or Non-CR/Non-PD
in between.  
Note 3: Special (and rare) cases where BOR is “NE” due to both too early SD and too late PD 
will be classified as “SD too early”.
2.6.1.3
Construction of waterfall graphs
Waterfall graphs will be used to depict the anti-tumor activity. These plots will display the best 
percentage change from baseline in the sum of diameters of all target lesions for each subject. 
Only subjects with measurable disease at baseline will be included in the waterfall graphs.
Special consideration is needed for assessments where the target lesion response is CR, PR or 
SD, but the appearance of a new lesion or a worsening of non-target lesions results in an overall 
lesion response of PD. As a conservative approach, such assessments will not be considered for 
display as bars in the graph, since the percentage change in the sum of diameters of target lesions 
reflects the non-PD target lesion response, but the overall lesion response is PD. A subject with 
only such assessments will be represented by a special symbol (e.g.) in the waterfall graph.
Assessments with “NE” target lesion response and assessments with unknown overall response 
will be excluded from the waterfall plots. Subjects without any valid assessments will be 
completely excluded from the graphs.
The total number of subjects displayed in the graph will be shown and this number will be used 
as the denominator for calculating the percentages of subjects with tumor shrinkage and tumor 


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growth. Footnote will explain the reason for excluding some subjects (due to absence of any 
valid assessment).
All possible assessment scenarios are described in Table 2-5.
Table 2-5
Assessments considered for calculation of best percentage change 
for waterfall graphs
Case
Target response
Overall lesion 
response
Calculate % change from baseline 
in sum of diameters?
1
UNK
Any
No, exclude assessment
2
Any
UNK
No, exclude assessment
3
CR/PR/SD
PD
No, flag assessment with 
4
PD
PD
Yes
5
CR/PR/SD
CR/PR/SD
Yes
Based on the above considerations, the following algorithm will be used to construct the graph:
1. Select “valid” post-baseline assessments to be included, i.e. for each subject and each 
assessment repeat the following four steps.
1.1. Check the target lesion response and overall lesion response. If at least one of them is 
UNK then exclude the whole assessment. Otherwise, go to step 1.2.
1.2. Check the overall lesion response. If it is PD then go to step 1.3. Otherwise go to step 
1.4.
1.3. Check target response. If it’s PD then go to step 1.4. Otherwise flag the assessment 
with .
1.4. Calculate the % change from baseline in target lesions. 
2. For each subject, go through all valid assessments identified in step 1 and find the 
assessment with best % change from baseline in target lesions. The “best” means best for 
the subject, i.e. the largest shrinkage or if a subject only has assessments with tumor 
growth take the assessment where the growth is minimal.
3. Construct the waterfall graph displaying the best % change from baseline for each subject. 
Subjects having only flagged assessment(s) will be displayed separately. 
The graph will be constructed using the data from the investigator/local radiologist assessments.
The best overall response (BOR) will be shown above each of the displayed bars in the graph, 
if the number of subjects displayed in the graph is small enough for the labels to be legible.
The order of the display from left to right will be as follows: 
1. Bars under the horizontal axis representing tumor shrinkage
2. Bars above the horizontal axis representing tumor growth
3. “Zero” bars with symbol.  
For each of the 3 categories above, n (%) (where % uses the total number of subjects displayed 
in the graph) will be displayed. If there are any subjects with zero change they will be as a 
separate category following subjects with tumor shrinkage.


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2.6.1.4
Disease control rate (DCR)
Disease control rate (DCR) is defined as the proportion of subjects with BOR of CR, PR, or SD 
or Non-CR/Non-PD. 
DCR will be evaluated according to RECIST 1.1. DCR based on RECIST1.1 will be calculated 
based on the FAS and according to the ITT principle. DCR and its 95% exact confidence 
interval (Clopper 1934) will be presented by treatment group.
2.6.1.5
Time to response (TTR)
Time to response (TTR) is defined as duration of time between the date of randomization and 
the date of first documented response of either CR or PR, which must be subsequently 
confirmed (although date of initial response is used, not date of confirmation).
TTR will be evaluated according to RECIST 1.1.
All subjects in the FAS will be included in TTR calculations. Subjects without a confirmed CR 
or PR will be censored at the study-maximum follow-up time (i.e., LPLV-FPFV) for subjects 
with a PFS event (i.e., disease progression or death due to any cause), or at the date of the last 
adequate tumor assessment for subjects without a PFS event. TTR will be listed and 
summarized by treatment group based on RECIST1.1. The distribution function of TTR will be 
estimated using the Kaplan-Meier method. The median TTR along with 95% CIs will be 
presented by treatment arm.
2.6.1.6
Duration of response (DOR)
Duration of response (DOR) is defined as the duration of time between the date of first 
documented response (CR or PR) and the date of first documented progression or death due to 
any cause.
Duration of response (DOR) only applies to subjects whose best overall response is complete 
response (CR) or partial response (PR) based on tumor response data per local review. If a 
subject has not had an event, DOR is censored at the date of last adequate tumor assessment. 
Subjects who never achieved a BOR of CR or PR will be excluded from the analysis. The 
distribution function of DOR will be estimated using the Kaplan-Meier method. The median 
DOR along with 95% CIs will be presented by treatment arm.
2.6.1.7
Duration of follow-up
Study follow-up will be summarized using the following methods:
Summary of duration between randomization and cut-off date, and follow-up times for OS, 
which are defined as follows:

Duration between randomization and data cut-off date = (Cut-off date – Date of  
randomization + 1) / 30.4375 (months).  This item will be summarized overall.

Follow-up time = (Date of event or censoring – Date of randomization + 1) / 30.4375 
(months) regardless of censoring. Date of censoring is defined as last contact date for OS. 
This item will be summarized by treatment arm.


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All summaries will be reported in months. Date of censoring is the same as defined for the OS 
analysis.
In addition, median time to censoring  will be computed by reversing censoring variable and 
performing Kaplan-Meier analysis (Schemper 1996 ).
2.6.2
Safety run-in Part
Overall response rate (ORR), and Disease control rate (DCR) by investigator’s assessment 
according to RECIST 1.1 will be presented by dose cohort. Duration of response (DOR) will 
be summarized by dose cohort. Waterfall plot will also be generated in one plot with dose cohort
as the plot legend.
2.7
Secondary objective: Safety analyses
Safety set will be used for all safety analyses.
2.7.1
Randomization part
2.7.1.1
Adverse events (AEs)
All safety outputs will use the safety set and will be presented by treatment group. The safety 
summary tables will include only ‘on-treatment’ events/assessments. The AEs started before 
the first dose but worsening during the treatment period are also considered as ‘on-treatment’ 
events. All safety events/assessments will be listed and those collected outside the on-
treatment window will be flagged..
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 
(
) 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 investigational treatment.
The following adverse event summaries will be produced by treatment arm; overview of 
adverse events and deaths, AEs by SOC and PT, AEs by PT summarized by relationship, 
seriousness, leading to study drug discontinuation, leading to dose interruption, leading to dose 
change, requiring additional therapy and leading to fatal outcome (SAE). In addition, a 
summary of serious and non-serious adverse events with number of occurrences will be 
produced (an occurrence is defined as >1 day between start and prior end date of record of same 
preferred term).


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2.7.1.1.1 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 the compound canakinumab. These groupings are defined using 
MedDRA terms, SMQs (standardized MedDRA queries), HLGTs (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 subjects 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. 
Table 2-6 provides AESI groupings.
Table 2-6
AESI groupings
AESI grouping
Infections
Opportunistic infections
Neutropenia
Abnormal liver parameters
Thrombocytopenia
Immunogenicity/allergenicity
Autoimmunity reactions
Malignancy
Interactions with vaccines
Interactions with drugs eliminated by CYP450 enzymes
Pulmonary complications: pulmonary hypertension and interstitial lung 
disease
Injection site reactions
Time to onset of AESI
Time to onset of CTC grade ≥2 AESI will be summarized using the Kaplan-Meier method by 
AESI grouping and treatment arm. Median time to onset and 95% CI will be provided and
ascending Kaplan-Meier plots will be generated by treatment arm. This will only be performed 
for AESI groupings of infections, opportunistic infections, neutropenia, abnormal liver 
parameters and thrombocytopenia (if there are sufficient number of events).


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Time to onset of CTC grade ≥2 AESI is defined as the time from the start of treatment to the 
start date of the first incidence of an event of CTC grade ≥2 i.e. time in days is calculated as 
(start date of first occurrence of the event) – (date of first dose of study treatment) +1. 
In the absence of an event during the on-treatment period, the censoring date applied will be the 
earliest of the following dates:

end date of on-treatment period (end of study treatment + 130 days).

death date

start date of new antineoplastic therapy defined in Section 2.6.1.1.2 before experiencing 
any CTC grade ≥2 AESI. 

data cut-off date.

withdrawal of informed consent date
The same analysis will be repeated for time to onset of CTC grade ≥3 AESI with similar 
censoring rules applied.
2.7.1.2
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, post treatment deaths will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened subjects.
2.7.1.3
Laboratory data
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include all assessments available for the lab parameter collected no later 
than 130 days after the last study treatment administration date (Section 2.1.2.10). Grading of 
laboratory values will be assigned programmatically as per NCI Common Terminology Criteria 
for Adverse Events (CTCAE) 
.
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.

Trends of selected lab parameter values (details will be specified in the TFL shell) over 
time (baseline and selected on-treatment timepoints) will be displayed via boxplots based 
on time windows and corresponding tables displaying the statistics used for the box plots 
by the selected time points. For a subject with multiple assessments in a time window, the 
average value will be used. If there are multiple assessments as baseline candidate, the 
central lab assessment will be defined as “baseline”. If there are multiple assessments 


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from the central lab or the local lab, the worst assessment will be defined as “baseline.” 
The time windows are defined in Table 2-7 for selected scheduled assessments:
Table 2-7
Time windows for lab assessments
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline 
On or before Study Day 1[a]
≤ Study Day 1
Week 3
Study Day 22
Study Days 2 to 32
Week 6
Study Day 43
Study Days 33 to 53
....... 
......
......
Week k
(with k = 9,12 …)
Study Day 21*(k/3)+1
Study Day 
21*(k/3)-9 to 21*(k/3)+11 
Safety follow-up
Post treatment study day 130
All on-treatment assessment 
after EOT(Last dose 
administration  date)
[a] Study Day 1 = first treatment date
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 subjects 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 


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
ALT or AST > 5xULN

ALT or AST > 8xULN

ALT or AST > 10xULN

ALT or AST > 20xULN

TBL > 2xULN

TBL > 3xULN
Combined elevations post-baseline:
For ALT and AST ≤ ULN at baseline;


ALT or AST > 3xULN & TBL > 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP ≥ 2xULN
For ALT or AST > ULN at baseline (Bsl)

Elevated ALT or AST (*) & TBL (> 2x Bsl and 2xULN)

Elevated ALT or AST (*) & TBL (> 2x Bsl and 2xULN) & ALP < 2xULN

Elevated ALT or AST (*) & TBL (> 2x Bsl and 2xULN) & 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 TBILI, ALT, AST and ALP values for subjects with a post-baseline 
TBILI > 2xULN, ALT> 3xULN or AST > 3xULN will be provided.  
Time to onset of grade 2 or worse and time to onset of grade 3 or worse liver function test
abnormalities will be summarized for the following liver function test parameters:
•
AST or ALT (whichever occurs first)
•
Total bilirubin
Time to onset will be summarized using Kaplan-Meier method. Median time to onset and 95% 
C.I. will be summarized. 
Time to onset of LFT abnormalities is defined as the time from the start of treatment to the start 
date of the first incidence of grade 2 or worse LFTs post-baseline (or grade 3 or worse), i.e., 
time in days is calculated as (start date of first occurrence of LFT abnormalities) – (date of first 
dose of study treatment) +1. A subject will be censored for time to onset if:
•
the subject dies without experiencing the LFT abnormality 
•
the subject receives a new anticancer therapy defined in Section 2.6.1.1.2 without 
experiencing the LFT abnormality or before LFT abnormality has occurred 
•
the subject discontinues from the study treatment without experiencing the LFT 
abnormality (up to 130 days after study treatment discontinuation)


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•
the subject is still ongoing at the analysis cut-off without experiencing the LFT 
abnormality
The censoring date will be the earliest date from the following dates: last date of study treatment
in the treatment phase + 130 days, analysis cut-off, the day before new anticancer therapy start 
date, death date and last on-treatment laboratory sampling date (for the particular parameter) 
during on-treatment period. For the time to onset of grade 2 or worse LFTs, subjects with grade 
2 or worse at baseline will be excluded from the analysis. For the time to onset of grade 3 or 
worse LFTs, subjects with grade 3 or worse at baseline will be excluded from the analysis.
Time to onset of neutropenia and thrombocytopenia:
Time to onset of grade 2 or worse and time to onset of grade 3 or worse neutropenia and 
thrombocytopenia will be summarized respectively. The censoring rule will be the same as used 
in time to onset of LFT abnormalities analysis.
2.7.1.4
Other safety data
2.7.1.4.1 ECG and cardiac imaging data
ECG abnormality for baseline and any post baseline assessments will be summarized by 
treatment arm. A listing of all ECG assessments will be produced by treatment arm and notable 
values will be flagged.
2.7.1.4.2 Vital sign
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), heart 
rate (beats per minute), 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 2-8
below.
Table 2-8
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


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Vital sign 
(unit)
Clinically notable criteria
above normal value 
below normal value
Diastolic blood 
pressure 
(mmHg)
>=105 with increase from baseline 
of >=15
<=50 with decrease from baseline 
of >=15
Pulse rate 
(bpm)
>=100 with increase from baseline 
of >25%
<=50 with decrease from baseline of 
> 25%
Body 
temperature
(°C)
>= 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. 
2.7.1.4.3 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.
2.7.2
Safety run-in part
Summaries of DLTs, AEs, SAEs, treatment related AEs, on-treatment deaths, AESI overview, 
Laboratory shift table based on key hematologic and biochemistry terms and Liver transaminase 
abnormality will be summarized by dose cohort. In addition, serious and non-serious adverse 
events with number of occurrences will be produced (an occurrence is defined as >1 day 
between start and prior end date of record of same preferred term). The listings specified for 
AE, LAB, death, and other safety data in Section 2.7.1 will be generated by dose cohort. 
2.8
Secondary objective: Pharmacokinetic endpoints
2.8.1
PK analysis in Randomization part
Pharmacokinetic data analysis will be performed for canakinumab and docetaxel concentrations.
PK concentration analyses will be performed for each study drug.


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PAS-canakinumab and PAS-docetaxel will be used in the pharmacokinetic data analysis for 
canakinumab and docetaxel 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 study drug
concentration will be presented at each scheduled time point for the PAS-study drug.
Individual concentration-time profiles for study drug evaluable concentrations with median will 
be displayed graphically for PAS-study drug on the semi-log view. In addition, the mean (+/-
SD) and geometric mean concentration-time profiles for study drug  over time will be displayed 
graphically for PAS-study drug on the linear and semi-log view. Only time points with n ≥ 4 
observations will be shown on the figure.
All individual plasma study drug concentration data will be listed by treatment for the FAS.
PK parameters for docetaxel
The descriptive statistics (n, mean, CV%, standard deviation (SD), median, geometric mean, 
geometric CV%, minimum and maximum) will be presented by treatment for PK parameters 
of docetaxel, except Tmax, where only n, median, minimum and maximum will be presented. 
PK parameters such as those listed in Table 2-9 will be estimated and reported, when 
applicable. PK parameters will be derived based on the non-compartmental methods using 
Phoenix WinNonlin® software version 6.4.
Table 2-9
Noncompartmental pharmacokinetic parameters
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x 
time x volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x 
volume-1)
Cmin or 
Ctrough
The minimum observed plasma or serum drug concentration (mass x volume-1)
Cmax
The maximum (peak) observed plasma or serum drug concentration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma or serum drug concentration (time)
Lambda_z
Smallest (slowest) disposition (hybrid) rate constant (time-1) may also be used for terminal 
elimination rate constant (time-1)
T1/2
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives
CL 
The total body clearance of drug from the plasma or serum (volume x time-1)
Vz 
The apparent volume of distribution during terminal phase (associated with z) (volume)
Note: Not all PK parameters are applicable to canakinumab or docetaxel.
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 


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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
In this analysis, the data from safety run-in and randomization parts will be pooled. 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 exposure and to 
determine the effects of intrinsic (i.e. demographic factors) and extrinsic covariates (e.g. 
concomitant medications, formulation) 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.
2.8.2
PK analysis in Safety run-in part
All analyses except population pharmacokinetic analysis specified in Section 2.8.1 will be 
performed for canakinumab and docetaxel concentrations collected in Safety run-in part. In 
addition, PK parameters for canakinumab will be summarized. 
The descriptive statistics (n, mean, CV%, standard deviation (SD), median, geometric mean, 
geometric CV%, minimum and maximum) will be presented by treatment for PK parameters 
of canakinumab, except Tmax, where only n, median, minimum and maximum will be 
presented. PK parameters such as those listed in Table 2-9 will be estimated and reported, 
when applicable. PK parameters will be derived based on the non-compartmental methods 
using Phoenix WinNonlin® software version 6.4.
2.9
Secondary objective: Immunogenicity
Immunogenicity data will be summarized using the safety set. Immunogenicity will be 
characterized descriptively by tabulating anti-drug antibodies (ADA) prevalence at baseline and 
ADA incidence on-treatment. A shift table of subjects with positive or negative anti-
canakinumab antibodies overall and by visit will be produced (“positive” corresponds to 
“worst”). A listing will be provided by subject with supporting information (i.e. ADA sample 
status at each timepoint (including titer for positive samples) and subject ADA status). In 
addition, a listing will also be provided for subjects with neutralizing antibodies (NAB) testing 
results. Immunogenicity data collected in Safety run-in part will be listed by dose cohort
2.10
Secondary objective: ECOG performance status
The ECOG PS scale (Table 2-10) will be used to assess physical health of patients, ranging 
from 0 (most active) to 5 (least active):


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Table 2-10
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 has been defined in Table 2-1 . If 2 assessments within a time window are 
equidistant from the target date, the assessment obtained prior to visit will be considered. If the 
closest assessment to the target date has two 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. For time to 
deterioration analysis described hereafter all post-baseline assessments will be considered.
Frequency counts and percentages of patients in each score category will be provided by 
treatment arm and time point. 
Time to definitive deterioration of the ECOG PS is the number of days between the date of 
randomization and the date of the assessment at which definitive deterioration is seen. The 
ECOG PS deterioration is considered definitive if there is an increase in the performance status 
by at least one category relative to the baseline or death due to any cause and if no improvement 
in ECOG PS is observed subsequent to the deterioration.
Baseline is the last available assessment on or before date of randomization. If a patient has 2 
ECOG PS values at the same date, the worst ECOG PS value will be taken as ‘baseline’.
Example: If the ECOG PS is 1 at baseline and then 1, 2, 1, 2, 3 at D22, D43, D64, D85, and 
D106 respectively, then the time to definitive worsening is D85.
Example: if the ECOG PS is 1 at baseline and then 1, 1, 2 at D22, D43, and D64 respectively, 
with no assessment of the ECOG PS after D64 then the time to definitive worsening is 64 days.
If a definitive deterioration is observed after any missing assessments, this event will be 
backdated to the first of the missing assessments before the deterioration. The first missing 
assessment date is calculated as the last available assessment before the definitive deterioration 
plus X, where X corresponds to the planned scheduled time point for ECOG PS (21 days).
For example, if a patient has an assessment at week Cycle 2 Day 1, misses the following two 
assessments on weeks Cycle 3 Day 1 and Cycle 4 Day1 and a definitive deterioration is 
observed on week Cycle 5 Day 1 , then the event will be backdated to Cycle 2 Day 1+21 days.
In addition, death is considered as a worsening of performance status if it occurs close to the 
last available assessment, where “close” is defined as twice the planned (i.e. protocol scheduled) 
period between two assessments. This avoids overestimating the time to definitive worsening 


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in patients dying after an irregular assessment scheme. Patients who die after more than twice 
the planned period between two assessments are censored at the date of their last available 
assessment of the performance status. 
For example, if the last assessment is at Cycle 2 Day 1 and the patient dies at Cycle 3 Day 15, 
the definitive deterioration date will be Cycle 3 Day 15. On the other hand, if the last assessment 
is at Cycle 2 Day 1 and the patient dies at cycle 5 Day 15, which is after more than twice the 
planned period between two assessments since the last assessment (Cycle 2 Day 1), then the 
definitive deterioration date will be week 3.
Patients receiving any further anti-neoplastic therapy before definitive worsening will be 
censored at the date of their last assessment before the start date of the therapy. Patients that 
have not worsened as of the cutoff date will be censored at the date of their last assessment 
before the cutoff.
Patients without baseline ECOG PS or without any post-baseline ECOG PS will be censored at 
the date of randomization with censoring reason being ‘No baseline score’ or ‘No post-baseline 
score’, respectively. However, patients without post-baseline ECOG PS who die within 48 days 
after date of randomization will be counted as having a definitive deterioration of the ECOG 
PS at the date of death.
This threshold corresponds to twice the protocol defined ECOG assessment interval plus twice 
the time window around each assessment: (2 x 21 days)+( 2 x 3 days), i.e. 48 days.
Kaplan-Meier estimates will be constructed for each treatment arm in each cohort. The median, 
25th and 75th percentiles for time to definitive deterioration for each treatment group will be 
obtained along with 95% confidence intervals.
2.11
Secondary objective: Patient-reported outcomes
The analyses below are for Randomization part.
Three patient-reported outcomes (PRO) questionnaires will be assessed: EORTC QLQ-C30, 
with it’s QLQ-LC13 lung cancer module, and the EQ-5D-5L. QLQ-C30 and QLQ-LC13 will 
be considered as the primary scale. Scoring of PRO data and methods for handling of missing 
items or missing assessments will be handled according to the scoring manual and user guide 
for each respective subject questionnaire (Fayers 2001, Van Reenen 2015). No imputation 
procedures will be applied for missing items or missing assessments.
The FAS will be used for analyzing PRO data. For all PRO analysis, nominal p-values will be 
presented without any statistical inference since there is no adjustment for multiplicity. The 
baseline is defined as the last PRO assessment on or prior to randomization. In the absence of 
a better definition to define clinically relevant changes in this population (lung cancer, adjuvant 
setting) a 10 point deterioration will be assumed to be clinically meaningful for the QLQ-LC13 
and QLQ-C30. Time to definitive 10-point deterioration symptom scores for each of chest pain, 
cough and dyspnea per QLQ-LC13 questionnaire are the three primary PRO variables of 
interest. Utilities derived from EQ-5D-5L, time to definitive deterioration in global health 
status/QoL, shortness of breath and pain per QLQ-C30 are secondary PRO variables of interest. 
The time to definitive 10-point deterioration is defined as the time from the date of 
randomization to the date of event, which is defined as at least 10 points absolute worsening 


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from baseline of the corresponding scale score, with no later change below this threshold, i.e. 
<10 points was observed or if this worsening was observed at the last assessment for the subject,
or death due to any cause (whichever occurs earlier). If a subject has not had an event, time to 
definitive deterioration will be censored at the date of the last adequate assessment. If 
deterioration occurs at the last adequate assessment, this will also be considered definitive. 
Subjects receiving any further anti-neoplastic therapy before definitive worsening will be 
censored at the date of their last assessment before starting this therapy. If a definitive 
deterioration is observed after two or more missing assessments, subject is censored at the date 
of their last available questionnaire prior to the deterioration. Subjects with no baseline data 
will be censored at day 1.
Death is considered as a deterioration event when it occurs within a period of time defined by 
2 times the period between two assessments as planned in the study protocol. This avoids 
overestimating the time to definitive worsening in subjects dying after an irregular assessment 
scheme. Subjects who die after more than twice the planned period between two assessments 
since the last assessment will be censored at the date of their last adequate assessment.
Censoring reasons for time to definitive deterioration will be summarized.
All assessments will be included in the time to definitive deterioration analysis. The distribution 
will be presented descriptively using Kaplan-Meier curves. Summary statistics from Kaplan-
Meier distributions will be determined, including the median time to definitive 10 point 
deterioration along with two-sided 95% confidence interval. Log-rank test stratified by 
randomization stratification factors will be performed. A Cox regression stratified by 
randomization stratification factors from IRT will be used to estimate the hazard ratio (HR), 
along with two-sided 95% confidence interval.
Descriptive statistics will be used to summarize the original scores, as well as change from 
baseline, of the QLQC30, QLQ-LC13, and EQ-5D-5L at each scheduled assessment time point 
for each treatment arm using time windows as described in Section 2.1.2.11. Additionally, 
change from baseline in the scale and subscale values at the time of each assessment will be 
summarized. Subjects with an evaluable baseline score and at least one evaluable post baseline 
score during the treatment period will be included in the change from baseline analyses.
In addition, a repeated measures model for longitudinal data will be used to estimate
differences in EORTC QLQ-C30/QLQ-LC13 domains as well as the VAS and utility scores 
of the EQ-5D-5L between treatment arms. The models will be first based on all assessments. 
In additional, the models will be repeated to include only assessments collected within 130 
days of last study treatment. Any assessments collected after the start of further anti-tumor 
therapy will not be included in the models. 
The modeling will mainly be done on the actual score. Note that the modeling of the change 
in score or the actual score is equivalent since adjustment for baseline score is considered.  This 
repeated measures model will include terms for treatment, the stratification factors, time, 
baseline value as main effects, and an interaction term for treatment by time. This analysis will 
be restricted to subjects with an evaluable baseline score and at least one evaluable post-
baseline score. The differences in least square means between the treatment arms and 
corresponding 95% confidence interval at selected time points will be presented. 


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Time will be considered as a continuous variable expressed in weeks. i.e. considering that PRO
follow a linear trend. As a first approach, an unstructured correlation matrix will be used to 
model the correlation within subjects. Other structures of the correlation matrix, including 
AR(1), will be investigated and simplified using likelihood ratio tested if appropriate.
If PRO is found not to follow a linear trend, the time variable might be considered as a 
categorical variable instead of continuous in the model.


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2.15
Interim analysis
Safety run-in part
Not Applicable
Randomized part
One interim analysis is planned after approximately 96 of the 137 targeted OS events (i.e., at 
approximately 70% information fraction) have been observed.. The primary intent of this 
interim analysis is to claim superior efficacy. There is no intent to assess futility at this interim 
analysis. The interim analysis will only be carried out after all subjects have been randomized 
and (if not withdrawn early) should have at least one post baseline assessment.
An α-spending function according to a two-look (Lan-DeMets) group sequential design with 
(O’Brien-Fleming) type stopping boundary (as implemented in East 6.4) will be used to 
construct the efficacy stopping boundaries (Lan et al 1983). Based on the choice of α-spending 
function described above and if the interim analysis is performed exactly after 96 OS events, 
the efficacy boundary in terms of p-value scale (or equivalently Z-statistic scale) at the interim 
is calculated as p = 0.0074 (or Z = 2.436 or HR=0.608). The observed (i.e. nominal) p-value 
has to be smaller than 0.0074 (or equivalently the observed Z-statistic has to be > Z-statistic 
scale boundary = 2.436 or equivalently the observed HR has to be smaller than 0.608) to 
conclude superior efficacy at the interim analysis.
Since the observed number of events at the interim analysis may not be exactly equal to the 
planned 96 OS events, the efficacy boundary will need to be recalculated using the pre-specified 
α-spending function and based on the actual number of observed events at interim and the total 
number of targeted events to calculate the exact information fraction. The observed p-value (or 
Z-test statistic) at the interim analysis will then be compared against the re-calculated efficacy 
boundary.
If the study continues to the final OS analysis, the final OS analysis will be performed when 
approximately 137 OS events have been observed. In practice, the final analysis will be based 
on the actual number of OS events observed at the cut-off date for the final OS analysis and α 
already spent at the interim analyses. The boundary for the final analysis will be derived 
accordingly from the pre-specified α-spending function such that the overall significance level 
across all analyses is maintained at 0.025.


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The statistical properties of the group sequential design are summarized for OS in Table 2-12
below.
Table 2-12
Simulated probabilities to stop for efficacy at the interim or final OS 
analysis
Scenario
Look
# OS events
Simulated 
cumulative 
probabilities (%)
Simulated 
incremental 
probabilities (%)
Under H0 (HR=1)
Interim
96
0.8
0.8
Final
137
2.4
1.6
Under Ha
(HR=0.57)
Interim
96
61.2
61.2
Final
137
89.7
28.5
Under HR=0.67
Interim
96
32.6
32.6
Final
137
65.0
32.4
Note: Simulation is performed in East 6.4 with number of simulations = 10,000 and 
randomization seed =1234.
Only the investigational drug (canakinumab) will be blinded in this study.
OS interim analysis will be performed by an independent statistician and reviewed by a data 
monitoring committee (DMC). Unblinded results from the Interim Analysis (IA) for OS will 
not be communicated to the Sponsor's clinical team or to any party involved in the study conduct 
(apart from the independent statistician and DMC members) until the DMC has determined that 
either: (i) interim OS analyses has crossed the pre-specified boundary for efficacy or (ii) the 
study needs to be terminated due to any cause including safety reasons. Investigators and 
subjects will remain blinded to study treatment until OS is statistically significant at the interim 
or final analyses. The final OS analysis will be performed by the sponsor’s clinical team.
Randomization data are kept strictly confidential until the time of unblinding and will not be 
accessible by anyone else involved in the study except for the independent biostatistician and 
programmer who will perform DMC analysis, the PK bioanalyst, and modeler and modeling 
programmer. The study bioanalyst will receive a copy of the randomization schedule to 
facilitate analysis of the samples. The independent biostatistician and programmer and 
bioanalyst will keep treatment allocation information confidential until clinical database lock.
3
Sample size calculation
3.1.1
Primary endpoint(s)
Safety run-in part
No formal statistical power calculations to determine sample size were performed for this part 
of the study. In the case that the starting dose (canakinumab 200 mg sc Q3W with the fixed 
dose combination of docetaxel 75 mg/m2 i.v. Q3W) is confirmed to be safe and tolerated, the 
safety run-in part is expected to enroll approximately 9 subjects in a cohort in order to have at 
least 6 evaluable subjects (i.e. who met the minimum exposure criterion and had sufficient 
safety evaluations during the first 6 weeks of canakinumab in combination with docetaxel 


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dosing). Otherwise, up to 18 additional subjects are foreseen to be enrolled to assess additional 
cohorts.
Randomized part
The sample size calculation is based on the primary variable OS. The hypotheses to be tested 
and details of the testing strategy are described in Section 2.5.2.2.
Based on available data (Herbst et al 2016, Rittmeyer et al 2017), the median OS in the 
docetaxel plus placebo arm is expected to be around 8 months. It is expected that treatment with 
docetaxel plus canakinumab will result in a 43% reduction in the hazard rate for OS, i.e., an 
expected hazard ratio of 0.57 (which corresponds to an increase in median OS to 14 months 
under the exponential model assumption).
Then in order to ensure 90% power to test the null hypothesis: OS hazard ratio = 1, versus the 
specific alternative hypothesis: OS hazard ratio = 0.57, it is calculated that a total of 137 deaths 
need to be observed. This calculation assumes analysis by a one-sided log-rank test at the overall 
2.5% level of significance, subjects randomized to the two treatment arms in a 1:1 ratio, and a 
2-look group sequential design with a Lan-DeMets (O’Brien-Fleming) alpha spending function 
using an information fraction of 70%. If the final analysis is performed when the targeted 137 
OS events are observed after exactly 96 OS events have been observed at IA, the observed 
hazard ratio will have to be < 0.711 to declare statistical significance. Assuming that enrolment 
will continue for 18 months with an accrual rate of approximately 5 subjects/month in the first 
3 months, and approximately 10 subjects/month for the next 3 months, and approximately 15 
subjects/months till the completion of enrollment, along with an assumed 5% dropout rate/year 
for OS, a total of 226 subjects will need to be randomized to observe the targeted 137 death 
events at about 8 months after the randomization date of the last subject, i.e., 26 months after 
the randomization date of the first subject. These calculations were made using the software 
package East 6.4.
4
Change to protocol specified analyses
Not applicable
5
Appendix
5.1
Imputation rules
5.1.1
Study treatment
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:
Use the study treatment start date
For subjects with missing study treatment start dates, no imputation will be made. If start date 
is missing then end-date should not be imputed.


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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
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  


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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. 
For partial date imputation in PR, randomization date instead treatment start date will be used 
in the above imputation algorithm.
5.1.2.1
Handling missing month/day in date of death/last known subject 
alive from survival eCRF page
For rare cases when either day is missing or both month and day are missing for the date of 
death/last known subject alive from survival eCRF page, the follow imputation rules will be 
implemented:
-
If only day is missing, then impute max [(1 mmm-yyyy), any valid date from database 
used for deriving last contact date +1]. 
-
If both day and month are missing, then impute max [(1 Jan-yyyy, any valid date from 
database used for deriving last contact date +1]. 
5.1.2.2
Other imputations
Incomplete date of initial diagnosis of cancer and date of most recent recurrence
5.2
Missing day is defaulted to the 1st  of the month and the missing 
month and day is defaulted to 01-Jan.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) 
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) 
. 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 
at the time of analysis will be used. For laboratory 
tests where grades are not defined by CTCAE
, results will be graded by the 


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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 
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 an 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 (mmol/L) = Calcium (mmol/L) + 0.020 [40 - albumin (g/L)]]
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
Analysis of time to events Data
Hypothesis and test statistic
The null hypothesis stating that OS survival distributions of the two treatment arms are 
equivalent will be tested against one-sided alternative. 
H01 (null hypotheses): Θ1≥ 0 vs. Ha1 (alternative hypotheses): Θ1 < 0
Where Θ1 is the log hazard ratio of OS in the canakinumab (investigational) arm vs. placebo 
(control) arm. Log-rank test will be used to test the difference between the treatment arms. The 
LIFETEST procedure in SAS with the TIME statement including a variable with survival times 
and a (right) censoring variable, and with STRATA statement including variables of 
stratification factors and with GROUP option under STRATA statement. As an output of the 
procedure, the rank statistic S and variance var(S) will be obtained. Under the null hypothesis, 
the test statistic Z=S/√[var(S)] is approximately normally distributed. The one-sided p-value 
will be obtained from normally distributed Z statistic.
One-sided will be obtained using Z statistic.


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Kaplan-Meier estimates
An estimate of the survival function in each treatment arm will be constructed using Kaplan-
Meier (product-limit) method as implemented in PROC LIFETEST with METHOD=KM
option. The PROC LIFETEST statement will use the option CONFTYPE=LOGLOG.
Median survival for each treatment arm will be obtained along with 95% confidence intervals
calculated from PROC LIFETEST output using the method of [Brookmeyer and Crowley
1982]. Kaplan-Meier estimates of the survival function with 95% confidence intervals at
specific time points will be summarized. The standard error of the Kaplan-Meier estimate
will be calculated using Greenwood’s formula [Collett 1994].
Hazard ratio
Hazard ratio will be estimated by fitting the Cox proportional hazards model using SAS 
procedure PHREG (with TIES=EXACT option in the MODEL statement). 
A stratified unadjusted Cox model will be, i.e. the MODEL statement will include the
treatment arm variable as the only covariate and the STRATA statement will include
stratification variable(s).
Hazard ratio with two-sided 95% confidence interval will be based on Wald test.
Treatment of ties
The STRATA statement in LIFETEST procedure will be used to analyze time to event data 
with ties. The PHREG procedure in SAS with option TIES=EXACT will be used to fit the Cox 
proportional hazards model.
Checking proportionality of hazard assumption
Plots (SURVIVAL LOGSURV LOGLOGS) generated by LIFETEST procedure in SAS will 
be used to provide visual checks of the proportional hazard assumption. 
LOGLOGS plots log (cumulative hazard)
The LOGLOG plot will show parallel curves if hazards are proportional.
5.4.2
Other secondary analysis
5.4.2.1
Patient reported outcomes: EORTC QLQ-C30/LC13 and
EQ-5D-5L/VAS 
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Section 2.11.
EORTC QLQ-C30 scale scores will be generated by first obtaining the raw scores adding up 
the item responses on the questions which make up each domain and then applying the linear 
transformation to the raw scores in accordance with the respective scoring manual provided by 
the developers. Scores in each scale will be generated if at least half of the items comprising 
the scale have been answered. For single item scales with missing responses and scales where 
less than half of the items have not been answered, scale scores will be set to missing.


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The scoring approach for the QLQ-LC13 is identical in principle to that for the symptom 
scales/single items of the QLQ-C30. The dyspnea scale of the QLQ-LC13 is the only multi item 
scale (all others are single item scales) and should only be used if all items comprising the scale 
have been answered.
For the calculation of EQ-5D-5L index value, the EQ-5D crosswalk value set for the UK using 
the time trade-off method will be used. If any one of the five dimensions of health state is 
missing, the index value will be set to missing.
A repeated measures model for longitudinal data will be used to compare the two treatment 
arms in terms of the domain scores over time. This longitudinal model will include terms for 
treatment, the randomization stratification factors, time of visit (duration in days from the time 
of baseline measurement to the time of a particular post baseline measurement), baseline value 
as fixed effects, and an interaction term for treatment by time. This analysis will be restricted 
to subjects with an evaluable baseline score and at least one evaluable post-baseline score. Time 
will be considered as a continuous variable in this analysis. As a first approach, an unstructured 
correlation matrix will be used to model the correlation within subjects. Other structures of the 
correlation matrix, including AR(1), will be investigated and simplified using likelihood ratio 
tested if appropriate. In particular situations, the non-convergence of the model may be caused
by few subjects with assessments at later timepoints. The possibility of removing few 
assessments later than a certain time point will be investigated if appropriate.
For the model considered, the SAS code will therefore be:
PROC MIXED data=dataset method=reml;
     CLASS subject trt timeC strat_factors;
     MODEL score = trt strat_factors time score_B trt*time / 
noint s ddfm=kr;
     REPEATED timeC / subject=subject type=un;
RUN;
/* score refers to the observed scores after Baseline
score_B refers to the baseline score
trt is the treatment variable
timeC refers to the time window as class variable
time refers to the time window
method=reml specifies that the restricted Maximum Likelihood Estimation 
method used
type=un specifies that an unstructured covariance matrix is used */
6
Reference
1.
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival 
Time. Biometrics, 38, 29 - 41. 


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2.
Clopper C.J. and Pearson E. S. (1934). The Use of Confidence or Fiducial Limits 
Illustrated in the Case of the Binomial, Biometrika Vol. 26, No. 4 (Dec., 1934), pp. 404-
413
3.
Collett D (1994). Modelling survival data in medical research. London, Chapman & Hall.
4.
European Medicines Agency (2020). Guidance on the management of clinical trials 
during the COVID-19 (coronavirus) pandemic
5.
Fayers P.M. et al. on behalf of the EORTC Quality of Life Group. The EORTC QLQ-C30 
Scoring Manual (3rd edition). Published by: European Organization for Research and 
Treatment of Cancer, Brussels 2001.
6.
Food and Drug Administration (2020). FDA Guidance on Conduct of Clinical Trials of 
Medical Products during COVID-19 Pandemic: Guidance for Industry, Investigators, 
and Institutional Review Boards (2020)
7.
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 
randomised controlled trial. Lancet p. 1540-50. .
8.
Lan KKG, DeMets DL (1983). Discrete sequential boundaries for clinical trials. 
Biometrika, 70, 649-53.
9.
Rittmeyer A, Barlesi F, Waterkamp D, et al (2017) Atezolizumab versus docetaxel in 
patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, 
multicentre randomised controlled trial. Lancet p. 255-265.
10. Rogatko, Xu, Tighiouart (2007) EWOC 2.0 Interactive Software for Dose Escalation in 
Cancer Phase I Clinical Trials.
11. Schemper M1, Smith TL (1996) A note on quantifying follow-up in studies of failure time, 
Control Clin Trials. 1996 Aug;17(4):343-6
12. Van Reenen M. et al. EQ-5D-5L User Guide – Basic information on how to use the EQ-
5D-5L instrument. 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_ Flyers/EQ-5D-
5L_UserGuide_2015.pdf.  Accessed Oct 2017.