Conditions: ALK-positive Non-small Cell Lung Cancer
Keywords: ALK-positive NSCLC non-small cell lung cancer brain metastasis metastatic to the brain and/or to leptomeninges ceritinib LDK378 NSCLC metastatic to the brain leptomeninges harboring a confirmed ALK rearrangement
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 156
Healthy volunteers: no

Brief summary:
This was a phase II, multi-center, open-label, five-arm study in which the efficacy and safety of oral ceritinib treatment was assessed in patients with NSCLC metastatic to the brain and/or to leptomeninges harboring a confirmed ALK rearrangement, using the FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria). If documentation of ALK rearrangement as described above was not locally available, a test to confirm ALK rearrangement was performed by a Novartis designated central laboratory. Patients waited for the central laboratory result of the ALK rearrangement status before initiating treatment with ceritinib.

Detailed description:
Approximately 160 patients diagnosed with ALK-positive metastatic NSCLC (according to the 7th edition of the AJCC \[American Joint Committee on Cancer\] Cancer Staging Manual) and active lesions in the brain and/or diagnosed with leptomeningeal carcinomatosis were included in the study, approximately 40 patients in Arm 1 and Arm 2, approximately 30 patients in Arms 3 and Arm 4, and approximately 20 patients in Arm 5. Additional patients were enrolled in Arm 4 to achieve approximately 60 patients in Arms 3 and 4 together (i.e. ALKi naïve patients), if enrollment rate in Arm 3 was slow.

* Arm 1 included patients with metastases in the brain without evidence of leptomeningeal carcinomatosis, previously treated with radiation to the brain and with prior exposure to an ALKi.
* Arm 2 included patients with metastases in the brain without evidence of leptomeningeal carcinomatosis, previously untreated with radiation to the brain but with prior exposure to an ALKi.
* Arm 3 included patients with metastases in the brain without evidence of leptomeningeal carcinomatosis, previously treated with radiation to the brain but with no prior exposure to an ALKi.
* Arm 4 included patients with metastases in the brain without evidence of leptomeningeal carcinomatosis, previously untreated with radiation to the brain and with no prior exposure to an ALKi
* Arm 5 included any patients with leptomeningeal carcinomatosis with or without evidence of active lesion at the baseline Gadolinium-enhanced brain MRI.

Note: Previous treatment with ALK inhibitors other than crizotinib was not allowed in Arms 1, 2, and 5.

Ceritinib was administered orally once daily at a dose of 750 mg (five 150 mg capsules) on a continuous dosing schedule. The treatment period started on Cycle 1 Day 1.

Complete tumor assessments including gadolinium enhanced brain MRI was repeated at Week 8 (on Cycle 3 Day 1) and every 8 weeks (i.e. every 2 cycles) thereafter or earlier if clinically indicated. Safety evaluations included (S)AEs, physical examination, vital signs, ECGs, laboratory parameters and WHO performance status. Blood and CSF samples for PK were also collected.

Arms:
arm 1: Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation). arm 2: Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation). arm 3: Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation). arm 4: Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation). arm 5: Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.

Interventions: intervention 1: Ceritinib
Intervention descriptions: intervention 1: LDK378 is a gelatin capsule, administered orally once daily at a dose of 750 mg (five 150 mg capsules) on a continuous dosing schedule on an empty stomach.

Protocol document:
Prot_001.pdf: 
Clinical Development
Ceritinib (LDK378)
Oncology Clinical Trial Protocol CLDK378A2205 / NCT02336451
A Phase II, multi-center, open-label, five-arm study to 
evaluate the efficacy and safety of oral ceritinib treatment 
for patients with ALK-positive non-small cell lung cancer 
(NSCLC) metastatic to the brain and/or to leptomeninges
Authors
Document type
Amended Protocol Version
EUDRACT number
2014-000578-20
Version number
06 (Clean)
Development phase
II
Document status
Final
Release date
16-May-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................7
List of tables ........................................................................................................................7
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................12
Protocol summary..............................................................................................................13
Amendment 6 (16-May-2018)...........................................................................................22
Amendment 5 (31-May-2017)...........................................................................................24
Amendment 4 (22-Aug-2016)...........................................................................................26
Amendment 3 ....................................................................................................................29
Amendment 2 ....................................................................................................................32
Amendment 1 ....................................................................................................................35
1
Background........................................................................................................................38
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............38
1.1.1
Locally advanced or metastatic non-small cell lung cancer 
(NSCLC) ...............................................................................................38
1.1.2
Targeted therapies in NSCLC ...............................................................39
1.1.3
ALK rearranged (ALK-positive, ALK+) NSCLC ................................40
1.2
Introduction to investigational treatment(s)...........................................................42
1.2.1
Overview of ceritinib ............................................................................42
1.3
Risk and benefits....................................................................................................54
2
Rationale............................................................................................................................57
2.1
Study rationale and purpose...................................................................................57
2.2
Rationale for the study design ...............................................................................59
2.3
Rationale for dose and regimen selection..............................................................61
3
Objectives and endpoints...................................................................................................62
4
Study design ......................................................................................................................65
4.1
Description of study design ...................................................................................65
4.1.1
Screening...............................................................................................65
4.1.2
Treatment duration................................................................................67
4.2
Timing of interim analyses and design adaptations...............................................69
4.3
End of study...........................................................................................................70
4.4
Early study termination..........................................................................................70
5
Population..........................................................................................................................71
5.1
Patient population..................................................................................................71


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5.2
Inclusion criteria ....................................................................................................71
5.3
Exclusion criteria...................................................................................................73
6
Treatment...........................................................................................................................76
6.1
Study treatment......................................................................................................76
6.1.1
Dosing regimen.....................................................................................76
6.1.2
Guidelines for continuation of treatment ..............................................77
6.1.3
Treatment duration................................................................................77
6.2
Dose escalation guidelines.....................................................................................78
6.3
Dose modifications................................................................................................78
6.3.1
Dose modification and dose delay ........................................................78
6.3.2
Treatment interruption and treatment discontinuation..........................79
6.3.3
Criteria for ceritinib dose modifications ...............................................79
6.3.4
Follow-up for toxicities.........................................................................86
6.3.5
Anticipated risks and safety concerns of the study treatment...............90
6.4
Concomitant medications ......................................................................................90
6.4.1
Permitted concomitant therapy .............................................................91
6.4.2
Prohibited concomitant therapy ............................................................92
6.5
Patient numbering, treatment assignment or randomization .................................94
6.5.1
Patient numbering .................................................................................94
6.5.2
Treatment assignment ...........................................................................95
6.5.3
Treatment blinding................................................................................95
6.6
Study drug preparation and dispensation...............................................................95
95
6.6.2
Drug supply and storage........................................................................96
6.6.3
Study drug compliance and accountability ...........................................96
6.6.4
Disposal and destruction .......................................................................96
7
Visit schedule and assessments .........................................................................................97
7.1
Study flow and visit schedule................................................................................97
105
7.1.2
Screening.............................................................................................106
7.1.3
Treatment period.................................................................................108
7.1.4
End of treatment visit including study completion or 
discontinuation....................................................................................108
7.1.5
Withdrawal of consent ........................................................................110
7.1.6
Follow up for safety evaluations.........................................................111
7.1.7
Lost to follow-up.................................................................................112


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7.2
Assessment types.................................................................................................112
7.2.1
Efficacy assessments...........................................................................112
7.2.2
Safety and tolerability assessments.....................................................117
122
7.2.4
CSF sampling in patients with leptomeningeal carcinomatosis at 
baseline................................................................................................124
125
7.2.6
Resource utilization.............................................................................127
7.2.7
Patient reported outcomes...................................................................127
8
Safety monitoring and reporting......................................................................................127
8.1
Adverse events.....................................................................................................127
8.1.1
Definitions and reporting ....................................................................127
8.1.2
Laboratory test abnormalities..............................................................129
8.1.3
Adverse events of special interest.......................................................129
8.2
Serious adverse events.........................................................................................129
8.2.1
Definitions...........................................................................................129
8.2.2
Reporting.............................................................................................130
8.3
Emergency unblinding of treatment assignment .................................................131
8.4
Pregnancies..........................................................................................................131
8.5
Warnings and precautions....................................................................................131
8.6
Data Monitoring Committee (DMC)...................................................................131
8.7
Steering Committee .............................................................................................132
8.8
Blinded Independent Review Committee (BIRC)...............................................132
9
Data collection and management.....................................................................................132
132
9.2
Site monitoring ....................................................................................................133
9.3
Data collection.....................................................................................................133
134
10 Statistical methods and data analysis ..............................................................................135
10.1
Analysis sets ........................................................................................................135
10.1.1
Full Analysis Set .................................................................................135
10.1.2
Safety Set ............................................................................................136
10.1.3
Per-Protocol Set ..................................................................................136
10.1.4
Dose-determining analysis set.............................................................136
136
10.2
Patient demographics/other baseline characteristics ...........................................136


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10.3
Treatments (study treatment, concomitant therapies, compliance) .....................136
10.4
Primary objective.................................................................................................136
10.4.1
Variable...............................................................................................136
137
10.4.3
Handling of missing values/censoring/discontinuations.....................137
137
10.5
Secondary objectives ...........................................................................................137
10.5.1
Key secondary objective(s).................................................................137
10.5.2
Other secondary efficacy objectives ...................................................137
10.5.3
Safety objectives .................................................................................140
141
141
10.6
Exploratory objectives.........................................................................................143
143
10.8
Sample size calculation........................................................................................144
10.9
Power for analysis of key secondary variables....................................................144
11 Ethical considerations and administrative procedures ....................................................145
11.1
Regulatory and ethical compliance......................................................................145
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................145
11.3
Informed consent procedures...............................................................................146
11.4
Discontinuation of the study................................................................................146
11.5
Publication of study protocol and results.............................................................146
11.6
Study documentation, record keeping and retention of documents.....................147
11.7
Confidentiality of study documents and patient records .....................................148
11.8
Audits and inspections.........................................................................................148
11.9
Financial disclosures............................................................................................148
12 Protocol adherence ..........................................................................................................148
12.1
Amendments to the protocol................................................................................148
13 References (available upon request)................................................................................150
14 Appendices ......................................................................................................................155
155
14.2
Appendix 2: Harmonization of efficacy analysis of solid tumor studies 
(RECIST 1.1).......................................................................................................158
14.2.1
Introduction.........................................................................................160
14.2.2
Efficacy assessments...........................................................................160
14.2.3
Definitions...........................................................................................160


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14.2.4
Disease measurability..........................................................................160
14.2.5
Eligibility based on measurable disease..............................................161
14.2.6
Methods of tumor measurement - general guidelines.........................161
14.2.7
Baseline documentation of target and non-target lesions ...................163
14.2.8
Follow-up evaluation of target and non-target lesions........................163
14.2.9
Follow-up and recording of lesions.....................................................164
14.2.10
Non-nodal lesions................................................................................164
14.2.11
Nodal lesions.......................................................................................164
14.2.12
Determination of target lesion response..............................................165
14.2.13
Determination of non-target lesion response ......................................167
14.2.14
New lesions .........................................................................................167
14.2.15
Evaluation of overall lesion response .................................................168
14.2.16
Efficacy definitions .............................................................................168
14.2.17
Best overall response...........................................................................169
14.2.18
Time to event variables .......................................................................171
14.2.19
Progression-free survival ....................................................................171
14.2.20
Overall survival...................................................................................171
14.2.21
Time to progression.............................................................................171
14.2.22
Time to treatment failure.....................................................................172
14.2.23
Duration of response ...........................................................................172
14.2.24
Time to response .................................................................................173
14.2.25
Definition of start and end dates for time to event variables ..............173
14.2.26
Handling of patients with non-measurable disease only at baseline...174
14.2.27
Sensitivity analyses .............................................................................175
14.2.28
Data handling and programming rules................................................177
14.2.29
Study/project specific decisions..........................................................177
14.2.30
End of treatment phase completion.....................................................177
14.2.31
End of post-treatment follow-up (study phase completion)................178
14.2.32
Medical validation of programmed overall lesion response ...............178
14.2.33
Programming rules..............................................................................179
14.2.34
Calculation of ‘time to event’ variables..............................................179
14.2.35
Incomplete assessment dates...............................................................179
14.2.36
Incomplete dates for last known date patient alive or death ...............179
14.2.37
Non-target lesion response..................................................................180
14.2.38
Study/project specific programming...................................................180
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14.2.40
References (available upon request) ...................................................181
14.3
Appendix 3: Response assessment in neuro-oncology (RANO) criteria for 
high-grade gliomas ..............................................................................................182
14.3.1
Antitumor effect - definitions..............................................................182
14.3.2
Response/progression categories ........................................................183
14.3.3
Methods for evaluation of measurable disease ...................................185
14.3.4
Evaluation of best response.................................................................185
14.3.5
Other effect measures..........................................................................185
14.4
Appendix 4: Cockcroft-Gault formula.................................................................187
List of figures
Figure 4-1
Study design..........................................................................................65
List of tables
Table 1-1
All grades (at least 5%) and grade 3-4 adverse events, regardless of 
study drug relationship, by preferred term in patients treated in the 
750 mg dose group 
...........................46
Table 1-2
Summary of best overall response based on investigator assessment 
in NSCLC patients in the 750 mg dose group, by prior ALK 
inhibitor status (Full Analysis Set NSCLC 750 mg) 
 
.........................................................................................49
Table 1-3
Analysis of duration of response based on investigator assessment 
in NSCLC patients in the 750 mg dose group using Kaplan-Meier 
method, by prior ALK inhibitor status (Full Analysis Set NSCLC 
750 mg– Confirmed PR or CR) 
...............50
Table 1-4
Analysis of PFS based on investigator assessment in NSCLC 
patients in the 750 mg dose group, by prior ALK inhibitor status 
(Full Analysis Set NSCLC 750 mg) 
........51
Table 1-5
ORR, DOR and PFS in NSCLC patients with brain metastases at 
baseline in the 750 mg dose group 
..........52
Table 2-1
Allocation into Study Arms based on prior radiation to brain 
(yes/no) and prior treatment with ALK inhibitor (yes/no)....................60
Table 3-1
Objectives and related endpoints ..........................................................63
Table 6-1
Dose and treatment schedule.................................................................77
Table 6-2
Dose reduction steps for ceritinib .........................................................80
Table 6-3
Criteria for dose reduction, interruption and re-initiation of 
ceritinib treatment .................................................................................81
Table 6-4
Follow-up evaluations for selected toxicities........................................90


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Table 6-5
Preparation and dispensing ...................................................................95
Table 6-6
Packaging and labeling .........................................................................96
Table 7-1
Visit evaluation schedule ......................................................................98
Table 7-2
Imaging assessment collection plan....................................................113
Table 7-3
WHO performance status scale...........................................................118
Table 7-4
Clinical laboratory parameters collection plan ...................................120
Table 7-5
ECG collection plan for patients 
 
(triplicate ECGs) .................................................................................122
 
123
124
125
Table 10-1
Exact binomial 95% confidence intervals for various observed 
ORRs...................................................................................................144
Table 10-2
Exact binomial 95% confidence intervals for various observed 
DCRs...................................................................................................144
Table 10-3
Exact binomial 95% confidence intervals for various observed 
OIRRs..................................................................................................145
 
 
155
156
156
157
Table 14-5
Response criteria for target lesions .....................................................165
Table 14-6
Response criteria for non-target lesions..............................................167
Table 14-7
Overall lesion response at each assessment ........................................168
Table 14-8
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................175
Table 14-9
Options for event dates used in PFS, TTP, duration of response........176
Table 14-10
Summary of the RANO response criteria ...........................................185


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List of abbreviations
AE
Adverse event
µg
Microgram
AJCC
American Joint Committee on Cancer
ALCL
Anaplastic large cell lymphoma
ALK
Anaplastic lymphoma kinase
ALKi
Anaplastic lymphoma kinase inhibitor
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical Classification System
AUC
Area under the plasma concentration versus time curve
AUC0-24h
Area under the plasma concentration versus time curve from time zero to 24 hours
AUCinf
Area under the plasma concentration versus time curve from time zero to infinity
AUClast
Area under the concentration-time curve from time zero to the last measurable concentration time
AUCtau
Area under the plasma concentration versus time curve from time zero to end of dosing period
BBB
Blood Brain Barrier
BIRC
Blinded Independent Review Committee
BLRM
Bayesian logistic regression model
BM
Brain metastases
BUN
Blood Urea Nitrogen
CI
Confidence interval
CL
Clearance
CL/F
Apparent clearance
Cmax
Maximum (peak) concentration of drug in plasma
Cmin
Minimum (trough) concentration of drug in plasma
CMO&PS
Chief Medical Office & Patient Safety
CNS
Central nervous system
CR
Complete response
CrCl
Creatinine Clearance
CRO
Contract Research Organization
CSR
Clinical study report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
D
Entered into database
DBP
Diastolic blood pressure
DCR
Disease control rate
DHEA
Dihydroepiandrosterone
DILI
Drug Induced Liver Injury
DLT
Dose limiting toxicity
DMC
Data Monitoring Committee
DMPK
Drug metabolism & pharmacokinetic
DOER
Duration of extracranial response
DOIR
Duration of intracranial response


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DOR
Duration of response
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDCR
Extracranial disease control rate
EGFR
Epidermal growth factor receptor
EIAED
enzyme inducing anti-epileptic medication
EML4-ALK
Echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase
EOS
End of study
EOT
End of treatment
eSAE
Electronic Serious Adverse Event
FAS
Full analysis set
FDA
Food and Drug Administration
FISH
Fluorescent in situ hybridization
GCP
Good Clinical Practice
HA
Health Authorities
hCG
human chorionic gonadotropin
HED
Human equivalent dose
Hgb
Hemoglobin
IB
Investigator’s brochure
IC50
Half maximal (50%) inhibitory concentration
ICF
Informed consent form
ICH
International Conference on Harmonization
IDCR
Intracranial disease control rate
IEC
Independent Ethics Committee
IGF1R
Insulin-like Growth Factor 1 Receptor
IHC
Immunohistochemistry
INR
International normalized ration
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine device
IUS
Intrauterine system
IV
Intravenous(ly)
LC 
Leptomeningeal Carcinomatosis
LDK378
Ceritinib
LFT
Liver function test
LLOQ
lower limit of quantification
MedDRA
Medical dictionary for regulatory activities
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
N/A
Not applicable
NSAIDs
Non-steroidal, anti-inflammatory drugs
NSCLC
Non-small cell lung cancer
OERR
Overall extracranial response rate
OIRR
Overall intracranial response rate
ORR
Overall response rate
OS
Overall survival


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OTC
Over the counter
PD
Progressive disease
PFS
Progression-free survival
PI
Principal investigator
PK
Pharmacokinetics
PPS
Per-protocol set
PR
Partial response
PS
Performance Status
QD
quaque diem/once daily
QTc
Corrected QT interval
QTcF
Corrected QT interval using Fridericia formula
R Value
ALT/ALP in x ULN
Racc
Accumulation ratio
RANO
Response Assessment in Neuro-Oncology
RBC
Red blood cell
RD
Recommended dose
RECIST
Response Evaluation Criteria In Solid Tumors
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SC
Steering Committee
SD
Stable disease
SEC
Safety event categories
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SI units
Standard international units
SRS
Stereotactic radiosurgery
SUSARs
Suspected unexpected serious adverse reactions
T1/2
Elimination half-life associated with the terminal slope (lambda_z) of a semilogarithmic 
concentration-time curve (time).
TKIs
Tyrosine kinase inhibitors
Tmax
The time to reach maximum plasma concentration
TTER
Time to extracranial response
TTIR
Time to intracranial response
TTR
Time to response
ULN
Upper limit of normal
VATS
Video-assisted thoracic surgery
VEGF-A
Vascular endothelial growth factor-A
Vss
Volume of distribution at steady state
WBC
White blood cells
WBRT
Whole brain radiation therapy
WHO
World Health Organization


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biological samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject or study patient
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q 21 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e., before starting any of the study procedures described 
in the protocol)
Investigational drug
The drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug”
Investigational treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This also 
includes approved drugs used outside of their indication/approved dosage, or 
that are tested in a fixed combination. Investigational treatment generally does 
not include other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used in within approved 
indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures 
that was not included in the investigational treatment
Patient number
A unique identifier number (consisting of the center number and a patient-
specific number) assigned to each patient who enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has 
spread from the original site to other parts of the body
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when 
study drug was discontinued whichever is later
Study treatment
Any drug administered to the patient as part of the required study procedures; 
includes investigational drug and any combination or control drug(s)
Study treatment discontinuation
Point/time when the patient permanently stops taking study treatment for any 
reason
Treatment group
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are 
enrolled
Variable
A quantity subject to variation of values used in the data analysis; derived 
directly or indirectly from data collected using specified assessments at 
specified time points
Withdrawal of consent
Withdrawal of consent occurs only when a patient does not want to participate 
in the study any longer, and does not want any further visits or assessments, 
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Protocol summary
Protocol number
CLDK378A2205
Title
A phase II, multi-center, open-label, five-arm study to evaluate the efficacy and 
safety of oral ceritinib treatment for patients with ALK-Positive Non-Small Cell Lung 
Cancer metastatic to the brain and/or to leptomeninges
Sponsor and
Clinical Phase
Novartis,
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
This is a phase II, multi-center, open-label, five-arm study to evaluate the efficacy 
and safety of oral ceritinib treatment for patients with ALK-positive NSCLC 
metastatic to the brain and/or to leptomeninges. Only patients whose tumors 
harbor ALK rearrangement will be enrolled in the study.
Primary Objective(s) and 
Key Secondary Objective
The primary objective is to evaluate the antitumor activity of ceritinib in patients 
with ALK-positive NSCLC metastatic to the brain and/or to leptomeninges based 
on whole body overall response rate (ORR), defined as the proportion of patients 
with a best overall confirmed response of complete response (CR) or partial 
response (PR) in the whole body as assessed per RECIST 1.1 by the investigator.
The key secondary objective is to evaluate whole body Disease Control Rate 
(DCR) in patients with ALK-positive NSCLC metastatic to the brain and/or to 
leptomeninges based on investigator assessment per RECIST 1.1
Secondary Objectives
1. To evaluate intracranial tumor-response related endpoints as assessed by 
investigators and Blinded Independent Review Committee (BIRC) (using modified 
RECIST 1.1 criteria)
2. To evaluate extracranial tumor-response related endpoints as assessed by 
investigators and BIRC (using RECIST 1.1 criteria)
3. To evaluate whole body tumor-response related endpoints as assessed by 
investigators and BIRC (using RECIST 1.1 criteria)
4. To evaluate overall survival (OS) in this patient population
5. To evaluate safety in this patient population
Study design
This is a phase II, multi-center, open-label, five-arm study in which the efficacy and 
safety of oral ceritinib treatment will be assessed in patients with NSCLC 
metastatic to the brain and/or to leptomeninges harboring a confirmed ALK 
rearrangement, using the FDA approved Vysis ALK Break Apart FISH Probe Kit 
(Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria). If 
documentation of ALK rearrangement as described above is not locally available, a 
test to confirm ALK rearrangement must be performed by a Novartis designated 
central laboratory. Patients must wait for the central laboratory result of the ALK 
rearrangement status before initiating treatment with ceritinib.
Population
Approximately 160 patients diagnosed with ALK-positive metastatic NSCLC 
(according to the 7th edition of the AJCC [American Joint Committee on Cancer]
Cancer Staging Manual) and active lesions in the brain and/or diagnosed with 
leptomeningeal carcinomatosis will be included in the study, approximately 40 
patients in Arm 1 and Arm 2, approximately 30 patients in Arms 3 and Arm 4, and 
approximately 20 patients in Arm 5. Additional patients may be enrolled in Arm 4 to 
i achieve approximately 60 patients in Arms 3 and 4 together (i.e. ALKi naïve 
patients), if enrollment rate in Arm 3 is slow.
●
Arm 1 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously treated with radiation to the brain and 
with prior exposure to an ALKi.
●
Arm 2 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously untreated with radiation to the brain but 


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with prior exposure to an ALKi.
●
Arm 3 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously treated with radiation to the brain but 
with no prior exposure to an ALKi.
●
Arm 4 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously untreated with radiation to the brain and 
with no prior exposure to an ALKi
●
Arm 5 will include any patients with leptomeningeal carcinomatosis with or 
without evidence of active lesion at the baseline Gadolinium-enhanced brain MRI.
Note: Previous treatment with ALK inhibitors other than crizotinib is not allowed in 
Arms 1, 2, and 5.
Inclusion criteria
For all patients:
1a. Histologically or cytologically confirmed diagnosis of metastatic NSCLC 
according to the 7th edition of the AJCC Cancer Staging Manual. In addition, 
the NSCLC must harbor an ALK rearrangement, as assessed using the FDA 
approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test 
and scoring algorithm (including positivity criteria). If documentation of ALK 
rearrangement as described above is not locally available, a test to confirm 
ALK rearrangement must be performed by a Novartis designated central 
laboratory. Patients must wait for the central laboratory result of the ALK 
rearrangement status before initiating treatment with ceritinib.
2a. Patients that require ALK rearrangement testing by a Novartis designated 
central laboratory must have a tumor tissue sample available as an archival 
sample (if possible obtained after the completion of the patient’s last 
therapeutic regimen) or as a new biopsy. If that is not possible, any tumor 
biopsy obtained at or since the time of diagnosis can be used (a maximum of 
two years from biopsy excision is preferred).
3.
At least one extracranial measurable lesion as defined by RECIST 1.1. A 
previously irradiated site lesion may only be counted as a target lesion if there 
is clear sign of progression since the irradiation.
4.
Patient is 18 years of age or older at the time of informed consent.
5.
Patients may or may not have neurological symptoms but must:
●
Be able to swallow and retain oral medication.
●
Be neurologically stable within at least 1 week prior to the first dose of 
study drug. Neurologically stable is defined as improved or stable neurological 
examination without increased doses of steroids to manage CNS symptoms 
within the last 5 days.
6a. Patients may have received prior chemotherapy, crizotinib (other ALK 
inhibitors are not allowed), biologic therapy or other investigational agents. 
Patients must have recovered from all toxicities related to prior anticancer 
therapies to grade ≤ 1 (CTCAE v 4.03). Patients with any grade of alopecia 
are allowed to enter the study.

Patients who have been treated with chemotherapy, with biological therapy 
or other investigational agent must have discontinued the treatment at 
least 2 weeks (14 days) prior to starting study drug. In case last 
chemotherapy contains nitrosourea or mitomycin C, the treatment must be 
discontinued at least 6 weeks prior to the first dose of study drug.

Patients, if previously treated with crizotinib must discontinue treatment at 
least 1 week (7 days) prior to the first dose of study drug.
7a. Patient must meet the following laboratory values at the screening visit:

Absolute Neutrophil Count ≥ 1.5 x 109/L

Platelets ≥ 75 x 109/L

Hemoglobin (Hgb) ≥ 8 g/dL

Serum creatinine < 1.5 mg/dL and /or calculated creatinine clearance 
(using Cockcroft-Gault formula) ≥ 30 mL/min

Total bilirubin ≤ 1.5 x ULN except for patients with Gilbert’s syndrome who 


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may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x 
ULN

Aspartate transaminase (AST) ≤ 3 x ULN, except for patients with liver 
metastasis, who are only included if AST ≤ 5 x ULN

Alanine transaminase (ALT) ≤ 3 x ULN, except for patients with liver 
metastasis, who are only included if ALT ≤ 5 x ULN

Alkaline phosphatase (ALP) ≤ 5.0 x ULN

Serum amylase ≤ 2 x ULN

Serum lipase ≤ ULN

Fasting plasma glucose ≤ 200 mg/dL (≤ 11.1 mmol/L)
8.
Patient must have the following laboratory values within normal limits or 
corrected to within normal limits with supplements during screening:

Potassium

Magnesium

Phosphorus

Total calcium (corrected for serum albumin)
9.
Patient has life expectancy ≥ 6 weeks.
10. Patient has a WHO performance status 0-2.
11. Patient has the ability to understand and provide signed informed consent.
12. Willingness and ability to comply with scheduled visits, treatment plans, 
laboratory tests and other study procedures.
Patients in Arm 1 to 4 must also meet the following inclusion criteria:
13. Patients must have active brain metastases from NSCLC, confirmed by 
Gadolinium-enhanced MRI without concomitant leptomeningeal 
carcinomatosis. Dose of steroids must be stable for 5 days before the baseline 
brain MRI.
Note: An active brain lesion is a lesion free of any local treatment (like 
stereotactic radiosurgery or whole brain radiation). The following lesions are 
considered active:

A newly diagnosed brain metastasis in a patient who has never received 
treatment to the brain or in a patient with previously treated brain 
metastases.

A brain lesion previously treated with whole brain radiation will only be 
considered active when there is an unequivocal size increase in its solid
component (cystic component of the lesion is not considered for 
progression determination) compared to the first available post-radiation 
radiological evaluation.

An enlarging brain lesion previously treated with SRS will only be 
considered active when the nature of the enlargement is clearly attributed 
to the tumoral component of the lesion and not to the radiation effect.
Patients in Arm 5 must also meet the following inclusion criteria:
14. Patients must be diagnosed with leptomeningeal carcinomatosis. The 
diagnosis requires either documentation of the presence of malignant cells 
detected at the cytological examination of the cerebrospinal fluid or a serious 
suspicion of leptomeningeal carcinomatosis, supported by imaging findings 
typical of LC on the Gadolinium-enhanced MRI of the brain or spine (in this 
latter case, the determination of the presence of malignant cells in CSF 
cytology is strongly recommended).
Exclusion criteria
1.
Patient with a history of treatment with ceritinib. Patient with known 
hypersensitivity to any of the excipients of ceritinib (microcrystalline cellulose, 
mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate).
2.
Patients who need whole brain radiation to control the brain metastases. 
Patients will not be eligible unless treated brain lesions are progressive or new 
brain lesions are observed since the post whole brain radiation therapy MRI.
3.
In case active brain lesions (single or not) require local treatment but other 


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active brain lesions do not and are not treated, patients will be excluded only if 
the local treatment (neurosurgical treatment or Stereotactic Radiosurgery) for 
the brain metastases is conducted within 2 weeks prior to starting study drug. 
Patients must have recovered from relevant toxicities related to these 
procedures to grade ≤ 1 (CTCAE v 4.03) prior to receiving the first dose of 
study drug.
4.
Planning of any brain local treatment (including but not limited to surgery, 
stereotactic radiosurgery, whole brain radiation, intrathecal chemotherapy) 
following the administration of the first dose of study drug.
5.
Patient who has received thoracic radiotherapy to lung fields ≤ 4 weeks prior 
to starting the study treatment or patients 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 the first 
dose of study drug is allowed.
6.
Patient has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-
pelvic) within 4 weeks prior to the first dose of 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 patients can 
receive study treatment ≥1 week after the procedure.
7.
Patient with a concurrent malignancy or history of a malignant disease other 
than 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.
8.
Patient has clinically significant, uncontrolled heart disease and/or recent 
cardiac event (within 6 months), such as:

Unstable angina within 6 months prior to screening.

Myocardial infarction within 6 months prior to screening.

History of documented congestive heart failure (New York Heart 
Association functional classification III-IV).

Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 
160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or 
without anti-hypertensive medication. Initiation or adjustment of 
antihypertensive medication (s) is allowed prior to screening.

Ventricular arrhythmias.

Supraventricular and nodal arrhythmias not controlled with medication.

Other cardiac arrhythmia not controlled with medication.

Corrected QT (QTcF) > 470 ms using Fridericia’s correction on the 
screening ECG (as mean of triplicate ECGs).
9.
Patient has impairment of GI function or GI disease that may significantly alter 
the absorption of ceritinib (e.g., ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, or malabsorption syndrome).
10. Patient receiving treatment with medications that meet one of the following 
criteria and that cannot be discontinued at least 1 week prior to the start of 
treatment with ceritinib and for the duration of the study (Appendix 1):

Strong inhibitors or strong inducers of CYP3A4/5.

Medications with a low therapeutic index that are primarily metabolized by 
CYP3A4/5 and/or CYP2C9.

Medications with a known risk of prolonging the QT interval or inducing 
Torsades de Pointes.
11. Patient is currently receiving treatment with warfarin sodium (Coumadin®) or 
any other coumarin-derivative anticoagulants.
12. Patient is receiving unstable or increasing doses of corticosteroids. If patients 
are on corticosteroids for endocrine deficiencies or tumor-associated 


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symptoms (non-CNS), dose must have been stabilized (or decreasing) for at 
least 5 days before first dose of study treatment. Note: Dose of steroids must 
be stable for 5 days before the baseline brain MRI.
13. Patient is receiving treatment with any enzyme-inducing anticonvulsant 
(Appendix 1) that cannot be discontinued at least 1 week before first dose of 
study treatment, and for the duration of the study. Patients on non enzyme-
inducing anticonvulsants are eligible.
14. Patient is pregnant or nursing (lactating) woman.
15a.Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective methods 
of contraception during dosing and for 3 months after stopping medication. 
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 tubal ligation at least six 
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). The vasectomized 
male partner should be the sole partner for that subject

Use of oral, injected or implanted 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 stable on the same 
pill for a minimum of 3 months before taking study treatment.
16. Sexually active males unless they use a condom during intercourse while 
taking the drug and for 3 months after the last dose of ceritinib treatment. Male 
patients should not father a child for 3 months after the last dose of ceritinib 
treatment. A condom is required to be used also by vasectomized men in 
order to prevent delivery of the drug via seminal fluid.
17. Patient has other severe, acute, or chronic medical conditions including 
uncontrolled diabetes mellitus or psychiatric conditions or laboratory 
abnormalities that in the opinion of the investigator may increase the risk 
associated with study participation, or that may interfere with the interpretation 
of study results.
18. Patient has history of interstitial lung disease or interstitial pneumonitis, 
including clinically significant radiation pneumonitis (i.e., affecting activities of 
daily living or requiring therapeutic intervention).
19. Patient has a history of pancreatitis or a history of increased amylase or lipase 
that was due to pancreatic disease.
20. Patient has been previously enrolled in the treatment phase of any ceritinib 
clinical study, regardless of which treatment group the patient was allocated or 
randomized to.
Investigational therapy
Ceritinib will be administered orally once daily at a dose of 750 mg (five 150 mg 
capsules) on a continuous dosing schedule. The treatment period will start on 
Cycle 1 Day 1.
Efficacy assessments
Complete tumor assessments including gadolinium enhanced brain MRI will be 
repeated at Week 8 (on Cycle 3 Day 1) and every 8 weeks (i.e. every 2 cycles) 
thereafter or earlier if clinically indicated.
Tumor response will be evaluated starting from the first day of treatment with 
ceritinib until the time of disease progression according to RECIST 1.1 as 
determined by investigator, withdrawal of consent for further follow-up, loss to 


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follow-up or death. This schedule of tumor assessment must continue regardless of 
dose interruptions. In patients who discontinue treatment in the absence of 
progression, tumor assessments will continue every 8 weeks until progression of 
disease, withdrawal of consent for further follow-up, loss to follow-up or death.
For patients presenting with baseline leptomeningeal carcinomatosis with 
documented malignant cells in the cerebrospinal fluid, CSF samples will be 
collected at a frequency determined by local clinical practice unless medically 
contra-indicated. Samples should be obtained from site of disease or initially 
positive cytology if possible. The investigator may determine if more frequent 
evaluations are needed in case of suspected disease progression and/or in 
accordance with local clinical practice. If there are any signs or radiologic or clinical 
neurological progression, a CSF will be collected if feasible. Clinical progression 
may be determined based on results of cytological or neurological evaluations.
Gadolinium-enhanced brain MRI scans and all other imaging data collected at 
baseline and during the conduct of the study will be submitted to the designated 
imaging vendor for BIRC review.
In this study, standard RECIST 1.1 will be used to evaluate the whole body 
(including intracranial and extracranial cancer lesions) response endpoints. 
Assessment of the overall response to treatment and other whole body response 
related endpoints will be conducted by investigators and BIRC.
Additionally, the intracranial and the extracranial metastatic disease will be 
evaluated as two separate entities. Modified RECIST 1.1 and RANO for High 
Grade Glioma (Wen et al 2010) criteria will be used to determine intracranial tumor 
response based on brain target lesions, if applicable, any brain non-target lesions 
and any brain new lesions. RECIST 1.1 will be used to evaluate the extracranial 
tumor response but brain will be excluded from the evaluation.
Safety assessments
Adverse Events (AEs) including:

Serious AEs (SAEs)

Laboratory profiles

hematology

biochemistry

urinalysis

coagulation

pregnancy test (females)

Physical examination

Vital signs

Electrocardiograms (ECG)

WHO performance status
Data analysis
The primary endpoint is the overall response rate (ORR), which is defined as the 
proportion of patients with a best overall confirmed response of CR or PR in the 
whole body, as assessed per RECIST 1.1 (Appendix 2) by the investigator.
The key secondary endpoint is the Disease Control Rate (DCR), which is defined 
as the proportion of patients with a best overall response of CR, PR or SD in the 
whole body, as assessed per RECIST 1.1 by the investigator.
Additionally, the following intracranial, extracranial and whole body (for lesions 
inside and outside the brain) tumor-response related endpoints (OIRR, IDCR, 
TTIR, DOIR, OERR, EDCR, TTER, DOER, TTR, DOR and PFS) will be assessed 
separately based on investigator assessment and BIRC assessment per RECIST 
1.1.
Intracranial endpoints:
Overall intracranial response rate (OIRR): OIRR is calculated based on 
response assessments in the brain for patients having measurable brain 
metastases at baseline. The OIRR is defined as the proportion of patients with a 


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best overall confirmed response of CR or PR in the brain as assessed per modified 
RECIST 1.1. OIRR will be estimated and the exact binomial 95% CI will be 
presented
Intracranial disease control rate (IDCR) at 8 and 16 weeks and overall: IDCR 
is calculated based on response assessments in the brain for patients having 
evaluable (measurable or non-measurable) brain metastases at baseline. In what 
follows, CR, PR and SD are possible responses only for patients with measurable 
brain metastases at baseline, while non-CR/non-PD is a possible response only for 
patients without measurable brain metastases at baseline.

The IDCR at 8 and 16 weeks is defined as the proportion of patients with CR, 
PR, SD or non-CR/non-PD assessment in the brain at Week 8 and Week 16 
intracranial tumor evaluations respectively.

IDCR overall is defined as the proportion of patients with a best overall 
response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per 
modified RECIST 1.1.
IDCR will be estimated and the exact binomial 95% CI will be presented.
Time to intracranial tumor response (TTIR): TTIR is defined as the time from the 
date of the first dose of ceritinib to the date of the first documented response (CR 
or PR) in the brain as assessed per modified RECIST 1.1 criteria for patients with 
measurable brain metastases at baseline.
The distribution function of TTIR will be estimated using the Kaplan-Meier method. 
The median TTIR along with 95% CI will be presented.
Duration of intracranial response (DOIR): Among patients with measurable brain 
metastases at baseline and a confirmed response (PR or CR) in the brain per 
modified RECIST 1.1, DOIR is defined as the time from the first documented 
response (PR or CR) in the brain to the date of the first documented disease 
progression in the brain or death due to any cause. The distribution function of 
DOIR will be estimated using the Kaplan-Meier method. The median DOIR along 
with 95% CI will be presented.
Extracranial endpoints:
Overall extracranial response rate (OERR): OERR is defined as the proportion 
of patients with a best overall confirmed response of CR or PR outside of the brain, 
as assessed per RECIST 1.1. OERR will be estimated and the exact binomial 95% 
CI will be presented.
Extracranial disease control rate (EDCR) at 8 and 16 weeks and overall:

EDCR at 8 and 16 weeks is defined as the proportion of patients with CR, PR 
or SD outside of the brain at Week 8 and Week 16 extracranial tumor 
evaluations, as assessed per RECIST 1.1.

EDCR overall is defined as the proportion of patients with a best overall 
response of CR, PR or SD outside of the brain as assessed per RECIST 1.1.
EDCR will be estimated and the exact binomial 95% CI will be presented.
Time to extracranial tumor response (TTER): TTER is defined as the time from 
the date of the first dose of ceritinib to the date of the first documented response 
(CR or PR) outside of the brain as assessed per RECIST 1.1 criteria. The 
distribution function of TTER will be estimated using the Kaplan-Meier method. The 
median TTER along with 95% CI will be presented.
Duration of extracranial response (DOER): Among patients with a confirmed 
response (PR or CR) outside of the brain per RECIST 1.1, DOER is defined as the 
time from the first documented response (PR or CR) outside of the brain to the 
date of the first documented disease progression outside of the brain or death due 
to any cause. The distribution function of DOER will be estimated using the 
Kaplan-Meier method. The median DOER along with 95% CI will be presented.
Whole body endpoints:
ORR by BIRC: The evaluation of ORR will be repeated based on BIRC 
assessment.
DCR by BIRC: The evaluation of DCR will be repeated based on BIRC 
assessment.


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Time to tumor response (TTR): TTR is defined as the time from the date of the 
first dose of ceritinib to the date of the first documented response (CR or PR) in the 
whole body as assessed per RECIST 1.1 criteria. The distribution function of TTR 
will be estimated using the Kaplan-Meier method. The median TTR along with 95% 
CI will be presented.
Duration of response (DOR): Among patients with a confirmed response (PR or 
CR) in the whole body per RECIST 1.1, DOR is defined as the time from the first 
documented response (PR or CR) to the date of the first documented disease 
progression or death due to any cause. The distribution function of DOR will be 
estimated using Kaplan-Meier method. The median DOR along with 95% CI will be 
presented.
Progression-free survival (PFS): PFS is defined as the time from the date of the 
first dose of ceritinib to the date of the first documented disease progression in the 
whole body per RECIST 1.1 or death due to any cause. A patient who has not 
progressed or died at the date of the analysis or when he/she receives any further 
anticancer therapy in the absence of disease progression will be censored at the 
time of the last adequate tumor evaluation before the earlier of the cut-off date or 
the anticancer therapy date. By default, if disease progression or death for any 
reason is documented after one single missing tumor evaluation, the actual event 
date of disease progression/death will be used for the PFS event date. If disease 
progression or death for any reason is documented after two or more missing 
tumor evaluations, the PFS time of these patients will be censored at the date of 
the last adequate tumor evaluation without PD. The distribution of PFS will be 
estimated using the Kaplan-Meier method. The median PFS along with 95% CI will 
be presented.
Overall survival (OS): OS time is defined as time from the date of first dose of 
ceritinib to the date of death due to any cause. OS time for patients who are alive 
at the end of the study or are lost to follow-up will be censored at the date of last 
contact. OS will be estimated using the Kaplan-Meier method. The median OS 
along with 95% CI will be presented. Kaplan-Meier curves will not be produced for 
Arm 5 alone if the number of patients enrolled in this arm is ≤ 10.
RANO exploratory objectives
Exploratory analyses will be conducted to evaluate intracranial endpoints by 
investigator and BIRC including OIRR, TTIR, DOIR for patients with measurable 
brain metastases at baseline, and IDCR for all patients in Arms 1 to 4 with active 
brain lesion at baseline using Response Assessment in Neuro-Oncology (RANO) 
criteria for high grade gliomas (Appendix 3).


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Key words
ALK, NSCLC, Ceritinib, brain metastasis


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Amendment 6 (16-May-2018)
Amendment rationale
As of April 11, 2018, 156 patients have been enrolled in this study: 42 patients to Arm 1; 40 
patients to Arm 2; 12 patients to Arm 3; 44 patients to Arm 4; and 18 patients to Arm 5. This 
study has been conducted as per protocol and the last patient was enrolled on August 31, 2017. 
At the time of this amendment all patients have already completed at least 24 weeks of 
treatment or discontinued treatment, thus the minimum patient follow-up needed to conduct 
the analyses for the primary and key secondary endpoints has been successfully achieved (this 
milestone has been reached on February 28, 2018). There are currently 45 ongoing patients 
still receiving ceritinib treatment in the study.
The end of the study had been planned once at least 75% of patients have died, have been lost 
to follow-up or have withdrawn consent for survival follow-up, following 24 weeks after last 
patient first treatment. Since the required follow-up for the primary and key secondary 
objectives have been reached and the roll over study will be made available for patients who 
are still ongoing on ceritinib, this amendment will allow ongoing patients benefiting from 
ceritinib to continue treatment with ceritinib by rolling over to this separate rollover study 
(and/or other options for continued treatment with ceritinib that are considered acceptable at 
the country level such as access to commercially available drug or managed access program). 
Therefore, the end of study LDK378A2205 will occur once all ongoing patients have been 
transitioned to the rollover study and/or other options for continued treatment or discontinued 
treatment before-hand.
The protocol originally defined that a primary analysis and study report would be performed 
after all patients have completed at least 24 weeks of treatment with ceritinib or have 
discontinued earlier and that the additional data collected thereafter would be reported in the 
final study report after the end of the study.
With this protocol amendment, a single final analysis and study report may be performed if 
the updated end of study criteria, as described above, is met before the primary analysis is 
conducted. If the end of the study criteria is not met by the time that the primary analysis is 
conducted, the additional follow up data will be reported in a final report, as initially planned.


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Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
List of changes to protocol:

List of Abbreviations: DS&E (Safety & Epidemiology) is removed and replaced with the 
updated CMO&PS (Chief Medical Office & Patient Safety)

Section 4.3: End of Study criteria is updated to reflect the available rollover protocol 
and/or other options for continued treatment with ceritinib. Updates for reporting data are 
made to account for if the EOS criteria is met before the primary analysis is conducted.

Section 7.1.5: Withdrawal of consent language is updated to align with the update ICF 
Withdrawal of Consent language, which has been updated to incorporate and reflect the 
European Economic Area (EEA) General Data Protection Regulation (GDPR) 
requirements.

Section 10: Updates for reporting data are made to account for if the EOS criteria is met 
before the primary analysis is conducted.

Section 10.1.3: Per-Protocol Set is not applicable.

Section 10.4.2: Clarified the patient arms to be used for analysis.

Section 10.4.4: Supportive analyses is not applicable.

Section 10.5.1: Clarified the patient arms to be used for analysis.

Section 10.5.2: Clarified the patient arms to be used for 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.


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Amendment 5 (31-May-2017)
Amendment rationale
As of May 31, 2017, 148 patients have been enrolled in this study: 42 patients to Arm 1; 40 
patients to Arm 2; 10 patients to Arm 3; 38 patients to Arm 4; and 18 patients to Arm 5.
Patients with a diagnosis of Leptomeningeal carcinomatosis (LC) have a poor prognosis 
without treatment, with median overall survival (OS) of about ~1-1.5 months from diagnosis
(Chamberlain 2010). Treatment with brain radiation may improve median overall survival 
(OS) to about 3 months (Morris et al 2012). Intrathecal chemotherapy for the treatment of 
NSCLC with LC is not clearly established (Park et al 2012) with a reported median OS of 5.5 
months in patients with cytological response and 1.4 months for patients with no cytological 
response. EGFR-mutated NSCLC patients with LC have 5-6 months median OS if treated 
with EGFR TKi. There is no data available regarding the best treatment for ALK-positive 
NSCLC with LC disease in the current literature.


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Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
List of changes to protocol:

Table 6-3: Updated to include “recommendation” versus “mandatory” actions for each 
dose modification guideline. Updates to bradycardia range and clarification for the use of 
QTcF when evaluating QT prolongation, as QTcF is used to assess eligibility.

Section 6.3.4: Minor updates to guidelines for the follow up of laboratory liver and 
pancreatic abnormalities sections by including R values to asses cholestatic versus 
hepatoceullar versus mixed livery injury.

Section: 8.2: Update of SAE Reporting guidelines to specify reporting for signing of 
molecular pre-screening ICF versus main study ICF. Also includes clarification of the 
reporting period for follow-up SAE information. The DS&E is updated to the CMO&PS 
department.

Section 11.5: Updated to outline the Novartis standards for publication of study protocol 
and results
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.


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Amendment 4 (22-Aug-2016)
Amendment rationale
As of Aug 22, 2016, 117 patients have been enrolled in this study: 34 patients to Arm 1; 38 
patients to Arm 2; 7 patients to Arm 3; 23 patients to Arm 4; and 15 patients to Arm 5.
The purpose of this amendment is:

To increase the sample size for Arms 1 and 2 to ~40 patients each in order to increase the 
robustness of the efficacy data from Arms 1 and 2 i.e. in the post crizotinib patient 
population. An increase of 20 patients (i.e. from 60 to 80 patients) in Arms 1 and 2 will 
enable the lower bound of the 95% CI of whole body ORR to be 48% which is clinically 
meaningful, if the observed whole body ORR is 60% (with 60 patients the lower bound 
for the 95% CI for ORR was 46.5%). Moreover, the addition of 20 patients in Arms 1 and 
2 will allow this trial to have an adequate number of patients (~50) with measurable brain 
metastases in prior crizotinib treated group to assess the intracranial response rate.

To increase the sample size for Arm 5 to ~20 patients to increase the robustness of 
efficacy data in patients with leptomeningeal carcinomatosis.

To allow for additional patients enrollment in Arm 4 in order to achieve approximately 60 
patients in Arms 3 and 4 together (i.e. ALKi naïve patients) if enrollment rate in Arm 3 is 
slow. This will increase the robustness of the efficacy data from Arms 3 and 4 (i.e. in 
ALKi naïve patient population).

To allow for one early analysis CSR that will included data from appropriate study arms 
that have finished enrollment much earlier than other arms due to differential recruitment 
rate among the five study arms. The early primary analysis will be performed after 
enrollment in those arms is complete and all treated patients in those arms have been 
followed for at least 24 weeks or discontinued treatment.

To analyze the secondary endpoints of IDCR (intracranial disease control rate) and EDCR 
(extracranial disease control rate) at 8 and 16 weeks (as opposed to 24) in order to 
characterize the IDCR and EDCR at early tumor assessment time points (1st and 2nd tumor 
assessments) and reduce the impact of early discontinuation of patients due to reasons 
other than intracranial/extracranial disease progression.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
List of changes to protocol:

Section 1.2.1: Zykadia is updated with the registered ® symbol.

Table 3-1: Secondary objective updated to clarify study population to be evaluated. Vital 
signs are added to endpoint analyses. IDCR and EDCR updated to 8 and 16 weeks.

Figure 4-1: Updated to N~40 for Arm 1 and Arm 2, and N~20 for Arm 5.

Section 4.1.1: The patient sample size for the study and each arm is updated and the study 
targets for patients with measurable brain metastases are updated.


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
Section 4.1.2: Reference to additional sentence clarifying ceritinib continuation after PD 
both intracranially and extracranially is included.

Section 4.1.2.2: Sentence added to clarify ceritinib continuation after PD both 
intracranially and extracranially.
 
 

Section 5.1: The patient population is updated to approximately 160.

Section 6.1.3: Sentence added to clarify ceritinib continuation after PD both intracranially 
and extracranially.

Section 6.3.4.2: Typo corrected to “liver” function tests.

Section 6.4.1.5: Ceritinib should be held in any situation when radiotherapy or surgery is 
required.

Section 6.4.2.1: Included “and palliative surgery” in reference to Section 6.4.1.5 Palliative 
radiosurgery and surgery.

Section 7.1.4.1: Sentence added to clarify ceritinib continuation after PD both 
intracranially and extracranially.

Section 7.2.1.3: Sentence added to clarify ceritinib continuation after PD both 
intracranially and extracranially.
 
 
analyzed for those arms included in the early primary analysis. A primary analysis of all 
study arms 1-5 and the subsequent report is clarified to not include data from an early 
analysis. 
 

Section 10.4.2: ORR statistical analysis is clarified.

Section 10.4.3: RAP is clarified to RAP document.
 

Section 10.5.1: Key secondary objective(s) is updated to clarify the data analyzed for 
secondary efficacy objectives.

Section 10.5.2: Other secondary efficacy objectives are clarified for data which will be 
used for analysis.

Section 10.5.2: IDCR at 24 weeks is updated to IDCR 8 and 16 weeks. EDCR at 24 weeks 
is updated to EDCR 8 and 16 weeks.

Section 10.5.3.1: Safety analysis will be presented by study arm and for all patients.

Section 10.5.3.4: RAP is clarified to RAP document.


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
Section 10.8: Sample size calculation is updated to N=160 and updated per arm. Arm 4 
may enroll additional patients in order to achieve approximately N=60 in Arms 3 + 4.

Table 10-1: Calculations are updated for N=140 in Arms 1-4 and includes analysis of 
Arms 1 and 2. N is updated to 40 for each of Arms 1 or 2.

Section 10.9: Update to N=140 in Arms 1-4 and subsequent evaluation for treatment 
groups.
 

Table 10-3: Include data for groups Arms 1-4, Arms 1+2, Arms 3+4.
 
 
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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Amendment 3
Amendment Rationale
As of November 2, 2015, 21 patients have been enrolled in this study.

The purpose of this amendment is to revise protocol language regarding the requirement 
to confirm ALK rearrangement at the Novartis designated central laboratory before 
initiating treatment with ceritinib.

Confirmation of ALK rearrangement by the Novartis designated central laboratory 
before initiating treatment with ceritinib will only be required if there is no locally 
available documentation of ALK rearrangement (ALK positive status) with the FDA 
approved Vysis ALK Break Apart FISH Probe Kit (Abbot Molecular Inc.) test and 
scoring algorithm (including positivity criteria).

If documentation of ALK rearrangement as described above is not locally available at 
the site, a test to confirm ALK rearrangement must be performed by the Novartis 
designated central laboratory and patients must wait for the central laboratory result 
of the ALK rearrangement status before initiating treatment with ceritinib.

This amendment also clarifies the eligibility criteria for enrollment of patients with prior 
exposure to ALK inhibitors in Arm 1, Arm 2, and Arm 5 to only allow enrollment of 
patients that have been treated with prior crizotinib. Patients previously treated with ALK 
inhibitors other than crizotinib are not permitted into the study. The change is made to 
ensure homogeneity in the group of patients with prior ALK-inhibitor exposure given the 
small sample size of each cohort. This patient population is also consistent with the 
currently approved indication for Zykadia (ceritinib) in many countries.

The amendment also provides follow up evaluations for hepatic toxicities and work-up 
guidelines for potential Drug Induced Liver Injury (DILI) cases in order to optimize 
patient safety.

Other changes were also implemented in this amendment:
-
Exclusion criteria for contraception use is being updated to reflect the current guidance.
-
Dose guidance modification for QTc text was updated to provide clarification on 
monitoring procedures.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

List of Abbreviations: updated to include DILI, R Value, eSAE and to change 
abbreviation of RAP to SAP

Table 2-1, Section 2.2, Section 4.1 and Figure 4-1: added footnote to restrict previous 
ALK inhibitors to only crizotinib to align with the currently approved indication based on 
regulatory feedback
 


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
Section 4.1.1, Section 7.1.1, Section 7.1.1.1, and Section 7.1.2: updated to clarify 
requirement of ALK rearrangement testing

Section 4.1.2 and Section 7.1.3: corrected language to remove erroneous use of the word
“equivocal”

Section 5.2: inclusion criteria #1 has been replaced by inclusion criteria #1a to clarify 
requirement of ALK rearrangement testing

Section 5.2: inclusion criteria #2 has been replaced by inclusion criteria #2a to clarify 
requirement of tumor tissue sample in accordance with ALK rearrangement testing

Section 5.2: inclusion criteria #6 has been replaced by inclusion criteria #6a to restrict 
previous ALK inhibitors to only crizotinib to align with the currently approved indication

Section 5.2: inclusion criteria #7 has been replaced by inclusion criteria #7a and updated
to correct typographical errors from the prior amendment regarding serum amylase 
laboratory value

Section 5.3: exclusion criteria #15 has been replaced by exclusion criteria #15a to update 
language regarding contraception

Table 6-3: table updated to fix a typographical error and further clarify QTc monitoring 
procedure for Grade 3 QT interval

Table 6-4: updated to elaborate on follow-up evaluations for hepatic toxicities

Section 6.3.4.2: updated language regarding hepatic toxicity evaluations and guidelines for 
potential Drug Induced Liver Injury (DILI) cases to reflect currently available safety data

Section 6.4.1.5: updated language to clarify ceritinib use during palliative surgical 
intervention

Table 7-1: updated footnote to clarify requirement of ALK rearrangement testing and 
required activities associated with pre-screening and screening phase

Section 7.1.2: updated language to clarify that investigators may repeat laboratory 
assessments before dosing if deemed clinically necessary and/or per institution policies

Section 7.2.3.2: updated language to allow patients to forgo CSF collection if deemed to 
be an unacceptable burden for patients

 

Section 7.2.4: updated to further align with inclusion criteria #14 and to clarify 
requirements for leptomeningeal carcinomatosis (LC) diagnosis

Section 7.2.5.2: updated to be consistent with protocol language

Section 8.1.1: paragraph added to clarify Adverse Event reporting for patients who have 
signed molecular pre-screening ICF in order to be consistent with language in Section 
7.1.2.2 and added language to clarify reporting requirements

Section 8.2.2: updated language for guidance of reporting of SAEs

Section 10.1.3 and Section 10.1.5: updated to align with the new Reporting and Analysis 
Process


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
Table 14-4: Added medications to reflect updated list of prohibited medications causing 
QTc prolongation
IRB/IEC
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 forms. 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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Summary of previous amendment(s)
Amendment 2
Amendment Rationale
The primary purpose of this amendment is to revise protocol sections based on additional 
clarifications related to safety and practical operationalization of the study, based on feedback 
from participating countries and further review.
In addition, updates to the protocol have been made based on currently available safety data. 
Pancreatic enzyme elevations (lipase and/or amylase) occur in patients treated with ceritinib. 
Clinical data suggest that a small proportion (<1%) of patients treated with ceritinib can 
develop clinical pancreatitis, and the causal role of ceritinib in these cases cannot be excluded. 
Due to this finding, the protocol has been amended to include relevant exclusion criteria, 
additional dose modification and follow up monitoring language for patients who may 
experience this safety finding.
Dose Modification language was further updated to provide additional guidance for 
monitoring patients with QTcF interval prolongation greater than 500 ms
 
 
Updated language for patient discontinuation was added to the protocol and to the Informed 
Consent Forms (ICF) to provide guidance on how to effectively manage patients who 
discontinue from the clinical trial.
Updated safety data was added to the protocol and to the ICF to be consistent with the 
Investigator’s Brochure Edition 7 (released on 12-Jun-2014). In addition, adverse events of 
special interest will be monitored for ceritinib.
An evaluation of the anticipated benefits and risks has been included in the protocol to 
comply with EU clinical trial regulations.
 
 
 
 
 
 
Additional minor edits have been made to protocol language for clarification as well as to 
maintain consistency and harmonization amongst other LDK378 global program protocols.
Changes to the Protocol
Main changes include:


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
Section 1.1: edits and/or additional information to clarify text and provide updated 
background information for study, based on pre-clinical and non-clinical data

Section 1.2: additional information provided based on updated clinical experience, related 
to safety and pharmacokinetic data from clinical studies

Section 1.3: risk/benefits rationale added to comply with EU clinical trial regulations

Sections 4.1.1 and 7.1.2; Table 7-1: modified language to allow greater flexibility in the 
time between pre-screening and screening for those patients who have locally available 
source documentation with confirmed ALK positive status by the FDA approved Vysis 
ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm 
(including positivity criteria); updated to increase operational flexibility at sites and 
minimize burden for patients during those two study phases

Section 4.1.2: further clarified terminology of disease progression when ‘equivocal’ per 
definitions of RECIST and updated timing of tumor assessment, based on regional 
feedback from participating countries

Sections 4.3 and 10: included language to distinguish primary analyses and associated 
clinical study report (CSR) that will be produced from that of CSR compiled at the end of 
the study

Section 4.3: updated section to replace terminology in reference to a rollover study

Section 4.4: updated terminology to match glossary and updated language with regard to 
patients who discontinue clinical trial

Section 5.2: inclusion criteria #2 and throughout protocol sections, where screening 
(Sections 4.1.1.1 and 7.1.2) and tumor sample requirements (7.1.1.1) are referenced, 
added language to further clarify preferred timing of archival samples

Section 5.2: inclusion criteria #14 updated requirement of documentation to supplement 
diagnosis of leptomeningeal carcinomatosis based on feedback from participating study 
site regarding the presence of typical signs of LC at the brain/spine MRI that are sufficient 
to establish a diagnosis since CSF cytology is not systematically positive

Section 5.3: exclusion criteria #8 to clarify that the threshold of QTcF >470 ms at 
screening visit should be based on the mean of the (triplicate) scheduled ECGs per Section 
7.2.2.7

Section 5.3: exclusion criteria #15 and 16 modified to remove incorrect wording of 
“reference chemotherapy” in respective criteria, as only reference to ceritinib is applicable 
this study

Section 5.3: exclusion criteria #19 added to exclude patients with history of pancreatitis or 
a history of increased amylase or lipase that was due to pancreatic disease

Section 5.3: exclusion criteria #20 added to exclude patients who have been previously 
enrolled in a ceritinib clinical study to prevent the same individual from enrolling in 
multiple studies within the LDK378 global program

Table 6-3: table was updated to provide guidance on dose modifications related to 
pancreatic laboratory abnormalities (amylase and lipase), creatinine, as well as for related 
changes on electrocardiograms


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
Table 6-4: table updated to include toxicity guidance for ≥ grade 3 amylase and lipase

Section 7.1.1.1: removed sentence regarding timeframe of ICF signature as the pre-
screening and screening phase is described in Table 7-1 and confirmation of ALK status 
from the Novartis-designated central laboratory is required to proceed.

Section 7.1.2.2: corrected language to omit the word “randomization” and replace with 
“enrollment” to the next study phase

Section 7.1.2.3: updated to reflect that demographics and confirmation of ALK status 
occurs at pre-screening

Section 7.1.4.1; Section 7.1.5; Section 7.1.7: updated to provide language to effectively 
manage patients who discontinue clinical trial

Section 7.2.1: includes additional information collected to supplement imaging review 
process, involving CRO and BIRC

Section 7.2.2.6 and Section 7.2.2.6.3: added to allow flexibility and provide instruction 
based on site feedback

Table 7-4: table updated to include missing laboratory collection of lipase

Section 7.2.3.2: added based on operationalization feedback from participating country

Section 7.2.3.2 and 7.2.4: added language regarding the need to rule out any applicable 
medical condition that would prevent a planned CSF sampling procedure

Section 7.2.3.3: updated language for use of new methods to measure ceritinib plasma and 
CSF samples in a more timely manner and at a possibly lower level, respectively

Section 7.2.4: updated for requirement of documentation to supplement diagnosis of 
leptomeningeal carcinomatosis

Section 7.2.5.1, Table 7-8: correction made for consistency with protocol and related 
Informed Consent Forms
 
Other changes include:

Glossary of terms: biological sample and withdrawal of consent were added to the table. 
Other terms and definitions not used or not applicable in this study were removed

Table 3-1: definition of modified RECIST provided as a footnote for clarity and reference 
to this table

Table 7-1: corrected formatting throughout table and removed typographical error that 
included cytology when not applicable in this study during screening phase

References: modified accordingly based on new information provided in protocol and 
updated typographical errors
IRB/IEC
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.


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The changes herein affect the Informed Consent forms. Sites are required to update and 
submit for approval a revised Informed Consent that takes into account the changes described 
in this protocol amendment.
Amendment 1
Amendment Rationale
The purpose of this amendment is to revise protocol sections and provide additional 
clarifications on study procedures related to ALK testing and BIRC review.
Main changes include:

Revision of Inclusion criteria #1 and addition of a new inclusion criteria #2 to clarify the 
need for central ALK rearrangement status determination for all patients at a Novartis 
designated laboratory before initiation of treatment with ceritinib.

Revision of Inclusion criteria #2: At least one extracranial measurable lesion as defined by 
RECIST 1.1. A previously irradiated site lesion may only be counted as a target lesion if 
there is clear sign of progression since the irradiation. Note: Enrollment of patients with 
only non-measurable brain metastases may be closed in one or more arms if it is 
determined that the target for patients with measurable brain metastases across study arms 
will not be met.

The measurability of brain metastases will be confirmed by BIRC per RECIST 1.1 on an 
ongoing basis to target a similar number of patients with measurable brain metastases in 
the subgroup of patients with prior radiotherapy to the brain (combined arms 1 and 3) and 
the subgroup of patients with no prior radiotherapy to the brain (combined arms 2 and 4). 
Enrollment of patients with only non-measurable brain metastases (even in the presence of 
extracranial measurable lesions) may be closed in one or more arms if it is determined that 
the above target for patients with measurable brain metastases will not be met.
Other changes include:

Revision of slice thickness requirements for brain Gadolinium-enhanced MRI.

In addition, editorial changes and text corrections were made for clarification, where 
required.

Removal of start of new anti-cancer therapy as a reason for stopping tumor assessments to 
allow for sensitivity analysis of PFS in ITT population.
Changes to the Protocol

Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

The following sections to the protocol were changed:

List of abbreviations: editorial updates.

Synopsis: clarifications on the data analysis section regarding primary and secondary 
endpoints.

Section 4.1.1, Section 7.2.1.3 and Section 8.8.: addition/clarification of text “The 
measurability of brain metastases will be confirmed by BIRC per RECIST 1.1 on an 


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ongoing basis to target a similar number of patients with measurable brain metastases in 
the subgroup of patients with prior radiotherapy to the brain (combined arms 1 and 3) and 
the subgroup of patients with no prior radiotherapy to the brain (combined arms 2 and 4). 
Enrollment of patients with only non-measurable brain metastases (even in the presence of 
extracranial measurable lesions) may be closed in one or more arms if it is determined that 
the above target for patients with measurable brain metastases will not be met”.

Section 4.1.1, Section 7.1.1 and Section 7.1.2: clarification of study procedures to align 
with changes made to inclusion criteria #1 and #2.

Section 4.1.2.1, Section 7.1.4.1 and Section 7.1.5.2: removal of start of new anti-cancer 
therapy as a reason for stopping tumor assessments to allow for sensitivity analysis of PFS 
in ITT population.

Section 5.2: revision of Inclusion criteria #1 and addition of new inclusion criteria #2 to 
clarify the need for central ALK rearrangement status determination for all patients at a 
Novartis designated laboratory before initiation of treatment with ceritinib.

Section 5.2: revision of Inclusion criteria #2: At least one extracranial measurable lesion 
as defined by RECIST 1.1. A previously irradiated site lesion may only be counted as a 
target lesion if there is clear sign of progression since the irradiation. Note: Enrollment of 
patients with only non-measurable brain metastases may be closed in one or more arms if 
it is determined that the target for patients with measurable brain metastases across study 
arms will not be met.

Section 5.3: revision of Exclusion criteria #8 to remove “(as mean of triplicate ECGs)” 
clarifying procedures.

Table 6-3: updated guidance for Grade 3 QTc interval prolongation.

Section 6.4.1.2: clarification of bisphosphonate treatment guidance.

Section 6.4.2.6: clarification of language on medications that are CYP2C9 and CYP3A4/5 
substrates with narrow therapeutic index.
 
 
 

Section 7.1.1 and Section 7.1.2: Clarifications on the molecular screening and screening 
procedures regarding tumor requirements and request for ALK rearrangement status 
determination by Novartis designated central laboratory.

Section 7.1.2: clarification under the screening section was added: the cardiac eligibility 
criteria should be assessed with the central ECG report. Also, updated language to allow 
re-screenings.

Section 7.1.2.2: revised language to clarify information to be collected for screening 
failures.

Section 7.2.1.1: revision of slice thickness requirements for brain Gadolinium-enhanced 
MRI: if technically possible slice thickness should preferably be 1mm, but it should not 
exceed 5 mm.

Section 7.2.2.6, Section 7.2.3.1 and 7.2.5.2: remove reference to laboratory manual.


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
Table 7-8: updated to reflect new tumor sample requirements.

Section 9.4: statement on diary data removed as it is not applicable in this study.

Section 13: updated reference list.

Appendix Table 14-2: list of medication to be used with caution updated and removal of
ritonavir, clarithromycin and telithromycin.

Editorial and typographical changes throughout the document as required.
IRB/IEC
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. In addition, if 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 
amended protocol.


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1
Locally advanced or metastatic non-small cell lung cancer (NSCLC)
Lung cancer has been among the most common cancers in the world for several decades. 
Worldwide, lung cancer occurred in approximately 1.8 million patients in 2012 and caused an 
estimated 1.6 million deaths. (Brambilla et al 2014). In 2012, approximately 160,000 and 
262,000 deaths, respectively, due to lung cancer were expected in the United States (US; 
Siegel et al 2012) and in the European Union (EU; Malvezzi et al 2012).
The World Health Organization (WHO) divides lung cancer into 2 major classes based on its 
biology, therapy, and prognosis: NSCLC and small cell lung cancer. NSCLC accounts for 
more than 85% of all lung cancer cases and includes 2 major types: (1) non-squamous 
carcinoma (including adenocarcinoma, large-cell carcinoma, other cell types); and (2) 
squamous cell (epidermoid) carcinoma. Adenocarcinoma (40% of lung cancers) is the most 
common type of lung cancer seen in the US and is also the most frequently occurring cell type 
in nonsmokers (NCCN Guidelines v13 2014).
Cigarette smoking remains the most important risk factor for lung cancer, although 
approximately 15% of all lung cancers are diagnosed in patients who never smoked.The high 
mortality rate of lung cancer could be explained in an advanced stage for most cases; only 25-
30% of new NSCLC cases are diagnosed with localized disease that is potentially curable 
with surgery (Nguyen et al 2012). The majority of patients is diagnosed with locally advanced 
or metastatic disease, for which surgery is not indicated.
Brain metastases (BM) are a common complication of patients with NSCLC. Ten to 35% of 
the patients newly diagnosed with NSCLC presents with synchronous BM (Preusser 2012, 
Olak 2000). One third of these patients are asymptomatic (Hendriks et al 2013). The incidence 
of synchronous BM may have increased in recent years as result of more aggressive staging 
procedures as recommend by guidelines and advances in neuro-imaging techniques.
If not present at the time of the initial presentation of the NSCLC disease, BM will develop 
during the length of the disease. It is estimated that 40 to 50% of all patients with NSCLC will 
develop BM at any stage of the treatment of their disease. This incidence is also increasing the 
last years resulting for the use of more effective systemic treatments translating into 
prolonged survival (Wen et al 1999). BM treatments are usually palliative with the intent to 
control the brain disease, which at best is achievable for a brief duration. Treatment options 
are limited and comprise of whole brain radiation therapy (WBRT) leading to a modest 
overall survival benefit. Additional local treatment such as neurosurgery or stereotactic 
radiosurgery (SRS) may contribute to longer brain disease control. (Bowden 2013, Patil 2012, 
Shaw 2013)
The role of systemic therapies in the treatment of BM remains unclear to date. For decades, 
systemic chemotherapies were believed to be of limited benefit. The brain, protected by a 


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blood-brain-barrier (BBB) with low permeability to large molecules, is usually seen as a 
pharmacologic sanctuary.
Patients with disease metastatic to the brain were generally excluded from most large studies 
evaluating chemotherapeutic agents as treatment for advanced or metastatic NSCLC. With the 
exception of platinum-based chemotherapy, most chemotherapeutic agents evaluated in small 
studies reveal modest activity on NSCLC brain lesions (response rate ranging from 5 to 27%)
(Vogelbaum 2010, Moscetti 2007, Barlesi 2011) due to insufficient drug penetration through 
the BBB, even if the BBB is potentially disrupted by the brain metastases.
Despite emerging data suggesting that systemic treatment may be considered a treatment 
option for patients with NSCLC metastatic to the brain, the current National Comprehensive 
Cancer Network (NCCN) Guidelines for the treatment of NSCLC patients with BM, still 
recommend localized treatment of the brain disease prior to initiating systemic treatment for 
advanced incurable patients (NCCN Guidelines v13 2014). Whole Brain Radiation Therapy 
(WBRT) is indicated in case of diffuse BM, without restriction, if the patient is neurologically 
asymptomatic. In case of solitary BM, Stereotactic Radiosurgery (SRS) followed or not by 
WBRT or neurosurgery always followed by WBRT are recommended prior to the start of 
platinum-based combination chemotherapy. Platinum-doublet chemotherapy (cisplatin or 
carboplatin in combination with other chemotherapy agents, with or without bevacizumab) is 
standard first line treatment for patients with a Performance Status (PS) of 0 and 1, or for 
selected patients with a PS of 2 with locally advanced or metastatic NSCLC, unless the lung 
cancer has a known “druggable” (molecularly targetable) gene mutation or aberration
rendering these patients candidates for first line targeted therapy (as discussed below) instead 
of chemotherapy. Although chemotherapy has led to clinical improvements in patients with 
locally advanced or metastatic NSCLC, the outcome of treatment in the first-line setting 
remains poor, with median progression-free survival (PFS) and overall survival (OS) of 5-7 
months and 10-16 months, respectively (Scagliotti 2008, Ciuleanu 2009, Ettinger 2010, Paz-
Ares 2012).
Overall, current treatments are not considered satisfactory for most NSCLC patients with BM 
and the prognosis continues to be poor, with a 5-year OS rate of only 15% (Nguyen et al 
2012). In particular, the prognosis for patients presenting with advanced, incurable disease is 
dismal, with a 5-year OS rate of 3.7% (Howlader et al 2009).
1.1.2
Targeted therapies in NSCLC
During the last few years, improved knowledge of NSCLC biology has led to the 
identification of molecular events crucial for malignant transformation and cancer cell 
survival and “molecular subsets” of NSCLC patients who may be candidates for targeted 
therapy. These aberrant molecular events are critical oncogenic drivers and represent potential 
therapeutic targets (Gettinger et al 2011). As a result, new targeted treatment options have 
been developed and are evolving. Erlotinib and gefitinib, epidermal growth factor receptor 
(EGFR) tyrosine kinase inhibitors (TKIs), have been approved for the treatment of NSCLC. 
In particular, EGFR TKIs represent a new paradigm in the treatment of NSCLC. Activating 
mutations in EGFR are found in 10-15% of Caucasian and 30-40% of Asian NSCLC patients 
and are associated with a higher response to EGFR TKIs (Ettinger et al 2010). Multiple large 
randomized clinical trials have demonstrated that patients harboring activating EGFR 


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mutations benefit more from EGFR TKIs than from standard chemotherapy in terms of 
overall response rate (ORR), PFS, toxicity profile, and quality of life (Ettinger 2010, Besse 
2013).
Given their low molecular weight, it is assumed that these agents may penetrate and reach 
brain metastases more readily and may be more effective than chemotherapies. Small studies 
reported clinical activity of EGFR TKIs in brain metastases of NSCLC patients harboring 
activating mutation of EGFR (Karachaliou 2013, Wu 2013). These observations open the way 
to reevaluate the role of systemic treatment for BM when highly effective drugs have a 
relatively low molecular weight.
1.1.3
ALK rearranged (ALK-positive, ALK+) NSCLC
The discovery of anaplastic lymphoma kinase (ALK) gene rearrangement in NSCLC in 2007 
(Soda et al 2007) represents another important milestone in the era of molecular targeted 
therapy in NSCLC.
ALK was first identified as a chromosome translocation-produced protein fusion in the 
majority of anaplastic large cell lymphomas (ALCL). When fused to other proteins, ALK 
becomes constitutively active, leading to increased catalytic kinase function, signal-
transduction activity, and oncogenic function. Other fusion partners of ALK have been 
described (e.g., KIF5B, TFG, KLC1 and PTPN3), but these are less common than EML4 
(Kruczynski et al 2012). Preclinical experiments have shown that the various ALK fusion
partners mediate ligand-independent dimerization/oligomerization of ALK resulting in 
constitutive kinase activity and in potent oncogenic activity both in vitro and in vivo. This 
activity can be effectively blocked by small-molecule inhibitors that target ALK.
Expression of EML4-ALK, a new fusion protein between ALK and the echinoderm 
microtubule-associated protein-like 4 (EML4) gene, in transgenic mice has been shown to 
induce tumor formation, suggesting the therapeutic potential of targeting the EML4-ALK 
fusion protein in NSCLC (Soda et al 2007). The frequency of EML4-ALK rearrangement in 
patients with NSCLC is relatively low; it is present in approximately 2-8% of tumors tested 
(Scagliotti 2012; Takeuchi 2009; Soda 2007; Takeuchi 2009; Soda 2007). However, 
considering the high incidence of lung cancer, this small percentage translates into about 
10,000 patients in the US alone (Kwak et al 2010).
Patients with ALK-rearranged NSCLC are similar to those with EGFR mutations (i.e., 
adenocarcinoma, nonsmokers or former smokers), up to 30% of smokers or former smokers 
has been included in the pivotal phase 3 study evaluating crizotinib after first line of treatment 
for ALK-rearranged NSCLC (Shaw et al 2013) except they are often younger. In addition, 
ALK rearrangements are found in patients with adenocarcinoma but not usually found in 
squamous cell or large cell carcinoma (Shaw et al 2009). ALK rearrangements and other 
oncogenic drivers such as mutant EGFR and oncogenic RAS are most of the time mutually 
exclusive, consistent with the notion that ALK rearrangement defines a unique molecular 
subset of NSCLC.
ALK-rearrangement may predispose patients to develop BM but current literature remains
controversial (Doebele 2012, Yang 2012, Kang 2013). It is interesting to note that ALK 
rearrangement in NSCLC is mostly observed in adenocarcinoma (90%) and large cell 


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carcinoma (10%) histologic subtypes. The adenocarcinoma subtype is known to be associated 
with an increased risk of developing BM (Saha 2013, Sanchez 2009). Shi et al (2006) reported 
a 58% incidence of BM in patients with adenocarcinoma of the lung and in 17.7% of patients 
with a large call carcinoma of the lung.
ALK rearrangements serve as a key strong oncogenic driver for NSCLC and represent a 
critical therapeutic target susceptible to targeted ALK kinase inhibition.
Crizotinib, an orally available small-molecule inhibitor of ALK and MET tyrosine kinases, is 
the first tyrosine kinase inhibitor to target ALK to have demonstrated a clinical activity and to 
be approved in the US as treatment of metastatic ALK-positive NSCLC. Advanced or 
metastatic ALK-positive NSCLC patients, after failure to a prior platinum-based 
chemotherapy, experienced a higher response rate (RR) to crizotinib (RR=65%;95%CI:58-72) 
compared to chemotherapy (RR=20%; 95CI:14-26) and a longer progression free survival 
(PFS) if treated with crizotinib compared with second-line chemotherapy (7.7 months versus 
3.0 months, HR=0.49; 95% CI, 0.37 – 0.64) (Shaw et al 2013).
The most frequent adverse events (AEs) with crizotinib treatment are visual disorders, 
occurring in approximately 60% of patients (Shaw et al 2013). Other common toxicities 
include gastro-intestinal (GI) disorders (diarrhea 60%, nausea 55%, vomiting 47%), 
elevations of liver enzymes (38%), edema (31%), fatigue (27%), upper respiratory infection 
(26%), dysgeusia (26%), dizziness (22%), dyspnea (13%), skin rash (9%) and alopecia (8%). 
Three AEs warranted warning and precautions in the package insert (pneumonitis, hepatic 
laboratory abnormalities and QT prolongation). In addition, rapid onset of hypogonadism in 
the majority of male patients taking crizotinib has been reported (Weickhardt et al 2012).
While crizotinib has impressive activity in patients with ALK rearranged NSCLC, these 
cancers invariably progress, typically within 1 year, with the development of resistance to 
crizotinib (Kwak et al 2010). Otterson et al (2012) reported CNS being the first site of 
progression in 46% of patients with ALK-positive NSCLC patients treated with crizotinib. 
Crizotinib, despite a 450 Dalton molecular weight has a low penetration to the brain. Costa et 
al (2012) evaluated a patient who developed isolated BM during crizotinib treatment. The 
crizotinib CSF concentration was measured at 0.616 ng/mL compared to 237 ng/mL in the 
plasma. This case indicates that crizotinib does not penetrate through the blood-brain barrier 
or penetrates insufficiently to prevent the onset of brain metastases.
Crizotinib may have clinical activity when used to treat ALK-positive NSCLC patients 
metastatic to the brain. Out of the 347 patients included in the pivotal phase III study 
PROFILE 1007, 120 patients (35%) presented with untreated asymptomatic or treated and 
stable brain metastases at baseline. They were equally distributed across study arm (60 were 
randomized to the chemotherapy arm and the other 60 to the crizotinib arm. (Shaw et al 2013). 
PFS was evaluated in subgroups of patients with or without BM at baseline. Hazard ratio still 
favored crizotinib compared to second-line chemotherapy in patients with BM (HR=0.67; 
95%CI: 0.44 – 1.03). The comparison to the result for the subgroup of crizotinib-treated 
patients without BM (HR=0.43; 95% CI, 0.30 – 0.60) suggest that crizotinib efficacy is better
in patients without BM than those with BM.
Crino et al. (ECC 2013 – Abst#3413) reviewed the intracranial activity of crizotinib when 
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seventy-five out of 888 patients treated with crizotinib were selected for this retrospective 
analysis because they were included in the PROFILE 1005 and 1007 studies with brain 
metastases. Intracranial endpoints were defined as including only intracranial sites of disease
and systemic endpoints, as including only extracranial sites of disease. The intracranial and 
extracranial response was evaluated using RECIST 1.1.
The reported Overall Intracranial Response Rate (CR+PR) in a subgroup of 109 patients with 
untreated BM was 7% (95%CI: 3-14) compared to an extracranial Response Rate of 53% 
(95% CI: 43-63). Out of these 109 patients, 22 presented with BM qualifying for target lesion 
following RECIST 1.1. The OIRR in these 22 patients was 18% (95% CI: 4-40). In the 
subgroup of 109 patients with untreated BM at baseline, the intracranial disease control rate at 
12 weeks was reported at 56% (95% CI: 46-66) and the median duration of intracranial 
response was 26.4 weeks (95% CI: 4.9 to 59.3 weeks). The systemic disease control rate at 12 
weeks in this group was reported at 63% (95% CI: 54-72) and the median duration of 
systemic response was 47.9 weeks (95% CI: 5.3 to 55.0 weeks).
Leptomeningeal carcinomatosis (LC) is a rare devastating disease resulting from the seeding 
of malignant cells to the leptomeninges and cerebrospinal fluid (CSF). LC is observed in 
approximately 5% of the patients diagnosed with metastatic NSCLC (Chamberlain 2010). The 
incidence of LC in ALK-positive NSCLC may be around 5 to 6% (Gainor et al 2013). Median 
survival without treatment is about 4-6 weeks and about 4 months with the available 
treatments (whole brain radiation therapy and intrathecal chemotherapy) (Lee 2013, Palma 
2013). The role of systemic treatment for LC has not been established. Case reports and small 
series of subjects indicate that LC control may be observed with the use of highly active 
targeted therapies like EGFR TKI (Lee et al 2013) or ALK TKI (Riess 2013, Ahn 2012).
There is a medical need for more effective treatment for patients with ALK-positive NSCLC 
metastatic to the CNS before and after failure to crizotinib.
1.2
Introduction to investigational treatment(s)
1.2.1
Overview of ceritinib
Ceritinib [5-Chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl) phenyl]-N4-[2 
(isopropylsulfonyl) phenyl]-2,4-pyrimidinediamine] is an orally available ALK inhibitor. 
Ceritinib is an approximately 20-fold more potent ALK inhibitor than crizotinib, it is more 
selective for ALK and does not inhibit MET.
In addition, ceritinib shows potent antitumor activity in crizotinib-resistant animal models (as 
described below) and the efficacy seen in the ongoing Phase I clinical trial in patients (with 
and without previous crizotinib therapy) led to the approval of ceritinib by the Food and Drug 
Administration (FDA) under the trade name ZYKADIA® on 29-Apr-2014 for the following 
indication:


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
‘ZYKADIA is indicated for the treatment of patients with ALK-positive metastatic 
NSCLC who have progressed on or are intolerant to crizotinib. This indication is approved 
under accelerated approval based on tumor response rate and duration of response. An 
improvement in survival or disease-related symptoms has not been established. Continued 
approval for this indication may be contingent upon verification and description of clinical 
benefit in confirmatory trials.’
Furthermore, the European Commission approved ZYKADIA on 06-May-2015 for the 
following indication:

Zykadia is indicated for the treatment of adult patients with anaplastic lymphoma kinase 
(ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with 
crizotinib.
Submissions to other health authorities worldwide have been completed in some countries and 
are underway in others.
1.2.1.1
Non-clinical experience
1.2.1.1.1 Pharmacology
Ceritinib inhibits ALK and ALK-mediated signaling pathways in a dose-dependent manner. It 
inhibits autophosphorylation of ALK, ALK-mediated phosphorylation of downstream 
signaling proteins, and proliferation of ALK-dependent cancer cells both in vitro and in vivo. 
Ceritinib is approximately 20-fold more potent than crizotinib in enzymatic inhibition assays 
of ALK kinase activity (Half maximal (50%) inhibitory concentration (IC50) of 0.15 nM for 
ceritinib and 3 nM for crizotinib). In a kinase panel of 35 additional enzymes, ceritinib 
demonstrated a high degree of selectivity for ALK inhibition by inhibiting only 2 other 
kinases (INSR and IGF1R) but with approximately 50-fold less potency than in inhibiting 
ALK.
Preclinical data showed inhibition of the kinase activity of the NPM-ALK fusion oncogene (in 
Karpas299 human ALCL cells) and of the EML4-ALK fusion oncogene (in H2228 human 
NSCLC cells) with ceritinib, which led to inhibition of cancer cell proliferation in vitro. 
Inhibition of the downstream signaling pathway by ceritinib correlated with inhibition of 
proliferation. In addition, inhibition of NPM-ALK and EML4-ALK in mouse and rat 
xenograft models resulted in inhibition of tumor growth and tumor regression in vivo. 
Ceritinib was also active in cell lines with ALK amplification or expression of activating point 
mutations. A single dose pharmacodynamic study and multiple daily dose efficacy study 
performed in Karpas299 and H2228 tumor models indicated that a 70% to 80% reduction in 
the ALK signaling pathway is required to achieve complete tumor regression.
1.2.1.1.2 Antitumor activity in xenograft models
Ceritinib is highly active in mouse and rat xenograft models of lung cancer and ALCL that 
carry an ALK rearrangement. In murine xenograft models of H2228 NSCLC and Karpas299 
ALCL cells, ceritinib dosed at 25 mg/kg daily, a dose below the maximum tolerated dose 
(MTD) defined in good clinical practice (GCP) toxicity studies (30 mg/kg in monkey and 50 
mg/kg in rat), resulted in complete regression of established tumors. When dosed at 50 mg/kg 


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daily for 14 days in the H2228 NSCLC model, ceritinib resulted in complete and prolonged 
tumor regressions (lasting for more than 4.5 months, the observation period). In the same 
experiments, crizotinib dosed at 100 mg/kg daily for 14 days resulted in complete tumor 
regression, but tumors re-grew within 2 weeks after stopping treatment.
Ceritinib also has potent antitumor activity against crizotinib-resistant H2228 NSCLC cell 
lines, including resistant variants carrying I1171T or C1156Y mutations in the ALK kinase 
domain. These data support the hypothesis that ceritinib may be clinically active in ALK-
rearranged NSCLCs in multiple treatment settings.


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1.2.1.2
Clinical experience
1.2.1.2.1 Clinical safety and tolerability
Ceritinib is associated with a manageable safety profile. For the 255 patients treated at the 
recommended dose of 750 mg in the ongoing study
 
The 


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most common adverse events regardless of study drug relationship (incidence ≥25%) were 
diarrhea, nausea, vomiting, alanine aminotransferase (ALT) increased, fatigue, abdominal 
pain, decreased appetite, aspartate aminotransferase (AST) increased, and constipation.
The incidence of grade 3-4 AEs, regardless of study drug relationship was <10% for all AEs 
except ALT increased (26.7%) (Table 1-1). The incidence of grade 3-4 AEs, regardless of 
study drug relationship, was <5% for all AEs except AST increased (8.2%), diarrhea (5.9%), 
hyperglycemia (5.5%), lipase increased (5.1%), and blood alkaline phosphatase (ALP) 
increased (5.1%).
Table 1-1
All grades (at least 5%) and grade 3-4 adverse events, regardless of 
study drug relationship, by preferred term in patients treated in the 
750 mg dose group 
Preferred term
Ceritinib
750 mg
N=255
All Grades
Grade 3/4
n (%)
n (%)
Total
255 (100.0)
184 (72.2)
Diarrhea
219 (85.9)
15 (5.9)
Nausea
205 (80.4)
11 (4.3)
Vomiting
153 (60.0)
10 (3.9)
Alanine Aminotransferase Increased
110 (43.1)
68 (26.7)
Fatigue
102 (40.0)
10 (3.9)
Abdominal Pain
91 (35.7)
3 (1.2)
Decreased Appetite
87 (34.1)
2 (0.8)
Aspartate Aminotransferase Increased
78 (30.6)
21 (8.2)
Constipation
73 (28.6)
0
Cough
62 (24.3)
0
Abdominal Pain Upper
58 (22.7)
2 (0.8)
Dyspnea
47 (18.4)
8 (3.1)
Asthenia
45 (17.6)
2 (0.8)
Blood Alkaline Phosphatase Increased
45 (17.6)
13 (5.1)
Back Pain
43 (16.9)
1 (0.4)
Headache
41 (16.1)
3 (1.2)
Weight Decreased
39 (15.3)
4 (1.6)
Blood Creatinine Increased
39 (15.3)
0
Pyrexia
38 (14.9)
0
Rash
32 (12.5)
0
Insomnia
31 (12.2)
0
Dyspepsia
26 (10.2)
1 (0.4)
Hypokalemia
26 (10.2)
11 (4.3)
Dizziness
26 (10.2)
0
Musculoskeletal Pain
25 (9.8)
0
Anemia
24 (9.4)
9 (3.5)
Edema Peripheral
24 (9.4)
0
Non-Cardiac Chest Pain
24 (9.4)
2 (0.8)
Hypomagnesemia
22 (8.6)
0


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Preferred term
Ceritinib
750 mg
N=255
All Grades
Grade 3/4
n (%)
n (%)
Productive Cough
22 (8.6)
0
Arthralgia
21 (8.2)
0
Hyperglycemia
21 (8.2)
14 (5.5)
Musculoskeletal Chest Pain
21 (8.2)
0
Lipase Increased
20 (7.8)
13 (5.1)
Pneumonia
20 (7.8)
10 (3.9)
Pain In Extremity
17 (6.7)
0
Muscle Spasms
17 (6.7)
0
Pruritus
17 (6.7)
1 (0.4)
Hyponatremia
16 (6.3)
9 (3.5)
Chest Discomfort
16 (6.3)
0
Dehydration
16 (6.3)
2 (0.8)
Urinary Tract Infection
16 (6.3)
2 (0.8)
Anxiety
16 (6.3)
2 (0.8)
Hypophosphatemia
15 (5.9)
7 (2.7)
Paresthesia
15 (5.9)
0
Influenza
14 (5.5)
0
Tremor
14 (5.5)
0
Gamma-Glutamyl Transferase Increased
13 (5.1)
7 (2.7)
Convulsion
13 (5.1)
6 (2.4)
Upper Respiratory Tract Infection
13 (5.1)
0
Dry skin
13 (5.1)
0
Stomatitis
13 (5.1)
0
Abdominal discomfort
13 (5.1)
0
Rhinorrhea
13 (5.1)
0
Visual Impairment
13 (5.1)
0
Dose reductions due to adverse events (AEs) occurred in 58.4% of patients treated with 
ceritinib at the 750 mg dose; 38.8% of patients had only 1 dose reduction. AEs leading to 
study drug discontinuations occurred in 10.2% of patients treated with ceritinib at the 750 mg 
dose. The most frequent AEs leading to study drug discontinuation were decreased appetite, 
pneumonia, ALP increased, pneumonitis, and respiratory failure.
Serious adverse events (SAEs) reported in 2% or more of the 255 patients treated at the 
recommended dose of 750 mg were convulsion, pneumonia, interstitial lung disease 
(ILD)/pneumonitis, dyspnea, hyperglycemia, and nausea. Fatal adverse reactions occurred in 
5% of patients, consisting of: pneumonia (4 patients), respiratory failure, ILD/pneumonitis, 
pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary 
tuberculosis, cardiac tamponade, and sepsis (1 patient each). Adverse events of special 
interest (AESIs) to be monitored for ceritinib have also been identified and include 
hepatotoxicity, interstitial lung disease/pneumonitis, QT prolongation, bradycardia, 
hyperglycemia, gastrointestinal toxicity (nausea, vomiting and diarrhea) and pancreatitis 


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(including lipase and amylase elevations). For additional details, refer to the [Investigator’s 
Brochure].
1.2.1.2.2 Clinical efficacy
, based on investigator assessment, data from the 
 Study 
demonstrated a high rate of rapid and durable responses with ceritinib in 
246 ALK-positive NSCLC patients treated in the 750 mg dose group (RD). For the 
corresponding efficacy data based on BIRC review assessment, see Section 1.3. In these
patients the ORR was 58.5% (95% CI: 52.1, 64.8) based on investigator assessment (Table 1-
2). Among the 144 ALK-positive NSCLC patients with a confirmed CR or PR based on 
investigator assessment, the median time to response was short at 6.1 weeks (range: 3.0 to 
24.1) and 86.1% of the patients achieved a response within 12 weeks. The estimated median 
DOR based on investigator assessment was long at 9.69 months (95% CI: 7.00, 11.40) (Table 
1-3).
Ceritinib showed this level of high anti-cancer activity regardless of prior ALK inhibitor 
status (i.e., whether or not the patient received previous treatment with an ALK inhibitor). A 
high ORR of 54.6% and 66.3% was observed in patients treated with a prior ALK inhibitor 
and in ALK inhibitor naïve patients, respectively, by investigator assessment (Table 1-2).
Rapid responses were observed in patients regardless of prior ALK inhibitor status, 6.1 weeks 
(range: 4.6 to 24.1) in the patients treated with a prior ALK inhibitor and 6.1 weeks (range: 
3.0 to 24.1) in the ALK inhibitor naïve patients. Further, the estimated median DOR was 
7.39 months (95% CI: 5.42, 10.12) in patients treated with a prior ALK inhibitor, the median 
DOR was not reached (95% CI: 9.59, NE) in the ALK inhibitor naïve patients, however the 
12-month DOR rate was 65.2% (95% CI: 46.4, 78.8) (Table 1-3).
 


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Table 1-2
Summary of best overall response based on investigator assessment 
in NSCLC patients in the 750 mg dose group, by prior ALK inhibitor 
status (Full Analysis Set NSCLC 750 mg) 
NSCLC with prior 
ALK inhibitor
NSCLC ALK 
inhibitor naïve
All NSCLC
N=163
N=83
N=246
n (%)
n (%)
n (%)
Best overall response
Complete response (CR)
2 (1.2)
1 (1.2)
3 (1.2)
Partial response (PR)
87 (53.4)
54 (65.1)
141 (57.3)
Stable disease (SD)
32 (19.6)
19 (22.9)
51 (20.7)
Progressive disease (PD)
16 (9.8)
0
16 (6.5)
Unknown
26 (16.0)
9 (10.8)
35 (14.2)
Overall response rate (ORR)
(CR or PR), n (%)
89 (54.6)
55 (66.3)
144 (58.5)
95% CI
(46.6-62.4)
(55.1-76.3)
(52.1-64.8)
This table presents data for all patients with ALK-positive NSCLC in the 750 mg treatment dose group, FAS-
NSCLC 750 mg group
Best overall response is based on investigator’s assessment of disease status using RECIST 1.0 criteria
CR and PR are confirmed by repeat assessments performed not less than 4 weeks after the criteria for response 
are first met.
Exact binomial 95% Confidence Interval


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Table 1-3
Analysis of duration of response based on investigator assessment in 
NSCLC patients in the 750 mg dose group using Kaplan-Meier method, 
by prior ALK inhibitor status (Full Analysis Set NSCLC 750 mg–
Confirmed PR or CR) 
NSCLC with prior ALK 
inhibitor
NSCLC ALK inhibitor 
naïve
All NSCLC
N=89
N=55
N=144
No. of events, n (%)
42 (47.2)
14 (25.5)
56 (38.9)
Progression
42 (47.2)
14 (25.5)
56 (38.9)
Death
0
0
0
No. of patients censored
47 (52.8%)
41 (74.5)
88 (61.1)
Kaplan-Meier estimates (%)
DOR rate [95% CI] at:
3 months
93.6
[85.4, 97.3]
90.0
[77.6, 95.7]
92.2
[86.0, 95.7]
6 months
56.4
[43.7, 67.4]
73.8
[58.3,84.3]
63.4
[53.7, 71.6]
12 months
17.9
[6.0, 35.1]
65.2
[46.4, 78.8]
33.0
[19.2, 47.6]
25th percentile (month) [95%CI]
4.17
[4.01, 5.09]
5.55
[3.52, NE]
4.21
[4.17, 5.52]
Median (month) [95%CI]
7.39
[5.42, 10.12]
NE
[9.59, NE]
9.69
[7.00, 11.40]
75th percentile (month) [95%CI]
11.07
[9.69, NE]
NE
[NE, NE]
NE
[11.07, NE]
This table presents data for patients with ALK-positive NSCLC in the 750 mg treatment dose, FAS-NSCLC 
750 mg group.
Percentiles with 95% CIs are calculated from PROC LIFETEST output using method of Brookmeyer and Crowley 
(1982).
% Event-free probability estimate is the estimated probability that a patient will remain event-free up to the 
specified time point.
% Event-free probability estimates are obtained from the Kaplan-Meier survival estimates; Greenwood formula is 
used for CIs of Kaplan-Meier (KM) estimates.
N : Total number of patients included in the analysis.
Based on the investigator assessment 115 PFS events (96 progressions and 19 deaths) were 
observed, and the median PFS was 8.21 months (95% CI: 6.70, 10.12) with 53.3% of the 
patients censored. The estimated median PFS was 6.90 months (95% CI: 5.39, 8.41) in 
patients treated with a prior ALK inhibitor, while the median PFS was not reached in ALK 
inhibitor naïve patients (95% CI: 8.31, NE) (Table 1-4).


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Table 1-4
Analysis of PFS based on investigator assessment in NSCLC patients 
in the 750 mg dose group, by prior ALK inhibitor status (Full Analysis 
Set NSCLC 750 mg) 
NSCLC with prior ALK 
inhibitor
NSCLC
ALK inhibitor naïve
All NSCLC
N=163
N=83
N=246
Number of PFS events, n (%)
89 (54.6)
26 (31.3)
115 (46.7)
Progression
74 (45.4)
22 (26.5)
96 (39.0)
Death
15 (9.2)
4 (4.8)
19 (7.7)
Number of patients Censored
74 (45.4)
57 (68.7)
131 (53.3)
Kaplan-Meier estimates (%)
PFS rate [95% CI] at
3 months
74.6
[66.8, 80.9]
88.1
[78.4, 93.6]
79.2
[73.3, 84.0]
6 months
53.8
[45.0, 61.9]
69.4
[56.7, 79.0]
59.2
[52.0, 65.6]
12 months
28.4
[19.0, 38.6]
61.3
[47.7, 72.3]
39.1
[30.8, 47.4]
25th percentile PFS (month) [95% CI]
2.89
[2.63, 4.27]
5.52
[4.17, 6.90]
4.17
[2.86, 4.63]
Median PFS (month) [95% CI]
6.90
[5.39, 8.41]
NE
[8.31, NE]
8.21
[6.70, 10.12]
75th percentile PFS (month) [95% CI]
12.48
[10.12, 12.78]
NE
[NE, NE]
NE
[12.58, NE]
This table presents data for patients with ALK-positive NSCLC in the 750 mg treatment dose, FAS-NSCLC 
750 mg group.
Percentiles with 95% CIs are calculated from PROC LIFETEST output using method of Brookmeyer and Crowley 
(1982).
% Event-free probability estimate is the estimated probability that a patient will remain event-free up to the 
specified time point.
% Event-free probability estimates are obtained from the Kaplan-Meier survival estimates; Greenwood formula is 
used for CIs of KM estimates.
N: Total number of patients included in the analysis.
Efficacy analyses were also performed for NSCLC patients in the 750 mg dose group who 
had brain metastasis (measurable or non-measurable) identified by the investigator at baseline 
(Table 1-5).


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Table 1-5
ORR, DOR and PFS in NSCLC patients with brain metastases at 
baseline in the 750 mg dose group
NSCLC with prior ALK 
inhibitor -
patients with brain 
metastases
NSCLC ALK inhibitor 
naïve -
patients with brain 
metastases
All NSCLC –
patients with brain 
metastases
Efficacy Parameter
n=98
n=26
n=124
ORR, n (%)
[95% CI]
49 (50.0)
[39.7, 60.3]
18 (69.2)
[48.2, 85.7]
67 (54.0)
[44.9, 63.0]
DOR, median (months)
[95% CI]
6.9
[4.8, 8.5]
NEa
[5.5, NE]
7.0
[5.5, 9.7]
PFS, median (months)
[95% CI]
6.7
[4.9, 8.4]
8.3
[4.6, NE]
6.9
[5.4, 8.4]
NE: Not estimable
a DOR rate at 6 months 65.9% [95% CI: 35.4, 84.5]
A total of 14 patients out of the 246 patients included in the 750 mg dose group had brain 
metastases at baseline considered to be target lesions by the investigator per RECIST 1.0. In 
these 14 patients, the OIRR was 50% (95% CI: 23.0, 77.0) (1 patient with confirmed CR in 
the brain and 6 patients with a confirmed PR in the brain). These responses were observed in 
4 patients treated with a prior ALK inhibitor (4 confirmed PR) and in 3 ALK inhibitor naïve 
patients (1 confirmed CR and 2 confirmed PR).
1.2.1.2.3 Clinical pharmacodynamics
Data are not available from the ongoing clinical studies.


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1.3
Risk and benefits
Overall benefit-risk
Ceritinib dosed at 750 mg once daily has remarkable anti-tumor activity and induces a high 
rate of rapid and durable responses and prolonged PFS in patients with advanced, ALK-
positive NSCLC, regardless of whether they had been previously treated with an ALK 
inhibitor or were ALK inhibitor naïve. The substantial anti-tumor activity and resulting 
clinical benefit combined with the clinically manageable safety profile of ceritinib strongly 
support a positive benefit/risk balance for ALK-positive NSCLC patients.
Efficacy
Patients with prior ALK inhibitor treatment: ALK-positive NSCLC patients previously 
treated with crizotinib who have progressed and patients intolerant to crizotinib have no 
effective treatment options, have a dismal prognosis, and represent a population with a high 
unmet medical need. In ALK-positive NSCLC patients failing treatment with crizotinib, 
independent from the resistance mechanism involved, ALK translocation is still present and is 
still the oncogenic driver in almost all of the cases. Chemotherapy is not expected to provide a 
meaningful clinical benefit in these patients, as was recently demonstrated in a Phase III study 
(PROFILE 1007) of crizotinib vs. chemotherapy in the second-line setting (Shaw et al 2013).
In ALK-positive NSCLC patients previously treated with an ALK inhibitor and multiple prior 
lines of anti-neoplastic therapy, based on an independent review of tumor assessments, 
 
, the response rate was 45.1% (95% CI: 37.1 - 53.3) and the median DOR was 
7.1 months (95% CI: 5.6 – NE). The median PFS was 6.7 months (95% CI: 5.5 - 7.7) in Study 
. The median PFS is similar (overlapping 95% CIs) to that reported for 
crizotinib in the second-line setting (7.7 months (95% CI: 6.0 - 8.8)) and similar or better than 
that reported for chemotherapy (4.2 months (95% CI: 2.8 - 5.7) with pemetrexed and 
2.6 months (95% CI: 1.6 - 4.0) with docetaxel) in the PROFILE 1007 study (Shaw et al 2013)
for patients with locally advanced or metastatic ALK-positive NSCLC who had received prior 
treatment with one platinum-containing chemotherapy regimen. Therefore, ceritinib fulfills an 
existing unmet medical need.
The efficacy of ceritinib seen in Study 
is highly encouraging in heavily 
pretreated patients with advanced disease, high tumor burden (including a high proportion of 
brain metastases at baseline), limited available therapeutic options, and dismal prognoses 
following prior ALK-targeted therapies, where the only options are chemotherapy and best 
supportive care.
ALK inhibitor naïve patients:
, based on an independent review of tumor 
assessments, the response rate in ALK inhibitor naïve NSCLC patients was 61.0% (95% CI: 
49.2 - 72.0) in Study
. The median DOR was not evaluable for treatment-
naïve patients. The median PFS for ceritinib in ALK-inhibitor naïve patients was not 
evaluable (95% CI: 13.7 - NE) as the majority of patients were ongoing without an event at 
the time of the data cut-off.


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Overall, these data suggest that ceritinib as a first-line ALK inhibitor treatment has 
remarkable anti-tumor activity and induces a consistently high rate of durable responses in 
ALK inhibitor naïve patients.
Safety
The safety profile of ceritinib is manageable (Section 1.2.1.2), with a low rate of AEs leading 
to discontinuation. Furthermore, patients’ perception of their quality of life was maintained or 
slightly improved with ceritinib treatment. The most common AEs were gastrointestinal 
(diarrhea, nausea, vomiting); increases in transaminases, decreased appetite, fatigue; 
abdominal pain, and constipation were also seen in ≥ 25% of patients. These AEs can be 
managed with symptomatic treatment and/or dose reductions or interruptions; only 8.8% of 
patients discontinued study drug due to an AE. No clinically meaningful differences in the 
safety profile were observed between ALK-positive NSCLC patients previously treated with 
an ALK inhibitor and ALK inhibitor naïve patients.
The risks identified with ceritinib treatment include hepatotoxicity, interstitial lung disease 
(ILD)/pneumonitis, QT interval prolongation, bradycardia, hyperglycemia, gastrointestinal 
toxicity (nausea, vomiting and diarrhea) and pancreatitis (including lipase and amylase 
elevations) (Section 8.1.3). These risks can be managed and ameliorated by early diagnosis 
and dose adjustment/interruption, or permanent discontinuation.
Risk management during study conduct
In order to manage the risks associated with ceritinib treatment, specific dose modifications 
and stopping rules during study conduct are described in the protocol. For patients who do not 
tolerate the initial protocol-specified dose, dose adjustments are provided in order to allow the 
patients to continue the study treatment (Section 6.3. and Table 6-2). Patients whose treatment 
is temporarily interrupted or permanently discontinued due to a study drug related AE or an 
abnormal laboratory value must be followed until resolution or stabilization of the event, 
whichever comes first, including all study assessments appropriate to monitor the event.
In addition, a thorough post-treatment safety follow-up is included (Section 7.1.4.1). Patients 
may voluntarily withdraw from study treatment at any time or on the advice of the 
investigator if he/she believes that continuation would be detrimental to the patient’s well-
being. When the patient discontinues from study treatment, an End of Treatment (EOT) visit 
must be performed as soon as possible and within 7 days of the last dose of ceritinib. Patients 
will also be contacted for the safety follow-up 30 days after their last dose of ceritinib to 
determine if they have experienced any new AEs and/or to follow resolution of ongoing AEs.
Detailed information on allowed and prohibited concomitant medications is provided in 
Section 6.4. In vitro drug metabolism studies show that the metabolism of ceritinib is 
mediated by CYP3A4/5. Appendix 1 contains several tables listing medications that are 
prohibited, permitted or to be used with caution during treatment with ceritinib. Prohibited 
medications should be discontinued at least 1 week prior to the start of treatment with 
ceritinib (see exclusion criteria #11).
Recommended guidelines for prophylactic or supportive treatment for expected toxicities, 
including management of study-drug induced AEs, are extensively described in Section 6.3.4.


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Furthermore, regarding adverse events of special interest (see Section 8.1.3):

Hepatotoxicity: Hepatotoxicity, as defined by TB > 2xULN and ALT and/or AST > 
3xULN and ALP < 2xULN, has been observed in <1% of patients treated with ceritinib. 
Increases to grade 3 or 4 ALT elevations were observed in 25% of patients receiving 
ceritinib. Concurrent elevations in ALT >3xULN and total bilirubin >2xULN, with 
normal alkaline phosphatase, occurred in less than 1% of patients in clinical studies. The 
majority of cases were manageable with dose interruption and/or dose reduction. Few 
events required discontinuation of ceritinib. Patients will be closely monitored by regular 
laboratory testing and related signs and symptoms. Risk to patients will also be minimized 
by restricting study enrollment to subjects with laboratory values for AST, ALT, ALP and 
bilirubin below certain thresholds (see inclusion criteria #7).

Interstitial lung disease/pneumonitis: severe, life-threatening, or fatal interstitial lung 
disease (ILD)/pneumonitis have been observed in patients treated with ceritinib in clinical 
studies. Most cases improved or resolved with interruption of ceritinib. Patients will be 
monitored for symptoms such as shortness of breath, cough or fever. Risk to patients will 
be minimized by excluding from study enrollment any patient with a history of interstitial 
lung disease or interstitial pneumonitis, including clinically significant radiation 
pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention) 
(see exclusion criteria #19).

QT interval prolongation: QTc prolongation has been observed in clinical studies in 
patients treated with ceritinib, which may lead to an increased risk for ventricular 
tachyarrhythmias (e.g., Torsade de pointes) or sudden death. A pharmacokinetic analysis 
suggested that ceritinib causes concentration-dependent increases in QTc. Repeated ECG 
tracings will be performed throughout the study to closely monitor cardiovascular safety. 
Risk to patients will also be minimized by excluding from study enrollment those patients 
with clinically significant, uncontrolled heart disease and/or a recent cardiac event (within 
6 months), including a corrected QT (QTcF) > 470 ms using Fridericia’s correction on the 
screening ECG (see exclusion criteria #8).

Bradycardia: asymptomatic cases of bradycardia have been observed in patients treated 
with ceritinib in clinical studies. Repeated ECG tracings will be performed throughout the 
study to closely monitor cardiovascular safety. Risk will also be minimized by monitoring 
concomitant use of other agents known to cause bradycardia (e.g., beta-blockers, non-
dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. 
Heart rate and blood pressure will also be monitored regularly during the study.

Hyperglycemia: events of hyperglycemia (all grades) have been reported in less than 10% 
of patients treated with ceritinib in clinical studies; 5% of patients reported a grade 3/4 
event. The risk of hyperglycemia was higher in patients with diabetes mellitus and/or 
concurrent steroid use. Patients will be closely monitored throughout the study for any 
signs and symptoms related to elevated blood glucose levels. Risk will be minimized by 
including subjects with fasting plasma glucose levels ≤ 200 mg/dL (≤ 11.1 mmol/L) at 
screening (see inclusion #7).

Gastrointestinal toxicity: diarrhea, nausea, and vomiting have been very commonly 
reported; 12.2% of patients reported a grade 3/4 event of diarrhea, nausea, or vomiting. 
Risk to patients will be minimized during the study by closely monitoring symptoms and 


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managing patients using standards of care, including anti-diarrheals, anti-emetics, or fluid 
replacement, as indicated.
a. Pancreatitis (including lipase and amylase elevations): in most cases, pancreatic enzyme 
elevations have been mild to moderate, and have typically reversed with interruption of 
ceritinib. Few patients have experienced pancreatitis with severe upper abdominal pain. 
Patients will be monitored closely for any related signs and symptoms. In order to 
minimize the risk to patients during the study, patients with a history of pancreatitis or a 
history of increased lipase or amylase levels that was due to pancreatic disease will be 
excluded. In addition, serum amylase must be ≤2 x ULN and serum lipase must be within 
normal limits at screening.
Conclusion
The outstanding anti-tumor activity and resulting clinical benefit combined with the 
manageable safety profile of ceritinib strongly support a positive benefit-risk balance for 
ALK-positive NSCLC patients, regardless of whether the patients had received prior ALK 
inhibitor treatment or not.
The risk to subjects in this trial will be minimized and managed by compliance with the 
eligibility criteria, close clinical monitoring, dose modifications/interruptions and permanent 
discontinuation as required. There may be unforeseen risks with LDK378 which could be 
serious. Refer to the [Investigator’s Brochure] for additional information regarding the safety 
profile of ceritinib.
2
Rationale
2.1
Study rationale and purpose
Brain metastases (BM) are a common complication of patients with NSCLC: 20 to 40% will 
develop BM within 2 years of diagnosis. BM treatments are usually palliative with the intent 
to achieve local control of the CNS disease. Treatment options may include surgical resection, 
stereotactic radiosurgery or whole brain radiation therapy. The combination of these 
modalities depends on the number and location of the BM. Whole brain radiation therapy is 
the standard treatment approach for multiple BM leading to a modest overall survival benefit. 
It is unclear to date if systemic therapies added to local treatment or following local treatment, 
may achieve a better control of the CNS disease.
In the last decade, research in the NSCLC field has focused on identifying distinct subtypes of 
NSCLC driven by specific genetic alterations that may be susceptible to targeted inhibition. 
The remarkable activity of EGFR Tyrosine Kinase inhibitors have changed the way patients 
harboring activating mutation are treated. EGFR TKI are used as first-line therapy instead of 
chemotherapy for these patients. Using TKI to inhibit the mutated EGFR affects several 
cellular regulating functions important in the proliferation and survival of cancer cells, 
translating into higher response rates and a longer PFS compared to 1st line chemotherapy. 
Given their low molecular weight, it is assumed that these agents may reach brain metastases 
more readily and may be more effective than chemotherapies. Small studies reported longer 
PFS and remarkable clinical activity with EGFR TKI in patients with NSCLC harboring an 


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activating mutation of EGFR and metastatic to the brain (Fan 2013, Zhuang 2013, Iuchi 2013). 
These observations open the way to reevaluate the role of systemic treatment for BM when 
highly effective drugs have a relatively low molecular weight.
ALK, a receptor tyrosine kinase, is involved in the genesis of several cancers through genetic 
aberrations involving translocation of the kinase domain with multiple fusion partners or 
activating mutations in the full-length receptor that result in ligand-independent constitutive 
activation. ALK rearrangement and EGFR mutation are known to be mutually exclusive in 
NSCLC. Similarly to what is observed with mutated EGFR in NSCLC, ALK rearrangements 
constitute a key and strong oncogenic driver for NSCLC and represent a critical target 
susceptible to targeted ALK inhibition. The inhibition of ALK translates into the control of 
the NSCLC. Crizotinib, the first ALK inhibitor to be evaluated in advanced or metastatic 
ALK-positive NSCLC patients after failure to a prior platinum-based chemotherapy, achieves 
a higher response rate (RR) (65%; 95%CI: 58-72) and a longer progression free survival (PFS) 
compared with second-line chemotherapy (7.7 months versus 3.0 months, HR=0.49; 95% CI, 
0.37 – 0.64) (Shaw et al 2013).
Crizotinib may have clinical activity in patients with ALK positive NSCLC metastatic to the 
brain, but its activity may be less remarkable in the brain than systemically (outside of the 
brain). Costa et al (2012) measured the concentration of crizotinib in both CSF and plasma 
and reported that the CSF-to-plasma ratio of crizotinib was 0.0026. Shaw et al (2013)
evaluated the progression free survival in a subgroup of patients with or without BM at 
baseline. The hazard ratio still favored crizotinib compared to second-line chemotherapy in 
patients with BM (HR=0.67; 95%CI: 0.44 – 1.03) but the results for the subgroup of patients 
without BM (HR=0.43; 95% CI, 0.30 – 0.60) suggest that crizotinib may not easily cross the 
blood brain barrier. Crizotinib does not prevent the onset of brain metastases - the brain is the 
first site of progression in 46% of patients with ALK-positive crizotinib-treated NSCLC 
(Otterson et al 2012). Another indication that crizotinib has lesser clinical activity in the brain 
is demonstrated in the low Overall Intracranial Response Rate (OIRR - CR+PR) reported in a 
group of 109 patients with ALK positive NSCLC with untreated brain metastases at baseline. 
The OIRR is 7% (95%CI: 3-14) compared to an extracranial Response Rate of 49% (95%CI: 
43-63) The OIRR across 22 patients out of the 109, who presented with measurable brain 
lesion at baseline is 18% (95% CI: 4-40) (Crino et al 2013).
Ceritinib, an orally available ALK inhibitor, is an approximately 20-fold more potent ALK 
inhibitor than crizotinib. Ceritinib shows potent antitumor activity in patients with ALK-
positive advanced or metastatic NSCLC progressing or not on crizotinib.
, data from the 
 Study 
demonstrated a high rate 
of rapid and durable responses with ceritinib in 246 ALK-positive NSCLC patients treated in 
the 750 mg dose group. In these patients the ORR was 58.5% (95% CI: 52.1, 64.8) based on 
investigator assessment. A high ORR of 54.6% and 66.3% was observed in patients treated 
with a prior ALK inhibitor and the ALK inhibitor naïve patients, respectively, (Table 1-2).
The estimated median PFS was 6.90 months (95% CI: 5.39, 8.41) in patients treated with a 
prior ALK inhibitor, while the median PFS was not reached in ALK inhibitor naïve patients 
(95% CI: 8.31, NE). Further, the estimated median DOR was 7.39 months (95% CI: 5.42, 
10.12) in patients treated with a prior ALK inhibitor, the median DOR was not reached (95% 


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CI: 9.59, NE) for the ALK inhibitor naïve patients, however the 12-month DOR rate was 
65.2% (95% CI: 46.4, 78.8).
A total of 14 patients out of the 246 patients included in the 750 mg dose group had brain 
metastases at baseline considered to be target lesions by the investigator per RECIST 1.0. In 
these 14 patients, the OIRR was 50% (95% CI: 23.0, 77.0) (1 patient with confirmed CR in 
the brain and 6 patients with a confirmed PR in the brain). These responses were observed in 
4 patients treated with a prior ALK inhibitor (4 confirmed PR) and in 3 ALK inhibitor naïve 
patients (1 confirmed CR and 2 confirmed PR).
Leptomeningeal carcinomatosis, another less frequent CNS complication observed in NSCLC,
is a rare devastating disease resulting from the seeding of malignant cells to the leptomeninges 
and cerebrospinal fluid (CSF). LC is observed in approximately 5% of the patients diagnosed 
with metastatic NSCLC. The incidence of LC in ALK-positive NSCLC may be around 5 to 
6% (Gainor et al 2013). Median survival without treatment is about 4-6 weeks and about 3 
months with the available treatments (whole brain radiation therapy and intrathecal 
chemotherapy). The role of systemic treatment for LC is not established. Case reports and 
small series of subjects indicate that LC control may be observed with the use of highly active 
targeted therapies like EGFR TKI or ALK TKI (Riess 2014, Lee 2013, Ahn 2012).
There is a medical need for more effective treatment for patients with ALK-positive NSCLC 
metastatic to the CNS before and after failure to crizotinib. The clinical activity of ceritinib in 
ALK positive NSCLC patients (progressing or not on crizotinib), its more potent inhibition of 
ALK and its more favorable brain distribution data in animals compared to crizotinib support 
the assessment of ceritinib as treatment of patients with ALK-positive NSCLC metastatic to 
the brain and/or to leptomeninges, irrespective of prior treatment with an ALK inhibitor.
2.2
Rationale for the study design
This is a phase II, multi-center, open-label, five-arm study to evaluate the efficacy and safety 
of oral ceritinib treatment for patients with ALK-positive NSCLC metastatic to the brain 
and/or to leptomeninges. Only patients whose tumors harbor ALK rearrangement will be 
enrolled in the study. The study will enroll approximately 160 patients globally.
Patient population
Patients with ALK-positive NSCLC and active metastases into the brain and/or to 
leptomeninges will be included in this study.
Patients without evidence of leptomeningeal carcinomatosis (LC) will be allocated into one of 
the following 4 arms taking into account the patient’s history of prior therapy: prior radiation 
therapy (whole brain or stereotactic radiation therapy) to the brain (yes/no) and a prior 
treatment with an ALK inhibitor (ALKi) (yes/no). Prior ALK inhibitor is limited to treatment 
with crizotinib in Arms 1, 2, and 5. All patients will have evaluable brain metastases 
following RECIST 1.1 as per investigator assessment.
The allocation of patients to arm 5 will be independent from the patient’s history of prior 
therapy but rather depend on the presence of neoplastic cells in the cerebrospinal fluid (CSF) 
as assessed and documented by the investigator at baseline. In the absence of neoplastic cells 
in the CSF, the allocation of patients to arm 5 will then depend on the diagnosis of typical 


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radiological leptomeningeal carcinomatosis on the baseline gadolinium-enhanced MRI of the 
brain (or the spine for suspected LC patients only) by an experienced neuroradiologist.
Table 2-1
Allocation into Study Arms based on prior radiation to brain (yes/no) 
and prior treatment with ALK inhibitor (yes/no)
Prior Radiation to the brain: 
YES
Prior Radiation to the brain: 
NO
Prior treatment with a ALKi1: YES
Arm 1
Arm 2
Prior treatment with a ALKi: NO
Arm 3
Arm 4
Leptomeningeal disease1
Arm 5
1Previous treatment with ALK inhibitors other than crizotinib is not allowed in Arms 1, 2 and 5.
The description of patients in each of the five study arms is as follows:

Arm 1 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously treated with radiation to the brain and with 
prior exposure to an ALKi.

Arm 2 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously untreated with radiation to the brain but with 
prior exposure to an ALKi.

Arm 3 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously treated with radiation to the brain but with no 
prior exposure to an ALKi.

Arm 4 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously untreated with radiation to the brain and with 
no prior exposure to an ALKi.

Arm 5 will include any patients with leptomeningeal carcinomatosis with or without 
evidence of active lesion at the baseline Gadolinium-enhanced brain MRI.
Note: An active brain lesion is a lesion free of any local treatment (like stereotactic 
radiosurgery or whole brain radiation). The following lesions are considered active:

A newly diagnosed brain metastasis in a patient who has never received treatment to 
the brain or in a patient with previously treated brain metastases.

A brain lesion previously treated with whole brain radiation will only be considered 
active when there is an unequivocal size increase in its solid component (cystic 
component of the lesion is not considered for progression determination) compared to 
the first available post-radiation radiological evaluation.

An enlarging brain lesion previously treated with SRS will only be considered active 
when the nature of the enlargement is clearly attributed to the tumoral component of 
the lesion and not to the radiation effect.
Whole body, intracranial and extracranial endpoints
Depending on the ability of ceritinib to cross the blood-brain barrier, its therapeutic activity in 
brain metastases may be different from its activity outside of the brain. This may affect the 
tumor overall response determined in a population of ALK+ NSCLC patients metastatic into 
the brain compared to patients without brain metastases. Whole body response and related 


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endpoints will be evaluated and will include the overall response rate (ORR), duration of 
response (DOR), disease control rate (DCR) and progression free survival (PFS) for all cancer 
lesions in and outside the brain per RECIST 1.1.
To differentially appreciate this, the intracranial activity of ceritinib without taking into 
consideration lesions situated outside of the brain will be evaluated and reported as an 
intracranial endpoint.
In contrast, the activity of ceritinib outside of the brain without inclusion of brain lesions
will be evaluated and will be reported as an extracranial endpoint.
2.3
Rationale for dose and regimen selection
In the dose-escalation phase of 
, 59 patients were treated at dose 
levels of 50 to 750 mg. Eight Dose Limiting Toxicities (DLTs) at Cycle 1 were observed in 6 
patients:

At 400 mg: grade 3 hypophosphatemia in one patient, and grade 3 transaminase increased 
evolving from grade 2 ALT increased in one patient.

At 600 mg: grade 3 diarrhea and grade 3 dehydration in one patient each.

At 750 mg: grade 3 diarrhea with grade 3 vomiting in one patient and intolerable grade 2 
diarrhea in one patient.
 
 
 
 
 
 
Further confirmation of the 750 mg dose as the appropriate MTD came from the 
incidence of DLTs in Cycle 1 in the first 10 patients treated at this dose in the expansion 
phase of the study. There were no first-cycle DLTs in these 10 patients, thus confirming the 
750 mg dose as a safe MTD and RD 
Among the different doses tested, the recommended dose (RD) for the expansion phase was 
determined to be 750 mg, the highest dose evaluated. The following safety and efficacy 
considerations were taken into account:

Safety data indicated that ceritinib is well tolerated at 750 mg for multiple cycles of 
therapy, without evident difference in the frequency of AEs versus immediate lower doses
(400-700 mg).

Although preliminary efficacy data indicated that tumor responses are observed 
consistently at doses of 400 mg and above, the response duration appeared to be shorter at 


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the lower doses. Nonclinical data from ALK-positive NSCLC xenograft models indicated 
that ceritinib should be dosed at the MTD to maximize efficacy, in particular against 
crizotinib resistant tumor models.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4.
The primary objective is to evaluate the antitumor 
activity of ceritinib in patients with ALK-positive 
NSCLC metastatic to the brain and/or to 
leptomeninges based on investigator assessment per 
RECIST 1.1
The primary endpoint is:
●
Overall response rate (ORR), defined as the proportion of patients with a best 
overall confirmed response of CR or PR in the whole body as assessed per RECIST 
1.1 by the investigator.
Key Secondary Objective
Refer to Section 10.5.
To evaluate Disease Control Rate (DCR) in patients 
with ALK-positive NSCLC metastatic to the brain 
and/or to leptomeninges based on investigator 
assessment per RECIST 1.1
The key secondary endpoint is:
●
Disease Control Rate (DCR) in the whole body as assessed per RECIST 1.1 by 
the Investigator
Secondary Objectives
Refer to Section 10.5.
1. To evaluate intracranial tumor-response related 
endpoints as assessed by investigators and Blinded 
Independent Review Committee (BIRC) (using 
modified RECIST 1.1 criteria)
2. To evaluate extracranial tumor-response related 
endpoints as assessed by investigators and BIRC 
(using RECIST 1.1 criteria)
3. To evaluate whole body tumor-response related 
endpoints as assessed by investigators and 
BIRC(using RECIST 1.1 criteria)
4. To evaluate overall survival (OS) in this patient 
population
5. To evaluate safety in this patient population
 
1. The following intracranial endpoints will be evaluated per modified RECIST 1.1*:
●
Overall Intracranial Response Rate (OIRR) by Investigator and BIRC for 
patients with measurable brain metastases at baseline
●
Intracranial Disease Control Rate (IDCR) at 8, 16 weeks and overall by 
Investigator and BIRC
●
Time to intracranial tumor response (TTIR) by Investigator and BIRC for 
patients with measurable brain metastases at baseline
●
Duration of intracranial response (DOIR) by Investigator and BIRC for 
patients with measurable brain metastases at baseline
2. The following extracranial endpoints will be evaluated per RECIST 1.1:
●
Overall Extracranial Response Rate (OERR) by Investigator and BIRC
●
Extracranial Disease Control Rate (EDCR) at 8, 16 weeks by Investigator 
and BIRC
●
Time to extracranial tumor response (TTER) by Investigator and BIRC
●
Duration of extracranial response (DOER) by Investigator and BIRC
3. The following whole body tumor-response related endpoints will be evaluated per 
RECIST 1.1:
●
Overall response rate (ORR) by BIRC
●
Disease control rate (DCR) by BIRC


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Objective
Endpoint
Analysis
●
Time to tumor response (TTR) by Investigator and BIRC
●
Duration of response (DOR) by Investigator by BIRC
●
Progression free survival (PFS) by Investigator by BIRC
4. Overall survival (OS)
5. AEs, ECGs, Vital signs and laboratory abnormalities
Exploratory objectives
Refer to Section 10.6.
1. To evaluate intracranial endpoints for patients with 
measurable brain metastases at baseline in Arms 1 to 
4 and for patients with active brain lesions at baseline 
in Arms 1 to 4 using the Response Assessment in 
Neuro-Oncology (RANO) criteria for high grade 
gliomas (Wen et al 2010) by investigators and BIRC.
1. Intracranial endpoints including OIRR, Time to Intracranial Tumor Response 
(TTIR), Duration of Intracranial Response (DOIR) for patients with measurable brain 
metastases at baseline in Arms 1 to 4, and IDCR in Arms 1 to 4 for patients with 
active brain lesions at baseline using the Response Assessment in Neuro-Oncology 
(RANO) criteria for high grade gliomas (Wen et al 2010) by investigators and BIRC.
*RECIST 1.1 will be modified to allow a specific evaluation of the intracranial response to the treatment. The usual criteria to select target lesions will be used but a 
maximum five target lesions located in the brain can be selected at baseline and evaluated at each assessment time point.


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4
Study design
4.1
Description of study design
This is a phase II, multi-center, open-label, five-arm study in which the efficacy and safety of 
oral ceritinib treatment for patients with ALK-positive NSCLC metastatic to the brain and/or 
to leptomeninges will be assessed.
Figure 4-1
Study design
Arm 5
N~20
• ALK-positive  NSCLC 
• Active (measurable and 
non-measurable) 
metastases to the brain 
and/or leptomeninges
Ceritinib 750 mg daily
Arm 2
N~40
Arm 1
N~40
•
Prior radiation to brain
•
Prior exposure to an ALK inhibitor
•
No evidence of LC
•
LC
•
With or without Active metastases
Gadolinium-enhanced
Brain MRI
•
Prior radiation to brain
•
No prior exposure to an ALK inhibitor
•
No evidence of LC
•
No Prior radiation to brain
•
No prior exposure to an ALK inhibitor
•
No evidence of LC
•
No prior radiation to brain
•
Prior exposure to an ALK inhibitor
•
No evidence of LC
Arm 3
N~30
Arm 4
N~30
Previous treatment with ALK inhibitors other than crizotinib is not allowed in Arms 1, 2 and 5.
4.1.1
Screening
All patients must harbor an ALK rearrangement as assessed using the FDA approved Vysis 
ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm 
(including positivity criteria) before initiating treatment with ceritinib.


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Eligibility assessment and baseline tumor burden evaluation will be conducted within 28 days 
prior to starting study drug except for gadolinium-enhanced brain MRI and brain specific 
eligibility evaluation which should be done within 14 days prior to starting study drug. See 
Section 7.1.2 for further details.
 
 
Following completion of screening procedures and verifying patient eligibility, patients will 
be allocated to one of the five study arms via IRT.

Arm 1 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously treated with radiation to the brain and with 
prior exposure to an ALKi.

Arm 2 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously untreated with radiation to the brain but with 
prior exposure to an ALKi.

Arm 3 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously treated with radiation to the brain but with no 
prior exposure to an ALKi.

Arm 4 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously untreated with radiation to the brain and with 
no prior exposure to an ALKi

Arm 5 will include any patients with leptomeningeal carcinomatosis with or without 
evidence of active lesion at the baseline Gadolinium-enhanced brain MRI.
Note: Previous treatment with ALK inhibitors other than crizotinib is not allowed in Arms 1, 
2 and 5
Note: An active brain lesion is a lesion free of any local treatment (like stereotactic 
radiosurgery or whole brain radiation). The following lesions are considered active:

A newly diagnosed brain metastasis in a patient who has never received treatment to the 
brain or in a patient with previously treated brain metastases.

A brain lesion previously treated with whole brain radiation will only be considered active 
when there is an unequivocal size increase in its solid component (cystic component of the 


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lesion is not considered for progression determination) compared to the first available 
post-radiation radiological evaluation.

An enlarging brain lesion previously treated with SRS will only be considered active 
when the nature of the enlargement is clearly attributed to the tumoral component of the 
lesion and not to the radiation effect.
Approximately 160 patients will be treated in the study, ~40 patients in each Arm 1 and Arm 
2, ~30 patients in each Arm 3 and Arm 4, and ~20 patients in Arm 5. Additional patients in 
Arm 4 may be enrolled in order achieve ~60 patients in Arms 3 and 4 together (i.e. ALKi 
naïve patients) if enrollment rate in Arm 3 is slow.
Furthermore the study targets to enroll and treat the following number of patients with 
measurable brain metastasis at baseline as per the investigator’s assessment in each of the 
below subgroups:

Patients with prior ALKi treatment (combined Arms 1 and 2): ~50 patients with 
measurable brain metastasis

Patients with no prior ALKi treatment (combined Arms 3 and 4): ~20 patients with 
measurable brain metastasis
The measurability of brain metastases will also be assessed by BIRC per RECIST 1.1 on an 
ongoing basis to target a similar number of patients with measurable brain metastasis at 
baseline as per BIRC in the above subgroups of patients. Enrollment of patients with only 
non-measurable brain metastases (even in the presence of extracranial measurable lesions)
may be closed in one or more arms if it is determined that the above target for patients with 
measurable brain metastases will not be met.
4.1.2
Treatment duration
The study treatment phase begins on Cycle 1, Day 1 with the first administration of ceritinib.
All patients will receive the same treatment regimen regardless of the arm to which they are 
allocated. A cycle of treatment is defined as 28 days of once daily treatment of ceritinib in all 
study arms.
Treatment with ceritinib will continue until the patient experiences disease progression (in the 
brain, outside of the brain or both) as determined by the investigator according to RECIST 1.1, 
unacceptable toxicity that precludes further treatment, pregnancy, start of a new anticancer 
therapy, discontinues treatment at the discretion of the patient or investigator, lost to follow-
up, death, or study is terminated by Sponsor. Exceptions to the discontinuation of study 
treatment after PD being confirmed by the investigator are described in Section 6.1.3.
4.1.2.1
Tumor assessments during study conduct
Complete tumor assessments including gadolinium enhanced brain MRI will be repeated at 
Week 8 (on Cycle 3 Day 1) and every 8 weeks (i.e. every 2 cycles) thereafter or earlier if 
clinically indicated.
Tumor response will be evaluated starting from the first day of treatment with ceritinib until 
the time of disease progression according to RECIST 1.1 as determined by investigator,
withdrawal of consent for further follow-up, loss to follow-up or death. This schedule of 


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tumor assessment must continue regardless of dose interruptions. In patients who discontinue 
treatment in the absence of RECIST-defined progression, tumor assessments will continue 
every 8 weeks until progression of disease, withdrawal of consent for further follow-up, loss 
to follow-up or death.
For patients presenting with baseline leptomeningeal carcinomatosis with documented 
malignant cells in the cerebrospinal fluid, CSF samples will be collected at a frequency 
determined by local clinical practice unless medically contra-indicated. Samples should be 
obtained from site of disease or initially positive cytology if possible. The investigator may 
determine if more frequent evaluations are needed in case of suspected disease progression 
and/or in accordance with local clinical practice. If there are any signs or radiologic or clinical 
neurological progression, a CSF will be collected if feasible. Clinical progression may be 
determined based on results of cytological or neurological evaluations.
Gadolinium-enhanced brain MRI scans and all other imaging data collected at baseline and 
during the conduct of the study will be submitted to the designated imaging vendor for BIRC
review.
In this study, standard RECIST 1.1 will be used to evaluate the whole body (including 
intracranial and extracranial cancer lesions) response endpoints. Assessment of the overall 
response to treatment and other whole body response related endpoints will be conducted by 
investigators and BIRC.
Additionally, the intracranial and the extracranial metastatic disease will be evaluated as two 
separate entities. RECIST 1.1 and RANO for High Grade Glioma (Wen et al 2010) criteria 
will be used to determine intracranial tumor response based on target brain lesions, if 
applicable, any non-target brain lesions and any new brain lesions. RECIST 1.1 will be used 
to evaluate the extracranial tumor response but brain will be excluded from the evaluation.
4.1.2.2
Central radiology review of locally assessed disease progression
In case patients have equivocal disease progression according to RECIST 1.1 (in the brain, 
outside of the brain or both) as determined by the investigator, a confirmatory tumor 
assessment should be done at least 4 weeks thereafter. While the investigator is waiting for the 
confirmatory tumor assessment, it is preferable that the patient continue on study treatment for 
as long as it is clinically acceptable. However, during this time, the investigator should do 
whatever is medically necessary for the patient.
If the investigator does not determine disease progression, the patient should continue 
receiving the study drug unless there is a medical need (i.e., rapid progression or clinical 
deterioration) for an immediate change in therapy.
If the investigator confirms disease progression, then the patient will discontinue study drug 
and subsequent follow-up tumor assessments will no longer be required (except in the cases 
described below).
Exceptions to the discontinuation of study treatment after progressive disease (PD) being 
confirmed by the investigator are:

In case of isolated brain progression with controlled disease outside of the brain, patients 
may continue the study drug during the treatment of the new brain lesion if appropriate. If 


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ceritinib has to be interrupted during the treatment of the new brain lesions, it may be 
resumed after the treatment of the brain lesion if:

Brain lesions are demonstrated to be controlled by gadolinium-enhanced MRI and if 
patient is neurologically stable within the last 2 weeks prior to the re-initiation of 
study drug.

The disease outside of the brain remains controlled prior to re-initiation of study drug. 
A new tumor assessment will be repeated if the last one available is older than 4 
weeks.

Time interval between last dose and re-initiation of study drug does not exceed 8 
weeks.

Patient will continue to be followed for safety and efficacy assessments as per 
schedule of assessment.

If patient had PD outside of the brain (with minimally symptomatic or no PD in the brain) 
but still derives clinical benefit from ceritinib following investigator’s judgment, patient 
may continue study drug and continue to be followed for safety and efficacy assessments
as per schedule of assessment.
In both cases, all imaging data acquired during tumor assessments conducted after PD has 
been confirmed by the investigator will continue to be submitted to the designated imaging 
vendor who will send it to the BIRC for review.
If the patient had PD both intracranially and extracranially but still derives clinical benefit 
from ceritinib following investigator’s judgment, patient may continue study drug and 
continue to be followed for safety assessments as per schedule of assessment.
4.1.2.3
End of Treatment (EOT)
When the patient discontinues from study treatment an End of Treatment (EOT) visit must be 
performed as soon as possible and within 7 days of the last dose of ceritinib. Patients will be 
contacted for the safety follow-up 30 days after their last dose of ceritinib to determine if they 
have experienced any new AEs and/or to follow resolution of ongoing AEs.
Following the cessation of tumor follow-up assessments, patients will be contacted every 3 
months to assess patient survival status and/or whether the patient started any other 
antineoplastic therapies since discontinuing study treatment. Patients do not need to visit the 
clinic during the survival follow-up.


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4.3
End of study
The study will end when both of the following conditions are met:
1. At least 24 weeks after last patient treated in the study.
2. At least 75% of patients have died, have been lost to follow-up, or have withdrawn 
consent for survival follow-up, or the last patient will be able to enter into a separate 
rollover study and/or other options for continued treatment, whichever comes first.
Patients still treated with the study medication and deriving clinical benefit will be offered to 
continue the treatment in a separate study (and/or other options for continued treatment with 
ceritinib that are considered acceptable at the country level such as access to commercially 
available drug or managed access program). In the separate study, Novartis will continue to 
supply ceritinib to patients who may benefit from continued treatment as per the 
Investigator’s opinion and safety will be monitored and reported to Health Authorities per 
regulatory requirements. Prior to the end of the current study (CLDK378A2205), this separate 
protocol will be submitted to Health Authorities and IRBs involved in the current study.
Primary analysis of any of the study arms or overall will occur only after enrollment in the 
specific study arms or overall is complete and all patients have completed at least 24 weeks of 
treatment with ceritinib or have discontinued earlier respectively. A clinical study report (CSR) 
that includes the primary analysis will be produced. If the end of study criteria is met before 
the primary analysis is conducted, a single final analysis and study report may be performed. 
If the end of the study criteria is not met by the time that the primary analysis is conducted, a 
final CSR will be produced reporting all available data collected up to last patient last visit 
(LPLV) including the additional study data collected after the primary analysis.
An early primary analysis of specific study arms may be performed before the overall 
completion of all study arms (i.e. enrollment complete in all five study arms and at least 24 
weeks follow up of treated patients unless they have discontinued treatment earlier), if 
required, due to differential enrollment rate across study arms. If the early analysis is 
performed for specific study arms a clinical study report (CSR) will be produced including the 
data from those study arms up to the data cut-off date.
Subsequently, another analysis will be performed after the overall completion of all study 
arms (i.e. enrollment complete in all five study arms and at least 24 weeks follow up of 
treated patients unless they have discontinued treatment earlier). This analysis will be 
considered as primary analysis for the study arms not included in the early analysis and for 
overall patients. A CSR will be produced that will include data from all study arms up to the 
data cut-off date.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this occur, the 
patient should be seen as soon as possible and the same assessments should be performed as 
described in Section 7 for a discontinued or withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing Institutional Review Boards (IRBs) and/or Ethics Committees (ECs) 
of the early termination of the trial.


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5
Population
5.1
Patient population
Approximately 160 patients diagnosed with ALK-positive metastatic NSCLC (according to 
the 7th edition of the AJCC Cancer Staging Manual) and active lesions in the brain and/or 
diagnosed with leptomeningeal carcinomatosis will be included in the study.
Written informed consent must be obtained prior to any screening procedures. The 
investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies while on treatment. Laboratory parameters may be 
retested within the 28-day screening period for an individual patient if such parameters meet 
an exclusion criterion when initially tested. Rescreening of patients who do not originally 
meet inclusion and/or exclusion criteria may be allowed at a later stage only after discussion 
with the sponsor on a case by case basis.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
For all patients:
1a. Histologically or cytologically confirmed diagnosis of metastatic NSCLC according to the 
7th edition of the AJCC Cancer Staging Manual. In addition, the NSCLC must harbor an 
ALK rearrangement, as assessed using the FDA approved Vysis ALK Break Apart FISH 
Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria). 
If documentation of ALK rearrangement as described above is not locally available, a test 
to confirm ALK rearrangement must be performed by a Novartis designated central 
laboratory. Patients must wait for the central laboratory result of the ALK rearrangement 
status before initiating treatment with ceritinib.
2a. Patients that require ALK rearrangement testing by a Novartis designated central 
laboratory must have a tumor tissue sample available as an archival sample (if possible 
obtained after the completion of the patient’s last therapeutic regimen) or as a new biopsy. 
If that is not possible, any tumor biopsy obtained at or since the time of diagnosis can be 
used (a maximum of two years from biopsy excision is preferred).
3. At least one extracranial measurable lesion as defined by RECIST 1.1. A previously 
irradiated site lesion may only be counted as a target lesion if there is clear sign of 
progression since the irradiation. Note: Enrollment of patients with only non-measurable 
brain metastases may be closed in one or more arms if it is determined that the target for 
patients with measurable brain metastases across study arms will not be met.
4. Patient is 18 years of age or older at the time of informed consent.
5. Patients may or may not have neurological symptoms but must:

Be able to swallow and retain oral medication.


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
Be neurologically stable within at least 1 week prior to the first dose of study drug. 
Neurologically stable is defined as improved or stable neurological examination 
without increased doses of steroids to manage CNS symptoms within the last 5 days.
6a. Patients may have received prior chemotherapy, crizotinib (other ALK inhibitors are not 
allowed), biologic therapy or other investigational agents. Patients must have recovered 
from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03). 
Patients with any grade of alopecia are allowed to enter the study.

Patients who have been treated with chemotherapy, with biological therapy or other 
investigational agent must have discontinued the treatment at least 2 weeks (14 days) 
prior to starting study drug. In case last chemotherapy contains nitrosourea or 
mitomycin C, the treatment must be discontinued at least 6 weeks prior to the first 
dose of study drug.

Patients, if previously treated with crizotinib must discontinue treatment at least 1 
week (7 days) prior to the first dose of study drug.
7a. Patient must meet the following laboratory values at the screening visit:

Absolute Neutrophil Count ≥ 1.5 x 109/L

Platelets ≥ 75 x 109/L

Hemoglobin (Hgb) ≥ 8 g/dL

Serum creatinine < 1.5 mg/dL and /or calculated creatinine clearance (using 
Cockcroft-Gault formula) ≥ 30 mL/min

Total bilirubin ≤ 1.5 x ULN except for patients with Gilbert’s syndrome who may 
only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN

Aspartate transaminase (AST) ≤ 3 x ULN, except for patients with liver metastasis, 
who are only included if AST ≤ 5 x ULN

Alanine transaminase (ALT) ≤ 3 x ULN, except for patients with liver metastasis, 
who are only included if ALT ≤ 5 x ULN

Alkaline phosphatase (ALP) ≤ 5.0 x ULN

Serum amylase ≤ 2 x ULN

Serum lipase ≤ ULN

Fasting plasma glucose ≤ 200 mg/dL (≤ 11.1 mmol/L)
8. Patient must have the following laboratory values within normal limits or corrected to 
within normal limits with supplements during screening:

Potassium

Magnesium

Phosphorus

Total calcium (corrected for serum albumin)
9. Patient has life expectancy ≥ 6 weeks.
10. Patient has a WHO performance status 0-2.
11. Patient has the ability to understand and provide signed informed consent.
12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests 
and other study procedures.


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Patients in Arm 1 to 4 must also meet the following inclusion criteria:
13. Patients must have active brain metastases from NSCLC, confirmed by Gadolinium-
enhanced MRI without concomitant leptomeningeal carcinomatosis. Dose of steroids must 
be stable for 5 days before the baseline brain MRI.
Note: An active brain lesion is a lesion free of any local treatment (like stereotactic 
radiosurgery or whole brain radiation). The following lesions are considered active:

A newly diagnosed brain metastasis in a patient who has never received treatment to 
the brain or in a patient with previously treated brain metastases.

A brain lesion previously treated with whole brain radiation will only be considered 
active when there is an unequivocal size increase in its solid component (cystic 
component of the lesion is not considered for progression determination) compared to 
the first available post-radiation radiological evaluation.

An enlarging brain lesion previously treated with SRS will only be considered active 
when the nature of the enlargement is clearly attributed to the tumoral component of 
the lesion and not to the radiation effect.
Patients in Arm 5 must also meet the following inclusion criteria:
14. Patients must be diagnosed with leptomeningeal carcinomatosis. The diagnosis requires 
either documentation of the presence of malignant cells detected at the cytological 
examination of the cerebrospinal fluid or a serious suspicion of leptomeningeal 
carcinomatosis, supported by imaging findings typical of LC on the Gadolinium-enhanced 
MRI of the brain or spine (in this latter case, the determination of the presence of 
malignant cells in CSF cytology is strongly recommended).
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patient with a history of treatment with ceritinib. Patient with known hypersensitivity to 
any of the excipients of ceritinib (microcrystalline cellulose, mannitol, crospovidone, 
colloidal silicon dioxide and magnesium stearate).
2. Patients who need whole brain radiation to control the brain metastases. Patients will not 
be eligible unless treated brain lesions are progressive or new brain lesions are observed 
since the post whole brain radiation therapy MRI.
3. In case active brain lesions (single or not) require local treatment but other active brain 
lesions do not and are not treated, patients will be excluded only if the local treatment 
(neurosurgical treatment or Stereotactic Radiosurgery ) for the brain metastases is 
conducted within 2 weeks prior to starting study drug. Patients must have recovered from 
relevant toxicities related to these procedures to grade ≤ 1(CTCAE v 4.03) prior to 
receiving the first dose of study drug.
4. Planning of any brain local treatment (including but not limited to surgery, stereotactic 
radiosurgery, whole brain radiation, intrathecal chemotherapy) following the 
administration of the first dose of study drug.
5. Patient who has received thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting 
the study treatment or patients who have not recovered from radiotherapy-related 
toxicities. For all other anatomic sites (including radiotherapy to thoracic vertebrae and 


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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 the first dose of study drug is allowed.
6. Patient has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 
4 weeks prior to the first dose of 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 patients can receive study treatment ≥1 week after the 
procedure.
7. Patient with a concurrent malignancy or history of a malignant disease other than 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.
8. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event 
(within 6 months), such as:

Unstable angina within 6 months prior to screening.

Myocardial infarction within 6 months prior to screening.

History of documented congestive heart failure (New York Heart Association 
functional classification III-IV).

Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without anti-
hypertensive medication. Initiation or adjustment of antihypertensive medication (s) is 
allowed prior to screening.

Ventricular arrhythmias.

Supraventricular and nodal arrhythmias not controlled with medication.

Other cardiac arrhythmia not controlled with medication.

Corrected QT (QTcF) > 470 ms using Fridericia’s correction on the screening ECG
(as mean of triplicate ECGs).
9. Patient has impairment of GI function or GI disease that may significantly alter the 
absorption of ceritinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
or malabsorption syndrome).
10. Patient receiving treatment with medications that meet one of the following criteria and 
that cannot be discontinued at least 1 week prior to the start of treatment with ceritinib and 
for the duration of the study (Appendix 1):

Strong inhibitors or strong inducers of CYP3A4/5.

Medications with a low therapeutic index that are primarily metabolized by 
CYP3A4/5 and/or CYP2C9.

Medications with a known risk of prolonging the QT interval or inducing Torsades de 
Pointes.
11. Patient is currently receiving treatment with warfarin sodium (Coumadin®) or any other 
coumarin-derivative anticoagulants.
12. Patient is receiving unstable or increasing doses of corticosteroids. If patients are on 
corticosteroids for endocrine deficiencies or tumor-associated symptoms (non-CNS), dose 


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must have been stabilized (or decreasing) for at least 5 days before first dose of study 
treatment. Note: Dose of steroids must be stable for 5 days before the baseline brain MRI.
13. Patient is receiving treatment with any enzyme-inducing anticonvulsant (Appendix 1) that 
cannot be discontinued at least 1 week before first dose of study treatment, and for the 
duration of the study. Patients on non enzyme-inducing anticonvulsants are eligible.
14. Patient is pregnant or nursing (lactating) woman.
15a.
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 3 months after stopping medication. 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 tubal ligation at least six 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). The vasectomized male 
partner should be the sole partner for that subject

Use of oral, injected or implanted 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 stable on the same pill for a 
minimum of 3 months before taking study treatment.
16. Sexually active males unless they use a condom during intercourse while taking the drug 
and for 3 months after the last dose of ceritinib treatment. Male patients should not father 
a child for 3 months after the last dose of ceritinib treatment. A condom is required to be 
used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
17. Patient has other severe, acute, or chronic medical conditions including uncontrolled 
diabetes mellitus or psychiatric conditions or laboratory abnormalities that in the opinion 
of the investigator may increase the risk associated with study participation, or that may 
interfere with the interpretation of study results.
18. Patient has history of interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis (i.e., affecting activities of daily living or 
requiring therapeutic intervention).
19. Patient has a history of pancreatitis or a history of increased amylase or lipase that was
due to pancreatic disease.
20. Patient has been previously enrolled in the treatment phase of any ceritinib clinical study, 
regardless of which treatment group the patient was allocated or randomized to.


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6
Treatment
6.1
Study treatment
For this study, the term “investigational or study drug” refers to LDK378 (ceritinib). All 
dosages prescribed and dispensed to the patient and all dose changes during the study must be 
recorded on the Dosage Administration Record electronic Case Report Form (eCRF).
LDK378 will be provided and supplied by Novartis. LDK378 is supplied as 150 mg hard 
gelatin capsules as individual open label patient supply. LDK378 will be dosed on a flat scale 
of 750 mg/day and not be adjusted to body weight or body surface area.
A complete cycle of treatment is defined as 28 days of once daily treatment of LDK378
(ceritinib).
6.1.1
Dosing regimen
LDK378 (ceritinib) will be administered orally once daily at a dose of 750 mg (five 150 mg 
capsules) on a continuous dosing schedule. The treatment period will start on Cycle 1 Day 1.
Each study site will be supplied with LDK378 by Novartis. LDK378 is supplied as 150 mg 
hard gelatin capsules as individual patient supply, packaged in bottles. Medication labels for 
the globally provided study treatment (LDK378) will comply with legal regulations of each 
country and be printed in local language. The storage conditions for the study treatment will 
be described on the medication label. LDK378 will be dispensed by the pharmacist or 
designee at the investigator’s institution.
Patients will self-administer LDK378 on an outpatient basis. The investigator must instruct 
the patient to take the study drug exactly as prescribed.
The general dose and treatment schedule of the study treatments are listed in Table 6-1.

All patients should take LDK378 daily at approximately the same time each day in the 
morning.
 

Patients should take LDK378 on an empty stomach (i.e. fast from food and drink, except 
water) at least 1 hour before or 2 hours after a light meal. Each dose of LDK378 should be 
taken with a glass of water and consumed over as short a time as possible (i.e. not slower 
than 1 capsule every 2 minutes).

Patients should be instructed to swallow whole capsules and not to chew or open them.

If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose.

Patients should be instructed not to make up missed doses or partial doses (i.e. when the 
entire dose is not taken as instructed). A missed or partial dose will be defined as a case 
when the full dose is not taken within 8 hours after the approximate time of the usually 
daily dosing. That day's dose (or part remaining dose) should be omitted and the patient 
should continue treatment with the next scheduled dose on the following day.


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Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or Regimen
LDK378
Gelatin capsule for oral use
750 mg (5 x 150 mg / 
capsule)
Once daily (28 day / cycle)
6.1.2
Guidelines for continuation of treatment
For guidelines for dose modification of treatment, refer to Section 6.3.
6.1.3
Treatment duration
Patients will continue ceritinib until they experience any of the following:

Disease progression (radiologically documented according to RECIST 1.1 in the brain, 
outside of the brain or both and confirmed by the investigator). Ceritinib therapy will 
continue until progressive disease has been confirmed by the investigator if clinically 
acceptable (exceptions to the discontinuation of study treatment after PD being confirmed
by the investigator are described below). If the investigator does not determine disease 
progression, the patient should continue receiving the study drug unless there is a medical 
need (i.e., rapid progression or clinical deterioration) for an immediate change in therapy

Unacceptable toxicity that precludes further treatment

Start of a new anti-cancer therapy

Pregnancy

Treatment is discontinued at the discretion of the investigator or patient

Lost to follow-up

Death

Study terminated by Sponsor
Exceptions to the discontinuation of study treatment after progressive disease (PD) being 
confirmed by the investigator are:

In case of isolated brain progression with controlled disease outside of the brain, patients 
may resume treatment with study drug after appropriate treatment of the brain lesion if:


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
Brain lesions are demonstrated to be controlled by gadolinium-enhanced MRI and if 
patient is neurologically stable within the last 2 weeks prior to the re-initiation of 
study drug.

The disease outside of the brain remains controlled prior to re-initiation of study drug. 
A new tumor assessment will be repeated if the last one available is older than 4 
weeks.

Time interval between last dose and re-initiation of study drug does not exceed 8 
weeks.

Patient will continue to be followed for safety and efficacy assessments as per 
schedule of assessment.

If patient had PD outside of the brain (with minimally symptomatic or no PD in the brain) 
but still derives clinical benefit from ceritinib following investigator’s judgment, patient 
may continue study drug and continue to be followed for safety and efficacy assessments
as per schedule of assessment.
In both cases, all imaging data acquired during tumor assessments conducted after PD has 
been confirmed by the investigator will continue to be submitted to the designated imaging 
vendor who will send it to the BIRC for review. In such cases, patients must complete the 
EOT visit only after permanent discontinuation of ceritinib.
If the patient had PD both intracranially and extracranially but still derives clinical benefit 
from ceritinib following investigator’s judgment, patient may continue study drug and 
continue to be followed for safety assessments as per schedule of assessment.
6.2
Dose escalation guidelines
Not applicable to this study.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patients to continue the study treatment. Any changes in 
ceritinib administration must be recorded on the Dosage Administration Record eCRF.
General guidelines for dose modifications for toxicities other than those listed 
in Table 6-3:
For grade 1 and tolerable grade 2 treatment-related toxicities, patients may continue at the 
current dose of study treatment. For intolerable grade 2 treatment-related toxicities, dosing 
should be interrupted until resolution to grade 1 or lower followed by dose reduction to the 
next dose level.
For grade 3 or grade 4 treatment-related toxicity that is not considered by the investigator to 
be life-threatening, patients should interrupt study treatment until resolution to grade 1 or 
lower; then study treatment may continue following a dose reduction to the next dose level, if, 
in the opinion of the Investigator, the patient continues to experience clinical benefit. For any 


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grade 3 or 4 treatment-related toxicity that is considered by the investigator to be life-
threatening, permanently discontinue study treatment.
More detailed ceritinib dose modification guidelines for selected toxicities are described in
Section 6.3.3 and Table 6-3. Any planned variance from these guidelines in view of patient 
safety must first be discussed with the sponsor unless there is an urgent need for action.
All dose modifications, interruptions or discontinuations must be based on the worst 
preceding toxicity as graded by the NCI Clinical Toxicity Criteria (NCI-CTCAE version 4.03).
6.3.2
Treatment interruption and treatment discontinuation
If the administration of ceritinib is temporarily interrupted for reasons other than toxicity, then 
treatment with ceritinib may be resumed at the same dose. The same applies if the patient 
experiences an unacceptable toxicity not specifically described in Table 6-3, provided this 
toxicity resolved to ≤ CTCAE grade 1.
If the treatment with ceritinib is withheld due to toxicity, scheduled visits and all assessments 
should continue to be performed (with the exception of the dosing of the withheld study drug), 
as described in Table 7-1.
If the treatment with ceritinib dosing is withheld for more than 28 consecutive days (counting 
from the first day when a dose was missed), due to treatment-related toxicity, then ceritinib 
should be permanently discontinued except in cases where the investigator believes the patient 
continues to derive clinical benefit. In such cases, treatment with ceritinib may be resumed at 
a lower dose. See Section 6.1.3 for exception in case of isolated brain progression with 
controlled disease outside of the brain.
Patients whose treatment is temporarily interrupted or permanently discontinued due to a 
study drug related AE or an abnormal laboratory value must be followed until resolution or 
stabilization of the event, whichever comes first, including all study assessments appropriate 
to monitor the event. Detailed guidelines for follow-up of study drug related AEs or abnormal 
laboratory values must be followed as described in Section 6.3.4.
All patients will be followed for safety until 30 days after the last dose of ceritinib. Patients 
whose treatment is temporarily interrupted or permanently discontinued due to an AE or 
abnormal laboratory value must be followed until resolution or stabilization of the event, 
whichever comes first, including all study assessments appropriate to monitor the event.
6.3.3
Criteria for ceritinib dose modifications
A ceritinib dose reduction will follow the guidelines described in Table 6-2. For each patient, 
a maximum of 3 dose modifications (in 150 mg decrements per reduction) is allowed after 
which the patient must be discontinued from treatment with ceritinib. Once the dose of 
ceritinib has been reduced, it cannot be re-escalated. If a patient continues treatment with 
ceritinib after RECIST-defined PD as determined by the investigator, the criteria for dose 
modification will also apply.


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Table 6-2
Dose reduction steps for ceritinib
Ceritinib dose levels
Dose* and schedule
Starting dose level
750 qd continuously
Dose level – 1
600 qd continuously
Dose level – 2
450 qd continuously
Dose level – 3
300 qd continuously **
*Dose reduction should be based on the worst preceding toxicity per NCI-CTCAE version 4.03
**Dose reduction below 300 mg/day is not allowed. If a dose reduction below 300 mg/day is required, the patient 
should be permanently discontinued from Ceritinib
Guidelines for dose modification and dose interruption of ceritinib are described in Table 6-3.


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Table 6-3
Criteria for dose reduction, interruption and re-initiation of ceritinib treatment
Worst toxicity (CTCAE 4.03 Grade)*
Dose Modifications for ceritinib
HEMATOLOGICAL
Neutropenia (ANC)
Grade 1 (ANC < LLN - 1.5 x 109/L)
Grade 2 (ANC < 1.5 and ≥ 1.0 x 109/L)
Grade 3 (ANC < 1.0 and ≥ 0.5 x 109/L)
Recommendation: Maintain dose level
Grade 4 (ANC < 0.5 x 109/L)
Mandatory: Omit dose until resolved to ≤ Grade 2, then it is recommended:
If resolved in ≤ 7 days, to maintain dose level
If resolved in > 7 days, to 1 dose level
Febrile neutropenia
(ANC < 1.0 x 109/L, with a single temperature of ≥ 38.3 °C or a sustained 
temperature of ≥38 °C for more than one hour )
Mandatory: Omit dose until clinically resolved and neutropenia ≤ Grade 2, then 1 dose 
level
Thrombocytopenia
Grade 1 (PLT < LLN - 75 x 109/L)
Grade 2 (PLT < 75 and ≥ 50 x 109/L)
Recommendation: Maintain dose level
Grade 3 (PLT < 50 and ≥25 x 109/L)
Mandatory: Omit dose until resolved to ≤ Grade 2, then it is recommended:
If resolved in ≤ 7 days, to maintain dose level
If resolved in > 7 days, to 1 dose level
Grade 4 (PLT < 25 x 109/L)
Mandatory: Omit dose until resolved to ≤ Grade 2, then 1 dose level
HEPATIC
Alkaline phosphatase and/or Gamma-glutamyl transpeptidase (GGT)
Isolated elevations of any grade
Recommendation: Maintain dose level
Total Bilirubin**
(for patients with Gilbert Syndrome these dose modifications apply to changes in direct [conjugated] bilirubin only)
Grade 1 (> ULN and ≤ 1.5 x ULN)
Recommendation: Maintain dose level with liver function test (LFTs)*** monitored as per 
protocol
Grade 2 (> 1.5 and ≤ 3.0 x ULN) with ALT or AST ≤ 3.0 x ULN
Mandatory: Omit dose until resolved to ≤ Grade 1, then it is recommended:
If resolved in ≤ 7 days, to maintain dose level
If resolved in > 7 days, to 1 dose level


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Worst toxicity (CTCAE 4.03 Grade)*
Dose Modifications for ceritinib
Grade 3 (> 3.0 and ≤ 10.0 x ULN) with ALT or AST ≤ 3.0 x ULN
Mandatory: Omit dose until resolved to ≤ Grade 1, then it is recommended:
If resolved in ≤ 7 days, to 1 dose level
If resolved in 7 days, to discontinue patient from ceritinib
Grade 4 (> 10.0 x ULN)
Mandatory: Permanently discontinue patient from ceritinib
AST or ALT
Grade 1 (> ULN and ≤ 3.0 x ULN)
Recommendation: Maintain dose level with LFTs*** monitored per protocol
Grade 2 (> 3.0 and ≤ 5.0 x ULN) without total bilirubin elevation to > 2.0 x 
ULN
Recommendation: Maintain dose level with LFTs*** monitored per protocol
Grade 3 (> 5.0 and ≤ 20.0 x ULN) without total bilirubin elevation to > 2.0 x 
ULN
Mandatory: Omit dose until resolved to ≤ Grade 1, then 1 dose level
Grade 4 (> 20.0 x ULN) without total bilirubin elevation to > 2.0 x ULN
Mandatory: Omit dose until resolved to ≤ Grade 1, then 1 dose level
AST or ALT and concurrent Total bilirubin
AST or ALT > 3.0 x ULN with total bilirubin > 2.0 x ULN in the absence of 
cholestasis or hemolysis
Mandatory: Permanently discontinue patient from ceritinib
Refer to Section 6.3.4.2 for additional follow-up
RENAL
Serum creatinine
Grade 1 (>1 and ≤1.5 x baseline; >ULN and ≤ 1.5 x ULN)
Recommendation: Maintain dose level
Grade 2 (> 1.5 and ≤ 3 x baseline; >1.5 and ≤3.0 x ULN)
Recommendation: Omit dose until resolved to ≤ Grade 1, then it is recommended:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then 1 dose level
Grade 3 (>3.0 x baseline; > 3.0 and ≤ 6.0 x ULN)
Mandatory: Omit dose until resolved to ≤ Grade 1, then 1 dose level
Grade 4 (> 6.0 x ULN)
Mandatory: Permanently discontinue patient from ceritinib
PANCREATIC
Amylase and/or lipase elevations (in the absence of clinical symptoms)
Grade 1 (> ULN and ≤1.5 x ULN)
Recommendation: Maintain dose level
Grade 2 (>1.5 - 2.0 x ULN)
Recommendation: Maintain dose level
Grade ≥3 (> 2.0 x ULN) 
Mandatory: Omit dose until resolved to ≤ Grade 1, then 1 dose level
Note: Withhold ceritinib for acute onset of new or progressive unexplained abdominal symptoms, such as severe pain or vomiting; perform diagnostic procedures
(e.g., abdominal CT scan or ultrasound) to exclude pancreatic pathology.


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Worst toxicity (CTCAE 4.03 Grade)*
Dose Modifications for ceritinib
GASTROINTESTINAL
Diarrhea****
Grade 1
Recommendation: Maintain dose level but adjust anti-diarrhea treatment
Grade 2 (despite maximal anti-diarrheal medication)
Recommendation: Omit dose until resolved to ≤ Grade 1, then maintain dose level.
If diarrhea returns as ≥ Grade 2, then omit dose until resolved to ≤ Grade 1, then ↓ 1 dose 
level
Grade 3 (despite maximal anti-diarrheal medication)
Mandatory: Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level
Grade 4 (despite maximal anti-diarrheal medication)
Mandatory: Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level
Nausea*****
Grade 1 or 2
Recommendation: Maintain dose level but adjust anti-emetic treatment
Grade 3 (despite standard anti-emetics)
Mandatory: Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level
Vomiting*****
Grade 1
Recommendation: Maintain dose level but adjust anti-emetic treatment
Grade 2 (despite standard anti-emetics)
Recommendation: Omit dose until resolved to ≤ Grade 1, then maintain dose level.
If vomiting returns as ≥ Grade 2, then suspend dose until resolved to ≤ Grade 1, then ↓ 1 
dose level.
Grade 3 (despite standard anti-emetics)
Mandatory: Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level
Grade 4 (despite standard anti-emetics)
Mandatory: Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level
METABOLIC
Any Grade hypophosphatemia
Recommendation: Treatment with phosphate supplements as clinically indicated and 
maintain dose level
Persistent hyperglycemia (glucose > 250 mg/dL, despite minimization of 
dose of steroids and optimal anti-hyperglycemic therapy)
Recommendation: Omit dose until hyperglycemia is adequately controlled, then resume 
ceritinib at ↓ 1 dose level
If adequate hyperglycemic control cannot be achieved with optimal medical management, 
permanently discontinue patient from ceritinib.
GENERAL DISORDERS
Fatigue (asthenia)
Grade 1 or 2
Recommendation: Maintain dose level
Grade 3
Recommendation: If grade 3 fatigue resolves to Grade 2 in ≤ 7 days, maintain dose level
If grade 3 fatigue lasts > 7 days, omit dose until resolved to ≤ Grade 2 and then dose 
level


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Worst toxicity (CTCAE 4.03 Grade)*
Dose Modifications for ceritinib
PULMONARY
Notes:
●
Recommendation: Withhold ceritinib for acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever and during 
diagnostic workup for pneumonitis/ILD.
●
During evaluation of potential grade 2, 3, and 4 pneumonitis, if an infectious etiology is confirmed (i.e., pneumonia) and pneumonitis is excluded, ceritinib dosing 
may resume at current dose level after the pneumonia resolves.
PNEUMONITIS
Any Grade treatment-related ILD/pneumonitis
Mandatory: Permanently discontinue patient from ceritinib
CARDIAC
Electrocardiogram QT corrected (QTc) interval prolonged******
Grade 1 (QTc 450-480 ms)
Grade 2 (QTc 481-500 ms)
Recommendation: Maintain dose level
Grade 3 (QTc ≥ 501 ms on at least two separate ECGs)
Mandatory: Omit dose until QTc is < 481ms, then ↓1 dose level
- Assess the quality of the ECG recording and the QT value and repeat if needed
Repeat ECG in 24 hours, or less, as clinically indicated; continue monitoring as clinically 
indicated until QTc < 481 ms
In addition:
-Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug treatment
- Review concomitant medication use for drugs with the potential to increase the risk of 
drug exposure related to QT prolongation
- Consider collecting 
 sample and record time and date of last study 
drug intake
After resumption of dosing:
-Repeat ECGs 7 days after dose resumption for all patients who had therapy interrupted 
due to QTc ≥ 501 ms.
Grade 4 (QTc ≥ 501 or > 60 ms change from baseline and Torsades de 
pointes or polymorphic ventricular tachycardia or signs/symptoms of 
serious arrhythmia)
Mandatory: Permanently discontinue patient from ceritinib


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Worst toxicity (CTCAE 4.03 Grade)*
Dose Modifications for ceritinib
Bradycardia
Grade 1 or 2
Recommendation: Omit dose until recovery to asymptomatic bradycardia (for patients with 
grade 2 bradycardia) and to a heart rate ≥ 50 bpm or to the baseline heart rate.
Evaluate concomitant medications known to cause bradycardia, and adjust the dose of 
ceritinib.
Exception: patients who entered the study with grade 1 bradycardia need only omit dose if 
bradycardia worsens to grade 2
Grade 3
Grade 4 (in patients taking a concomitant medication also known to cause 
bradycardia or a medication known to cause hypotension)
Mandatory: Omit dose until recovery to asymptomatic bradycardia or to a heart rate ≥ 50 
bpm or baseline heart rate
If the concomitant medication can be adjusted or discontinued, resume ceritinib at ↓ 1 dose 
level with frequent monitoring
Grade 4 (in patients who are not taking a concomitant medication also 
known to cause bradycardia or known to cause hypotension)
Mandatory: Permanently discontinue ceritinib.
* Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. All dose modifications should be based on the worst preceding toxicity.
** If Grade 3 or 4 hyperbilirubinemia is due to the indirect (non-conjugated) component only, and hemolysis as the etiology has been ruled out as per institutional 
guidelines (e.g., review of peripheral blood smear and haptoglobin determination), then ↓ 1 dose level and continue treatment at the discretion of the Investigator.
***LFTs include albumin, ALT, AST, total bilirubin, alkaline phosphatase and GGT
**** Dose modifications apply to patients who experience diarrhea despite appropriate antidiarrheal medication. This medication should be started at the first sign of 
abdominal cramping, loose stools or overt diarrhea (see Section 6.3.4.7)
***** Dose modifications apply to patients who experience nausea and/or vomiting despite appropriate antiemetic medication. This medication should be started at the first 
sign of nausea and/or vomiting (see Section 6.3.4.6.)
****** QTcF should be used when evaluating QT prolongation.


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6.3.4
Follow-up for toxicities
An unscheduled visit should be performed in all cases below where toxicity monitoring is 
recommended more frequently than defined by the schedule of assessments (Table 7-1).
6.3.4.1
Guidelines for the follow-up of laboratory hematologic abnormalities
In case of any occurrence of febrile neutropenia, neutropenia ≥ grade 3 or thrombocytopenia ≥ 
grade 3, tests must be performed weekly (or more frequently if clinically indicated) until the 
event resolves to ≤ grade 2. Subsequent monitoring must be performed every 4 weeks. See 
Table 6-4.
6.3.4.2
Guidelines for the follow-up of laboratory liver abnormalities and 
potential drug-induced liver injury (DILI) cases
In patients with any clinically relevant laboratory liver abnormality, as defined below, hepatic 
toxicity monitoring must include ALL of the following liver function tests (LFTs): albumin, 
ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), alkaline phosphatase 
and GGT. Note: for patients with Gilbert Syndrome, total and direct bilirubin must be 
monitored, but intensified monitoring applies to changes in direct bilirubin only.
In case of any occurrence of ALT/AST/total bilirubin increase to grade 2 the LFTs must be 
monitored weekly (or more frequently if clinically indicated) until the event resolves to ≤ 
grade 1. Thereafter monitoring must be continued every other week (or more frequently if 
clinically indicated) for two additional cycles (e.g. 8 weeks). If there is no recurrence of grade 
2 ALT/AST/total bilirubin elevations during this period, subsequent monitoring must be 
performed every 4 weeks. For patients with liver metastasis and grade 2 AST/ALT at baseline, 
increased monitoring is required for grade 3/4 AST/ALT; follow guidelines for grade 3 or 4 
AST/ALT.
In case of any occurrence of ALT/AST/total bilirubin increase to grade 3 or 4, LFTs must be 
monitored weekly (or more frequently if clinically indicated) until the event resolves to ≤ 
grade 1. Thereafter monitoring must be continued every other week (or more frequently if 
clinically indicated) for four additional cycles (e.g. 16 weeks). If there is no recurrence of ≥ 
grade 2 ALT/AST/total bilirubin elevations during this period, subsequent monitoring must be 
performed every 4 weeks.
Patients who discontinue study treatment due to liver toxicity must be monitored weekly (or 
more frequently if clinically indicated) until the event resolves to ≤ grade 1 or stabilization 
occurs (no CTCAE grade change over 4 weeks). Refer to Table 6-4.
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential Drug Induced Liver Injury (DILI), and should be considered as 
clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:


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
For patients 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 patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: ALP elevation > 2.0 x ULN with R value (ALT/ALP in x ULN) < 2 in patients without 
bone metastasis, or elevation of ALP liver fraction in patients 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), hepatocellular (R >5), or mixed (R >2 and <5) liver injury).
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing 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.

Laboratory tests should include ALT, AST, albumin, creatinine kinase, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.

A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.

Further testing for acute hepatitis A, B, C or E infection and liver imaging (eg, biliary tract) 
may be warranted.

 

Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
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”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented.
6.3.4.3
Guidelines for the follow-up of laboratory renal abnormalities
In case of any occurrence of serum creatinine grade 2, tests must be performed weekly (or 
more frequently if clinically indicated) until the event resolves to ≤ grade 1. Subsequent 
monitoring must be performed every 4 weeks.
In case of any occurrence of serum creatinine ≥ grade 3, tests must be performed twice weekly 
(or more frequently if clinically indicated) until the event resolves to ≤ grade 1. Subsequent 
monitoring must be performed every 4 weeks. See Table 6-4.


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6.3.4.4
Guidelines for the follow-up of laboratory pancreatic abnormalities
In case of any occurrence of lipase or amylase increase to grade 3 or 4, both lipase and 
amylase must be monitored weekly (or more frequently if clinically indicated) until the event 
resolves to ≤ grade 1 (or to baseline).
After resumption of dosing, monitoring must be continued weekly (or more frequently if 
clinically indicated) for one additional cycle (i.e. 4 weeks). If there is no recurrence of ≥ grade 
2 amylase or lipase elevations during this period, subsequent monitoring must be performed 
every 4 weeks.
Patients who discontinue study treatment due to pancreatic toxicity must be monitored weekly 
(or more frequently if clinically indicated) until the event resolves to ≤ grade 1 or stabilization 
occurs (no CTCAE grade change over 4 weeks) (refer to Table 6-4).
If amylase and/or lipase elevations are accompanied by new or progressive unexplained 
abdominal symptoms such as severe pain or vomiting, withhold ceritinib, assess for history of 
alcohol consumption and biliary tract disorders, review concomitant medications, and perform 
diagnostic procedures (e.g., abdominal CT scan or ultrasound) to exclude pancreatic 
pathology.
See also dose modification guidelines described in Table 6-3.
6.3.4.5
Guidelines for monitoring pneumonitis
Monitor patients for pulmonary symptoms indicative of pneumonitis. In addition, withhold 
ceritinib for acute onset of new or progressive unexplained pulmonary symptoms, such as 
dyspnea, cough and fever and during diagnostic workup for pneumonitis/ILD.
See also dose modification guidelines described in Table 6-3.
6.3.4.6
Guidelines for the treatment of study drug induced nausea and 
vomiting
Nausea and vomiting are among the most frequently reported AEs following treatment with 
ceritinib and patients must therefore be closely monitored for the appearance of these AEs.
The investigator should consider/investigate potential concomitant medication, food or 
comorbidity driven causes of nausea and/or vomiting and remedy these causes if possible (e.g. 
discontinuation of concomitant medication, dietary modification, treatment of comorbidity).
Individualized supportive and anti-emetic treatment should be initiated, as appropriate, at the 
first signs and/or symptoms of these AEs. In patients with vomiting, the patient should be 
monitored for signs of dehydration and instructed to take preventive measures against 
dehydration.
Concomitant medication for the treatment of nausea and/or vomiting should follow local 
practice and the investigator’s best judgment. For moderate emetogenic drugs, such as
ceritinib, International Guidelines for anti-emetic treatment recommend early treatment with 
5-HT3-receptor antagonists (5-HT3RAs).
Dose adaptation of ceritinib in case of treatment related nausea and/or vomiting must follow 
the guidelines presented above in Table 6-3.


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6.3.4.7
Guidelines for the treatment of study drug induced diarrhea
The investigator should consider/investigate potential concomitant medication, food or 
comorbidity driven causes of diarrhea (including infectious causes) and remedy these causes 
if possible (e.g. discontinuation of concomitant medication, dietary modification, treatment of 
comorbidity).
The patient should be monitored for signs of dehydration and instructed to take preventive 
measures against dehydration as soon as diarrhea occurs. Antidiarrheal medication must be 
initiated at the first sign of abdominal cramping, loose stools or overt diarrhea. Concomitant 
medication for the treatment of diarrhea should follow local practice and the investigator’s 
best judgment and may follow the “Recommended guidelines for the treatment of cancer 
treatment-induced diarrhea” (Benson et al 2004). For example:

For uncomplicated diarrhea (grade 1 or 2 without complicating signs or symptoms), 
loperamide given at a standard dose (e.g. initial administration of 4 mg, then 2 mg every 
2-4 hours, maximum of 16 mg/day), along with oral hydration and dietetic measures 
should be considered. Note: complicating signs or symptoms include: moderate to severe 
cramping, decreased performance status, fever, neutropenia, frank bleeding or dehydration.

For complicated diarrhea (all grade 3 or 4, grade 1-2 with complicating signs or 
symptoms), management should involve intravenous (IV) fluids, and consider treatment 
with octreotide (at starting dose of 100 to 150 µg SC tid or 25 to 50 µg IV) and antibiotics 
(e.g. fluoroquinolone) should be given.
Dose adaptation of ceritinib in case of treatment related diarrhea must follow the guidelines 
presented above in Table 6-3.
6.3.4.8
Guidelines for treatment of hypophosphatemia
In the phase I study 
, there were 9 cases of grade 3 
hypophosphatemia in all dose groups, one of which was a DLT that contributed to the MTD 
determination – this patient was able to continue ceritinib at the same dose. One patient in the 
750 mg group had a grade 3 hypophosphatemia that resolved after dose adjustment or 
interruption; in the remaining 8 cases, patients were able to continue therapy without dose 
modification. Hypophosphatemia was a commonly reported AE (6.3%), regardless of 
relationship to ceritinib treatment. Therefore, phosphate levels will be checked at baseline and 
during treatment. In cases of hypophosphatemia at baseline, phosphate supplements should be 
started before treatment with ceritinib. For any grade of hypophosphatemia during the study, 
treatment with phosphate supplements should be given as clinically indicated and the ceritinib 
dose can be maintained.


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Table 6-4
Follow-up evaluations for selected toxicities
Toxicity
Follow-up evaluation*
Investigations 
(hematologic)
Febrile neutropenia, neutropenia or thrombocytopenia ≥ CTCAE Grade 3
Test weekly (or more frequent) until ≤ Grade 2
Subsequent monitoring must be performed every 4 weeks
Investigations 
(hepatic)
Total bilirubin/ALT/AST Grade 2: (patients with liver metastasis and grade 2 AST/ALT at 
baseline increased monitoring required for grade 3 ALT/AST. Follow guidelines for grade 
3 or 4 AST/ALT
Test weekly (or more frequent) until ≤ Grade 1
Thereafter, continue to test every 2 weeks (or more frequent) for 2 cycles (8 weeks). If 
no recurrence of ≥ Grade 2 event, continue monitoring every cycle (4 weeks)
Total bilirubin/ALT/AST ≥ Grade 3:
Test weekly (or more frequent) until ≤ Grade 1
Thereafter, continue to test every 2 weeks (or more frequent) for 4 cycles (16 weeks). If 
no recurrence of ≥ grade 2 event, continue monitoring every cycle (4 weeks)
Discontinuation due to liver toxicity:
Test weekly (or more frequent) until ≤ Grade 1 or stabilization
Investigations (renal)
Serum creatinine Grade 2:
Test weekly (or more frequent) until Grade 1
Thereafter, test every cycle (4 weeks)
Serum creatinine ≥ Grade 3:
Tests twice weekly (or more frequent) until ≤ Grade 1
Thereafter, test every cycle (4 weeks)
Investigations 
(pancreatic)
Amylase/lipase ≥ Grade 3 :
Test weekly (or more frequently) until ≤ Grade 1. After resumption of dosing, continue to 
test weekly for one additional cycle 4 weeks). If no recurrence of ≥ grade 2 event, 
continue monitoring every cycle (4 weeks) 
*Note: this table refers to the evaluation schedule only. Refer to Table 6-3 for dose modifications required for 
applicable toxicities.
6.3.5
Anticipated risks and safety concerns of the study treatment
Appropriate eligibility criteria and specific dose modification and stopping rules are included 
in this protocol. Recommended guidelines for prophylactic or supportive treatment for 
expected toxicities, including management of study-drug induced AEs, e.g., diarrhea are 
provided in Section 6.3.4. Refer to preclinical toxicity and or clinical data found in the 
[Investigator Brochure].
6.4
Concomitant medications
In general, the use of any concomitant medication/therapy deemed necessary for the care of 
the patient (e.g. such as anti-emetics, anti-diarrhea) is permitted (see Section 6.4.1), except 
when specifically prohibited (see Section 6.4.2).
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications including herbal/natural medications 
(excluding study treatment and prior antineoplastic treatments and blood transfusions), 
surgeries and procedures (including physical therapy) administered within 28 days prior to the 
first dose of administration of ceritinib through 30 days after the last dose of ceritinib will be 
recorded in the Concomitant Medications or Surgical and Medical Procedures eCRF, 
respectively. Medications include not only physician prescribed medications, but also all 
over-the-counter medications, herbal medications (prohibited, see Section 6.4.2.8), food and 
or vitamin supplements.


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6.4.1
Permitted concomitant therapy
6.4.1.1
Corticosteroids
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to induce 
CYP3A enzymes, thereby increasing the risk of reducing ceritinib drug exposure to sub-
therapeutic levels.
If possible, systemic corticosteroid treatment should not be given during the study, except for:

Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye 
drops or local injections (e.g. intra-articular);

If clinically indicated, corticosteroid therapy such as dexamethasone or prednisone may be 
used to control CNS tumor associated symptoms. All efforts will be made to minimize the 
dose of corticosteroids to what is strictly needed and to decrease dose as soon as possible. 
If dose needs to be increased to control CNS tumor associated symptoms, all efforts will 
be made to stabilize (or decrease) the dose for at least 5 days before the first dose of study 
treatment. Note: Dose of steroids must be stable for 5 days before the baseline brain MRI.
Every effort should be made to maintain a stable (or decreasing) dose of steroids in 
subsequent brain MRIs.
6.4.1.2
Bisphosphonates
The use of bisphosphonates is allowed regardless of indication provided patients have been on 
stable doses optimally for at least 4 weeks prior to the start of treatment. Patients requiring 
initiation of bisphosphonate treatment during the course of the study should be evaluated for 
progressive disease, unless disease progression is excluded and clearly documented in the 
patients’ source documentation. The same guidelines apply to the use of denosumab for the 
treatment of bone metastatic disease.
No drug-drug interaction is expected between ceritinib and bisphosphonates as the two drugs 
are eliminated through different elimination pathways. Bisphosphonates are not inhibitors of 
human CYP450 enzymes involved in the metabolism of LDK378 and do not undergo 
metabolism in vivo.
6.4.1.3
Drugs that are metabolized by CYP450 enzymes
In vitro drug metabolism studies show that the metabolism of ceritinib is mediated by 
CYP3A4/5. Ceritinib is a time-dependent CYP3A4/5 inhibitor and is also a potent reversible 
inhibitor of CYP2A6, 2E1, 2C9 and 3A4/5 and may consequently increase exposure to drugs 
metabolized by these enzymes at clinically relevant concentrations. Clinical studies have not 
yet been performed to confirm the potential effect of ceritinib on substrate drugs metabolized 
by these enzymes in patients. The risk for CYP2A6 and CYP2E1 is largely mitigated by the 
low potential for drugs metabolized by these enzymes to be co-administered with ceritinib.
Concomitant treatment of ceritinib with weak inhibitors or inducers of CYP3A4/5 is permitted.
Caution is advised when ceritinib is co-administered with drugs that are moderate inhibitors 
or inducers of CYP3A4/5 (Table 14-2 of Appendix 1). Duration of concomitant treatment 
should be kept as short as possible (e.g. less than 1 week), or completely avoided whenever 
possible. Patients receiving such medications must be monitored closely for any potentiation 


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of toxicity or decrease of clinical benefit due to any individual concomitant medications, and 
may require dose titration or adjustment. Note that co-administration of ceritinib with strong 
inhibitors or inducers of CYP3A4/5 is prohibited (refer to Section 6.4.2.5).
Concomitant treatment of ceritinib with medications known to be metabolized by CYP2C9 
and CYP3A4 is allowed with caution (Table 14-2 of Appendix 1), except for drugs which 
have narrow therapeutic index/sensitive substrates for these CYP isoforms (Table 14-1 of 
Appendix 1).
6.4.1.4
Non-enzyme inducing anti-epileptic drugs
Non-enzyme inducing anti-epileptic medication (Non-EIAED) is allowed. See Table 14-3 of 
Appendix 1.
6.4.1.5
Palliative radiotherapy and surgery
Local radiotherapy for analgesic purposes or for lytic lesions at risk of fracture, or for 
progression of the brain metastases may be carried out if required. If palliative radiotherapy is 
initiated after start of study treatment, the reason for its use must be clearly documented and 
progression as per RECIST 1.1 must be assessed and documented.
For patients with a RECIST-documented PD into the brain that are candidates to continue 
study drug beyond progression (see Section 6.1.3
for exceptions to study drug 
discontinuation), as determined by the Investigator, may undergo radiotherapy and/or surgical 
resection as palliative localized therapy to treat metastatic lesions.
In any situation, when radiotherapy or surgery is required, ceritinib should be held for at least 
4 days prior to radiotherapy and at least 1 day prior to any surgery and may be resumed ≥3 
days after completing radiotherapy or minor surgery, and ≥2 weeks after major surgery.
6.4.1.6
Gastric protection agents
The use of gastric protection agents including antacids, H2-antagonists, and proton pump 
inhibitors (PPIs; Table 14-2 of Appendix 1) is allowed. However, PPIs should be used with 
caution due to the theoretical effects of long-acting pH elevating agents (i.e., prolonged acid 
suppression) on reducing ceritinib absorption. When the concurrent use of a H2-antagonist or 
an antacid with ceritinib is necessary, the H2 blocker must be administered 10 hours before or 
2 hours after the ceritinib dose, and the antacid must be administered 2 hours before or 2 
hours after the ceritinib dose. Time restrictions for the concurrent use of PPIs and ceritinib are 
not applicable due to the long-acting effects of PPIs on gastric pH (i.e., separation of doses 
will not likely impact this interaction).
6.4.2
Prohibited concomitant therapy
6.4.2.1
Other anticancer therapy
Anticancer therapy (chemotherapy, targeted therapy, biologic therapy or radiation therapy 
(except palliative radiotherapy and palliative surgery as described in Section 6.4.1.5), and 
anti-cancer surgery) other than the study treatment must not be given to patients while they 
are enrolled in the treatment portion of the trial. If such agents are required then the patient 


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must be permanently discontinued from the treatment portion of the study. See Section 6.1.3
for exceptions in case of isolated brain progression with controlled disease outside of the brain.
6.4.2.2
Other investigational therapies
Other investigational therapies must not be used while the patient is on the study.
6.4.2.3
Warfarin and coumarin derivatives
Therapeutic doses of warfarin sodium or any other coumarin-derivative anticoagulant are not 
permitted. Ceritinib is an inhibitor of 2C9, the major metabolizing enzyme of warfarin. A 
clinically relevant increase in warfarin exposure is possible.
6.4.2.4
Enzyme inducing anti-epileptic drug
Use of EIAEDs is not permitted. Refer to Table 14-3 of Appendix 1 for a list of prohibited 
EIAED.
If a patient is currently taking an EIAED, he/she must have discontinued the EIAED therapy 
for at least 1 week prior to starting study drug.
If a patient was previously on a non-EIAED and needs to permanently change anticonvulsant 
agent but cannot change to another non-EIAED, the patient will be taken off ceritinib.
6.4.2.5
Strong CYP3A inhibitors and inducers
In vitro metabolism studies suggest that oxidative metabolism of ceritinib is predominantly 
mediated by CYP3A4/5.
Strong inhibitors or inducers of CYP3A4/5 are prohibited. Patients receiving concomitant 
medications known to strongly inhibit and/or induce CYP3A4/5 that are deemed medically 
necessary should be excluded from the study. Refer to Table 14-1 of Appendix 1 for a list of 
these medications. Please note that this list may not be comprehensive.
6.4.2.6
Medications that are CYP2C9 and CYP3A4/5 substrates with narrow 
therapeutic index
Ceritinib is a potent inhibitor of drugs metabolized by CYP2C9 and CYP3A4/5 in vitro. 
Because of the potential risk for drug-drug interactions, using medications known to be 
metabolized by these enzymes and that have a narrow therapeutic index is not permitted 
concomitantly with ceritinib. Refer to Table 14-1 of Appendix 1 for a list of these medications. 
Please note that this list may not be comprehensive.
6.4.2.7
Herbal medications
Herbal preparations/medications are not allowed throughout the study, as a potential drug-
drug interaction is always possible. These herbal medications include, but are not limited to: 
St. John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng.
Patients should stop using herbal medications at least 7 days prior to first dose of study 
treatment.


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6.4.2.8
Medications that may prolong the QT interval or have a known risk of 
inducing Torsades de Pointes
Ceritinib has potent activity on the hERG channel with an IC50 of 0.4 μM. There were no
ceritinib-related effects in vivo in monkeys at doses as high as 100 mg/kg (human equivalent 
dose [HED] of 1950 mg).
Serial ECGs were collected following a single dose and at steady-state to evaluate the effect 
of ceritinib on the QT interval in an open-label, dose-escalation, and expansion study 
. A total of 304 patients were treated with ceritinib doses ranging from 50 
to 750 mg with 255 patients treated with ceritinib 750 mg. One of 304 patients (<1%) was 
found to have a QTc >500 msec and 10 patients (3.3%) had an increase from baseline 
QTc >60 msec. A central tendency analysis of the QTc data at average steady-state 
concentrations demonstrated that the upper bound of the 2-sided 90% CI for QTc was 16 
msec at ceritinib 750 mg. A pharmacokinetic/pharmacodynamic analysis suggested 
concentration-dependent QTc interval prolongation.
Concomitant administration of ceritinib with drugs known to have a high risk of increasing 
the QTc interval, and drugs known to increase the QTc interval that are also primarily 
metabolized by CYP3A4/5 should be avoided. Concomitant use of ceritinib and any 
medication included in Table 14-4 of Appendix 1 titled “List of prohibited QT prolonging 
drugs” (i.e., drugs that are generally accepted by the Qtdrugs.org Advisory Board of the 
Arizona CERT to have a known risk of causing Torsades de Pointes) is not permitted.
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned 
when the patient is first enrolled for screening and is retained as the primary identifier for the 
patient 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 patient number suffixed to it, so that each patient is numbered uniquely across the 
entire database. Upon signing the informed consent form, the patient is assigned to the next 
sequential Subject No. available to the investigator through the Oracle Clinical Remote Data 
Capture interface.
At the pre-screening and screening visit, the investigator or designated staff will contact the 
Interactive Response Technology (IRT) system and provide the requested identifying 
information for the patient to register them into the IRT system. 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 patient fails to start treatment for any reason, the reason will be entered into 
the Screening Disposition eCRF page.
If the patient is a screen failure, IRT should be notified within 2 working days that the patient 
was a screen failure and was not enrolled.


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6.5.2
Treatment assignment
Following completion of pre-screening and screening procedures the IRT system must again 
be contacted to verify patient eligibility, allocation to one of the five study arms and enroll the 
patient in the study before the patient receives the first dose on C1D1.
The Investigator or his/her delegate will contact the IRT and confirm that the patient fulfills 
all the inclusion/exclusion criteria. The IRT will be used to link the patient to a study arm and 
will specify unique medication numbers for the first packages of study treatment to be 
dispensed to the patient.
All patients will receive the same treatment regimen regardless of the arm to which they are 
allocated. A cycle of treatment is defined as 28 days of once daily treatment of ceritinib in all 
study arms.
6.5.3
Treatment blinding
Not applicable.
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drug as per protocol. Study drug will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF.
The site pharmacy will receive open label medication containing LDK378 capsules. 
Medication will be dispensed based on the appropriate dose with instructions from the 
investigator on how to take the medication.
Table 6-5
Preparation and dispensing
Study treatments
Dispensing
Preparation
LDK378
Capsules including instructions for administration are 
dispensed by study personnel on an outpatient basis.
Patients will be provided with adequate supply of study 
treatment for self-administration at home until at least 
their next scheduled study visit.
Not applicable


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6.6.2
Drug supply and storage
Study treatments must be received by designated personnel 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, the study treatment should be stored 
according to the instructions specified on the drug labels and in the [Investigator’s Brochure].
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit.
Compliance will be assured by administrations of the study treatment under the supervision of 
investigator or his/her designee.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out and as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
6.6.3.3
Handling of other study treatment
Not applicable.
6.6.4
Disposal and destruction
The study drug 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.


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7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X” the visits when they are 
performed. Each treatment cycle is 28 days (the 28 days cycle length is fixed regardless of 
whether the dose of ceritinib is withheld). All visits are to be scheduled according to the 
appropriate number of calendar days from Cycle 1 Day 1 of study drug administration. A visit 
window of +/- 1 day in Cycle 1 and +/- 3 days in Cycle 2 onwards is allowed. Imaging 
evaluations may be performed +/-7 days of the due date of the assessment. Note: If treatment 
with ceritinib is withheld at any time during the study, all study visits, safety and 
efficacy assessments should continue according to the appropriate number of calendar 
days from Cycle 1 Day 1 as per the schedule of assessments.
All data obtained from these assessments must be supported in the patients’ source 
documentation. No eCRF will be used as a source document. The table indicates which 
assessments produce data to be entered into the database (D) or remain in the source 
documents only (S).


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Table 7-1
Visit evaluation schedule
Category
Protocol 
section
Screening Phase
(Day -28 to Day -1)
Treatment Phase
Post treatment follow 
up phase
Survival 
follow-up 
phase
Cycle 1
(28 days)
Subsequent 
cycles
(28 days)
End of 
treatment 
(EOT)
Visit name
Molecular
Pre-
Screening
General 
Screening
Brain 
specific 
evaluation
(Day -14 
to Day -1)
Cycle 
1
Day 1
Cycle 
1
Day 8
Cycle 
1
Day 
15
Cycle 2 Day 
1; Cycle 3 
Day 1; etc.
End of 
treatment 
visit
Tumor 
follow-
up if no 
PD - at 
the EOT
End of 
post-
treatment 
evaluation 
(Study 
Phase 
completion)
Survival 
follow-
up
Obtain molecular pre-
screening ICF and IRT 
registration 
D
7.1.2.
X
Collect tumor biopsy, 
either archival or new 
tumor sample for ALK
rearrangement testing 
D
7.1.1.
X
ALK test performed on 
archival specimen or in 
newly obtained tumor 
tissue biopsy at NVS 
central laboratory
D
7.1.1.1.
X
Confirmation of ALK 
status by central 
laboratory
D
7.1.1.
7.1.2.
X
Obtain Main Informed 
Consent and IRT 
registration
D
7.1.2.
X* (see 
footnote) 
X


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Category
Protocol 
section
Screening Phase
(Day -28 to Day -1)
Treatment Phase
Post treatment follow 
up phase
Survival 
follow-up 
phase
Cycle 1
(28 days)
Subsequent 
cycles
(28 days)
End of 
treatment 
(EOT)
Visit name
Molecular
Pre-
Screening
General 
Screening
Brain 
specific 
evaluation
(Day -14 
to Day -1)
Cycle 
1
Day 1
Cycle 
1
Day 8
Cycle 
1
Day 
15
Cycle 2 Day 
1; Cycle 3 
Day 1; etc.
End of 
treatment 
visit
Tumor 
follow-
up if no 
PD - at 
the EOT
End of 
post-
treatment 
evaluation 
(Study 
Phase 
completion)
Survival 
follow-
up
End of Phase Disposition 
Page
D
7.1.
X
Screening Phase 
Disposition (eCRF)
X
End of 
Treatment 
Phase 
Completion 
(eCRF)
X
End of Post-
Treatment 
Follow-Up
Demography
D
7.1.2.2.
X
Inclusion/
exclusion criteria
D
5.1.
5.2.
X
Eligibility check
D
6.5.1.
X
Allocation to study arms 
via IRT
D
6.5.2.
X
Relevant medical history/ 
current medical 
conditions
D
7.1.2.3.
X
Smoking history
D
7.1.2.3.
X
Diagnosis and extent of 
cancer
D
7.1.2.3.
X
Prior antineoplastic 
therapies (meds, surgery, 
radiation)
D
7.1.2.3.
X


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Category
Protocol 
section
Screening Phase
(Day -28 to Day -1)
Treatment Phase
Post treatment follow 
up phase
Survival 
follow-up 
phase
Cycle 1
(28 days)
Subsequent 
cycles
(28 days)
End of 
treatment 
(EOT)
Visit name
Molecular
Pre-
Screening
General 
Screening
Brain 
specific 
evaluation
(Day -14 
to Day -1)
Cycle 
1
Day 1
Cycle 
1
Day 8
Cycle 
1
Day 
15
Cycle 2 Day 
1; Cycle 3 
Day 1; etc.
End of 
treatment 
visit
Tumor 
follow-
up if no 
PD - at 
the EOT
End of 
post-
treatment 
evaluation 
(Study 
Phase 
completion)
Survival 
follow-
up
Prior and concomitant 
medication
D
7.1.2.3.
Continuous
X
X
Neurological examination
S
7.2.2.5.
X
X
X
X
X
X
X
Physical examination
S
7.2.2.1.
X
X
X
X
X
Performance status 
(WHO)
D
7.2.2.4.
X
X
X
X
Height
D
7.2.2.3.
X
Weight
D
7.2.2.3.
X
X
X
X
Vital signs
D
7.2.2.2.
X
X
X
X
X
X
Hematology
D
7.2.2.6.1.
X
X
X
X
X
Blood chemistry
D
7.2.2.6.2.
X
X
X
X
X
Urinalysis (dipstick) with 
micro-analysis
D
7.2.2.6.3.
X
Serum pregnancy test
D
7.2.2.6.4.
X
Urine pregnancy test 
(prior to dosing)
D
7.2.2.6.4.
X
X
X
Coagulation
D
7.2.2.6.5.
X


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Category
Protocol 
section
Screening Phase
(Day -28 to Day -1)
Treatment Phase
Post treatment follow 
up phase
Survival 
follow-up 
phase
Cycle 1
(28 days)
Subsequent 
cycles
(28 days)
End of 
treatment 
(EOT)
Visit name
Molecular
Pre-
Screening
General 
Screening
Brain 
specific 
evaluation
(Day -14 
to Day -1)
Cycle 
1
Day 1
Cycle 
1
Day 8
Cycle 
1
Day 
15
Cycle 2 Day 
1; Cycle 3 
Day 1; etc.
End of 
treatment 
visit
Tumor 
follow-
up if no 
PD - at 
the EOT
End of 
post-
treatment 
evaluation 
(Study 
Phase 
completion)
Survival 
follow-
up
CT scan or MRI of chest 
and abdomen
D
7.2.1.
X
X
Starting on 
C3D1 then 
every 2nd 
cycle (i.e. 
every 8 
weeks)
X
X
Every 8 
weeks 
following 
EOT 
until PD
Whole body bone scan
D
7.2.1.
X
Gadolinium-enhanced 
brain MRI
D
7.2.1.
X
X
Starting on 
C3D1 then 
every 2nd 
cycle (i.e. 
every 8 
weeks)
X
X
Every 8 
weeks) 
following 
EOT 
until PD


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Category
Protocol 
section
Screening Phase
(Day -28 to Day -1)
Treatment Phase
Post treatment follow 
up phase
Survival 
follow-up 
phase
Cycle 1
(28 days)
Subsequent 
cycles
(28 days)
End of 
treatment 
(EOT)
Visit name
Molecular
Pre-
Screening
General 
Screening
Brain 
specific 
evaluation
(Day -14 
to Day -1)
Cycle 
1
Day 1
Cycle 
1
Day 8
Cycle 
1
Day 
15
Cycle 2 Day 
1; Cycle 3 
Day 1; etc.
End of 
treatment 
visit
Tumor 
follow-
up if no 
PD - at 
the EOT
End of 
post-
treatment 
evaluation 
(Study 
Phase 
completion)
Survival 
follow-
up
CT scan or MRI of other 
metastatic sites (e.g. 
neck, spine, pelvis, etc.).
Localized bone CT scan, 
MRI or x-ray (for any 
lesions identified on the 
whole body bone scan 
that are not visible on the 
chest/abdomen CT scan 
or MRI).
Photography (for any skin 
lesions)
D
7.2.1.
X
(if clinically indicated)
X
Starting on 
C3D1 then 
every 2nd 
cycle (i.e. 
every 8 
weeks) only 
if positive at 
baseline or 
clinically 
indicated
X
Only if 
positive at 
baseline or 
clinically 
indicated
X
Every 8 
weeks) 
following 
EOT 
until PD; 
only if 
positive 
at 
baseline 
or 
clinically 
indicated
Ceritinib administration
D
6.1.1.
Continuous daily dosing
Adverse events
D
8.1.
Continuous
ECG
D
7.2.2.7.1.
X
X
X
X
X
X
Meal record
D
7.2.3.1.
C2D1


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Category
Protocol 
section
Screening Phase
(Day -28 to Day -1)
Treatment Phase
Post treatment follow 
up phase
Survival 
follow-up 
phase
Cycle 1
(28 days)
Subsequent 
cycles
(28 days)
End of 
treatment 
(EOT)
Visit name
Molecular
Pre-
Screening
General 
Screening
Brain 
specific 
evaluation
(Day -14 
to Day -1)
Cycle 
1
Day 1
Cycle 
1
Day 8
Cycle 
1
Day 
15
Cycle 2 Day 
1; Cycle 3 
Day 1; etc.
End of 
treatment 
visit
Tumor 
follow-
up if no 
PD - at 
the EOT
End of 
post-
treatment 
evaluation 
(Study 
Phase 
completion)
Survival 
follow-
up
Healthcare Resource 
Utilization
D
7.2.6.
X - Continuous
Antineoplastic therapies 
since discontinuation of 
study treatment
D
7.1.6.3.
X
X
Every 
12 
weeks
Survival assessment
D
7.1.6.3.
X
Every 
12 
weeks


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Category
Protocol 
section
Screening Phase
(Day -28 to Day -1)
Treatment Phase
Post treatment follow 
up phase
Survival 
follow-up 
phase
Cycle 1
(28 days)
Subsequent 
cycles
(28 days)
End of 
treatment 
(EOT)
Visit name
Molecular
Pre-
Screening
General 
Screening
Brain 
specific 
evaluation
(Day -14 
to Day -1)
Cycle 
1
Day 1
Cycle 
1
Day 8
Cycle 
1
Day 
15
Cycle 2 Day 
1; Cycle 3 
Day 1; etc.
End of 
treatment 
visit
Tumor 
follow-
up if no 
PD - at 
the EOT
End of 
post-
treatment 
evaluation 
(Study 
Phase 
completion)
Survival 
follow-
up
* Patients that have locally available source documentation with confirmed ALK positive rearrangement by the FDA approved Vysis ALK Break Apart FISH Probe Kit 
(Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria) may directly proceed with signing the Main informed consent form (ICF) and conducting 
evaluations associated with the screening visit to determine eligibility before initiating treatment with ceritinib. These patients will still have to be first registered in IRT as 
having undergone Molecular pre-screening phase before proceeding to screening phase in IRT.
Patients without locally available source documentation (as described above) must sign pre-screening ICF and wait for the central laboratory results of the ALK 
rearrangement status before entering the screening phase of the CLDK378A2205 study.


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7.1.1.1
Tumor sample requirements for central laboratory analysis
Re-pre-screening of patients with an ALK-negative status confirmed by a Novartis-designated 
central laboratory may be allowed only after discussion with the sponsor on a case by case 
basis. The ALK status (positive or negative) will be registered in IRT upon final confirmation 
from the Novartis-designated central laboratory.
 


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7.1.2
Screening
Rescreening of patients during the screening period may be allowed and laboratory 
parameters may be retested within the 28-day screening window (day -28 to day -1) period for 
an individual patient 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 urine pregnancy test) unless deemed clinically necessary 
by investigator and/or required as per local institutional policies. The cardiac eligibility 
criteria should be assessed with the central ECG report. Tumor imaging assessments will be 
performed at screening between Day -28 and Day -1 except for brain specific eligibility 
evaluations which will be performed between Day -14 and Day -1.


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Imaging assessments other than imaging of the brain or spine imaging already completed 
during the regular work-up of the patient 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.
Brain or spine MRI already completed during the regular work-up of the patient within 14
days prior to start of treatment, including before signing the main study ICF can be considered 
as the baseline images for this study.
7.1.2.1
Eligibility screening
Following registering in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT 
system. Allocation to one of the five study arms will also be registered via IRT. Please refer to 
and comply with the detailed guidelines in the IRT manual.
7.1.2.3
Patient demographics and other baseline characteristics
Data to be collected on patient characteristics at pre-screening and screening include:

Demography (including: date of birth, age, patient initials, gender, childbearing potential, 
race and ethnicity, or as allowed by local regulations)


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
Relevant medical history

History of smoking

NSCLC diagnosis and extent of disease, including:

Date of diagnosis of NSCLC

ALK status documentation

Site of active disease

Characteristics of disease

Concomitant molecular alteration when available (and results of all the tests 
performed even if wild type)

Prior antineoplastic therapies (medications, radiation, surgeries)

Prior and Concomitant Medications, surgical and medical procedures

Neurological examination and use of steroids to control CNS symptoms
All other medications taken within 28 days before the first dose of study treatment is 
administered must be recorded on the Prior and Concomitant medication eCRF page and 
updated on a continual basis if there is new change to the medication.
7.1.3
Treatment period
The study treatment phase begins on Cycle 1, Day 1 with the first administration of ceritinib. 
Treatment with ceritinib will continue until the patient experiences disease progression (in the 
brain, outside of the brain or both) as determined by the investigator according to RECIST 1.1, 
unacceptable toxicity that precludes further treatment, pregnancy, start of a new anticancer 
therapy, discontinues treatment at the discretion of the patient or investigator, lost to follow-
up, death, or study is terminated by Sponsor. Exceptions to the discontinuation of study drug 
upon confirmation of PD by the investigator are detailed in Section 4.1.2.2.
Patients will be assessed as per visit schedule in Table 7-1.
Visit windows of ± 1 calendar day will be applicable to scheduled study assessments during 
Cycle 1. Visit windows of ± 3 days from scheduled study assessments will apply during and 
beyond Cycle 2. The only exception is imaging assessments, which have a ± 7 day window at 
all scheduled time points.
7.1.4
End of treatment visit including study completion or discontinuation
A patient will be defined as on the study if they are continuing to have any study data 
collected, i.e. if the patient is being treated with ceritinib, is in efficacy follow-up after 
discontinuing ceritinib or is in survival follow-up.
7.1.4.1
Study treatment discontinuation
Patients may voluntarily withdraw from study treatment at any time. If a patient decides to 
discontinue from the study treatment, the investigator must make every effort (e.g., telephone, 
e-mail, letter) to determine the primary reason for this decision and record this information in 
the patient’s chart and on the appropriate eCRF pages. They may be considered withdrawn if 


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they state an intention to withdraw, fail to return for visits, or become lost to follow-up for 
any other reason.
The investigator should discontinue study treatment for a given patient if he/she believes that 
continuation would be detrimental to the patient’s well-being.
Patients must permanently stop the study treatment if one of the following occurs:

Pregnancy

Study Terminated by Sponsor

Patient/guardian decision

Physician decision

Lost to follow-up

Death
Patients may permanently stop the study treatment for one of the following reasons:

Progression of disease (radiological as assessed by investigator)

AEs

Non-compliance with study treatment

Technical Problems

Protocol deviation
Patients who become pregnant during the trial must be withdrawn (Section 8.4). Patients who 
become pregnant must cease all tumor assessments regardless of whether or not they 
developed Progressive Disease.
Patients who discontinue study treatment during the treatment phase should be scheduled for a 
visit as soon as possible and within 7 days after the last dose of study treatment, at which time 
all of the assessments listed for the EOT visit will be performed. If a patient withdraws from 
treatment at a study visit, EOT assessments do not need to be repeated. An End of Treatment 
Phase Disposition eCRF page should be completed, giving the date and reason for stopping 
ceritinib treatment.
Exceptions to the discontinuation of study treatment after progressive disease (PD) being 
confirmed by the investigator are:

In case of isolated brain progression with controlled disease outside of the brain, patients 
may resume treatment with study drug after appropriate treatment of the brain lesion if:

Brain lesions are demonstrated to be controlled by gadolinium-enhanced MRI and if 
patient is neurologically stable within the last 2 weeks prior to the re-initiation of 
study drug

The disease outside of the brain remains controlled prior to re-initiation of study drug. 
A new tumor assessment will be repeated if the last one available is older than 4 
weeks.

Time interval between last dose and re-initiation of study drug does not exceed 8 
weeks

Patient will continue to be followed for safety and efficacy assessments as per 
schedule of assessment.


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
If patient had PD outside of the brain (with minimally symptomatic or no PD in the brain) 
but still derives clinical benefit from ceritinib following investigator’s judgment, patient 
may continue study drug and continue to be followed for safety and efficacy assessments
as per schedule of assessment.
In both cases, all imaging data acquired during tumor assessments conducted after PD has 
been confirmed by the investigator will continue to be submitted to the designated imaging 
vendor who will send it to the BIRC for review. In such cases, patients must complete the 
EOT visit only after permanent discontinuation of ceritinib.
If the patient had PD both intracranially and extracranially but still derives clinical benefit 
from ceritinib following investigator’s judgment, patient may continue study drug and 
continue to be followed for safety assessments as per schedule of assessment.
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following 
the last dose of study treatment.
If patients refuse to return for these visits or are unable to do so, every effort should be made 
to contact them or a knowledgeable informant by telephone to determine the survival status.
Patients who discontinue study treatment should be considered withdrawn from the study after 
the final visit assessments are performed or when it is clear that the patient will not return for 
these assessments.
If a patient discontinues study treatment, but continues study assessments, (e.g. during post 
treatment follow up phase as detailed in Table 7-1), the patient remains on study until such 
time as he/she completes protocol criteria for ending study assessments. At that time, the 
reason for study completion should be recorded on the End of Post Treatment (Study Phase 
Completion) Disposition eCRF page.
The Investigator must contact the IRT to register the patient's discontinuation from treatment.
Patients who discontinue study treatment should enter the survival follow-up period or 
continue tumor assessments when appropriate. Tumor assessments will continue until 
investigator’s determined disease progression, patient withdraws consent from tumor 
assessments, patient is lost to follow-up, death or study terminated by Sponsor.
7.1.4.2
Replacement policy
Patients lost to follow-up or withdrawing consent from the study without observed PFS events
will be censored for the primary analysis and will not be replaced.
7.1.5
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not allow any 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 patient’s decision to withdraw his/her consent 
and record this information.


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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 patient are not allowed unless safety findings require 
communication 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 
assessments table.
Novartis will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and ROW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to 
applicable legal requirements.
7.1.6
Follow up for safety evaluations
7.1.6.1
Safety follow up
All patients will be followed for AEs and SAEs for at least 30 days following the last dose of 
study treatment at the end of treatment phase.
At the end of this period, the investigator should assess and discuss with the patient any AE 
observed/concomitant medication taken since discontinuation of study treatment.
Patients whose treatment is permanently discontinued due to an AE (clinical or based on 
abnormal laboratory value) must be followed until resolution or stabilization of the event, 
whichever comes first. In case of an abnormal laboratory value, blood tests should be repeated 
until resolution or stabilization.
7.1.6.2
Post-treatment follow-up
All patients who discontinued treatment during the treatment phase for reasons other than 
death, lost to follow-up, pregnancy or disease progression as per investigator assessment 
(Section 7.1.3) will continue tumor assessments as per Table 7-1 (every 8 weeks) thereafter 
until PD as per investigator assessment, withdrawal of consent or death. Once the patient 
ceases tumor follow-up, the reason for completion should be recorded on the End of Post 
Treatment Disposition (Study Phase Completion) eCRF page.
7.1.6.3
Survival follow-up
All patients who had PD as per investigator assessment, have started a new anti-neoplastic 
therapy, and/or withdrew consent from further study assessments will subsequently be 
followed for survival information every 12 weeks until death, lost to follow-up or withdrawal 
of consent for survival follow-up. The investigator or his designee will collect this survival 


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information and any new anti-neoplastic therapies for all patients until the final survival 
analysis.
Follow-up can be done via a phone contact. Antineoplastic therapies will be captured on the 
'Antineoplastic therapies since discontinuation of study treatment' eCRF page following the 
last dose of the study treatment.
7.1.7
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g., dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition eCRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Whole body and extracranial tumor response will be assessed by investigator and by BIRC 
according to the Novartis guideline version 3.1 (Appendix 2) based on RECIST 1.1 
(Eisenhauer et al 2009).
Additionally, intracranial tumor response will be assessed by investigator and by BIRC using 
modified RECIST 1.1 and the Response Assessment in Neuro-Oncology (RANO) criteria for 
high grade gliomas (Wen et al 2010) (Appendix 3).
Imaging data will be centrally collected and checked for quality by an imaging Contract 
Research Organization (CRO) designated by Novartis. Patient neurological status, 
corticosteroid dose and cytology results, as well as, information regarding prior interventions 
and pre-existing radiographic findings that mimic metastatic disease at baseline/screening, 
should also be transmitted to the imaging CRO for review by BIRC. Further details regarding 
transmission of the information can be found in the imaging CRO site operations manual.
The imaging assessment collection plan is presented in Table 7-2.


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Table 7-2
Imaging assessment collection plan
Procedure
Screening/Baseline
During Treatment/Follow-up
CT or MRI of Chest and Abdomen
Mandated
Mandated at week 8 on Cycle 3 
Day 1, then every 2nd cycle (i.e., 
every 8 weeks)
Gadolinium enhanced MRI of the brain
Mandated
Mandated at week 8 on Cycle 3 
Day 1, then every 2nd cycle (i.e., 
every 8 weeks)
Whole body bone scan
Mandated
If clinically indicated
●
Spine MRI (for suspected LC patients 
only)
●
CT scan or MRI of other metastatic 
sites (e.g., neck, pelvis, etc.)
●
Localized bone CT scan, MRI or x-ray 
(for any lesions identified on the whole 
body bone scan that are not visible on the 
chest/abdomen (and pelvis if applicable) 
CT scan or MRI)
●
Photography (for any skin lesions)
Only if clinically indicated
At week 8 on Cycle 3 Day 1, then 
every 2nd cycle (i.e., every 8 weeks) 
only if positive at baseline or 
clinically indicated
7.2.1.1
Baseline imaging (+/- photography) assessment
Imaging assessments will be performed at screening/baseline Day -28 to Day -1 prior to Cycle 
1 Day 1 except for brain specific eligibility evaluations which will be performed between Day 
-14 and Day -1.
Any imaging assessments other than imaging of the brain or spine imaging already completed 
during the regular work-up of the patient 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 brain or spine imaging assessments already completed during the regular work-up of the 
patient within 14 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 first dose of study drug cannot be considered 
baseline images. The following assessments are required at screening/baseline:

CT scan or MRI of chest and abdomen

Gadolinium enhanced MRI of the brain (and spine for suspected LC patients only)

Whole body bone scan

Additional CT scan or MRI of other metastatic sites (e.g., neck, pelvis, etc.)

Localized bone CT scan, MRI or x-ray (for any lesions identified on whole body bone 
scan not visible on chest/abdomen (and pelvis if applicable) CT scan or MRI)

Photography (for any skin lesions) if clinically significant
If a patient is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts, however if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen 
and pelvis (as applicable) should be performed.


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Gadolinium-enhanced MRI of the brain (and spine for suspected LC patients only) will be 
used at each efficacy assessment time point. If technically possible, slice thickness should 
preferably be 1 mm, but it should not exceed 5 mm.
A whole body bone scan should be performed per institutional standard of care for all patients 
to detect any skeletal metastases present [e.g., Tc-99 bone scan, whole body bone MRI, FDG-
PET or sodium fluoride positron emission tomography (NaF PET)]. Localized CT, MRI or X-
rays should be acquired for all skeletal lesions identified on the screening bone scan, which 
are not visible on the chest, abdomen and pelvis CT/MRI.
If clinically indicated, CT or MRI of other areas (neck, pelvis) of disease as appropriate 
should be performed.
Color photography, including a metric ruler to estimate the size of the lesion, must be 
acquired for all skin lesions present per instructions provided in the photography manual from 
the designated vendor.
Chest x-ray and ultrasound should not be used for lesion evaluation in this study.
Required conditions for baseline tumor assessment
Patients will be allocated into one of the following 5 arms based on investigator assessment at 
baseline:

Arm 1 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously treated with radiation to the brain and with 
prior exposure to an ALKi.

Arm 2 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously untreated with radiation to the brain but with 
prior exposure to an ALKi.

Arm 3 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously treated with radiation to the brain but with no 
prior exposure to an ALKi.

Arm 4 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously untreated with radiation to the brain and with 
no prior exposure to an ALKi

Arm 5 will include any patients with leptomeningeal carcinomatosis with or without 
evidence of active lesion at the baseline Gadolinium-enhanced brain MRI.
Note: Previous treatment with ALK inhibitors other than crizotinib is not allowed in Arms 1, 
2 and 5
An active brain lesion is a lesion free of any local treatment (like stereotactic radiosurgery or 
whole brain radiation). The following lesions are considered active:

A newly diagnosed brain metastasis in a patient who has never received treatment to the 
brain or in a patient with previously treated brain metastases.

A brain lesion previously treated with whole brain radiation will only be considered active 
when there is an unequivocal size increase in its solid component (cystic component of the 


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lesion is not considered for progression determination) compared to the first available 
post-radiation radiological evaluation.

An enlarging brain lesion previously treated with SRS will only be considered active when 
the nature of the enlargement is clearly attributed to the tumoral component of the lesion 
and not to the radiation effect.
Whole body: All tumor assessments conducted at each time point will be used to evaluate the 
response to treatment. Standard RECIST 1.1 will be used at baseline to select target and non-
target lesions located in the brain and outside of the brain and to assess the overall response to 
the treatment.
In the brain: Gadolinium-enhanced MRI of the brain (if technically possible, slice thickness 
should preferably be 1 mm, but it should not exceed 5 mm) will be used at each efficacy 
assessment time point (starting at Week 8 and every 8 weeks thereafter) to evaluate the brain 
lesions. RECIST 1.1 will be modified to allow a specific evaluation of the intracranial 
response to the treatment. The usual criteria to select target lesions will be used but a 
maximum five target lesions located in the brain can be selected at baseline and evaluated at 
each assessment time point. Brain non-target lesions will be recorded at baseline and 
evaluated at each time point. OIRR will be assessed on the brain target lesions, brain non-
target lesions and brain new lesions and will follow the standard RECIST 1.1 criteria for 
response. The RANO criteria will be utilized in conjunction with the RECIST 1.1 criteria 
specifically to evaluate intracranial endpoints in each of arm 1, arm 2, arm 3 and arm 4 for 
patients with active brain lesion at baseline.
Outside of the brain: CT scan or MRI of the chest and abdomen and a whole body bone scan 
will be conducted at baseline. Additionally, localized CT, MRI or X-rays of all skeletal 
lesions identified at screening will be performed if not visible on the chest, abdomen and 
pelvis CT (or MRI). CT scan or MRI of the chest and abdomen will be conducted at each 
tumor assessment time point (starting at Week 8 and every 8 weeks thereafter) along with 
other positive tests at baseline per Table 7-1. Other assessments may be indicated in case of 
clinically suspected progression. RECIST 1.1 will be used to allow a specific evaluation of the 
extracranial response to treatment. Only lesions located outside of the brain will be considered 
for the selection of target and non-target lesions at baseline, and evaluated at each assessment 
time point. OERR will be assessed on the target lesions, non-target lesions and new lesions 
located outside of the brain and will follow the standard RECIST 1.1 criteria for response.
Leptomeningeal carcinomatosis: Gadolinium enhanced MRI of the brain and spine (if 
technically possible, slice thickness should preferably be 1 mm, but it should not exceed 5 
mm) will be used at each assessment time point starting at Week 8 and every 8 weeks 
thereafter. For patient presenting with a baseline leptomeningeal carcinomatosis with 
documented malignant cells in the cerebrospinal fluid, CSF will be collected at a frequency 
determined by local clinical practice unless medically contraindicated.
7.2.1.2
Subsequent imaging for response assessment
Tumor evaluations as described in Table 7-2 should be performed using the same imaging 
modality used at baseline, irrespective of study treatment interruption or actual dosing (see 
Table 7-1).


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Tumor assessment for response determination will be made every 8 weeks starting from Day 
1 of cycle 3 (+/- 7 days window). The 8 weeks interval should be respected regardless of 
whether treatment with ceritinib is temporarily withheld.
Clinical suspicion of disease progression at any time requires a physical examination and 
radiological confirmation to be performed promptly rather than waiting for the next scheduled 
radiological assessment.
Each lesion that is measured at baseline must be measured by the same method (either same 
radiological 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. If an off-
schedule imaging assessment is performed because progression is suspected, subsequent 
imaging assessments should be performed in accordance with the original imaging schedule.
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of oral and IV contrast media. At the 
discretion of the Investigators, FDG-PET scans may be performed to document PD per 
RECIST 1.1 (Appendix 2).
All study imaging (including any off-schedule imaging studies) performed to evaluate 
progression or response should be submitted to the designated imaging vendor for quality 
control and review by the BIRC. If an off-schedule scan is performed for response 
confirmation purposes, subsequent imaging assessments should be performed in accordance 
with the original imaging schedule.
7.2.1.3
Transmission of efficacy data to BIRC
All radiological assessments will be read locally and should be submitted promptly after 
acquisition to the imaging CRO designated by Novartis. 
 
 
 
 
 
 
 
 
 
 
 
 
In case patients have equivocal disease progression according to RECIST 1.1 (in the brain, 
outside of the brain or both) as determined by the investigator, a confirmatory tumor 
assessment should be done at least 4 weeks thereafter. While the investigator is waiting for the 
confirmatory tumor assessment, it is preferable that the patient continues on study treatment 
for as long as it is clinically acceptable. However, during this time, the investigator should do 
whatever is medically necessary for the patient.


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If the investigator does not determine disease progression, the patient should continue 
receiving the study drug unless there is a medical need (i.e., rapid progression or clinical 
deterioration) for an immediate change in therapy.
If the investigator confirms disease progression, then the patient will discontinue study drug 
and subsequent follow-up tumor assessments are no longer required (except in the cases 
described below).
Exceptions to the discontinuation of study treatment after progressive disease (PD) being 
confirmed by the investigator are:

In case of isolated brain progression with controlled disease outside of the brain, patients 
may resume treatment with study drug after appropriate treatment of the brain lesion if:

Brain lesions are demonstrated to be controlled by gadolinium-enhanced MRI and if 
patient is neurologically stable within the last 2 weeks prior to the re-initiation of 
study drug

The disease outside of the brain remains controlled prior to re-initiation of study drug. 
A new tumor assessment will be repeated if the last one available is older than 4 
weeks.

Time interval between last dose and re-initiation of study drug does not exceed 8 
weeks

Patient will continue to be followed for safety and efficacy assessments as per 
schedule of assessment.

If patient had PD outside of the brain (with minimally symptomatic or no PD in the brain) 
but still derives clinical benefit from ceritinib following investigator’s judgment, patient 
may continue study drug and continue to be followed for safety and efficacy assessments
as per schedule of assessment.
In both cases, all imaging data acquired during tumor assessments conducted after PD has 
been confirmed by the investigator will continue to be submitted to the designated imaging 
vendor who will send it to the BIRC for review.
Patients will continue to have scans performed as per protocol (Table 7-1) until investigator’s
assessed disease progression according to RECIST 1.1 inside the brain, outside the brain or 
both.
If the patient had PD both intracranially and extracranially but still derives clinical benefit 
from ceritinib following investigator’s judgment, patient may continue study drug and 
continue to be followed for safety assessments as per schedule of assessment.
7.2.2
Safety and tolerability assessments
Safety will be monitored by the assessments described below as well as the collection of AEs 
at every visit. For details on AE collection and reporting, refer to Section 8. Significant 
findings that were present prior to the signing of informed consent must be included in the 
relevant medical history/current medical conditions page on the patient’s eCRF. Significant 
new findings that begin or worsen after informed consent must be recorded on the Adverse 
Event page of the patient’s eCRF.


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7.2.2.1
Physical examination
Physical examinations will include an examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes and, 
extremities. Information about the physical examination must be present in the source 
documentation at the study center. For the assessment schedule refer to Table 7-1.
Significant findings that were present prior to the signing of informed consent must be 
included in the Medical History page on the patient’s eCRF. Significant new findings that 
begin or worsen after informed consent must be recorded on the Adverse Event page of the 
patient’s eCRF.
7.2.2.2
Vital signs
Vital signs include body temperature, blood pressure and pulse measurements. Blood pressure 
(systolic and diastolic) and pulse should be measured after the patient has been sitting for five 
minutes.
For the assessment schedule refer to Table 7-1.
7.2.2.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured. Height will be measured at screening only. For 
the assessment schedule for weight refer to Table 7-1.
7.2.2.4
Performance status
WHO performance status will be assessed as per the assessment schedule (refer to Table 7-1). 
Assessment of WHO performance status (Table 7-3) will be performed within the time 
windows described above of the scheduled assessment, even if study treatment is being held. 
More frequent examinations may be performed at the investigator’s discretion, if medically 
indicated.
Table 7-3
WHO performance status scale
Score
Performance 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 housework, 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
7.2.2.5
Neurological examination
Baseline neurological examination should evaluate the following:

General appearance, including posture, motor activity and meningeal signs

Mini mental status exam (Folstein et al 1975), including speech observation


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
Cranial nerves testing from Cranial Nerve II to XII

Motor system, including muscle atrophy, tone and power

Sensory system, including position, light touch and sensory function

Reflexes, including deep tendon reflexes, plantar reflexes

Coordination (finger-nose testing, dysdiadokinesia, heel-shin testing), gait and Rhomberg 
test.
The baseline neurological examination will be recorded in the source documentation.
Significant findings that were present prior to the signing of informed consent must be 
included in the Medical History page on the patient’s eCRF.
During the conduct of the study, a more basic neurological examination can be conducted to 
assess the known neurological abnormalities detected at baseline. Significant new findings 
that begin or worsen after informed consent must be recorded on the Adverse Event page of 
the patient’s eCRF.
In case of suspicion of neurological deterioration, the complete neurological examination 
should be conducted and recorded in the source documentation.
7.2.2.6
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 7-1). 
Dipstick urinalysis will be performed locally (unless local institution policies dictate 
otherwise), except in the case of any out of range parameter on scheduled local urinalysis, 
when a urine sample will be sent to central laboratory for further analysis. Laboratory values 
obtained during the Screening phase will be used to assess patient’s eligibility. The time 
windows granted for laboratory evaluations are identical to the corresponding visit time 
windows for each visit (refer to Section 7.1).
The site does not need to wait for the results of centrally-analyzed laboratory assessments 
when an immediate clinical decision needs to be made and in those cases locally unscheduled 
testing may be performed.
Details on the collection, shipment of samples and reporting of results by the central 
laboratory are provided to investigators separately.


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Table 7-4
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, lipase, GGT
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, serum pregnancy test
At subsequent cycles, urinary 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
7.2.2.6.1 Hematology
Hematology assessments of the parameters listed in Table 7-4 will be tested as per the 
schedule of assessments (Table 7-1).
7.2.2.6.2 Clinical chemistry
Blood chemistry assessments of the parameters listed in Table 7-4 will be tested as per the 
schedule of assessments (Table 7-1).
7.2.2.6.3 Urinalysis
Dipstick measurements will be performed as per Table 7-4 and according to the schedule of 
assessments. Any significant findings on dipstick will be followed up with microscopic 
evaluation as per Table 7-4. In the event this is not allowed per institution or local clinical 
practice, site must ensure completion, as well as record of rationale for use and results of local 
lab analysis are available in source documentation and clinical database.
7.2.2.6.4 Pregnancy and assessments of fertility
During screening, a serum pregnancy test will be completed (Day -28 to Day -1). On Cycle 1 
Day 1 prior to dosing and at subsequent cycles and at EOT, urinary pregnancy test (dipstick) 
will be performed. The time windows granted for pregnancy testing are identical to the 
corresponding visit time windows for each visit. Refer to Table 7-1. If local requirements 
dictate otherwise, local regulations should be followed.
Women who are determined not to be of child bearing potential before the study will only be 
tested at screening. When non-child bearing potential status is determined during the study, 
further pregnancy testing will not be continued. Women are considered post-menopausal if 
they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms), and otherwise not of child 
bearing potential if they have had surgical bilateral oophorectomy (with or without 
hysterectomy) or 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 


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level assessment is she considered not of child bearing potential (such testing is not covered 
as part of the study assessments). If local requirements dictate otherwise, local regulations 
should be followed.
The time windows granted for pregnancy testing are identical to the corresponding visit time 
windows for each visit. Refer to Table 7-1.
If a positive pregnancy test is performed in between study visits, the patient must immediately 
notify the investigator.
Male patients must notify the investigator in case their partner is confirmed with positive 
pregnancy test results during the treatment period.
7.2.2.6.5 Coagulation
International normalized ratio (INR) and prothrombin time (PT) or Quick Test will be 
measured at screening only.
7.2.2.7
Cardiac assessments
7.2.2.7.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed as described in Table 7-5.

At the screening visit in triplicate for all patients and

At other defined time points as triplicate ECGs for all patients 
 
 (Table 7-5).
Baseline is defined as the pre-dose assessment on Cycle 1 Day 1 before study drug 
administration.
All ECGs recorded for each time point will be transmitted electronically to a central 
laboratory and will be centrally reviewed by an independent reviewer in a blinded fashion in 
regards to time, and day (i.e., Cycle 1 Day 1, Cycle 2 Day 1) identifiers. Any original ECG 
not transmitted electronically to the central laboratory should be forwarded for central review. 
Review of all ECGs from a particular patient should be performed by a single reader. The 
ECG lead for interval duration measurements should be pre-specified. Baseline and all 
subsequent ECGs should be based on the same lead.
Detailed instructions regarding the ECG collection will be provided to the investigators in a 
separate manual prior to the start of the study. 
 
The triplicate ECGs should be taken approximately 2-4 
minutes apart.
An ECG may be repeated at the discretion of the investigator at any time during the study and 
as clinically indicated. Each ECG tracing should be labeled with the study number, patient 
initials (where regulations permit), patient number, date, and kept in the source documents at 
the study site.


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Table 7-5
ECG collection plan for patients 
(triplicate 
ECGs)
Cycle
Day
Time
ECG Type
Screening
-28 to -1
Anytime
12 Lead
1
1
Predose
12 Lead
1
8
Predose
12 Lead
1
15
Predose
12 Lead
2
1
Predose
12 Lead
2
1
any time between 4 to 10 hr postdose
12 Lead
3
1
Predose
12 Lead
4
1
Predose
12 Lead
5
1
Predose
12 Lead
6
1
Predose
12 Lead
Subsequent cycles and EOT
1
Predose
12 Lead
Clinically significant abnormalities present when the patient signed informed consent should 
be reported on the Medical History eCRF page. Clinically significant findings must be 
discussed with Novartis prior to enrolling the patient in the study. New or worsened clinically 
significant findings occurring after informed consent must be recorded on the Adverse Events 
eCRF page.


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7.2.4
CSF sampling in patients with leptomeningeal carcinomatosis at 
baseline
For patients presenting with a baseline leptomeningeal carcinomatosis (LC), diagnosis must 
be confirmed with documented malignant cells in the cerebrospinal fluid, or if suspected, 
supported by imaging findings on the Gadolinium-enhanced MRI of the brain or spine (in this 
latter case, the determination of the presence of malignant cells in CSF cytology is strongly 
recommended and a CSF sample for cytological evaluation should be taken within the 14 days 
before initiation of study drug at C1D1). Patients with known and documented positive 
cytology at screening do not need to be retested. Samples should be obtained from site of 
disease or initially positive cytology if possible.
During the study CSF will be collected at a frequency determined by local clinical practice 
unless medically contra-indicated and/or deemed to be an unacceptable burden to patient. The 
investigator may determine if more frequent evaluations are needed in case of suspected 
disease progression and/or in accordance with local clinical practice. If there are any signs or 
radiologic or clinical neurological progression, a CSF will be collected if feasible. Clinical 
progression may be determined based on results of cytological or neurological evaluations.
Before any CSF collection, the treating physician should rule out any medical condition that
would prevent the safe conduct of a lumbar puncture, including but not limited to an increased 
intracranial pressure, a thrombocytopenia or a bleeding diathesis, an active infection.


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7.2.6
Resource utilization
Direct collection of health care resource utilization (HCRU) data related to the treatment of 
brain metastases will be collected (such as hospitalization, inpatient and outpatient treatment, 
radiotherapy and radiosurgery).
7.2.7
Patient reported outcomes
Not applicable.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained.
For patients whose ALK status is unknown and who sign the molecular pre-screening ICF, 
AEs which occur after signature of this consent will only be captured if they meet the 
definition of serious as outlined in Section 8.2 and are reported to be causally related to study 
procedures (e.g. an invasive procedure such as biopsy). Once the main study ICF is signed, all 
AEs per the descriptions below will be captured in the Adverse Event eCRF.Abnormal 
laboratory values or test results occurring after informed consent constitute adverse events 
only if they induce clinical signs or symptoms, are considered clinically significant, require 
therapy (e.g., hematologic abnormality that requires transfusion or hematological stem cell 
support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s eCRF. Adverse event monitoring should 
be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose 
of study treatment. 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.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 (dated 14 June 2010). If CTCAE grading does not exist for an 
adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to 
Grades 1 - 4, will be used. CTCAE Grade 5 (death) will not be used in this study but is 
collected as seriousness criteria; rather, information about deaths will be collected though a 
Death eCRF.


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Abnormal laboratory values or test results occurring after signing the ICF constitute adverse 
events only if they induce clinical signs and symptoms, or require therapy, (e.g., any 
hematologic abnormality that requires transfusion of hematological stem cell support) or 
changes in medication(s) are considered clinically significant and should be recorded on the 
Adverse Event eCRF under signs, symptoms or diagnosis associated with them. In addition,
isolated abnormal laboratory values that are considered clinically significant (e.g. cause study 
discontinuation or constitute in and of itself a Serious Adverse Event) should be recorded on 
the Adverse Events eCRF.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine:

The severity grade (CTCAE Grade 1-4)

Its duration (Start and end dates)

Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)

Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)

Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)

Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)

Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
and which seriousness criteria have been met
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines 
for hematological malignancies), should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, 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.


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8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
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
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 patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
For patients with unknown ALK mutational status and who sign the molecular pre-screening 
ICF, SAE collection will start upon signing the molecular pre-screening ICF. SAEs will only 
be reported if the event is suspected to be causally related to a study procedure as assessed by 
the investigator (e.g., an invasive procedure such as biopsy). SAEs will be followed until 
resolution or until clinically relevant improvement or stabilization. If the main ICF is not 
signed (molecular screen failure), SAE collection ends 30 days after the last study related 
procedures.
For patients with known ALK mutational status who sign the main study ICF, SAE collection 
starts at time of main study informed consent whether the patient is a screen failure or not.
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any additional information for the SAE including 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 
should be reported separately as a new event.
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the submission process and requirements for signatures are to be found 
in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, and whether the patient 
continued or withdrew from study participation.
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 Novartis study treatment, an oncology 


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Novartis Chief Medical Office and Patient Safety (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 drug that this SAE has been reported. Suspected 
Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable. This is an open-label study.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis immediately (within 24 hours) of learning of its occurrence. 
Patients who become pregnant during the trial must be withdrawn. The pregnancy will be 
followed up from the estimated date of delivery plus 3 months to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis DS&E. Pregnancy follow-up should be recorded on the 
same form and should include an assessment of the possible relationship to the investigational 
treatment of any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported on the SAE Report Form.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment. A pregnancy outcome informed consent will be provided by Novartis. Consent to 
report information regarding these pregnancy outcomes should be obtained from the mother.
Women of childbearing potential should be advised to use highly effective contraception 
methods while they are receiving study treatment and up to 3 months after treatment has been 
stopped.
If a pregnancy occurs while on study treatment, the newborn will be followed for at least 3 
months.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee (DMC)
Not applicable.


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8.8
Blinded Independent Review Committee (BIRC)
A BIRC will review all the study radiographic and photographic data to determine tumor 
response and progression. The designated imaging vendor will be responsible for assembling 
and managing the BIRC. 
 
 
 
 
 
 
 
 
9
Data collection and management


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9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria 
and documentation of SAEs. Additional checks of the consistency of the source data with the 
eCRFs are performed according to the study-specific monitoring plan.
9.3
Data collection
Electronic Data Capture (EDC) is used for this study. The designated investigator staff will 
enter the data required by the protocol into the electronic Case Report Forms (eCRFs). 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 EDC system 
until they have been trained. Automatic validation programs check for data discrepancies in 
the eCRFs and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator (PI) is responsible for assuring that the data entered into eCRFs is 
complete, accurate, and that entry and updates are performed in a timely manner.
 
 


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In addition, data entered into IRT for screening, enrollment/allocation of study treatment, 
discontinuation, subsequent drug assignment and patient identifiers (i.e. date of birth, gender, 
and patient ID) will be transferred electronically to Novartis as described in the Data Transfer 
Specification for designated IRT vendor.
 
 
 
 
 
 
 
 
 
 
 
 
9.4
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 staffs 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 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.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). Data that will be processed centrally includes:

IRT data including information regarding screening, enrollment/allocation of study 
treatment, subsequent drug assignments and discontinuation

Central imaging review data (i.e. CT/MRI, Bone scans and photography results)

Centrally analyzed laboratory data including clinically (chemistry, hematology, 
coagulation, urinalysis, etc.), 
 CSF, blood/tumor biomarker and safety parameters.


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
ECG data
Randomization codes and data about all study treatments dispensed to the patient will be
tracked using IRT. The system will be supplied by the vendor(s), who will also manage the 
database. The data will be sent electrically to Novartis personnel.
At the conclusion of the study, the occurrence of any protocol deviations will be determined.
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and the data available for data analysis. 
 
 
After database lock, the investigator will receive a CD-ROM or paper copies of the patient 
data for archiving at the investigative site.
10
Statistical methods and data analysis
The data from all participating centers in this protocol will be combined to perform analysis.
Primary analysis of any of the study arms or overall will occur only after enrollment in the 
specific study arms or overall is complete and all patients have completed at least 24 weeks of 
treatment with ceritinib or have discontinued earlier respectively. If the end of study criteria is 
met before the primary analysis is conducted, a single final analysis and study report may be 
performed. If the end of the study criteria is not met by the time that the primary analysis is 
conducted, a final CSR will be produced reporting all available data collected up to last 
patient last visit (LPLV) including the additional study data collected after the primary 
analysis.
 
 
 
 
Subsequently, an analysis of all study arms 1 to 5 and overall for all enrolled patients will be 
performed after the required enrollment in all 5 arms is complete and all treated patients have 
been followed for at least 24 weeks or have discontinued treatment earlier. Although available 
data from all study arms will be included in this analysis, this analysis will be considered as
primary analysis for all patients and for the study arms not included in the early analysis CSR.
For the study arms that were included in the early analysis CSR, the early analysis will be 
considered as their primary analysis.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) will include all patients who receive at least one dose of ceritinib.


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The FAS will be used for summaries of baseline characteristics and all efficacy analyses 
unless otherwise specified.
10.1.2
Safety Set
The Safety Set will include all patients who receive at least one dose of ceritinib. All safety 
data will be analyzed using the Safety Set. In this study the FAS and safety set are identical.
10.1.3
Per-Protocol Set
Not applicable.
10.1.4
Dose-determining analysis set
Not applicable.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by study arm based on the FAS. Categorical data will be presented as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 
minimum, and maximum will be presented.
10.3
Treatments (study treatment, concomitant therapies, compliance)
The safety set will be used for the analyses below.
The actual dose and duration in days of ceritinib as well as the dose intensity (computed as the 
ratio of total dose received and actual duration) and the relative dose intensity (computed as 
the ratio of dose intensity and planned dose received/planned duration), will be listed and 
summarized by study arm. Dose reductions and dose delays (including the reasons for these) 
will be listed and summarized by study arm.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by study arm.
10.4
Primary objective
The primary objective is to evaluate the antitumor activity of ceritinib in patients with ALK-
positive NSCLC metastatic to the brain and/or to leptomeninges.
10.4.1
Variable
The primary variable is the overall response rate (ORR), which is defined as the proportion of 
patients with a best overall confirmed response of CR or PR in the whole body, as assessed 
per RECIST 1.1 (Appendix 2) by the investigator.


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10.4.2
Statistical hypothesis, model, and method of analysis
The primary analysis will be performed on the FAS. The primary efficacy endpoint ORR will 
be estimated and the exact 95% confidence interval (CI) provided. ORR will also be 
summarized by prior radiotherapy to the brain (yes, no), prior ALK inhibitor use (yes, no) and 
overall using the data from Arms 1 through 4 in the analysis of Arms 1 to 5. Arm 5 will be 
summarized separately.
10.4.3
Handling of missing values/censoring/discontinuations
Confirmed partial or complete responses reported prior to any additional anticancer therapy 
will be considered as responses in the calculation of ORR, irrespective of the number of 
missed assessments before response.
Patients with a best overall response of “Unknown” per RECIST 1.1 will be considered as 
non-responders in estimating the ORR.
Descriptive tables displaying missing tumor assessments prior to progression or study 
discontinuation will be specified in the RAP document.
Patients who have disease progression and continue to receive treatment after progression will 
qualify for progressive disease at the time of progression and will be counted as PD in ORR 
and other efficacy endpoint derivations.
10.5
Secondary objectives
10.5.1
Key secondary objective(s)
The key secondary objective is to evaluate Disease Control Rate (DCR). The DCR is defined 
as the proportion of patients with a best overall response of CR, PR or SD in the whole body, 
as assessed per RECIST 1.1 by the investigator.
DCR will be estimated and the exact binomial 95% CI will be presented. DCR will also be 
summarized by prior radiotherapy to the brain (yes, no), prior ALK inhibitor use (yes, no) and 
overall using the data from Arms 1 through 4. Arm 5 will be summarized separately.
10.5.2
Other secondary efficacy objectives
The following intracranial, extracranial and whole body (for lesions in and outside the brain)
tumor-response related endpoints (OIRR, IDCR, TTIR, DOIR, OERR, EDCR, TTER, DOER, 
TTR, DOR and PFS) will be assessed separately based on investigator assessment and BIRC 
assessment per RECIST 1.1.
All the endpoints described below will be summarized by prior radiotherapy to the brain (yes, 
no), prior ALK inhibitor use (yes, no) and overall using the data from Arms 1 through 4. 
Secondary efficacy endpoints will also be summarized using data from Arm 5 separately.


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Intracranial endpoints:
Overall intracranial response rate (OIRR): OIRR is calculated based on response 
assessments in the brain for patients having measurable brain metastases at baseline. The 
OIRR is defined as the proportion of patients with a best overall confirmed response of CR or 
PR in the brain as assessed per modified RECIST 1.1. OIRR will be estimated and the exact 
binomial 95% CI will be presented.
Intracranial disease control rate (IDCR) at 8 and 16 weeks and overall: IDCR is 
calculated based on response assessments in the brain for patients having evaluable 
(measurable or non-measurable) brain metastases at baseline. In what follows, CR, PR and SD 
are possible responses only for patients with measurable brain metastases at baseline, while 
non-CR/non-PD is a possible response only for patients without measurable brain metastases 
at baseline.

The IDCR at 8 and 16 weeks is defined as the proportion of patients with CR, PR, SD or 
non-CR/non-PD assessment in the brain at Week 8 and Week 16 intracranial tumor 
evaluations respectively.

IDCR overall is defined as the proportion of patients with a best overall response of CR, 
PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by the 
investigator.
IDCR will be estimated and the exact binomial 95% CI will be presented.
Time to intracranial tumor response (TTIR): TTIR is defined as the time from the date of 
the first dose of ceritinib to the date of the first documented response (CR or PR) in the brain 
as assessed per modified RECIST 1.1 criteria for patients with measurable brain metastases at 
baseline.
The distribution function of TTIR will be estimated using the Kaplan-Meier method. The 
median TTIR along with 95% CI will be presented.
Duration of intracranial response (DOIR): Among patients with measurable brain 
metastases at baseline and a confirmed response (PR or CR) in the brain per modified 
RECIST 1.1, DOIR is defined as the time from the first documented response (PR or CR) in 
the brain to the date of the first documented disease progression in the brain or death due to 
any cause. The distribution function of DOIR will be estimated using the Kaplan-Meier 
method. The median DOIR along with 95% CI will be presented.
Extracranial endpoints:
Overall extracranial response rate (OERR): OERR is defined as the proportion of patients 
with a best overall confirmed response of CR or PR outside of the brain, as assessed per 
RECIST 1.1. OERR will be estimated and the exact binomial 95% CI will be presented.
Extracranial disease control rate (EDCR) at 8 and 16 weeks and overall:

EDCR at 8 and 16 weeks is defined as the proportion of patients with CR, PR or SD 
outside of the brain at Week 8 and Week 16 extracranial tumor evaluations respectively, 
as assessed per RECIST 1.1.

EDCR overall is defined as the proportion of patients with a best overall response of CR, 
PR or SD outside of the brain as assessed per RECIST 1.1.


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EDCR will be estimated and the exact binomial 95% CI will be presented.
Time to extracranial tumor response (TTER): TTER is defined as the time from the date of 
the first dose of ceritinib to the date of the first documented response (CR or PR) outside of 
the brain as assessed per RECIST 1.1 criteria. The distribution function of TTER will be 
estimated using the Kaplan-Meier method. The median TTER along with 95% CI will be 
presented.
Duration of extracranial response (DOER): Among patients with a confirmed response (PR 
or CR) outside of the brain per RECIST 1.1, DOER is defined as the time from the first 
documented response (PR or CR) outside of the brain to the date of the first documented 
disease progression outside of the brain or death due to any cause. The distribution function of 
DOER will be estimated using the Kaplan-Meier method. The median DOER along with 95% 
CI will be presented.
Whole body endpoints:
ORR by BIRC: The evaluation of ORR will be repeated based on BIRC assessment.
DCR by BIRC: The evaluation of DCR will be repeated based on BIRC assessment.
Time to tumor response (TTR): TTR is defined as the time from the date of the first dose of 
ceritinib to the date of the first documented response (CR or PR) in the whole body as 
assessed per RECIST 1.1 criteria. The distribution function of TTR will be estimated using 
the Kaplan-Meier method. The median TTR along with 95% CI will be presented.
Duration of response (DOR): Among patients with a confirmed response (PR or CR) in the 
whole body per RECIST 1.1, DOR is defined as the time from the first documented response 
(PR or CR) to the date of the first documented disease progression or death due to any cause. 
The distribution function of DOR will be estimated using Kaplan-Meier method. The median 
DOR along with 95% CI will be presented.
Progression-free survival (PFS): PFS is defined as the time from the date of the first dose of 
ceritinib to the date of the first documented disease progression in the whole body per 
RECIST 1.1 or death due to any cause. A patient who has not progressed or died at the date of 
the analysis or when he/she receives any further anticancer therapy in the absence of disease 
progression will be censored at the time of the last adequate tumor evaluation before the 
earlier of the cut-off date or the anticancer therapy date. By default, if disease progression or 
death for any reason is documented after one single missing tumor evaluation, the actual event 
date of disease progression/death will be used for the PFS event date. If disease progression or 
death for any reason is documented after two or more missing tumor evaluations, the PFS 
time of these patients will be censored at the date of the last adequate tumor evaluation 
without PD. The distribution of PFS will be estimated using the Kaplan-Meier method. The 
median PFS along with 95% CI will be presented.
Overall survival (OS): OS time is defined as time from the date of first dose of ceritinib to 
the date of death due to any cause. OS time for patients who are alive at the end of the study 
or are lost to follow-up will be censored at the date of last contact. OS will be estimated using 
the Kaplan-Meier method. The median OS along with 95% CI will be presented. Kaplan-


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Meier curves will not be produced for Arm 5 alone if the number of patients enrolled in this 
arm is ≤ 10.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
study arm and for all patients.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. Post-treatment period: starting at day 31 after last dose of study medication.
The safety summary tables will include only data collected during the on-treatment period. 
However, all safety data will be listed with data collected during the pre-treatment and post-
treatment period flagged.
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs observed during the on-
treatment period. However, all safety data (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and after the on-treatment 
period will be flagged.
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and/ or preferred term, severity (based on CTCAE grades), 
type of AE, and relation to study treatment by study arm. Deaths reportable as SAEs and non-
fatal SAEs will be listed by patient and tabulated by type of AE and study arm.
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment.
For each specified category, number and percentage of patients with at least one event per 
category will be summarized by study arm.
10.5.3.3 Laboratory abnormalities
For laboratory tests covered by the CTCAE version 4.03, the study’s biostatistical and 
reporting team will grade laboratory data accordingly. For laboratory tests covered by 
CTCAE, a Grade 0 will be assigned for all non-missing values not graded as 1 or higher (In 
the unlikely case when a local laboratory normal range overlaps into the higher (i.e. non-zero) 
CTC grade, the laboratory value will still be taken as within normal limits and assigned a 
CTC grade of zero.). Grade 5 will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.


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The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests:

shift tables using CTCAE grades to compare baseline to the worst on-treatment value

for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high)
Listing of all laboratory data with values flagged to show the corresponding CTCAE grades 
and the classifications relative to the laboratory normal ranges will be generated.
A separate listing will display notable laboratory abnormalities (i.e., newly occurring CTCAE 
grade 3 or 4 laboratory toxicities).
 
 
10.5.3.4 Other safety data
Data from other tests (including ECGs and vital signs) will be summarized and listed, notable 
values will be flagged, and any other information collected will be listed as appropriate.
Definitions of notably abnormal results will be provided in the RAP document.
10.5.3.5 Tolerability
Tolerability will be summarized in terms of dose reductions or drug interruption due to an AE.


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10.5.5.2 Data handling principles
Not applicable
10.5.5.3 Data analysis principles
10.5.5.3.1
Analysis sets
, all statistical 
analyses of biomarker data will be performed on patients with biomarker data.


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10.5.5.3.3
Advanced analysis methods
Not applicable
10.6
Exploratory objectives
RANO exploratory objectives
Exploratory analyses will be conducted to evaluate intracranial endpoints by investigator and 
BIRC including OIRR, TTIR, DOIR for patients with measurable brain metastases at baseline, 
and IDCR for all patients in Arms 1 to 4 with active brain lesion at baseline using Response 
Assessment in Neuro-Oncology (RANO) criteria for high grade gliomas (Appendix 3).


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10.8
Sample size calculation
The study will enroll approximately 160 patients, with approximately 40 patients each in 
Arms 1 and 2 and ~30 patients each in Arms 3 and 4 and at least 20 patients in Arm 5 (See 
Table 2-1). It is assumed that 5% of the patients diagnosed with brain metastases have 
leptomeningeal carcinomatosis. Additional patients in Arm 4 may be enrolled in order achieve 
approximately 60 patients in Arms 3 and 4 together (i.e. ALKi naïve patients) if enrollment 
rate in Arm 3 is slow.
An observed ORR of 50% in 140 patients planned for Arms 1-4 will result in an exact 
binomial 95% CI with a lower bound greater than 40% which is clinically meaningful and 
exceeds the ORR expected with available therapies (Shaw 2012). Table 10-1 provides the 
exact binomial 95% CI for various observed ORRs for the 140 patients and for each of the 
strata.
Table 10-1
Exact binomial 95% confidence intervals for various observed ORRs
Sample Size
Observed ORR
Number of Patients with 
Confirmed PR or CR
Exact 95% CI
N=140 (overall
Arms 1-4)
50%
70
(41.44%, 58.56%)
60%
84
(51.39%, 68.18%)
N=80 (Arms 1 
and 2)
40%
32
(29.20%, 51.56%)
50%
40
(38.60%, 61.40%)
60%
48
(48.44%, 70.80%)
N=40 (each of 
Arms 1 or 2)
40%
16
(24.87%, 56.67%)
50%
20
(33.80%, 66.20%)
N=30 (each of 
Arms 3 or 4)
60%
18
(40.60%, 77.34%)
70%
21
(50.60%, 85.27%)
10.9
Power for analysis of key secondary variables
Estimation of the DCR is the key secondary objective of the study. An observed DCR of 65% 
in 140 patients in Arms 1-4 will result in an exact binomial 95% CI with a lower bounder 
greater than 55%. Table 10-2 provides the exact binomial 95% CI for various observed DCRs 
for the 140 patients and for each of the strata.
Table 10-2
Exact binomial 95% confidence intervals for various observed DCRs
Sample Size
Observed DCR
Number of Patients with SD, PR or 
CR
Exact 95% CI
N=140 (overall
Arms 1-4)
65%
91
(56.49%, 72.86%)
75%
105
(66.98%, 81.93%)
N=80 (Arms 1 
and 2)
60%
48
(48.44%, 70.80%)
70%
56
(58.72%, 79.74%)
N=40 (each of 
Arms 1 or 2)
60%
24
(43.33%, 75.14%)
70%
28
(53.47%, 83.44%)
N=30 (each of 
Arms 3 or 4)
70%
21
(50.60%, 85.27%)
80%
24
(61.43%, 92.29%)


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An additional secondary objective of the study is estimation of the OIRR for patients with 
measurable brain metastases at baseline. As described in Section 4.1.1, the study targets 
enrolling approximately 70 patients with measurable brain metastases: ~50 patients with prior 
ALKi treatment (Arms 1 and 2) and ~20 patients with no prior ALKi treatment (Arms 3 and 
4). An observed OIRR of 50% in 70 patients with measurable brain metastases in Arms 1-4 
will result in an exact binomial 95% CI with a lower bound greater than 35%. An observed 
OIRR of 60% in 50 patients with measurable brain metastases previously treated with and 
ALKi (Arms 1 and 2) will result in an exact binomial 95% CI with a lower bound greater than 
45%. An observed OIRR of 60% in 20 patients with measurable brain metastases not 
previously treated with and ALKi (Arms 3 and 4) will result in an exact binomial 95% CI 
with a lower bound greater than 36%. The reported OIRR with Crizotinib is 18% (95% CI: 5 -
40) for patients with measurable brain metastases and prior radiation therapy to the brain, and 
33% (95% CI: 13 - 59) for patients without prior radiation to the brain; recent whole brain 
radiation was allowed (Crino et al 2013).
Table 10-3
Exact binomial 95% confidence intervals for various observed OIRRs
Observed 
OIRR
Number of Patients with Confirmed PR 
or CR in the brain
Exact 95% CI
N=70 (Overall 
Arms 1-4)
45%
32
(33.74%, 58.06%)
50%
35
(37.80%, 62.20%)
55%
39
(43.34%, 67.59%)
60%
42
(47.59%, 71.53%)
N=50 (prior ALKi 
treatment, Arms 
1+2)
40%
20
(26.41 %, 54.82 %)
45%
23
(31.81 %, 60.68 %)
50%
25
(35.53%, 64.47%)
55%
28
(41.25%, 70.01%)
60%
30
(45.18%, 73.59%)
N=20 (no prior 
ALKi treatment, 
Arms 3+4)
50%
10
(27.20%, 72.80%)
55%
11
(31.53%, 76.94%)
60%
12
(36.05%, 80.88%)
65%
13
(40.78%, 84.61%)
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 


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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 Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their eCRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication 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 requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.4.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. www.clinicaltrials.gov before study 
start. In addition, results of interventional clinical trials in adult patients are posted on 


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www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of study completion (i.e., LPLV), those for interventional clinical trials involving 
pediatric patients within 6 months of study completion.
Novartis followed the ICMJE authorship guidelines (www.icmje.org) and other specific 
guidelines of the journal or congress to which the publications will be submitted.
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no 
honorarium provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (eCRF) is the primary data 
collection instrument for the study. The investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported in the eCRFs and all other required reports. Data 
reported on the eCRF, that are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the eCRF 
must be recorded. Any missing data must be explained. Any change or correction to a paper 
eCRF should be dated, initialed, and explained (if necessary) and should not obscure the 


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original entry. For electronic eCRFs an audit trail will be maintained by the system. The 
investigator should retain records of the changes and corrections to paper eCRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the 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/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
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/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient 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 


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site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days.


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13
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Appendices


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14.2
Appendix 2: Harmonization of efficacy analysis of solid tumor 
studies (RECIST 1.1)
Guidelines for Response, Duration of Overall Response, TTF, TTP, PFS and 
Overall Survival (based on RECIST 1.1)


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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
LPLV
Last patient last visit
MRI
Magnetic resonance imaging
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
TTP
Time to progression
UNK
Unknown


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14.2.1
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 14.2.2 and the definition of best response in
Section 14.2.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.2.18 is summarizing the “time to 
event” variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.2.28
of this guideline describes data handling and programming rules. This section is to be referred 
to in the RAP (Reporting and Analysis Plan) to provide further details needed for 
programming.
14.2.2
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.
14.2.3
Definitions
14.2.4
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 14.2.26.
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 baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease.


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
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.
14.2.5
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). Guidance on how patients with just non-measurable 
disease at baseline will be evaluated for response and also handled in the statistical analyses is 
given in Section 14.2.26.
14.2.6
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 
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.


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
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 change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. 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 the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.

If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan).

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.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. 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.

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 


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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.
14.2.7
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 14.2.4.

Nodal target: See Section 14.2.4.
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 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
14.2.8
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 


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for the target (Table 14-5) and non-target lesions (Table 14-6) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target 
and non-target lesions together (Table 14-7) as well as the presence or absence of new lesions.
14.2.9
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 number.
14.2.10
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.
14.2.11
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.
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination.


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14.2.12
Determination of target lesion response
Table 14-5
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 mm2.
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. Methodology change See Section 14.2.6.
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 three 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 14-5 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 
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, 


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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.


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14.2.13
Determination of non-target lesion response
Table 14-6
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 
baseline.
1. Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of the 
treating physician does prevail and the progression status should be confirmed later on by the review panel (or 
study chair).
Notes on non-target lesion response

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 any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD).

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 14.2.12 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
14.2.14
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.


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
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 14.2.15).

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 14.2.6.
14.2.15
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 14-7.
Table 14-7
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 14.2.8.
If there are no baseline scans available at all, then the overall lesion response at each 
assessment should be considered Unknown (UNK).
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen.
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.
14.2.16
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.2.26 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.


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14.2.17
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 30 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) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)
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 


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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.
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.


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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).
14.2.18
Time to event variables
The protocol should state which of the following variables is used in that study.
14.2.19
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.
14.2.20
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.
14.2.21
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.


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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.
14.2.22
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation 
is typically related to intolerance of the study drug. In some protocols, time to treatment 
failure may be considered as a sensitivity analysis for time to progression. The list of 
discontinuation reasons to be considered or not as treatment failure may be adapted according 
to the specificities of the study or the disease.
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation 
due to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to 
treatment failure for patients who did not experience treatment failure will be censored at last 
adequate tumor assessment.
14.2.23
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.


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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.
14.2.24
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 14.2.23. 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.
14.2.25
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 


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assessment date is calculated as the earliest date of all measurement dates at that evaluation 
number.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.2.26).
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.
14.2.26
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 


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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 measurable 
disease is derived slightly differently according to Table 14-8.
Table 14-8
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 14.2.8.
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.
14.2.27
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 
progression 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.


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Based on definitions outlined in Section 14.2.25, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics-April 
2005) as a reference, the following analyses can be considered:
Table 14-9
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) N/A
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
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 14.2.25.
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 14.2.25.
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), i.e. censoring at last adequate assessment may be 
used as a default in this case.
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 14-9 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.
14.2.28
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).
14.2.29
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).
14.2.30
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 


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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

Death

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)
14.2.31
End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study 
treatment and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

New therapy for study indication

Progressive disease

Study terminated by the sponsor
14.2.32
Medical validation of programmed overall lesion response
As RECIST 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) 


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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), these UNK 
assessments may be re-evaluated by clinicians 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.
14.2.33
Programming rules
The following should be used for programming of efficacy results:
14.2.34
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
14.2.35
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 14.2.25). 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.
14.2.36
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.


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14.2.37
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)’.
14.2.38
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.


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14.2.40
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.
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005.
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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14.3
Appendix 3: Response assessment in neuro-oncology (RANO)
criteria for high-grade gliomas
Antitumor response will be primarily evaluated by the Response Assessment in Neuro-
Oncology (RANO) working group (Wen et al 2010) criteria in this study. The RANO Criteria 
updates its established predecessor, the modified Macdonald Criteria (Macdonald et al 1990), 
by adding assessment of non-enhancing lesions.
Patients will undergo Contrast MRI assessments for response evaluation starting at Week 8 
and every 8 weeks thereafter to evaluate brain lesions, as outlined in the Visit schedule Table 
7-1 and Table 7-2.
The following components will be taken into account when assessing a patient’s overall 
response at an individual evaluation.

Tumor evaluation eCRF page for measureable enhancing lesions (T1-Gd+)

Tumor evaluation eCRF page for non-measurable enhancing lesions (T1-Gd+)

Tumor evaluation eCRF page for non-enhancing lesions (T2/FLAIR)

Tumor evaluation eCRF page for new lesion

Concomitant medication eCRF page for steroid usage

Clinical status eCRF page for KPS and other clinical evaluation finding

Overall response eCRF page for response category (CR/PR/PD/SD/NA)
14.3.1
Antitumor effect - definitions
Evaluable for toxicity
All participants who receive at least one dose of study treatment will be evaluable for toxicity 
from the time of their first treatment.
Evaluable for objective response
Only those participants who have measurable disease present at baseline (cycle 1, day 1 scan) 
and have received at least one dose of therapy will be considered evaluable for response. 
These participants will have their response classified according to the definitions stated below. 
(Note: Participants who exhibit objective disease progression or die prior to the end of cycle 1 
will also be considered evaluable.)
Measurable disease
Bidimensionally, contrast-enhancing, measurable lesions with clearly defined margins by CT 
or MRI scan, with a minimal diameter of 10mm, and visible on 2 axial slices which are at 
least 5 mm apart with 0 mm skip. Measurement of tumor around a cyst or surgical cavity, if 
necessary, requires a minimum thickness of 3 mm. If there are multiple measurable lesions, 
the investigator must choose a minimum of two and a maximum of five of the largest lesions 
to be followed before a participant is entered on study. The remaining lesions will be 
considered non-measureable for the purpose of objective response determination. Unless 


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progression is observed, objective response can only be determined when all measurable and 
non-measurable lesions are assessed.
Non-measurable evaluable disease
Unidimensionally measurable lesions, masses with margins not clearly defined, lesions with 
maximal diameter < 10mm.
14.3.2
Response/progression categories
Complete response (CR)
All of the following criteria must be met:
a. Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this scan 
will be considered only stable disease.
b. No new lesions.
c. All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline.
d. Participants must be on no steroids or on physiologic replacement doses only.
e. Stable or improved non-enhancing (T2/FLAIR) lesions
f.
Stable or improved clinically, for clinical signs and symptoms present at baseline and 
recorded to be disease related
Participants with non-measurable disease cannot have a complete response. The best 
response possible is stable disease.
Partial response (PR)
All of the following criteria must be met:
a. Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks. 
In the absence of a confirming scan 4 weeks later, this scan will be considered only stable 
disease.
b. No progression of non-measurable disease.
c. No new lesions.
d. All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline.
e. The steroid dose at the time of the scan evaluation should be no greater than the dose at 
time of baseline scan.
f.
Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan.
g. Stable or improved, for clinical signs and symptoms present at baseline and recorded to be 
disease related clinically.
Participants with non-measurable disease cannot have a partial response. The best
response possible is stable disease.


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Progressive disease (PD)
The following criterion must be met:
a. 25% increase in sum of the products of perpendicular diameters of enhancing lesions (over 
best response or baseline if no decrease) on stable or increasing doses of corticosteroids 
and/or one or more of the of the following:
b. Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of 
corticosteroids steroids compared to baseline scan or best response following initiation of 
therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, 
infection, seizures, post-operative changes, or other treatment effects).
c. Any new lesion
d. Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection, etc.). The definition of clinical deterioration is left to the discretion of the 
investigator but it is recommended that a decline in the Karnofsky Performance Score 
(KPS) from 100 or 90 to 70 or less, a decline in KPS of at least 20 from 80 or less, or a 
decline in KPS from any baseline to 50 or less, for at least 7 days, be considered 
neurologic deterioration, unless attributable to co-morbid events or changes in 
corticosteroid dose.
e. Failure to return for evaluation due to death or deteriorating condition.
f.
Clear progression of non-measurable disease
Stable disease (SD)
All of the following criteria must be met:
a. Does not qualify for CR, PR, or progression.
b. All measurable and non-measurable sites must be assessed using the same techniques as 
baseline.
c. Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline scan. In the event that the corticosteroid dose has been increased, the 
last scan considered to show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose.
d. Stable clinically.
Unknown response status
Progressive disease has not been documented and one or more measurable or non-measurable 
lesions have not been assessed.
These RANO Response Criteria are also summarized in Table 14-10:


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Table 14-10
Summary of the RANO response criteria
CR
PR
SD
PD#
T1-Gd +
None
≥50% decrease
<50% decrease but 
<25% increase
≥25% increase*
T2/FLAIR
Stable or decrease
Stable or decrease
Stable or decrease
Increase*
New Lesion
None
None
None
Present*
Corticosteroids
None
Stable or decrease
Stable or decrease
NA**
Clinical Status
Stable or improve
Stable or improve
Stable or improve
Deterioration*
Requirement for 
Response
All
All
All
Any*
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease
*: Progression when this criterion is met **: Increase in corticosteroids alone will not be taken into account in 
determining progression in the absence of persistent clinical deterioration
14.3.3
Methods for evaluation of measurable disease
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or 
digital measurement tool. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 14 days before the beginning of the 
treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.
14.3.4
Evaluation of best response
The best overall response is the best response recorded from the start of the treatment until 
disease progression (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). If a response recorded at one scheduled MRI does not 
persist at the next regular scheduled MRI, the response will still be recorded based on the 
prior scan, but will be designated as a non-sustained response. If the response is sustained, i.e. 
still present on the subsequent MRI, it will be recorded as a sustained response, lasting until 
the time of tumor progression. Participants without measurable disease may only achieve SD 
or PD as their best “response.”
14.3.5
Other effect measures
14.3.5.1 Neurological exam
Although not used for determining response, it is useful to evaluate changes in the 
neurological exam compared to the previous exam. The following scale may be used:
+2
Definitely better
+1
Possibly better
0
Unchanged
-1
Possibly worse
-2
Definitely worse
14.3.5.2 Performance status
Participants will be graded according to KPS score


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14.3.5.3 Overall survival time
From date of first dose (date of first post-surgery treatment for participants in Dose Level 1) 
to date of death due to any cause.
14.3.5.4 Progression-free survival time:
From date of first dose (date of first post-surgery treatment for participants in Dose Level 1) 
to date of progression or death. Participants who stop treatment for causes other than 
progression may be censored if other therapy is initiated or if regular assessments for 
assessing progression are no longer available.


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14.4
Appendix 4: Cockcroft-Gault formula
Female:
Male:

SAP_000.pdf: 
Clinical Development 
LDK378 (Ceritinib) 
LDK378A2205 / NCT02336451
A Phase II, multi-center, open-label, five-arm study to 
evaluate the efficacy and safety of oral ceritinib treatment 
for patients with ALK-positive non-small cell lung cancer 
(NSCLC) metastatic to the brain and/or to leptomeninges 
RAP Module 3 (SAP) – Detailed Statistical Methodology 
Author: 
, Trial Statistician; 
, Program 
Statistician; 
 CP Statistician; 
, 
Biomarker Statistician  
Document type: 
RAP Documentation 
Document status: 
Amendment 1.0 
Release date: 
11-Mar-2019
Number of pages: 
56 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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LDK378A2205 SAP Amendment 1.0 
 
CONFIDENTIAL - For Business Use Only 
Document History – Changes compared to previous version of RAP module 3. 
Version 
Date 
Changes 
Draft 1.0 
05-Aug-2015 
Original version 
Amendment 1.0 
11-Mar-2019 
Section 1: 
• Standard languages added to clarify that the SAP 
should be finalized before database lock 
Section 1.1: 
• Details added describing the study design with 
regards to each study arm 
• Timeline for primary and final analysis updated to 
align with protocol amendment 6 
Section 1.2: 
• Details added for the definition of primary 
endpoint in Section 1.2.1 
• Details and clarification added for other secondary 
objectives for endpoints and study arms in Section 
1.2.2 
Section 2.1: 
• Study arms used with regard to the general 
presentation of descriptive summaries updated 
• Subgroup analysis removed 
Section 2.2: 
• Per-protocol set was removed 
• 
 
Section 2.3: 
• By prior radiation to the brain and by prior ALK 
inhibitor use analyses removed 
• Details of summaries of diagnosis and extent of 
cancer, medical history, and prior anti-cancer 
therapy were updated to align with eCRF 
Section 2.4: 
• Summary of major protocol deviations leading to 
exclusion from PPS removed 
Section 2.5: 
• By prior radiation to the brain and by prior ALK 
inhibitor use analyses removed 
• Details of summaries of disposition were updated 
to align with eCRF 
Section 2.6: 


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Version 
Date 
Changes 
• Baseline definitions for general efficacy and safety 
evaluations moved from Section 2.8.2 
• Exposure by prior radiation to the brain and by 
prior ALK inhibitor use analyses removed 
• Kaplan-Meier analysis for dose reduction or 
interruption removed 
Section 2.7: 
• Definition and derivation algorithm of best overall 
response moved from Section 2.8.1.2 to Section 
2.7.1. The cut-off for SD too early and PD too late 
was updated based on tumor assessment schedule. 
• Subgroup analysis and PPS analysis were 
removed from Section 2.7.4 
Section 2.8: 
• Description of secondary efficacy endpoints 
moved from Section 2.8.1 to Section 2.8.1.2 
• Table 2-1 updated to remove supportive analysis 
and subgroup analysis. IDCR and EDCR at week 
8 and week 16 added. 
• PPS analysis and subgroup analysis removed from 
Section 2.8.1.1  
• OIRR, TTIR and DOIR analyses based on all 
patients added in Section 2.8.1.2 
• IDCR and EDCR at week 24 updated to at week 8 
and week 16. Algorithms on derivation of IDCR 
and EDCR at 8 and 16 weeks added. Similar 
analyses based on patients with measurable brain 
metastases added for IDCR in Section 2.8.1.2 
• Methods used for TTIR, TTER and TTR analyses 
changed from KM method to descriptive summary 
in Section 2.8.1.2 
• The strategy of handling start of new anticancer 
therapy updated from censoring to the new 
standard of ignoring for DOIR, DOER, DOR and 
PFS analyses in Section 2.8.1.2. 
• Supportive and PPS analyses for ORR and DCR 
per BIRC removed in Section 2.8.1.2 
• Gap analyses removed from Section 2.8.1.2 
• On treatment deaths, by primary SOC and PT, 
AESI leading to study drug discontinuation, two 
safety disclosure tables added and subgroup 
analysis for AEs removed in Section 2.8.2 


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Version 
Date 
Changes 
• Lab parameter updated to include RBC and direct 
bilirubin; Urinalysis listings were removed; 
Categories for liver function tests updated in 
Section 2.8.2 
• The denominator used for the percentage 
calculation for ECG abnormality was further 
clarified; respiration rate removed from vital sign 
analysis; Clarification for the analysis of WHO PS 
added in Section 2.8.2.1 
• 
 
• 
 
• Sample size calculation and power analysis 
updated to align with protocol amendment in 
Section 2.9 and Section 2.10 
• A preliminary interim analysis for arm 5 added in 
Section 2.11 
Section 3: 
• Table 3 added to include the changes to protocol 
specified analyses 
Section 4:  
• Patient classification into analysis sets removed  
• Further details were added for the derivation of 
last contact date in Section 4.2 
• Age derivation added as Section 4.4 
• “New anticancer therapy will defined for whole 
body, intracranial, and extracranial separately” 
added; PFS censoring reasons updated in Section 
4.6.1. 
• Details of PROC LIFETEST added in Section 
4.6.4 
• Baseline ECG definition updated in Section 4.7 
• Imputation rule for death date updated in Section 
4.8.6 
• Imputation rule for concomitant medication date 
added as Section 4.8.2 and imputation incomplete 
dates for disease progression prior to start of study 
drug added as Section 4.8.8 


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Table of contents 
Table of contents ................................................................................................................. 5 
List of tables ........................................................................................................................ 7 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design............................................................................................................. 8 
1.2 
Objectives ................................................................................................................ 9 
1.2.1 
Primary objective .................................................................................... 9 
1.2.2 
Key secondary and other secondary objectives ...................................... 9 
1.2.3 
Exploratory objectives .......................................................................... 10 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis .......................................................................................................... 11 
2.2 
Analysis sets .......................................................................................................... 11 
2.3 
Patient demographics and other baseline characteristics ....................................... 12 
2.4 
Protocol deviations ................................................................................................ 14 
2.5 
Patient disposition .................................................................................................. 14 
2.6 
Treatments (study drug, concomitant therapies, compliance) ............................... 15 
2.7 
Analysis of the primary variable ............................................................................ 18 
2.7.1 
Variable ................................................................................................. 18 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 19 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 19 
2.7.4 
Supportive analyses ............................................................................... 19 
2.8 
Analysis of secondary variables ............................................................................ 20 
2.8.1 
Efficacy ................................................................................................. 20 
2.8.2 
Safety ..................................................................................................... 26 
 
 33 
 
 34 
 
 34 
2.8.6 
Patient-report outcomes ........................................................................ 34 
 
 34 
2.9 
Sample size calculation .......................................................................................... 35 
2.10 
Power for analysis of key secondary variables ...................................................... 36 
2.11 
Interim analysis ...................................................................................................... 37 
3 
Changes to protocol specified analyses ............................................................................. 37 
4 
Additional details on implementation of statistical methodology ..................................... 38 
4.1 
Data included in the analyses ................................................................................ 38 
4.2 
Last contact date .................................................................................................... 38 


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4.3 
Month derivation ................................................................................................... 39 
4.4 
Age derivation ....................................................................................................... 39 
4.5 
Dose interruptions and dose changes ..................................................................... 39 
4.6 
Efficacy endpoints ................................................................................................. 40 
4.6.1 
Implementation of RECIST guidelines ................................................. 40 
4.6.2 
Implementation of RANO guidelines (protocol Appendix 3)............... 44 
4.6.3 
Sources for overall lesion response ....................................................... 46 
4.6.4 
Kaplan-Meier estimates ........................................................................ 47 
4.6.5 
Confidence interval for response rates .................................................. 47 
4.7 
Safety evaluations .................................................................................................. 48 
4.7.1 
Multiple assessments within post-baseline visits .................................. 48 
4.7.2 
Baseline ................................................................................................. 48 
4.7.3 
Laboratory Parameters .......................................................................... 49 
4.8 
Handling of missing or partial dates ...................................................................... 50 
4.8.1 
AE date imputation ............................................................................... 50 
4.8.2 
Concomitant medication date imputation ............................................. 52 
4.8.3 
Incomplete date of initial diagnosis of cancer, date of first 
recurrence/progression and date of most recent recurrence .................. 52 
4.8.4 
Incomplete date for anti-neoplastic therapies ....................................... 53 
4.8.5 
Incomplete assessment dates for tumor assessment .............................. 53 
4.8.6 
Incomplete date for death ...................................................................... 54 
4.8.7 
Incomplete dates for last dose of study drug ......................................... 54 
4.8.8 
Incomplete dates for disease progression prior to start of study drug ... 54 
 
 55 
5 
Reference: .......................................................................................................................... 55 
 
 
 


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List of tables 
Document History – Changes compared to previous version of RAP module 3. ...................... 2 
Table 1-1 
Allocation into Study Arms based on prior radiation to brain 
(yes/no) and prior treatment with ALK inhibitor (yes/no) ...................... 8 
Table 2-1 
Summary of tumor-related efficacy endpoints and analysis 
populations ............................................................................................ 20 
Table 2-4 
Exact binomial 95% confidence intervals for various observed 
ORRs ..................................................................................................... 35 
Table 2-5 
Exact binomial 95% confidence intervals for various observed 
DCRs ..................................................................................................... 36 
Table 2-6 
Exact binomial 95% confidence intervals for various observed 
OIRRs .................................................................................................... 36 
Table 3-1 
Changes to protocol specified analysis or descriptions and rationale ... 37 
Table 4-1 
Overall lesion response at each assessment: patients with non-
target disease only ................................................................................. 42 
Table 4-2 
Inclusion/exclusion of assessments used in waterfall graph ................. 43 
Table 4-3 
Summary of the RANO response criteria ............................................. 46 
Table 4-4 
Sources for overall lesion response ....................................................... 46 
Table 4-5 
AE/treatment date abbreviations ........................................................... 51 
Table 4-6 
AE partial date imputation algorithm .................................................... 51 
Table 4-7 
AE/treatment date relationship and imputation legend ......................... 52 
Table 4-8 
AE imputation example scenarios ......................................................... 52 
 
 


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1 
Introduction 
This Statistical Analysis Plan (SAP) describes the planned statistical methods for all safety, 
efficacy, 
, 
 analyses for study LDK378A2205 final clinical study 
report.  
The content of this SAP is based on LDK378A2205 study protocol Amendment 6. All decisions 
regarding final analysis, as defined in the SAP document, have been made prior to database 
lock of the study data. 
1.1 
Study design 
This is a phase II, multi-center, open-label, five-arm study in which the efficacy and safety of 
oral ceritinib treatment will be assessed in patients with NSCLC metastatic to the brain and/or 
to leptomeninges harboring an ALK rearrangement using the FDA approved Vysis ALK Break 
Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity 
criteria). The study will enroll approximately 160 patients globally. 
Patients with ALK-positive NSCLC and active metastases to the brain and/or to leptomeninges 
will be included in this study. Patients without evidence of leptomeningeal carcinomatosis (LC) 
will be allocated into 1 of the 4 arms taking into account the patient’s history of prior therapy: 
prior radiation therapy (whole brain or stereotactic radiation therapy) to the brain (yes/no) and 
prior treatment with an ALK inhibitor (ALKi) (yes/no) (Table 1-1). The allocation of patients 
into the five study arms are described below.  
Table 1-1 
Allocation into Study Arms based on prior radiation to brain (yes/no) 
and prior treatment with ALK inhibitor (yes/no) 
 
Prior Radiation to the brain: 
YES 
Prior Radiation to the brain: 
NO 
Prior treatment with a ALKi1: YES 
Arm 1 
Arm 2 
Prior treatment with a ALKi: NO 
Arm 3 
Arm 4 
Leptomeningeal disease1 
Arm 5 
1Previous treatment with ALK inhibitors other than crizotinib is not allowed in Arms 1, 2 and 5. 
The description of patients in each of the five study arms is as follows: 
• Arm 1 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously treated with radiation to the brain and with 
prior exposure to an ALKi. 
• Arm 2 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously untreated with radiation to the brain but with 
prior exposure to an ALKi. 
• Arm 3 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously treated with radiation to the brain but with no 
prior exposure to an ALKi. 
• Arm 4 will include patients with metastases in the brain without evidence of 
leptomeningeal carcinomatosis, previously untreated with radiation to the brain and with 
no prior exposure to an ALKi. 


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• Arm 5 will include any patients with leptomeningeal carcinomatosis with or without 
evidence of active lesion at the baseline Gadolinium-enhanced brain MRI. 
All patients will receive the same treatment regimen regardless of the arm to which they are 
allocated. Treatment with ceritinib will continue until the patient experiences disease 
progression (in the brain, outside of the brain or both) as determined by the investigator 
according to RECIST 1.1, unacceptable toxicity that precludes further treatment, pregnancy, 
start of a new anticancer therapy, discontinues treatment at the discretion of the patient or 
investigator, lost to follow-up, death, or study is terminated by the Sponsor. 
Tumor response will be evaluated starting from the first day of treatment with ceritinib until the 
time of disease progression according to RECIST 1.1 as determined by investigator, withdrawal 
of consent for further follow-up, loss to follow-up or death. This schedule of tumor assessments 
must continue regardless of dose interruptions. In patients who discontinue treatment in the 
absence of progression, tumor assessments will continue every 8 weeks until progression of 
disease, withdrawal of consent for further follow-up, loss to follow-up or death. 
Primary analysis of any of the study arms or overall will occur only after enrollment in the 
specific study arms or overall is complete and all patients have completed at least 24 weeks of 
treatment with ceritinib or have discontinued earlier respectively. The study will end when both 
of the following conditions are met: 
1. At least 24 weeks after last patient treated in the study. 
2. At least 75% of patients have died, have been lost to follow-up, or have withdrawn 
consent for survival follow-up, or the last patient will be able to enter into a separate 
rollover study and/or other options for continued treatment, whichever comes first. 
If the end of study criteria is met before the primary analysis is conducted, a single final analysis 
and study report may be performed. If the end of the study criteria is not met by the time that 
the primary analysis is conducted, a final CSR will be produced reporting all available data 
collected up to last patient last visit (LPLV) including the additional study data collected after 
the primary analysis. 
1.2 
Objectives 
1.2.1 
Primary objective 
The primary objective is to evaluate the antitumor activity of ceritinib in patients with ALK-
positive NSCLC metastatic to the brain and/or to leptomeninges based on investigator 
assessment per RECIST 1.1. The primary endpoint is the overall response rate (ORR) defined 
as the proportion of patients with a best overall confirmed response of complete response 
(CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by the 
investigator. 
1.2.2 
Key secondary and other secondary objectives 
The key secondary objective is to evaluate Disease Control Rate (DCR) in patients with ALK-
positive NSCLC metastatic to the brain and/or to leptomeninges based on investigator 
assessment per RECIST 1.1. The DCR is defined as the proportion of patients with a best overall 
response of CR, PR or SD in the whole body, as assessed by the investigator per RECIST 1.1. 


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Other secondary objectives are: 
• To evaluate intracranial tumor-response related endpoints (OIRR, IDCR, TTIR and DOIR)  
as assessed by investigators and Blinded Independent Review Committee (BIRC) (using 
modified RECIST 1.1 criteria)  
• To evaluate extracranial tumor-response related endpoints (OERR, EDCR, TTER and 
DOER) as assessed by investigators and BIRC (using RECIST 1.1 criteria) 
• To evaluate whole body tumor-response related endpoints as assessed by investigators (TTR, 
DOR and PFS) and BIRC (ORR, DCR, TTR, DOR and PFS) (using RECIST 1.1 criteria) 
• To evaluate overall survival (OS) in patients with ALK-positive NSCLC metastatic to the 
brain and/or to leptomeninges  
• To evaluate safety in patients with ALK-positive NSCLC metastatic to the brain and/or to 
leptomeninges  
• 
 
 
1.2.3 
Exploratory objectives 
• To evaluate intracranial endpoints for patients with measurable brain metastases at baseline 
in Arms 1 to 4 (OIRR, TTIR and DOIR) and for patients with active brain lesions at baseline 
in Arms 1 to 4 (IDCR) using the Response Assessment in Neuro-Oncology (RANO) criteria 
for high grade gliomas (Wen et al 2010) by investigators and BIRC. 
2 
Statistical methods 
This section and its subsections will be imported to Section 9.7 of the CSR after the analyses 
have been conducted.  
The text will be changed to the past tense when imported into the CSR; references to Section 4 
of the RAP, where additional details are provided for programming implementation, may be 
removed in the CSR.  
In what follows, study drug refers to LDK378 (certinib). 


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2.1 
Data analysis 
Data will be analyzed by Novartis Oncology Biostatistics and Statistical Programming 
personnel according to the data analysis Section 10 of the LDK378A2205 protocol, which will 
be available in Appendix 16.1.1 of the Clinical Study Report (CSR). Important information is 
given in the following sections and details are provided, as applicable, in Section 4 from which 
Appendix 16.1.9 of the CSR will be extracted.  
SAS® version 9.4 (or later version if available at time of database lock) will be used in all 
analyses. 
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 withdrawal of informed consent will not be 
reported. Due to expected small size of enrollment at individual centers, no center effect will 
be assessed. Each analysis will use all data in the database up to the analysis cutoff date, 
determined prior to database lock. Data collected after patients’ withdrawal of informed consent 
for further participation in the study will not be reported (except for death date, which might be 
obtained from public records). 
Section 4.1 provides further details regarding data to be included in the analyses.  
General presentation of descriptive summaries 
Qualitative data (e.g., gender, race) will be summarized by frequency counts and percentages. 
Percentages will be calculated using the number of patients in the relevant population or 
subgroup, as the denominator.   
Continuous data (e.g., age, body weight) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum). 
All baseline characteristics, efficacy (except intracranial endpoints by RANO) and safety 
analyses will be presented by study arm (Arm 1, Arm 2, Arm 3, Arm 4 and Arm 5) and for all 
patients. 
In addition, all efficacy endpoints, except intracranial endpoints by RANO, will be presented 
by prior radiation to the brain (Arms 1+3 vs. Arms 2+4) and by prior ALK inhibitor use (Arms 
1+2 vs. Arms 3+4) and overall, for patients from Arms 1 through 4, unless otherwise specified. 
Intracranial endpoints by RANO will be presented by study arm for patients in Arm1 to Arm 4 
and overall, for patients from Arms 1 through 4. 
2.2 
Analysis sets 
A patient is considered to be enrolled into the study if they have signed a study informed 
consent. Only patients who have signed a study informed consent will be included in the 
analysis data sets. 
Full Analysis Set 
The Full Analysis Set (FAS) consists of all patients who received at least one dose of study 
drug.  


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The FAS will be used for summaries of baseline characteristics and all efficacy analyses, unless 
otherwise specified. 
The following endpoints will be analyzed on a subset of FAS:  
Patients with measurable brain metastases: Overall intracranial response rate (OIRR), Time to 
intracranial tumor response (TTIR) and Duration of intracranial response (DOIR)  
Safety Set 
The Safety Set consists of all patients who received at least one dose of study drug. All safety 
data will be analyzed using the Safety Set. The FAS and Safety Set in this study are identical. 
2.3 
Patient demographics and other baseline characteristics 
The FAS will be used for all patient demographic and baseline characteristic summaries and 
listings, unless otherwise specified. Summaries will be produced by study arm and for all 
patients. Listings will be produced by study arm. 


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Basic demographic and background data 
All demographic and baseline disease characteristics data will be summarized by study arm and 
for all patients. Categorical data (e.g. gender, race, ethnicity, WHO performance status, age 
groups: <65, 65-<85, ≥85 years, smoking history) will be summarized by frequency count and 
percentages. Continuous data (e.g. age, weight, height) will be summarized by descriptive 
statistics (as defined in Section 2.1).  
Diagnosis and extent of cancer 
Descriptive statistics and frequency counts and percentages will be tabulated by study arm,  as 
appropriate, for diagnosis and extent of cancer based on the data collected on the electronic 
Case Report Form (eCRF) including primary site of cancer, predominant histology/cytology, 
histological grade, time (in months) from initial diagnosis of primary site, stage at initial 
diagnosis, stage at time of study entry, time (in months) from initial diagnosis to first 
recurrence/progression, time (in months) from most recent relapse/progression, metastatic sites 
of cancer, number of metastatic sites of cancer, types of intracranial and extracranial lesions 
(target and non-target lesions) at baseline based on investigator and BIRC assessment, 
Intracranial lesion (target and non-target) location at baseline, disease burden (intracranial, 
extracranial and whole body) at baseline for target lesion based on investigator and BIRC (based 
on the data collected on the RECIST eCRF page). 
Medical history 
Medical history and ongoing conditions, including cancer-related conditions and symptoms, 
will be summarized and listed by study arm. Separate summaries will be presented for ongoing 
and historical medical conditions. The summaries will be presented by primary system organ 
class and preferred term, in each study arm and all patients. Medical history and current medical 
conditions are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Prior anti-cancer therapy 
Prior anti-neoplastic (anti-cancer) therapy will be listed in three separate categories: 1. 
medications, 2. radiotherapy, and 3. surgery.   
The number and percentage of patients who received any prior anti-neoplastic medications, 
prior antineoplastic therapy Crizotinib, prior anti-neoplastic radiotherapy, prior anti-neoplastic 
radiotherapy to the brain, or prior anti-neoplastic surgery will be summarized by study arm and 
for all patients.  
Prior anti-neoplastic medications will be summarized by study arm. Summaries will include 
chemotherapy (medication) setting, other therapy (medication) setting, number of prior 
regimens (crizotinib and other), therapy type, setting, best response at last treatment, time from 
last treatment start to progression and duration of last treatment best response. Prior 
antineoplastic medications will also be summarized by ATC class, preferred term and study 
arm. Prior antineoplastic therapy crizotinib will be summarized by study arm and includes 
setting, best response at last crizotinib treatment, time from last crizotinib treatment start to 
progression, duration of last crizotinib treatment best response and reason for discontinuation 
of last crizotinib treatment. 


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For radiotherapy and radiotherapy to the brain, time since last radiotherapy end to treatment 
start, locations, setting and method of last therapy will be summarized. For prior surgery, time 
since last surgery, procedure and residual disease at last surgery will be summarized. ATC class 
and preferred term will also summarize steroid use at the start of study drug. 
Screening phase disposition  
A patient who signs study informed consent but fails to satisfy all of the eligibility criteria for 
any reason will be considered a screen failure. These patients are not treated with study drug. 
Frequency counts and percentages will be tabulated for all enrolled patients as follows: 
• Number (%) of patients who completed screening phase (based on the presence of study 
phase completion date and the ‘Next phase entered’ is ‘Treatment’ in the ‘Screening Phase 
Disposition’ page);  
• Number (%) of patients who discontinued  during screening phase ( based on the presence 
of date of discontinuation and discontinuation / “subject status”  reason  entered and  ‘Will 
the subject continue into the next phase of the trial’ is ‘No’ in the ‘Screening Phase 
Disposition’ page); 
• Reasons for screening phase discontinuation (based on reasons recorded in Screening 
Phase Disposition’ page). 
All screen failure patients with reasons for screen failure will be listed.  
2.4 
Protocol deviations 
Frequency counts and percentages of patients in the FAS with any CSR reportable protocol 
deviations (related to study inclusion/exclusion criteria, conduct of the trial, patient 
management or patient assessment) will be tabulated by the deviation category by study arm 
and for all patients.  
All protocol deviations will be listed.  
2.5 
Patient disposition 
The FAS will be used for the patient disposition summary tables and listings. The following 
will be tabulated by study arm. 
Related to the treatment phase: 
• Number (%) of patients who are still on-treatment (based on the absence of the ‘End of 
Treatment Disposition’ page);  
• Number (%) of patients who discontinued treatment (based on completion of the ‘End of 
Treatment Disposition’ page with date of discontinuation and reason of discontinuation/ 
‘Subject Status’ entered); 
• Number (%) of patients who entered post treatment follow-up phase from treatment phase 
(based on ‘Next Phase Entered’ is ‘Post-treatment follow-up’ on the ‘End of Treatment 
Disposition’ page for patients who discontinued treatment); 
• Number (%) of patients who entered survival follow-up from treatment phase (based on 
‘Will the subject be followed for survival’ is ‘Yes’ on the ‘End of Treatment Disposition’ 
page for patients who discontinued treatment); 


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• Number (%) of patients who discontinued from study from treatment phase (based on ‘Will 
subject continue into the next phase of the trial’ is ‘No’ as entered on the ‘End of Treatment 
Disposition’ page for patients who discontinued treatment); 
• Primary reasons for study treatment discontinuation (based on discontinuation reasons 
entered under ‘Subject Status’ in the ‘End of Treatment Phase Disposition’ page). 
Related to the post-treatment follow-up phase: 
• Number (%) of patients who are still in the post-treatment follow-up phase (based on 
presence of ‘End of Treatment Disposition’ and absence of ‘End of Post Treatment Phase 
Disposition’ page); 
• Number (%) of patients who discontinued from the post-treatment follow-up (based on 
completion of ‘End of Post Treatment Phase Disposition’’ page with date of discontinuation 
and discontinuation reasons entered under ‘Subject Status’); 
• Number (%) of patients who entered survival follow-up (based on completion of ‘End of 
Post Treatment Phase Disposition’’ page with date of discontinuation and discontinuation 
reasons entered under ‘Subject Status’ and ‘Will the subject be followed for survival’ is 
‘Yes’ for patients who discontinued from the post-treatment follow-up); 
• Number (%) of patients who discontinued from study (based on completion of ‘End of Post 
Treatment Phase Disposition’ page with date of discontinuation and discontinuation reasons 
entered under ‘Subject Status’ and ‘Will subject be followed for survival’ is ‘No’ for 
patients who discontinued from the post-treatment follow-up); 
• Primary reasons for discontinuation from the post-treatment follow-up (based on 
discontinuation reasons entered under ‘Subject Status’ in the ‘End of Post Treatment 
Phase Disposition’ page). 
2.6 
Treatments (study drug, concomitant therapies, compliance) 
The Safety Set will be used for all medication data summaries and listings unless otherwise 
specified. Summaries will be produced by study arm and for all patients. Listing will be 
produced by study arm. 
Study drug and study treatment 
Study drug and study treatment both refer to LDK378 (ceritinib) and will be used 
interchangeably. 
Date of first/last 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 was administered and recorded on the Dosage Administration Record (DAR) 
eCRF. For the sake of simplicity, the date of first administration of study drug will also be 
referred to as start date 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 was administered and recorded on the DAR eCRF. This date will also be referred to 
as the last date of study drug. 
Study day 


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The study day for all assessments (e.g. tumor assessment, death, disease progression, tumor 
response, performance status, adverse event onset, laboratory abnormality occurrence, vital sign 
measurement, dose interruption etc.) will be calculated using the start date of study drug as the 
origin. For assessments occurring after or on the start date of study drug, study day will be 
calculated as: 
Study Day = Date of the assessment/ Event date - start date of study drug + 1. 
The first day of study drug is therefore study day 1.  
For any assessment or events such as baseline disease characteristics or medical history (e.g., 
time since diagnosis of disease) occurring prior to the start of the study drug, study day will be 
negative and will be calculated as: 
Study Day = Event date - start date of study drug. 
The study day will be displayed in the relevant data listings. 
Baseline 
Baseline is the result of an investigation describing the “true” uninfluenced state of the patient. 
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the date of start of study treatment is taken as “baseline” value or “baseline” 
assessment. 
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken or ‘‘baseline” assessment.  
If an assessment is planned to be performed prior to the first dose of study treatment in the 
protocol and the assessment is performed on the same day as the first administration of study 
treatment, it will be assumed that it was performed prior to study treatment administration, if 
assessment time point is not collected or is missing. 
If assessment time points are collected, the observed time point will be used to determine pre-
dose on study day 1 for baseline calculation. Unscheduled assessments will be used in the 
determination of baseline. See Section 4.7.2 for further details on derivation of baseline for 
laboratory data and ECGs.  
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1, one being reported to the cycle 1 day 1 visit, the 
other reported to the end of treatment (EOT) visit. Data reported at the EOT visit are not eligible 
for baseline selection. 
Dose exposure and intensity 
Definitions of duration of exposure, cumulative dose, average daily dose, dose intensity (DI), 
relative dose intensity (RDI), as well as intermediate calculations, include: 
• Duration of exposure (days): 
last date of study drug  − first date of study drug + 1 
(periods of interruption are not excluded)  
• Cumulative dose (mg): 
total dose of study drug taken by a patient in the study 
• Number of dosing days (days): 
duration of exposure − number of zero dose days 


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• Average daily dose (mg/day): 
cumulative dose (mg) ∕ number of dosing days (days) 
• DI (mg/day): 
cumulative dose (mg) ∕ duration of exposure (days) 
• RDI (%): 
100 × [DI (mg/day) ∕ planned dose intensity (750 
mg/day)] 
Note: given the planned ceritinib dose of 750 mg/day, the planned dose intensity can be 
calculated as: 
PDI (mg/day) = cumulative planned dose (mg)/Duration of exposure (days), 
where  
cumulative planned dose (mg) = Protocol planned dose of 750 (mg)* Duration of 
exposure. 
then, RDI (%) which is calculated as 100*DI/PDI can be simplified as shown above. 
Duration of exposure to study drug, cumulative dose, average daily dose, DI and RDI will be 
summarized by study arm and for all patients. In addition, the duration of exposure to study 
drug will be categorized into time intervals and frequency counts and percentages of patients 
with exposure in each time interval will be presented. Frequency counts and percentages of 
patients who have dose changes, reductions or interruptions, and the corresponding reasons, 
will be summarized by study arm and for all patients. Time to first dose reduction and time to 
first dose interruption will be summarized by study arm and for all patients, using summary 
statistics along with frequency counts and percentages for pre-specified time intervals  
Listings of all doses of the study drug along with dose change and dose interruption reasons 
will be produced.   
Section 4.5 provides further details on the definition of dose changes and interruptions. 
Concomitant therapy 
Concomitant therapies are defined as any medications (excluding study drug, prior 
antineoplastic treatments and blood transfusions), surgeries or procedures (including physical 
therapy) administered in the study and are recorded in the Prior and Concomitant Medications 
and the Surgical and Medical Procedures eCRF, respectively. 
Concomitant medications will be coded using the WHO Drug Reference Listing (WHO DRL) 
dictionary that employs the WHO Anatomical Therapeutic Chemical (WHO ATC) 
classification system. Surgeries or procedures will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. All summaries will be tabulated using 
frequency counts and percentages by study arm. 
Concomitant therapies will be summarized by ATC class and preferred term by study arm and 
for all patients. These summaries will include: 1) medications starting on or after the start of 
study drug but starting no later than 30 days after last dose of study drug; and 2) medications 
starting prior to the start of study drug but continuing after the start of study drug. 
All concomitant therapies and surgeries and medical procedures will be listed. Any concomitant 
therapies starting and ending prior to the start of study drug or starting more than 30 days after 
the last date of study drug will be flagged in the listings.  


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Antineoplastic therapy after discontinuation of study drug 
The FAS will be used for all listings and summaries of antineoplastic therapies initiated after 
discontinuation of study drug. All summaries will be tabulated by study arm and for all patients, 
using frequency counts and percentages. 
Antineoplastic medications initiated after discontinuation of study drug will be summarized by 
Anatomical Therapeutic Chemical (ATC) class, preferred term and listed. 
Antineoplastic radiotherapy since discontinuation of study treatment will be summarized and 
listed. 
Antineoplastic surgery since discontinuation of study treatment will be summarized by primary 
system organ class and preferred term and listed. 
2.7 
Analysis of the primary variable 
The primary objective is to evaluate the anti-tumor activity of ceritinib in patients with ALK-
positive NSCLC metastatic to the brain and/or to leptomeninges.  
2.7.1 
Variable 
The primary endpoint used to evaluate the anti-tumor activity of ceritinib is the overall response 
rate (ORR), which is defined as the proportion of patients with a best overall confirmed response 
(BOR) of CR or PR in the whole body, as assessed per RECIST 1.1 by the investigator. 
Best overall response 
The BOR will be assessed based on reported lesion responses at different evaluation time points. 
Both CR and PR must be confirmed by repeat assessments performed not less than 4 weeks 
after the criteria for response are first met. The next scheduled assessment may be used for 
purposes of confirmation of response.   
BOR 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  
PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying as a CR)  
• SD = at least one SD assessment (or better) > 7 weeks after start of study drug (and not 
qualifying as a  CR or PR) 
• PD = progression ≤ 17 weeks after start of study drug (and not qualifying as a CR, PR or 
SD) 
• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 7 weeks or progression within the first 17 weeks) 
The cut-off for SD too early and PD too late were chosen based on tumor assessment schedule. 
Only tumor assessments performed before the start of any further anti-neoplastic therapies (i.e. 
any additional secondary anti-neoplastic therapy or anti-cancer surgery) will be considered in 


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the assessment of BOR.  If a patient receives any further anti-neoplastic therapy while on study, 
any subsequent assessments will be excluded from the BOR determination. Further anti-
neoplastic therapies will be identified from the data collected on ‘Anti-neoplastic therapies 
since last date of study drug’ as appropriate. Clinical deterioration will not be considered as 
documented disease progression. Patients with BOR ‘unknown’ will be summarized by reason 
for having unknown status. The following reasons will be used: 
• No valid post-baseline assessment 
• All post-baseline assessments have overall response UNK 
• New anti-neoplastic therapy started before first post-baseline assessment 
• Stable disease (SD) too early (≤ 7 weeks after start date of study drug) 
• PD too late (> 17 weeks after start date of study drug). 
Special (and rare) cases where BOR is ‘unknown’ due to both early SD and late PD will be 
classified as ‘SD too early’. In case, a patient had only a non-measurable disease at baseline, 
same cut-off (≤ 7 weeks after start date of study drug) will be applied for a response of non -
CR/non-PD too early. 
2.7.2 
Statistical hypothesis, model, and method of analysis 
The primary efficacy analysis will be performed on the FAS. This is an estimation based study 
and no statistical testing of hypothesis will be conducted.  
The primary efficacy endpoint ORR per investigator in the whole body will be estimated and 
the 95% exact binomial (Clopper and Pearson 1934) confidence intervals (CIs) will be provided 
by study arm and for all patients. Exact binomial confidence intervals will be used since the 
confidence limits based on the normal approximation are not bounded by the [0, 1] interval, 
meaning that for rates close to 0 or 1, the upper limit of the normal approximation interval for 
the proportion could exceed 1 or the lower limit could be negative.  
Additionally, the ORR in the whole body will also be summarized by prior radiation to the brain, 
prior ALK inhibitor use and overall using the data from Arms 1 through 4.  
2.7.3 
Handling of missing values/censoring/discontinuations 
Confirmed PR or CR reported prior to any additional anticancer therapy will be considered as 
responses in the calculation of the ORR, irrespective of the number of missed assessments 
before response. 
Patients with a best overall response (BOR) of ‘Unknown’ per RECIST 1.1 will be considered 
as non-responders when estimating ORR. Patients who have disease progression and continue 
to receive study drug after progression will qualify for PD at the time of progression and will 
be counted as PD in the derivation of ORR and any other efficacy endpoints. 
2.7.4 
Supportive analyses 
Waterfall plots representing the best percentage change from baseline in the sum of the tumor 
diameters for target lesions will be produced by prior ALKi use (Yes/No) for FAS. See Section 
4.6.1 for details on construction of waterfall graphs. 


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2.8 
Analysis of secondary variables 
2.8.1 
Efficacy 
Table 2-1 summarizes all tumor related endpoints and the population for analysis. The 
definitions and details on the derivation of the secondary endpoints are given in the following 
sections. Confirmation of response is required for all response endpoints, as per RECIST 1.1 
and RANO. Further details and rules needed for programmatic implementation of RECIST 1.1 
guidelines and RANO guidelines are provided in Section 4.6.1 and Section 4.6.2 respectively. 
Table 2-1 
Summary of tumor-related efficacy endpoints and analysis 
populations 
Category 
Efficacy endpoints * 
By investigators or 
BIRC 
Primary analysis 
population# 
Primary endpoint 
ORR 
Investigators 
FAS 
Key secondary endpoint 
DCR 
Investigators 
FAS 
Other secondary endpoints 
 
 
 
   Intracranial endpoints 
OIRR 
Both 
FAS and FAS subset**  
 
IDCR 
Both 
FAS and FAS subset** 
 
IDCR at week 8 and 
week 16 
Both 
FAS 
 
TTIR 
Both 
FAS and FAS subset**  
 
DOIR 
Both 
FAS and FAS subset** 
   Extracranial endpoints 
OERR 
Both 
FAS 
 
EDCR 
Both 
FAS 
 
EDCR at week 8 and 
week 16 
Both 
FAS 
 
TTER 
Both 
FAS 
 
DOER 
Both 
FAS 
  Whole body endpoints 
ORR 
BIRC 
FAS 
 
DCR 
BIRC 
FAS 
 
TTR 
Both 
FAS 
 
DOR 
Both 
FAS 
 
PFS 
Both 
FAS 
 
OS 
N/A 
FAS 
Exploratory endpoints 
 
 
 
Intracranial endpoints 
OIRR by RANO 
Both 
FAS subset** 
 
TTIR by RANO 
Both 
FAS subset** 
 
DOIR by RANO 
Both 
FAS subset** 
 
IDCR by RANO 
Both 
FAS 
#: Efficacy endpoints per RECIST or Modified RECIST will be analyzed 1) by study arm and for all patients 
and 2) by prior radiation to brain and prior ALK inhibitor use and overall for patients in arm 1-4. Efficacy 
endpoints per RANO will be analyzed by study arm and overall for patients in arm 1-4. 
*: Efficacy endpoints are evaluated by RECIST 1.1 or Modified RECIST 1.1 unless otherwise noted. 
 **: FAS subset with measurable brain metastases at baseline. 


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2.8.1.1 
Key secondary endpoint 
The key secondary objective is to evaluate Disease Control Rate (DCR). The DCR is defined 
as the proportion of patients with best overall response (BOR) of CR, PR or SD in the whole 
body, as assessed per RECIST 1.1 by the investigator. 
DCR will be estimated and the exact binomial 95% CI (Clopper & Pearson, 1934) will be 
presented by study arm and for all patients.  
Supportive and sensitivity analyses 
The DCR will also be summarized by prior radiation to the brain and by prior ALK inhibitor 
use. 
2.8.1.2 
Other secondary endpoints 
The following intracranial, extracranial and whole body (for lesions in and outside the brain) 
tumor-response related endpoints will be assessed separately based on investigator assessment 
and BIRC assessment per RECIST 1.1 (OERR, EDCR, TTER, DOER, ORR, DCR, TTR, DOR 
and PFS) or Modified RECIST 1.1 (OIRR, IDCR, TTIR, DOIR). 
2.8.1.2.1 Intracranial endpoints 
Overall intracranial response rate (OIRR): OIRR is calculated based on response 
assessments in the brain for patients having measurable brain metastases at baseline. The OIRR 
is defined as the proportion of patients with a best overall confirmed response of CR or PR in 
the brain as assessed per modified RECIST 1.1.  
OIRR will be estimated and the exact binomial 95% CI will be presented by study arm and for 
all patients. OIRR will also be summarized by prior radiotherapy to the brain (yes, no) and prior 
ALK inhibitor use (yes, no) and overall using the data from Arms 1 through 4. OIRR by the 
investigator and by BIRC will be summarized separately. 
Same analysis on OIRR will be conducted for patients having evaluable (measurable or non-
measurable) brain metastases at baseline. 
Intracranial disease control rate (IDCR) at 8 and 16 weeks and overall: IDCR is calculated 
based on response assessments in the brain for patients having evaluable (measurable or non-
measurable) brain metastases at baseline. In what follows, CR, PR and SD are possible 
responses only for patients with measurable brain metastases at baseline, while non-CR/non-
PD is a possible response only for patients without measurable brain metastases at baseline. 
• The IDCR at 8 and 16 weeks is defined as the proportion of patients with CR, PR, SD 
or non-CR/non-PD assessment in the brain at Week 8 and Week 16 intracranial tumor 
evaluations respectively, taking into consideration 4-week window for each 
assessment, i.e., assessment done between study day 29 and 85 (both inclusive) for 
week 8 and study day 86 and 141 (both inclusive) for week 16, as per modified 
RECIST 1.1. If there are multiple tumor assessments within the defined window, the 
following rules should be used hierarchically to select the overall response 
contributing to the xx-week IDCR rate:  
1) PD - If at least one tumor assessment with overall response of PD;  
2) Unknown - if all tumor assessment with overall responses of unknown; 


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3) CR/PR/SD - Overall response from the latest tumor assessment within the 
window  
The assessment of SD too early or PD too late will be considered as Unknown and 
following the same rule specified in SAP Section 2.7.1. 
• IDCR overall is defined as the proportion of patients with a best overall response of CR, 
PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1. 
IDCR will be estimated and the exact binomial 95% CI will be presented by study arm and for 
all patients. IDCR will also be summarized by prior radiotherapy to the brain (yes, no) and prior 
ALK inhibitor use (yes, no) and overall using the data from Arms 1 through 4. IDCR by the 
investigator and by BIRC will be summarized separately. 
Same analysis on overall IDCR will be conducted for patients having measurable brain 
metastases at baseline. 
Time to intracranial tumor response (TTIR): TTIR is defined as the time from the date of 
the first dose of ceritinib to the date of the first documented response (CR or PR) in the brain 
as assessed per modified RECIST 1.1 criteria for patients with measurable brain metastases at 
baseline. 
TTIR will be summarized by frequency counts in time intervals and using descriptive statistics 
for patients with confirmed CR or PR. 
These analyses of TTIR will be performed separately based on investigator and BIRC 
assessment. 
Same analysis on TTIR will be conducted for patients having evaluable (measurable or non-
measurable) brain metastases at baseline. 
Duration of intracranial response (DOIR): Among patients with measurable brain metastases 
at baseline and a confirmed response (PR or CR) in the brain per Modified RECIST 1.1, DOIR 
is defined as the time from the first documented response (PR or CR) in the brain to the date of 
the first documented disease progression in the brain or death due to any cause. If a patient has 
not had an event, DOIR is censored at the date of last adequate tumor assessment. 
The censoring and event date options to be considered for the main analysis are presented in 
Table 2-2. Please note that the intracranial/extracranial/whole body tumor assessments apply to 
intracranial (DOIR), extracranial (DOER) and whole body (DOR and PFS) endpoints, 
respectively. 
Table 2-2 
Outcome and event dates for DOIR, DOER, DOR and PFS analyses 
 
Situation 
Date 
Outcome 
A 
No baseline intracranial/extracranial/ whole 
body assessment 
Date of first dose of study 
drug a 
Censored 
 
B 
Progression at or before next scheduled 
intracranial/extracranial/ whole body 
assessment 
Date of progression 
 
Progressed 
 
C1 
Progression or death after exactly one 
missing intracranial/extracranial/ whole body 
assessment 
Date of progression (or 
death) 
Progressed 
 


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Situation 
Date 
Outcome 
C2 
Progression or death after two or more 
missing intracranial/extracranial/ whole body 
assessments 
Date of last adequate 
intracranial/extracranial/ 
whole body assessment b 
Censored 
 
D 
No progression 
Date of last adequate 
intracranial/extracranial/ 
whole body assessment b 
Censored 
 
E 
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression 
based on investigator claim 
N/A 
 
 
Information ignored. 
Outcome derived based 
on radiology data only. 
F 
New anticancer therapy given 
Ignore the new anticancer 
therapy and follow 
situations above (ITT 
approach) 
As per above situations 
 
a 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 
b After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 14.2.25 of 
(Appendix 2) of the LDK378A2205 protocol. 
DOIR will be described by study arm using Kaplan-Meier methods, including estimated median 
(in months) with 95% CI, 25th and 75th percentiles and Kaplan-Meier estimated probabilities 
with corresponding 95% CIs at pre-specified time points. 
DOIR will also be summarized by prior radiotherapy to the brain (yes, no) and prior ALK 
inhibitor use (yes, no) using the data from Arms 1 through 4. 
These analyses of DOIR will be performed separately based on investigator assessment and 
based on BIRC assessment.  
Same analysis on DOIR will be conducted for patients having evaluable (measurable or non-
measurable) brain metastases at baseline. 
2.8.1.2.2 Extracranial endpoints 
Overall extracranial response rate (OERR): OERR is defined as the proportion of patients 
with a best overall confirmed response of CR or PR outside of the brain, as assessed per RECIST 
1.1.  
OERR will be estimated and the exact binomial 95% CI will be presented by study arm and for 
all patients. OERR will also be summarized by prior radiotherapy to the brain (yes, no) and 
prior ALK inhibitor use (yes, no) and overall using the data from Arms 1 through 4.  
OERR by the investigator and by BIRC will be summarized separately. 
Extracranial disease control rate (EDCR) at 8 and 16 weeks and overall: 
• EDCR at 8 and 16 weeks is defined as the proportion of patients with CR, PR or SD 
outside of the brain at Week 8 and Week 16 extracranial tumor evaluations respectively, 
as assessed per RECIST 1.1. Same method will be used as for IDCR. See details in 
Section 2.8.1.2.1.  
• EDCR overall is defined as the proportion of patients with a best overall response of CR, 
PR or SD outside of the brain as assessed per RECIST 1.1. 


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EDCR will be estimated and the exact binomial 95% CI will be presented by study arm. EDCR 
will also be summarized by prior radiotherapy to the brain (yes, no) and prior ALK inhibitor 
use (yes, no) and overall using the data from Arms 1 through 4.  
EDCR by the investigator and by BIRC will be summarized separately. 
Time to extracranial tumor response (TTER): TTER is defined as the time from the date of 
the first dose of ceritinib to the date of the first documented response (CR or PR) outside of the 
brain as assessed per RECIST 1.1 criteria.  
TTER will be summarized by frequency counts in time intervals and using descriptive statistics 
for patients with confirmed CR or PR.   
These analyses of TTER will be performed separately based on investigator assessment and 
based on BIRC assessment. 
Duration of extracranial response (DOER): Among patients with a confirmed response (PR 
or CR) outside of the brain per RECIST 1.1, DOER is defined as the time from the first 
documented response (PR or CR) outside of the brain to the date of the first documented disease 
progression outside of the brain or death due to any cause.  
DOER will be described by study arm using Kaplan-Meier methods, including estimated 
median (in months) with 95% CI, 25th and 75th percentiles and Kaplan-Meier estimated 
probabilities with corresponding 95% CIs at pre-specified time points. . 
Additionally, DOER will also be presented by prior radiotherapy to the brain (yes, no) and prior 
ALK inhibitor use (yes, no) and overall using the data from Arms 1 through 4. 
These analyses of DOER will be performed separately based on investigator assessment and 
based on BIRC assessment. 
2.8.1.2.3 Whole body endpoints 
ORR by BIRC: The evaluation of ORR will be repeated based on BIRC assessment by study 
arm and for all patients. Additionally, ORR by BIRC will also be presented by prior 
radiotherapy to the brain (yes, no) and prior ALK inhibitor use (yes, no) and overall using the 
data from Arms 1 through 4. 
DCR by BIRC: The evaluation of DCR will be repeated based on BIRC assessment by study 
arm and for all patients. Additionally, DCR by BIRC will also be presented by prior 
radiotherapy to the brain (yes, no) and prior ALK inhibitor use (yes, no) and overall using the 
data from Arms 1 through 4. 
Time to tumor response (TTR): TTR is defined as the time from the date of the first dose of 
ceritinib to the date of the first documented response (CR or PR) in the whole body as assessed 
per RECIST 1.1 criteria. 
TTR will be summarized by frequency counts in time intervals and using descriptive statistics 
for patients with confirmed CR or PR. 
 


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These analyses of TTR will be performed separately based on investigator assessment and based 
on BIRC assessment. 
Duration of response (DOR): Among patients with a confirmed response (PR or CR) in the 
whole body per RECIST 1.1, DOR is defined as the time from the first documented response 
(PR or CR) to the date of the first documented disease progression or death due to any cause. 
DOR will be described by study arm and for all patients using Kaplan-Meier methods, including 
estimated median (in months) with 95% CI, 25th and 75th percentiles and Kaplan-Meier 
estimated probabilities with corresponding 95% CIs at pre-specified time points. 
Additionally, DOR will also be presented by prior radiotherapy to the brain (yes, no) and prior 
ALK inhibitor use (yes, no) and overall using the data from Arms 1 through 4. 
These analyses of DOR will be performed separately based on investigator assessment and 
based on BIRC assessment. 
Progression-free survival (PFS): PFS is defined as the time from the date of the first dose of 
ceritinib to the date of the first radiologically documented disease progression in the whole body 
per RECIST 1.1 or death due to any cause. A patient who has not progressed or died at the date 
of the analysis cut-off will be censored at the time of the last adequate tumor evaluation 
performed on or before the cut-off date. By default, if disease progression or death for any 
reason is documented after one single missing tumor evaluation, the actual event date of disease 
progression/death will be used for the PFS event date. If disease progression or death for any 
reason is documented after two or more missing tumor evaluations, the PFS time of these 
patients will be censored at the date of the last adequate tumor evaluation without PD. Refer to 
Table 2-2 for censoring and event date options and outcomes for PFS. See also Section 4.6.1 
describing the special case of a missing baseline tumor assessment. 
PFS will be described by study arm using Kaplan-Meier methods, including estimated median 
(in months) with 95% CI, 25th and 75th percentiles and Kaplan-Meier estimated probabilities 
with corresponding 95% CIs at pre-specified time points. Censoring reasons will also be 
summarized. 
These analyses will be performed separately based on investigator assessment and based on 
BIRC assessment. Additionally, PFS will also be presented by prior radiotherapy to the brain 
(yes, no) and prior ALK inhibitor use (yes, no) and overall using the data from Arms 1 through 
4. 
Overall survival (OS): OS time is defined as time from the date of first dose of ceritinib to the 
date of death due to any cause. OS time for patients who are alive by the date of the analysis 
cut-off or are lost to follow-up will be censored at the date of last contact.  
OS will be described by study arm using Kaplan-Meier methods, including estimated median 
(in months) with 95% CI, 25th and 75th percentiles and Kaplan-Meier estimated probabilities 
with corresponding 95% CIs at pre-specified time points. Censoring reasons will also be 
summarized.  
OS will be analyzed by study arm using the data from study arms 1 through 5. However, Kaplan-
Meier curves of OS will not be produced for Arm 5 alone if the number of patients enrolled in 
this arm is ≤ 10.  


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Additionally, OS will also be presented by prior radiotherapy to the brain (yes, no) and prior 
ALK inhibitor use (yes, no) and overall using the data from Arms 1 through 4. 
Duration of Follow-up  
Follow-up in the study will be summarized using the following methods to provide a 
comprehensive assessment of follow-up for all patients.  
Summary of duration between start date of study drug and cut-off date, and follow-up times for 
PFS/OS, are defined as follows: 
• Duration between start date of study drug and data cut-off date = (Cut-off date – Start date 
of study drug + 1) / 30.4375 (months). 
• Follow-up time = (Date of event or censoring – Start date of study drug + 1) / 30.4375 
(months) regardless of censoring.  Date of censoring is defined as the last adequate tumor 
assessment date for PFS or last contact date (when the patient is known as alive) for OS.  
All summaries will be reported in months (see Section 4.3). The calculations for PFS will be 
based on investigator assessment and BIRC assessment.  
Exploratory endpoints 
 
 
 
 
 
 
OIRR by RANO: OIRR by RANO will be estimated and the exact binomial 95% CI will be 
presented by study arm. OIRR by the investigator and by BIRC will be summarized separately. 
IDCR by RANO: IDCR by RANO will be estimated and the exact binomial 95% CI will be 
presented by study arm. IDCR by the investigator and by BIRC will be summarized separately. 
TTIR by RANO: Similar to TTIR by Modified RECIST 1.1, TTIR by RANO will be analyzed 
using frequency count and descriptive statistics by study arm.  
These analyses of TTIR will be performed separately based on investigator assessment and 
based on BIRC assessment. 
DOIR by RANO: Similar to DOIR by Modified RECIST 1.1, DOIR by RANO will be 
analyzed using Kaplan-Meier methods by study arm.  
 
 
2.8.2 
Safety 
All safety analyses will be performed based on the Safety Set by study arm (Arms 1 to 5) and 
all patients.  
Observation periods for the analyses 


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The overall observation period will be divided into three mutually exclusive segments: 
• Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study drug 
• On-treatment period: 
o For discontinued patients, from day of first dose of study drug to 30 days after last 
dose of study drug 
o For ongoing patients, from day of first dose of study drug to the data cut-off date 
• Post-treatment period: starting at day 31 after last dose of study drug 
The safety summary tables will include only assessments collected during the on-treatment 
period.  
For select items, shift tables or change from baseline summaries generated for laboratory, ECG, 
vital signs and change score (WHO PS) generation may use data from pre-treatment period for 
baseline calculations.  
All data, regardless of observation period, will be listed and assessments collected during the 
pre-treatment and post-treatment period will be flagged in all the listings. 
Adverse events (AEs) 
 
AEs will be coded using MedDRA using the latest version available prior to clinical database 
lock and will be graded using Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03. If CTCAE grading exists for an AE, grades 1, 2, 3, or 4 corresponding to the 
severity of mild, moderate, severe, and life-threatening, respectively, will be used. CTCAE 
grade 5 (death) will not be used in this study; rather, this information will be collected on the 
“End of Treatment Disposition”, “End of Post Treatment Phase Disposition” or “Death” eCRF 
pages. 
All AE summaries will be summarized (frequency counts and percentages) by primary system 
organ class (SOC) and/or preferred term (PT), maximum severity grades, and relation to study 
drug except where otherwise noted. A patient with multiple CTC grades for an AE will be 
summarized under the maximum CTC grade recorded for the event.  
The following AE summaries will be produced: 
• AEs regardless of study drug relationship 
• AEs suspected to be study drug related 
• All deaths, by primary SOC and PT 
• On treatment deaths, by primary SOC and PT 
• SAEs regardless of study drug relationship 
• SAEs suspected to be study drug related 
• AEs associated with discontinuation of study drug 
• AEs requiring dose adjustment 
• AEs requiring study drug interruption 
• AEs requiring dose adjustment or study drug interruption 
• AEs requiring significant additional therapy 


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• AEs excluding SAEs 
 
Per safety disclosure, two tables for on-treatment death/SAE and non-SAE will be 
summarized but not included in the CSR.  
Adverse events of special interest 
Adverse events of special interest (AESIs) are defined as AEs within the following categories/ 
groupings of preferred terms: 
• Hepatotoxicity 
• Interstitial lung disease/pneumonitis 
• QTc prolongation 
• Hyperglycemia 
• Bradycardia 
• GI toxicity (nausea, diarrhea, and vomiting) 
• Pancreatitis  
AESIs are defined at the project level and may be updated based on emergent data to reflect 
new AESIs at the time of analysis. The AESIs listed above will be identified based on a list of 
preferred terms. The final list of preferred terms is available in the electronic case retrieval 
strategy and will be presented in a separate annex of the document. These AESIs will be 
summarized for each grouping, by preferred term, as follows: 
• All AESIs  
• CTC grade 3/4 AESIs 
• AESIs suspected to be study drug related 
• CTC grade 3/4 AESIs suspected to be drug related 
• Serious AESIs 
• AESI leading to study drug discontinuation 
• AESIs requiring dose adjustment or study drug interruption 
• AESIs requiring dose adjustment 
• AESIs requiring study drug interruption 
Laboratory data 
For laboratory data assessments, data from all sources (central and local laboratories) will be 
combined. The summaries will include all laboratory assessments collected in the on-treatment 
period. All laboratory assessments will be listed and those collected prior to first dose of study 
drug or later than 30 days after study drug discontinuation will be flagged in the listings.  
Laboratory data will be classified (by Novartis Oncology Statistical Programming) into CTC 
grades according to the NCI CTCAE v4.03. For all reports, CTC grade is always obtained on 
the converted measurement in SI unit.  Grade 5 will not be used. The CTC grade 0 will be 
assigned as below in different scenarios:   


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1. For laboratory parameters defined by criteria based on normal range only, a severity grade 
of 0 will be assigned when the value is within normal limits.    
2. For laboratory, parameters whose grade is defined by criteria based on normal range and 
absolute values (e.g. platelet count decrease). A severity grade of 0 will be assigned when 
the value is within normal limits.  
3. For laboratory parameters whose grade is defined by criteria based on normal range and the 
change from baseline value, with no other associated clinical criteria such as concomitant 
medication (e.g. creatinine increased) the following will be applied. For the baseline grading 
and for the grading of post-baseline laboratory values with missing baseline grading, the 
grade will be derived using the criteria based only on the normal range as per CTCAE v4.03. 
A severity grade of 0 will be assigned when the post-baseline value is ≤ ULN (for hyper) or 
≥ LLN (for hypo). 
Parameters for which a grading does not exist will be classified into low/normal/high group by 
means of laboratory normal ranges. 
The following summaries will be produced for the hematology and biochemistry laboratory 
data (by laboratory parameter): 
• Shift tables using CTC grades to compare baseline to the worst post-baseline value for 
laboratory parameters with CTC grades  
• Shift tables using low, normal, high (as well as low and high combined) classifications to 
compare baseline to the worst post-baseline value for laboratory parameters where CTC 
grades are not defined.  
The following lab parameters will be summarized:  
• Hematology: absolute lymphocytes, absolute neutrophils, hemoglobin (anemia), WBC, 
platelet counts, absolute basophils, absolute eosinophils, absolute monocytes, RBC. 
• Biochemistry: alkaline phosphatase (ALP), SGPT (ALT), SGOT (AST), total bilirubin, 
amylase, lipase, potassium (hyper and hypo), sodium (hyper and hypo), creatinine, glucose 
(hyper and hypo), phosphate, albumin, calcium (corrected for albumin), magnesium, 
creatinine clearance, direct bilirubin, blood urea nitrogen (BUN) or urea, GGT. 
• For bi-directional parameters, both hyper and hypo summaries will be presented.  
All hematology and biochemistry will be listed as per protocol. Further, following laboratory 
parameters will be presented in listings and will not be summarized:  
• Coagulation: INR, pro-thrombin time (PT) or Quick Test. 
Other laboratory parameters collected and not described above may be summarized if clinically 
indicated.  
The following listings will be produced for the laboratory data for all laboratory parameters 
where CTC grades are defined: 
• Listing of patients with laboratory abnormalities of CTC grade 3 or 4. 
• Listing of all laboratory data with values flagged to show the corresponding CTC grades 
and the classifications relative to the laboratory reference ranges. 


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Liver function tests (LFTs) of interest for ceritinib are total bilirubin (TBILI), ALT, AST and 
ALP.  In what follows, AT refers to ALT or AST values. LFTs will be summarized as follows: 
• Shift tables of baseline vs. worst post-baseline on-treatment values for the categories: 
o TBILI ≤ 2xULN, TBILI > 2xULN and missing TBILI 
o ALT ≤ 3xULN, ALT > 3xULN and missing ALT 
o AST ≤ 3xULN, AST > 3xULN and missing AST 
o ALP < 2xULN, ALP ≥ 2xULN and missing ALP 
• Frequency counts and percentages of patients with worst post-baseline on-treatment 
values in the categories: 
o ALT > 3xULN, ALT > 5xULN, ALT > 10xULN, ALT > 20xULN 
o AST > 3xULN, AST > 5xULN, AST > 10xULN, AST > 20xULN 
o AT > 3xULN, AT > 5xULN, AT > 10xULN, AT > 20xULN 
o TBILI > 2xULN 
o Concurrent ALT > 3xULN and TBILI > 2xULN 
o Concurrent AST > 3xULN and TBILI > 2xULN 
o Concurrent AT > 3xULN and TBIL>2xULN 
o Concurrent AT > 3xULN and TBILI > 2xULN and ALP < 2xULN 
o Concurrent AT > 3xULN and TBILI > 2xULN and ALP ≥ 2xULN 
Concurrent measurements are those occurring on the same date. 
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a post-baseline 
TBILI > 2xULN, ALT> 3xULN or AST > 3xULN will be provided. 
2.8.2.1 
Other safety data 
ECGs 
ECG data will be analyzed based on central laboratory reported results. The summaries will 
include all ECG assessments performed in the on-treatment period.  All ECG assessments will 
be listed, and those collected prior to first dose of study drug or later than 30 days after study 
drug discontinuation will be flagged in the listing.  
Selecting Primary QT Correction for Heart Rate 
The analysis of QT data is complicated by the fact that the QT interval is highly correlated with 
heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected value, 
denoted QTc, which is independent of heart rate. This QTc interval is intended to represent the 
QT interval at a standardized heart rate. Several correction formulas have been proposed in the 
literature. For this analysis we will use some of those methods of correction, as described below. 
The QT interval corrected for heart rate by the Bazett’s formula, QTcB, is defined as  
RR
QT
QTcB =
, 
the QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as  


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3 RR
QT
QTcF =
 , 
where RR represents the RR interval of the ECG, in seconds.   
Although Bazett’s correction is the historical standard, it does not perform well when heart rate 
fluctuates. Fridericia’s formula may perform better under these conditions.  An alternate 
correction to achieve the goal of getting uncorrelated QTc and RR is based on linear or log-
linear regression methods which yield, theoretically, uncorrelated QTc and RR. 
Linear regression method: 
• Fit a model QT = a + b * RR to baseline data  
• Use the estimated slope,  , 𝑏𝑏෠ , to correct QT 
• Corrected QT for heart rate will be computed as follows: 
QTcP = QT + 𝑏𝑏෠ * (1- RR) 
Data will be summarized using QTcF and QTcB. However, if these are not appropriate for the 
data set due to an observed large correlation between corrected QT and HR using the baseline 
assessments, the results will also be summarized using QTcP. 
ECG Summaries 
The following analyses will be performed for each applicable ECG parameters (RR, PR, QRS, 
QT, ventricular rate – denoted as HR in what follows, and QTc) as noted. 
• Pearson correlation between QT and HR, QTc (QTcB, QTcF and, if applicable, QTcP) and 
HR using individual (non-averaged) baseline assessments and separately using on-treatment 
assessments  
• For each of the ECG parameters (HR, and QT, QTc, QRS, PR intervals), descriptive 
statistics at baseline, at each post-baseline time point and changes from baseline at each 
post-baseline time point  
• For each of the QTc and QT intervals, shift tables based on notable parameter categories 
(≤450, >450 - ≤480, >480 - ≤500, >500 ms) at baseline and the worst post-baseline value 
observed 
• Frequency counts and percentages of patients having notable ECG values according to the 
following categories:            
o QT parameter (QT, QTc) increase from baseline >30 ms,  >60 ms 
o Newly occurring post-baseline QT parameter > 450 ms, > 480 ms, > 500 ms 
o HR increase from baseline > 25% and value > 100 bpm 
o HR decrease from baseline > 25% and value < 50 bpm 
o PR increase from baseline > 25% and value > 200 ms 
o Newly occurring post-baseline PR > 200 ms and ≤220 ms, > 220 ms 
o QRS increase from baseline > 25% and value > 110 ms 
o Newly occurring post-baseline QRS > 110 ms and ≤ 120ms, > 120 ms 


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       The denominator to calculate percentages for each category is the number of patients at risk 
for a specific category. For new abnormality post baseline values, this is the number of 
patients with both baseline and post baseline, and baseline not meeting the criteria. For 
abnormal change from baseline, this is the number of patients with both baseline and post 
baseline evaluations. A newly occurring post-baseline ECG notable value is defined as a 
post-baseline value that meets the criterion post-baseline but did not meet the criterion at 
baseline  
• Frequency counts and percentages of patients with newly occurring post-baseline 
qualitative ECG abnormalities (morphology) will be summarized. The denominator to 
calculate percentages for any newly occurring ECG abnormality, each abnormality type and 
each individual finding is the number of patients with both a baseline and a post-baseline 
evaluation, and baseline being normal, i.e. those patients who are at risk of developing this 
abnormality.  A newly occurring post-baseline qualitative ECG abnormality is defined as a 
post-baseline abnormal finding which was not present at baseline 
Patients with notable ECG interval values and newly occurring qualitative ECG abnormalities 
will be listed by patient, time point and the corresponding notable values and abnormality 
findings will be included in the listings. 
Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point. However, they will be used in the 
analysis of notable ECG changes and the shift table analysis of notable QT parameters. 
Vital signs 
Vital sign assessments will be performed in order to characterize basic body function. The 
parameters collected are weight (kg), body temperature (°C), pulse rate (beats per minute), and 
sitting systolic and diastolic blood pressure (mmHg).  
Clinically notable elevated values are defined as: 
• Systolic BP: ≥ 160 mmHg and an increase ≥ 20 mmHg from baseline 
• Diastolic BP: ≥ 100 mmHg and an increase ≥ 15 mmHg from baseline. 
• Body temperature: ≥ 39.1°C 
• Weight: increase from baseline of ≥ 10% 
• Pulse rate: ≥ 120 bpm with increase from baseline of ≥15 bpm 
Clinically notable below normal values are defined as: 
• Systolic BP: ≤ 90 mmHg and a decrease ≥ 20 mmHg from baseline 
• Diastolic BP: ≤ 50 mmHg and a decrease ≥ 15 mmHg from baseline 
• Body temperature: ≤ 35°C 
• Weight: decrease from baseline of ≥ 10% 
• Pulse rate: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm  
Vital signs shift table based on values classified as notable low, normal, notable high or notable 
(high and low) at baseline and worst post-baseline will be produced for pulse rate, diastolic BP 
and systolic BP. 


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Descriptive statistics will be tabulated by study arm for baseline and changes from baseline to 
worst post-baseline value for each vital sign measure.  
Patients with clinically notable vital sign abnormalities will be listed by study arm. All vital 
sign assessments will be listed by study arm, patient and vital sign parameter. 
In the listings, clinically notable values will also be flagged. 
WHO performance status 
The WHO performance assessment allows patients to be classified as to their functional 
impairment, the definition of scores in relation to their performance status is provided in  Table 
2-3, ranging from 0 (most active) to 5 (dead): 
Table 2-3 
WHO 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 
 
For all analyses regarding WHO, non-missing post-baseline questionnaire assessments within 
30 days of last dose of study treatment, and before the start of any further anti-neoplastic 
therapies will be used. 
Shift tables of WHO performance status at baseline to worst post-baseline WHO status by score 
will be provided; shift tables of WHO performance status at baseline to best post-baseline WHO 
status by score will also be provided.  WHO performance status at each time point will be listed. 


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2.8.6 
Patient-report outcomes 
Not applicable. 


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2.9 
Sample size calculation 
The study will enroll approximately 160 patients, with approximately 40 patients each in 
Arms 1 and 2 and ~30 patients each in Arms 3 and 4 and at least 20 patients in Arm 5 (See 
Table 2-4). It is assumed that 5% of the patients diagnosed with brain metastases have 
leptomeningeal carcinomatosis. Additional patients in Arm 4 may be enrolled in order achieve 
approximately 60 patients in Arms 3 and 4 together (i.e. ALKi naïve patients) if enrollment 
rate in Arm 3 is slow. 
An observed ORR of 50% in 140 patients planned for Arms 1-4 will result in an exact binomial 
95% CI with a lower bound greater than 40% which is clinically meaningful and exceeds the 
ORR expected with available therapies (Shaw 2012). Table 2-4 provides the exact binomial 95% 
CI for various observed ORRs for the 140 patients and for each of the strata. 
Table 2-4 
Exact binomial 95% confidence intervals for various observed ORRs 
Sample Size 
Observed ORR 
Number of Patients with 
Confirmed PR or CR 
Exact 95% CI 
N=140 (overall 
Arms 1-4) 
50% 
70 
(41.44%, 58.56%) 
60% 
84 
(51.39%, 68.18%) 
N=80 (Arms 1 
and 2) 
40% 
32 
(29.20%, 51.56%) 
50% 
40 
(38.60%, 61.40%) 
60% 
48 
(48.44%, 70.80%) 
N=40 (each of 
Arms 1 or 2) 
40% 
16 
(24.87%, 56.67%) 
50% 
20 
(33.80%, 66.20%) 
N=30 (each of 
Arms 3 or 4) 
60% 
18 
(40.60%, 77.34%) 
70% 
21 
(50.60%, 85.27%) 


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2.10 
Power for analysis of key secondary variables 
Estimation of the DCR is the key secondary objective of the study. An observed DCR of 65% 
in 140 patients in Arms 1-4 will result in an exact binomial 95% CI with a lower bound greater 
than 55%. Table 2-5 provides the exact binomial 95% CI for various observed DCRs for the 
140 patients and for each of the strata. 
Table 2-5 
Exact binomial 95% confidence intervals for various observed DCRs 
Sample Size 
Observed DCR 
Number of Patients with SD, PR 
or CR 
Exact 95% CI 
N=140 (overall 
Arms 1-4) 
65% 
91 
(56.49%, 72.86%) 
75% 
105 
(66.98%, 81.93%) 
N=80 (Arms 1 
and 2) 
60% 
48 
(48.44%, 70.80%) 
70% 
56 
(58.72%, 79.74%) 
N=40 (each of 
Arms 1 or 2) 
60% 
24 
(43.33%, 75.14%) 
70% 
28 
(53.47%, 83.44%) 
N=30 (each of 
Arms 3 or 4) 
70% 
21 
(50.60%, 85.27%) 
80% 
24 
(61.43%, 92.29%) 
An additional secondary objective of the study is estimation of the OIRR for patients with 
measurable brain metastases at baseline. As described in Section 4.1.1 of the study protocol, 
the study targets enrolling approximately 70 patients with measurable brain metastases: ~50 
patients with prior ALKi treatment (Arms 1 and 2) and ~20 patients with no prior ALKi 
treatment (Arms 3 and 4). An observed OIRR of 50% in 70 patients with measurable brain 
metastases will result in an exact binomial 95% CI with a lower bound greater than 35%. An 
observed OIRR of 60% in 50 patients with measurable brain metastases previously treated with 
ALKi (Arms 1 and 2) will result in an exact binomial 95% CI with a lower bound greater than 
45%. An observed OIRR of 60% in 20 patients with measurable brain metastases not previously 
treated with ALKi (Arms 3 and 4) will result in an exact binomial 95% CI with a lower bound 
greater than 36% (Table 2-6). The reported OIRR with crizotinib is 18% (95% CI: 5 - 40) for 
patients with measurable brain metastases and prior radiation therapy to the brain, and 33% (95% 
CI: 13 - 59) for patients without prior radiation to the brain; recent whole brain radiation was 
allowed (Crino et al 2013). 
Table 2-6 
Exact binomial 95% confidence intervals for various observed OIRRs 
 
Observed 
OIRR 
Number of Patients with 
Confirmed PR or CR in the brain 
Exact 95% CI 
N=70 (Overall 
45% 
32  
 (33.74%, 58.06%) 


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Arms 1-4) 
50% 
35  
 (37.80%, 62.20%) 
55%  
39  
 (43.34%, 67.59%) 
60%  
42  
 (47.59%, 71.53%) 
N=50 (prior 
ALKi 
treatment, Arms 
1+2) 
 
40% 
20 
(26.41 %, 54.82 %) 
45% 
23 
(31.81 %, 60.68 %) 
50% 
25 
(35.53%, 64.47%) 
55% 
28 
(41.25%, 70.01%) 
60% 
30 
(45.18%, 73.59%) 
N=20 (no prior 
ALKi treatment, 
Arms 3+4) 
50%  
10 
(27.20%, 72.80%) 
55%  
11 
(31.53%, 76.94%) 
60%  
12 
(36.05%, 80.88%) 
65% 
13 
(40.78%, 84.61%) 
 
 
 
 
 
 
 
 
 
 
 
3 
Changes to protocol specified analyses 
Table 3-1 summarizes the changes to protocol-specified analyses and associated rationale for 
inclusion in Appendix 16.1.9 (Documentation of Statistical Methods) of the CSR. 
Table 3-1 
Changes to protocol specified analysis or descriptions and rationale  
Protocol Section 
Protocol Description 
Change 
Section 10.5.2 
The distribution function of TTIR 
will be estimated using the Kaplan-
Meier method. The median TTIR 
along with 95% CI will be 
presented.  
TTIR will be summarized by prior 
radiotherapy to the brain (yes, no), 
prior ALK inhibitor use (yes, no) 
and overall using the data from 
Arms 1 through 4. 
Similar for TTER and TTR. 
TTIR will be summarized by 
frequency counts in time 
intervals and using descriptive 
statistics for patients with 
confirmed CR or PR. 
This analysis is removed. 
This update was made because 
median value is not estimable 
using KM method due to low 
response rate. Descriptive 
statistics suggested median 


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values were consistent across 
study arms. 
Section 10.5.2 
A patient who has not progressed or 
died at the date of the analysis or 
when he/she receives any further 
anticancer therapy in the absence of 
disease progression will be censored 
at the time of the last adequate 
tumor evaluation before the earlier 
of the cut-off date or the anticancer 
therapy date. 
A patient who has not 
progressed or died at the date of 
the analysis cut-off will be 
censored at the time of the last 
adequate tumor evaluation 
performed on or before the cut-
off date. 
This update was made to align 
with the latest “Guidelines for 
response, duration of overall 
response, TTF, TTP, 
progression-free survival, and 
overall survival”. 
 
4 
Additional details on implementation of statistical 
methodology 
The sections below contain additional details on statistical methodology that will be included 
in Appendix 16.1.9 (Documentation of Statistical Methods) of the CSR as well as rules details 
on programing rules that will be followed to implement the analyses described in Section 2. 
4.1 
Data included in the analyses 
This section provides additional details to those included in Section 2.1. 
Each analysis (primary analysis and final analysis) will include the 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. For example, if the cut-off date is 30DEC2008, an AE starting on 
28DEC2008 will be reported, whereas an adverse event starting on 31DEC2008 will not be 
reported. 
4.2 
Last contact date 
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the latest complete date among the following: 
• All patient assessment dates (e.g. blood draws (laboratory, 
), vital signs, performance 
status, ECG, tumor assessments)  
• Start and end dates of antineoplastic therapies administered after study drug 
discontinuation (with non-missing medication/procedure term). 
• AE start and end dates (with non-missing verbatim AE term present) 
• From ‘Survival information’ eCRF: 


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• Last known date patient alive if answer to question ‘Is  subject alive?’ is ‘lost to 
follow-up’;  
• Date of assessment if answer to question ‘Is  subject alive?’ is Yes 
Note: If answer to question ‘Is subject alive?’ is ‘unknown’, neither ‘last known date 
patient alive’ nor ‘date of assessment’ is used 
• Study drug start and end dates from DAR with non-missing dose. Doses of 0 are allowed.  
• Concomitant medications/Surgical and Medical Procedures start and end dates 
• Date of discontinuation/study phase completion on the ‘End of treatment discontinuation’ 
and the ‘End of Post Treatment Phase Disposition’ eCRFs. 
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 patient was 
seen or contacted on that date. 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. 
Only dates associated with patient visits or actual examinations of the patient will be used in 
the derivation. Dates associated with a technical operation unrelated to patient status such as 
the date a blood sample was processed will not be used. Assessment dates after the cutoff date 
will not be applied to the last contact date.  
Partial date imputation is allowed for event (death)/censoring if the date is coming from 
‘Survival information’ eCRF only.  If the day is missing for the ‘Date of assessment’ when 
answer to question ‘Is subject alive?’ is Yes, or ‘Last known date patient alive’ when answer to 
question ‘Is  subject alive?’ is ‘lost to follow-up’, it will be imputed to 1st day of the month and 
year. If imputed date is after cut-off date, then this date will not be applied to derive the last 
contact date. 
4.3 
Month derivation 
For all derivations, a month will be calculated as (365.25 / 12) = 30.4375 days. If duration is to 
be reported in months, duration in days will be divided by 30.4375. 
4.4 
Age derivation 
Age for enrolled patients or screen failures will be calculated based on the date when the patient 
signed the main study informed consent from the date of birth. 
4.5 
Dose interruptions and dose changes 
This section provides additional details to those included in Section 2.6. Both dose interruption 
and dose change are analyzed based on CRF pages based on the dose actually taken by the 
patients. 
An interruption is defined as a 0 mg dose taken on one or more days. What follows defines how 
dose interruptions will be counted in the case of multiple dose interruptions. 
• If an interruption occurs consecutively for at least two days due to the same reason, then it 
will be counted only once (example: If the actual dose on days 1-3 is 750 mg and actual 


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dose on days 4-5 is 0 mg and dose interruption on days 4-5 is due to AE, then the total 
number of dose interruptions is 1). 
• If an interruption occurs consecutively for at least two days due to different reasons, then it 
will be counted for each reason (example: If the actual dose on days 1-3 is 750 mg and 
actual dose on days 4-5 is 0 mg and dose interruption on day 4 is due to AE and dose 
interruption on day 5 is due to dosing error, then the total number of dose interruptions is 
2).  
• If an interruption occurs for more than one day due to the same reason, but the days are not 
consecutive , i.e. there is at least one dosing day in between, then each dose interruption 
will be counted as a different occurrence (example: if the actual dose on days 1, 3 and 5, is 
750 mg and actual dose on days 2 and 4 is 0mg, and dose interruptions on day 2 and 4 are 
both due to dosing error, the total number of dose interruptions is 2).  
A dose change is defined as a change in dosing from one record to the next. However, a dose 
interruption will not be counted as a dose change. For example, for LDK378, in the sequence 
750 mg – 0 mg – 600 mg, the 600 mg dose will be counted as a dose change (with reason 
documented), preceded by a 0 mg due to interruption (with reason documented). Dose 
reductions are a subset of dose changes where dose changes to higher than protocol planned 
dose are excluded. 
4.6 
Efficacy endpoints  
For further details on efficacy endpoints, see Section 14 (Appendixes 2 and 3) of the 
LDK378A2205 protocol. For the evaluation of tumor-response related endpoints, response is 
assessed by investigator and BIRC according to RECIST 1.1 with the exception of intracranial 
endpoints following Modified RECIST 1.1. Additionally, intracranial endpoints are also 
evaluated by investigator and BIRC as exploratory endpoints according to RANO criteria. 
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Sections 2.7 and 2.8.1. 
4.6.1 
Implementation of RECIST guidelines 
Disease progression 
PD should only be assigned if it is demonstrated by an objective assessment method as per 
RECIST 1.1 (whole body and extracranial) or Modified RECIST 1.1 (intracranial) (e.g. 
radiologic scan, histology for bronchoscopy, photos for skin lesions). If a new lesion is detected 
using an objective assessment method other than radiologic scan, it should be entered on the 
‘New lesion’ RECIST eCRF with appropriate method (or method=‘Other’).  
In particular, discontinuation due to disease progression or death due to progressive disease, 
without supporting objective evidence (as defined above), will not be considered as PD in the 
determination of BOR, the derivation of any efficacy endpoint or efficacy analysis.  
Change in imaging modality 
Per RECIST 1.1, 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 change in technique (e.g. from CT to 


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MRI, or vice-versa), or a change in any other imaging modality. A change from conventional 
to spiral CT and vice versa while keeping same contrast use (e.g. switching from spiral CT with 
contrast to CT with contrast) is not considered a change in imaging modality . 
A change in methodology will result by default in a UNK (unknown) overall lesion response 
assessment. However, a response assessment other than the Novartis calculated UNK response 
may be accepted from the investigator or BIRC if a definitive response assessment can be 
justified based on the available information. Potential discrepancies between the modality used 
and overall lesion response reported by the investigator (e.g. change in modality but investigator 
assessment of response is different from UNK) will be queried during the data validation 
process. 
Determination of missing adequate tumor assessments 
For the computation of ORR (for primary analysis), patients without any radiological 
assessment after the start date of study drug will be counted as failure. 
Partial or complete responses reported prior to any additional anticancer therapy will be 
considered for ORR computation irrespective of the number of missed assessments before 
response. The anticancer therapy will be defined for intracranial, extracranial and whole body 
separately: e.g., radiotherapy to the brain wil only be considered as anticancer therapy for 
intracranial and whole body endpoints but not for extracranial endpoint. In this section, the 
‘missing adequate assessment’ is defined as assessment not done or assessment with overall 
lesion response equal to UNK.  For the sake of simplicity, the ‘missing adequate assessment’ 
will also be referred as ‘missing assessment’. 
As detailed in Section 14 (Appendix 2) of the LDK378A2205 protocol and Table 2-2 of SAP, 
the PFS censoring and event date options depend on the presence and the number of missing 
tumor assessments. For example, an event occurring after two or more missing assessments is 
censored in the analysis of PFS at the last adequate tumor assessment before the event date. 
An exact rule to determine whether there is none, one or two missing assessments is therefore 
needed. This rule will be based on the distance between the last adequate tumor assessment date 
and the event date. 
If the distance is larger than threshold D1 or D2 then the analysis will assume one or two missing 
assessments, respectively. The threshold D1 will be defined as the protocol specified interval 
between the tumor assessments plus the protocol allowed window around the assessments. 
Similarly, the threshold D2 is defined as two times the protocol specified interval between the 
tumor assessments plus the protocol allowed window around the assessments. In this study, the 
protocol defined schedule of tumor assessment is every 8 weeks and each assessment is 
expected to be performed at the scheduled time point plus or minus 1 week, i.e. the window is 
2 weeks, then any distance larger than D1 = 8+2 = 10 weeks means one missing assessment and 
any distance larger than D2 = (2*8) + 2 = 18 weeks means two missing assessments. 
The same definition of D2 will be used to determine the PFS censoring reason.  
Possible censoring reasons for PFS are: 
1: Ongoing without event 
2: Lost to follow-up 


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3: Withdrew consent 
4: Adequate assessment no longer available 
5: Event after >=2 missing tumor assessments 
Non-measurable disease at baseline 
As specified in Section 14 (Appendix 2) of the LDK378A2205 protocol, the RECIST 1.1 
criteria imply that only patients with measurable disease at baseline (at least one extracranial 
measurable lesion as per inclusion criteria) should be included in the study. If a patient without 
measurable disease is enrolled, the intent-to-treat (ITT) principle requires including these 
patients in the analyses. Hence, analyses will be based on FAS including patients with either 
measurable or non-measurable disease. Therefore, a rule needs to be specified on how to handle 
these cases. 
As specified in Table 3-1 of Section 14 (Appendix 2) of the LDK378A2205 protocol, overall 
lesion response can be derived for patients without measurable disease at baseline as follows 
(Table 4-1). 
Table 4-1 
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 In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination.  
Missing baseline tumor assessment 
As specified in Section 14 (Appendix 2) of the protocol, since the timing of PD cannot be 
determined for patients with missing baseline tumor assessment, these patients are censored in 
the PFS analysis at the start date of treatment. This rule, however, only applies to the ‘PD 
component’ of the PFS or DOR assessment.   
Patients without baseline tumor assessment who die within D2 distance from start date of 
treatment will be counted as having an event in the primary analysis of PFS.  All deaths will be 
counted in the OS analysis regardless of presence or absence of the baseline tumor assessment. 
Construction of waterfall graphs 
The 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 the measured diameter of all target lesions 
for each patient.  The proportions of patients with various degrees of tumor shrinkage or growth 
can then represent a useful efficacy metric. 


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However, caution needs to be paid to the assessments, where an occurrence of a new lesion or 
worsening in non-target lesions (resulting in PD as an overall lesion response at given 
assessment) contradicts the measurements obtained on target lesions.  These assessments will 
not be displayed as bars in the graph. If such a “contradicting” assessment represents the only 
post-baseline assessment for a patient, then the patient will be represented by a special symbol 
(e.g. *) in the waterfall graph. 
The assessments with unknown target response and also assessments with unknown overall 
response will be excluded. Patients without any valid assessments will be completely excluded 
from the graphs. 
The total number of patients displayed in the graph needs to be shown and this number will be 
used as a denominator when calculating the percentages of patients with tumor shrinkage and 
tumor growth.  Footnote will explain the reason for excluding some patients (due to absence of 
any valid assessment). 
All possible assessment scenarios are described in Table 4-2. 
Table 4-2 
Inclusion/exclusion of assessments used in waterfall graph 
Criteria for inclusion/exclusion 
Possible 
source 
of 
contradictions 
Target response 
Overall 
lesion 
response 
Include in waterfall 
Non-target 
response 
New lesion? 
CR/PR/SD 
PD 
Yes but as * only 
PD 
any 
CR/PR/SD 
PD 
Yes but as * only 
any 
Yes 
UNK 
UNK or PD 
No 
any 
any 
CR/PR/SD 
UNK 
No 
UNK 
No 
CR/PR/SD 
CR/PR/SD 
Yes as a bar 
SD/IR 
No 
PD 
PD 
Yes as a bar 
any 
any 
The following algorithm will be used to construct the graph: 
1. Select “valid” post-baseline assessments to be included, i.e. for each patient and each 
assessment repeat the following four steps: 
1.1. Check the target lesion response and overall lesion response at each assessment.  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 PD, then go to step 1.3. Otherwise, go to step 1.4 
1.3. Check target response.  If PD, then go to step 1.4.  Otherwise flag the assessment . 
1.4. Calculate the % change from baseline in target lesions.  
2. For each patient, 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 patient, i.e. the largest shrinkage or if a patient only has assessments with tumor growth 
take the assessment where the growth is minimal. (Example 1: Patient 1 has the following % 


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changes from baseline at assessments 1, 2, 3, 4 and 5, respectively: -10%; -25%; -13%; -4% 
and +6%. His/her best % change is then -25%. Example 2: Patient 2 has the following % 
changes from baseline at assessments 1, 2 and 3, respectively: +5%; +18% and +35%. 
His/her best % change is then +5%. 
3. Construct the waterfall graph displaying the best % change from baseline for each patient. 
Patients having only  flagged assessment(s) will be displayed separately.  
The recommended way of the display from left to right is: 
1. Bars above the horizontal axis representing tumor growth  
2. Bars under the horizontal axis representing tumor shrinkage 
3.  “Zero” bars with  symbol representing patients with contradiction 
4.6.2 
Implementation of RANO guidelines (protocol Appendix 3) 
As described in the protocol, intracranial endpoints (OIRR, IDCR, DOIR, and TTIR in the brain) 
will also be evaluated by RANO criteria as exploratory endpoints. This section provides some 
details on how to derive these intracranial endpoints by RANO and further details are included 
in the protocol Appendix 3. 
RANO vs. RECIST 1.1 
In this study, intracranial endpoints will be evaluated by both RECIST 1.1 and RANO. 
Measurable disease by RANO is defined as bi-dimensionally, contrast-enhancing, measurable 
lesions with clearly defined margins by CT or MRI scan, with a minimal diameter of 10mm, 
and visible on 2 axial slices which are at least 5 mm apart with 0 mm skip. Measurement of 
tumor around a cyst or surgical cavity, if necessary, requires a minimum thickness of 3 mm.  
The major differences between RECIST 1.1 and RANO include: 
• The measurability criteria for target lesion by RANO is based on two dimensions and is 
more stringent than the RECIST 1.1 criteria, therefore, the number of target lesions by 
RANO is no more than the number of target lesions by RECIST 1.1; 
• In RECIST 1.1, only one diameter is recorded for each target lesion, while in RANO, two 
perpendicular diameters are measured for each target lesion; 
• In RANO, corticosteroids use and clinical status are also considered for determining 
overall response; 
• There are two types of non-target lesions by RANO: non-enhancing lesions and non-
measurable enhancing lesions. Both types of non-target lesions contribute to the non-
target lesion response. 
Overall Lesion Response Collected on RANO eCRF page 
Intracranial endpoints by RANO will be derived based on the collected overall lesion response 
on eCRF page “RANO Overall Lesion Response” (ZR domain, ZRCAT = ”RESPONSE 
ASSESSMENT IN NEURO-ONCOLOGY”, and ZRSCAT = ”OVERALL LESION 
RESPONSE”). The derivation of intracranial endpoints (OIRR, IDCR, DOIR, TTIR and TTP 
in the brain) by RANO is the same as by RECIST 1.1. 


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Calculation of Overall Lesion Response by RANO 
Overall lesion responses by RANO are also calculated from the following components: 
1. Target lesion measurements; 
2. Non-target lesion response; 
3. New lesion present (Yes/No); 
4. Corticosteroids use; 
5. Clinical status. 
All these components are collected on the following eCRF pages: 
1. RANO target lesion - Measurable enhancing lesion (T1) (ZI domain, ZICAT = 
”MODIFIED RANO CRITERIA FOR BRAIN METASTASES”, ZISCAT = ”TARGET 
ENHANCING T1”); 
2. RANO non-target lesion - Non-measurable enhancing lesion (T1) (ZI domain, ZICAT = 
”MODIFIED RANO CRITERIA FOR BRAIN METASTASES”, ZISCAT = ”NON-
TARGET ENHANCING T1”); 
3. RANO non-target lesion - Non-enhancing lesion (T2/FLAIR) (ZI domain, ZICAT = 
”MODIFIED RANO CRITERIA FOR BRAIN METASTASES”, ZISCAT = ”NON-
TARGET NON ENHANCING T2/FLAIR”); 
4. RANO New Lesion (ZI domain, ZICAT = ”MODIFIED RANO CRITERIA FOR BRAIN 
METASTASES”, ZISCAT = ”NEW”); 
5. Corticosteroids use and clinical status are collected on the Modified RANO Assessment 
(ZR domain, ZRCAT = ”MODIFIED RANO CRITERIA FOR BRAIN METASTASES”, 
ZISCAT = ”RESPONSE ASSESSMENT”). 
Unlike in RECIST 1.1, each target lesion by RANO criteria has two perpendicular diameters 
collected. In order to calculate the target lesion response, the product of the two perpendicular 
diameters is calculated for each target lesion. Then the sum of the products of all target lesions 
is compared to the baseline or nadir to determine the target lesion response.  
The non-target lesion response is collected on the field of “Non-target lesion present” in the 
Modified RANO Assessment page, and is evaluated based on both non-target lesion eCRF 
pages as shown above. However, no derivation will be performed from individual non-target 
lesion status to non-target lesion response.  
The RANO response/progression criteria are summarized in Table 4-3.  
Please note that patients with non-measurable disease in brain at baseline are allowed to be 
enrolled in the study. According to RANO criteria, these patients with non-measurable disease 
in brain cannot have a response of CR or PR in the brain, and the best response they can achieve 
is stable disease (SD) in the brain. 


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Table 4-3 
Summary of the RANO response criteria 
 
CR 
PR 
SD 
PD 
T1-Gd+ target 
lesions 
None 
≥50% decrease 
from baseline 
<50% decrease from 
baseline but <25% 
increase from nadir 
≥25% increase 
from nadir* 
T1-Gd+ non-
target lesions 
Stable or improved 
Stable or 
improved 
Stable or improved 
Increase* 
T2/FLAIR 
Stable or improved 
Stable or 
improved 
Stable or improved 
Increase* 
New Lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or 
decrease 
Stable or decrease 
NA** 
Clinical Status 
Stable or improve 
Stable or improve 
Stable or improve 
Deterioration* 
Requirement for 
Response 
All 
All 
All 
Any* 
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease 
*: Progression when this criterion is met **: Increase in corticosteroids alone will not be taken into account 
in determining progression in the absence of persistent clinical deterioration 
Two fields in the Modified RANO Assessment page will not be used for any data analysis in 
the study: “New enhancement outside radiation field?”, “Tumor present in histopathology”. 
As in RECIST 1.1, PD should only be assigned if it is demonstrated by an objective assessment 
method as per RANO. Discontinuation due to disease progression or death due to progressive 
disease, without supporting objective evidence, will not be considered as PD.  
As in RECIST 1.1, the same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. The details of 
change in imaging modality are described in Section 4.6.1. 
The same principle will be followed for determining missing adequate tumor assessments, as 
described in section 4.6.1.  
4.6.3 
Sources for overall lesion response 
The tumor endpoints derivation is based on the sequence of overall lesion responses at each 
assessment/time point. However, the overall lesion response at a given assessment/time point 
will be provided from different sources as illustrated in Table 4-4. 
Table 4-4 
Sources for overall lesion response  
Source 1 
Investigator (local radiology) reported overall lesion response 
(intracranial, extracranial and whole body) 
Source 2 
BIRC (Blinded Independent review committee) reported overall lesion 
response (intracranial, extracranial and whole body) 
In this study, Source 1 will be used for the primary endpoint ORR, the key secondary endpoint 
DCR and other secondary endpoint calculations based on investigator assessment (OIRR, IDCR, 
TTIR, DOIR, OERR, EDCR, TTER, DOER, DOR, TTR, and PFS).  Source 2 will be used to 
calculate OIRR, IDCR, TTIR, DOIR, OERR, EDCR, TTER, DOER, ORR, DCR, DOR, TTR, 


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and PFS by BIRC. In addition, OIRR, TTIR, DOIR, and IDCR are also assessed according to 
RANO from both Source 1 and 2. 
4.6.4 
  Kaplan-Meier estimates 
To analyze time to event variables (DOIR, TTIR, DOER, TTER, DOR, TTR, OS and PFS) an 
estimate of the survival function will be constructed using Kaplan-Meier (product-limit) 
method as implemented in SAS PROC LIFETEST with METHOD=KM option (see example 
below). The TIME statement will include a variable with survival times (survtime in the 
example below) and a (right) censoring variable (censor in the example below) with a value of 
1, representing censoring: 
PROC LIFETEST data = dataset   
METHOD = KM  
CONFTYPE=LOGLOG; 
TIME survtime*censor(1); 
RUN; 
/* survtime represents variable containing event/censor times; 
censor represents censoring variable (1 = censored, 0 = event); */ 
Kaplan-Meier survival and failure function estimates from this procedure will be used to 
construct the Kaplan-Meier figures. 
Median survival will be obtained along with 2-sided 95% CIs calculated from PROC 
LIFETEST output using the method of Brookmeyer & Crowley, 1982. 
Kaplan-Meier estimates with 2-sided 95% CIs at specific time points will be summarized.  The 
time points can be expressed in weeks or in months depending on the time-to-event variable.  
The CIs will be constructed using Greenwood’s formula [Collet, 1994, p.23] for the standard 
error of the Kaplan-Meier estimate. 
The PROC LIFETEST statement will use the option CONFTYPE=LOGLOG. The 
CONFTYPE option specifies the transformation applied to the survival function to obtain the 
point-wise confidence intervals and the confidence intervals for the quartiles of the survival 
times. The LOGLOG keyword specifies the complementary log-log transformation (Collett, 
1994; Lachin, 2000) g(x)=log(-log(x)) which ensures that the point-wise confidence intervals 
are always within interval [0,1]. Although the LOGLOG is the default option in SAS v 9.4, it 
should be explicitly shown. 
The Kaplan-Meier graphs will be constructed using SAS software. 
4.6.5 
Confidence interval for response rates 
The estimate of the response rates (OIRR, IDCR, OERR, EDCR ORR, DCR) will be 
summarized in terms of percentage rates with 95% CIs. An exact binomial confidence interval 
(implemented using SAS procedure FREQ with EXACT statement for one-way tables) will be 
calculated (Clopper and Pearson,1934).  
SAS procedure FREQ will be used to estimate the proportion of responders (binary outcome = 
1 or “Yes”), along with the associated 95% (=100 × (1 – two-sided alpha level)) two-sided exact 
binomial CI. These estimates are obtained as follows: 


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proc freq data = dataset; 
 
table binary event /  
binomial( 
level = “Yes”) 
alpha = two-sided alpha level; 
exact binomial; 
When there are no responders, SAS does not produce a CI by default. To obtain a CI in this 
situation, PROC FREQ is used as specified above except changing level=”No”. From the results 
of this modified procedure, the values in percent of the LCL and UCL of a 0% response rate are 
calculated as follows: 
LCLLEVEL=”Yes” (%) = 100% - UCLLEVEL=”No” (%) 
UCLLEVEL=”Yes” (%) = 100% - LCLLEVEL=”No” (%) 
4.7 
Safety evaluations 
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Section 2.8.2. 
4.7.1 
Multiple assessments within post-baseline visits 
For all analyses regarding abnormal assessments or analyses based on worst or best post-
baseline value (laboratory, ECGs, vital signs, WHO performance status), all post-baseline 
values will be included (scheduled, unscheduled, repeat). All unscheduled and repeat 
measurements will be included in listings. 
Laboratory Data  
For laboratory data, assessments can be collected from both local and central laboratory on the 
same date. For shift tables using CTC grades to compare baseline to the worst post-baseline 
value, the assessment with worst post-baseline value is used for analyses irrespective of the 
source. For LFT summaries, where concurrent measurements are used in the calculation of 
number and percentage of patients with worst post-baseline values, the assessment with worst 
post-baseline value is used (since worst values are based on the largest ratio of lab value to its 
ULN for each patient) although the worst values for the different parameters may be coming 
from different laboratories. 
ECGs 
For all patients, 3 ECGs are targeted to be measured at the protocol-defined (nominal) time-
points. If a patient has more than one measurement at a nominal time point, the average of all 
available measurements associated with the nominal time point will be used for the analyses.   
4.7.2 
Baseline 
As defined in Section 2.6, the last available assessment before or on the date of start of study 
drug is defined as “baseline” value or “baseline” assessment. 
Laboratory data  


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If both central and local laboratory assessments were performed on the same date and 
corresponding to the baseline assessment date, then the central laboratory assessment will be 
used for the calculation of baseline. 
ECGs  
Baseline for ECG measurement is the average of all available measurements (unscheduled, if 
applicable) taken prior to dosing on the date associated with the last available ECG 
measurement before or on the date of start of study treatment. To determine whether ECG 
measurement was taken prior to dosing, ECG time will be compared with dosing time, if 
available. Unscheduled assessments will be included in the calculation of the average if ECG 
time is before dosing time. Study day 1 scheduled pre-dose ECGs will be considered to have 
been obtained prior to study drug administration if dosing time or ECG time is missing. 
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement. 
For unscheduled assessments on study day 1, 
• if dosing time is non-missing, then the assessment is classified as post-baseline if ECG 
time is later than dosing time. 
• if dosing time is missing, the assessment is classified as post-baseline. 
The same ECG assessments will be used for both qualitative and quantitative baseline 
evaluations. 
4.7.3 
Laboratory Parameters 
This section provides further detail on the analysis of laboratory parameters that will be listed 
and summarized as described in Section 2.8.2.  
Hematology 
Hematologic tests include: Hemoglobin, platelets, white blood cells (WBC), red blood cells 
(RBC), differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils (% or 
absolute) 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available (this is mainly for neutrophils and lymphocytes, because CTC grading 
is based on the absolute counts).  
The method to convert the value is straightforward: for each patient, the original lab value (%) 
is divided by 100 and multiplied by WBC count e.g. for neutrophils (NEU): 
NEU count = (WBC count) * (NEU%value/100) 
In order to derive the corresponding absolute normal range,  the rule to be applied depends on 
the availability of the % range and the absolute range for the differential: 
• If % range missing and absolute range missing, then use pre-defined normal range 
reported in the Merck manual 


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• If %  absolute range NOT missing (% range is or isn’t missing), then use the absolute 
range provided by the site 
• If % range NOT missing and absolute range missing, then the % normal limits (i.e. LLN 
and ULN) are divided by 100 and multiplied by the corresponding normal limits of 
WBC count, e.g. for neutrophils NEU): 
LLN for NEU count = (LLN for WBC count)* (LLN for NEU%value /100) 
ULN for NEU count = (ULN for WBC count)*(ULN for NEU%value/100) 
Biochemistry 
The following calculation will be applied for corrected calcium in SI unit: 
Corrected calcium (mmol/L)=measured total Ca (mmol/L)+0.02 (40-serum albumin[g/L]), 
where 40 represents the average albumin level in g/L. 
4.8 
Handling of missing or partial dates 
For patients not known to have died prior to the cut-off date: 
• All events with start date before or on the cut-off date, and with end date missing or 
after the cut-off date or after the date of withdrawal of informed consent will be reported 
as “continuing”.  
• This approach applies, in particular, to AEs and concomitant medication reports. For these 
events, the end date will not be imputed and therefore will not appear in the listings.  
If imputation of an end date is required for a specific analysis (e.g. for a dose administration 
record with missing end date or last date of study drug after the cut-off date), the end date will 
be imputed by the minimum of death date, cut-off date and withdrawal of informed consent 
date for the purpose of calculating duration of exposure to study drug and dose intensity. The 
imputed date will be displayed and flagged in the listings. 
4.8.1 
AE date imputation 
Date imputation is the creation of a new, complete date from a partial one according to an agreed 
and acceptable algorithm. Missing date for AE will be handled according to rules specified 
below. A partial date is simply an incomplete date e.g. DDOCT2001: the days are missing from 
this DDMMMYYYY date. 
Partial AE start dates, if left partial, would ultimately mean the following 
It would not be possible to place the AE in time. 
Therefore the treatment/dosage at the time of the event would be unknown. 
Therefore the event could not be reported/summarized appropriately – if at all. 
Therefore it is important to perform date imputation to ensure that as many data events are 
represented as correctly as possible. Of course partial and/or missing dates should also be 
caught as edit checks and passed back to the investigator for resolution. 
There will be no attempt to impute the following: 


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• Missing AE start dates 
• AE start dates missing the year 
• Partial/missing AE end dates 
The following Table 4-5 explains the abbreviations used. 
Table 4-5 
AE/treatment date abbreviations  
 
Day 
Month 
Year 
Partial Adverse Event 
Start Date 
<not used> 
AEM 
AEY 
Treatment Start Date 
(TRTSTD) 
<not used> 
TRTM 
TRTY 
The following matrix Table 4-6 describes the possible combinations and their associated 
imputations. In the light grey boxes the upper  text indicates the imputation and the lower text 
the relationship of the AE start date to the treatment start date (TRTSTD). 
Table 4-6 
AE partial date imputation algorithm 
 
 
AEM MISSING 
 
AEM < TRTM 
AEM = TRTM 
AEM > TRTM 
AEY MISSING 
NC 
Uncertain 
NC 
Uncertain 
NC 
Uncertain 
NC 
Uncertain 
AEY < TRTY 
( D ) 
Before TRTSTD 
( C ) 
Before TRTSTD 
( C ) 
Before TRTSTD 
( C ) 
Before TRTSTD 
AEY = TRTY 
( B ) 
Uncertain 
( C ) 
Before TRTSTD 
( B ) 
Uncertain 
( A ) 
After TRTSTD 
AEY > TRTY 
( E ) 
After TRTSTD 
( A ) 
After TRTSTD 
( A ) 
After TRTSTD 
( A ) 
After TRTSTD 


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The following Table 4-7 is the legend to the above table. 
Table 4-7 
AE/treatment date relationship and imputation legend 
Relationship 
 
Before TRTSTD 
Indicates AE start date prior to Treatment 
Start Date 
After TRTSTD 
Indicates AE start date after Treatment Start 
Date 
Uncertain 
Insufficient to determine the relationship of 
AE start date to Treatment Start Date 
Imputation Calculation 
NC / Blank 
No convention/imputation 
( A ) 
01MONYYYY 
( B ) 
TRTSTD+1 
( C ) 
15MONYYYY 
( D ) 
01JULYYYY 
( E ) 
01JANYYYY 
The following Table 4-8 gives a few examples. 
Table 4-8 
AE imputation example scenarios 
Partial 
AE start date 
Treatment 
start date 
Relationship 
Imputation 
Calculation 
Imputed Date 
12mmyyyy 
20OCT2001 
Uncertain 
NC 
<blank> 
ddmmm2000 
20OCT2001 
Before 
( D ) 
01JUL2000 
ddmmm2002 
20OCT2001 
After 
( E ) 
01JAN2002 
ddmmm2001 
20OCT2001 
Uncertain 
( B ) 
21OCT2001 
ddSEP2001 
20OCT2001 
Before 
( C ) 
15SEP2001 
ddOCT2001 
20OCT2001 
Uncertain 
( B ) 
21OCT2001 
ddNOV2001 
20OCT2001 
After 
( A ) 
01NOV2001 
4.8.2 
Concomitant medication date imputation 
The imputation of the start date of concomitant medication will follow the same conventions 
as for AE date. Partial concomitant medication end dates will not be imputed. 
4.8.3 
Incomplete date of initial diagnosis of cancer, date of first 
recurrence/progression and date of most recent recurrence  
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan.  


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4.8.4 
Incomplete date for anti-neoplastic therapies 
Prior therapies 
Start date:  
The same rule which is applied to the imputation of AE/concomitant medication start date 
will be used with the exception that for scenario (B) will be replaced to be ‘start date of 
study drug -1’. 
End date: 
Imputed date = min (start date of study drug, last day of the month), if day is missing; 
Imputed date = min (start date of study drug, 31DEC), if month and day are missing. 
If the end date is not missing and the imputed start date is after the end date, use the end 
date as the imputed start date. 
If both the start date and the end date are imputed and if the imputed start date is after the 
imputed end date, use the imputed end date as the imputation for the start date. 
Post therapies 
Start date: 
Imputed date = max (last date of study drug + 1, first day of the month), if day is missing; 
Imputed date = max (last date of study drug + 1, 01JAN), if day and month are missing.  
End date: No imputation.  
4.8.5 
Incomplete assessment dates for tumor assessment 
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, the 
incomplete date(s) are not considered for calculation of the assessment date and assessment date 
is calculated as the latest of all investigation 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 PD, the 
assessment date is calculated as the earliest date of all investigation dates at that evaluation 
number.  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 the previous and the following assessment. 
If both a previous and following assessments are not available, this assessment will not be used 
for any calculations.  
In case of multiple imaging scans performed within an evaluation, if some imaging dates for 
tumor assessment under the same evaluation for a patient are before as well as after cut-off, the 
entire evaluation will not be included for analyses based on the pre-specified cut-off. 


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4.8.6 
Incomplete date for death 
All dates must be completed with day, month and year. 
If the day or month is missing, death date will be imputed to the maximum of the full (non-
imputed) last contact date (excluding the date of death) and the following: 
• Missing day: 
 
 1st day of the month and year of death 
• Missing day and month:    Jan 1st of the year of death  
4.8.7 
Incomplete dates for last dose of study drug 
Scenario 1  
If the last date of study drug is after the cut-off date or is completely missing and there is no 
end of treatment eCRF page and no death date the patient should be considered to be on-going 
and use the cutoff date for the analysis as the last dosing date. 
Scenario 2  
If the last date of study drug is completely or partially missing and there is EITHER an end of 
treatment eCRF page OR a death date available then imputed last dose date: 
 
= 31DECYYYY, if only Year is available and Year < Year of min (EOT visit date, death 
date)  
= Last day of the month, if both Year and Month are available and EITHER 
     -- Year = Year of min (EOT visit date, death date) and Month < the month of min (EOT 
visit date, death date) OR, 
    -- Year < Year of min (EOT date, death date) irrespective of the month 
    = min (EOT visit date, death date), for all other cases. 
The imputed date will be compared with start date of study drug.  
If the imputed date < start date of study drug, then last date of study drug is set to start date 
of study drug; 
 
Otherwise, use the imputed date. 
4.8.8 
Incomplete dates for disease progression prior to start of study drug 
If day of PD associated with prior antineoplastic medication is missing then imputed PD date: 
= min (midpoint between the end date of the prior antineoplastic medication and the end of the 
month, start date of LDK, start date of prior medication from the next regimen), if end date of 
prior antineoplastic medication is in the same month as the PD date, 
= min (15th of the month of the PD date, start date of LDK, start date of prior medication from 
the next regimen), if end date of prior antineoplastic medication is in a month prior to the PD 
date 
= 15th of the month of the PD date, if end date of prior antineoplastic medication is in a month 
after the PD date. 


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If both day and month of PD associated with prior antineoplastic medication are missing then 
imputed PD date: 
= min (midpoint between the end date of the prior antineoplastic medication and the end of the 
year, start date of LDK, start date of prior medication from the next regimen), if end date of 
prior antineoplastic medication is in the same year as the PD date 
= min (July 1 of the year of the PD date, start date of LDK, start date of prior medication from 
the next regimen), if end date of prior antineoplastic medication is in a year prior to the PD date 
= July 1 of the year of the PD date, if end date of prior antineoplastic medication is in a year 
after the PD date 
Completely missing PD dates will not be imputed. The start date of medication from the next 
regimen is based on the earliest start date of any medication(s) from the next regimen. For the 
mid-point calculation, if odd days in between, (e.g. last dose of medication is 27 June 2012, and 
end of the month is 30 June 2012), then use the next day from the midpoint calculation (e.g. 
mid-point is 29 June 2013). 
5 
Reference: 
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time, 
Biometrics 38, 29 - 41.    
Clopper CJ, Pearson ES (1934).  The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika; 26, 404-413. 
Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall. 
Crinò L, Ahn MJ, Ou SH, et al (ECC 2013 – Abst#3413) Clinical Experience with 
Crizotinibin Patients with Advanced ALK-positive Non-Small Cell Lung Cancer and Brain 
Metastases. 
FDA (2007). Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs 
and Biologics, US Department of Health and Human Services. 
Kalbfleisch JD, Prentice RL. (2002) The Statistical Analysis of Failure Time Data. Wiley Series 
in Probability and Statistics. 


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Klein JP, Moeschberger ML. (1997) Survival analysis: techniques for censored and truncated 
regression. New York, NY: Springer-Verlag.Jung, Sin-Ho and Kim, Kyung Mann (2004). On 
the estimation of the binomial probability  in multistage clinical trials. Statistics in Medicine 23, 
881-896.  
Shaw AT, Kim DW, Nakagawa K, et al (2012) Phase III study of crizotinib versuspemetrexed 
or docetaxel chemotherapy in patients with advanced ALK-positive non-small cell lung cancer 
(NSCLC) (PROFILE 1007). Ann Oncol 23 (Suppl; abstr LBA1). 
Wen PY, Macdonald DR, Reardon DA, et al (2010) Updated response assessment criteria for 
high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 
28(11):1963-72. doi: 10.1200/JCO.2009.26.3541. Epub 2010 Mar 15.