Conditions: Non-Small Cell Lung Cancer
Keywords: Non-Small Cell lung Cancer NSCLC ALK LDK378 ALK-rearranged ALK-positive advanced non-small cell lung cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 103
Healthy volunteers: no

Brief summary:
A single-Arm, open-label, multi-center, phase I/II study in which the pharmacokinetics, safety, tolerability and efficacy of LDK378 will be assessed in adult Chinese patients with locally advanced or metastatic NSCLC harboring a confirmed ALK rearrangement. Patients must have demonstrated progression during or after crizotinib treatment whether or not previously treated with cytotoxic chemotherapy. Approximately 100 patients will be enrolled. For the first 15 patients enrolled in this study, patients will have an additional 5-day PK run-in period before treatment period. The pharmacokinetics profile of LDK378 in Chinese adult patients with ALK-rearranged NSCLC will be evaluated.

Detailed description:
This is a phase I/II, open-label, multi-center study in which the PK, safety, tolerability and efficacy of LDK378 will be assessed in adult Chinese patients with locally advanced or metastatic NSCLC harboring a confirmed ALK rearrangement (positive) as assessed using the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) or positive as assessed by immunohistochemistry (IHC) test (Ventana Medical Systems, Inc) using rabbit monoclonal primary antibody assay (D5F3).

Patients must have demonstrated progression during or after crizotinib treatment whether or not previously treated with cytotoxic chemotherapy.

Approximately 100 patients with locally advanced or metastatic NSCLC which carry ALK -rearrangement will be enrolled in the study. The first 15 patients to be enrolled in the study will have PK sampling over 120-hour during the 5-day PK run-in period following a single oral dose at 750 mg. After the PK run-in period, the treatment period will start in which LDK378 will be given starting on Cycle 1 Day 1 in a continuous daily oral dosing in 28-day cycles. Separated from these 15 patients, the rest of the enrolled patients will receive LDK378 treatment at 750 mg QD on Cycle 1 Day 1.

Tumor response will be evaluated every 8 weeks (i.e. every 2 cycles) starting from the first day of treatment with LDK378 until the time of RECIST-defined PD by investigator assessment, withdrawal of consent for further follow-up, loss to follow-up or death.

Arms:
arm 1: daily dosing, 28-day cycle patients

Interventions: intervention 1: LDK378
Intervention descriptions: intervention 1: 750 mg once daily

Protocol document:
Prot_001.pdf: 
Clinical Development
LDK378
Protocol CLDK378A2109 / NCT02040870
A phase I/II, multicenter, open-label, single-arm study of 
LDK378, administered orally in adult Chinese patients with 
ALK-rearranged (ALK-positive) advanced non-small cell 
lung cancer (NSCLC) previously treated with crizotinib
Authors
Document type
Amended Protocol Version
EUDRACT number
Not applicable
Version number
03 (Clean)
Development phase
I/II
Document status
Final
Release date
07-Oct-2015
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 ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Protocol summary:.............................................................................................................13
Amendment 3 ....................................................................................................................19
Summary of previous amendments ...................................................................................20
1
Background........................................................................................................................25
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............25
1.1.1
Locally advanced or metastatic non-small cell lung cancer 
(NSCLC) ...............................................................................................25
1.1.2
Targeted therapies in NSCLC ...............................................................26
1.1.3
ALK-rearranged (ALK-positive, ALK+) NSCLC................................26
1.2
Introduction to investigational treatment(s) and other study treatment(s).............27
1.2.1
Overview of LDK378 ...........................................................................27
1.3
Risk and Benefits...................................................................................................37
2
Rationale............................................................................................................................40
2.1
Study rationale and purpose...................................................................................40
2.2
Rationale for the study design ...............................................................................41
2.3
Rationale for dose and regimen selection..............................................................42
3
Objectives and endpoints...................................................................................................45
4
Study design ......................................................................................................................47
4.1
Description of study design ...................................................................................47
4.2
Timing of interim analyses and design adaptations...............................................49
4.3
Definition of end of the study................................................................................49
4.4
Early study termination..........................................................................................50
5
Population..........................................................................................................................50
5.1
Patient population..................................................................................................50
5.2
Inclusion criteria ....................................................................................................50
5.3
Exclusion criteria...................................................................................................52
6
Treatment...........................................................................................................................55
6.1
Study treatment......................................................................................................55
6.1.1
Dosing regimen.....................................................................................55
6.1.2
Guidelines for continuation of treatment ..............................................56
6.1.3
Treatment duration................................................................................56
 


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6.1.4
Definition of treatment cycle ................................................................57
6.2
Dose modifications................................................................................................57
6.2.1
Dose modification and dose delay ........................................................57
6.2.2
Treatment interruption and treatment discontinuation..........................57
6.2.3
Criteria for LDK378 dose modifications ..............................................58
6.2.4
Follow-up for toxicities.........................................................................64
6.2.5
Anticipated risks and safety concerns of the study treatment...............68
6.3
Concomitant medications ......................................................................................68
6.3.1
Permitted concomitant therapy .............................................................69
6.3.2
Prohibited concomitant therapy ............................................................70
6.4
Patient numbering, treatment assignment or randomization .................................72
6.4.1
Patient numbering .................................................................................72
6.4.2
Treatment assignment or randomization...............................................73
6.4.3
Treatment blinding................................................................................73
6.5
Study drug preparation and dispensation...............................................................73
6.5.1
Study drug packaging and labeling.......................................................73
6.5.2
Drug supply and storage........................................................................74
6.5.3
Study drug compliance and accountability ...........................................74
6.5.4
Disposal and destruction .......................................................................74
7
Visit schedule and assessments .........................................................................................75
7.1
Study flow and visit schedule................................................................................75
7.1.1
Molecular screening..............................................................................84
7.1.2
Screening...............................................................................................84
7.1.3
PK Run-in period ..................................................................................86
7.1.4
Treatment period...................................................................................86
7.1.5
Discontinuation of study treatment .......................................................86
7.1.6
Withdrawal of Consent .........................................................................88
7.1.7
Follow up period ...................................................................................89
7.2
Assessment types...................................................................................................90
7.2.1
Efficacy assessments.............................................................................90
7.2.2
Safety and tolerability assessments.......................................................92
7.2.3
Pharmacokinetics ..................................................................................97
99
7.2.5
Resource utilization.............................................................................100
100
8
Safety monitoring and reporting......................................................................................101
 


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8.1
Adverse events.....................................................................................................101
8.1.1
Definitions and reporting ....................................................................101
8.1.2
Laboratory test abnormalities..............................................................103
8.1.3
Adverse events of special interest.......................................................103
8.2
Serious adverse events.........................................................................................104
8.2.1
Definitions...........................................................................................104
8.2.2
Reporting.............................................................................................104
8.3
Emergency unblinding of treatment assignment .................................................105
8.4
Pregnancies..........................................................................................................105
8.5
Warnings and precautions....................................................................................106
8.6
Data Monitoring Committee................................................................................106
8.7
Steering Committee .............................................................................................106
9
Data collection and management.....................................................................................106
9.1
Data confidentiality .............................................................................................106
9.2
Site monitoring ....................................................................................................107
9.3
Data collection.....................................................................................................107
9.4
Database management and quality control..........................................................108
10 Statistical methods and data analysis ..............................................................................109
10.1
Analysis sets ........................................................................................................109
10.1.1
Full Analysis Set .................................................................................109
10.1.2
Safety Set ............................................................................................109
10.1.3
Per-Protocol Set ..................................................................................109
10.1.4
Dose-determining Analysis Set...........................................................109
10.1.5
Pharmacokinetic Analysis Set.............................................................110
10.1.6
Other analysis Sets ..............................................................................110
10.2
Patient demographics/other baseline characteristics ...........................................110
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................110
10.3.1
Study Treatment..................................................................................110
10.3.2
Concomitant therapies.........................................................................110
10.4
Primary objectives ...............................................................................................110
10.4.1
Variable...............................................................................................111
10.4.2
Statistical hypothesis, model, and method of analysis........................111
10.4.3
Handling of missing values/censoring/discontinuations.....................112
10.4.4
Supportive analyses.............................................................................112
10.5
Secondary objectives ...........................................................................................112
10.5.1
Key secondary objective .....................................................................112
 


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10.5.2
Other secondary efficacy objectives ...................................................113
10.5.3
Safety objectives .................................................................................114
116
117
117
10.8
Interim analysis....................................................................................................117
10.9
Sample size calculation........................................................................................118
10.10 Power for analysis of key secondary variables....................................................118
11 Ethical considerations and administrative procedures ....................................................118
11.1
Regulatory and ethical compliance......................................................................118
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................118
11.3
Informed consent procedures...............................................................................119
11.4
Discontinuation of the study................................................................................119
11.5
Publication of study protocol and results.............................................................119
11.6
Study documentation, record keeping and retention of documents.....................120
11.7
Confidentiality of study documents and patient records .....................................120
11.8
Audits and inspections.........................................................................................121
11.9
Financial disclosures............................................................................................121
12 Protocol adherence ..........................................................................................................121
12.1
Amendments to the protocol................................................................................121
13 References (available upon request)................................................................................122
14 Appendices ......................................................................................................................125
14.1
Appendix 1: List of prohibited concomitant medications and concomitant 
medications requiring caution for LDK378.........................................................125
14.2
Appendix 2: Harmonization of efficacy analysis of solid tumor studies 
(RECIST 1.1).......................................................................................................128
14.2.1
Introduction.........................................................................................130
14.2.2
Efficacy assessments...........................................................................130
14.2.3
Efficacy definitions .............................................................................138
14.2.4
Data handling and programming rules................................................147
14.2.5
References (available upon request) ...................................................151
14.3
Appendix 3: ALK Immunohistochemistry..........................................................152
14.4
Appendix 4: Cockcroft-Gault formula.................................................................154
 


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List of figures
Figure 1-1
Comparison of LDK378 with crizotinib for their anti-tumor 
activity in a mouse H2228 NSCLC model when dosed once a day......29
Figure 1-2
Anti-tumor activity of LDK378 in a crizotinib-resistant mouse 
H2228 model with an ALK C1156Y mutation.....................................30
Figure 1-3
Anti-tumor activity of LDK378 in a crizotinib-resistant mouse 
H2228 model without ALK mutations..................................................30
Figure 4-1
Study Design .........................................................................................48
List of tables
Table 1-1
All grades (at least 10%) and grade 3-4 adverse events, regardless 
of study drug relationship, by preferred term in patients treated in 
the 750 mg dose group (Data cut-off date: 31-Oct-2013).....................33
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) (Cut-off date: 
31-Oct-2013).........................................................................................35
Table 3-1
Objectives and related endpoints ..........................................................45
Table 6-1
Dose and treatment schedule.................................................................56
Table 6-2
Dose reduction steps for LDK378.........................................................58
Table 6-3
Criteria for interruption and re-initiation of LDK378 treatment...........59
Table 6-4
Follow-up evaluations for selected toxicities........................................68
Table 6-5
Preparation and dispensing ...................................................................73
Table 6-6
Packaging and labeling .........................................................................74
Table 7-1
Visit evaluation schedule ......................................................................76
Table 7-2
WHO performance status scale.............................................................93
Table 7-3
Clinical laboratory parameters collection plan .....................................94
Table 7-4
ECG collection plan for patients with extensive PK assessment (in 
15 patients who enrolled in PK run-in; triplicate ECGs)......................96
Table 7-5
ECG collection plan for patients with sparse PK assessment 
(triplicate ECGs) ...................................................................................96
Table 7-6
Pharmacokinetic blood collection for LDK378 extensive PK 
assessment (in 15 patients who enrolled in PK run-in).........................97
Table 7-7
Pharmacokinetic blood collection for LDK378 sparse PK 
assessment.............................................................................................98
Table 10-1
Noncompartmental pharmacokinetic parameters................................111
 


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Table 14-1
Prohibited medications that are strong inducers or inhibitors of 
CYP3A, or CYP3A substrates with narrow therapeutic index, or 
sensitive CYP2C substrates with narrow therapeutic index** ...........125
Table 14-2
List of medications to be used with caution........................................126
Table 14-3
List of prohibited enzyme-inducing anti-epileptic drugs....................127
Table 14-4
List of prohibited QT prolonging drugs..............................................127
Table 14-5
Response criteria for target lesion.......................................................135
Table 14-6
Response criteria for non-target lesions..............................................137
Table 14-7
Overall lesion response at each assessment ........................................138
Table 14-8
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................145
.146
Table 14-10
Clinical Interpretation of VENTANA anti-ALK (D5F3) Staining.....153
 


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List of abbreviations
AE
Adverse event
µg
Microgram
ALCL
Anaplastic large cell lymphoma
ALK
Anaplastic lymphoma kinase
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical Classification System
AUC
Area under the plasma (serum, or blood) concentration versus time curve
AUC0-24h
Area under the plasma (serum, or blood) concentration versus time curve from time 
zero to 24 hours
AUCinf
Area under the plasma (serum, or blood) 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 (serum, or blood) concentration versus time curve from time 
zero to end of dosing period
BIRC
Blind Independent Review Committee
BLRM
Bayesian logistic regression model
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
CMV
Cytomegalovirus
CNAE
Clinically notable adverse event
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
DOR
Duration of response
DS&E
Safety & Epidemiology
 


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EBV
Epstein-Barr Virus
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EGFR 
Epidermal growth factor receptor
EML4-ALK
Echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase
 
EOS
End of study
EOT
End of treatment
EU
European Union
FAS
Full analysis set
FDA
Food and Drug Administration
FISH
Fluorescent in situ hybridization
FSH 
Follicle-stimulating hormone
GCP
Good Clinical Practice
GI
Gastrointestinal
HA
Health Authorities
hCG
human chorionic gonadotropin
HED
Human equivalent dose
Hgb
Hemoglobin
HSV
Herpes Simplex Virus
IB
Investigator’s brochure
IC50
Half maximal (50%) inhibitory concentration
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IGF1R
Insulin-like Growth Factor 1 Receptor
IHC
Immunohistochemistry
ILD
Interstitial lung disease
INR
International normalized ration
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine system
IV
Intravenous(ly)
LFT
Liver function test
LH
Luteinizing hormone
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
OIRR
Overall intracranial response rate
ORR
Overall response rate
 


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OS
Overall survival
OTC
Over the counter
PAS
Pharmacokinetic Analysis Set
PD
Progressive disease
PFS
Progression-free survival
PI
Principal investigator
PK
Pharmacokinetics
PPS
Per-protocol set
PR
Partial response
QD 
quaque diem/once daily
QTc
Corrected QT interval
QTcF
Corrected QT interval using Fridericia formula
Racc 
Accumulation ratio
RAP
Report and Analysis Plan
RBC
Red blood count
RD
Recommended Dose
R Value
ALT/ALP in x ULN
RECIST
Response Evaluation Criteria In Solid Tumors
SAE
Serious adverse event
SBP 
Systolic blood pressure
SC
Steering Committee
SD
Stable disease
SEC
Safety event categories
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SHBG
Sex hormone binding globulin
SI units
Standard international units
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).
TBIL
Total Bilirubin 
TKIs
Tyrosine kinase inhibitors
Tmax
The time to reach maximum plasma concentration
TTR
Time to response
ULN
Upper limit of normal
VATS
Video-assisted thoracic surgery
VEGF-A
Vascular endothelial growth factor-A
Vss
Plasma volume of distribution
WBC
White blood cells
WHO
World Health Organization
WNL
Within Normal Limits
 


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic 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
Control drug
A study treatment used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug
Cycles
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g., 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.
Premature patient 
withdrawal
Point/time when the patient exits from the study before the planned completion of all 
study drug administration and assessments; all study drug administration is 
discontinued and no further assessments are planned, unless the patient is to be 
followed for progression and/or survival
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
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 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.
 


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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, and does not 
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Protocol summary:
Protocol number
CLDK378A2109
Title
A phase I/II, multicenter, open-label, single-arm study of LDK378, administered 
orally in adult Chinese patients with ALK-rearranged (ALK-positive) advanced non-
small cell lung cancer (NSCLC) previously treated with crizotinib
Brief title
A phase I/II study of LDK378 in ALK+ advanced NSCLC previously treated with 
crizotinib
Sponsor and
Clinical Phase
Novartis, 
Phase I/II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
While crizotinib has a high activity in patients with ALK-rearranged NSCLC, these 
cancers invariably progress, typically in less than one year, because of the 
development of resistance to crizotinib. For these patients there is no alternative 
ALK-targeted therapy at relapse. Therefore, the development of ALK inhibiting 
TKIs (tyrosine kinase inhibitors) with clinical activity against ALK-rearranged
NSCLC resistant to crizotinib is crucial.
The available data from the ongoing phase I study indicate that LDK378 has been 
well tolerated by patients with ALK-rearranged NSCLC at doses up to the MTD of 
750 mg QD, and LDK378 has substantial antitumor activity in chemotherapy-
treated patients with ALK-rearranged NSCLC whose disease has failed crizotinib 
therapy.
Primary Objective(s) and 
Key Secondary Objective
Primary objectives: To characterize the pharmacokinetics of LDK378 in Chinese 
adult patients with ALK-rearranged NSCLC following single and multiple daily oral 
doses of LDK378. To assess the safety and tolerability of LDK378 after continuous
750 mg once daily dose in Chinese adult patients with ALK-rearranged NSCLC.
Key secondary objective: To demonstrate the antitumor activity of LDK378, as 
measured by overall response rate (ORR) to LDK378 by investigator assessment.
Secondary Objectives
To evaluate response related endpoints as
assessed by investigator:
1. Duration of response (DOR)
2. Disease control rate (DCR)
3. Time to Response (TTR)
4. Overall intracranial response rate (OIRR)
5. Progression-free survival (PFS)
6. Overall survival (OS)
ORR and OIRR will also be evaluated as assessed by Blind Independent Review 
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Study design
This is a phase I/II, open-label, multi-center study in which the pharmacokinetics, 
safety, tolerability and efficacy of LDK378 will be assessed in adult Chinese 
patients with locally advanced or metastatic NSCLC harboring a confirmed ALK 
rearrangement. The study includes a phase I component for the first 15 patients (5 
day PK run-in period) and a phase II component for all the patients with continuous 
dosing. Patients must have demonstrated progression during or after crizotinib 
treatment whether or not previously treated with cytotoxic chemotherapy and have
no available ALK-targeted treatment options. Approximately 100 patients will be 
enrolled. For the first 15 patients enrolled in this study, patients will have an 
additional 5-day PK run-in period before treatment period. The pharmacokinetics 
profile of LDK378 in Chinese adult patients with ALK-rearranged NSCLC will be 
evaluated. Additional patients may be enrolled in the study with PK run-in period in 
case PK profiles from some of the enrolled patients are deemed not evaluable due 
to early discontinuation from the study or due to vomiting events on the day of PK 
sampling. Treatment with LDK378 750 mg qd will continue until the patient 
experiences unacceptable toxicity that precludes further treatment, discontinues 
treatment at the discretion of the investigator or patient, starts a new anti-cancer 
therapy and/or dies. LDK378 may be continued beyond RECIST-defined PD if, in 
the judgment of the investigator, there is evidence of clinical benefit. Patients who 
discontinue the study medication in the absence of progression will continue to be 
followed for tumor assessment until the time of PD.
Population
Chinese adult patients with ALK-rearranged locally advanced or metastatic NSCLC 
that has progressed during or after crizotinib therapy no matter whether or not 
previously treated with cytotoxic chemotherapy.
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Histologically or cytologically confirmed diagnosis of NSCLC that carries an 
ALK rearrangement defined as positive using the FDA approved Vysis ALK Break 
Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including 
positivity criteria) or positive as assessed by the CFDA approved 
immunohistochemistry (IHC) test (Ventana Medical Systems, Inc) using rabbit 
monoclonal primary antibody assay (D5F3) and associated scoring algorithm. If 
documentation of ALK rearrangement is not available as described above, a test to 
confirm ALK rearrangement must be performed using an archival tumor obtained at 
or since the time of diagnosis or a new tumor biopsy obtained prior to the first 
LDK378 dose. The test will be performed at a Novartis designated central 
laboratory (by IHC test using rabbit monoclonal primary antibody assay (D5F3), 
Ventana Medical Systems, Inc). Patients must wait for the result of the ALK 
rearrangement status before initiating treatment with LDK378.
2. Age 18 years or older at the time of informed consent.
3. Patients must have stage IIIB or IV NSCLC at the time of study entry and have 
had progressive disease during or after crizotinib treatment whether or not 
previously treated with cytotoxic chemotherapy. If treated with chemotherapy, 
maximum 2 lines are allowed.
●
Patients must have progressive disease at study entry. Patients are not 
eligible if crizotinib was discontinued due to toxicity.
●
Patients must have received their last dose of crizotinib ≥ 1 week prior to 
the first dose of LDK378 and recovered from crizotinib toxicities (as defined in 
inclusion criteria #4)
●
Prior targeted therapies will not count as a line of cytotoxic chemotherapy 
(i.e. patients may have received prior treatment with these drugs excluding 
ALK-inhibitors maximum 2 lines are allowed).
●
(Neo-) adjuvant cytotoxic chemotherapy will count as one prior line of 
treatment if relapse occurred within 12 months from the end of the adjuvant 
cytotoxic chemotherapy
●
Note: A cytotoxic chemotherapy line in locally advanced disease is 
defined as an anticancer regimen that contains at least 1 cytotoxic 
 


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chemotherapy agent and is given for at least 21 days or more. If a cytotoxic 
chemotherapy regimen was discontinued for a reason other than disease 
progression and lasted less than 21 days, then this regimen does not count as 
a prior line of chemotherapy
4. Patients must have recovered from all toxicities related to prior anticancer 
therapies to ≤ 2 (CTCAE v 4.03). The exception to this criterion is for patients with 
grade 2 nausea/vomiting and/or grade 2 diarrhea despite optimal supportive 
therapy who will not be allowed to participate in the study. Patients with any grade 
of alopecia are allowed to enter the study.
5. Patients must meet the following laboratory values at the screening visit:
●
WBC count ≥ 4.0 x 109 /L
●
Absolute Neutrophil Count ≥ 1.5 x 109/L
●
Platelets ≥ 100 x 109/L
●
Hemoglobin (Hgb) ≥ 9 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) < 2.5 x ULN, except for patients with liver 
metastasis, who are only included if AST < 5 x ULN
●
Alanine transaminase (ALT) < 2.5 x ULN, except for patients with liver 
metastasis, who are only included if ALT < 5 x ULN
●
Alkaline phosphatase (ALP) < 5.0 x ULN
6. Patient must have the following laboratory values WNL (within normal limits) or 
corrected to within normal limits with supplements during screening:
●
Potassium
●
Magnesium
●
Phosphorus
●
Total calcium (corrected for serum albumin)
7. Life expectancy ≥ 12 weeks.
8. World Health Organization (WHO) performance status 0-2.
9. At least one 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.
10. Written informed consent for the main study must be obtained prior to any 
screening procedures. If consent cannot be expressed in writing, it must be 
formally documented and witnessed, ideally via an independent trusted witness.
11. Willingness and ability to comply with scheduled visits, treatment plans, 
laboratory tests and other study procedures.
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patients with known hypersensitivity to any of the excipients of LDK378 
(microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and 
magnesium stearate).
2. Patients with symptomatic central nervous system (CNS) metastases who are 
neurologically unstable or have required increasing doses of steroids within the 2 
weeks prior to study entry to manage CNS symptoms.
3. History of carcinomatous meningitis.
4. Presence 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.
5. 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
 


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●
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 antihypertensive 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 (QTc) > 470 msec using Fredericia correction (QTcF) 
(QTcF = QT/RR1/3) on the screening ECG
6. Prior therapy with other investigational ALK inhibitors (only prior treatment with 
crizotinib is allowed).
7. Patients who have 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 starting study treatment is allowed.
8. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 
weeks prior (2 weeks for resection of brain metastases) to starting study drug or 
who have not recovered from side effects of such procedure. Video-assisted 
thoracic surgery (VATS) and mediastinoscopy will not be counted as major surgery 
and patients can be enrolled in the study ≥1 week after the procedure.
9. Patients 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 LDK378 and for the duration of the study (see 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
●
Medication with a known risk of prolonging the QT interval or inducing 
Torsades de Pointes
10. Impairment of GI function or GI disease that may significantly alter the 
absorption of LDK378 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, or malabsorption syndrome).
11. Patients who are currently receiving treatment with warfarin sodium 
(Coumadin®) or any other coumarin-derivative anticoagulants.
12. Patients receiving unstable or increasing doses of corticosteroids. If patients 
are on corticosteroids for endocrine deficiencies or tumor-associated symptoms, 
(other than CNS-related), dose must have been stabilized (or decreasing) for at 
least 5 days before first dose of study treatment.
13. Patients receiving treatment with any enzyme-inducing anticonvulsant 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. Investigational agents within 4 weeks or ≤ 10 × half-life of the agent (whichever 
is longer) before first dose of study treatment.
15. Pregnant or nursing (lactating) women, where pregnancy is defined as the state 
of a female after conception and until the termination of gestation, confirmed by a 
positive hCG laboratory test.
16. Women of child-bearing potential, defined as all women physiologically capable 
of becoming pregnant, unless they are using highly effective contraception during 
the study and for 3 months after stopping LDK378 treatment. Highly effective 
contraception is defined as any of:
●
Total abstinence: when this is in line with the preferred and usual lifestyle 
of the patient. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
 


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contraception].
●
Sterilization: have had surgical bilateral oophorectomy (with or without 
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 partner sterilization (at least 6 months prior to screening). (With the 
appropriate post-vasectomy documentation of the absence of sperm in the 
ejaculate). [For female patients on the study the vasectomized male partner 
should be the sole partner for that patient].
●
Use of a combination of any two of the following (a+b or a+c or b+c):
a.
Use of oral, injected or implanted hormonal methods of 
contraception that have comparable efficacy (failure rate < 1%), for 
example hormonal vaginal ring or transdermal hormone contraception.
b.
Placement of an intrauterine device (IUD) or intrauterine system 
(IUS)
c.
Barrier methods of contraception: Condom or Occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository.
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.
Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at 
least six weeks prior to screening. In the case of oophorectomy alone, only when 
the reproductive status of the woman has been confirmed by follow up hormone 
level assessment is she considered not of child bearing potential.
17. Sexually active males must use a condom during intercourse while taking the 
drug and for 3 months after stopping LDK378 treatment and should not father a 
child in this period. A condom is required to be used also by vasectomized men in 
order to prevent delivery of the drug via seminal fluid.
18. Other severe, acute, or chronic medical 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.
19 History of interstitial lung disease or interstitial pneumonitis, including clinically 
significant radiation pneumonitis (i.e., affecting activities of daily living or requiring 
therapeutic intervention).
Investigational and 
reference therapy
LDK378 (750 mg daily)
Efficacy assessments
Radiological Tumor Assessment
Response will be determined locally according to the Novartis guideline 
(Appendix 2) on the Response Evaluation Criteria in Solid Tumors (RECIST), 
based on RECIST Version 1.1 (Eisenhauer et al 2009) as evaluated by investigator 
assessment. Additionally, imaging data will be centrally collected, checked for 
quality and independently reviewed by an imaging vendor designated by Novartis 
and will be the basis of supportive analyses.
CT/MRI scans will be performed at baseline within 28 days before start of 
treatment and subsequently every 8 weeks from treatment start until progression of 
disease. See Table 7-1 for details.
Tumor imaging procedures include:
●
Chest CT/MRI
●
Abdominal/Pelvic CT/MRI
●
Additional radiological assessments (e.g. brain imaging, bone scan, PET) as 
clinically indicated
Safety assessments
Adverse Events (AEs) including:
 


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●
Serious AEs (SAEs)
●
Laboratory profiles
●
hematology
●
biochemistry
●
urinalysis
●
coagulation
●
pregnancy test (females)
●
hormones (males only)
●
Physical examination
●
Vital signs
●
Electrocardiograms (ECG)
●
WHO performance status
Other assessments
Sparse and extensive PK
Extensive ECG
Data analysis
Using the PAS, PK concentration versus time profiles of LDK378 will be 
summarized separately for patients with extensive PK assessment and patients 
with sparse PK sampling. The mean and individual concentration versus time 
profiles of LDK378 will be displayed graphically for full PK profile and trough 
collections.
LDK378 PK parameters, including but not limited to AUClast, AUC0-24h, AUCinf, 
Cmax, Tmax, Lambda z, terminal T1/2, T1/2,acc, Racc, CL/F (or CLss/F at steady 
state)and Vz/F, as appropriate will be derived from PK run-in patients with 
extensive PK assessment. All PK parameters will be summarized.
The PK parameters and concentration data will be listed
Safety data including adverse events, vital signs, ECG and laboratory 
abnormalities will be summarized and listed.
For efficacy, ORR as assessed by investigator will be estimated and the binomial 
exact 95% CI provided. DOR will be listed by patient and described using Kaplan-
Meier methods and relevant statistics. DCR will be estimated and the binomial 
exact 95% CI provided. PFS, and OS will be described using Kaplan-Meier 
methods and appropriate summary statistics.
Efficacy data will be listed.
 
 
 
 
 
 
Key words
ALK, NSCLC, LDK378
 


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Amendment 3
Amendment rationale
As of 29-Sep-2015, of 103 patients treated, 66 patients have been discontinued from treatment 
and 37 are still receiving study treatment.
The amendment 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 change was implemented in this amendment: Dose guidance modification for QTc text 
is being updated to provide clarification on monitoring procedure.
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 updated with commonly used abbreviations

Table 6-3: “Refer to Section 6.2.4.2 for additional follow-up” was added for AST or ALT 
and concurrent Total bilirubin management. Follow-up description updated for Grade 3 
QTc interval prolonged. 

Section 6.2.4.2: Updated on following up evaluations for hepatic toxicities and work-up 
guidelines for potential Drug Induced Liver Injury (DILI) cases to align with Novartis 
Oncology trial standard language.
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 of a revised Informed Consent that takes into 
account the changes described in this amended protocol.
 


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Summary of previous amendments
Amendment rationale
As of the release date of this amendment the recruitment has been completed. 125 patients 
have been screened in the study, and 103 have been treated.
This amendment has been implemented to include availability of new safety data and to 
clarify sections of the protocol where additional guidance was required:

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 
LDK378. Clinical data suggest that a small proportion (<1%) of patients treated with 
LDK378 can develop clinical pancreatitis, and the causal role of LDK378 in these cases 
cannot be excluded. Due to this finding, the protocol has been amended to include 
additional dose modification and follow up monitoring language for patients who may 
experience this safety finding.

The definition of end of the study has been clarified.

The guidance regarding study treatment discontinuation and withdrawal of consent has 
been clarified.

Editorial changes and text corrections were made for clarification where required.
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 updated with commonly used abbreviations

Glossary of terms updated with definitions for biological samples, study drug 
discontinuation and withdrawal of consent

‘Changes to the protocol’ section of the amendment 1 rational updated

Section 1.2.1.1.3: Updated nonclinical PK and metabolism data from recent studies.

Section 1.2.1.2.1 and Section 1.2.1.2.2: clinical safety and tolerability and clinical efficacy 
data updated

Section 1.2.1.2.4: added new sentence about impact of fat content on LDK378 absorption

Section 1.3: New section ‘Risk and Benefits’ added

Table 1-3, Table 1-4 and Table 1-5 have been removed

Section 4.1, Section 7.1.5, Section 7.1.7.2, and Section 7.2.1.2,: “Start of a new anti-
cancer therapy” was removed from the list of allowable reasons to stop collection of tumor 
assessments.

Section 4.3: the definition of the end of the study has been updated

Section 6.2.1: sub-title has been updated to specify that guidelines are related to toxicities 
other than those listed in Table 6-3
 


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
Section 6.2.4.8: added new section ‘Guidelines for the follow-up of laboratory pancreatic 
abnormalities’

Table 6-3: updated with criteria for dose modification and dose delay of LDK378 
treatment for renal, pancreatic and cardiac toxicity

Table 6-4: updated instructions on follow-up evaluations in case of pancreatic toxicity

Section 6.3.1.2: updated bisphosphonates use and interaction with LDK378

Section 6.3.1.5: updated with LDK378 dosing guidance in association to radiotherapy and 
surgical resection in order to align with program level language

Section 6.3.1.6: updated to align with program level language

Section 6.3.2.6: clarification that concomitant use of medications that are CYP2C9 and 
CYP3A4/5 substrates with narrow therapeutic index is not permitted with LDK378

Table 7.1: Protocol sections numbers have been updated

Section 7.1.5: section renamed ‘discontinuation of study treatment’. Content of Sections 
7.1.5.1 and 7.1.5.1.1 added to Section 7.1.5. Sections 7.1.5.1 is now ‘replacement policy’.
Discontinuation of study treatment and withdrawal have been clarified.

Section 7.1.6: added new section ‘withdrawal of consent’. Consequently section ‘Follow 
up period’ and related subsections were renumbered.

Section 7.1.7.4: definition of lost to follow up has been clarified

Table 7-3: Lipase has been added to blood chemistry

Section 8.1.3: adverse events of special interest have been clarified

Section 3 Table 3-1, Section 10.4.1.1 and Table 10-1: PK parameters have been clarified

Section 10.5.3: added clarification for “on-treatment period”.

Section 10.8: details of the interim analysis have been clarified

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.
Amendment 1
Amendment rationale
As of the release date of this amendment, 61 patients have been screened to the study, and 50
have been treated. 
to clarify sections of the protocol where additional 
guidance was required.
Main changes include:
 


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
 

 
 
Other changes include:

Clarification of Exclusion Criterion 16 to include Male partner sterilization (at least 6 
months prior to screening).

Clarification of Inclusion Criterion 3 to include washout period for previous crizotinib 
treatment.

Update on safety data from ongoing study 
 to the background section.

Update from safety data to the dose modification guidance with LDK378.

Update from safety data to the criteria for interruption and re-initiation of LDK378 
treatment table.

Clarification that additional patients may be enrolled in the PK run-in period.

Addition of treatment guidance for concomitant medication treatment with 
bisphosphonates.

Updated treatment guidance for gastric protection agents.

Clarification on the statistical analysis sections.

In addition, editorial changes and text corrections were made for clarification, where 
required.
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:

Section 1.2.1: inclusion of FDA approval of LDK378 (ceritinib) under trade name 
Zykadia™.

Section 1.2.1.1.3: updated nonclinical PK and metabolism data from recent studies. 
Evaluation of DDI potential was re-conducted. Using both FDA and EMA 2012 DDI 
guidance, the mechanistic static model determined that the inhibitory potential of LDK378 
is low for CYP2C8 and CYP2B6 (AUCR <1.25). Sentence regarding LDK378 being a 
potent reversible inhibitor of CYP2C8 and CYP2B6 was therefore removed.

Section 1.2.1.1.4: updated to include LDK378 and reference of IB.

Section 1.2.1.2.1: clinical safety and tolerability updated from ongoing study 
CLDK378X2101.

Section 1.2.1.2.2: clinical efficacy updated from ongoing study 

Section 1.2.1.2.4: clinical PK data updated from recent clinical PK studies.
 


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
Section 2.1: data added from ongoing study 
regarding responses of 
LDk378 in ALK positive NSCLC.

Section 2.3: rationale for LDK378 dose and regimen selection further clarified.

Section 4.1: updates made to study design that additional patients may be enrolled in the 
study with PK run-in period in case PK profiles from some of the enrolled patients are 
deemed not evaluable due to early discontinuation from the study or due to vomiting 
events on the day of PK sampling.

Section 4.2: the timing of interim analysis has been updated to be after 30 patients 
completed 16 weeks (4 cycles).

Section 4.3 updated terminology for the rollover study.

Section 5.2: updated inclusion criterion 3 to include washout period for previous crizotinib 
treatment.

Section 5.3: updated prohibited medications.

Section 5.3: exclusion criterion 16 to include Male partner sterilization (at least 6 months 
prior to screening).

Table 6-3: updates to criteria for the interruption and re-initiation of LDK378 treatment 
based on updated safety data.

Section 6.3.1.1: clarifications on corticosteroid use.

Section 6.3.1.2: addition of bisphosphonate treatment guidance.

Section 6.3.1.3: clarification for drugs that are metabolized by CYP450 enzymes.

Section 6.3.2.3: updates to section regarding warfarin and coumarin derivatives.

Section 6.3.2.6: removal of CYP2C8 substrate.

Section 6.3.2.7: updates on gastric protection agents.

Section 6.3.2.9: updated information on QTc prolongation from updated clinical data.

Section 7.1.2: clarification under the screening section was added: The cardiac eligibility 
criteria should be assessed with the central ECG report.

Section 7.1.3, 7.2.3 and 10.4.2.1: updates to section regarding the enrollment of 
Additional patients may be enrolled in the study with PK run-in period in case PK profiles 
from some of the enrolled patients are deemed not evaluable due to early discontinuation 
from the study or due to vomiting events on the day of PK sampling.

Section 7.2.3: update volume sampling for PK tubes from 1.5 mL to 2 mL to reflect actual 
tube size used by central laboratory. Removal of redundant language regarding laboratory 
manual.

Section 9.3: deletion of non-applicable language on IRT data transfers.

Section 10.1.1: deletion of non-applicable language for screening failures.

Section 10.1.5: updates to clarify pharmacokinetic analysis set (PAS) language.

Section 10.4.1: minor update to list of LDK378 PK parameters that will be derived for PK 
run-in patients.

Section 10.4.2.1: Update to non-compartmental method program language. Minor 
revisions to summary statistics wording.
 


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
Section 10.5.2.1: minor changes to endpoint analysis for other secondary objectives.

Section 10.5.3.2: minor changes to adverse event section to bring clarity and to align with 
LDK378 program.

Section10.8: The timing of primary analysis has been updated to be after all 100 patients 
completed 24 weeks (6 cycles).

Section 10.9: 
 

Section 10.10: 
 

Appendix 14.1: Table title for prohibited concomitant medications requiring caution 
updated with a notation for LDK378, deletion of CYP2C8 substrates and paclitaxel and 
updated footnotes for clarification.

Appendix Table 14-2: list of medication to be used with caution updated and deletion of 
CYP2B6 and CYP2C8 substrates, addition of simvastatin, removal of clarithromycin and 
telithromycin.

Editorial and typographical changes through 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 the most common cancer in the world for several decades. In 2008,
there were an estimated 1.61 million new cases, representing 12.7% of all new cancers
worldwide. It was also the most common cause of death from cancer, with 1.38 million deaths
(Ferlay et al 2010). In 2012, an estimated 160,000 deaths were expected in the US (Siegel et 
al 2012) and 262,000 in the European Union (Malvezzi et al 2012). In China in 2005, there 
were 497,908 new cases and 428,936 deaths, the highest one among for all malignant tumors
(Wu et al 2007). Particularly in males, the highest lung cancer incidence rates are in Central 
and Eastern Europe (57.0 per 100,000 by age-standardized), Southern Europe (49.0), North 
America (48.5) and Eastern Asia (45.0). Chinese women have higher lung cancer rates (21.3 
cases per 100,000 females) than those in European countries such as Germany (16.4) and Italy 
(11.4) (Jemal et al 2011).
The World Health Organization (WHO) divides lung cancer into 2 major classes: non-small 
cell lung cancer (NSCLC) and small cell lung cancer. NSCLC accounts for more than 85% of 
all lung cancer cases including 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 United States and is also the most frequent cell type in nonsmokers (NCCN 
Guidelines v2. 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 are diagnosed with locally
advanced or metastatic disease, for which surgery is not indicated.
As summarized in the current National Comprehensive Cancer Network (NCCN) Guidelines 
for NSCLC, platinum-based combination chemotherapy is superior to best supportive care for 
patients with advanced, incurable disease (NCCN Guidelines v3. 2012). Platinum-doublet 
chemotherapy (cisplatin or carboplatin in combination with other chemotherapy agents, with 
or without bevacizumab) is standard firstline treatment of locally advanced or metastatic 
NSCLC, unless a patient has a known “druggable” gene mutation or aberration, and is 
therefore a candidate for a targeted therapy (as discussed below). 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).
 


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Overall, current treatments are not considered satisfactory for most NSCLC patients and the 
prognosis continues to be poor despite chemotherapy treatment, 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, improvement in the knowledge of NSCLC biology has led to the 
identification of molecular events crucial for malignant transformation and cancer cell 
survival. These aberrant molecular events serve as critical oncogenic drivers for these cancers 
and, therefore, represent potential therapeutic targets (Gettinger et al 2011). As a result, new 
targeted treatment options for these patients are evolving. Bevacizumab, a monoclonal 
antibody directed against vascular endothelial growth factor-A (VEGF-A), and erlotinib, an 
epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), have been approved 
for the treatment of NSCLC (Gettinger et al 2011).
The case of EGFR TKIs illustrates a new paradigm in the treatment of NSCLC. There is 
increasing evidence that activating mutations of EGFR define a small subset of patients with 
NSCLC who have sensitivity to EGFR TKIs (Ettinger et al 2010). Six randomized trials have 
demonstrated that patients harboring activating EGFR mutations benefit more from EGFR 
TKIs than from standard chemotherapy in terms or response rate, PFS, toxicity profile and 
quality of life. In particular, the success of EGFR TKIs highlights the importance of 
identifying specific NSCLC molecular drivers to appropriately direct targeted agents to 
specific patient populations.
1.1.3
ALK-rearranged (ALK-positive, ALK+) NSCLC
Another clinically relevant molecular subset of NSCLC is driven by recently discovered 
echinoderm microtubule-associated protein-like 4 (EML4) anaplastic lymphoma kinase (ALK) 
translocation.
ALK is a receptor tyrosine kinase of the insulin receptor superfamily that plays a role in 
neural development and function. It is translocated, mutated, or amplified in several tumor 
types, including NSCLC, neuroblastoma, and anaplastic large cell lymphoma (ALCL), and 
these alterations play a key role in the pathogenesis of these tumors. Other fusion partners of 
ALK have been described (e.g. KIF5B, TFG, KLC1 and PTPN3 (Kruczynski et al 2012), but 
these are less common than EML4. Preclinical experiments have shown that the various ALK 
fusion partners mediate ligand-independent dimerization 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.
EML4-ALK rearrangement in patients with NSCLC is a relatively rare event and is present in 
approximately 2-8% of NSCLCs (Scagliotti G et al 2012; Takeuchi K et al 2009; Soda et al 
2007). In a small scale research in China, the proportion of EML4-ALK is 6.3% in 239 
NSCLC patients (She-Juan An 2012). In another small cohort study which included 103 
Chinese NSCLC patients, EML4-ALK fusion gene was identified in 11.6% (12/103) of the 
patients. In patients with adenocarcinoma lacking EGFR and KRAS mutations, the prevalence
of EML4-ALK translocation could be as high as 42.8% (Xuchao Zhang 2010).It is most 
commonly seen in younger patients with adenocarcinoma histology with never or light 
 


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smoking history. ALK rearrangements and other oncogenic drivers such as mutant EGFR and 
oncogenic RAS are generally mutually exclusive, consistent with the notion that ALK 
rearrangement defines a unique molecular subset of NSCLC (Gainor et al 2013). In these 
patients, ALK rearrangements serve as a key and strong oncogenic driver for NSCLC and 
represent a critical therapeutic target susceptible to targeted ALK kinase inhibition.
Crizotinib, a dual c-MET and ALK inhibitor, is the first clinically available TKI targeting 
ALK. Crizotinib was associated with clinically meaningful response rates of 50% and 61% in 
two single-arm trials in 255 patients with locally advanced or metastatic ALK-positive 
NSCLC (Kwak et al 2010). Responses were rapid, with the majority of patients achieving an 
objective response within the first 8 weeks of treatment, and durable, with a median duration 
of response (DOR) of 48.1 and 41.9 weeks, respectively. Based on these data, crizotinib 
received accelerated approval under the trade name Xalkori® in the US and conditional 
marketing authorization in the EU under the same trade name (Ou 2011). Subsequently, 
crizotinib received approval in Switzerland, Japan, China, Canada, as well as other countries 
worldwide. The clinical benefit of crizotinib compared to chemotherapy in terms of median 
PFS (7.7 and 3.0 months, respectively), quality of life, and control of symptoms has been 
confirmed in a phase III study in the second-line setting (Shaw et al 2013), and based on these 
data the Food and Drug Administration (FDA) granted regular approval for crizotinib in 
November 2013. The most frequent adverse events (AEs) with crizotinib treatment are visual 
disorders, occurring in approximately 62% of patients (Ou et al 2011). Other common 
toxicities include gastro-intestinal (GI) disorders (nausea 53%, vomiting 40%, diarrhea 43%), 
edema (28%), fatigue (20%), dizziness (16%), neuropathy (13%), elevations of liver enzymes 
(13%) and skin rash (10%). 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 in less than 1 year, because of the development of 
resistance to crizotinib. For these patients there is no alternative ALK-targeted therapy at 
relapse. Therefore, the development of ALK TKIs with clinical activity against ALK-positive 
NSCLC resistant to crizotinib is crucial.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of LDK378
LDK378 [5-Chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2 
(isopropylsulfonyl) phenyl ] -2,4-pyrimidinediamine] is an orally available ALK inhibitor. 
 
In addition, LDK378 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 accelerated approval of LDK378 (ceritinib) 
This document (090095a8879a53ab in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI.
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by the US FDA under the trade name ZYKADIA™ on 29-Apr-2014 for the following 
indication:

‘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.
1.2.1.1
Submissions to other health authorities worldwide have been 
completed in some countries and are underway in others. Non-clinical 
experience
1.2.1.1.1 Pharmacology
LDK378 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.
 
In a kinase 
panel of 35 additional enzymes, LDK378 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 ALK inhibition.
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 LDK378, which led to inhibition of cancer cell proliferation in vitro. The 
inhibition of the downstream signaling pathway by LDK378 correlated with the inhibition of 
proliferation. In addition, inhibition of NPM-ALK and EML4-ALK in mouse and rat cell 
xenograft models resulted in inhibition of tumor growth and tumor regression in vivo.
LDK378 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
LDK378 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, LDK378 dosed at 25 mg/kg daily, a dose below the maximum tolerated dose 
(MTD) in clinical studies, resulted in complete regression of established tumors. When dosed 
 


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at 50 mg/kg daily for 14 days in the H2228 NSCLC model, LDK378 resulted in complete and 
prolonged (lasting for more than 4.5 months, the observation period) tumor regressions. 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 (Figure 1-1).
Figure 1-1
Comparison of LDK378 with crizotinib for their anti-tumor activity in a 
mouse H2228 NSCLC model when dosed once a day
LDK378 also demonstrated strong antitumor activity in mouse H2228 NSCLC models that 
developed resistance to crizotinib after continuous treatment with crizotinib at 100 mg/kg/day. 
One of these crizotinib-resistant H2228 models was found to carry a secondary C1156Y 
mutation in the ALK kinase domain, the same mutation found in patients who progressed on 
crizotinib (Choi et al 2010; Huang et al 2013). While this model was resistant to crizotinib 
100 mg/kg, a dose of 50 mg/kg LDK378 slowed tumor growth at the plasma exposure (AUC0-
24h) of 29,745 h.ng/mL. LDK378 caused complete tumor regression at 100 mg/kg after 14 
days of treatment at the plasma exposure (AUC0-24h) of 57,800 h.ng/mL, although the tumors 
started to progress after approximately 30 days of treatment in this C1156Y model (Figure 1-2) 
[internal data].
Similar to some of the patients who progressed on crizotinib while maintaining the ALK 
translocation but had no secondary mutations in ALK, several crizotinib-resistant H2228 
models were found to carry EML4-ALK that had no secondary mutations in ALK (ALK wild 
type). When LDK378 was tested in one of these ALK wild type crizotinib resistant models, it 
also demonstrated potent antitumor activity inhibiting tumor growth at 50 mg/kg and causing 
tumor regression at 100 mg/kg (Figure 1-3). The anti-tumor activity of LDK378 in these 
models may be related to the higher potency for ALK inhibition as compared to crizotinib. In 
the clinic, patients likely will harbour tumors with a mix of ALK wild type and ALK mutated 
cancer cells, especially after progression on crizotinib,
These data support that LDK378 may be clinically active in ALK-rearranged NSCLCs that 
have become resistant to crizotinib.
 


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Figure 1-2
Anti-tumor activity of LDK378 in a crizotinib-resistant mouse H2228 
model with an ALK C1156Y mutation
Figure 1-3
Anti-tumor activity of LDK378 in a crizotinib-resistant mouse H2228 
model without ALK mutations
1.2.1.1.3 Nonclinical pharmacokinetics (PKs) and metabolism
In general, LDK378 was moderately absorbed in rats (37%) and monkeys (>40%). Oral 
bioavailability was complete in fed dogs, suggesting the possible existence of a positive food 
effect. The formulation used in these bioavailability determinations was a 0.5% 
methylcellulose suspension except for in the mouse where a solution formulation was used. 
LDK378 is highly bound to plasma protein (>94%) in all species. Following oral 
administration of [14C] LDK378 to LEH male rats, radioactivity was widely distributed. The 
highest tissue exposures were found in intestine wall, uveal tract, pituitary gland, bile, adrenal 
 


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cortex, harderian gland, liver, spleen, lymph node, lung, kidney, thyroid, bone marrow, 
adrenal medulla and pancreas (25- to 710-fold higher exposure relative to blood). Although 
the brain to blood concentration ratio of drug-related radioactivity was low compared to these 
other tissues brain-to-blood exposure (AUCinf) ratio of approximately 15%, it was higher than 
the 3% background associated with brain vasculature at all monitored time points. This 
indicates that drug-related radioactivity crossed the blood-brain barrier. Unchanged LDK378
was the major component in feces and bile of intact and bile duct-cannulated rats. In the rat, 
LDK378 underwent oxidation leading to the formation of four oxygenated metabolites 
(designated as M23.6, M30.6, M35.8, and M33.4). In addition, LDK378 underwent sulfation 
leading to M36.8 and oxidation followed by sulfation resulting in the presence of M29.5. 
LDK378 also underwent glucuronidation leading to M26.8 and M27.6. The major metabolite 
in feces was designated M33.4 (oxygenation) accounting for approximately 7% of the dose. 
All other metabolites in feces and bile were minor (<5% of the dose). In rats dosed with [14C] 
LDK378, LDK378 -derived radioactivity was excreted predominantly via the fecal route 
(>99%), and renal excretion was a minor pathway for excretion (<1%). Fecal excretion was 
the result of biliary excretion (69%) and gastrointestinal (GI) secretion (31%). Since parent 
drug was the major component in bile and feces after intravenous (i.v.) administration, 
enterohepatic circulation may occur.
CYP3A4/5 is the major hepatic enzyme metabolizing LDK378 in a human in vitro system. 
The metabolic drug-drug interaction (DDI) potential of LDK378 as an inhibitor was evaluated 
using pooled human liver microsomes. Based on the assessment of clinical significance of in 
vitro results using the appropriate DDI decision tree described in FDA draft DDI guidance 
2012 and EMA DDI guideline 2012, at clinically relevant concentrations, LDK378 is unlikely
to inhibit CYP1A2, 2B6, 2C8, 2C19 or 2D6. Only CYP2A6, 3A4, 2C9 and possibly CYP2E1 
need to be considered as possible victims of in vivo inhibition by LDK378. LDK378 is also a 
time-dependent CYP3A inhibitor (Ki: 1.47 µM and Kinact: 0.0642 min-1), but shows no 
apparent time-dependent inhibition of CYP1A2, 2C9 or 2D6 at LDK378 concentrations of up 
to 50 µM.
LDK378 is likely a P-gp substrate, but not BCRP or MRP2 substrate. It does not inhibit P-gp, 
BCRP or MRP2 at concentrations up to 1.5 μM in vitro.
Kinetic PK/pharmacodynamic modeling was performed in the nude rat H2228 model 
(constitutively expressing ELM4-ALK gene) and the nude rat Karpas 299 model (expressing 
NPM-ALK). The minimal pharmacologic dose in humans was estimated to be 100 mg/day for 
tumor stasis.
1.2.1.1.4 Safety pharmacology and toxicology
LDK378 was evaluated for safety in 2- and 4-week studies in rats and monkeys. The principal 
toxicity induced by LDK378 was a systemic inflammation characterized by increased 
neutrophil counts in the peripheral blood and mixed cell/neutrophilic inflammation of the 
biliopancreatic ducts, pancreas, and/or duodenum. Gastrointestinal toxicity was observed in 
both species characterized by body weight loss, decreased food consumption, emesis 
(monkey), diarrhea, and at high doses, by histopathologic lesions including erosion, mucosal 
inflammation, and foamy macrophages in the duodenal crypts and ampullae of rats and 
monkeys, respectively. The liver (bile duct) was also affected in both species only at the 
 


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highest dose levels studied (100 mg/kg/day in the 2-week studies for both rat and monkeys 
and 50 and 30 mg/kg/day in the 4-weeks studies in rat and monkeys, respectively), and 
included increases in liver transaminases in a few animals at high doses, and mixed cell 
inflammation, erosion and cytoplasmic vacuolation of the bile duct epithelium. The pancreas 
was a target organ in the rat, but not the monkey, with acinar cell atrophy and mixed cell 
inflammation noted at middle and high doses. Target organ effects showed partial to complete 
recovery during the 4-week non-dosing period. No effects in the rat central nervous system or 
on the respiratory system were observed at single, high doses (100 mg/kg).
LDK378 has potent activity on the hERG channel with an IC50 of 0.4 μc. However, there 
were no LDK378-related effects in vivo in monkeys at doses as high as 100 mg/kg (human 
equivalent dose [HED] of 1950 mg).
Preclinical studies (in vitro 3T3 NRU assay, refer to [Investigators Brochure]) indicated a low 
risk of phototoxicity with use of LDK378. However, a preliminary analysis from an in vivo 
ultraviolet local lymph node assay (UV LLNA) demonstrated no phototoxic potential with 
LDK378.
Preclinical studies including an in vitro 3T3 NRU assay, and a definitive in vivo ultraviolet 
local lymph node assay (UV LLNA) together demonstrate no phototoxic risk with LDK378
(refer to [Investigators Brochure]).
1.2.1.2
Clinical experience
1.2.1.2.1 Clinical safety and tolerability
LDK378 is associated with a generally manageable safety profile. For the 255 patients treated 
at the recommended dose (RD) of 750 mg in the ongoing study CLDK378X2101, the median 
duration of exposure as of the 31-Oct-2013 cut-off date was 26.9 weeks (range 0.4 to 82.3 
weeks). The 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) 
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Table 1-1
All grades (at least 10%) and grade 3-4 adverse events, regardless of 
study drug relationship, by preferred term in patients treated in the 
750 mg dose group (Data cut-off date: 31-Oct-2013)
Preferred term
LDK378
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
Dose reductions due to AEs occurred in 58.4% of patients treated with LDK378 at the 750 mg 
dose; 38.8% of patients had only 1 dose reduction. The most frequent AEs requiring dose 
adjustments or interruptions reported in >5% of the patients were: ALT increased, nausea, 
AST increased, vomiting, diarrhea, fatigue, and abdominal pain. Adverse events (AEs) 
leading to study drug discontinuations occurred in 10.2% of patients treated with LDK378 at 
the 750 mg dose. The most frequent AEs leading to study drug discontinuations 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 
 


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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 to be monitored for ceritinib have also been identified and include: hepatotoxicity, 
interstitial lung disease/pneumonitis, QT interval prolongation, bradycardia, hyperglycemia
gastrointestinal toxicity (nausea, vomiting and diarrhea) and pancreatitis (including lipase and 
amylase elevations). For additional details, refer to [Investigator’s Brochure].
As of 29-Apr-2013, 19 patients have been treated with LDK378 in a phase I Japanese study 
[CLDK378X1101]. Patients have been treated on a once daily schedule at the following dose 
levels: 300 mg, 450 mg, 600 mg, and 750 mg. A total of 19 patients are evaluable for adverse 
events. Gastrointestinal toxicities, including nausea, diarrhea and vomiting were the most 
common adverse events, occurring in 94.7%, 73.7% and 73.7% of patients, respectively. 
Blood creatinine increased (63.2%), decreased appetite (52.6%), fatigue (36.8%), abdominal 
pain, constipation, hyperuricaemia (each 26.3%), ALT increased, anaemia, AST increased, 
headache, neutropenia, pyrexia, rash, rash maculopapular (each 21.1%) were also common. 
All other adverse events occurred in less than 20% of patients. Grade 3 and 4 adverse events 
were much less common. ALT increased and tumor pain occurred in two patients. All other 
grade 3 or 4 events occurred in one patient. During the escalation part of the study two 
patients experienced dose limiting toxicity (DLT), one at 600 mg qd (lipase increased), and 
one at 750 mg qd (drug-induced liver injury). The DLTs resolved in all patients, however, one 
patient discontinued the study due to drug-induced liver injury. Following clinical review by 
the investigators and Novartis, and assessment of the probability of DLT by BLRM, 750 mg 
qd was determined to be the MTD. At the 750 mg dose level the probability of overdose (DLT 
rate ≥ 33%) based on the BLRM was 7.3%, which satisfied the overdose criterion of < 25%. 
Following determination of the MTD in January 2013 the dose expansion phase of the study 
opened at the 750 mg qd dose level, and accrual to the expansion group is ongoing.
1.2.1.2.2 Clinical efficacy
As of 31-Oct-2013, data from the ongoing Study [CLDK378X2101] demonstrated a high rate 
of rapid and durable responses with LDK378 in 246 ALK-positive NSCLC patients treated in 
the 750 mg dose group (RD). The Full Analysis Set (FAS) consisted of all patients with ALK-
positive NSCLC in the 750 mg treatment dose group (FAS-NSCLC 750 mg group). In these 
patients the Overall Response Rate (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 Complete Response (CR) or Partial Response (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 Duration of 
Response (DOR) based on investigator assessment was long at 9.69 months (95% CI: 7.00, 
11.40) 
LDK378 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 
 


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(range: 4.6 to 24.1) in patients treated with a prior ALK inhibitor and 6.1 weeks (range: 3.0 to 
24.1) in 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 andthe median DOR was 
not reached (95% CI: 9.59, NE) in ALK inhibitor naïve patients, however the 12-month DOR 
rate was 65.2% (95% CI: 46.4, 78.8) 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) Finally, LDK378 demonstrated 
activity in patients with brain metastases at baseline. Among the 98 patients with brain 
metastasis who had received prior ALK-inhibitor treatment, the ORR was 50% (95% CI: 39.7, 
60.3), DOR was 6.9 months (95% CI: 4.8, 8.5), and PFS was 6.7 months (95% CI: 4.9, 8.4). 
For additional details, refer to the [Investigator’s Brochure]. The analysis by the BIRC 
assessment was similar to the analysis by the investigator assessment.
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) (Cut-off date: 31-Oct-2013)
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
1.2.1.2.3 Clinical pharmacodynamics
Data are not available from the ongoing clinical study.
1.2.1.2.4 Clinical pharmacokinetics
In adult patients with tumors characterized by genetic abnormalities in ALK 
 
and in healthy volunteers 
, 
and 
, single-dose pharmacokinetics (PK) of LDK378 in humans has 
the following features: (1) LDK378 was slowly absorbed, with median peak plasma 
concentration occurring at approximately 4 to 6 h in patients, and approximately 6 to 8 h in 
healthy subjects. Following Cmax, LDK378 concentrations declined in a mono-exponential 
manner. The geometric mean apparent terminal half-life ranged from 31 to 41 h across the 
 


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400 to 750 mg dose groups in patients and 36 to 48 h across the 450 to 750 mg dose groups in 
healthy subjects. (2) Cmax and AUClast increased dose-proportionally following single oral 
administration of LDK378 across the 50 to 750 mg dose groups in patients. (3) moderate to 
high variability in LDK378 PK parameters has been observed in both healthy subjects and 
patients. Following single oral doses of 450 to 750 mg in healthy subjects when LDK378 was 
given alone, the inter-subject variability (geometric mean coefficient of variation; CV% range) 
was 42-74% and 35-72% for AUClast and Cmax, respectively. The corresponding values in 
patients were 93% and 87% following single oral doses of 50 to 750 mg based on a model 
developed for dose proportionality analysis.
Multiple-dose PK of LDK378 following repeated daily oral dosing in patients has the 
following features: (1) following LDK378 750 mg once daily dosing, steady-state was 
reached by approximately 15 days with a geometric mean accumulation ratio of 6.2 after 3 
weeks: (2) LDK378 demonstrated nonlinear PK over time, as indicated by the observed 
difference in apparent clearance (CL/F) between single-dose (88.5 L/h at 750 mg) and steady-
state at Cycle 2 Day 1 (33.2 L/h at 750 mg). As LDK378 is a substrate as well as a time-
dependent inhibitor of CYP3A, it is likely that this PK nonlinearity could be attributed to 
auto-inhibition of LDK378. In contrast with single dose data, Ctrough on Cycle 2 Day 1 after 
repeated daily dosing increased with dose in a greater than dose-proportional manner.
In the human ADME study 
, the majority of the radioactivity dose in 
humans was eliminated in the feces (mean: 91.0%) with only a minor amount eliminated in 
the urine (mean: 1.3%) following a single oral dose of 750 mg of [14C]LDK378 to healthy 
male subjects. The mean percentage of the dose eliminated in the feces as unchanged 
LDK378 was 68.0% while all the metabolites were present at low levels, with no individual 
metabolite contributing greater than 2.3% to the radioactivity AUC. Hepatic metabolism and 
potentially biliary excretion and GI secretion all contribute to LDK378 elimination in humans 
while the kidney appears to play a negligible role. The primary biotransformation pathways of 
LDK378 that were observed included mono-oxygenation, O-dealkylation, and N-formylation. 
Unchanged LDK378 was the most abundant drug-related component found in both the plasma 
and excreta.
CYP3A was identified as the major CYP isozyme responsible for the metabolism of LDK378 
in humans. An inhibition DDI study conducted in healthy volunteers indicated that 
ketoconazole (200 mg bid for 14 days), a strong CYP3A inhibitor, increased the Cmax and 
AUCinf of a single 450 mg oral dose of LDK378 by 1.2-fold and 2.9-fold, respectively, 
compared with LDK378 alone 
. These results demonstrated that 
concurrent use of strong CYP3A inhibitors may markedly increase LDK378 exposure and 
should be avoided. An induction DDI study conducted in healthy volunteers indicated that 
rifampin (600 mg daily for 14 days), a strong CYP3A inducer, decreased the Cmax and 
AUCinf of a single 750 mg oral dose of LDK378 by 44% and 70%, respectively, compared 
with LDK378 alone [Study LDK378A2106]. These results demonstrated that concurrent use 
of strong CYP3A inducers may markedly decrease LDK378 exposure and should be avoided.
A food effect study was conducted in healthy volunteers 
. Compared to the 
fasted state, a low-fat meal increased Cmax and AUCinf of a single oral dose of LDK378 500 
mg in healthy subjects by 43% and 58%, respectively, whereas a high-fat meal increased 
Cmax and AUCinf by 41% and 73%, respectively.
 


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To further clarify if low fat content has an impact on the extent of LDK378 absorption, a food 
effect assessment with a very low-fat light snack (containing approximately 100-300 calories 
and 1.5 grams of fat) was also explored in a relative bioavailability study conducted in healthy 
subjects 
. PK data from the light snack cohort showed that when a 
single 750 mg oral dose of ceritinib was administered with a light snack, the Cmax and 
AUCinf increased by 45% and 54% respectively, compared to the fasted condition. This 
magnitude of increase is similar to that caused by a low-fat meal as described in Study 
, suggesting that even a very low-fat meal could lead to a clinically 
meaningful LDK378 exposure increase.
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, as of 
31-Oct-2013, 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 
[CLDK378X2101]. 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 
 


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following prior ALK-targeted therapies, where the only options are chemotherapy and best 
supportive care.
ALK inhibitor naïve patients: As of 31-Oct-2013, 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.
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 7.1.7.2). 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.
 


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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 6.2.4.
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 
ceritinibIncreases 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 
 


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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 
managing patients using standards of care, including anti-diarrheals, anti-emetics, or fluid 
replacement, as indicated.

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
ALK rearrangement is a relatively rare event in NSCLC with a frequency of just 2-8% that 
results in aberrant ALK activation. ALK fusion proteins possess potent oncogenic activity 
both in vitro and in vivo. In these patients, ALK rearrangements serve as a key and strong 
oncogenic driver for NSCLC and represent a critical therapeutic target susceptible to ALK 
kinase inhibition by small-molecule inhibitors that target ALK, like crizotinib.
Currently, crizotinib is the only drug that is approved specifically for this subset of patients 
with ALK-positive NSCLC. Nevertheless, 40-50% of patients fail to achieve a response and a 
high proportion of patients (including the responders) will experience tumor progression 
within one year of crizotinib treatment as shown by a recently presented phase III trial of 
crizotinib in second line ALK-positive patients (Shaw et al 2013). To date, following 
 


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progression on crizotinib, these patients have no effective ALK-targeted treatment options. 
Since ALK aberrant activation remains the key oncogenic driver in these tumors, novel ALK 
targeted therapies with activity against ALK-positive NSCLC that have progressed after 
crizotinib are needed.
 
 
 
As of 31-Oct-2013, data from the ongoing Study 
demonstrated a high rate 
of rapid and durable responses with LDK378 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. 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% 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).
Therefore, these data provided the rationale for the ongoing global phase II 
 
and phase III study 
 in ALK-positive NSCLC failing crizotinib. The 
purpose of this phase I/II study is to characterize the PK, safety and efficacy data of LDK378 
when used as a single agent in Chinese ALK-rearranged advanced NSCLC patients who have 
been pretreated with crizotinib and have no available ALK-targeted therapy. This study will 
support LDK378 registration in China.
2.2
Rationale for the study design
This is a phase I/II, open-label, multi-center study to assess PK, safety, tolerability and 
efficacy of LDK378 in Chinese adult patients with ALK-rearranged locally advanced or 
metastatic NSCLC who have been previously treated with crizotinib. The study includes a 
phase I component for the first 15 patients (5 day PK run-in period) and a phase II component 
for all the patient with continuous dosing (see below). Patients must have progressive disease 
during or after crizotinib treatment whether or not they have been previously treated with 
cytotoxic chemotherapy. These patients do not have any available ALK-targeted treatment 
option to date. Data from the ongoing phase I study 
 suggest that 
advanced NSCLC patients respond to LDK378 after failing crizotinib.
Indeed two single arm studies, the phase I study 
 and a phase II study 
 will support LDK378 global registration in this indication. Therefore, it 
is reasonable to use a single arm study in Chinese patients to support registration of LDK378 
in NSCLC patients that progress after crizotinib in China.
Two phase I studies, the 
global study and 
Japanese
study, have already determined the MTD/RP2D (recommended phase 2 dose) for LDK378 
single agent to be 750 mg/day. However as required by the Health Authority in China, a 
 


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dedicated study is necessary to assess pharmacokinetics profile in Chinese patients. This 
phase I/II single-arm study will be conducted to meet China registration requirements and to 
characterize the pharmacokinetics, safety and efficacy of LDK378 in Chinese patients with 
ALK-rearranged NSCLC treated with crizotinib.
The primary objective of this study is to characterize PK profile, safety and tolerability in this 
population. The primary measure of PK profile is plasma concentration-time profiles of 
LDK378 and PK parameters, including but not limited to AUClast, AUC0-24h, Cmax, Tmax, 
terminal T1/2, effective T1/2, acc, Racc, CL/F and Vz/F, as appropriate. Based on the PK data 
during PK run-in period from the study 
, LDK378 has an apparent terminal 
half-life of approximately 36 hours, which could lead to drug accumulation following once 
daily dosing. Therefore, to characterize the PK profile following a single dose in Chinese 
patients, a 5-day PK run-in period is designed as the phase I component of the study prior to a 
treatment period of continuous daily dosing for all enrolled patients (phase II component). 
Safety will be measured in terms of type, incidence, and severity of adverse events and 
serious adverse events; changes from baseline in vital signs, laboratory test results and ECGs, 
severity of adverse events will be assessed based upon CTCAE v.4.03.
The key secondary objective is to evaluate anti-tumor activity of LDK378 in this population. 
The primary measure of antitumor activity is the overall response rate (ORR) according to 
RECIST criteria 1.1 and will be estimated based on investigator assessment. ORR is an 
appropriate endpoint that can be adequately assessed in the context of this single arm trial. A 
high ORR may predict clinical benefit in this rare population of patients with ALK-rearranged 
NSCLC that has progressed during or after crizotinib therapy and for whom there is no 
available ALK-targeted therapy. Data on ORR will be supplemented with data on duration of 
response (DOR) and time to response (TTR).
The study will also assess progression-free survival (PFS), overall survival (OS) and 
 
. These endpoints are 
considered to be important supportive endpoints to better assess the potential clinical benefit 
of LDK378.
2.3
Rationale for dose and regimen selection
In the dose-escalation phase of Study
, 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:
 


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
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.
Based on the Bayesian logistic regression model (BLRM) used to guide dose escalation, the 
probability of overdose (>25% probability that the DLT rate ≥33%) at Cycle 1 was 3.3% at 
the 750 mg dose level. However, during the dose-escalation discussion between the 
investigators and the sponsor, further dose escalation was considered to be medically 
inappropriate due to the increasing frequency of persistent grade 1-2 nausea, vomiting and 
diarrhea, and the occasional occurrence of grade 3-4 ALT and AST increases with prolongued 
treatment. Further confirmation of the 750 mg dose as the appropriate Maximum Tolerated 
Dose (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 [Study X2101-Section 
11.3].
Among the different doses tested, the 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 LDK378 is generally 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 
the lower doses. Nonclinical data from ALK-positive NSCLC xenograft models indicated 
that LDK378 should be dosed at the MTD to maximize efficacy, in particular against 
crizotinib resistant tumor models.
Demographic data and PK parameters were compared between non-Asian patients and Asian 
patients in 
. Concerning demographic characteristics, the median baseline 
body weight of the Asian population was 60 kg, which was 17% lower than that of the non-
Asian population of 72 kg. Ethnic sensitivity analysis indicated that after three weeks of daily 
dosing at 750 mg, Cmax and AUC0-24 were only 1.26-fold (1180 ng/mL vs. 938 ng/mL) and 
1.04-fold (23100 ng*h/mL vs. 22200 ng*h/mL) higher in the Asian population compared to 
those seen in the non-Asian population, respectively. The accumulation ratio at steady-state 
obtained in the Asians and non-Asians were also similar (Asians: 5.89 vs. non-Asians: 6.46). 
Another phase I clinical trial 
 is ongoing in Japanese patients (See Section 
1.2.1.2.1) The PK exposure results in the Japanese patients determined during escalation 
phase were within the range of the results determined in the non-Japanese patients from 
. Overall, there was no marked ethnic difference (≤ 30% difference) in PK 
parameters between Asian and All others groups.
Therefore, considering the pre-clinical data (e.g. higher anti-tumor activity with higher doses), 
available PK data across Asian and non-Asian population and clinical safety and efficacy data 
(good tolerability and efficacy of 750 mg), the dose of LDK378 750 mg QD is anticipated to 
 


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be tolerable and efficacious in Chinese patients. In study [CLDK378A2109], LDK378 will be 
administered orally, once daily at a dose of 750 mg, continuously in 28-day cycles. A single 
oral dose of LDK378 at 750 mg will be given to the first enrolled 15 patients during the PK 
run-in period (5 days) prior to initiating study drug on Cycle 1 Day 1.
 


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3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To characterize the pharmacokinetics profile of LDK378 in 
Chinese adult patients with ALK-rearranged NSCLC
previously treated with crizotinib following single and multiple 
daily oral dose of LDK378
To assess the safety and tolerability of LDK378 after 
consecutive 750 mg once daily dose in Chinese adult patients 
with ALK-positive NSCLC
Plasma concentration of LDK378 and PK parameters, including but not 
limited to AUClast, AUC0-24h, AUCinf, Cmax, Tmax, Lambda_z terminal 
T1/2, T1/2,acc, Racc, CL/F (or CLss/F at steady state) and Vz/F, as 
appropriate
Adverse events, vital signs, ECGs and laboratory abnormalities
Key secondary
Refer to Section 10.5.1
To demonstrate the antitumor activity of LDK378, as 
measured by overall response rate (ORR) to LDK378 by 
investigator assessment
ORR per RECIST 1.1 calculated as the proportion of patients with a best 
overall response defined as complete response (CR) or partial response (PR) 
by investigator assessment
Other secondary
Refer to Section 10.5.2
To evaluate response related endpoints as
assessed by investigator:
1. Duration of response (DOR)
2. Disease control rate (DCR)
3. Time to Response (TTR)
4. Overall intracranial response rate (OIRR)
5. Progression-free survival (PFS)
6. Overall survival (OS)
ORR and OIRR will also be evaluated as assessed by BIRC.
The following endpoints will be evaluated by investigator assessment per 
RECIST 1.1:
1. DOR, calculated as the time from the date of the first documented CR or 
PR to the first documented progression or all cause death
2. DCR, calculated as the proportion of patients with best overall response 
of CR, PR, or SD
3. TTR, calculated as the time from first dose of LDK378 to first documented 
response (CR+PR)
4. OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients 
who have measureable disease in the brain at baseline
5. PFS, defined as time from first dose of LDK378 to progression or death 
due to any cause
6. OS, defined as time from first dose of LDK378 to death due to any cause
ORR and OIRR as assessed by BIRC will be the basis of supportive 
 


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4
Study design
4.1
Description of study design
This is a phase I/II, open-label, multi-center study in which the PK, safety, tolerability and 
efficacy of LDK378 will be assessed in adult Chinese patients with locally advanced or 
metastatic NSCLC harboring a confirmed ALK rearrangement, defined as positive using the 
FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and 
scoring algorithm (including positivity criteria) or positive as assessed by the CFDA approved 
immunohistochemistry (IHC) test (Ventana Medical Systems, Inc) using rabbit monoclonal
primary antibody assay (D5F3) and associated scoring algorithm.
If documentation of ALK rearrangement is not available as described above, a test to confirm 
ALK rearrangement must be performed using an archival tumor obtained at or since the time 
of diagnosis or a new tumor biopsy obtained prior to the first LDK378 dose. The test will be 
performed at a Novartis designated central laboratory (by IHC test using rabbit monoclonal 
primary antibody assay (D5F3), Ventana Medical Systems, Inc). Patients must wait for the 
result of the ALK rearrangement status before initiating treatment with LDK378.
Patients must have demonstrated progression during or after crizotinib treatment whether or 
not previously treated with cytotoxic chemotherapy and have no available ALK-targeted 
treatment options.
Overall approximately 100 patients with locally advanced or metastatic NSCLC which harbor
ALK -rearrangement will be enrolled in the study. Patients will have a screening period, a 
treatment period, an end of treatment (EOT) assessment and a follow up period.
The study begins with a screening period, up to and including 28 days prior to the first dose of 
LDK378, to assess eligibility.
The first 15 enrolled patients will enter a 5-day PK run-in period during the phase I 
component of this study. The phase II component of the study will start on Cycle 1 Day 1 for 
all enrolled patients.
The first 15 patients to be enrolled in the phase I component of the study will have PK 
sampling over 120-hour during the 5-day PK run-in period following a single oral dose at 750 
mg. This will be done in order to characterize the PK profile, safety and tolerability of 
LDK378 after single dosing in this population.
After the PK run-in period, the treatment period for the first 15 patients will start on Cycle 1 
Day 1 in which LDK378 will be given as continuous daily oral dosing at 750 mg QD in 28-
day cycles. Apart from these 15 patients, the rest of the enrolled patients will start treatment 
with LDK378 at 750 mg QD on Cycle 1 Day 1 in 28-day cycles as phase II component of the 
study.
Data from all patients entering the 28-day cycles treatment period will be used to characterize 
the PK profile, safety and tolerability of LDK378 as continuous 750 mg once daily dose as 
well as to demonstrate the antitumor activity of LDK378 as measured by ORR by investigator 
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Figure 4-1
Study Design
Screening
Day -28 to Day -1
100 ALK+ NSCLC patients
5 day Run-In
First 15 enrolled patients
(Phase I component)
85 patients
Treatment
Daily dosing, 28-day cycles
(Phase II component)
End of Treatment*
Due to disease PD
Within 7 days after last dose
*Patient may continue LDK378 despite 
progression if there is continued clinical 
benefit. EoT should only be performed 
once LDK378 is permanently discontinued
End of Treatment
Not due to disease PD
Within 7 days after last dose
Safety follow-up
30 Days after last dose
Safety follow-up
30 Days after last dose
Continue tumor and 
 
Every 8 weeks from EoT until PD
Study evaluation complete
Study evaluation complete
Survival follow-up
Every 3 months after final tumor assessment
Patients will take LDK378 once daily, at approximately the same time each day in the 
morning. On days when a PK sample is obtained, the patient will take LDK378 during the 
clinic visit as instructed by the study staff. Treatment with LDK378 will continue until the 
patient experiences unacceptable toxicity that precludes further treatment, discontinues 
treatment at the discretion of the patient or investigator, starts a new anti-cancer therapy or 
dies. Clinical and laboratory assessments will be performed as described in Section 7. If the 
patient experiences RECIST-defined progressive disease (PD) on LDK378 as assessed by the 
investigator, treatment with the study drug may be continued if, in the judgment of the 
investigator, there is still evidence of clinical benefit. These patients will be counted as PD for 
ORR, DOR, DCR and PFS calculations.
 


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Tumor response will be evaluated every 8 weeks (i.e. every 2 cycles) starting from the first 
day of treatment with LDK378 until the time of RECIST-defined PD by investigator 
assessment, withdrawal of consent for further follow-up, loss to 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.
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 LDK378. Patients will be 
contacted for the safety follow-up 30 days after their last dose of LDK378 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 determine whether the patient has died 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.
4.2
Timing of interim analyses and design adaptations
An interim analysis will be performed after the first 30 patients enrolled have completed at 
least 16 weeks (4 cycles) of treatment with LDK378 or have discontinued earlier. The interim 
analysis will focus on full pharmacokinetics profile, safety and preliminary efficacy data. See 
also Section 10.8.
4.3
Definition of end of the study
The primary data analysis will be performed after all patients have undergone at least 24
weeks (6 cycles) of treatment with LDK378 or have discontinued earlier. At this time, the 
primary clinical study report (CSR) will be produced. Following the primary analysis time 
point, the study will remain open. Patients still being followed on the study, either still on 
treatment, efficacy follow up post-treatment discontinuation in the absence of PD, or in 
survival follow up, will continue as per the schedule of assessments.
The study will end once at least 75% of patients have died, have been lost to follow-up or 
have withdrawn consent for survival follow-up, The final analysis of study data will be 
conducted at the end of the study. All available data from all patients up to this cutoff date 
will be analyzed.
At the end of study (EOS), the patients who are still receiving treatment with LDK378 
because they have continuing CR, PR or SD or because they are deriving clinical benefit in 
the opinion of the investigator despite having a RECIST 1.1 defined progressive disease will 
be offered enrollment into a separate protocol. In this protocol, Novartis will continue to 
supply LDK378 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 ([CLDK378A2109]), the 
separate protocol will be submitted to Health Authorities and IRBs involved in the current 
study.
 


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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 as for a discontinued or 
prematurely withdrawn patient as described in Section 7 should be performed. 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 IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
This study of LDK378 will be conducted in Chinese adult patients with ALK-rearranged 
locally advanced or metastatic NSCLC that has progressed during or after crizotinib treatment 
whether or not previously treated with cytotoxic chemotherapy.
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 any additional parallel 
investigational drug or device studies while on treatment. Rescreening will not be allowed.
However, 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.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Histologically or cytologically confirmed diagnosis of NSCLC, that carries an ALK 
rearrangement defined as positive using the FDA approved Vysis ALK Break Apart FISH 
Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria) 
or positive as assessed by the CFDA approved immunohistochemistry (IHC) test (Ventana 
Medical Systems, Inc) using rabbit monoclonal primary antibody assay (D5F3) and 
associated scoring algorithm. If documentation of ALK rearrangement is not available as 
described above, a test to confirm ALK rearrangement must be performed using an 
archival tumor obtained at or since the time of diagnosis or a new tumor biopsy obtained
prior to the first LDK378 dose. The test will be performed at a Novartis designated central 
laboratory (by IHC test using rabbit monoclonal primary antibody assay (D5F3), Ventana 
Medical Systems, Inc). Patients must wait for the result of the ALK rearrangement status 
before initiating treatment with LDK378.
2. Age 18 years or older at the time of informed consent.
 


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3. Patients must have stage IIIB or IV NSCLC at the time of study entry and have had 
progressive disease during or after crizotinib treatment whether or not previously treated 
with cytotoxic chemotherapy. If treated with chemotherapy, maximum 2 lines are allowed.

Patients must have progressive disease at study entry. Patients are not eligible if 
crizotinib was discontinued due to toxicity.

Patients must have received their last dose of crizotinib ≥ 1 week prior to the first
dose of LDK378 and recovered from crizotinib toxicities (as defined in inclusion 
criteria #4)

Prior targeted therapies will not count as a line of cytotoxic chemotherapy (i.e. 
patients may have received prior treatment with these drugs excluding ALK-inhibitors 
– See exclusion criteria # 6).

(Neo-) adjuvant cytotoxic chemotherapy will count as one prior line of treatment if 
relapse occurred within 12 months from the end of the adjuvant cytotoxic 
chemotherapy

Note: A cytotoxic chemotherapy line in locally advanced disease is defined as an 
anticancer regimen that contains at least 1 cytotoxic chemotherapy agent and is given 
for at least 21 days or more. If a cytotoxic chemotherapy regimen was discontinued 
for a reason other than disease progression and lasted less than 21 days, then this 
regimen does not count as a prior line of chemotherapy
4. Patients must have recovered from all toxicities related to prior anticancer therapies to
grade ≤2 (CTCAE v 4.03). The exception to this criterion is for patients with grade 2
nausea/vomiting and/or grade 2 diarrhea despite optimal supportive therapy who will not
be allowed to participate in the study. Patients with any grade of alopecia are allowed to
enter the study.
5. Patients must meet the following laboratory values at the screening visit:

WBC count ≥ 4.0 x 109 /L

Absolute Neutrophil Count ≥ 1.5 x 109/L

Platelets ≥ 100 x 109/L

Hemoglobin (Hgb) ≥ 9 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) < 2.5 x ULN, except for patients with liver metastasis, 
who are only included if AST < 5 x ULN

Alanine transaminase (ALT) < 2.5 x ULN, except for patients with liver metastasis, 
who are only included if ALT < 5 x ULN

Alkaline phosphatase (ALP) < 5.0 x ULN
 


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6. Patient must have the following laboratory values WNL (within normal limits) or 
corrected to within normal limits with supplements during screening:

Potassium

Magnesium

Phosphorus

Total calcium (corrected for serum albumin)
7. Life expectancy ≥12 weeks.
8. World Health Organization (WHO) performance status 0-2.
9. At least one 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.
10. Written informed consent for the main study must be obtained prior to any screening 
procedures. If consent cannot be expressed in writing, it must be formally documented and 
witnessed, ideally via an independent trusted witness.
11. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests 
and other study procedures.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patients with known hypersensitivity to any of the excipients of LDK378 (microcrystalline
cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate).
2. Patients with symptomatic central nervous system (CNS) metastases who are
neurologically unstable or have required increasing doses of steroids within the 2 weeks
prior to study entry to manage CNS symptoms.
3. History of carcinomatous meningitis.
4. Presence 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.
5. 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 
antihypertensive medication. Initiation or adjustment of antihypertensive medication 
(s) is allowed prior to screening

Ventricular arrhythmias

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
Other cardiac arrhythmia not controlled with medication

Corrected QT (QTc) > 470 msec using Fredericia correction (QTcF) (QTcF = 
QT/RR1/3) on the screening ECG
6. Prior therapy with other investigational ALK inhibitors (only prior treatment with 
crizotinib is allowed).
7. Patients who have 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 starting study treatment is allowed.
8. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior (2
weeks for resection of brain metastases) to starting study drug or who have not recovered
from side effects of such procedure. Video-assisted thoracic surgery (VATS) and
mediastinoscopy will not be counted as major surgery and patients can be enrolled in the
study ≥1 week after the procedure.
9. Patients 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 LDK378
and for the duration of the study (see Appendix I):

Strong inhibitors or strong inducers of CYP3A4/5

Medications with a low therapeutic index that are primarily metabolized by
CYP3A4/5, and/or CYP2C9

Medication with a known risk of prolonging the QT interval or inducing Torsades de 
Pointes
10. Impairment of GI function or GI disease that may significantly alter the absorption of 
LDK378 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or 
malabsorption syndrome).
11. Patients who are currently receiving treatment with warfarin sodium (Coumadin®) or any
other coumarin-derivative anticoagulants.
12. Patients receiving unstable or increasing doses of corticosteroids. If patients are on
corticosteroids for endocrine deficiencies or tumor-associated symptoms, (other than 
CNS-related), dose must have been stabilized (or decreasing) for at least 5 days before 
first dose of study treatment.
13. Patients receiving treatment with any enzyme-inducing anticonvulsant 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. Investigational agents within 4 weeks or ≤10 × half-life of the agent (whichever is longer)
before first dose of study treatment.
15. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
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16. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective contraception during the study
and for 3 months after stopping LDK378 treatment. Highly effective contraception is 
defined as any of:

Total abstinence: when this is in line with the preferred and usual lifestyle of the 
patient. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception].

Sterilization: have had surgical bilateral oophorectomy (with or without 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 partner sterilization (at least 6 months prior to screening) (With the appropriate 
post-vasectomy documentation of the absence of sperm in the ejaculate). (For female 
patients on the study the vasectomized male partner should be the sole partner for that 
patient).

Use of a combination of any two of the following (a+b or a+c or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception that have 
comparable efficacy (failure rate < 1%), for example hormonal vaginal ring or 
transdermal hormone contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
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.
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least six weeks prior to screening. In the 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential.
17. Sexually active males must use a condom during intercourse while taking the drug and for
3 months after stopping LDK378 treatment and should not father a child in this period. A
condom is required to be used also by vasectomized men in order to prevent delivery of
the drug via seminal fluid.
18. 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.
19. History of interstitial lung disease or interstitial pneumonitis, including clinically 
significant radiation pneumonitis (i.e., affecting activities of daily living or requiring 
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6
Treatment
6.1
Study treatment
For this study, the term “investigational or study drug” refers to LDK378. All dosages 
prescribed and dispensed to the patient and all dose changes during the study must be 
recorded on the Dosage Administration Record 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.
6.1.1
Dosing regimen
LDK378 will be administered orally once daily at a dose of 750 mg on a continuous dosing 
schedule in treatment period. The first 15 patients enrolled in the phase I component of the 
study will have PK sampling over 120-hour during the single-dose PK run-in period following 
a single oral dose at 750 mg. After the PK run-in period, the treatment period will start in 
which LDK378 will be given starting on Cycle 1 Day 1 in a continuous daily oral dosing 
regimen. The investigator must instruct the patient to take the study drug exactly as prescribed. 
Separately from these 15 patients, all the other enrolled patients will receive LDK378 
treatment at 750 mg qd on Cycle 1 Day 1. 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. On days that PK samples are obtained, the patient will take LDK378 during the 
clinic visit after the pre-dose PK samples and prior to post-dose PK samples, when
instructed by the study staff.

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)
6.1.1.1
Additional dosing guidelines for pharmacokinetic sampling
On days with PK sampling the following additional guidelines should be followed:

The patient should take the dose in the clinic at least two hours after a light breakfast. The 
patient does not have to fast overnight (See Section 7).

The pre-dose sample should be drawn just before LDK378 dosing. The sampling time of 
the pre-dose PK sample and the dosing time of LDK378 must be precisely recorded in the 
eCRF. Furthermore, the dosing time of LDK378 on the previous day must be precisely 
recorded in the eCRF.

If vomiting occurs within the first 6 hours post-treatment on a PK day, the exact time of 
the first vomiting episode must be noted.
6.1.2
Guidelines for continuation of treatment
For guidelines for dose modification of treatment, refer to Section 6.2.
Patients who have RECIST-defined PD by investigator assessment, but who, in the opinion of 
the investigator, have evidence of continued clinical benefit from LDK378 may continue to 
receive the study medication. In such cases, these patients must continue to be followed for 
safety assessments as per the schedule of assessments, but imaging assessments will no longer 
be required.
6.1.3
Treatment duration
Patients should continue LDK378, and should follow the protocol safety assessments as 
scheduled, until they experience any of the following:

Disease progression (radiologically documented according to RECIST 1.1 by the 
investigator assessment) with the exception of patients, who, in the investigator’s 
judgment, continue to show evidence of clinical benefit despite RECIST-defined PD (see 
Section 6.1.2)

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
 


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Patients who permanently discontinue the study drug for any reason other than disease 
progression must, if consenting to further follow-up, continue efficacy follow-up assessments 
as scheduled in the protocol until the time of confirmed disease progression or death.
After discontinuing LDK378, further treatment for NSCLC is left to the physician’s discretion.
6.1.4
Definition of treatment cycle
A treatment cycle is defined as 28 calendar days from the start of treatment with LDK378 
(Day 1, cycle 1) for the purposes of scheduling procedures and evaluations.
6.2
Dose modifications
6.2.1
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 patient to continue the study treatment. Any changes in 
LDK378 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 
grade 3 or 4 treatment-related toxicity that is considered by the investigator to be life-
threatening, permanently discontinue study treatment.
More detailed LDK378 dose modification guidelines are described in Section 6.2.3. for 
selected toxicities. 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).
6.2.2
Treatment interruption and treatment discontinuation
If the administration of LDK378 is temporarily interrupted for reasons other than toxicity, 
then treatment with LDK378 may be resumed at the same dose. The same applies if the 
patient experiences an unacceptable toxicity not specifically described in Table 6-3 or Section 
6.2.2, provided this toxicity resolved to ≤ CTCAE grade 1.
If the treatment with LDK378 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), 
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If the treatment with LDK378 dosing is withheld for more than 28 consecutive days (counting 
from the first day when a dose was missed), due to toxicity, then LDK378 should be 
permanently discontinued except in cases where the investigator believes the patient continues 
to derive clinical benefit. In such cases, treatment with LDK378 may be resumed at a lower 
dose.
Patients who discontinue the study due to a study drug related AE or an abnormal laboratory 
value must be followed as described in Section 6.2.4.
All patients will be followed for safety until 30 days after the last dose of LDK378. 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.
6.2.3
Criteria for LDK378 dose modifications
An LDK378 dose reduction will follow the guidelines described in Table 6-2. For each patient, 
a maximum of 3 dose modifications is allowed after which the patient must be discontinued 
from treatment with LDK378. Once the dose of LDK378 has been reduced, it cannot be re-
escalated. If a patient continues treatment with LDK378 after RECIST-defined PD as 
determined by the investigator, the criteria for dose modification will also apply.
Table 6-2
Dose reduction steps for LDK378
LDK378 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
**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 LDK378
Guidelines for dose modification and dose interruption of LDK378 are described in
Table 6-3.
 


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Table 6-3
Criteria for interruption and re-initiation of LDK378 treatment
Worst toxicity (CTCAE 4.03 Grade)*
Dose Modifications for LDK378
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)
Maintain dose level
Grade 4 (ANC < 0.5 x 109/L)
Omit dose until resolved to ≤ Grade 2, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then 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 )
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)
Maintain dose level
Grade 3 (PLT < 50 and ≥25 x 109/L)
Omit dose until resolved to ≤ Grade 2, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then 1 dose level
Grade 4 (PLT < 25 x 109/L)
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
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)
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
Omit dose until resolved to ≤ Grade 1, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then 1 dose level
Grade 3 (> 3.0 and ≤ 10.0 x ULN) with ALT or AST ≤ 3.0 x ULN
Omit dose until resolved to ≤ Grade 1, then:
If resolved in ≤ 7 days, 1 dose level
If resolved in 7 days discontinue patient from LDK378
 


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Worst toxicity (CTCAE 4.03 Grade)*
Dose Modifications for LDK378
Grade 4 (> 10.0 x ULN)
Permanently discontinue patient from LDK378
AST or ALT
Grade 1 (> ULN and ≤ 3.0 x ULN)
Maintain dose level with LFTs*** monitored per protocol
Grade 2 (> 3.0 and ≤ 5.0 x ULN) without total bilirubin elevation to > 2 x 
ULN
Maintain dose level with LFTs*** monitored per protocol
Grade 3 (> 5.0 and ≤ 20.0 x ULN) without total bilirubin elevation to > 2 x 
ULN
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
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
Permanently discontinue patient from LDK378 Refer to Section 6.2.4.2 for additional follow-
up
PANCREATIC
Amylase and/or lipase elevations (in the absence of clinical symptoms)
Grade 1 (> ULN and ≤1.5 x ULN)
Maintain dose level
Grade 2 (>1.5 - 2.0 x ULN)
Maintain dose level
Grade ≥3 (> 2.0 x ULN) 
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.
RENAL
Serum creatinine
Grade 1 (>1 and ≤1.5 x baseline; > ULN and ≤1.5 x ULN)
Maintain dose level
Grade 2 (>1.5 and ≤3.0 x baseline; >1.5 and ≤3.0 x ULN)
Omit dose until resolved to ≤ Grade 1, then:
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)
Omit dose until resolved to ≤ Grade 1, then 1 dose level
Grade 4 (> 6.0 x ULN)
Permanently discontinue patient from LDK378
 


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Worst toxicity (CTCAE 4.03 Grade)*
Dose Modifications for LDK378
GASTROINTESTINAL
Diarrhea****
Grade 1 
Maintain dose level but adjust anti-diarrhea treatment
Grade 2 (despite maximal anti-diarrheal medication)
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)
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level
Grade 4 (despite maximal anti-diarrheal medication)
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level
Nausea*****
Grade 1 or 2 
Maintain dose level but adjust anti-emetic treatment
Grade 3 (despite standard anti-emetics)
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level
Vomiting*****
Grade 1 
Maintain dose level but adjust anti-emetic treatment
Grade 2 (despite standard anti-emetics)
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)
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level
Grade 4 (despite standard anti-emetics)
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level
METABOLIC
Any Grade hypophosphatemia
Treatment with phosphate supplements as clinically indicated and maintain dose level
Persistent hyperglycemia (glucose> 250 mg/dL) despite optimal anti-
hyperglycemic therapy
Omit dose until hyperglycemia is adequately controlled, then resume LDK378 at ↓ 1 dose 
level
If adequate hyperglycemic control cannot be achieved with optimal medical management, 
permanently discontinue patient from LDK378.
GENERAL DISORDERS
Fatigue (asthenia)
Grade 1 or 2
Maintain dose level
Grade 3
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 LDK378
PULMONARY
Notes:
●
Withhold LDK378 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, then consider 
resuming LDK378 at current dose level after the pneumonia resolves.
PNEUMONITIS
Any Grade treatment-related ILD/pneumonitis
Permanently discontinue patient from LDK378
CARDIAC
Electrocardiogram QT corrected (QTc) interval prolonged
Grade 1 (QTc 450-480 ms)
Grade 2 (QTc 481-500 ms)
Maintain dose level
Grade 3 (QTc ≥ 501 ms on at least two separate ECGs)
Omit dose until QTc is less than 481 ms, 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 a time-matched PK 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)
Permanently discontinue patient from LDK378
 


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Worst toxicity (CTCAE 4.03 Grade)*
Dose Modifications for LDK378
Bradycardia
Grade 1 or 2
Omit dose until recovery to asymptomatic bradycardia or to a heart rate ≥ 60 bpm
Evaluate concomitant medications known to cause bradycardia, and adjust the dose of 
LDK378.
Grade 3
Grade 4 (in patients taking a concomitant medication also known to cause 
bradycardia or a medication known to cause hypotension)
Omit dose until recovery to asymptomatic bradycardia or to a heart rate ≥ 60 bpm
If the concomitant medication can be adjusted or discontinued, resume LDK378 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)
Permanently discontinue LDK378.
* 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 6.3.2.5)
***** 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 6.3.2.6)
 


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6.2.4
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).
6.2.4.1
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.
6.2.4.2
Guidelines for the follow-up of laboratory liver abnormalities
In patients with any clinically relevant laboratory liver abnormality, as defined below, hepatic 
toxicity monitoring must include ALL of the following live 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.
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. 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.
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 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:

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 
 


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
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 or hepatocellular 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. 

Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study. 

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.
6.2.4.3
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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6.2.4.4
Guidelines for monitoring pneumonitis
Monitor patients for pulmonary symptoms indicative of pneumonitis. In addition, withhold 
LDK378 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.
6.2.4.5
Guidelines for the treatment of study drug induced nausea and 
vomiting
Nausea and vomiting are among the most frequently reported AES following treatment with 
LDK378 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 
LDK378, International Guidelines for anti-emetic treatment recommend early treatment with 
5-HT3-receptor antagonists (5-HT3RAs).
Dose adaptation of LDK378 in case of treatment related nausea and/or vomiting must follow 
the guidelines presented above in Table 6-3.
6.2.4.6
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.
 


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
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 LDK378 in case of treatment related diarrhea must follow the guidelines 
presented above in Table 6-3.
6.2.4.7
Guidelines for treatment of hypophosphatemia
In the phase I study [CLDK378X2101], there were 3 cases of grade 3 hypophosphatemia, one 
of which was a DLT that contributed to the MTD determination – this patient was able to 
continue LDK378 at the same dose. In all cases patients were able to continue therapy without 
dose modification. Hypophosphatemia was not among the commonly reported AEs (i.e., < 
15%), regardless of relationship to LDK378 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 LDK378. For any grade of 
hypophosphatemia during the study, treatment with phosphate supplements should be given as 
clinically indicated, and the LDK378 dose can be maintained.
6.2.4.8
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 ceritininb, then perform 
diagnostic procedures (e.g., abdominal CT scan or ultrasound) to exclude pancreatic 
pathology.
See also dose modification guidelines described in Table 6-3.
 


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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:
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 (or to baseline). After resumption of 
dosing, continue to test weekly for one additional cycle (4 weeks). If no reoccurrence 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
6.2.5
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 6.2.4. Refer to preclinical toxicity and or clinical data found in the 
[Investigator Brochure].
6.3
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 6.3.1), except 
when specifically prohibited (see Section 6.3.2).
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 LDK378 through 30 days after the last dose of LDK378 will be 
recorded in the Concomitant Medications or Surgical and Medical Procedures eCRF, 
respectively. Medications include not only physician prescribed medications, but also all 
 


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over-the counter medications, herbal medications (prohibited, see Section 6.3.2.7), food and 
or vitamin supplements.
6.3.1
Permitted concomitant therapy
6.3.1.1
Corticosteroids
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to induce 
CYP3A enzymes, thereby increasing the risk of reducing LDK378 drug exposure to sub-
therapeutic levels. Systemic corticosteroid treatment must 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);

Stable doses of corticosteroid therapy such as dexamethasone and prednisone (e.g. for 
tumor associated symptoms) are permitted during the course of the study. If increasing 
doses of corticosteroids are required, LDK378 must be withheld and the corticosteroid 
dose must have been stabilized (or decreasing) for at least 5 days before LDK378 is 
resumed.
6.3.1.2
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.
No drug-drug interaction is expected between LDK378 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.
The same guidelines apply to the use of denosumab for the treatment of bone metastatic 
disease.
6.3.1.3
Drugs that are metabolized by CYP450 enzymes
In vitro drug metabolism studies show that the metabolism of LDK378 is mediated by 
CYP3A4/5. LDK378 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 enzymes at clinically relevant concentrations Clinical studies 
have not yet been performed to confirm the potential effect of LDK378 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 LDK378.
Concomitant treatment of LDK378 with weak inhibitors or inducers of CYP3A4/5 is 
permitted. Caution is advised when LDK378 is co-administered with drugs that are moderate 
inhibitors or inducers of CYP3A4/5 (Table 14-2 of Appendix 1). Duration of concomitant 
 


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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 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 
LDK378 with strong inhibitors or inducers of CYP3A4/5 is prohibited (refer to 
Section 6.3.2.5).
Concomitant treatment of LDK378 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).
6.3.1.4
Non-enzyme inducing anti-epileptic drugs
Non-enzyme inducing anti-epileptic medication (Non-EIAED) is allowed.
6.3.1.5
Palliative radiotherapy and surgery
Local radiotherapy for analgesic purposes or for lytic lesions at risk of fracture 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. 
Patients who develop progressive disease but are still deriving clinical benefit from ceritinib 
therapy, as determined by the Investigator may undergo radiotherapy and/or surgical resection 
as palliative localized therapy to treat metastatic lesions. Ceritinib should be held for at least 4 
days prior to radiotherapy and at least 1 day prior to any surgery. Ceritinib may be resumed 
≥3 days after completing radiotherapy or minor surgery, and ≥2 weeks after major surgery.
6.3.1.6
Gastric protection agents
The use of gastric protection agents except for proton pump inhibitors (PPIs) is allowed (see 
Section 6.3.2.7). When the concurrent use of a H2-antagonists or an antacid is necessary, the 
H2 blocker may be administered 10 hours before and 2 hours after LDK378 dose, or the 
antacid be administered 2 hours before or 2 hours after LDK378 dose. Time restrictions for 
the concurrent use of PPIs and LDK378 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).
6.3.2
Prohibited concomitant therapy
6.3.2.1
Other anticancer therapy
Anticancer therapy (chemotherapy, targeted therapy, biologic therapy or radiation therapy 
(except palliative radiotherapy as described in Section 6.3.1.5), 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 must be permanently 
discontinued from the treatment portion of the study.
 


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6.3.2.2
Other investigational therapies
Other investigational therapies must not be used while the patient is on the study.
6.3.2.3
Warfarin and coumarin derivatives
Therapeutic doses of warfarin sodium or any other coumarin-derivative anticoagulant are not 
permitted. LDK378 is an inhibitor of and CYP2C9, the major metabolizing enzyme of 
warfarin. A clinically relevant increase in warfarin exposure is possible.
6.3.2.4
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 LDK378.
6.3.2.5
Strong CYP3A inhibitors and inducers
In vitro metabolism studies suggest that oxidative metabolism of LDK378 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.
6.3.2.6
Medications that are, CYP2C9 and CYP3A4/5 substrates with narrow 
therapeutic index
LDK378 is a potent inhibitor of drugs metabolized by the cytochromes 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 LDK378. Refer to Table 14-1 of Appendix 1 for a list of these 
medications. Please note that this list may not be comprehensive.
6.3.2.7
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 LDK378 absorption. When the concurrent use of a H2-antagonist or 
an antacid with LDK378 is necessary, the H2 blocker must be administered 10 hours before or 
2 hours after the LDK378 dose, and the antacid must be administered 2 hours before or 2 
hours after the LDK378 dose. Time restrictions for the concurrent use of PPIs and LDK378
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).
 


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6.3.2.8
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.
6.3.2.9
Medications that may prolong the QT interval or have a known risk of 
inducing Torsades de Pointes
LDK378 has potent activity on the hERG channel with an IC50 of 0.4 μM. However, there 
were no LDK378-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 LDK378 on the QT interval in an open-label, dose-
escalation, and expansion study ([CLDK378X2101]). A total of 304 patients were treated with 
LDK 378 doses ranging from 50 to 750 mg with 255 patients treated with LDK378 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. At average steady-state concentrations the upper bound 
of the 2-sided 90% CI for QTc change from baseline was 16 msec at LDK 378 750 mg. A 
pharmacokinetic/pharmacodynamic analysis suggested concentration-dependent QTc interval 
prolongation.
Concomitant administration of LDK378 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 LDK378 and any 
medication included in Table 14-1 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.
6.4
Patient numbering, treatment assignment or randomization
6.4.1
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 RDC interface.
At the 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, even 
 


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if the patient is re-screened. If the patient fails to start treatment for any reason, the reason will 
be entered into the Screening Disposition eCRF page.
Following completion of screening procedures The IRT system must again be contacted to
verify patient eligibility and enroll the patient in the study before the patient receives the first 
dose (at PK-run in Day 1 for the first 15 patients and at C1D1 for all other patients). 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.
6.4.2
Treatment assignment or randomization
Not applicable.
6.4.3
Treatment blinding
Not applicable.
6.5
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) 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
6.5.1
Study drug packaging and labeling
The study medication packaging has a 2-part label. Immediately before dispensing the 
package to the patient, site personnel will detach the outer part of the label from the packaging 
and affix it to the source document (Drug Label Form) for that patient’s unique patient 
number.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug but no information about the 
patient.
 


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Table 6-6
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
LDK378
150 mg capsules
LDK378 (daily)
6.5.2
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].
6.5.3
Study drug compliance and accountability
6.5.3.1
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, and will be verified by determinations of LDK378 in plasma 
and/or urine.
6.5.3.2
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.
6.5.3.3
Handling of other study treatment
Not applicable.
6.5.4
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 LDK378 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 LDK378 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
TBC
Screening 
Phase
PK Run-In 
Phase a,b
Treatment Phase
Post-treatment efficacy 
follow-up if no PD at 
the EOT
Survival 
follow-
up
Cycles 1
(28 d)
Subsequent 
cycles
(28 d)
End of study 
treatment 
(EOT)
Visit name
Screening 
Visit (Day 
-28 to Day 
-1)
Run-In
Day 1
Run-In Days 
2, 3, 4 and 5
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
End of 
post-
treatment 
study 
phase
Survival 
follow-
up
Obtain Main 
Informed 
Consent
D
7.1.2
X
Collection of 
documentation 
of ALK 
rearrangement 
OR confirmation 
of ALK status by 
central 
laboratory 
D
7.1.1
7.1.2
New 
biopsy 
preferred 
and/or 
archival 
tissue & 
pathology 
report
ALK test 
performed on 
archival 
specimen
D
7.1.1.1
X
ALK test 
performed on 
new tumor 
biopsy
D
7.1.1.1
X
 


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Protocol No. CLDK378A2109
Category
Protocol 
section
TBC
Screening 
Phase
PK Run-In 
Phase a,b
Treatment Phase
Post-treatment efficacy 
follow-up if no PD at 
the EOT
Survival 
follow-
up
Cycles 1
(28 d)
Subsequent 
cycles
(28 d)
End of study 
treatment 
(EOT)
Visit name
Screening 
Visit (Day 
-28 to Day 
-1)
Run-In
Day 1
Run-In Days 
2, 3, 4 and 5
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
End of 
post-
treatment 
study 
phase
Survival 
follow-
up
End of Phase 
Disposition 
Page
D
7.1
X
X
X
Demography
D
7.1.2.3
X
Inclusion/ 
exclusion 
criteria
D
5.2
5.3
X
Eligibility check
D
6.4.1
X
Relevant 
medical history/ 
current medical 
conditions
D
7.1.2.3
X
History or 
smoking
D
7.1.2.3
X
Diagnosis and 
extent of cancer
D
7.1.2.3
X
 


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Protocol No. CLDK378A2109
Category
Protocol 
section
TBC
Screening 
Phase
PK Run-In 
Phase a,b
Treatment Phase
Post-treatment efficacy 
follow-up if no PD at 
the EOT
Survival 
follow-
up
Cycles 1
(28 d)
Subsequent 
cycles
(28 d)
End of study 
treatment 
(EOT)
Visit name
Screening 
Visit (Day 
-28 to Day 
-1)
Run-In
Day 1
Run-In Days 
2, 3, 4 and 5
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
End of 
post-
treatment 
study 
phase
Survival 
follow-
up
Prior 
antineoplastic 
therapies 
(meds, surgery, 
radiation)
D
7.1.2.3
X
Prior and 
concomitant 
medications
D
7.1.2.3
Continuous
Physical 
examination
S
7.2.2.1
X
X
X
X
X
X
X
Performance 
status
D
7.2.2.4
X
X
X
X
X
Height
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
X
Laboratory 
assessments
7.2.2.5
Hematology
D
7.2.2.5.1
X
X
X
X
X
X
X
Blood chemistry
D
7.2.2.5.2
X
X
X
X
X
X
X
Urinalysis 
(dipstick) with 
micro-analysis
D
7.2.2.5.3
X
X
 


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Protocol No. CLDK378A2109
Category
Protocol 
section
TBC
Screening 
Phase
PK Run-In 
Phase a,b
Treatment Phase
Post-treatment efficacy 
follow-up if no PD at 
the EOT
Survival 
follow-
up
Cycles 1
(28 d)
Subsequent 
cycles
(28 d)
End of study 
treatment 
(EOT)
Visit name
Screening 
Visit (Day 
-28 to Day 
-1)
Run-In
Day 1
Run-In Days 
2, 3, 4 and 5
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
End of 
post-
treatment 
study 
phase
Survival 
follow-
up
Serum 
pregnancy test
D
7.2.2.5.4
X
Urine 
pregnancy test 
(prior to dosing)
7.2.2.5.4
X
X
X
X
Testosterone 
(total and free), 
LH, FSH, 
steroid hormone 
binding globulin 
(SHBG) (males 
only)
D
7.2.2.5.5
X
X
X
X
X
Coagulation
D
7.2.2.5.6
X
Imaging Tumor 
Evaluations
7.2.1
CT scan or MRI 
of chest and 
abdomen
D
7.2.1
X
Cycles 3
then every 2nd
cycle (i.e. every 8 
weeks)
X
Every 8 
weeks 
following 
EOT until 
PD
Whole body 
bone scan
D
7.2.1
X
 


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Protocol No. CLDK378A2109
Category
Protocol 
section
TBC
Screening 
Phase
PK Run-In 
Phase a,b
Treatment Phase
Post-treatment efficacy 
follow-up if no PD at 
the EOT
Survival 
follow-
up
Cycles 1
(28 d)
Subsequent 
cycles
(28 d)
End of study 
treatment 
(EOT)
Visit name
Screening 
Visit (Day 
-28 to Day 
-1)
Run-In
Day 1
Run-In Days 
2, 3, 4 and 5
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
End of 
post-
treatment 
study 
phase
Survival 
follow-
up
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 
CT scan or 
MRI)
Photography 
(for any skin 
lesions)
D
7.2.1
X (if 
clinically 
indicated)
Cycles 3 then 
every 2nd cycle 
(i.e. every 8 
weeks): only if 
positive at 
baseline or 
clinically 
indicated
Only if positive 
at baseline or 
clinically 
indicated
Every 8 
weeks 
following 
EOT until 
PD (only 
if positive 
at 
baseline 
or 
clinically 
indicated)
 


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Protocol No. CLDK378A2109
Category
Protocol 
section
TBC
Screening 
Phase
PK Run-In 
Phase a,b
Treatment Phase
Post-treatment efficacy 
follow-up if no PD at 
the EOT
Survival 
follow-
up
Cycles 1
(28 d)
Subsequent 
cycles
(28 d)
End of study 
treatment 
(EOT)
Visit name
Screening 
Visit (Day 
-28 to Day 
-1)
Run-In
Day 1
Run-In Days 
2, 3, 4 and 5
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
End of 
post-
treatment 
study 
phase
Survival 
follow-
up
CT scan or MRI 
of brain
D
7.2.1
X
Cycles 3 then 
every 2nd cycle 
(i.e. every 8 
weeks): only if 
clinically 
indicated or 
positive at 
baseline
Only if 
clinically 
indicated or 
positive at 
baseline
Every 8 
weeks 
following 
EOT until
PD (only 
if clinically 
indicated 
or 
positive at 
baseline)
Study drug 
administration
6.1.1
LDK378 dosing
D
6.1.1
X
Continuous
Safety
8.1
Adverse events
D
8.1
Continuous
ECG
D
7.2.2.6.1
Table 7-
4 Table 
7-5
X
See Table 7-4 and Table 7-5 for ECG schedule
 


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Protocol No. CLDK378A2109
Category
Protocol 
section
TBC
Screening 
Phase
PK Run-In 
Phase a,b
Treatment Phase
Post-treatment efficacy 
follow-up if no PD at 
the EOT
Survival 
follow-
up
Cycles 1
(28 d)
Subsequent 
cycles
(28 d)
End of study 
treatment 
(EOT)
Visit name
Screening 
Visit (Day 
-28 to Day 
-1)
Run-In
Day 1
Run-In Days 
2, 3, 4 and 5
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
End of 
post-
treatment 
study 
phase
Survival 
follow-
up
PK sampling
D
7.2.3
Table 7-
6
Table 7-
7
See Table 7-6 and Table 7-7 for PK schedule
Meal record
D
7.2.3
X
X
X
X
Cycle 2 Day 1 
only
Survival follow-
up
7.1.7.3
 


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Protocol No. CLDK378A2109
Category
Protocol 
section
TBC
Screening 
Phase
PK Run-In 
Phase a,b
Treatment Phase
Post-treatment efficacy 
follow-up if no PD at 
the EOT
Survival 
follow-
up
Cycles 1
(28 d)
Subsequent 
cycles
(28 d)
End of study 
treatment 
(EOT)
Visit name
Screening 
Visit (Day 
-28 to Day 
-1)
Run-In
Day 1
Run-In Days 
2, 3, 4 and 5
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
End of 
post-
treatment 
study 
phase
Survival 
follow-
up
Antineoplastic 
therapies since 
discontinuation 
of study 
treatment
D
7.1.7.3
X
X
Survival 
assessment
D
7.1.7.3
X
 


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7.1.1
Molecular screening
Histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC 
that carries an ALK rearrangement, defined as positive using the FDA approved Vysis ALK 
Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including 
positivity criteria) or positive as assessed by the CFDA approved immunohistochemistry (IHC) 
test (Ventana Medical Systems, Inc) using rabbit monoclonal primary antibody assay (D5F3) 
and associated scoring algorithm. If documentation of ALK rearrangement is not available as 
described above, a test to confirm ALK rearrangement must be performed using an archival 
tumor obtained at or since the time of diagnosis or a new tumor biopsy obtained prior to the 
first LDK378 dose. The test will be performed at a Novartis designated central laboratory (by 
IHC test using rabbit monoclonal primary antibody assay (D5F3), Ventana Medical Systems, 
Inc). Patients must wait for the result of the ALK rearrangement status before initiating 
treatment with LDK378.
7.1.1.1
Tumor sample requirements for central laboratory analysis
The Informed Consent Form (ICF) will allow for a tumor sample to be collected and shipped 
to a Novartis-designated central laboratory for analysis. Archival tumor tissue (block or slides) 
and/or a fresh tumor biopsy will be tested for ALK rearrangement and will be used to 
determine study eligibility for patients that do not have available documentation of ALK 
rearrangement at Screening. Acceptable archival tumor tissue may consist of a formalin fixed 
paraffin embedded (FFPE) block tumor tissue or at least 7, preferably 15, slides 4-5 µm thick. 
Archival specimens must be submitted with a copy of the corresponding pathology report. 
Results of the assay will be sent to the site. If delays are experienced in processing the sample, 
the screening site will be informed.
If a tumor tissue block is provided, the remaining tissue will be returned to the site upon 
request.
If both archival and fresh tumor tissue is made available for analysis, ALK status testing will 
be conducted using the fresh specimen and the archival tumor tissue will be used for 
exploratory studies. If biopsies from multiple tumor sites are available, the primary (vs. 
metastatic) tumor is the preferred sample for ALK status testing.
 
7.1.2
Screening
Written informed consent must be obtained before any study specific procedure is performed. 
Screening assessments to confirm eligibility into the main study should be performed as per 
the schedule of assessments. Patients that do not have available documentation of ALK 
rearrangement at Screening must wait for result of the ALK rearrangement status before 
initiating treatment with LDK378.
 


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Re-screening of patients will not be allowed, but laboratory parameters which do not meet the 
inclusion criteria may be re-tested within the screening window (Day -28 to Day -1). 
Laboratory assessments performed as part of the screening evaluations will not be required to 
be repeated prior to dosing (except urine pregnancy test). 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. Any imaging assessments 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.
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. Please refer to and comply with the detailed guidelines in the IRT manual.
7.1.2.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screening failure.
The following eCRFs must be completed for screening failure patients:

Screening Phase Disposition page (including reason for not being started on treatment)

Informed consent

Demography

Adverse Events (only if an SAE occurs)

Inclusion/Exclusion criteria
7.1.2.3
Patient demographics and other baseline characteristics
Data to be collected on patient characteristics at screening include:

Demography (including: date of birth, age, patient initials, gender, childbearing potential, 
race and ethnicity, or as allowed by local regulations)

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

Prior antineoplastic therapies (medications, radiation, surgeries)
 


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
Prior and Concomitant Medications, surgical and medical procedures
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
PK Run-in period
The first 15 patients enrolled will participate in a single-dose PK run-in period. Additional 
patients may be enrolled in the study with PK run-in period in case PK profiles from some of 
the enrolled patients are deemed not evaluable due to early discontinuation from the study or 
due to vomiting events on the day of PK sampling. In order to characterize the 
pharmacokinetics of LDK378 in Chinese patients, a single-dose PK run-in period of 5 days 
will be completed. Since the Cycle 1 Day 1 pre-dose PK collection is considered the 120 
hours post-dose PK time point of the PK run-in period, if possible, Cycle 1 Day 1 should 
immediately follow the 5-day PK run-in phase. If a break between Day 5 of the PK run-in 
period and Day 1 of Cycle 1 occurs, a 120 hour post-dose PK sample should be collected on 
the 6th day of the PK run-in phase and no pre-dose PK sample should be collected at Cycle 1 
Day 1.
For details of assessments during the PK run-in period, refer to Table 7-4.
7.1.4
Treatment period
The study treatment phase begins on Cycle 1, Day 1 with the first administration of LDK378 
and will continue until unacceptable toxicity that precludes further treatment, start of a new 
anti-cancer therapy, treatment is discontinued at the discretion of the investigator and/or 
patient death. If a patient experiences disease progression (radiologically documented 
according to RECIST 1.1 by investigator assessment), LDK378 administration may be 
stopped, or may be continued if the patient is continuing to derive clinical benefit in the 
opinion of the investigator.
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.
7.1.5
Discontinuation of study treatment
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 LDK378, is in efficacy follow-up after 
discontinuing LDK378, or is in survival follow-up.
Patients may voluntarily withdraw from study treatment for any reason at any time. In this 
situation, the patient should be encouraged to consent to be followed for tumor assessments 
until the development of Progressive Disease (as assessed by investigator) and/or survival. 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 
 


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record this information in the patient’s chart and on the appropriate CRF pages. They may be 
considered withdrawn if 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, on balance, 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

Use of prohibited treatment

- Any protocol deviation that results in a significant risk to the patient’s safety
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 NOT be 
considered withdrawn from the study. They 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 LDK378 treatment.
Patients who have RECIST-defined PD by investigator assessment, but who, in the opinion of 
the investigator, have evidence of continued clinical benefit from LDK378 may continue to 
receive this drug. These patients will continue assessments as detailed in Table 7-1 except 
tumor and 
. In such cases, patients must complete the EOT visit only after 
permanent discontinuation of LDK378. An End of Treatment Phase Disposition eCRF page 
should be completed, giving the date and reason for stopping the study treatment.
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.
 


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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. They may be considered withdrawn if they state an intention to withdraw, 
fail to return for visits, or become lost to follow-up for any other reason.
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.
If using IRT, the Investigator must contact the IRT to register the subject’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 the 
investigator assessment determined disease progression, patient withdraws consent from 
tumor assessments patient is lost to follow-up, death or study terminated by Sponsor.
If a patient will have no further study data collected because he/she withdraws from the study 
completely, the investigator must determine the primary reason for a patient’s premature 
withdrawal from the study and record this information on the Study Phase Completion 
Disposition eCRF as applicable. The investigator must show "due diligence" by documenting 
in the source documents steps taken to contact the patient, e.g., dates of telephone calls, 
registered letters, etc. They may be considered withdrawn if they state an intention to 
withdraw, fail to return for visits, or become lost to follow-up for any other reason. If the 
patient was still taking study medication at the time of the withdrawal, the End of Treatment 
eCRF should also be completed.
Patients may voluntarily withdraw from the study or be discontinued from the study at the 
discretion of the investigator at any time.
7.1.5.1
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.
7.1.6
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 want any further visits or assessments, and does not want any 
further study related contact.
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations).
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information. Study
treatment must be discontinued and no further assessments conducted.
 


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Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.
7.1.7
Follow up period
7.1.7.1
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.
7.1.7.2
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 and 
 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.
7.1.7.3
Survival follow-up
All patients who progressed (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. The investigator or his designee will collect this survival 
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.
7.1.7.4
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 
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7.2
Assessment types
7.2.1
Efficacy assessments
Tumor evaluation will be determined locally by investigator assessment according to the 
Novartis guideline (Version 3.1, Appendix 2) on the Response Evaluation Criteria in Solid 
Tumors (RECIST), based on RECIST Version 1.1 (Eisenhauer et al 2009). The investigator 
assessment will be used for the primary endpoint analysis. Additionally, imaging data will be 
centrally collected, checked for quality and independently reviewed by an imaging vendor 
designated by Novartis and will be the basis of supportive analyses.
7.2.1.1
Baseline assessments
Tumor evaluation will be performed at baseline within 28 days of, and prior to study 
treatment.
Contrast-enhanced CT (or MRI) 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.
Required conditions for tumor assessment at baseline

Patients must have measurable disease as per RECIST v1.1 (Appendix 2). Measurable 
lesions include lytic or mixed (lytic + blastic) bone lesions with an identifiable soft tissue 
component that meets the measurability criteria per RECIST v1.1 (Appendix 2).

Patients with only non-measurable lesions are not eligible.

If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.

Any potentially measurable lesion that has been previously treated with radiotherapy 
should be considered as a non-measurable lesion. However, if a lesion previously treated 
with radiotherapy has clearly progressed since the radiotherapy, it can be considered as a 
measurable lesion.

All measurable lesions up to a maximum of 5 nodal and/or non-nodal lesions in total (and 
a maximum of 2 lesions per organ), representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline.
Required image assessments for tumor assessment at baseline
The following assessments will be performed:

Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) of chest and 
abdomen.

The preferred radiologic technique is CT with intravenous (i.v.) contrast. If a patient 
is known to have a contraindication to CT contrast media or develops a 
contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts) plus a contrast-enhanced MRI (if possible) 
of the abdomen should be performed.
 


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
A whole body bone scan according to institutional guidelines (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 of all skeletal lesions identified on the screening bone scan, 
which are not visible on the chest and abdomen CT/MRI (and pelvis CT/MRI if applicable)

Brain CT or MRI scan should be completed in order to assess CNS disease. Contrast 
enhanced brain MRI is preferred, however, if MRI contrast is contraindicated, then brain 
MRI without contrast or brain CT with/without contrast is acceptable.

Color photographs (with a metric ruler) if skin lesions are present.

CT or MRI of any other site of disease not captured by any of the above listed images (e.g., 
pelvis, neck) as clinically indicated.
Any imaging assessments 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. After screening, scans need not be repeated, 
unless clinically indicated. If indicated, the same methodology as at screening should be used.
Chest x-ray or ultrasound should not be used to measure tumor lesions.
7.2.1.2
Subsequent image assessments for response determination
Tumor assessment for response determination will be made every 8 weeks starting from Day 
1 of cycle 1 (+/- 7 days window). The 8 weeks interval should be respected regardless of 
whether treatment with LDK378 is temporarily withheld.
Post-baseline tumor assessments
The following assessments will be performed at on-study scheduled visits (see Table 7-1):

Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) of chest and 
abdomen.

Localized CT, MRI or X-rays of all skeletal lesions identified on the screening bone scan, 
which are not visible on the chest and abdomen CT/MRI (and pelvis CT/MRI if 
applicable). Whole body bone scans need not be repeated after baseline unless clinically 
indicated.

Brain CT or MRI, if brain metastases were identified at baseline.

Color photographs (with a metric ruler) if skin lesions were documented at baseline.

CT or MRI of any other site of disease documented at baseline (e.g., pelvis, neck).
For post-baseline tumor assessments, all lesions that were present at baseline must be 
accounted for using the same technique as used at baseline so that the comparison is 
consistent. If possible, a single radiologist should perform all tumor response evaluations for 
an individual patient.
All study imaging performed, including any intercurrent imaging studies, whether or not 
suspected to fulfill a progression or response criterion, should be submitted to the designated 
imaging CRO for quality control promptly after acquisition.
 


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Criteria required for determining partial or complete response should be confirmed by a 
subsequent imaging assessment at least 4 weeks later. If an off-schedule imaging assessment 
is performed to confirm response or if progression is suspected, subsequent imaging 
assessments should be performed in accordance with the original imaging schedule unless the 
next scheduled imaging timepoint is within 2 weeks, in which case the scheduled imaging 
timepoint can be omitted.
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 progressive 
disease per RECIST 1.1 (Appendix 2).
Duration of post-baseline tumor assessments
Tumor assessments will be done until RECIST-defined PD by investigator assessment, death, 
lost to follow-up, or patient decision involving withdrawal of consent.
If a patient discontinues study treatment in the absence of PD, tumor assessments will 
continue to be done every 8 weeks until RECIST-defined PD by investigator assessment, 
death, lost to follow-up, or patient decision involving withdrawal of consent.
If a patient continues treatment with LDK378 after RECIST-defined PD by investigator 
assessment, no further imaging assessments on study are required.
Imaging evaluations will also be performed at the End of Treatment (EOT) visit. If a patient is 
known to have PD at a scheduled study visit, EOT imaging evaluations do not need to be 
repeated for the EOT visit.
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.
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, 
extremities, and a basic nervous system evaluation. 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.
 


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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 
patients 
participating 
in 
the 
extensive 
ECG 
subset, 
see
Section 7.2.2.6.1 and Table 7-6.
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 7-2) 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 7-2
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
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, 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 in a separate [Laboratory Manual].
 


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Table 7-3
Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hemoglobin, platelets, white blood cells (WBC), red blood cells (RBC), differential 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils [% or absolute])
Blood Chemistry
Albumin, ALT, AST, calcium (at screening calcium corrected for albumin 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 (dipstick).
If local requirements dictate otherwise, local regulations should be followed
Hormones
(males only)
Testosterone (total and free), LH, FSH, sex hormone binding globulin (SHBG)
Coagulation
INR and pro-thrombin time (PT) or Quick Test
7.2.2.5.1 Hematology
Hematology assessments of the parameters listed in Table 7-3 will be tested as per the 
schedule of assessments (Table 7-1).
7.2.2.5.2 Clinical Chemistry
Blood chemistry assessments of the parameters listed in Table 7-3 will be tested as per the 
schedule of assessments (Table 7-1).
7.2.2.5.3 Urinalysis
Dipstick measurements will be performed as per Table 7-3 and according to the schedule of 
assessments. Any significant findings on dipstick will be followed up with microscopic 
evaluation as per Table 7-3.
7.2.2.5.4 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 
level assessment is she considered not of child bearing potential (such testing is not covered 
 


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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 patients must immediately notify the investigator.
Male patient must notify the investigator in case their partner is resulted pregnant during the
treatment period.
7.2.2.5.5 Hormones
Testosterone (total and free), LH, FSH and steroid hormone binding globulin (SHBG) will be 
tested in male patients only and as per the schedule of assessments (Table 7-1).
7.2.2.5.6 Coagulation
International normalized ratio (INR) and prothrombin time (PT) or Quick Test will be 
measured at screening only.
7.2.2.6
Cardiac assessments
7.2.2.6.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed as described in Table 7-4 and Table 7-5.

At the screening visit in triplicate for all patients.

At other defined time points as triplicate ECGs for first 15 patients run-in with extensive 
PK assessments during run-in period (Table 7-4) and patients with trough and sparse PK 
assessments (Table 7-5).
Baseline is defined as the pre-dose prior to 1st dose of LDK378.
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 treatment, time, and day (i.e., Cycle 1 Day1, 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. ECGs should be performed within 30 minutes 
prior to the collection of PK sample. 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 7-4
ECG collection plan for patients with extensive PK assessment (in 15 
patients who enrolled in PK run-in; triplicate ECGs)
Cycle
Day
Time
ECG Type
Screening
-28 to -1
Anytime
12 Lead
PK run-in
1
Pre-dose
12 Lead
PK run-in
1
Post-dose 4 hours (within 30 minutes before PK)
12 Lead
PK run-in
1
Post-dose 6 hours (within 30 minutes before PK)
12 Lead
PK run-in
2
Post-dose 24 hours (within 30 minutes before PK)
12 Lead
1
8
Pre-dose
12 Lead
1
8
Post-dose 2-4 hours (within 30 minutes before PK)
12 Lead
1
8
Post-dose 5-7 hours (within 30 minutes before PK)
12 Lead
1
15
Pre-dose
12 Lead
2
1
Pre-dose
12 Lead
2
1
Post-dose 4 hours (within 30 minutes before PK)
12 Lead
2
1
Post-dose 6 hours (within 30 minutes before PK)
12 Lead
2
1
24 hours post-dose of C2D1 (Pre-dose on C2D2)
12 Lead
3
1
Pre-dose
12 Lead
4
1
Pre-dose
12 Lead
5
1
Pre-dose
12 Lead
6 and subsequent cycles
1
Pre-dose
12 Lead
EOT
1
Pre-dose
12 Lead
Table 7-5
ECG collection plan for patients with sparse PK assessment (triplicate 
ECGs)
Cycle
Day
Time
ECG Type
Screening
-28 to -1
Anytime
12 Lead
1
1
Pre-dose
12 Lead
1
1
Post-dose 2-4 hours (within 30 minutes before PK)
12 Lead
1
1
Post-dose 5-7 hours (within 30 minutes before PK)
12 Lead
1
1
24 hours post-dose of C1D1 (Pre-dose on C1D2)
12 Lead
1
8
Pre-dose
12 Lead
1
8
Post-dose 2-4 hours (within 30 minutes before PK)
12 Lead
1
8
Post-dose 5-7 hours (within 30 minutes before PK)
12 Lead
1
15
Pre-dose
12 Lead
2
1
Pre-dose
12 Lead
2
1
Post-dose 4 hours (within 30 minutes before PK)
12 Lead
2
1
Post-dose 6 hours (within 30 minutes before PK)
12 Lead
3
1
Pre-dose
12 Lead
4
1
Pre-dose
12 Lead
5
1
Pre-dose
12 Lead
6 and subsequent cycles
1
Pre-dose
12 Lead
EOT
1
Pre-dose
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 
 


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significant findings occurring after informed consent must be recorded on the Adverse Events 
eCRF page.
7.2.3
Pharmacokinetics
Pharmacokinetic blood collection plan
Extensive PK assessment consisting of pre-dose trough PK, sparse post-dose PK as well as 
intensive PK sampling during the 5-day PK run-in period and Cycle 2 Day 1 will be collected 
in the first 15 enrolled patients to obtain approximately 12 evaluable full PK profiles 
(Table 7-6). Additional patients may be enrolled in the study with PK run-in period in case 
PK profiles from some of the enrolled patients are deemed not evaluable due to early 
discontinuation from the study or due to vomiting events on the day of PK sampling.
Separated from this subset of patients with extensive PK assessment, sparse post-dose PK 
samples will be collected on Cycle 1 Day 1, Cycle 1 Day 8 and Cycle 2 Day 1, in addition to 
pre-dose trough PK in the rest of the enrolled patients (Table 7-7).
Meal records will be collected on PK run-in period Day 1 for the first 15 enrolled patients. 
Meal records will also be collected for all patients on Cycle 1 Day 1, Cycle 1 Day 8 and Cycle 
2 Day 1. The start and end time of meals will be recorded. Complete dosing information, 
including the date and time of actual blood draw and time of the last study drug dose prior to 
the sampling, should be obtained on all sampling days and recorded on the PK eCRF and/or 
CRO requisition form(s). An additional blood sample (unscheduled) will be collected in the 
event that a patient experiences an AE which requires either dose modification or premature 
termination from the study medication.
Table 7-6
Pharmacokinetic blood collection for LDK378 extensive PK 
assessment (in 15 patients who enrolled in PK run-in)
Dose Reference
Identification (ID)
PK sample 
number
Scheduled time points (hours)
Dose ID 
following PK 
sampling
Dose ID prior 
to PK 
sampling
Cycle
Day
Scheduled time 
(hours)
Description
1
1
PK run-in
1
0 hr a
Pre-dose
1
2
PK run-in
1
0.5 hr ± 10 min
Post-dose
1
3
PK run-in
1
1 hr ± 15 min
Post-dose
1
4
PK run-in
1
2 hr ± 15 min
Post-dose
1
5
PK run-in
1
3 hr ± 15 min
Post-dose
1
6
PK run-in
1
4 hr ± 15 min
Post-dose
1
7
PK run-in
1
6 hr ± 15 min
Post-dose
1
8
PK run-in
1
8 hr ± 15 min
Post-dose
1
9
PK run-in
2
24 hr ± 120 min
Post-dose
1
10
PK run-in
3
48 hr ± 120 min
Post-dose
1
11
PK run-in
4
72 hr ± 120 min
Post-dose
1
12
PK run-in
5
96 hr ± 120 min
Post-dose
1
13
1
1
0 hr a
Pre-dose of Cycle 1 
Day 1 (i.e. 120 hr post-
dose in PK run-in)
 


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Dose Reference
Identification (ID)
PK sample 
number
Scheduled time points (hours)
Dose ID 
following PK 
sampling
Dose ID prior 
to PK 
sampling
Cycle
Day
Scheduled time 
(hours)
Description
2
111 b
14
1
8
0 hr a
Pre-dose
2
15
1
8
2-4 hr
Post-dose
2
16
1
8
5-7 hr
Post-dose
3
112 b
17
1
15
0 hr a
Pre-dose
4
113 b
18
2
1
0 hr a
Pre-dose
4
19
2
1
1 hr ± 15 min
Post-dose
4
20
2
1
2 hr ± 15 min
Post-dose
4
21
2
1
4 hr ± 15 min
Post-dose
4
22
2
1
6 hr ± 15 min
Post-dose
4
23
2
1
8 hr ± 15 min
Post-dose
4
24
2
1
24 hr ± 120 min
24 hr post-dose of
C2D1 (i.e. Pre-dose on
C2D2)
5
114 b
25
3
1
0 hr a
Pre-dose
6
115 b
26
4
1
0 hr a
Pre-dose
7
116 b
27
5
1
0 hr a
Pre-dose
8
117 b
28
6
1
0 hr a
Pre-dose
3001 + c
NA
NA
Unscheduled c
Unspecified
a PK sample should be taken immediately prior to the next administration of LDK378.
b Dose reference IDs with three digits refer to the dose administered and dosing time of the last dose prior to 
collection of the corresponding PK sample
c Sample numbers for any unscheduled blood collection for LDK378 will start with 3001.
Table 7-7
Pharmacokinetic blood collection for LDK378 sparse PK assessment
Dose Reference 
Identification (ID)
PK sample 
number
Scheduled time points (hours)
Dose ID 
following PK 
sampling
Dose ID 
prior to PK 
sampling
Cycle
Day
Scheduled time 
(hours)
Description
11
301
1
1
0 hr a
Pre-dose
11
302
1
1
2-4 hr
Post-dose
11
303
1
1
5-7 hr
Post-dose
11
304
1
1
24 hr ± 120 min
24 hr post-dose of
C1D1 (i.e. Pre-
dose on C1D2)
12
101 b
305
1
8
0 hr a
Pre-dose
12
306
1
8
2-4 hr
Post-dose
12
307
1
8
5-7 hr
Post-dose
13
102 b
308
1
15
0 hr a
Pre-dose
14
103 b
309
2
1
0 hr a
Pre-dose
14
310
2
1
4 hr ± 15 min
Post-dose
14
311
2
1
6 hr ± 15 min
Post-dose
15
104 b
312
3
1
0 hr a
Pre-dose
 


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Dose Reference 
Identification (ID)
PK sample 
number
Scheduled time points (hours)
Dose ID 
following PK 
sampling
Dose ID 
prior to PK 
sampling
Cycle
Day
Scheduled time 
(hours)
Description
16
105 b
313
4
1
0 hr a
Pre-dose
17
106 b
314
5
1
0 hr a
Pre-dose
18
107 b
315
6
1
0 hr a
Pre-dose
1001 + c
NA
NA
Unscheduled c
Unspecified
a PK sample should be taken immediately prior to the next administration of LDK378.
b Dose reference IDs with three digits refer to the dose administered and dosing time of the last dose prior to 
collection of the corresponding PK sample
c Sample numbers for any unscheduled blood collection for LDK378 will start with 1001.
At the specified time points detailed in Table 7-4 and Table 7-5, 2 mL of blood (per sample) 
will be collected for the measurement of the plasma concentrations of LDK378. All blood 
samples will be taken by either direct venipuncture or an indwelling cannula inserted in a 
forearm vein. Complete instructions for sampling processing, handling and shipment will be 
provided in the [Laboratory Manual]. All samples should be packed carefully as per the 
instructions in the manual, ensuring sufficient dry ice is used to keep samples frozen during 
shipment. Sample labels will include the following information: protocol number, subject ID, 
study day, actual date and time of blood collection, aliquot/matrix. Additional information 
may be added. A list of samples, including the date, subject number, and the time of sampling 
should be included in the shipment. Any missing samples should be indicated on the list. 
Residual plasma samples from this study may also be used for exploratory analysis to further 
characterize the PK of LDK378 and all of its metabolite(s). This may include using leftover 
samples for protein binding analysis or metabolite profiling (e.g., other metabolites and 
markers for metabolic enzyme activity such as 4- beta hydroxyl cholesterol levels), if there is 
sufficient sample remaining.
7.2.3.1
Analytical method
The plasma samples from all patients will be assayed for LDK378 concentrations, using a 
validated liquid chromatography-tandem mass spectrometry assay (LC-MS/MS). Values 
below the lower limit of quantification (LLOQ) of approximately 1.0 ng/mL or lower will be 
reported as 0.00 ng/mL. Missing values will be labeled accordingly.
 


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7.2.5
Resource utilization
Direct collection of health care resource utilization (HCRU) data (such as occurrences of 
hospitalization) is not planned for this study, but may be explored based on data contained 
within the SAEs eCRF.
 


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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.
 


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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 CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. 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; rather, 
information about deaths will be collected though a Death eCRF.
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 clinical 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 clinical 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
 


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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.
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.
8.1.3
Adverse events of special interest
 
 
 
Details regarding these adverse events are provided in the [Investigator’s Brochure] for 
ceritinib. Potential emergent new AEs will be monitored during the course of the study.
 


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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 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the 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
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 SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE 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.
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 send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department.
The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E), specific to the site, are listed in the investigator folder
 


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provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original 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, whether the blind was broken or not, 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 
Novartis Drug Safety and Epidemiology (DS&E) 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.
 


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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
Not applicable.
8.7
Steering Committee
A Steering Committee (SC), comprised of investigators in NSCLC management from the 
study, will be formed prior to initiation of the trial. The purpose of the SC is to provide overall 
guidance regarding design of the study, conduct and execution of the trial to include (but not 
limited to) safety, accrual and contribution to scientific input for publications.
Responsibilities of the SC and communication flow between, SC and Novartis will be 
included in the SC charter document.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
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Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results.
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 CRFs 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 CRFs, 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 CRFs 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 CRF 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 
CRFs 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 (eCRF). The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements, Investigator site staff will not be given access to the 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 eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.
Radiological and photography data will be acquired by the sites and interpreted locally.
 


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All ECGs will be transmitted electronically to a central laboratory and will be centrally 
reviewed by an independent reviewer. Any original ECG not transmitted electronically to the 
central laboratory should be forwarded for central review.
PK 
 samples drawn during the course of the study will be 
collected from the investigator sites and analyzed by a Novartis assigned laboratory or 
contracted central laboratories. The site staff designated by the investigator will enter the 
information required by the protocol onto the PK 
 Collection eCRFs, 
 as well as the designated laboratory’s requisition forms that will be printed on 2-
part paper. One copy of the requisition form will be forwarded to the central laboratory along 
with the corresponding samples with required information (including study number, subject 
ID, etc.) and the other copy will be retained by the site. The field monitor will review the 
relevant eCRFs for accuracy and completeness and will work with the site staff to adjust any 
discrepancies as required. The field monitor will also review the requisition forms for 
completeness.
 
9.4
Database management and quality control
EDC is used for the study. Novartis personnel (or a designated CRO) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated 
investigator site staff are required to respond promptly to queries and to make any necessary 
changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using 
the 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 relating to PK samples, 
, ECGs and imaging 
will be processed centrally and the results will be sent electronically to Novartis (or a 
designated CRO).
 


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Enrollment will be tracked using an Interactive Response Technology (IRT). The system will 
be supplied by a vendor(s), who will also manage the database. The data will be sent 
electronically to Novartis personnel (or a designated CRO).
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. 
Authorization is required prior to making any database changes to locked data, by joint 
written agreement between the Global Head of Biostatistics and Data Management and the 
Global Head of Clinical Development.
After database lock, the investigator will receive a CD-ROM or paper copies of the patient 
data for archiving at the investigational site.
10
Statistical methods and data analysis
The data from all participating centers in this protocol will be combined. Novartis and/or a 
designated CRO will perform all analyses. Any data analyses performed independently by any 
investigator should be submitted to Novartis before publication or presentation.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) consists of all patients who receive at least one dose of LDK378.
Unless otherwise specified the FAS will be the analysis set used for all analyses and listings.
Patients who were screened but never started treatment will be listed.
10.1.2
Safety Set
The Safety Set consists of all patients who receive at least one dose of LDK378.
10.1.3
Per-Protocol Set
The Per-Protocol Set (PPS) will consist of a subset of patients in the FAS who are compliant 
with requirements of the Clinical Study Protocol (CSP). The PPS consists of patients who 
have an adequate tumor assessment at baseline, a follow-up tumor assessment >7 weeks after 
starting treatment (unless disease progression is observed before that time), and no major 
protocol deviations.
All major protocol deviations leading to exclusion from the PPS will be detailed in the 
Reporting and Analysis Plan (RAP).
10.1.4
Dose-determining Analysis Set
Not applicable.
 


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10.1.5
Pharmacokinetic Analysis Set
The Pharmacokinetic Analysis Set (PAS) consists of all patients who receive at least one dose 
of LDK378 and provide at least one evaluable PK sample.
The definition of an evaluable PK blood sample will be further specified in the RAP.
10.1.6
Other analysis Sets
All exploratory analyses intended to be discussed in the CSR will be defined in the RAP.
Additional analyses may be performed on a program or company level. These will be planned
and reported separately from this study.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for all patients for the FAS. Categorical data will be presented as frequencies 
and percentages. For continuous data, mean, standard deviation, median, minimum, and 
maximum will be presented. All demographic data will be listed in detail.
10.3
Treatments (study treatment, concomitant therapies, compliance)
The Safety Set will be used for all medication data summaries and listings unless otherwise 
specified.
10.3.1
Study Treatment
The actual dose and duration of exposure in days to LDK378 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. Dose changes and dose interruptions (including the reasons for 
these) will be listed and summarized.
10.3.2
Concomitant therapies
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized.
10.4
Primary objectives

To characterize the PK profile of LDK378 in Chinese adult patients with ALK-rearranged
NSCLC following single and multiple once daily oral doses of LDK378.

To assess safety and tolerability of LDK378 at 750 mg once daily dose in Chinese adult 
patients with ALK-rearranged locally advanced or metastatic NSCLC.
 


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10.4.1
Variable
10.4.1.1 To characterize PK profile of LDK378
LDK378 PK parameters, including but not limited to AUClast, AUC0-24h, AUCinf, Cmax, 
Tmax, Lambda z, terminal T1/2, T1/2,acc, Racc, CL/F (or CLss/F at steady state) and Vz/F, 
as appropriate will be derived from the 15 patients who participated in the PK run-in period 
prior to a treatment period of continuous daily dosing.
10.4.1.2 To assess safety and tolerability of LDK378
Adverse events, vital signs, ECGs and laboratory abnormalities
10.4.2
Statistical hypothesis, model, and method of analysis
10.4.2.1 To characterize PK profile of LDK378
Extensive PK assessment consisting of pre-dose trough PK, sparse post-dose PK as well as 
intensive PK sampling during the 5-day PK run-in period and Cycle 2 Day 1 will be collected 
in the first 15 enrolled patients to obtain approximately 12 evaluable full PK profiles 
(Table 7-6). Additional patients may be enrolled in the study with PK run-in period in case 
PK profiles from some of the enrolled patients are deemed not evaluable due to early 
discontinuation from the study or due to vomiting events on the day of PK sampling. 
Separated from this subset of patients with extensive PK assessment, sparse post-dose PK 
samples will be collected on Cycle 1 Day 1, Cycle 1 Day 8 and Cycle 2 Day 1, in addition to 
pre-dose trough PK in the rest of the enrolled patients (Table 7-7).
Pharmacokinetic parameters of LDK378, including, but not limited to the following detailed 
in Table 10-1, will be calculated from the individual concentration-time profile obtained 
following the administration of LDK378. These PK parameters will be estimated, as 
appropriate. The non-compartmental method will be used on Phoenix WinNonlin (Version 6.2  
Pharsight, Mountain View, CA).
Table 10-1
Noncompartmental pharmacokinetic parameters
AUClast
The area under the concentration-time curve from time zero to the last measurable 
concentration time (ng*h/mL)
AUC0-24h
The area under the plasma concentration-time curve calculated from time zero to 24 hours 
(ng*h/mL)
AUCinf
The area under the plasma concentration- time curve from time zero to infinity
Cmax
The observed maximum plasma concentration following administration (ng/mL)
Tmax
The time to reach peak or maximum concentration (h)
Lambda_z
Terminal elimination rate constant (1/h)
T1/2
Elimination half-life determined as 0.693/lambda_z (h)
T1/2,acc
The effective half-life determined according to Racc (h)
Racc
Accumulation ratio calculated as AUCtau,ss/AUCtau,sd where tau is the dosing interval
CL/F
The total body clearance from plasma (L/h). CLss/F is calculated from AUCtau assuming 
steady state (CLss/F = Dose/AUCtau) (L/h)
Vz/F
The apparent volume of distribution during the terminal elimination phase (L)
 


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Using the PAS, summary statistics (n, mean, SD, coefficient of variation (CV) for mean, 
geometric mean, CV for geometric mean, median, minimum and maximum) will be presented 
for concentration versus time profiles of LDK378. This will be done separately for patients in 
PK run-in with extensive PK assessment and the rest of the patients with sparse PK sampling.
The mean and individual concentration versus time profiles of LDK378 will be displayed 
graphically for full PK profile and trough collections.
Summary statistics including n, mean, SD, CV for mean, geometric mean, CV for geometric 
mean, median, minimum and maximum will be presented for all PK parameters with the 
exception of Tmax. For Tmax, median, minimum and maximum will be presented for patients 
in the PAS with extensive PK assessment.
 
 
The PK parameters and concentration data will be listed.
10.4.2.2 To assess safety and tolerability of LDK378
Please refer to Section 10.5.3.
10.4.3
Handling of missing values/censoring/discontinuations
Concentration values below the lower limit of quantitation (LLOQ) will be displayed in 
listings as zero with a footnote to explain and handled as zero in any calculations of summary 
statistics, but handled as missing for the calculation of the geometric means and their CV. 
Any missing PK concentration data will not to be imputed.
10.4.4
Supportive analyses
Not applicable.
10.5
Secondary objectives
All efficacy assessments (ORR, DOR, DCR, TTR, OIRR, PFS) will be analyzed as per 
investigator assessment. Confirmation of response is required for all response endpoints, as 
per RECIST 1.1. ORR and OIRR as assessed by BIRC will be the basis of supportive analyses.
All efficacy analyses will be performed based on the FAS, unless otherwise specified. All 
efficacy data will be listed.
10.5.1
Key secondary objective

To evaluate anti-tumor activity of LDK378 in terms of ORR
10.5.1.1 Endpoint for key secondary objective
ORR is defined as the proportion of patients with a best overall confirmed response of CR or 
PR, as assessed per RECIST 1.1 by the investigator.

Confirmed partial or complete responses 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.
 


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
Patients with a best overall response of ‘Unknown’ or ‘Not Assessed’ per RECIST 1.1 
will be considered as non-responders in estimating the ORR.

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 calculations.
10.5.1.2 Analysis for key secondary objective
The analysis of ORR will be performed on the FAS. The ORR will be estimated and the 95% 
confidence interval (CI) based on the exact binomial distribution will be provided.
10.5.2
Other secondary efficacy objectives

To evaluate efficacy endpoints as assessed by investigator: duration of response (DOR), 
disease control rate (DCR), time to response (TTR), overall intracranial response rate 
(OIRR) and progression free survival (PFS).

To evaluate efficacy endpoints as assessed by BIRC: ORR.

To evaluate overall survival (OS).
10.5.2.1 Endpoint and analysis for other secondary objectives
Duration of response
Among patients with a confirmed response (PR or CR) per RECIST 1.1, duration of response 
(DOR) is defined as the time from first documented response (PR or CR) to the date of first 
documented disease progression or death due to any cause. DOR will be listed by patient and 
described using Kaplan-Meier curves and relevant statistics. Censoring rules for DOR follow 
those for PFS below.
Disease control rate
The disease control rate (DCR), defined as the proportion of patients with best overall 
response of CR, PR, or SD per RECIST 1.1 will be estimated and the 95% CI based on the 
exact binomial distribution will be provided.
Time to response
Time to response (TTR) is defined as the time from the date of the first dose of LDK378 to 
first documented response (CR or PR, which must be confirmed subsequently) per RECIST 
1.1 for patients with a confirmed PR or CR. TTR will be described using appropriate 
summary statistics.
Progression-free survival
Progression-free survival (PFS) is defined as the time from the date of first dose of LDK378 
to the date of first documented disease progression 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 
 


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anticancer therapy date. By default, if disease progression or death 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 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.
PFS assessed by the investigators will be described using Kaplan-Meier methods and 
appropriate summary statistics.
Overall survival
Overall survival (OS) is defined as the time from the date of first dose of LDK378 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 described using Kaplan-Meier methods and appropriate summary statistics.
Overall intracranial response rate (OIRR)
OIRR is calculated based on response assessments in the brain for patients having measurable
brain metastases at baseline (i.e. at least one target lesion in the brain). OIRR is defined as the 
ORR based on target and non-target lesions in the brain and defined as the proportion of 
patients with a best overall confirmed response of CR or PR in the brain, as assessed per 
RECIST 1.1 by the investigator.
ORR and OIRR will also be assessed by BIRC and be the basis of supportive analysis.
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.
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:

For treatment discontinued patients , from day of first dose of study medication to 30 
days after last dose of study medication

For ongoing patients, from day of first dose of study drug to the data cut-off date
3. Post-treatment period: starting at day 31 after last dose of study medication.
The safety summary tables will include assessments from the on-treatment period, unless 
otherwise specified. Shift tables or change from baseline summaries will use data from the 
pre-treatment period for baseline calculations. Further details will be included in the 
Reporting and Analysis Plan (RAP).
 


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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 AEs will be summarized by system organ class and or preferred term, 
maximum severity (based on CTCAE grades v4.03), and relation to study treatment.
Clinically notable adverse events (CNAE) categories 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.
CNAEs will be defined at the project level and may be regularly updated based on emergent 
data. For each specified category, number and percentage of patients with at least one event 
per category will be summarized.
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. 
Grade 5 will not be used.
For some cases (e.g. white blood cell differentials), the lower limits of normal ranges used in 
CTCAE definitions will have to be replaced by a clinical meaningful limit expressed in 
absolute counts.
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.
The following summaries will be generated separately for hematology and biochemistry 
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) classification to compare baseline to the worst on-
treatment value.
All laboratory data will be listed with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges.
A separate listing will display notable laboratory abnormalities (i.e., newly occurring CTCAE 
grade 3 or 4 laboratory toxicities).
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change from baseline in laboratory tests over time or 
box plots may be specified in the RAP.
 


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10.5.3.4 Other safety data
Other safety data collected will be listed and summarized using descriptive statistics as 
appropriate. Notable values may be flagged. Notable/Abnormal values for safety data will be 
further specified in the RAP and will be used for shift tables.
Analyses will be performed on the safety set.
ECG

shift table baseline to worst on-treatment result.

listing of ECG evaluations for all patients with at least one abnormality.
Vital signs

shift table baseline to worst on-treatment result

table with descriptive statistics at baseline and change from baseline to worst post-baseline 
time points.
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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10.8
Interim analysis
An interim analysis will be performed after the first 30 patients enrolled have completed at 
least 16 weeks (4 cycles) of treatment with LDK378 or have discontinued earlier. The interim 
analysis will focus on full pharmacokinetics profile, safety and preliminary efficacy, including 
but not limited to:
 


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
Pharmacokinetics: PK analysis will be performed. Plasma concentration of LDK378, and 
PK parameters for patients with extensive PK assessment will be summarized and listed.

Safety: all adverse events observed by the data cutoff date will be summarized and listed. 
Separate summaries will be provided for SAE and death, respectively. Abnormal results 
on laboratory assessment and ECG will be presented and listed in detail.

Efficacy: ORR observed by the data cutoff date will be estimated with corresponding 
binomial exact 95% CI.
Details of the analysis will be defined in RAP.
The primary clinical study report (CSR) will be produced after all patients have undergone at 
least 24 weeks (6 cycles) of treatment with LDK378 or have discontinued earlier. All 
available data from all patients up to this cutoff date will be analyzed. The additional data for 
any patients continuing to receive study treatment, as allowed by the protocol, will be further 
summarized in a report once these patients completed the study (addendum of the clinical 
study report).
10.9
Sample size calculation
Overall approximately 100 patients will be enrolled. This sample size was deemed to be
adequate to assess safety, and tolerability and demonstrate the anti-tumor activity of LDK378 
in Chinese patients.
The first 15 patients being enrolled in the phase I component will have a 5-day PK run-in 
period so to obtain approximately 12 evaluable PK profiles.
 
 
10.10
Power for analysis of key secondary variables
The study is not powered for formal hypothesis testing. However, with a total of 100 patients, 
if the observed ORR (key secondary endpoint) is 45% (45 responders in 100 treated patients), 
this will result in an exact binomial 90% CI of - [36.5% ,53.7%].
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 CRFs.
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 assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
 


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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 (CRF) 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 CRFs and all other required reports. Data reported 
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic CRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper CRFs.
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.
 


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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 
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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Zhang X, Wu YL. Fusion of EML4 and ALK is associated with development of lung 
adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression.
Mol Cancer. 2010 Jul 13;9:188. doi: 10.1186/1476-4598-9-188.
 


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14
Appendices
14.1
Appendix 1: List of prohibited concomitant medications and
concomitant medications requiring caution for LDK378
Table 14-1
Prohibited medications that are strong inducers or inhibitors of 
CYP3A, or CYP3A substrates with narrow therapeutic index, or 
sensitive CYP2C substrates with narrow therapeutic index**
CYP2C9 substrates with narrow therapeutic index
warfarin
Phenytoin
CYP3A4/5 substrates with narrow therapeutic index
astemizole*
diergotamine
pimozide
alfentanil
cisapride*
ergotamine
quinidine*
terfenadine*
cyclosporine
Fentanyl
tacrolimus
sirolimus
Strong CYP3A4/5 inhibitors
Macrolide antibiotics:
Antivirals:
Antifungals:
Others:
clarithromycin
Indinavir
itraconazole
conivaptan
telithromycin
Lopinavir
ketoconazole
elvitegravir
troleandomycin
Nelfinavir
posaconazole
mibefradil
Ritonavir
voriconazole
nefazodone
saquinavir
Tipranavir
Strong CYP3A/5 inducers
avasimibe
carbamazepine
phenobarbital
phenytoin
rifabutin
Rifampin
St. John’s wort
* Compounds with risk of QT prolongation
For an updated list of CYP2C substrates, CYP3A substrates, inhibitors and inducers, please reference the 
Novartis Oncology Clinical Pharmacology internal memo: drug-drug interactions (DDI) database, Oct 2010, which 
is compiled primarily from the FDA’s “Guidance for Industry, Drug Interaction Studies”, the Indiana University 
School of Medicine’s Drug Interactions Database, and the University of Washington’s Drug Interaction Database.
**Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with a 
known potent inhibitor.
Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades 
de Pointes).
 


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Table 14-2
List of medications to be used with caution
CYP2C9 substrates
losartan
Irbesartan
diclofenac
ibuprofen
piroxicam
tolbutamide
glipizide
acenocoumarol
celecoxib
sulfamethoxazole
tolbutamide
torsemide
CYP3A4/5 substrates
dronedarone
capravirine
aripiprazole
simvastatin
alprazolam
Ritonavir
haloperidol
quinine
diazepam
Telaprevir
imatinib
tamoxifen
amlodipine
atorvastatin
nilotinib
tolvaptan
diltiazem
everolimus
methadone
trazodone
nifedipine
boceprevir
vincristine
nisoldipine
erythromycin
brecanavir
verapamil
nitrendipine
Moderate CYP3A4/5 inhibitors
ciprofloxacin
Darunavir
grapefruit juice
dronedarone
erythromycin
fosamprenavir
aprepitant
tofisopam
amprenavir
Diltiazem
casopitant
atazanavir
Verapamil
cimetidine
Moderate CYP3A4/5 inducers
bosentan
Efavirenz
etravirine
modafinil
nafcillin
Ritonavir
talviraline
tipranavir
Proton pump inhibitors
esomeprazole
lansoprazole
omeprazole
pantoprazole
rabeprazole
The list of CYP2C9 and 3A4/5 substrates, 3A4/5 inhibitors and inducers is from the Novartis Oncology Clinical 
Pharmacology internal memo: drug-drug interactions (DDI) database, Oct 2010, which is compiled primarily from 
the Indiana University School of Medicine’s “Clinically Relevant” Table 
(http://medicine.iupui.edu/flockhart/table.htm), the University of Washington’s Drug Interaction Database 
(druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction Studies”.
 


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Table 14-3
List of prohibited enzyme-inducing anti-epileptic drugs
Prohibited enzyme-inducing anti-epileptic drugs
carbamazepine
Ethotoin
felbamate
fosphenytoin
phenobarbital
Phenytoin
primidone
topiramate
Table 14-4
List of prohibited QT prolonging drugs
Prohibited medications causing QTc prolongation
Antiarrhythmic:
Anticancer:
Antibiotic:
Antianginal:
amiodarone
arsenic trioxide
azithromycin
bepridil
disopyramide
vavdetanib
clarithromycin*
Antipsychotic:
dofetilide
Antihistamine:
erythromycin*
chlorpromazine
flecainide
astemizole*
moxifloxacin
haloperidol*
ibutilide
terfenadine*
sparfloxacin
mesoridazine
procainamide
Antimalarial:
Antinausea:
pimozide
quinidine*
chloroquine
domperidone
thioridazine
sotalol
halofantrine
droperidol
Opiate agonist:
Antilipemic:
Anti-infective:
GI stimulant:
levomethadyl
probucol
pentamidine
cisapride*
methadone
Antidepressant:
citalopram
Please note: *CYP3A substrate
Source: Arizona Center for Education and Research on Therapeutics (CERT), Drugs that prolong the QT interval 
and/or induce Torsades de Pointes, http://.azcert.org/medical-pros/drug-lists/drug-lists.cfm
 


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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, Progression-Free Survival and Overall Survival
(based on RECIST 1.1)
Document type:
TA Specific Guideline
Document status:
Version 3.1: 29-Nov-2011
Version 3:0: 19-Oct-2009
Version 2:0: 18-Jan-2007
Version 1:0: 13-Dec-2002
Release date:
29-Nov-2011
List of contributors
Authors (Version 3.1):
 
 
Authors (Version 3):
 
Authors (Version 2):
Authors (Version 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
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
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 14.2.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.2.3.2 is summarizing the “time to 
event” variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.2.4 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.
14.2.2.1 Definitions
14.2.2.1.1
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in 
order to classify lesions appropriately at baseline. In defining measurability, a distinction also 
needs to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 14.2.3.2.8.
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 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.
14.2.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the 
study in some situations (e.g. in Phase III studies where PFS is the primary endpoint). 
However, it is recommended that patients be excluded from trials where the main focus is on 
the Overall Response Rate (ORR). 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 14.2.3.2.8.
14.2.2.2 Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
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.
 


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
Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they 
are superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
14.2.2.3 Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.2.2.1.1.

Nodal target: See Section 14.2.2.1.1.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. 
Each target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.

Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
 


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14.2.2.4 Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 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.
14.2.2.4.1
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for 
the evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate 
lesion evaluation data are examined by the investigator in order to derive the overall visit 
response. Therefore all such data applicable to a particular visit should be associated with the 
same assessment number.
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance 
of the cut from the longest diameter; such lesions may appear to have responded or progressed 
on subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are 
not expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
 


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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.
14.2.2.4.2
Determination of target lesion response
Table 14-5
Response criteria for target lesion
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 14.2.2.2.
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance 
(i.e., the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually 
present and/or not visualized for technical reasons in this previous assessment. If it is not 
possible to change the 0 value, then the investigator/radiologist has to decide between the 
following 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.
 


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
Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.

Nodal lesion decrease to normal size: When nodal disease is included in the sum of 
target lesions and the nodes decrease to “normal” size they should still have a 
measurement recorded on scans. This measurement should be reported even when the 
nodes are normal in order not to overstate progression should it be based on increase in the 
size of nodes.

Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) 
of the two split lesions should be added together and the sum recorded in the diameter 
field on the 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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14.2.2.4.3
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 14.2.2.4.2 for assigning PD following a CR for 
the non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
14.2.2.4.4
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
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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 14.2.2.5).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.2.2.2.
14.2.2.5 Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target 
lesion response, non-target lesion response and presence of new lesions as shown below in 
Table 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 14.2.2.4
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.
14.2.3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.2.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
 


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14.2.3.1 Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the 
protocol should specifically describe if these will be included in the determination of best 
overall response and/or whether these additional assessments will be required for sensitivity 
or supportive analyses. As a default, any assessments taken more than 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 
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Overall lesion responses of CR must stay the same until progression sets in, with the 
exception of a UNK status. A patient who had a CR cannot subsequently have a lower status 
other than a PD, e.g. PR or SD, as this would imply a progression based on one or more 
lesions reappearing, in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective 
status at that assessment should be SD. Once a confirmed PR was seen, the overall lesion 
response should be considered PR (or UNK) until progression is documented or the lesions 
totally disappear in which case a CR assignment is applicable. In studies where confirmation 
of response is not required after a single PR the overall lesion response should still be 
considered PR (or UNK) until progression is documented or the lesion totally disappears in 
which case a CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the 
subsequent visits. Assuming that non-target lesions did not progress, the overall lesion 
response would be PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the 
PR for this patient. All subsequent assessments are considered PR even if tumor 
measurements decrease only by 20% compared to baseline (200 mm to 160 mm) at the 
following assessments.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:

Investigator overall lesion response

Central Blinded Review overall lesion response

Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)
The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses.
Based on the patients’ best overall response during the study, the following rates are then 
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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.
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).
14.2.3.2 Time to event variables
The protocol should state which of the following variables is used in that study.
14.2.3.2.1
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
14.2.3.2.2
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date 
the patient was last seen alive / last known date patient alive, the date of death and the reason 
of death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be 
censored at the date of last known date patient alive.
 


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14.2.3.2.3
Time to progression
Some studies might consider only death related to underlying cancer as an event which 
indicates progression. In this case the variable “Time to progression” might be used. TTP is 
defined as PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate 
tumor assessment.
14.2.3.2.4
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.
14.2.3.2.5
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.
 


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For summary statistics on “responders” only the following definitions are appropriate. 
(Specific definitions for an all-patient analysis of these endpoints are not appropriate since the 
status of patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in 
which a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to 
be confirmed) or SD the start and end date as well as censoring is defined the same as that for 
time to progression.
14.2.3.2.6
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 14.2.3.2.5. 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.
 


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14.2.3.2.7
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest 
of all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that 
assessment is CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the 
assessment date is calculated as the earliest date of all measurement dates at that evaluation 
number.
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 14.2.3.2.8).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.
 


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
Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
14.2.3.2.8
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered 
into the study, either because of a protocol violation or by design (e.g. in Phase III studies
with PFS as the primary endpoint). In such cases the handling of the response data requires 
special consideration with respect to inclusion in any analysis of endpoints based on the 
overall response evaluations.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with 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 14.2.2.4.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with 
only non-measurable disease at baseline, handling patients with a best response of CR as 
“responders” with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses 
which exclude these particular patients. Endpoints such as PFS which are reliant on the 
determination and/or timing of progression can incorporate data from patients with only non-
measurable disease.
 


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14.2.4
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
14.2.4.1 Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
 


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The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
14.2.4.2 End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc.
The end of treatment visit and its associated assessments should occur within 7 days of the 
last study treatment.
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

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)
14.2.4.3 End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study 
treatment and post-treatment evaluations but prior to collecting survival follow-up.
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
 


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
Death

New therapy for study indication

Progressive disease

Study terminated by the sponsor
14.2.4.4 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) 
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.
14.2.4.5 Programming rules
The following should be used for programming of efficacy results:
14.2.4.5.1
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
14.2.4.5.2
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 14.2.3.2.7). If all measurement dates have 
no day recorded, the 1st of the month is used.
 


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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.
14.2.4.5.3
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
14.2.4.5.4
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
14.2.4.5.5
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.2.4.5.6
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see
Table 14-9)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
*Adequate assessment is defined in Section 14.2.3.2.7. This reason is applicable when 
adequate evaluations are missing for a specified period prior to data cut-off (or prior to any 
other censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason 
should also be noted:
 


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
This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.
14.2.5
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791.
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47.
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465.
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: ALK Immunohistochemistry
The population for this study includes adult Chinese patients with locally advanced or 
metastatic NSCLC harboring a confirmed ALK rearrangement, defined as positive using the 
FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and 
scoring algorithm (including positivity criteria) or positive as assessed by the CFDA approved 
immunohistochemistry (IHC) test (Ventana Medical Systems, Inc) using rabbit monoclonal 
primary antibody assay (D5F3) and associated scoring algorithm. If documentation of ALK 
rearrangement is not available as described above, a test to confirm ALK rearrangement must 
be performed using an archival tumor obtained at or since the time of diagnosis or a new 
tumor biopsy obtained prior to the first LDK378 dose. The test will be performed at a 
Novartis designated central laboratory (by IHC test using rabbit monoclonal primary antibody 
assay (D5F3), Ventana Medical Systems, Inc). Patients must wait for the result of the ALK 
rearrangement status before initiating treatment with LDK378.
Overview
The VENTANA anti-ALK (D5F3) Rabbit Monoclonal Primary Antibody (VENTANA anti-
ALK (D5F3) IHC assay will be used to determine ALK IHC status and to select ALK-
positive patients for enrollment in Study [CLDK378A2301]. The anti-ALK (D5F3) rabbit 
monoclonal antibody IHC assay is currently being developed by Ventana Medical Systems as 
a companion diagnostic to LDK378. For study CLDK378A2301, the VENTANA anti-ALK 
(D5F3) assay will be used for investigational purposes only. VENTANA anti-ALK (D5F3) is 
intended for laboratory use in the detection of the anaplastic lymphoma kinase (ALK) protein 
in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue 
stained with a VENTANA BenchMark XT® immunohistochemical (IHC) automated slide 
stainer. It is indicated as an aid in identifying patients eligible for treatment with LDK378.
Device Description
The VENTANA anti-ALK (D5F3) IHC assay is an automated IHC staining assay system 
comprising a pre-diluted, ready-to-use anti-ALK (D5F3) rabbit monoclonal primary antibody, 
the BenchMark® XT automated slide-staining platform, OptiView DAB detection kit, 
OptiView Amplification kit, Rabbit Monoclonal Negative Control Ig and VENTANA anti-
ALK 2-in-1 cell line control slides. The reagents and the IHC procedure are optimized for use 
on the BenchMark XT® automated slide stainer, utilizing NexES software (Ventana System 
Software).
Scoring System
The IHC scoring system evaluates specific VENTANA anti-ALK (D5F3) staining in NSCLC 
tumor cells by the presence of a strong, granular, cytoplasmic staining pattern. Pathologists 
must rely on the Negative Reagent Control (NRC) slides to distinguish non-specific staining 
from specific ALK positivity. Samples must be assessed for morphological damage and the 
presence of viable tumor versus necrosis. Light, granular, cytoplasmic stippling in alveolar 
macrophages can occur on anti-ALK (D5F3) and/or NRC slides as an artifact of the detection 
system. This staining artifact should be noted on the Slide Evaluation Form comment field but 
 


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should NOT be interpreted as ALK-positive staining. Some background staining has also been 
observed on normal mucosa in NSCLC specimens, as well as in necrotic tumor areas; this 
staining also should not be interpreted as ALK-positive staining. Case slide sets failing to 
show specific staining of the case tissue with VENTANA anti-ALK (D5F3) as defined in the 
following table cannot be considered ALK-positive.
Table 14-10
Clinical Interpretation of VENTANA anti-ALK (D5F3) Staining
Clinical Interpretation
Staining Description
Positive for ALK
Presence of strong granular cytoplasmic staining in tumor cells (any 
percentage of positive tumor cells).
Known staining artifacts should be excluded, including:
light cytoplasmic stippling in alveolar
macrophages,
cells of neural origin (nerve and ganglion cells),
glandular epithelial staining, and
cells within lymphocytic infiltrate.
Some background staining also may be observed within normal mucosa in 
NSCLC (including mucin) and in necrotic tumor areas, which also should be 
excluded from the clinical evaluation.
Negative for ALK
Absence of strong granular cytoplasmic staining in tumor cells.
 


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

SAP_000.pdf: 
Clinical Development
LDK378
CLDK378A2109 / NCT02040870
A phase I/II multicenter, open-label, single-arm study of LDK378, 
administered orally in adult Chinese patients with ALK-rearranged 
(ALK-positive) advanced non-small cell lung cancer (NSCLC) 
previously treated with crizotinib
Statistical Analysis Plan (SAP)
Author:
Document type:
SAP Documentation
Document status:
Final 1.0
Release date:
13-Feb-2017
Number of pages:
61
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes
V2.0               
05-Jun-2014
Final version 2.0
Amendment 1
17-Dec-2014
The content and language of this RAP document were 
modified to align with protocol amendment 1 and to 
align with the analyses implemented in other LDK378 
studies. Further details are described below: 
Section 2.4: 
 
 
 
Figure 1.1: Number updated to reflect the sample size 
change.
Section 3.1.1.6 Derivation rules for baseline (including 
ECG) were further clarified.  
Section 3.1.2: Updated timing primary CSR analysis to 
be after all patients completed 24 weeks (6 cycles) of 
treatment. 
Section 3.1.3: “Efficacy analysis set” definitions were 
added for the efficacy population used for interim 
analysis. 
A new major PD “Patient has been previously treated 
with more than 2 lines of chemotherapy” was added.
Added criteria that patient should take study drug 
according to the original assigned dose for at least 5 
consecutive days without interruption or dose 
modification prior to the PK sampling day (except for 
PK run-in Day 1 for patients with extensive 
assessment ) for evaluable full PK profile 
Section 3.1.4  Table of patients classification rules are 
added. 
Section 3.2.2 & Section 3.2.6: Version information 
added to MedDRA and WHO drug dictionary.


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Version
Date
Changes
Section 3.2.8: Clarification added for pharmacokinetic 
analysis using PAS.
 
CLss/F is added as a secondary parameter for PK 
analysis.
Section 3.2.9.1, Section 3.2.8:  Minor changes to 
adverse event section to align with protocol amendment 
01 and LDK378 program. 
Section 3.2.9.2 The wording for the derivation of CTC 
grading for  laboratory values was clarified  and 
corrected to cover cases such as creatinine increased 
grading when the post-baseline value is ≤ULN 
Section 3.2.9.4. Added shift tables for ECOG status 
from baseline to best post baseline.
Section 3.3: 
 
Section 3.4: Confidence interval provided for the larger 
sample size. 
Section 4.1.1: This section is removed as this RAP now 
is in alignment with the new updated protocol.
Section 4.2.2: Source of ORR derived based on the 
raw data per investigator was removed. This source is 
used only for data cleaning purposes.
Section 4.3: Categories to describe whether the 
questionnaire was completed were updated to align 
with CRF.
Section 4.4: More details and clarification added for PK 
analyses.


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Version
Date
Changes
Amendment 2
18-Jan-2016
Appendix 
1: 
Tables/Listings 
on 
concomitant 
medications and significant non drug therapies were 
split into separate listings as per NCDS. 
The list of output for IA was updated.
Naming conventions have been updated for some 
outputs to align with LDK378 program. 
Section 2.4:

Updates in study design section to remove “start of 
a new anti-cancer therapy” from the list of 
allowable reasons to stop collection of tumor
assessments to align with protocol amendment 2.  
Section 3.1

The major inclusion/exclusion criteria leading to 
exclusion from PPS were updated in 3.1.3 per team 
discussion; the classification rules in section 3.1.4 
were updated and further clarified. 
Section 3.2

Listing of ALK status in section 3.2.2 was removed 
as the same has been mentioned in the 
 
 

Updates in the PK parameter table to align with 
protocol v03.

Additional AE summaries were added and the list 
of AESI’s was updated in Sec 3.2.9.1.  

The list of laboratory values to be summarized was 
updated in section 3.2.9.2. 

Denominator for new abnormality post baseline 
ECGs were clarified in Section 3.2.9.3.                      
The interval to define “lost to follow up” for 
overall survival was updated to 18 weeks per LDK 
phase II practice. 

 
 

Section 4.1:Clarification on the handling of 
missing date in section 4.1.2. 
Section 4.2


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Version
Date
Changes
Addendum 1
03-Mar-2016

Clarified that change in contrast use in conventional 
or spiral CT is not considered a change in modality 
in Sec 4.2.1. 

The language on PFS censoring rules was updated 
in Sec 4.7.1. 

Updated the guidelines for the display of the 
waterfall graph in Sec 4.2.1. 
Section 4.4

Specified the calculation of inter-patient CV% for 
SS Ctrough.   
Section 4.5 

List of output for FIR updated
Section 3.2.10

The definition of disease control rate (DCR) was 
updated as the proportion of patients with best 
overall response of CR, PR, SD, or Non-CR/Non-
PD.  Patients with a best overall response of Non-
CR/Non-PD will also be included in the numerator 
for DCR calculation. 
Amendment 3
03-Jan-2017
Section 3.2.10.2 – Progression free survival
Added two extra summary tables of PFS by brain 
metastasis at baseline status for SCE
Section 3.2.10.2 – Overall intracranial response rate
Added definition and summary table of OIRR with 
measurable/non-measurable brain metastases
Section 4.1.6
Added the calculation rules for dose interruptions and 
dose changes in details
Amendment 4
13-Feb-2017
Section 3.2.9.1 – Safety evaluation
Added two AE tables for safety disclosure in EudraCT 
and CT.gov.
 


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Table of contents
Table of contents .................................................................................................................6
List of tables ........................................................................................................................8
1
Introduction .........................................................................................................................9
1.1
Document content....................................................................................................9
1.2
References................................................................................................................9
2
Study objectives and study design.......................................................................................9
2.1
Primary objectives ...................................................................................................9
2.2
Secondary objectives ...............................................................................................9
2.2.1
Key secondary objective .........................................................................9
2.2.2
Other secondary objectives .....................................................................9
10
2.4
Study design...........................................................................................................10
2.5
Study flow and visit schedule................................................................................12
3
Draft of Section 9.7 of CSR - Statistical methods planned in the protocol and 
determination of sample size.............................................................................................12
3.1
Draft of Section 9.7.1 of CSR - Statistical and analytical plans............................12
3.1.1
Definitions.............................................................................................12
3.1.2
Data included in analyses before the completion of the study..............14
3.1.3
Analysis sets..........................................................................................15
3.1.4
Classification into Analysis Sets...........................................................17
3.1.5
General statistical methodology............................................................18
3.2
Statistical methods used in reporting.....................................................................19
3.2.1
General presentation of descriptive summaries ....................................19
3.2.2
Patient demographics and other baseline characteristics ......................19
3.2.3
Protocol deviations................................................................................21
3.2.4
Patient disposition.................................................................................21
3.2.5
Study treatment .....................................................................................22
3.2.6
Concomitant therapy.............................................................................22
3.2.7
Antineoplastic therapy after discontinuation of study drug ..................23
3.2.8
Pharmacokinetic evaluation – primary analysis of the trial ..................23
3.2.9
Safety evaluation...................................................................................26
3.2.10
Efficacy evaluation................................................................................33
38
3.2.12
Interim analysis .....................................................................................39
3.3
Section 9.7.2 Sample size calculation....................................................................39


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3.4
Power for analysis of key secondary variables......................................................39
4
Appendix 16.1.9 of CSR- Documentation of statistical method.......................................40
4.1
Statistical methods.................................................................................................40
4.1.1
Difference between SAP and protocol..................................................40
4.1.2
Handling of missing or partial dates .....................................................40
4.1.3
Laboratory data .....................................................................................45
4.1.4
Last contact date....................................................................................46
4.1.5
Month derivation...................................................................................46
4.1.6
Dose interruptions and dose changes ....................................................46
4.2
Efficacy endpoints .................................................................................................47
4.2.1
Implementation of RECIST guidelines.................................................47
4.2.2
Sources for overall lesion response.......................................................51
4.2.3
Kaplan-Meier estimates ........................................................................51
4.2.4
OIRR calculations in patients with measurable brain metastases.........52
4.2.5
Confidence intervals..............................................................................53
53
4.4
PK analyses............................................................................................................55
4.5
First Interpretable Results......................................................................................56
4.5.1
First interpretable results for Interim analysis ......................................56
4.5.2
First interpretable results for final analysis...........................................57
5
Reference:..........................................................................................................................57
Appendix 1: List of output for interim analysis .......................................................................59


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List of tables
Document History – Changes compared to previous version of RAP module 3. ......................2
Figure 1-1
Study design..........................................................................................11
Table 3-1
Patient classification rules.....................................................................17
Table 3-1
Noncompartmental pharmacokinetic parameters..................................24
Table 3-2
WHO performance scale.......................................................................33
Table 3-3
Outcome and event dates for PFS and DOR analyses ..........................36
Table 4-1
AE/treatment date abbreviations...........................................................41
Table 4-2
AE partial date imputation algorithm....................................................41
Table 4-3
AE/treatment date relationship and imputation legend.........................42
Table 4-4
AE imputation example scenarios.........................................................42
Table 4-5
Inclusion/exclusion of assessments used in waterfall graph.................50
Table 4-6
Sources for overall lesion response.......................................................51


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1
Introduction
1.1
Document content
This Statistical Analysis Plan (SAP) describes the planned statistical analysis methods for the 
final clinical study report of LDK378A2109. It is structured as

a draft of Section 9.7 (Statistical methods planned in the protocol and determination of
sample size) of the clinical study report (CSR)

and also a draft of Appendix 16.1.9 (Documentation of statistical methods) of the CSR.
Appendix 16.1.9 text will contain details of statistical methods and issues that are more 
detailed than would be included in the CSR text. It is written in the future tense. It will be 
reviewed and updated (including conversion to past tense) for entry into the clinical study 
report after the analysis has taken place.
The detailed statistical methodology is similar to the RAP module 3 addendum 2 for the 
primary clinical study report (CSR) which is stored in the CREDI folder: CREDI 
Projects/L/LDK378/CREDI Studies/LDKA2109/Administrative Files (study level)/RAP or 
RAMP Meeting, except for the changes noted in the document history.
1.2
References
The following documents are used or referred to for the RAP generation:

Clinical Trial Protocol CLDK378A2109 amendment version 03 ( 07Oct, 2015)

Casebook CLDK378A2109 version 02 (05Aug, 2015)
2
Study objectives and study design
2.1
   Primary objectives

To characterize the pharmacokinetics of LDK378 in Chinese adult patients with ALK-
rearranged NSCLC previously treated with crizotinib following single and multiple daily 
oral doses of LDK378. 

To assess the safety and tolerability of LDK378 after continuous 750 mg once daily dose in 
Chinese adult patients with ALK-rearranged NSCLC.
2.2
    Secondary objectives
2.2.1
Key secondary objective

To demonstrate the antitumor activity of LDK378, as measured by overall response rate 
(ORR) to LDK378 by investigator assessment.
2.2.2
Other secondary objectives
To evaluate response related endpoints as assessed by the investigators per RECIST 1.1:

Duration of response (DOR)


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
Disease control rate (DCR)

Time to Response (TTR)

Overall intracranial response rate (OIRR)

Progression-free survival (PFS)

Overall survival (OS)
ORR and OIRR will also be evaluated as assessed by Blind Independent Review Committee 
(BIRC).
2.4
Study design
This is a phase I/II, open-label, multi-center study to assess the PK, safety, tolerability and
efficacy of LDK378 in adult Chinese patients with locally advanced or metastatic NSCLC 
harboring a confirmed ALK rearrangement. Patients must have demonstrated progression
during or after crizotinib treatment whether or not previously treated with cytotoxic 
chemotherapy and have no available ALK-targeted treatment options.
Overall approximately 100 patients will be enrolled in the study. The first 15 enrolled patients 
will enter a 5-day PK run-in period during the phase I component of this study. They will have 
PK sampling over 120-hour during the run-in period following a single oral dose at 750 mg. 
Additional patients may be enrolled in the study with the 5-day PK run-in period in case PK 
profiles from some of the enrolled patients are deemed not evaluable 
The phase II component of the study will start on Cycle 1 Day 1 for all enrolled patients. During 
this period LDK378 will be given as continuous daily oral dosing at 750 mg QD in 28 -day 
cycles. 
Extensive PK assessment will be collected for the first 15 enrolled patients to obtain 
approximately 12 evaluable full profiles. Sparse PK samples will be collected for the rest of 
patients. Adverse events will be collected at every visit after informed consent obtained. 
Laboratory assessment including hematology and blood chemistry will be taken at screening,
run-in Day 1 for the first 15 enrolled patients, Day 1, Day 8, Day 15 for cycle 1 and Day 1 for 
subsequent cycles. Separate ECG monitoring schedules will also be collected for patients with 
extensive PK assessment and those with sparse assessment. 


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Tumor response will be evaluated every 8 weeks (i.e. every 2 cycles) starting from the first day 
of treatment with LDK378 until the time of RECIST-defined Progressive disease (PD) by 
investigator assessment, withdrawal of consent for further follow-up, loss to follow-up or death. 
This schedule of tumor assessment will continue regardless of dose interruptions. For 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.
Treatment with LDK378 will continue until the patient experiences a RECIST-defined PD on 
LDK378 as assessed by the investigator, an unacceptable toxicity that precludes further 
treatment, discontinues treatment at the discretion of the patient or investigator, starts a new 
anti-cancer therapy or dies. Please refer to Figure 1-1 for flow chart of the study design. 
If the patient experiences RECIST-defined progressive disease (PD), treatment with the study 
drug may be continued if, in the judgment of the investigator, there is still evidence of clinical 
benefit. When the patient discontinues from study treatment an End of Treatment (EOT) visit 
must be performed within 7 days of the last dose of LDK378. Patients will be contacted for the 
safety follow-up 30 days after their last dose of LDK378. Following the cessation of tumor 
follow-up assessments, patients will be contacted every 3 months to determine survival status
and/or whether the patient started any other antineoplastic therapies since discontinuing study 
treatment. 
Figure 2-1
Study design
Screening
Day -28 to Day -1
100 ALK+ NSCLC patients
5 day Run-In
First 15 enrolled patients
(Phase I component)
85 patients
Treatment
Daily dosing, 28-day cycles
(Phase II component)
End of Treatment*
Due to disease PD
Within 7 days after last dose
*Patient may continue LDK378 despite 
progression if there is continued clinical 
benefit. EoT should only be performed 
once LDK378 is permanently 
discontinued
End of Treatment
Not due to disease PD
Within 7 days after last dose
Safety follow-up
30 Days after last dose


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Safety follow-up
30 Days after last dose
Continue tumor and 
 
Every 8 weeks from EoT until PD
Study evaluation complete
Study evaluation complete
Survival follow-up
Every 3 months after final tumor assessment
2.5
Study flow and visit schedule
See Table 7-1 in the protocol.
3
Draft of Section 9.7 of CSR - Statistical methods planned in
the protocol and determination of sample size
3.1
Draft of Section 9.7.1 of CSR - Statistical and analytical plans
3.1.1
Definitions
3.1.1.1
Study drug and study treatment
Study drug and study treatment both refer to LDK378 and will be used interchangeably.
3.1.1.2
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 is administered and recorded on the Dosage Administration Record (DAR)
electronic Case Report Form (eCRF). For the sake of simplicity, the date of first administration 
of study drug will also be referred 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 is administered and recorded on the DAR eCRF. This date is also referred as last 
date of study drug.
3.1.1.3
Duration of exposure and Intensity
Definitions of duration of exposure, cumulative dose, average daily dose, actual dose intensity
(DI), planned dose intensity (PDI), 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


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
Number of dosing days (days):
    duration of exposure − number of zero dose days

Average daily dose (mg/day):          cumulative dose (mg) ⁄ number of dosing days, drug 
free day(s) in PK run-in period are not counted

DI (mg/day):                                     cumulative dose (mg) ⁄ duration of exposure (days)

PDI (mg/day):                                   cumulative planned dose (mg) / duration of exposure
(days)

RDI (%):                                           100 × DI (mg/day) ⁄ PDI (mg/day)
The cumulative planned dose is defined as the total planned dose according to the planned
dosing schedule during the study treatment exposure. It is therefore calculated as follows: 
cumulative planned dose (mg) = protocol planned dose of 750 (mg)* duration of exposure.
For the first 15 patients who are planned to receive a single dose during the PK run-in period 
(of 5 days), and patients receive daily dosing thereafter, the cumulative planned dose is 
calculated as follows:
Cumulative planned dose (mg) =

750 (mg) * (duration of exposure -4), if duration of exposure (day) >5

750 (mg), if duration of exposure (day) ≤5
The similar procedure for calculation is applied to calculation of dosing days for the first 15 
patients enrolled in the PK run-in period;  
Number of dosing days (days) =

duration of exposure – (number of zero dose days + 4), if duration of exposure (day) >5

duration of exposure,  if duration of exposure (day) ≤5
3.1.1.4
Dose interruption and dose change
Dose interruption and dose change will be listed and summarized as reported in the DAR eCRF.
Dose reductions are a subset of dose changes where dose changes to higher than protocol 
planned dose are excluded.
3.1.1.5
Study day 
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) will be calculated using the start date of study drug as the 
origin. This also applies to patients who received single dose at PK run-in period. For 
assessments occurring after or on the start date of study drug, study day will be calculated as:
Study Day =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.


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The study day will be displayed in the data listings.
3.1.1.6
Baseline
Baseline is the result of an investigation describing the “true” uninfluenced state of the patient. 
The last available assessment before or on the start date of study drug is defined as “baseline” 
value or “baseline” assessment. For cases when the assessment is planned to be performed 
before the first dose of study drug and the assessment is performed on the same day as the first 
administration of study drug:

If either the assessment or first dose time point is not collected or is missing, it will be 
assumed that the assessment was performed prior to study drug administration.

If both assessment and first dose 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 unless otherwise 
specified. 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 (or PK run-in 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.
Laboratory data 
If both central and local laboratory assessments are 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 each ECG measurement is the average of the pre-dose replicate measurements on 
the baseline day. Unscheduled assessments will not be included in the calculation of the average. 
Study day 1 (PK run-in day 1 for the first 15 patients and Cycle 1 day 1 for the rest patients) 
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 the same as an unscheduled post-dose measurement.
For unscheduled assessments on study day 1, if dosing time is non-missing, then the assessment 
is considered as post-baseline if ECG collection time is later than dosing time. If dosing time is 
missing, these unscheduled assessments will be considered as post-baseline.
3.1.2
Data included in analyses before the completion of the study
An interim analysis will be performed after the first 30 patients enrolled have completed at least 
4 cycles of treatment with LDK378 or have discontinued earlier. For the interim analysis, all 
data from patients on or before the interim analysis cut-off date will be used.
The primary CSR will be produced after all patients have undergone at least 24 weeks (6 cycles) 
of treatment with LDK378 or have discontinued earlier. All available data from all patients up 
to this cutoff date will be analyzed. Only data with an assessment date or event start date (e.g. 
vital sign assessment date or start date of an adverse event) prior to or on the cut-off date will 


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be included in each analysis. (Example: If the cut-off date is e.g. 15-Oct-2011, an AE starting 
on 13-Oct-2011 will be reported, whereas an AE with a start date on 17-Oct-2011 will not be 
reported).
3.1.3
Analysis sets
A patient is considered to be enrolled into the study if they have signed the study informed 
consent. Only patients who have signed study informed consent prior to study procedures will 
be included in the analysis data sets.
Full Analysis Set
The Full Analysis Set (FAS) consists of all patients who receive at least one dose of LDK378.
Unless otherwise specified the FAS will be the analysis set used for all analyses and listings.
Efficacy Analysis Set (Interim analysis only)
The Efficacy Analysis Set (EAS) is used in the interim analysis for the analysis of tumor 
response data based on investigator assessments. It is a subset of the FAS, and consists of 
patients who received the first dose of LDK378 at least 16 weeks prior to the analysis cutoff 
date. The EAS will be the primary data set used in interim analysis for the analysis of tumor 
response data (ORR and DOR based on investigator assessments).
Safety Set
The Safety Set consists of all patients who receive at least one dose of LDK378. All safety data 
will be analyzed using the Safety Set.
The FAS and Safety Set in this study are identical.
Per-Protocol Set
The Per-Protocol Set (PPS) will consist of a subset of patients in the FAS who are compliant
with requirements of the Clinical Study Protocol (CSP). The PPS consists of patients who have 
an adequate tumor assessment at baseline, a follow-up tumor assessment >7 weeks after starting 
treatment (unless disease progression is observed per investigator’s assessment before that time), 
and no major protocol deviations. PPS will be used in the supportive analysis of ORR. 
The major protocol deviations that will lead to removal of patients from the PPS are listed below: 

No confirmation of ALK positive status by the Abbott Molecular Inc FDA-approved FISH 
assay or by the CFDA approved IHC Ventana test prior to first dose.   Patient has a 
histologically or cytologically confirmed diagnosis of NSCLC that is not ALK positive as 
assessed by the Abbott Molecular Inc FDA-approved FISH assay or by the CFDA approved 
IHC Ventana test.

No histological or cytological diagnosis of NSCLC

Neither Stage IIIB nor IV NSCLC

WHO performance status equal to 3 or 4 at screening


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
No prior treatment with crizotinib

Prior treatment with crizotinib  with no noted PD  during or after crizotinib treatment OR 
prior treatment with crizotinib discontinued due to toxicity

Patient has been previously treated with more than 2 lines of chemotherapy prior to study 
entry

No documentation of disease progression at study enrollment

No measurable lesion from RECIST 1.1 evaluation at baseline per investigator
assessment. For analysis by BIRC assessment based on PPS, ‘No measurable lesion at 
baseline’ is based on BIRC assessment per RECIST 1.1.  

RECIST lesions previously been irradiated has been chosen as target lesions without a clear 
progression since irradiation

Patient has received an ALK inhibitor investigational agent (except Crizotinib)
before first dose of study treatment.

Patient has a history of carcinomatous meningitis

Patient with symptomatic central nervous system (CNS) metastases neurologically unstable 
or has required increasing doses of steroids within the 2 weeks prior to study entry.
Pharmacokinetic Analysis Set
The Pharmacokinetic Analysis Set (PAS) consists of all patients who received at least one dose 
of LDK378 and have at least one evaluable PK sample.
Depending on whether the sample is part of a full profile or a sparse sample, the specific criteria 
are listed as follows.
A sparse PK sample is considered to be evaluable if:

The patient takes study drug according to the original assigned dose for at least 5 
consecutive days without interruption or dose modification prior to the PK sampling day 
(except for PK run-in Day 1 for patients with extensive assessment and Cycle 1 Day 1), 
AND

On the PK collection day, the patient takes study drug according to the originally assigned 
dose, 

Vomiting doesn’t occur within 6 hours following the last dose intake prior to the PK sample 
draw, AND

For the pre-dose sample, draw occurs between 18 to 30 hours after the last dose intake
(except for PK run-in Day 1 for patients with extensive assessment and Cycle 1 Day 1), and

For the pre-dose sample, the draw occurs before the next dose intake, and

A sample can be considered to be not evaluable as per scientific judgment of the clinical 
pharmacology expert
An evaluable full PK profile is defined as:


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
The patient takes study drug according to the original assigned dose for at least 5 
consecutive days without interruption or dose modification prior to the PK sampling day 
(except for PK run-in Day 1 for patients with extensive assessment and Cycle 1 Day1), 
AND

No vomiting occurs within 6 hours following the last dose intake prior to the PK sample 
draw, AND

On the PK collection day, the patient takes study drug according to the originally assigned 
dose, AND

Additionally, an entire profile can be considered non-evaluable as per scientific judgment 
of the clinical pharmacology expert even if the above criteria are fulfilled. Reason will be 
documented in the merged PK datasets.
Any blood samples missing blood collection date or time, or missing associated study drug 
dosing date or time will be excluded.
Frequency counts and percentages (using FAS as denominator) of patients in each of the above 
defined analysis sets will be summarized. In addition, listings of patients included in each of 
the analysis sets will be provided.
3.1.4
Classification into Analysis Sets
Patients were excluded from the analysis populations defined above based on the protocol
deviations entered in the database and/or on specific subject classification rules, see Table 3-1
below.
Table 3-1
Patient classification rules 
Analysis Population
Patient classification rules leading to exclusion
Full Analysis Set
Patients who did not receive at least one dose of study drug
Efficacy Analysis Set 
(Interim analysis only) 
Patient did not receive at least one dose of LDK378 OR 
First
dose of LDK378 < 16 weeks prior to data cut-off
Safety Set
Patients who did not receive at least one dose of study drug.
Per Protocol Set
Protocol deviations that will lead to removal of patients from 
Per Protocol Set, i.e. INCL01, INCL02, INCL03, INCL04, 
INCL07, INCL08, INCL09, INCL10, INCL11, INCL12, 
INCL13, INCL33，EXCL02, EXCL03, EXCL04
Patient who do not have an adequate tumor assessment at 
baseline, or a follow-up tumor assessment > 7 weeks after 
starting treatment (unless disease progression is observed 
before that time). For PPS (inv.) patients with no target 
lesions at baseline per investigator are excluded; for PPS 
(BIRC) patients with no target lesions at baseline per BIRC 
are excluded.
Pharmacokinetic analysis set
Patients who do not have at least one evaluable PK sample
All protocol deviations and subject classification rules will be finalized before database lock.


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Below lists handling of some special cases in analysis set classification: 

If informed consent is not properly obtained from the patient (signed and dated prior to any 
study related procedures), data from the patient will be excluded from all analysis 
populations including table summaries and listings. 

If a patient withdraws consent (based on ‘Was informed consent withdrawn’ is ‘Yes’ for 
study informed consent in the “Withdrawal of informed consent” page)

If consent withdrawal date is before start of treatment date, or start of treatment date is 
missing, then patients’ data will not be included into any analysis. 

If consent withdrawal date is after start of treatment date, then all data collected before 
withdrawal will be included in the analysis, and data collected after consent withdrawal 
will be excluded from the date of withdrawal by programming cut-off. 

If a patient does not meet inclusion/exclusion criteria:

If  patient is not treated, then the patient data will be listed in screening failures (see 
section 3.2.2) 

If patient is treated, then the patient data will be included in FAS and safety set, but 
might be excluded from PPS depending on whether this violation is a major protocol 
deviation or not. 
3.1.5
General statistical methodology
3.1.5.1
Multiple assessments within post-baseline visits
If there are multiple measurements/samples within the same post-baseline visit, the last
measurement/sample within the visit (sorted by date and as available by time or repeat
measurements) will be used in the analysis by visit or overall. For any analyses regarding 
abnormal assessments or analyses based on worst (or best in the case of ECOG status) post-
baseline value (laboratory, ECGs, vital signs, ECOG performance status), all post-baseline 
values will be included (scheduled, unscheduled, repeat). For any other analyses, only 
scheduled visits will be included. 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 Common Terminology Criteria (CTC) v4.03 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 Liver function test (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.  
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For all patients, triplicate ECGs are targeted to be measured at the protocol-defined (nominal) 
time-points. If any patient had more than one measurement at a specific time point, the average 
of all available measurements (only scheduled one) associated with the nominal time point will 
be used for the analyses. 
3.1.5.2
Center pooling
Center effects will not be analyzed and the main analyses will therefore be conducted with the 
pooled datasets.
3.2
Statistical methods used in reporting
3.2.1
General presentation of descriptive summaries
Qualitative data (e.g., sex, race, etc.) will be summarized by frequency count and percentages. 
Percentages are calculated using the number of patients in the relevant population as the 
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive
statistics (i.e. mean, standard deviation, median, minimum, and maximum).
Summary statistics for PK concentrations and PK parameters include the following unless
otherwise specified: n, mean, SD, coefficient of variation (CV) for mean, geometric mean, CV% 
for geometric mean, median, minimum and maximum.
3.2.2
Patient demographics and other baseline characteristics
The FAS will be used for all patient demographic and baseline characteristic summaries and 
listings, unless otherwise specified.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed. 
Categorical data (e.g. sex, age groups: <65 and ≥65 years, race, ethnicity, WHO performance 
status, smoking history) will be summarized by frequency counts and percentages. Continuous 
data (e.g. age, weight, height, and Body Mass Index (BMI)) will be summarized by descriptive
statistics. Height is collected only once in the study. Baseline weight is the last non -missing 
value observed before the first administration of study drug. BMI will be calculated using height 
and baseline weight:
BMI (kg/m2) = weight [kg] / (height [m]) 2   
Patient demographic characteristics will be summarized by quartile of average SS Ctrough
using Pharmacokinetic Analysis Set (see Section 3.2.8)
Diagnosis and extent of cancer
Descriptive statistics and frequency counts and percentages will be tabulated, as appropriate,
for diagnosis and extent of cancer based on the data collected on the eCRF including primary 
site of cancer, details of tumor histology/cytology, histological grade, stage at initial diagnosis,
stage at time of study entry, time (in months) since initial diagnosis of primary site, time (in 


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months) from initial diagnosis to first recurrence/progression, time (in months) since most 
recent relapse/progression, current extent of disease (metastatic sites), number of metastatic 
sites at baseline, types of lesions (target and non-target lesions) at baseline, number of target 
lesions at baseline, and disease burden at baseline for target lesion (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. Separate summaries will be presented for ongoing and historical 
medical conditions. The summaries will be presented by primary system organ class (SOC) and
preferred term (PT). Medical history and current medical conditions are coded using the latest 
Medical Dictionary for Regulatory Activities (MedDRA) terminology prior to database lock.
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 anti-neoplastic radiotherapy or prior anti-neoplastic surgery will be summarized. 
All patients must have received crizotinib for inclusion in the study; reason for crizotinib 
discontinuation, best response on crizotinib, duration of best response, and time from start of 
last crizotinib treatment to progression (date of progression on crizotinib - start date of last 
crizotinib + 1) will be summarized.
Prior anti-neoplastic medications will be summarized by chemotherapy (medication) setting, 
other therapy (medication) setting, number of prior regimens of chemotherapy. Prior 
antineoplastic medications will also be summarized by Anatomical Therapeutic Chemical 
(ATC) class and PT using the latest WHO drug dictionary prior to database lock.
The summary of prior anti-neoplastic radiotherapy will include a summary of radiotherapy
locations and settings at last radiotherapy. 
The summary of prior anti-neoplastic surgery will include the time between the last surgery to
start of treatment, procedure at last surgery and residual disease at last surgery.
Screening phase disposition
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screening failure. These patients are not treated with study drug. Frequency counts 
and percentages will be tabulated for all patients as follows:

Number (%) of patients who completed screening phase (based on the presence of study 
phase completion date/ “subject status” is checked as “completed” and the ‘Next phase 
entered’ is ‘Treatment’ or ‘Treatment run-in’ 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);


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
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 and summarized by 
criteria.
3.2.3
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. Major protocol 
deviations will be tabulated separately. 
All protocol deviations will be listed. 
3.2.4
Patient disposition
The FAS will be used for the patient disposition summary tables and listings. The following 
will be tabulated.
Relating to treatment phase:

Number (%) of patients entered “Treatment run-in” (PK run-in) phase 

Number (%) of patients entered “Treatment” phase

Number (%) of patients who are still on treatment (based on the absence of the ‘End of 
Treatment Phase Disposition’ page); 

Number (%) of patients who discontinued treatment (based on completion of the ‘End of 
Treatment Phase 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 
Phase Disposition’ page for patients who discontinued treatment);

Number (%) of patients who entered survival follow-up from treatment phase (based on 
‘Will subject continue into the next phase of the trial’ is ‘No’ and ‘Will the subject be 
followed for survival’ is ‘Yes’ on the ‘End of Treatment Phase Disposition’ page for patients 
who discontinued the treatment);

Number (%) of patients who discontinued from study from treatment phase (based on ‘Will 
subject continue into the next phase of the trial’ is ‘No’ and ‘Will the subject be followed 
for survival’ is ‘No’ on the ‘End of Treatment Phase Disposition’ page for patients who 
discontinued the treatment);

Primary reasons for treatment discontinuation (based on discontinuation reasons entered 
under ‘Subject Status’ in the ‘End of Treatment Phase Disposition’ page);
Relating to the post-treatment follow-up phase:

Number (%) of patients who are still in the post-treatment follow-up phase (based on 
presence of the ‘End of Treatment Phase Disposition’ page and absence of the‘ End of Post-
treatment Phase Disposition’ page);


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
Number (%) of patients who discontinued from the post-treatment follow-up phase (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 from post-treatment phase (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 phase);

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 the subject be followed for survival’ is ‘No’ for 
patients who discontinued from the post-treatment follow-up phase);

Primary reasons for discontinuation from the post-treatment follow-up phase (based on 
discontinuation reasons entered under ‘Subject Status’ in the ‘Post-treatment Phase 
Completion’ page).
3.2.5
Study treatment
Duration of exposure to study drug, cumulative dose, average daily dose, DI and RDI (including 
categories: <50%, 50%-<75%, 75%-<90%, 90%-110%, ≥110%) will be summarized. In 
addition, the duration of exposure to study drug will be categorized into time intervals; 
frequency counts and percentages of patients with exposure in each time interval will be 
presented. The number of patients with dose changes, reductions and interruptions, and the 
corresponding reasons will be presented. 
Time to first dose reduction and time to first dose interruption will be presented graphically 
using Kaplan-Meier methodology. Patients who did not have a dose reduction will be censored 
at the date of the last dose of study drug. Summary statistics of time to first dose 
reduction/interruption will be presented for patients with at least one dose reduction/interruption. 
All information relevant to drug administration will be listed using safety set.
3.2.6
Concomitant therapy
Concomitant therapies are defined as any medications (excluding study drugs, 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 ATC classification system. Surgeries or procedures will be
coded using the latest MedDRA terminology prior to database lock. All summaries will be 
tabulated using frequency counts and percentages.
Concomitant therapies will be summarized by ATC class and PT. Surgeries and medical
procedures will be summarized by primary system organ class and PT. These summaries will 
include 


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
medications/surgeries and medical procedures starting on or after the start of study treatment
but starting no later than 30 days after last dose of study treatment, and

medications/surgeries and medical procedures starting prior to the start of study treatment
but continuing after the start of study treatment.
All concomitant therapies and surgeries and medical procedures will be listed. Any concomitant
therapies/surgeries and medical procedures starting and ending prior to the start of study 
treatment or starting more than 30 days after the last date of study treatment will be flagged in 
the listing. 
3.2.7
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 using frequency counts and
percentages.
Antineoplastic medications initiated after discontinuation of study drug will be summarized and
listed by ATC class and PT.
Antineoplastic radiotherapy and surgery information since discontinuation of study treatment
will be summarized and listed.
3.2.8
Pharmacokinetic evaluation – primary analysis of the trial
The primary objective is to characterize the PK profile of LDK378 in Chinese adult patients 
with ALK-rearranged NSCLC previously treated with crizotinib following single and multiple 
once daily oral doses of LDK378. 
Extensive PK assessment consisting of pre-dose trough PK, sparse post-dose PK as well as
intensive PK sampling during the 5-day PK run-in period and Cycle 2 Day 1 will be collected
in the first 15 enrolled patients to obtain approximately 12 evaluable full PK profiles. Separated 
from this subset of patients with extensive PK assessment, sparse post-dose PK samples will be 
collected on Cycle 1 Day 1, Cycle 1 Day 8 and Cycle 2 Day 1, in addition t o pre-dose trough 
PK in the rest of the enrolled patients. 
Only PK trough plasma concentrations with non-missing date and time and for which the last 
prior dose date and time are non-missing will be included in the PK analysis. Unscheduled 
samples are not included in summary analysis. These samples will be flagged in the 
corresponding concentration listing.
For patients with extensive PK data, the following PK parameters of LDK378 will be calculated 
from the individual concentration-time profile obtained from serial PK samples (see Table 3-
1). The non-compartmental method will be used with the aid of using Phoenix WinNonlin 
(Version 6.2 - Pharsight, Mountain View, CA).
Among the parameters, Cmax, Tmax, AUC0-24h, AUClast and AUCinf are considered as 
primary; and the following are considered secondary: T1/2, T1/2, acc, Lambda_z, Racc, CL/F
(or CLss/F at steady state), Vz/F.


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Table 3-2
Noncompartmental pharmacokinetic parameters
Parameter
Descriptor
Primary or 
Secondary
AUClast
The area under the concentration-time curve from time 
zero to the last measurable concentration time
(ng*h/mL)
          Primary
AUC0-24h
The area under the plasma concentration-time curve 
calculated from time zero to 24 hours (ng*h/mL)
         Primary
AUCinf
The area under the plasma concentration- time curve 
from time zero to infinity (ng*h/mL)
          Primary
Cmax
The observed maximum plasma concentration following 
administration  (ng/mL)
Primary
Tmax
The time to reach peak or maximum concentration (h)
Primary
Lambda_z 
Terminal elimination rate constant (1/h)
        Secondary
T1/2 
Elimination half-life determined as 0.693/lambda_z (h)
        Secondary
T1/2,acc 
The effective half-life determined according to Racc (h)
       Secondary
Racc
Accumulation ratio calculated using AUCtau, ss/AUCtau, 
sd where tau is the dosing interval 
Secondary
CL/F
The total body clearance from plasma (L/h).  CLss/F is 
calculated from AUCtau assuming steady state (CLss/F
= Dose/AUCtau) (L/h)
Secondary
Vz/F
The apparent volume of distribution during the terminal 
elimination phase (L)
        Secondary
Note: the above pharmacokinetic parameter nomenclature follows Novartis internal guidance 
[DMPK R0900136]
LDK378 concentrations
Summary statistics, including n, mean, SD, CV for mean, geometric mean, CV for geometric 
mean, median, minimum and maximum, will be tabulated for concentration versus time profile 
of LDK378 using PAS. This will be done separately for patients in PK run-in with extensive 
PK assessment and the rest of the patients with sparse PK sampling. The PK concentration 
versus time profiles of LDK378 will also be displayed graphically for full PK profile and trough
collections.
PK concentration data will be listed using FAS.
LDK378 PK parameters
Primary and secondary PK parameters except Tmax will be summarized using the same 
reporting approach as for LDK378 concentrations. For Tmax, median, minimum and maximum 
will be presented.
Using FAS, the PK parameters will be presented in listings.
Trough concentration 
Evaluable concentrations at the following time points will be used: pre-dose samples (in either 
a full profile, or as a single pre-dose collection), 24h on C1D1 (for sparse assessment), and 24h 
on C2D1 for patients with extensive PK data.


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The trough concentration obtained throughout the study will be plotted separately for patients 
in PK run-in with extensive PK assessment and the rest of patients with sparse PK sampling. 
Only time points with n≥4 observations will be shown in the figure.
No model based analyses will be conducted. 
Average steady state (SS) Ctrough
 
 
Steady state trough PK concentration (SS Ctrough) is defined as evaluable trough 
concentrations at steady state. This means both the 15 patients in PK run-in with extensive PK 
assessment and the rest of patients with sparse PK sampling will be considered.
Inter/Intra patient variation
The intra-patient and inter-patient variations will be evaluated using data from patients with 
more than one steady state evaluable trough PK measurements. The intra-patient and inter-
patient variations will be estimated using random effects model with patient as random effect.
 
 
 


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Handling of concentrations below LLOQ or missing
Concentration values below the lower limit of quantitation (LLOQ) (< 1.0 ng/mL) will be 
displayed in listings as zero with a footnote to explain and handled as zero in calculations of 
summary statistics except for geometric means and associated CVs where they will be set to 
missing. Any missing PK parameter data will not be imputed.
3.2.9
Safety evaluation
All safety analyses will be performed based on the Safety Set.
Grouping for the analyses
Safety summaries will include data from the following three mutually exclusive segments:

Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study treatment.

On-treatment period: 

For discontinued patients, from day of first dose of study drug to 30 days after last 
dose of study drug

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 during the on-treatment period, unless 
otherwise specified. For select items, shift tables or change from baseline summaries generated 


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for laboratory, ECG, vital signs and change score generation may use data from pre-treatment 
period for baseline calculations. 
All data, regardless of observation period, will be listed and assessments collected in pre-
treatment and post-treatment period will be flagged in all the listings.
3.2.9.1
Adverse events (AEs)
Summary tables for AEs will include only AEs observed during the on-treatment period. 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 does not exist 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 Phase Disposition”, “Post-treatment Phase Completion” or “Death” eCRF 
pages.
All AE summaries will be summarized (frequency counts and percentages) by SOC and/or PT, 
maximum severity grades (based on CTCAE 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. 
Deaths reportable as SAEs and non-fatal SAEs will be listed by patient. AEs leading to study 
discontinuation and AEs requiring dose adjustment or interruption will be listed separately. 
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 or study drug interruption

AEs requiring dose adjustment

AEs requiring study drug interruption

AEs requiring concomitant medication or non-drug therapy 

AEs excluding SAEs

On-treatment deaths and serious adverse events by primary SOC and PT

Non-serious adverse events (threshold = 5%) by primary SOC and PT
Adverse events of special interest
AESIs are defined as AEs within the following categories/ groupings of PTs:

Hepatotoxicity

Interstitial lung disease/Pneumonitis


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
QTc prolongation

Hyperglycemia

Bradycardia

GI toxicity (including nausea, diarhea, vomiting)

Pancreatitis (including lipase or amylase increases)
AESIs are also referred to as clinically notable adverse events (CNAEs) in the protocol. CNAEs 
are defined at the project level and may be updated based on emergent data to reflect new 
CNAEs of interest at the time of analysis. The CNAEs listed above will be identified based on 
a list of PTs. Both the final categories of AESI and the list of preferred terms should refer to the 
Case Retrieval Strategy at the time of database lock, which will be finalized in a separate 
document. These CNAEs will be summarized for each grouping, by PT, as follows:

All CNAEs

CTC grade 3/4 CNAEs

CNAEs suspected to be study drug related

Serious CNAEs

CNAEs leading to study drug discontinuation 

CNAEs requiring dose adjustment or study drug interruption. 

CNAEs requiring dose adjustment

CNAEs requiring study drug interruption
3.2.9.2
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 no later than 30 
days after study drug discontinuation. All laboratory assessments will be listed and those 
collected in post-treatment period 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. The CTC grade 0 will be assigned as below in different 
scenarios:  

For lab parameters defined by criteria based on normal range only, a severity grade of 0 will 
be assigned when the value is within normal limits.   

For lab 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. 

For lab 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 lab values with missing baseline grading, the 
grade will be derived using the criteria based only on the normal range as per CTCAE v4.03. 


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A severity grade of 0 will be assigned when the post-baseline value is ≤ ULN (for  hyper) 
or ≥ LLN (for hypo).

For CTC grades of glucose (fasting or non-fasting), glucose fasting values will be used. For 
glucose non-fasting values, Grade 1 or 2 will be reassigned to Grade 0.
Grade 5 will not be used. 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) , white 
blood cell (WBC), platelet counts , absolute basophils, absolute eosinophils, absolute 
monocytes, red blood cells(RBC)

Biochemistry: alkaline phosphatase (ALP), alanine aminotransferase (ALT) , aspartate 
aminotransferase (AST), total bilirubin, amylase, potassium , sodium, creatinine, 
glucose(fasting), phosphate, albumin, calcium (corrected for albumin), magnesium, 
creatinine clearance, direct bilirubin, blood urea nitrogen (BUN) or urea, lipase, Gamma 
glutamyl transferase (GGT)
For bi-directional parameters, both hyper and hypo summaries will be presented. 

Hormones (males only): Testosterone, LH, FSH, sex hormone binding globulin (SHBG).
In addition, for hematology and biochemistry parameters, a summary table with frequency 
counts and percentages of patients of new and worsen abnormalities based on CTC grade will 
be presented.
The following laboratory parameters will be presented in listings and will not be summarized:

Urinalysis: macroscopic panel (dipstick) (bilirubin, blood, glucose, ketones, WBC, nitrite, 
pH, protein, specific gravity, urobilinogen), Urinalysis Microscopic panel (RBC, WBC, 
casts, crystals, bacteria, epithelial cells).

Coagulation: INR, pro-thrombin time (PT) or Quick Test
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.
Liver function tests (LFTs) of interest for LDK378 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:


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
TBILI ≤ 2xULN, TBILI > 2xULN and missing TBILI

ALT ≤ 3xULN, ALT > 3xULN and missing ALT

AST ≤ 3xULN, AST > 3xULN and missing AST

ALP <2xULN, ALP ≥2xULN and missing ALP

Frequency counts and percentages of patients with worst post-baseline on-treatment 
values in the categories:

ALT > 3xULN, ALT > 5xULN, ALT > 10xULN, ALT > 20xULN

AST > 3xULN, AST > 5xULN, AST > 10xULN, AST > 20xULN

AT > 3xULN, AT > 5xULN, AT > 10xULN, AT > 20xULN

TBILI > 2xULN

Concurrent ALT > 3xULN and TBILI > 2xULN

Concurrent AST > 3xULN and TBILI > 2xULN

Concurrent AT > 3xULN and TBILI > 2xULN 

Concurrent AT > 3xULN and TBILI > 2xULN and ALP < 2xULN

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.
3.2.9.3
ECGs
ECG data will be analysed based on central reading. The summaries will include all ECG 
assessments performed no later than 30 days after the last date of study drug.  All ECG 
assessments will be listed, and those collected 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 
3 RR
QT
QTcF
    
where RR represents the RR interval of the ECG, in seconds.  


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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, 
^
b , to correct QT

Corrected QT for heart rate will be computed as follows:
QTcP = QT + 
^
b * (1- RR)
Log-linear regression method:

Fit a model Loge(QT) = a + b * Loge(RR) to baseline data 

Use the estimated slope, 
^
b , to correct QT

Corrected QT for heart rate will be computed as follows:
bˆ
RR
QT
QTcLogP 
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 one of QTcP or QTcLogP.
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 RR, QTc (QTcB, QTcF and, if applicable, one of QTcP 
or QTcLogP) and RR 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:           

QT parameter (QT, QTc) increase from baseline >30 ms,  >60 ms

Newly occurring post-baseline QT parameter > 450 ms, > 480 ms, > 500 ms

HR increase from baseline > 25% and value > 100 bpm

HR decrease from baseline > 25% and value < 50 bpm

PR increase from baseline > 25% and value > 200 ms


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
Newly occurring post-baseline PR > 200 ms and ≤220 ms, > 220 ms

QRS increase from baseline > 25% and value > 110 ms

Newly occurring post-baseline QRS > 110 ms and ≤ 120 ms, > 120 ms
The denominator to calculate percentages for each category is the number of patients at risk 
for a specific category. For new abnormality post baseline, the denominator is the number 
of patients with both a baseline and a post-baseline evaluation and baseline not meeting the 
criterion. 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 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, the corresponding notable values and abnormality findings.
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.
3.2.9.4
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), 
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 for baseline and change from baseline to worst post-
baseline value for each vital sign measurement.
Patients with at least one clinically notable vital sign abnormalities will be listed. All vital sign 
assessments will be listed by patient and vital sign parameter.
In the listings, clinically notable values will also be flagged.
WHO performance status
ECOG performance scale is provided in Table 3-2 and is used to assess physical health of 
patients, ranging from 0 (most active) to 5 (dead):
Table 3-3
WHO performance 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 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
Shift tables of WHO performance status at baseline to worst post-baseline WHO status by score
will be presented; shift tables of ECOG performance status at baseline to best post-baseline 
ECOG status by score will also be provided. WHO performance status at each time point will 
be listed.
3.2.10
Efficacy evaluation
All efficacy analyses will be performed based on the FAS, unless otherwise specified. 
3.2.10.1 Overall response rate – key secondary objective
The key secondary objective in this study is to evaluate anti-tumor activity of LDK378 in term 
of ORR as assessed by the investigator per RECIST 1.1. ORR is defined as the proportion of 
patients with a best overall confirmed complete response (CR) or partial response (PR) per 
RECIST 1.1.
Best overall response
The best overall response 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. Best overall confirmed 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.


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
PR = at least two determinations of PR or better at least 4 weeks apart before progression
(and not qualifying for a CR).

SD = at least one SD assessment (or better) > 6 weeks after start of treatment (and not
qualifying for CR or PR).

PD = progression ≤12 weeks after 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 progression within the first 12 weeks)
Confirmed partial or complete responses 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. Unconfirmed PR and unconfirmed CR are considered as stable 
disease (SD) if > 6 weeks after start of treatment, otherwise considered as unknown. Patients 
who are of unknown clinical response will be treated as non-responders.
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 
the assessment of best overall response. Further anti-neoplastic therapies will be identified via 
protocol deviations or from the data collected on ‘Anti-neoplastic therapies since
discontinuation of study drug’ as appropriate. Clinical deterioration will not be considered as 
documented disease progression. Patients with best overall response ‘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 (<= 6 weeks after start date of study drug)

PD too late (> 12 weeks after start date of study drug)
Special (and rare) cases where best overall response is ‘unknown’ due to both early SD and late 
PD will be classified as ‘SD too early’.
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 calculations. 
The analysis of ORR will be performed on the FAS. The ORR will be estimated and the 95% 
confidence interval (CI) based on the exact binomial distribution will be provided.
Supportive Analyses
The supportive analyses will be based on BIRC assessment of ORR for FAS. The analys is of 
ORR will also be repeated using PPS. 
Concordance/discordance of best overall response between BIRC and investigator assessments 
will be summarized and also presented in detail by listings. Waterfall plots representing the best 
percentage change from baseline in the sum of the tumor measured diameters for target lesions 
will be produced.


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3.2.10.2 Other secondary efficacy objectives 
The other secondary efficacy objectives are:

To evaluate DOR, DCR, TTR, OIRR and PFS both by investigator assessment and BIRC 
assessment

To evaluate ORR and OIRR by BIRC 

To evaluate OS
Duration of Response
Among patients with a confirmed response (PR or CR) per RECIST 1.1 by investigator, DOR 
is defined as the time from first documented response (PR or CR) to the date of first documented 
disease progression or death due to any cause. If a patient has not had an event, DOR is censored 
at the date of last adequate tumor assessment.
The censoring and event date options to be considered for the DOR analysis follow those for 
PFS below.
DOR will be described in tabular and graphical format using Kaplan-Meier methods including 
estimated median (in months) with 95% CI, 25th and 75th percentiles (Brookmeyer and Crowley 
1982, Klein and Moeschberger 1997) and Kaplan-Meier estimated probabilities with 
corresponding 95% CIs (Kalbfleisch and Prentice 1980) at several time points (including at 
least 3, 6, 9, 12, 15 and 18 months). 
Refer to Section 4.2.3.3 for further details regarding derivation of Kaplan –Meier estimates.
Disease control rate
DCR, defined as the proportion of patients with best overall response of CR, PR, SD, or Non-
CR/Non-PD per RECIST 1.1 by investigator will be estimated and the 95% CI (Clopper & 
Pearson, 1934) based on the exact binomial distribution will be provided.
Time to response
Time to overall response of CR or PR (TTR) is defined as the time from start of study drug to 
first documented response (CR or PR, which must be confirmed subsequently) for patients with 
a confirmed CR or PR. 
TTR will be summarized in 2-month intervals using descriptive statistics. The analysis will be 
performed based on investigator assessment.
Progression-free survival
PFS is defined as the time from the date of first dose of study drug to the date of the first
documented disease progression per RECIST 1.1 by investigator, or death due to any cause. 
If a patient has not progressed or is not known to have died at the date of analysis cut-off or has 
received any anticancer therapy other than study drug, PFS will be censored at the date of the 
last adequate tumor evaluation before the cut-off date or before the start of the new anticancer
therapy date, whichever is earlier. Clinical deterioration will not be considered as a qualifying


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event for progression. Refer to Table 3-3 for censoring and event date options and outcomes for 
PFS.
In particular, PFS will be censored at the last adequate tumor assessment if one of the following 
occurs: absence of event; the event occurred after a new anticancer therapy is given; the event 
occurred after two or more missing tumor assessments (see Section 4.2.1). See also Section 
4.2.1 describing the special case of a missing baseline tumor assessment.
PFS will be described in tabular and graphical format using Kaplan-Meier methods as described 
for DOR, including estimated median (in months) with 95% CI, 25th and 75th percentiles and 
Kaplan-Meier estimated probabilities with corresponding 95% CIs at several time points 
(including at least 3, 6, 12, 18 and 24 months). Censoring reasons will also be summarized (see 
Section 4.2.1)
Table 3-4
Outcome and event dates for PFS and DOR analyses
Situation
Date
Outcome
A
No baseline assessment
Date of first dose of 
study drug a
Censored
B
Progression at or before next scheduled
Assessment
Date of progression
Progressed
C1
Progression or death after exactly one
missing assessment
Date of progression (or 
death)
Progressed
C2
Progression or death after two or more
missing assessments
Date of last adequate 
assessment 
Censored
D
No progression
Date of last adequate 
assessment 
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
Date of last adequate 
assessment 
Censored
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
In addition, summary tables of PFS by brain metastasis at baseline status (presence vs. 
absence) will be generated by investigator and BIRC assessment respectively. 
Overall survival
OS is defined as the time from the first dose of study drug to the date of death due to any cause. 
If the patient is alive at the date of the analysis cut-off or lost to follow-up, then OS will be 
censored at the last contact date prior to data cutoff date (see Section 4.1.4 for further details on 
derivation of last contact date).
OS will be described in tabular and graphical format using Kaplan-Meier methods as described 
for DOR, including estimated median (in months) with 95% CI, 25 th and 75th percentiles and 
Kaplan-Meier estimated probabilities with corresponding 95% CIs at several time points 


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(including at least 3, 6, 12, 18 and 24 months). Censoring reasons (‘Alive’ or ‘Lost to follow-
up’) will be summarized. Patients not known to have died will be censored for ‘Lost to follow-
up’ if the time between their last contact date and the analysis cut-off date is longer than four 
cycles  plus 2 weeks, i.e., 18 weeks for this study.
Overall intracranial response rate 
OIRR is calculated based on response assessments in the brain for patients 1) having both 
measurable and/or non-measurable brain metastases at baseline (i.e. at least one target/and or 
non-target lesion in the brain); 2) having measurable brain metastases at baseline (i.e., at least 
one target lesion in the brain). OIRR is defined as the proportion of patients with a best overall 
confirmed response of CR or PR in the brain, as assessed per RECIST 1.1 by the investigator. 
OIRR will be estimated and the 95% CI based on the exact binomial distribution will be 
provided. For details on the OIRR calculations see section 4.2.4.
The following analyses will be performed:

Best overall intracranial response per investigator assessment (Full analysis set -
Patients with measurable and/or non-measurable disease in the brain at baseline as per 
investigator review)

Best overall intracranial response per investigator assessment (Full analysis set –
patients with measurable disease in the brain at baseline as per investigator review)
Supportive analyses
DOR, DCR, TTR, PFS and OIRR will also be assessed by BIRC using the same analytical 
conventions as analysis by investigator assessment and serve as the basis of supportive analysis.
Duration of Follow-up and Gap Analyses
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. 
Summaries will also be tabulated for the gap time for PFS/OS follow-up compared to the cutoff 
date.  Gap analysis is the summary of gap time (months) for PFS/OS follow-up as compared to
cut-off date. Gap time for PFS/OS is defined as follows

For patients who are censored regardless of follow-up status, 
Gap time = (data cut-off date – censoring date)/30.4375 (months).


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
For patients who completed study phase or prematurely discontinued from the study due to 
certain reasons e.g. withdraw consent, lost to follow-up,
Gap time = (min(data cut-off date, study discontinuation date)- censoring date)/30.4375  
(months).

For 
patients 
who 
are 
censored 
but 
still 
in 
follow-up,
Gap time = (data cut-off date – censoring date)/30.4375 (months).
Quartiles, minimum and maximum as well as the frequency count and percentage of patients in 
each of <4, 4-<8, 8-<12, 12-<18, ≥18 months will be reported for PFS and OS gap time for 
patients who were censored. 
All summaries will be reported in months (see Section 4.1.5). The calculations for PFS will be 
based on investigator assessment. Date of censoring is the same as defined for the PFS and OS 
analysis. 


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3.2.12
Interim analysis
An interim analysis will be performed after the first 30 patients enrolled have completed at least 
4 cycles of treatment with LDK378 or have discontinued earlier. The interim analysis will focus 
on full pharmacokinetics profile, safety and preliminary efficacy data listed as below. For 
details on the extent of interim analysis, please refer to appendix 1 List of output for interim 
analysis

Pharmacokinetics: A statistical analysis will be performed on the PK data. Plasma 
concentration of LDK378 and PK parameters will be summarized and listed.

Safety: all adverse events observed by the data cutoff date will be summarized and listed.
Separate summaries will be provided for SAE and death, respectively. Abnormal results on 
laboratory assessment and ECG will be presented and listed in detail.

Efficacy: ORR observed by the data cutoff date will be estimated with corresponding
binomial exact 95% CI.  
3.3
Section 9.7.2 Sample size calculation
Overall approximately 100 patients will be enrolled This sample size was deemed to be 
adequate to assess safety, and tolerability and demonstrate the anti-tumor activity of LDK378 
in Chinese patients.
The first 15 patients being enrolled in the phase I component will have a 5-day PK run-in period 
so to obtain approximately 12 evaluable PK profiles. 
3.4
Power for analysis of key secondary variables
With a total of 100 patients, if the observed ORR (key secondary endpoint) is 45% (45
responders in 100 treated patients), this will results in an exact binomial 90% CI of [36.5%, 
53.7%].


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4
Appendix 16.1.9 of CSR- Documentation of statistical 
method
4.1
Statistical methods
The statistical methodologies used are described and discussed in Section 9.7 of the CSR. In
Section 16.1.9, details of the statistical methods and their justification are provided for the 
statistical reviewers.
All analyses will be performed using SAS® Version 9.4 (or later version if available at time of 
database lock).
4.1.1
Difference between SAP and protocol
Not applicable.
4.1.2
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 report. For these 
events, the end date will not be imputed and therefore will not appear in the listings.
For patients known to have died prior to or on 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 have the end date 
imputed to the death date. 

This approach applies, in particular, to AEs and concomitant medication report. For these 
events, the imputed end date 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 treatment after the cut-off date), the end date 
will be imputed to the min (cut-off date, death date, 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.
4.1.2.1
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.


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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:

Missing AE start dates

AE start dates missing the year

Partial/missing AE end dates
The following Table 4-1 explains the abbreviations used.
Table 4-1
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 4-2 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 4-2
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 4-3 is the legend to the above table.
Table 4-3
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 4-4 gives a few examples.
Table 4-4
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
4.1.2.2
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.
4.1.2.3
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. 
If the imputed first recurrence date is after recent recurrence date, use the recent recurrence date 
as first recurrence.


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If the imputed recent recurrence date is before the first recurrence, use the first recurrence date 
as the most recent recurrence.If both first recurrence and recent recurrence are imputed and the 
imputed first recurrence is after the recent recurrence, then use the imputed recent recurrence 
as the first recurrence date.
4.1.2.4
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 
treatment -1’.
End date:
Imputed date = min (start date of study treatment, last day of the month), if day is missing;
Imputed date = min (start date of study treatment, 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 treatment + 1, first day of the month), if day is 
missing;
Imputed date = max (last date of study treatment + 1, 01JAN), if day and month are missing.
End date: No imputation
4.1.2.5
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. 


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4.1.2.6
Incomplete date for death or last contact
All dates must be completed with day, month and year.
If the day or month is missing, death will be imputed to the maximum of the full (non-imputed)
last contact date (excluding the date of death) and the following:

Missing day:
15th day of the month and year of death

Missing day and month:
July 1st  of the year of death
If the day is missing from the date of last contact it will be imputed to 15th day of the month and 
year of last contact only if derived from the survival page.
4.1.2.7
Incomplete dates for disease progression on Crizotinib prior to the 
start of study drug. 
If day of progression associated with the ‘Prior Antineoplastic Therapy – Crizotinib’ page is 
missing then the imputed PD date is:
= min (midpoint between the end date of the prior crizotinib medication and the end of the 
month, start date of LDK), if end date of prior crizotinib medication is in the same month 
as the PD date. 
=  min (15th of the month of the PD date, start date of LDK), if end date of prior crizotinib 
medication is in a month prior to the PD date. 
= 15th of the month of the PD date, if end date of crizotinib medication is in a month after 
the PD date. 
If both day and month of progression associated with the ‘Prior Antineoplastic Therapy –
Crizotinib’ page is missing then the imputed PD date is:
= min (midpoint between the end date of the prior crizotinib medication and the end of the 
year, start date of LDK) if end date of prior crizotinib medication is in same year as the PD 
date
= min (July 1 of the year of the PD date, start date of LDK), if end date of prior crizotinib 
medication is in a year prior to the PD date. 
= July 1 of the year of the PD date, if end date of prior crizotinib medication is in a year 
after the PD date. 
Completely missing PD dates will not be imputed. For the midpoint calculation, if odd days in 
between (e.g last dose of criztonib is 27 June 2012, and end of the month is 30 June 2012), then 
use the next day from the midpoint calculation (e.g midpoint is 29 June 2013). 
4.1.2.8
Incomplete dates for last dose of study drug
Scenario 1 
If the last date of study drug is after the cut-ff 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


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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 date, death date)
= Last day of the month, if both Year and Month are available and Year = Year of min (EOT 
date, death date) and Month < the month of min (EOT date, death date)
   = min (EOT 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.
4.1.3
Laboratory data
This section provides further detail on the laboratory parameters that will be listed and 
summarized as described in Section 3.2.9.2.
Hematology
Hematologic tests include: a complete blood count (CBC) consisting of RBCs, a total white 
blood cell count (WBC) with differential (total neutrophil [including bands], lymphocyte, 
monocyte, eosinophil, and basophil counts), hemoglobin, and platelet count.
The following rules will be applied to derive the WBC differential counts when only 
percentages are available (this is mainly important for neutrophils and lymphocytes, because
the CTC grading is based on the absolute counts).
The method to convert the value is straightforward: for each subject, the original lab value (%)
is divided by 100 and multiplied by the 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

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


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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.
4.1.4
Last contact date
The last contact date is used for censoring in the OS analyses and 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 (blood draws (laboratory, PK), vital signs, performance status, 
, ECG, tumor assessments)

Start and end dates of antineoplastic therapies administered after study treatment
discontinuation.

AE start and end dates

Last date of contact collected on the ‘Survival information’ eCRF (do not use if answer to 
question ‘Is subject alive ?’ is ‘Unknown’)

Study drug start and end dates

Date of discontinuation on the ‘End of Treatment Phase Disposition’ and/or the “End of 
post-treatment phase disposition” eCRFs.
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 derive the last contact date.
4.1.5
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.
4.1.6
Dose interruptions and dose changes
This section provides additional details to those included in Section 3.1.1.4.
All calculations of dose interruptions and dose changes are based on the dose actually taken by 
the patient.
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.

For the first 15 patients who are planned to receive a single dose on the first day of the PK 
run-in period, the rest four days of PK run-in period will not be counted as an interruption. 

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 
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 


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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.
Dose reductions are a subset of dose changes where dose changes to higher than protocol 
planned dose are excluded.
4.2
Efficacy endpoints 
For further details on efficacy endpoints, see Section 14 (Appendix II) of the protocol. For the 
evaluation of tumor-response related endpoints, response is assessed by investigator and BIRC 
according to RECIST 1.1.
Response and progression evaluation will be performed according to the Novartis RECIST 1.1 
guidelines, included in Section 14 (Appendix II) of the LDK378A2109 protocol.
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Sections 3.2.10
4.2.1
Implementation of RECIST guidelines
Disease progression
PD should only be assigned if it is confirmed by an objective assessment method as per RECIST 
1.1 (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 best overall response, 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 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology will 
result by default in a UNK (unknown) overall lesion response assessment. 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. 
However, a response assessment other than the Novartis calculated UNK response may be 


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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, 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. 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 II) of the LDK378A2109 protocol, 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
3: Withdrew consent
4: Adequate assessment no longer available
5: Initiation of new cancer therapy
6: Event after >=2 missing tumor assessments
PFS censoring reason is then derived by the following sequence of rules. 
-
If patient is considered to have a PFS event then PFS censoring reason is set to missing.
-
Else if patient has had no baseline assessment then PFS censoring reason = 4


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-
Else if patient has a PFS event after two or more missing assessments (If (PFS Event 
date <= Censoring date and (PFS Event date - Date of LATA) >= D2)) then 
CNSRREAS=6:
-
Else if patient has no PFS event, and patient is censored at a date after two or more 
missing assessments ((Censoring date - Date of LATA) >= D2) then CNSRREAS = 4
-
Else if censoring date equals the start date of further anti-neoplastic therapy 
(NWTHYDT) then CNSRREAS = 5
-
Else if Censoring date equals date of discontinuation due to consent withdrawal 
(IFCWDDT) then CNSRREAS = 3
-
Else if Censoring date equals date of discontinuation due to loss to follow-up 
(LOSFUDT) then CNSRREAS = 2
-
Else if the Censoring date equal the analysis cut-off date and the time between  LATA 
and the cut-off is greater than D2 days then CNSRREAS = 4
-
Else if the Censoring date equal the analysis cut-off date and the time between  LATA 
and the cut-off is less than or equal to D2 days then CNSRREAS = 1
Where min date = minimum of non-missing (analysis cut-off date, start date of further anti-
neoplastic therapy, date of withdrawal of consent, date of discontinuation due to loss to follow-
up)
Non-measurable disease at baseline
As specified in Section 14 (Appendix II) of the LDK378A2109 protocol, the RECIST 1.1 
criteria imply that only patients with measurable disease at baseline 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. These patients will be included in analyses 
based on FAS including patients with either measurable or non-measurable disease and will be 
excluded from the analyses based on PPS.
As specified in Table 14-8 of Section 14 (Appendix II) of the LDK378A2109 protocol, overall 
lesion response can be derived for patients without measurable disease at baseline.
Missing baseline tumor assessment
As specified in Table 14-9 of Section 14 (Appendix II) of the LDK378A2109 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 date of treatment start. 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 treatment start 
date 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 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.  A footnote will explain the reason for excluding some patients (due to absence 
of any valid assessment).
All possible assessment scenarios are described in Table 4-5.
Table 4-5
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


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growth take the assessment where the growth is minimal. (Example 1: Patient 1 has the 
following % 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. 
Both BIRC assessment and investigator assessment will be used in the construction of the 
waterfall plot.
The recommended way of the display from left to right is:
1. Bars under the horizontal axis representing tumor shrinkage
2. Bars above the horizontal axis representing tumor growth
3. “Zero” bars with symbol representing patients with contradiction
4. ‘#’ below or above the vertical bars represent patients with a PFS event.
4.2.2
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 4-6.
Table 4-6
Sources for overall lesion response 
Source 1
Investigator (local radiology) reported overall lesion response
Source 2
BIRC (Blinded Independent review committee) reported overall lesion
Response
In this study, Source 1 will be used for the key secondary endpoint (ORR) derivation and other 
secondary endpoint calculations per investigator (DOR, DCR, TTR, OIRR and PFS).
For secondary endpoints based on BIRC assessment (ORR and OIRR), Source 2 will be used 
for the endpoint derivation. 
4.2.3
Kaplan-Meier estimates
To analyze time to event variables (PFS, OS, DOR and TTR), an estimate of the survival 
function will be constructed using Kaplan-Meier (product-limit) method as implemented in 
PROC LIFETEST with METHOD=KM option (see example below). The median time to event 
and estimated event rates at different time points will be estimated, along with associated 95%
two-sided CIs derived based on the complementary log-log transformation. This will be
conducted via the SAS procedure LIFETEST. 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;


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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 [Collett, 1994] for the standard error 
of the Kaplan-Meier estimate.
The Kaplan-Meier curves, medians and Kaplan-Meier estimates with 95% CIs at specific time
points will also be displayed.
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) 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 9.1, it should be 
explicitly shown.
The Kaplan-Meier graphs will be constructed using SAS software.
4.2.4
OIRR calculations in patients with measurable brain metastases
A patient with measurable brain metastases at baseline is defined as a patient having at least 1
target lesion in brain. Inclusion of response assessments based on lesion locations in the brain
for each assessment (including baseline to identify whether patients have measurable brain
metastases) uses the following list of terms collected based on investigator and BIRC tumor
data: brain lesions, brain (multiple, right frontal, left temporal left parietal ) , brain metastases 
(occipital, multiple, bilateral diffuse, bilateral cerebral, cerebellum), CNS, cerebellum, cerebral 
cortex (frontal, occipital, parietal or temporal).The following steps will be taken to calculate the 
best overall intracranial response (BOIR) for patients with measurable brain metastases at 
baseline:
1. If only target lesions in brain and no non-target lesions in brain are identified at baseline,
calculate the longest diameter from all lesions in the brain (selected from list above), and
new lesions in brain (if any, based on the list) to derive responses per assessment. Non-
target lesion response status is not considered since no non-target lesions were identified in 
the brain at baseline.
2. If both target and non-target lesions in the brain are identified at baseline, calculate the
longest diameter from all lesions in the brain (selected from list above), use all non-target


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lesions response status in the brain (selected from list above) and new lesions in the brain
(if any, based on the list) to derive responses per assessment.
3. For each assessment, derive overall intracranial response.
4. For the whole set of derived overall intracranial responses, calculate BOIR.
For this subset of patients, calculate OIRR.
4.2.5
Confidence intervals
ORR/DCR/OIRR 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 & Pearson,1934).
SAS procedure FREQ will be used to estimate the proportion of responders (binary outcome = 
1 or “Yes”), along with the associated 95% two-sided Pearson-Clopper CI. These estimates are 
obtained as follows:
PROC FREQ DATA = dataset;
     TABLE binary event /
     binomial(p = null proportion level = “Yes”)
     alpha = 0.05;
     EXACT binomial;
RUN;
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” (%)
 
 
 
 
 
 
 


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4.4
PK analyses
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Section 3.2.8 .
The random effects model with subject as random effect will be used to estimate the intra-
patient and inter-patient variation. The following SAS code will be used:
PROC MIXED data = pk dataset;
     CLASS subject;
     MODEL log_ Ctrough = / ddfm=kr solution;
     RANDOM subject;
Run;
/* log_Ctrough refers to log transformed SS Ctrough concentration */
The inter-patient CV% for SS Ctrough will be calculated as:
CV%=sqrt(exp(variance estimate for random patient effect from SS Ctrough model)-1)*100
The intra-patient CV% for SS Ctrough will be calculated as:
CV%=sqrt(exp(residual variance from SS Ctrough model)-1)*100
 
     
     
 
 
 
 
     
 
 
Additional details for derivation of PK analysis set and parameters:
When deriving the PK analysis set, flags will be generated for evaluable full PK profile and 
evaluable sparse PK sample, as well as for each individual criterion under evaluable full PK 
profile and evaluable sparse PK sample (see Section 3.1.3). 
When presenting figures and concentration summaries associated with full PK profile, the flag 
for evaluable full profile should be used; when presenting sparse PK samples related outputs, 
the flag for evaluable sparse sample should be used. A patient is evaluable for PK analysis if 


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he/she has an evaluable full PK flag or an evaluable sparse PK sample flag.  In addition, 
evaluable trough sample flag and evaluable steady state trough sample flag will also be provided 
for trough samples and steady state trough sample, respectively. The evaluability criteria are
the same as that for a sparse sample. 
Evaluable full PK profile flag should be applied to run-in patients with extensive PK collection 
on the PK run-in Day 1 (from 0 hour to 120 hr post-dose sample), and C2D1 (from 0 hr to 24 
hr post-dose). 
Evaluable sparse PK sample flag should be applied to PK samples collected on:

C1D8, C1D15, C3D1 to C6D1 for run-in patients

all PK samples collected as per Table 7-7 in protocol for non run-in patients

0  hour pre-dose for PK run-in day 1and  C2D1 for run-in patients

120 hr post-dose for PK run-in day 1 and 24 hr post-dose for C2D1 for run-in patients
Evaluable trough sample flag should be applied to trough samples collected on 

all 0 hour pre-dose samples

120 hr post-dose in run-in for run-in patients (it is also 0 hr pre-dose on C1D1 for run-in 
patients)

24 hr for C2D1 for run-in patients (it is also 0 hr pre-dose on C2D2 for run-in patients)

24 hr on C1D1 for non run-in patients (it is also 0 hr pre-dose on C1D2)
4.5
First Interpretable Results
4.5.1
First interpretable results for Interim analysis 
There will be a database lock following the first 30 patients enrolled have completed at least 4 
cycles of treatment with LDK378. First interpretable results (FIR) are the most important 
statistical outputs to be delivered after this database lock. For this study, FIR at interim analysis 
will include: 

Table of demographics and other baseline characteristics

Table of patient disposition

Table of analysis sets

Table of disease history 

Table of prior antineoplastic therapy overall and on crizotinib

Table of duration of exposure and relative dose intensity.Table of summary of PK 
concentrations for LDK378

Table of summary of PK parameters for LDK378 

Figure of geometric mean and arithmetic mean (SD) trough concentration-time profiles for 
LDK378


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
Figure of geometric mean and arithmetic mean (SD) concentration-time profiles for 
LDK378 

Overall summary of adverse events

Adverse events (at least 10%), regardless of study drug relationship, by preferred term and
maximum grade (Safety set)

SAE and death information provided in text

Table of ALT, AST, ALP and total bilirubin abnormalities

Table of notable ECG values

Best overall response per investigator assessment
4.5.2
First interpretable results for primary analysis 

Table of demographics and other baseline characteristics

Table of subject disposition

Table of analysis sets

Table of disease history 

Table of Prior antineoplastic therapy overall and on Crizotinib

Table of duration of exposure and relative dose intensity

Table of summary of PK parameters for LDK378

Figures of geometric mean and arithmetic mean (SD) trough concentration-time profiles 
for LDK378

Figure of geometric mean and arithmetic mean (SD) concentration-time profiles for 
LDK378 

Overall summary of adverse events and clinically notable AEs

Adverse events (at least xx%), regardless of study drug relationship, by preferred term and 
maximum grade

SAE and death information provided in text

Table of ALT, AST, ALP and total bilirubin abnormalities

Table of notable ECG values

Best overall response per investigator and BIRC assessment

Best overall intracranial response and duration of response per investigator and BIRC 
assessment

Progression free survival per investigator and BIRC assessment 

Summary of Summary of duration between start of treatment and cut-off date, and follow-
up time for long-term outcomes
5
Reference:
Gehan EA, George SL (1970) Cancer Chemother Rep  54:225-235
Allison PD (2000). Survival analysis using the SAS system. Cary, NC, SAS Institute Inc.


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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.
Collett D (1994). Modelling survival data in medical research. London, Chapman & Hall.
Dmitrienko A et al. (2005). Analysis of clinical trials using SAS. SAS Institute Inc., SAS press.
Fayers PM et al., on behalf of the EORTC Quality of Life Group (2001). The EORTC QLQ-
C30 Scoring Manual (3rd Edition). Published by: European Organisation for Research and 
Treatment of Cancer, Brussels.
FDA (2007). Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs 
and Biologics, US Department of Health and Human Services.
Hollen, PJ, Gralla, RJ, Kris, MG (1995). Lung Cancer Symptom Scale (LCSS): Administration, 
Scoring, and Procedures Manual.
Kalbfleisch JD, Prentice RL. (2002) The Statistical Analysis of Failure Time Data. Wiley Series 
in Probability and Statistics.


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Appendix 1: List of output for interim analysis
Tables

Patient disposition – screening phase (Full analysis set)

Patient disposition – treatment and post treatment phase (Full analysis set)

Protocol deviations by deviation category (Full analysis set)

Analysis sets (Full analysis set)

Demographics (Full analysis set)

Disease history (Full analysis set)

Prior antineoplastic therapy- Overall (Full analysis set)

Prior antineoplastic therapy – Crizotinib (Full analysis set)

Prior antineoplastic therapy – Radiotherapy (Full analysis set) 

Summary of best overall response per investigator assessment (Efficacy analysis set)

Reasons for best overall response equal to unknown per investigator assessment(Efficacy 
analysis set)

Summary of 
PK concentrations of LDK378 by time point in PK run-in patients
(Pharmacokinetic analysis set)

Summary of PK concentrations of LDK378 by time point in non PK run-in patients 
(Pharmacokinetic analysis set)

Summary of primary PK parameters for  LDK378 (Pharmacokinetic analysis set)

Summary of secondary PK parameters for LDK378 ((Pharmacokinetic analysis set)

Duration of exposure to study drug (Safety set)

Dose changes and dose interruptions of study drug (Safety set)

Summary statistics of exposure of study drug (Safety set)

Biochemistry laboratory values: shift table based on CTC grade (Safety set) 

New or worsened biochemistry abnormalities based on CTC grade (Safety set)

Shift tables for ALT, AST, Alkaline phosphatase and Total bilirubin (Safety set)

Summary of ALT, AST, Alkaline, phosphatase and Total bilirubin abnormalities (Safety 
set)

Change from baseline in ECG intervals by study day and time point  (Safety set)

ECG shift table based on notable values (Safety set)

Number and percentage of patients with notable ECG changes from baseline (Safety set)

Summary of newly occurring ECG abnormalities (Safety set)Adverse events, regardless of 
study drug relationship, by primary system organ class,  preferred term,and maximum grade
(Safety set)


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
All and grade 3/4 adverse events, regardless of study drug relationship, by preferred term
(Safety set)

On-treatment deaths, by primary cause, by primary system organ class and preferred term
(Full analysis set) 

Adverse events, suspected to be study drug related, by primary system organ class, preferred 
term and maximum grade (Safety set) 

All and grade 3/4 adverse events, suspected to be study drug related, by preferred term
(Safety set)

Serious adverse events, regardless of study drug relationship, by primary system organ class ,
preferred term and maximum grade (Safety set) 

Adverse events leading to study drug discontinuation, regardless of study drug relationship,
by primary system organ class, preferred term and maximum grade (Safety set)

Adverse events requiring dose adjustment or study drug interruption , regardless of study 
drug relationship, by primary system organ class, preferred term and maximum grade 
(Safety set) 

Overall summary of Adverse events (Safety set)

Clinically notable adverse events (Safety set)
Figures:

Geometric mean and arithmetic mean (SD) trough concentration-time profiles for LDK378
in PK run-in patients (Pharmacokinetic analysis set)

Geometric mean and arithmetic mean (SD) trough concentration-time profiles for LDK378
in non PK run-in patients (Pharmacokinetic analysis set)

Geometric mean and arithmetic mean (SD) concentration-time profiles for LDK378
(Pharmacokinetic analysis set) 
Listings: 

Tumor assessments and responses per investigator assessment (Full analysis set)Deaths 
(Full analysis set)

Serious adverse events (Safety set)

Adverse events leading to study drug discontinuation (Safety set)

Adverse events requiring dose adjustment (Safety set)

Adverse events requiring dose interruption (Safety set)

Clinically notable adverse events (Safety set)

Patients with laboratory abnormalities of CTC Grade 3 or 4 (Safety set) 

Treatment and study completion (Full analysis set)

Protocol deviations (Full analysis set)

Patient demographics (Full analysis set)


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
Disease history and baseline characteristics (Full analysis set)

Prior antineoplastic therapy – Radiotherapy (Full analysis set) 

Prior antineoplastic therapy – Medications (Full analysis set)

Dose administration records for study drug (Safety set)

Plasma PK concentration for LDK378 (Full analysis set)

PK parameters for LDK378 by time point(Full analysis set)

Adverse events (Safety set)

Hematology: primary hematology variables (Safety set)

Hematology: WBC and differentials (Safety set)

Biochemistry: Liver function tests and related variables (Safety set)

Biochemistry: renal variables (Safety set)

Patients with worst post-baseline total bilirubin > 2xULN and ALT>3xULN( Safety set)

ECG intervals per patients (Safety set)

ECG findings (Safety set)