Clinical trial NCT01685138
Conditions: Non-Small Cell Lung Cancer
Keywords: Non-Small Cell Lung Cancer Non small cell lung carcinoma NSCLC ALK LDK378 Ceritinib crizotinib naïve adult patients ALK-activated non-small cell lung cancer treatment of lung cancer after first metastasis lung cancer lung adenocarcinoma
Sponsor: Novartis Pharmaceuticals
Start date: 2012-12-20; Completion date: 2018-01-22
Enrollment: 124 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A single-arm, open-label, two-stage multicenter, phase II study. Patients were pre-screened for ALK positive status. Treatment with LDK378 at 750 mg qd was continued until the patient experienced unacceptable toxicity that precluded further treatment, discontinued treatment at the discretion of the investigator or patient, started a new anticancer therapy and/or died. LDK378 was continued beyond RECIST defined progressive disease (PD) as assessed by the investigator, if in the judgment of the investigator, there was evidence of clinical benefit. Patients who discontinued the study medication in the absence of progression continued to be followed for tumor assessment until the time of PD as assessed by the investigator. Male and female patients aged 18 or over with ALK-rearranged non-small cell cancer (NSCLC) were screened for eligibility. Patients had to have received no prior crizotinib, and had to be chemotherapy-naïve or been pretreated with cytotoxic chemotherapy (up to three prior lines).

Detailed description:

Arms: arm 1: Participants on this arm took oral LDK378 750 mg once daily.
Interventions: intervention 1: LDK378
Intervention descriptions: intervention 1: LDK378/Ceritinib was supplied as 150 mg hard gelatin capsules and administered orally

Protocol documents:
Prot_000.pdf: 
Clinical Development
LDK378
Clinical Trial Protocol CLDK378A2203 / NCT01685138
A phase II, multicenter, single-arm study of oral LDK378 in 
crizotinib naïve adult patients with ALK-activated non-small 
cell lung cancer
Authors
 
Document type
Amended Protocol Version 
EUDRACT number
2012-003474-36
Version number
04 (Clean)
Development phase
II
Document status
Final
Release date
11-Dec-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............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary..............................................................................................................11
Amendment 4 ....................................................................................................................14
Amendment 3 ....................................................................................................................15
Amendment 2 ....................................................................................................................18
Amendment 1 ....................................................................................................................20
1
Background........................................................................................................................24
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............24
1.1.1
Locally advanced or metastatic non-small cell lung cancer 
(NSCLC) ...............................................................................................24
1.1.2
Targeted therapies in NSCLC ...............................................................24
1.1.3
ALK positive NSCLC...........................................................................25
1.2
Introduction to investigational treatment(s) and other study treatment(s).............26
1.2.1
Overview of LDK378 ...........................................................................26
1.3
Risks and benefits..................................................................................................33
2
Rationale............................................................................................................................36
2.1
Study rationale and purpose...................................................................................36
2.2
Rationale for the study design ...............................................................................37
2.3
Rationale for dose and regimen selection..............................................................38
3
Objectives and endpoints...................................................................................................38
4
Study design ......................................................................................................................41
4.1
Description of study design ...................................................................................41
4.2
Tumor sample requirements ..................................................................................42
4.2.1
Archival tissue.......................................................................................43
4.2.2
New biopsies .........................................................................................43
4.2.3
Tumor samples analyses .......................................................................43
4.3
Definition of end of the study................................................................................44
4.4
Early study termination..........................................................................................45
5
Population..........................................................................................................................45
5.1
Patient population..................................................................................................45
5.2
Inclusion criteria ....................................................................................................46


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5.3
Exclusion criteria...................................................................................................47
6
Treatment...........................................................................................................................50
6.1
Study treatment......................................................................................................50
6.1.1
Dosing regimen.....................................................................................50
6.1.2
Guidelines for continuation of treatment ..............................................51
6.1.3
Treatment duration................................................................................51
6.1.4
Definition of treatment cycle ................................................................52
6.2
Dose modifications................................................................................................52
6.2.1
Dose modification and dose delay ........................................................52
6.2.2
Treatment interruption and treatment discontinuation..........................52
6.2.3
Criteria for LDK378 dose modifications ..............................................53
6.2.4
Follow-up for toxicities.........................................................................59
6.3
Concomitant medications ......................................................................................63
6.3.1
Permitted concomitant therapy .............................................................64
6.3.2
Prohibited concomitant therapy ............................................................65
6.4
Patient numbering, treatment assignment or randomization .................................67
6.4.1
Patient numbering .................................................................................67
6.4.2
Treatment assignment or randomization...............................................67
6.4.3
Treatment blinding................................................................................67
6.5
Study drug preparation and dispensation...............................................................67
68
68
6.5.3
Study drug compliance and accountability ...........................................68
6.5.4
Disposal and destruction .......................................................................69
7
Visit schedule and assessments .........................................................................................69
7.1
Study flow and visit schedule................................................................................69
7.1.1
Pre-screening.........................................................................................75
7.1.2
Screening...............................................................................................75
7.1.3
Treatment period...................................................................................76
7.1.4
Discontinuation of study treatment .......................................................77
7.1.5
Follow-up period...................................................................................78
7.1.6
Lost to follow-up...................................................................................78
7.2
Assessment types...................................................................................................79
7.2.1
Efficacy assessments.............................................................................79
7.2.2
Safety and tolerability assessments.......................................................82
86


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88
7.2.5
Resource utilization...............................................................................89
89
8
Safety monitoring and reporting........................................................................................90
8.1
Adverse events (AEs) ............................................................................................90
8.1.1
Definitions and reporting ......................................................................90
8.1.2
Laboratory test abnormalities................................................................91
8.1.3
Adverse events of special interest.........................................................92
8.2
Serious adverse events...........................................................................................92
8.2.1
Definitions.............................................................................................92
8.2.2
Reporting...............................................................................................92
8.3
Emergency unblinding of treatment assignment ...................................................93
8.4
Pregnancies............................................................................................................93
8.5
Warnings and precautions......................................................................................93
8.6
Data Monitoring Committee (DMC).....................................................................94
8.7
Steering Committee (SC).......................................................................................94
9
Data collection and management.......................................................................................94
94
9.2
Site monitoring ......................................................................................................95
95
96
10 Statistical methods and data analysis ................................................................................97
10.1
Analysis sets ..........................................................................................................97
10.1.1
Full Analysis Set ...................................................................................97
10.1.2
Safety Set ..............................................................................................97
10.1.3
Per-Protocol Set ....................................................................................97
98
10.2
Patient demographics/other baseline characteristics .............................................98
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................98
10.4
Primary objective...................................................................................................98
10.4.1
Variable.................................................................................................98
10.4.2
Statistical hypothesis, model, and method of analysis..........................98
10.4.3
Handling of missing values/censoring/discontinuations.......................99
10.4.4
Supportive analyses...............................................................................99
10.5
Secondary objectives .............................................................................................99
10.5.1
Key secondary objective(s)...................................................................99


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10.5.2
Other secondary efficacy objectives ...................................................100
10.5.3
Safety objectives .................................................................................100
102
102
103
104
10.7
Interim analysis....................................................................................................104
10.8
Sample size calculation........................................................................................105
10.9
Power for analysis of key secondary variables....................................................105
11 Ethical considerations and administrative procedures ....................................................105
11.1
Regulatory and ethical compliance......................................................................105
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................105
106
11.4
Discontinuation of the study................................................................................106
11.5
Publication of study protocol and results.............................................................106
107
107
11.8
Audits and inspections.........................................................................................108
11.9
Financial disclosures............................................................................................108
12 Protocol adherence ..........................................................................................................108
12.1
Amendments to the protocol................................................................................108
13 References (available upon request)................................................................................109
14 Appendices ......................................................................................................................111
 
112
114


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List of figures
Figure 1-1
Waterfall plot of reduction in sum of longest tumor diameters ............31
Figure 4-1
Study design..........................................................................................44
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: 
).....................29
Table 1-2
Study CLDK378X2101 Response Rate................................................31
Table 3-1
Objectives and related endpoints ..........................................................39
Table 6-1
Dose and treatment schedule.................................................................50
Table 6-2
Dose reduction steps for LDK378.........................................................53
Table 6-3
Criteria for interruption and re-initiation of LDK378 treatment...........54
Table 6-4
Follow-up evaluations for selected toxicities........................................59
.67
.68
Table 7-1
Visit evaluation schedule ......................................................................70
Table 7-2
WHO performance status scale.............................................................83
Table 7-3
Clinical laboratory parameters collection plan .....................................84
86
87
Table 10-1
Operating characteristics of Simon’s optimal two-stage design.........105
 
 
112
112
113
113


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List of abbreviations
AE
Adverse event
ALCL
Anaplastic large cell lymphoma
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
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
AUCtau
Area under the plasma (serum, or blood) concentration versus time curve from time zero to end 
of dosing period
AUClast
Area under the concentration-time curve from time zero to the last measurable concentration 
time
BIRC
Blinded Independent Review Committee
BLRM
Bayesian logistic regression model
CI
Confidence interval
CL
Clearance
DBP
Diastolic blood pressure
Cmax
Maximum (peak) concentration of drug in plasma
Cmin
Minimum (trough) concentration of drug in plasma
CMV
Cytomegalovirus
CNS
Central nervous system
CR
Complete response
CRO
Contract Research Organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DCR
Disease control rate
D
Entered into database
DILI
Drug Induced Liver Injury
DLT
Dose limiting toxicity
DMC
Data Monitoring Committee
DOR
Duration of response
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
EOT
End of treatment
FAS
Full analysis set
FDA
Food and Drug Administration
FISH
Fluorescent in situ hybridization
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice


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GGT
Gamma-glutamyl transpeptidase 
HA
Health Authorities
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
IUD
Intrauterine device
IUS
Intrauterine system
IV
Intravenous(ly)
IEC
Independent Ethics Committee
ILD 
Interstitial Lung Disease
IRB
Institutional Review Board
LFT
Liver function test
LH
Luteinizing hormone
LLN
Lower limit of normal
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
N/A
Not applicable
NCCN
National Comprehensive Cancer Center
NSCLC
Non-small cell lung cancer
OIRR
Overall intracranial response rate
ORR
Overall response rate
PD
Progressive disease
PFS
Progression-free survival
PI
Principal investigator
PK
Pharmacokinetics
PPS
Per-protocol set
PR
Partial response
QTc
Corrected QT interval
QTcF
Corrected QT interval using Fridericia formula
QD
quaque diem/once daily
R value
ALT/ALP in x ULN
Racc
Accumulation ratio
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analysis
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


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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 semi logarithmic 
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
Vss
Plasma volume of distribution
VATS
Video-assisted thoracic surgery
VEGF-A
Vascular endothelial growth factor-A
WHO
World Health Organization


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biological samples
A biological specimen including , for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study subject or study patient
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (eg, q 21 days)
Enrollment
Point/time of patient entry into the study; the point at which informed consent must 
be obtained (ie, 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”
Subject 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
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, completion of treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has spread 
from the original site to other parts of the body
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study drug 
was discontinued whichever is later
Study drug
Any drug administered to the patient as part of the required study procedures; 
includes investigational drug and any combination or control drug(s)
Study drug discontinuation
Point/time when patient permanently stops taking study drug for any reason; 
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 
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Protocol summary
Protocol number
CLDK378A2203
Title
A phase II, multicenter, single-arm study of oral LDK378 in crizotinib naïve adult 
patients with ALK-activated non-small cell lung cancer
Brief title
LDK378 in non-small cell lung cancer patients with ALK rearrangements who are 
crizotinib naïve
Sponsor and Clinical 
Phase
Novartis, Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
ALK+ NSCLC patients have only crizotinib as an effective ALK targeted treatment 
option and therefore novel ALK targeted therapies with activity against ALK+ NSCLC 
are needed.
The available data indicate that LDK378 has substantial antitumor activity in patients 
with ALK rearranged NSCLC
Primary Objective and 
Key Secondary 
Objective(s)
Primary objective: To demonstrate the antitumor activity of LDK378, as measured by 
overall response rate (ORR) to LDK378 by investigator assessment
Key secondary objectives: To evaluate response related endpoints as assessed by 
investigator and blinded independent review committee (BIRC): duration of response 
(DOR), disease control rate (DCR), time to response (TTR), overall intracranial 
response rate (OIRR); and to assess ORR by BIRC assessment
Secondary Objectives
Objective 1: To evaluate the safety profile of LDK378
Objective 2: To evaluate progression-free survival (PFS)
Objective 3: To evaluate overall survival (OS)
Study design
This is a single-arm, open-label, two-stage multicenter, phase II study. Patients will be 
pre-screened for ALK positive status. Treatment with LDK378 at 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 as assessed by the investigator, if in the judgment of the investigator, 
there is evidence of clinical benefit. In these patients tumor assessment should 
continue as per the schedule of assessments until treatment with LDK378 is 
permanently discontinued. Patients who discontinue the study medication in the 
absence of progression will continue to be followed for tumor assessment until the 
time of PD as assessed by the investigator.
The study will use a Simon’s optimal two-stage design. Stage 1 will consist of 43 
patients and their data up to 6 cycles of treatment unless a patient has discontinued 
treatment earlier or a confirmed response to treatment has been observed prior to 
completing 6 cycles. The trial will be stopped at Stage 1 if 16 or fewer responses are 
observed. If at the time that the last patient is enrolled to Stage 1 a minimum of 17 
responses have not yet been observed, accrual may be temporarily suspended during 
the analysis of Stage 1. Stage 2 will include an additional 62 patients. The primary 
analysis will occur when all 105 patients have completed 6 cycles of treatment or 
discontinued treatment earlier.
Population
Male and female patients aged 18 or over with ALK-rearranged NSCLC. Patients 
must have received no prior crizotinib, and must be chemotherapy-naïve or have 
been treated with cytotoxic chemotherapy (up to 3 prior lines).


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Inclusion criteria

Histologically or cytologically confirmed diagnosis of stage IIIB or IV NSCLC that 
carries an ALK rearrangement, as per the FDA-approved Vysis ALK break-apart 
FISH assay (Abbott Molecular Inc.).

Age 18 years or older at the time of informed consent.

Patients must have stage IIIB or IV NSCLC.

Patients may have received up to 3 lines of cytotoxic chemotherapy to treat their 
stage IIIB or IV NSCLC

Patients who have been treated with chemotherapy must have progressed during 
or after the last chemotherapy regimen received prior to the first dose of LDK378

Patients must have a tumor tissue sample available, preferably being a new biopsy 
but otherwise being an archival sample collected either at the time of diagnosis of 
NSCLC or any time since, for assessing ALK rearrangements using the FDA-
approved Vysis ALK break-apart FISH assay.

Patients must have recovered from all toxicities related to prior anticancer 
therapies to grade ≤ 2, except 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.
Exclusion criteria

Prior treatment with crizotinib, or any other ALK inhibitor investigational agent, for 
NSCLC

Patients with known hypersensitivity to any of the excipients of LDK378.

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.

History of carcinomatous meningitis.

Presence or history of a malignant disease other than NSCLC that has been 
diagnosed and/or required therapy within the past 3 years.

Clinically significant, uncontrolled heart disease.
Investigational and 
reference therapy
LDK378
Efficacy assessments
Tumor assessment by RECIST 1.1 as evaluated by investigator and by a BIRC
Safety assessments

Hematology, biochemistry, urinalysis, coagulation, pregnancy test and hormones 
(males only)

ECG

Performance status

Vital signs

Adverse events
Other assessments

Trough and sparse PK


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Data analysis
The cut-off date for the primary analysis of this trial will be the time when all 105 
patients have completed 6 cycles of treatment or have discontinued treatment. The 
ORR per RECIST 1.1 by investigator assessment and by BIRC assessment will be 
estimated and the 90% confidence interval (CI) provided. If the true ORR is 50% 
(under the alternative hypothesis), approximately 105 patients are required to reject 
the null hypothesis of ORR ≤ 35% with a one-sided alpha of 0.05 based on Simon’s 
optimal two-stage design. If 45 or more responses are seen in 105 total patients 
(estimated ORR of 42.9%), then the null hypothesis will be rejected and the trial 
declared positive. If the study is terminated early at the end of Stage 1, then the study 
will be considered to have failed to reject the null hypothesis. The uniformly minimum 
variance unbiased estimator (UMVUE) and the 90% CI from 
Atkinson and Brown (1985) will also be presented.
DOR will be listed by patient and may be described using Kaplan-Meier methods and 
relevant statistics if appropriate. DCR and OIRR will be estimated and the 90% CI 
provided. TTR, PFS, and OS will be described using Kaplan-Meier methods and 
appropriate summary statistics.
Adverse events and laboratory abnormalities will be summarized and listed.
Key words
ALK, NSCLC, LDK378


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Amendment 4
Amendment rationale
As of the release date of this amendment the recruitment has been completed and 132 patients 
have been screened to the study. A total of 124 patients have been treated.
This amendment has been implemented to:

Update the protocol to include follow up evaluations for hepatic toxicities and work-up 
guidelines for potential Drug Induced Liver Injury (DILI) cases in order to optimize the 
patient safety.

Update the dose guidance modification for QTcF text to provide clarification on 
monitoring procedure.

Update the guidance related to corticosteroids use

Update of the definition of the End of Study

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 font for insertions.
The following sections were changed:

List of abbreviations updated with commonly used abbreviations such as R value, TBIL, 
DILI, EBV, CMV, and HSV

Section 4.3: the definition of the End of Study has been updated to allow patients’ 
transition to othe clinical studies or to patient support programs 

Section 6.2.4.2: updated guidelines to monitor liver abnormalities for patients with 
transaminase increase combined with total bilirubin (TBIL) increase which may be 
indicative of potential DILI

Table 6-3: updated dose modification guidelines to monitor Grade 3 QTc prolongation 

Section 6.3.1.1: updating corticosteroide use guidance and wording on increasing doses of 
corticosteroids use has been removed.

Section 8.2.2: Updated reporting instructions. 

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. 


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Amendment 3
Amendment rationale
As of the release date of this amendment the recruitment has been completed and 132 patients 
have been screened to the study. A total of 124 patients have been treated.
This amendment has been implemented to include availability of new safety data as presented 
in the Investigator’s Brochure and to clarify sections of the protocol where additional 
guidance was required:

Update of safety data in the protocol to match the Investigator’s Brochure Edition 7 
(released on 12 Jun 2014). The associated Informed Consent Form (ICF) has been updated 
separately to this protocol

Update of the LDK378 dose modification and follow up of toxicities in case of elevations 
of pancreatic enzymes (lipase and/or amylase) 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 

An evaluation of the anticipated benefits and risks has been added to the protocol to 
comply with EU clinical trial regulations. 

Revision of sections 7.1.4, 7.1.5 and 7.1.6 related to study discontinuation to bring 
clarification and additional guidance regarding study treatment discontinuation and 
withdrawal of consent 
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 font for insertions.
The following sections were changed:

List of abbreviations updated with commonly used abbreviations such as GGT, ILD and 
NCCN

Glossary of terms updated with definitions for biological samples, study drug 
discontinuation and withdrawal of consent

Section 1.2.1.2.1: clinical safety and tolerability data updated to reflect data most recently 
available from ongoing study CLDK378X2101

Section 1.2.1.1.3, Section 6.3.1.2: Updated nonclinical PK and metabolism data from 
recent studies. Evaluation of DDI potential was re-conducted for NDA submission. Using 
the 2012 FDA Draft Guidance “Drug Interaction Studies – Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations” and the 2012 EMA “Guideline 
on the Investigation of Drug Interactions,” the mechanistic static model determined that 


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the inhibitory potential of LDK378 is low for CYP2C8 and CYP2B6 (AUCR <1.25). As 
such, the sentence regarding LDK378 being a potent reversible inhibitor of CYP2C8 and 
CYP2B6 was removed

Section 1.2.1.2.4: updated to reflect the most recently available food effect study data  

Section 1.3: added new section “Risks and benefits”

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

Section 6.2.2: section updated with instructions that guidelines for follow-up of study drug 
related AEs or abnormal laboratory values must be followed as described in Section 6.2.4

Section 6.2.3: clarification that dose reductions will be in 150 mg decrements per 
reduction and that once the dose of LDK378 has been reduced due to toxicity, it should 
not be re-escalated

Table 6-3: updated to reflect the most recently available data where criteria for 
interruption and re-initiation of LDK378 treatment are now less stringent (such as 
allowing maintenance of dose level in the case of neutropenia Grade 3 and elevated 
ALT/AST Grade 2), while for other criteria, more stringent dose modifications have been 
introduced (such as for elevated ALT/AST Grade 2 and concurrent total bilirubin >2.0 
xULN, pneumonitis all grades and QTC prolongation Grade 3). Criteria for interruption 
and re-initiation of LDK378 treatment for bradycardia, hyperglycemia and pancreatitis has 
been added to Table 6-3

Section 6.2.4.2 and Table 6-4: updated guidelines to monitor liver abnormalities for 
patients with baseline liver metastases and  elevated ALT/AST Grade 2 

Section 6.2.4.3: addition of guidelines for the follow-up of laboratory pancreatic 
abnormalitiesTable 6-4: addition of follow-up evaluations for pancreatic toxicities

Section 6.2.4.6: updated safety data for hypophosphatemia

Section 6.2.4.8: addition of guidelines for anticipated risks and safety concerns for the 
study treatment

Section 6.3.1.1: clarification added when increasing doses of corticosteroids are used

Section 6.3.1.2: updated CYP450 drug interactions with LDK378

Section 6.3.1.4: updated with LDK378 dosing guidance in association to radiotherapy and 
surgical resection in order to align with program level language

Section 6.3.2.1: addition of targeted therapy to other anticancer therapies 

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

Section 6.3.2.8: updated with most recent data on QTc prolongation from ongoing study 
CLDK378X2101  

Section 7.1.4: The title of the section is changed to reflect updated guidance on how to 
follow subjects who discontinue study treatment, either some or all of the visits, withdraw 
consent or are lost to follow-up

Section 7.1.4.2: added new section ‘Withdrawal of consent‘

Section 7.1.6: added new section ‘Lost to follow–up‘ 


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
Section 4.1 and 7.2.1.2: deletion of the start of new anti-cancer therapy as an allowable 
reason to stop collecting tumor assessments to enable sensitivity analysis of PFS following 
a pure intent-to-treat principle where start of new antineoplastic therapy does not result in 
censoring for PFS

Table 7-3:clinical laboratory parameters collection plan upated with lipase

Section 8.1.3: updated with the list of adverse events of special interest

Section 13: update to the list of references

Appendix 14.1: table title for prohibited concomitant medications requiring caution has 
been updated with a notation for LDK378, deletion of CYP2C8 substrates and paclitaxel, 
and updated footnotes for clarification

Appendix Table 14-2: list of medications to be used with caution updated with deletion of 
CYP2B6 and CYP2C8 substrates, clarithromycin and telithromycin

Editorial and typographical changes throughout the document as required
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. The changes herein affect the Informed Consent. Sites are required to update 
and submit for approval a revised Informed Consent that takes into account the changes
described in this protocol amendment.
Updates to the safety data in the associated Informed Consent Form (ICF) to match the 
Investigator’s Brochure Edition 7 (released on 12 Jun 2014) have been performed separately 
to this protocol on 15 Sep 2014. 


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Summary of previous amendments
Amendment 2
Amendment rationale
As of the release date of this amendment, 57 patients have been screened to the study. 45 
patients have been treated.
This amendment has been implemented to address the availability of new safety data as 
represented in the latest Investigator Brochure, to amend the eligible study population, and to 
clarify sections of the protocol where additional guidance was required:

Addition a secondary endpoint of overall intracranial response rate (OIRR) due to the 
interest in LDK378 activity in the brain

Allowing pre-screening during prior chemotherapy treatment and prior to progression of 
disease

Allowing the enrolment of chemotherapy-naive patients to target the ALK-inhibitors-
naive population regardless of previous chemotherapy

Update of safety data in the protocol and associated Informed Consent Form (ICF) to 
match the Investigator Brochure Edition 4 (release on 28 June 2013).

Change in definition of duration of response (DOR) in response to health authority 
feedback and based on the advanced cancer under study and it being difficult to ascertain 
whether a death is due to the underlying cancer
In addition, editorial changes and text corrections were made for clarification, where required.
This amendment will result in a change to the study population. There is no anticipated 
extension in the duration or release of results of the study.
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 were changed:

Sections 1.2.1.2.1, 1.2.1.2.2 and 2.1: clinical safety and efficacy data updated to reflect 
data most recently available from ongoing studies

Section 1.2.1.2.4: updated with most recent data from clinical pharmacology studies

Sections 1, 5 and 6: Information available on pneumonitis cases reported during LDK378 
treatment to date have been summarized, an exclusion criteria for patients with 
pneumonitis added, and dose modification criteria added for patients who experience 
pneumonitis during the course of the study.

Sections 2.2, 4.1 and 5: study population changed to allow patients who are chemotherapy 
naïve to enter the trial.

Section 3: Changed the definition of duration of response (DOR) from ‘time from first 
documented response (PR or CR) to the date of first documented disease progression or 


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death due to underlying cancer’ to ‘time from first documented response (PR or CR) to the 
date of first documented disease progression or death due to any cause’.

Sections 3 and 10: Secondary endpoint of overall intracranial response rate (OIRR) added
 
 
 
 

Section 5.2: inclusion criteria for potassium, magnesium, phosphorus and total calcium 
changed from requirement to be ≥ LLN to within normal range.

Section 5.3: exclusion criteria updated to specifically disallow patients with uncontrolled 
diabetes mellitus from entry to the trial.

Section 6.1.1: guidance on dosing with LDK378 in relation to food intake has been 
updated to reflect latest data on clinical pharmacology.
 

Section 6.2.3: added guidance that once the dose of LDK378 has been reduced due to 
toxicity, it should not be re-escalated.

Section 7.2.1.1: clarification that all imaging assessments performed in the 6 weeks 
leading up to first dose may be counted as baseline assessments.

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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Amendment 1
Amendment rationale
As of the release date of this amendment, 5 patients have been screened to the study. 3 
patients have been treated.
This amendment has been implemented to address six main items with the original protocol 
released for the study, reflecting the availability of new toxicity data, addressing requests 
from health authorities, and clarifying sections of the protocol where additional guidance was 
required:

To add an ECG assessment for all patients 6 hours after first dose

To provide general guidance on dose modification

To provide guidance on dose modification in response to QTc prolongation

To provide guidance for treatment of hypophosphatemia

To clarify tumor sample collection requirements
In addition, editorial changes and text corrections were made for clarification, where required.
This amendment will result in no change to the study population. There is no anticipated 
extension in the duration or release of results of the study.
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 of the protocol were changed:
In Section 1.1.3, information on ALK positive NSCLC data and regulatory approvals status 
have been updated.
 
In Section 1.2.1.1.4, based on emerging safety data made available, LDK378 may have an 
effect on the QT interval, hence the last sentence regarding “…suggesting that there is no
clinical risk for QTc prolongation” was removed. Additionally data regarding phototoxicity 
was added. 
In Section 1.2.1.2.1, information on hypophosphatemia and QT data was added.
 
 
In Section 4.1, naming of the FDA-approved FISH test has been updated and aligned 
throughout the entire document.


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In Section 4.2, sub-sections have been added to bring clarity to the tumor samples 
requirements. In addition, the new biopsy sampling timing has been corrected to ‘time of 
progression’ instead of ‘end of treatment’.
In Section 4.3, sentence has been added to confirm Novartis will commit to their reporting 
obligations, for patients receiving LDK378 on a separate protocol.
In Section 5.2, in inclusion criteria no 1, 3 and 4, locally advanced or metastatic were replaced 
by Stage IIIb or IV, for clarity purpose. In inclusion criteria no 3, it has been clarified that 
patients must have progressed during or after the last chemotherapy regimen received prior to 
the first dose of LDK378. In addition, in inclusion no 4, cytotoxic chemotherapy definition 
has been slightly corrected to include duration of 21 days. In inclusion no 7, abbreviation for 
Alanine transaminase has been corrected to ALT. An additional inclusion criterion was added 
for laboratory parameters for magnesium, potassium, phosphorus and calcium, and the 
inclusion criteria for creatinine clearance was changed from > 50 mL/min to > 30 mL min to 
allow inclusion of patients with moderate renal impairment . Renal clearance of LDK378 is 
less than 1% in rats and monkeys and in preliminary data from a human ADME study. In 
addition, in the CLDK378X2101 phase I study of over 200 patients, no significant renal 
toxicities were reported, and in the small subgroup of patients with mild renal impairment no 
excess toxicities were noted.
In Section 5.3, exclusion criteria no 5, additional information regarding QTcF calculation has 
been added as it was missing in the original document. In addition, medications with a known 
risk of prolonging the QT interval or inducing Torsades de Pointes has been added as a sub-
bullet in exclusion no 10. Tumor-associated symptoms have been clarified in exclusion no 13.
In Section 6.1.1, meal instructions have been updated to reflect the updated data from food 
effect study.
In Section 6.2.1, general guidelines for dose modifications have been added as per Health 
Authorities request.
In Section 6.2.2, treatment interruption guidance for reasons other than toxicity has been 
added as it was missing from the original document, and treatment interruption guidance for 
toxicity has been updated to be aligned with the treatment schedule of 28 days cycles.
In Table 6-3 and Table 6-4, ‘total’ was added for bilirubin as it was missing from the original 
document. In addition, guidance on dose modification in response to QTc prolongation was 
added as it was missing from the original document. Table 6-4 was moved to the end of 
section 6.2.4.1, to be consistent with the text.
In Section 6.2.4.2, ‘total’ was added for bilirubin as it was missing from the original 
document.
In Section 6.2.4.6, guidance for the treatment hypophosphatemia was added as it was missing 
in the text.
In Section 6.3.1, clarification has been made when corticosteroids are use when used for CNS 
related symptoms.
In Section 6.3.1.5, the use of gastric protection agents has been further clarified.


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In Section 6.3.2, a sub-section has been added regarding medications that may prolong the QT 
interval or have a known risk of inducing Torsades de Pointes.
In Section 6.4.1, the use of the IRT system has been clarified at the screening visit. 
Information has been as well added in regard to the use of the IRT system when the patient is 
enrolled.
In Section 7.1, Table 7-1 was corrected to reflect the current assessments performed as some 
were not captured in the original document.
In Section 7.1.3.2, criteria for patient withdrawal have been clarified to reflect Health 
Authorities’ request.
In Section 7.2.1, it has been specified that Contrast-enhanced CT needs to be performed with 
IV contrast, and that upper abdomen needs to be evaluated. In addition, it is now allowed to 
provide as protocol required baseline scans, the scans that were already completed during the 
regular work-up of the patient within 6 weeks prior to start of treatment and before signing the 
main study ICF.
In Section 7.2.2.5, laboratory evaluations have been re-worded to make the distinction 
between central/local assessments for out-of-schedule assessments and out-of-range 
parameters.
In Section 7.2.2.6, an ECG assessment has been added for all patients 6 hours after first dose. 
Further changes have been done to bring clarity to the section.
In Section 8.4, clarification has been made that patients who become pregnant during the trial 
will be withdrawn from study as requested by Health Authorities, and that pregnancy should 
be followed until 3 months following delivery.
In Section 10, minor changes have been done throughout the section to bring clarity and to 
align with LDK378 program analysis standards. The definition of the per-protocol set was 
changed to include patients who have a follow-up tumor assessment > 7 weeks (rather than 8 
weeks) after starting treatment to take into consideration the +/-1 week window associated 
with tumor assessments; the definition of safety data set was changed to align with the 
LDK378 program standard (now includes all patients who receive at least one dose of study 
drug).
In Section 14 Appendix I, Table 14-1 references have been updated. Table 14-2 has been 
updated with a list of proton pump inhibitors, as it was missing in the original document. In 
addition a new table showing the list of prohibited QT prolonging drugs has been added as per 
Health Authorities request.
Editorial changes were performed throughout the document.


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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). This year, approximately 160,000 deaths are expected in the US 
(Siegel et al 2012) and 262,000 in the European Union (Malvezzi et al 2012).
The World Health Organization (WHO) divides lung cancer into 2 major classes based on its 
biology, therapy, and prognosis: non-small cell lung cancer (NSCLC) and small cell lung 
cancer. NSCLC accounts for more than 85% of all lung cancer cases, and it includes 2 major 
types: (1) non-squamous carcinoma (including adenocarcinoma, large-cell carcinoma, other 
cell types); and (2) squamous cell (epidermoid) carcinoma. Adenocarcinoma (40% of lung 
cancers) is the most common type of lung cancer seen in the United States and is also the 
most frequently occurring cell type in nonsmokers (NCCN Guidelines® v3.2012).
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.
One reason for the high mortality rate of lung cancer is the advanced stage at diagnosis; 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 and they are not candidates for surgery.
As summarized in the current NCCN Guidelines for NSCLC, data show that platinum-based 
combination therapy is superior to best supportive care for patients with advanced, incurable 
disease. Platinum-doublets (cisplatin or carboplatin in combination with other chemotherapy 
agents, with or without bevacizumab) is the standard in first line treatment of locally 
advanced or metastatic NSCLC, unless a patient has a known “druggable” mutation, and is a 
candidate for a targeted therapy (as discussed below). Docetaxel, pemetrexed, erlotinib, or 
platinum doublet (with or without bevacizumab) are recommended as second-line 
chemotherapy regimens for patients who have experienced disease progression during or after 
first-line therapy. The reported response rates to second-line chemotherapy have generally 
been less than 10%. 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 overall survival rate of only 15% (Nguyen et al 2012).
1.1.2
Targeted therapies in NSCLC
During the last few years, improved knowledge of NSCLC biology led to the identification of 
molecular events crucial for malignant transformation and cancer cell survival. These aberrant 
molecular events are critical oncogenic drivers and, therefore, represent potential therapeutic 
targets (Gettinger et al 2011). As a result, new targeted treatment options are evolving. 


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Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor-A 
(VEGF-A), and erlotinib and gefitinib, epidermal growth factor receptor (EGFR) tyrosine 
kinase 
inhibitors 
(TKIs), 
have 
been 
approved 
for 
the 
treatment 
of 
NSCLC 
(Gettinger et al 2011). In particular, the case of epidermal growth factor receptor (EGFR) 
tyrosine kinase inhibitors (TKIs) represents a new paradigm in the treatment of NSCLC. 
Mutations in EGFR are found in 10–26% of NSCLC patients and are associated with response 
to oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and 
erlotinib, and the monoclonal antibody to EGFR, cetuximab (National Cancer Institute PDQ®).
Multiple large randomized clinical trials have demonstrated that patients harboring activating 
EGFR mutations benefit more from EGFR TKIs than from standard chemotherapy in terms of 
response rate, progression free survival, toxicity profile and quality of life (reviewed in 
NCCN Guidelines® v3.2012). 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 positive NSCLC
The discovery of anaplastic lymphoma kinase (ALK) rearrangement in NSCLC in 2007 
(Soda et al 2007) represents another important milestone in the era of molecular targeted 
therapy in NSCLC.
ALK was first identified as a chromosome translocation-produced protein fusion in the 
majority of anaplastic large cell lymphomas (ALCL). When fused to other proteins, ALK 
becomes constitutively active, leading to increased catalytic kinase function, signal-
transduction activity, and oncogenic function. Expression of EML4-ALK - a new fusion 
protein between ALK and the echinoderm microtubule-associated protein-like 4 (EML4) 
gene- in transgenic mice has been shown to induce tumor formation, suggesting the 
therapeutic potential of targeting the EML4-ALK fusion protein in NSCLC (Soda et al 2007). 
The frequency of EML4-ALK rearrangement in patients with NSCLC is relatively low; it is 
present in approximately 2-8% of tumors tested (Scagliotti 2012; Takeuchi 2009; Soda 2007). 
However, considering the high incidence of lung cancer, this small percentage translates into 
about 10,000 patients in the United States alone (Kwak et al 2010).
These patients are similar to those with EGFR mutations (i.e., adenocarcinoma, nonsmokers 
or light smokers) except they are often younger. In addition, ALK rearrangements are found 
in patients with adenocarcinoma but are usually not been found in squamous cell or large cell 
carcinoma (Shaw et al 2009). ALK rearrangements and other oncogenic drivers such as 
mutant EGFR and oncogenic RAS are generally mutually exclusive, consistent with the 
notion that ALK rearrangement defines a unique molecular subset of NSCLC. 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, an orally available small-molecule inhibitor of ALK and MET tyrosine kinases, 
has been rapidly and successfully developed in patients with advanced NSCLC who have 
EML4-ALK rearrangements and have progressed on previous therapy. Crizotinib was 
associated with clinically meaningful response rates of 50% and 61%, respectively, in two 
single-arm trials in 255 patients with locally advanced or metastatic ALK-positive NSCLC 


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(Ou 2011). 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 of 9.78 and 11.22 months, respectively, in each of the studies. Based on these data, 
crizotinib (Xalkori®) received accelerated approval by the US Food and Drug Administration 
in August 2011 for the treatment of ALK-rearranged NSCLC. It has also been approved in 
South Korea, Switzerland, Japan and Canada and received conditional marketing 
authorization in the EU on 23-Oct-2012 for the treatment of adult patients with previously 
treated ALK-positive advanced NSCLC. Retrospective comparison of these data for the 
subset of patients treated in the second-line to ALK-positive positive patients who were 
treated with other second-line chemotherapy suggested an overall survival advantage (median 
OS: not reached versus 6 months, HR=0.36, p=0.004) (Shaw et al 2011).
While crizotinib has substantial activity in patients with ALK rearranged NSCLC, these 
cancers invariably progress, typically within 1 year, because of the development of resistance 
to crizotinib (Ou 2011).
CH5424802 is another ALK inhibitor in clinical development. As opposed to crizotinib, 
CH5424802 is a specific ALK inhibitor. In a phase 1 trial in patients with ALK positive 
NSCLC who have failed prior chemotherapy, but were crizotinib naïve, a response rate of 
85% was reported in 20 patients with measurable lesions (Kiura et al 2012). These data 
highlight the fact that NSCLC harboring ALK rearrangements are responsive to specific ALK 
inhibitors, with a response rate higher to that expected with chemotherapy and at least 
comparable to the response rate obtained after crizotinib. In addition, these data also reaffirm 
that ALK rearrangement represent the key oncogenic driver in these tumors and that specific 
ALK inhibition provides substantial anti-tumor activity.
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. 
LDK378 is an approximately 20-fold more potent ALK inhibitor than crizotinib, it is more 
selective for ALK and does not inhibit MET.
In addition, LDK378 shows potent antitumor activity in crizotinib-resistant animal models.
These features support the hypothesis that LDK378 could be active in NSCLC patients whose 
disease has progressed on crizotinib.
1.2.1.1
Non-clinical experience
1.2.1.1.1 Pharmacology
 
 
 
 


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1.2.1.1.2 Antitumor activity in xenograft models
1.2.1.1.3 Non-clinical pharmacokinetics (PKs) and metabolism


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1.2.1.1.4 Safety pharmacology and toxicology


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1.2.1.2
Clinical experience
1.2.1.2.1 Clinical safety and tolerability
LDK378 is associated with a manageable safety profile (Table 1-1). 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 
 cut-off date was 26.9 weeks (range 0.4 
to 82.3 weeks). The most common AEs regardless of study drug relationship (incidence ≥25%) 
were diarrhea, nausea, vomiting, alanine aminotransferase (ALT) increased, fatigue, 
abdominal pain, decreased appetite, aspartate aminotransferase (AST) increased, and 
constipation. 
The incidence of grade 3-4 AEs, regardless of study drug relationship was <10% for all AEs 
except ALT increased (26.7%) (Table 1-1). The incidence of grade 3-4 AEs, regardless of 
study drug relationship was <5% for all AEs except AST increased (8.2%), diarrhea (5.9%), 
hyperglycemia (5.5%), lipase increased (5.1%), and blood alkaline phosphatase (ALP) 
increased (5.1%).
Table 1-1
All grades (at least 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: 
)
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)


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Preferred term
LDK378
750 mg
N=255
All Grades
Grade 3/4
n (%)
n (%)
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. 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 
5% of patients, consisting of: pneumonia (4 patients), respiratory failure, ILD/pneumonitis, 
pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary 
tuberculosis, cardiac tamponade, and sepsis (1 patient each). Adverse events of special 
interest (AESIs) to be monitored for LDK378 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].
1.2.1.2.2 Clinical efficacy
LDK378 has demonstrated potent antitumor activity in patients with advanced, ALK-
rearranged NSCLC (Shaw et al 2013). Among 114 response-evaluable patients with at least 
18 weeks of follow-up prior to 28 Feb, 2013, or who discontinued study earlier, and were 
treated with LDK378 doses of 400 mg qd or higher, 66 (58%) patients have responded (Table 
1-2). In addition, the response rate to LDK378 is similar regardless of prior ALK inhibitor 
therapy. In patients with NSCLC treated at ≥400 mg qd, who had previously received 
crizotinib, the response rate was 57%, and in those who had not previously received crizotinib 
it was 60%. Post-baseline tumor measurements are available for 104 of the 114 response 
evaluable patients. A waterfall plot displaying the maximum decrease from baseline in the 
sum of the longest tumor diameters (Figure 1-1) shows that the large majority of patients 
treated with LDK378 had a reduction in tumor burden. The median duration of response in 


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patients who responded and were treated at ≥400 mg qd was 8.2 months (95% CI: 6.9, not 
estimable), and 71% had a duration of response of 6 months or longer.
Table 1-2
Study CLDK378X2101 Response Rate
Response rate (RECIST v1.0)
N
CR
n (%)
CR + PR
n (%)
All NSCLC, ≥400 mg/d
114
1 (1)
66 (58)
NSCLC, at 750 mg
78
0
47 (60)
ORR by prior crizotinib treatment
NSCLC prior crizotinib, ≥400 mg/d
79
1 (1)
45 (57)
NSCLC prior crizotinib, 750 mg/d
49
0
29 (59)
NSCLC crizotinib naive, ≥400 mg/d
35
0
21 (60)
NSCLC crizotinib naïve 750 mg/d
29
0
18 (62)
Figure 1-1
Waterfall plot of reduction in sum of longest tumor diameters
The available data from the ongoing phase I study indicate that LDK378 has substantial 
antitumor activity in patients with ALK-rearranged NSCLC whose disease has failed 
crizotinib therapy or who are naïve to crizotinib therapy.
1.2.1.2.3 Clinical pharmacodynamics
Data are not available from the ongoing clinical study.


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1.2.1.2.4 Clinical pharmacokinetics


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1.3
Risks and benefits
Overall benefit-risk 
LDK378 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 LDK378 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 LDK378 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 
, 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, LDK378 fulfills 
an existing unmet medical need.
The efficacy of LDK378 seen in Study [CLDK378X2101] 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.
 
 
 
 
 
Safety
The safety profile of LDK378 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 LDK378 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 LDK378 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 LDK378 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 6.2 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. 
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 LDK378. Patients 
will also 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.


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Detailed information on allowed and prohibited concomitant medications is provided in 
Section 6.3. In vitro drug metabolism studies show that the metabolism of LDK378 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 LDK378. Prohibited 
medications should be discontinued at least 1 week prior to the start of treatment with 
LDK378 (see exclusion criteria #8).
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: cases of hepatotoxicity occurred in less than 1% of patients treated with 
LDK378 in clinical studies. Increases to grade 3 or 4 ALT elevations were observed in 
25% of patients receiving LDK378. 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 LDK378. 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 LDK378 in clinical 
studies. Most cases improved or resolved with interruption of LDK378. 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 LDK378, which may lead to an increased risk for ventricular 
tachyarrhythmias (e.g., Torsade de pointes) or sudden death. A pharmacokinetic analysis 
suggested that LDK378 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 #5).

Bradycardia: asymptomatic cases of bradycardia have been observed in patients treated 
with LDK378 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 LDK378 in clinical studies; 5% of patients reported a grade 3/4 
event. The risk of hyperglycemia was higher in patients with diabetes mellitus and/or 


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concurrent steroid use. Patients will be closely monitored throughout the study for any 
signs and symptoms related to elevated blood glucose levels.

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 
LDK378. Few patients have experienced pancreatitis with severe upper abdominal pain. 
Patients will be monitored closely for any related signs and symptoms.
Conclusion
The outstanding anti-tumor activity and resulting clinical benefit combined with the 
manageable safety profile of LDK378 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 LDK378. 
2
Rationale
2.1
Study rationale and purpose
ALK rearrangement is a relatively rare event in NSCLC with a frequency of 2-8% 
(Scagliotti 2012; Takeuchi 2009; Soda 2007). This rearrangement results in aberrant ALK 
activation. ALK fusion proteins possess potent oncogenic activity both in vitro and in vivo. 
This activity can be effectively blocked by small-molecule inhibitors that target ALK.
The purpose of this phase II study is to evaluate the antitumor activity and safety profile of the 
novel ALK inhibitor LDK378 when used as a single agent in patients with ALK-rearranged 
locally advanced or metastatic NSCLC who have not been pretreated with crizotinib.


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2.2
Rationale for the study design
This is a prospective, multi-center, open-label, single arm, phase II study with two-stage 
design to evaluate the efficacy and safety of single-agent LDK378 in patients with ALK-
rearranged NSCLC not previously treated with crizotinib. Patients may have received up to 
three prior lines of cytotoxic chemotherapy. In such cases, patients must have progressed 
during or after the chemotherapy regimen received prior to the first dose of LDK378. Patients 
will also be eligible for the study if they have never been treated with chemotherapy for their 
NSCLC.
The primary objective is to demonstrate the antitumor activity of LDK378 in this population. 
The primary measure of antitumor activity is the ORR according to RECIST 1.1 and will be 
estimated based on investigator assessment. In addition, there will be an independent 
radiological review by a blinded independent review committee (BIRC). Response rate is an 
appropriate primary endpoint that can be adequately assessed in the context of this single arm 
phase II trial. A high ORR may predict clinical benefit in this rare population of patients with 
ALK-rearranged NSCLC. Indeed, crizotinib was approved by certain Health Authorities in 
this indication based on data from two single arm trials using ORR based on investigator 
assessment as primary endpoint. Data on ORR will be supplemented with data on duration of 
response (DOR) and time to response (TTR).
Based on the data available with LDK378 in crizotinib naïve patients in the ongoing phase I 
study at the time of the study design, the present study will use a two-stage design. The Data 
Monitoring Committee will evaluate the ORR data from Stage 1 and, based on pre-specified 
response criteria (see Section 10.7), will make the recommendation whether to proceed to 
Stage 2 or stop the trial.


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The study will also assess progression-free survival (PFS), overall survival (OS) and impact 
on Patient Reported Outcomes (PROs) with LDK378 treatment. These endpoints are 
considered to be important supportive endpoints to better assess the potential clinical benefit 
of LDK378. In addition an evaluation of the activity of LDK378 on brain metastases will be 
included as a secondary objective in this study.
Safety will be monitored throughout the course of the study.
2.3
Rationale for dose and regimen selection
 
 
 
 
 
 
 
 
 
 
 
 
 
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4.
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 or partial response (CR+PR) 
as assessed by investigator
Key secondary
Refer to Section 10.5.1.
To evaluate response related endpoints as assessed by 
investigator and Blinded Independent Review Committee 
(BIRC):
1.
Duration of response (DOR)
2.
Disease control rate (DCR)
3.
Time to Response (TTR)
4.
Overall intracranial response rate (OIRR)
And to assess:
5. ORR by BIRC assessment
The following endpoints will be evaluated by investigator assessment and 
BIRC 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 death due to any cause
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 
And:
5. ORR (CR+PR) per RECIST 1.1 as assessed by BIRC
Other secondary
Refer to Section 10.5.2.
1.
To evaluate the safety profile of LDK378
2.
To evaluate progression-free survival (PFS)
3.
To evaluate overall survival (OS)
1.
Adverse events and laboratory abnormalities
2.
PFS, defined as time from first dose of LDK378 to progression or death 
due to any cause, as assessed by BIRC and investigator assessment
3.
OS, defined as time from first dose of LDK378 to death due to any cause


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Objective
Endpoint
Analysis


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4
Study design
4.1
Description of study design
This is a single-arm, open-label, two-stage, multicenter, phase II study in which the efficacy 
and safety of LDK378 will be evaluated in patients with locally advanced or metastatic 
NSCLC harboring a confirmed ALK rearrangement, defined as 15% or more positive lung 
tumor cells as assessed by the FDA-approved FISH test (Abbott Molecular Inc.) using Vysis 
break-apart probes.
Overview of the study design
Patients will be pre-screened to test for ALK positivity. The test to confirm ALK 
rearrangement must be performed either using archival tissue or, preferably, using a new 
biopsy prior to study entry according to the above criteria, i.e. with the FDA-approved Vysis 
ALK break-apart FISH assay. The test will be performed at a Novartis designated central 
laboratory.
After confirmation of ALK positivity, the study begins with a screening period to assess 
eligibility, up to and including 28 days prior to the first dose of LDK378.
Patients must not have received prior crizotinib. Patients may have been treated with cytotoxic 
chemotherapy (up to 3 lines). In such cases, patients must have progressed during or after the 
last chemotherapy regimen received prior to the first dose of LDK378. Patients will also be 
eligible for the study if they have never been treated with chemotherapy for their NSCLC.
The study will use a Simon’s optimal two-stage design. Stage 1 will consist of 43 patients and 
their data up to 6 cycles of treatment unless a patient has discontinued treatment earlier or a 
confirmed response to treatment has been observed prior to completing 6 cycles. The trial will 
be stopped at Stage 1 for futility if 16 or fewer responses are observed. If at the time that the 
last patient is enrolled to Stage 1 a minimum of 17 responses have not yet been observed, 
accrual may be temporarily suspended during the analysis of Stage 1. The Data Monitoring 
Committee will periodically review response data and will make the appropriate 
recommendation regarding transition into Stage 2 or stopping enrollment (see Section 8.6).
Stage 2 will include an additional 62 patients. The primary analysis will occur when all 105 
patients have completed 6 cycles of treatment or discontinued treatment earlier. Patients will 
follow the study design shown in Figure 4-1 and have study assessments as described in 
Section 7.
The treatment period begins on Day 1 of Cycle 1. All patients will be treated with LDK378, 
administered orally, at a starting dose of 750 mg. A total of approximately 105 patients will be 
enrolled in the study. Patients will take LDK378 once daily, at approximately the same time 
each day. 
 
 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. If the patient experiences RECIST-defined progressive disease (PD) on LDK378 as 


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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.
Assessments of tumor response and progression will be performed every 8 weeks (i.e. every 2 
cycles), starting from the first day of treatment with LDK378. This schedule of tumor 
assessment every 8 weeks must continue regardless of dose interruptions. Tumor assessment 
should continue until:

For patients who experience PD as assessed by the investigator, tumor assessments should 
continue every 8 weeks until LDK378 is permanently discontinued (i.e. if the patient 
continues treatment with LDK378 after PD, tumor assessments should continue until 
LDK378 is permanently discontinued).

For patients who discontinue treatment in the absence of PD, tumor assessments should 
continue every 8 weeks from the EOT visit until PD is assessed by the investigator.
Tumor evaluations will always cease if the patient withdraws consent (unless the patient 
agrees to continue efficacy assessments in absence of dosing with LDK378, see Section 
7.1.4.1), or dies.
All tumor imaging assessments will be submitted for independent radiological assessment of 
response by a Blinded Independent Review Committee (BIRC).
Clinical and laboratory assessments will be performed as described in Section 7.
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 end of tumor assessments, the Study Phase Completion Disposition eCRF must 
be completed. Patients will be contacted every 3 months to obtain information pertaining to 
survival status until death, loss to follow-up, withdrawal of consent to survival follow-up, or 
the end of the study (as defined in Section 4.3). Patients do not need to visit the clinic during 
the survival follow-up.
4.2
Tumor sample requirements
There are two parts to the tumor sample requirements of the trial:

In order to test ALK status at the molecular pre-screening stage, all patients must have a 
tumor tissue sample available, preferably as a newly obtained tumor biopsy or, if a new 
biopsy is not obtainable or the patient does not agree, an archival tumor biopsy collected 
either at the time of NSCLC diagnosis or any time since. All available tumor tissue, 
whether new biopsy or archival sample, should be sent to the central laboratory at pre-
screening.

If a new biopsy was not collected at molecular pre-screening, patients must be asked at 
screening if they are willing to provide a new tumor tissue biopsy (although participation 
is optional). Consent for this sample must be obtained via the additional optional Informed 
Consent Form (ICF). 
 


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4.2.1
Archival tissue
Acceptable archival tumor tissue may consist of a formalin fixed paraffin embedded (FFPE) 
NSCLC tumor block or at least 7, preferably 15, slides 5 µm thick. If a tumor block is 
provided, the remaining tissue will be returned to the site upon request. Note: Cytology 
samples from pleural fluid can not be used for testing ALK status.
4.2.2
New biopsies
Preferably, a new tumor biopsy should be obtained at pre-screening if the patient agrees on 
the molecular pre-screening consent form.
4.2.3
Tumor samples analyses
Any tumor tissue sample obtained will be utilized for two purposes:

Determination of ALK status using the FDA-approved Vysis ALK break-apart FISH assay 
(Abbott Molecular Inc.): the test to assess ALK rearrangement will be performed by a 
Novartis designated central laboratory. The test will be performed on the new tumor 
biopsy obtained at pre-screening if the patient has consented to the biopsy. If a new biopsy 
is not available, the test to determine ALK status will be performed using the archival lung 
tumor tissue. Note: Cytology samples from pleural fluid can not be used for testing ALK 
status.

 
 


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Figure 4-1
Study design
4.3
Definition of end of the study
There will be no interim analysis of efficacy. The primary analysis will occur once all patients 
have completed at least 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 will 
continue as per the schedule of assessments.


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Following the cut-off date for the analysis reported in the primary CSR, the study will remain 
open. Ongoing patients will continue to receive study treatment and be followed as per the 
schedule of assessments, as long as patients derive benefit from LDK378. The end of study 
defined as the earliest occurrence of one of the following:

At least 75% of patients have died or all patients discontinued from the study.

Other clinical studies (e.g. roll-over protocol or other) or patient support programs become 
available that can continue to provide LDK378 in this patient population and all patients 
ongoing are eligible to be transferred to them.

At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative setting to patients who in the opinion of the 
Investigator are still deriving clinical benefit.
The final analysis will occur at the end of the study. All available data from all patients up to
this cut-off date will be analyzed and summarized in a final CSR.
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 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 crizotinib-naïve adult patients with ALK-
rearranged (as determined by the FDA-approved Vysis ALK break-apart FISH assay) locally 
advanced or metastatic NSCLC who are either chemotherapy-naïve or who have been 
previously treated with cytotoxic chemotherapy (up to 3 lines).
The investigator or designee must ensure that only patients who meet all of the inclusion and 
none of the exclusion criteria are offered treatment in the study.
See Section 7.1.1 for details on pre-screening procedures.
Patients enrolled in this study are not permitted to participate in 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.


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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 stage IIIB or IV NSCLC that 
carries an ALK rearrangement defined as 15% or more positive tumor cells as assessed by 
the FDA-approved FISH test (Abbott Molecular Inc.) using Vysis break-apart probes. 
Patients will be pre-screened to test for ALK positivity. The test to confirm ALK 
rearrangement must be performed either using archival tissue or, preferably, using a new 
biopsy prior to the first dose of LDK378 according to the above criteria, i.e. with the 
FDA-approved Vysis ALK break-apart FISH assay. The test will be performed at a 
Novartis designated central laboratory.
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.
4. Patients must be chemotherapy-naïve or have received up to 3 lines of prior cytotoxic 
chemotherapy to treat their stage IIIB or IV NSCLC. If patients received chemotherapy, 
such patients must have progressed during or after the last chemotherapy regimen received 
prior to the first dose of LDK378.

Prior erlotinib or gefitinib will not count as a line of cytotoxic chemotherapy (i.e. 
patients may have received prior treatment with these drugs)

(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 or metastatic (stage IIIB or 
IV) disease is defined as an anticancer regimen that contains at least 1 cytotoxic 
chemotherapy agent and is given for 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.
5. Patients must have a tumor tissue sample available, preferably being a new biopsy but 
otherwise being an archival sample collected either at the time of diagnosis of NSCLC or 
any time since, for assessing ALK rearrangements using the FDA-approved Vysis ALK 
break-apart FISH assay (see Section 4.2).
6. 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.
7. Patients must meet the following laboratory values at the screening visit:

Absolute neutrophil count (ANC) ≥1.5 x 109/L

Platelets ≥ 75 x 109/L

Hemoglobin (Hgb) > 8 g/dL

Calculated creatinine clearance (using Cockcroft-Gault formula) > 30 mL/min


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
Total bilirubin < 1.5 x ULN (Upper limit of normal), except for patients with 
Gilbert’s syndrome, who may only be included if total bilirubin < 3.0 x ULN or direct 
bilirubin < 1.5 x ULN

Aspartate transaminase (AST) < 3 x ULN, except for patients with liver metastasis, 
who are only included if AST < 5 x ULN

Alanine transaminase (ALT) < 3 x ULN, except for patients with liver metastasis, 
who are only included if ALT < 5 x ULN

Patients must have the following laboratory values within the laboratory normal limits 
or corrected to within normal limits with supplements during screening:

Potassium

Magnesium 

Phosphorus 

Total calcium (corrected for serum albumin) 
8. Life expectancy ≥ 12 weeks.
9. World Health Organization (WHO) performance status 0-2.
10. 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.
11. 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.
12. 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. Prior treatment with crizotinib, or any other ALK inhibitor investigational agent, for 
NSCLC
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. Clinically significant, uncontrolled heart disease, 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)


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
Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without anti-
hypertensive medication. Initiation or adjustment of antihypertensive medication (s) is 
allowed prior to screening

Ventricular arrhythmias

Supraventricular and nodal arrhythmias not controlled with medication

Other cardiac arrhythmia not controlled with medication

Corrected QT (QTc) > 470 msec using Fridericia correction (QTcF) on the screening 
ECG (as mean of triplicate ECG)
6. 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 patients who have not recovered from 
radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to 
starting study treatment is allowed.
7. 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.
8. 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:

Strong inhibitors or strong inducers of CYP3A4/5 (Appendix I)

Medications with a low therapeutic index that are primarily metabolized by 
CYP3A4/5, CYP2C8 and/or CYP2C9 (Appendix I)

Medications with a known risk of prolonging the QT interval or inducing Torsades de 
Pointes (Appendix I)
9. 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).
10. Patients who are currently receiving treatment with warfarin sodium (Coumadin®) or any 
other coumarin-derivative anticoagulants.
11. 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.
12. Patients receiving treatment with any enzyme-inducing anticonvulsant (Appendix I) 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.
13. Investigational agents within 4 weeks or ≤ 10 x half-life of the agent (whichever is longer) 
before first dose of study treatment.


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14. 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.
15. 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 30 days after stopping treatment. Highly effective contraception is defined as any 
of:
1. Total abstinence: when this is in line with the preferred and usual lifestyle of the 
subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception].
2. 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.
3. Male partner sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). [For female subjects on the study the vasectomized 
male partner should be the sole partner for that patient].
4. 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.
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.
16. 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.
17. Other severe, acute, or chronic medical or psychiatric conditions including uncontrolled 
diabetes mellitus or laboratory abnormalities that in the opinion of the investigator may 
increase the risk associated with study participation, or that may interfere with the 
interpretation of study results.
18. Patients with known hypersensitivity to any excipients of LDK378 (microcrystalline 
cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate).
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).


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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 patient supply, packaged in bottles. LDK378 will be dosed on a 
flat scale of 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. A complete cycle of treatment is defined as 28 days of once daily treatment of 
LDK378. The investigator must instruct the patient to take the study drug exactly as 
prescribed.
 
 
 
 

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.
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)


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6.1.2
Guidelines for continuation of treatment
For guidelines for dose modification of treatment, refer to Section 6.2.
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 as assessed by 
the investigator. Patients who have RECIST-defined PD as assessed by the investigator, 
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 and efficacy assessments as per the schedule of 
assessments.

Unacceptable toxicity that precludes further treatment

Start of a new anti-cancer therapy

And/or treatment is discontinued at the discretion of the investigator or patient or the 
patient is lost to follow-up.
Patients who permanently discontinue the study drug for any reason other than disease 
progression must, if agreeing to further follow-up, continue efficacy assessments as scheduled 
in the protocol until the time of confirmed disease progression.
After discontinuing LDK378, further treatment for NSCLC is left to the physician’s discretion.


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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.
LDK378 dose modification guidelines are described in Section 6.2.3 and Table 6-3. Any 
planned variance from these guidelines in view of patient safety must first be discussed with 
the sponsor unless there is an urgent need for action.
All dose modifications, interruptions or discontinuations must be based on the worst 
preceding toxicity as graded by the NCI Clinical Toxicity Criteria (NCI-CTCAE version 4.03).
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 or grade 3 treatment-related toxicities, 
dosing should be interrupted until at least resolution to grade 1 followed by dose reduction. 
For any grade 4 toxicity, patients should interrupt study treatment until resolution to at least 
grade 1, followed by either dose reduction or treatment discontinuation. Treatment with the 
study drug may subsequently be continued at a reduced dose level if in the opinion of the 
investigator the patient continues to experience clinical benefit and after discussion with the 
sponsor.
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 will 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 6.2.3, 
provided this toxicity resolved to ≤ CTCAE grade 1.If the treatment with LDK378 is withheld 
due to toxicity, scheduled visits and all assessments (including tumor assessments) will 
continue to be performed (with the exception of the dosing of the withheld study drug), as 
described in Table 7-1.
If the treatment with LDK378  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.
If the treatment with LDK378 dosing is withheld for more than 28 consecutive days (counting 
from the first day when a dose was missed) for reasons other than toxicity, then LDK378 
should be permanently discontinued. If dosing was withheld for up to 28 consecutive days for 


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reasons other than toxicity, then treatment with LDK378 may be resumed at the same dose if 
the patient is continuing to derive clinical benefit. 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. 
Detailed guidelines for follow-up of study drug related AEs or abnormal laboratory values 
must be followed as described in Section 6.2.4.
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 reductions will be allowed. All dose reductions will be in 150 mg 
decrements per reduction. The patient must be discontinued from treatment with LDK378 if 
further reduction is necessary.
Once the dose of LDK378 has been reduced due to toxicity, it cannot be re-escalated.
Table 6-2
Dose reduction steps for LDK378
LDK378 dose levels
Dose* and schedule
Starting dose level
750 mg qd continuously
Dose level – 1
600 mg qd continuously
Dose level – 2
450 mg qd continuously
Dose level – 3
300 mg qd continuously **
*Dose reduction should be based on the worst preceding toxicity as per NCI-CTCAE version 4.03
**Dose reduction below 300 mg/day is not allowed. If a dose reduction below 300 mg/day is required, the patient 
should be permanently discontinued from 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
Dose changes must be recorded on the Dosage Administration Record eCRF.
Dose Modifications for LDK378 as specified in Section 6.2.3.
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 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 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


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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
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 >  2.0x 
ULN
Maintain dose level with LFTs*** monitored per protocol
Grade 3 (> 5.0 and ≤ 20.0 x ULN) without total bilirubin elevation to > 2.0 x 
ULN
Omit dose until resolved to ≤ Grade 1 (or to baseline) 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 (or to baseline) then 1 dose level
AST or ALT and concurrent Total Bilirubin
AST or ALT > 3.0 x ULN and total bilirubin > 2.0x 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 LDK378 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 -1.5 x ULN)
Maintain dose level
Grade 2 (>1.5 and ≤3.0 x baseline; > 1.5 -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 - 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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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 omit 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
CARDIAC


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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 < 481ms, then ↓ 1 dose level
- Assess the quality of the ECG recording and the QT value and repeat if needed
Repeat ECG in 24 hours, or less, as clinically indicated; continue monitoring as clinically 
indicated until QTc < 481 ms
In addition:-Determine the serum electrolyte levels (in particular hypokalemia, 
hypomagnesemia). If abnormal, correct abnormalities before resuming study drug treatment
- Review concomitant medication use for drugs with the potential to increase the risk of drug 
exposure related to QT prolongation
 
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 > 60ms change from baseline and Torsades de 
pointes or polymorphic ventricular tachycardia or signs/symptoms of 
serious arrhythmia)
Permanently discontinue patient from 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


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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
* 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 (fractionated if total bilirubin > 2.0 x ULN), 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 6.2.4.4)
***** 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 6.2.4.5)


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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.
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)
ALT/AST/total bilirubin 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)
ALT/AST/total bilirubin ≥ 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
Patients with liver metastasis and grade 2 AST/ALT at baseline, increased monitoring is 
required; for grade 3 or 4 AST/ALT follow guidelines for grade 3 or 4 AST/ALT
Investigations 
(renal)
Serum creatinine Grade 2:
Test weekly (or more frequent) until Grade 1
Thereafter, test every cycle (4 weeks)
Serum creatinine ≥ Grade 3:
Test twice weekly (or more frequent) until ≤ Grade 1
Thereafter, test every cycle (4 weeks)
Investigations 
(pancreatic)
Amylase/lipase ≥ Grade 3:
Test weekly (or more frequently) until ≤ Grade 1. After resumption of dosing, continue to 
test weekly for one additional cycle (4 weeks). If no reoccurrence of ≥ Grade 2 event, 
continue monitoring every cycle (4 weeks)
*Note: this table refers only to the evaluation schedule to monitor selected toxicities. Refer to Table 6-3 for dose 
modifications required for applicable toxicities
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 liver function tests (LFTs): albumin, 
ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), alkaline phosphatase 
and GGT. Note: for patients with Gilbert Syndrome, total and direct bilirubin must be 
monitored, but intensified monitoring applies to changes in direct bilirubin only.
In case of any occurrence of ALT/AST/total bilirubin increase to grade 2 the LFTs must be 
monitored weekly (or more frequently if clinically indicated) until the event resolves to ≤ 


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grade 1. Thereafter monitoring must be continued every other week (or more frequently if 
clinically indicated) for two additional cycles (e.g. 8 weeks). If there is no recurrence of grade 
≥2 ALT/AST/total bilirubin elevations during this period, subsequent monitoring must be 
performed every 4 weeks. For patients with liver metastasis and grade 2 AST/ALT at baseline,
increased monitoring is required; for grade 3 and 4 AST/ALT; follow guidelines for grade 3 
or 4 AST/ALT.
In case of any occurrence of ALT/ AST/total bilirubin increase to grade 3 or 4, LFTs must be 
monitored weekly (or more frequently if clinically indicated) until the event resolves to ≤ 
grade 1 or to baseline. Thereafter monitoring must be continued every other week (or more 
frequently if clinically indicated) for four additional cycles (e.g. 16 weeks). If there is no 
recurrence of ≥ grade 2 ALT/AST/ total bilirubin elevations during this period, subsequent 
monitoring must be performed every 4 weeks.
Patients who discontinue study treatment due to liver toxicity must be monitored weekly (or 
more frequently if clinically indicated) until the event resolves to ≤ grade 1 or stabilization 
occurs (no CTCAE grade change over 4 weeks).
Refer to Table 6-4.
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential 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 

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. 


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
A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.

Further testing for acute hepatitis A, B, C or E infection and liver imaging (eg, biliary tract) 
may be warranted. 
 
 

Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented.
6.2.4.3
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 descried in Table 6-3.
6.2.4.4
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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6.2.4.5
Guidelines for the treatment of study drug induced diarrhea
The investigator should consider/investigate potential concomitant medication, food or 
comorbidity driven causes of diarrhea (including infectious causes) and remedy these causes 
if possible (e.g. discontinuation of concomitant medication, dietary modification, treatment of 
comorbidity).
The patient should be monitored for signs of dehydration and instructed to take preventive 
measures against dehydration as soon as diarrhea occurs. Antidiarrheal medication must be 
initiated at the first sign of abdominal cramping, loose stools or overt diarrhea. Concomitant 
medication for the treatment of diarrhea should follow local practice and the investigator’s 
best judgment and may follow “the recommended guidelines for the treatment of cancer 
treatment-induced diarrhea” (Benson et al 2004). For example:

For uncomplicated diarrhea (grade 1 or 2 without complicating signs or symptoms), 
loperamide given at a standard dose (e.g. initial administration of 4 mg, then 2 mg every 
2-4 hours, maximum of 16 mg/day), along with oral hydration and dietetic measures 
should be considered. Note: complicating signs or symptoms include: moderate to severe 
cramping, decreased performance status, fever, neutropenia, frank bleeding or dehydration.

For complicated diarrhea (all grade 3 or 4, grade 1-2 with complicating signs or 
symptoms), management should involve intravenous (IV) fluids, and consider treatment 
with octreotide (at starting dose of 100 to 150 µg sub-cutaneous 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.
6.2.4.6
Guidelines for the treatment of study drug induced nausea and 
vomiting
Nausea and vomiting are among the most frequently reported AEs following treatment with 
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.


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6.2.4.7
Guidelines for the treatment of hypophosphatemia
In the phase I study [CLDK378X2101], as of 
 there were 9 cases of grade 3 
hypophosphatemia in all dose groups, one of which was a DLT that contributed to the MTD 
determination – this patient was able to continue LDK378 at the same dose. One patient in the 
750 mg group had grade 3 hypophosphatemia that resolved after dose adjustment or 
interruption; in the remaining 8 cases, patients were able to continue therapy without dose 
modification. Hypophosphatemia was a commonly reported AE (6.3%), regardless of 
relationship to 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
Recommendations for the monitoring of cases of interstitial lung 
disease (ILD)/pneumonitis toxicity
Monitor patients for pulmonary symptoms indicative of ILD/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.
Exclude other cases of pneumonitis, and follow dose modification guidelines as described in 
Table 6-3. 
6.2.4.9
Anticipated risks and safety concerns of the study treatment
Appropriate eligibility criteria, 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 IB.
6.3
Concomitant medications
In general, the use of any concomitant medication/therapy deemed necessary for the care of 
the patient (e.g. anti-emetics, anti-diarrheal) 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 
over-the counter medications, herbal medications (prohibited, see Section 6.3.2.7), food or 
vitamin supplements.


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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. If possible, systemic corticosteroid treatment should not be given during 
the study, except for:

Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye 
drops or local injections (e.g. intra-articular);

Stable doses of corticosteroid therapy such as dexamethasone and prednisone (e.g. for 
tumor associated symptoms) are permitted during the course of the study.
6.3.1.2
Drugs that are metabolized by CYP450 enzymes
 
 
 
 
 
 
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 I). Duration of concomitant 
treatment should be kept as short as possible (e.g. less than 1 week), or completely avoided 
whenever possible. Patients receiving such medications must be monitored closely for any 
potentiation 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 I), except for drugs which 
have narrow therapeutic index/sensitive substrates for these CYP isoforms (refer to 
Section 6.3.2.6 and Table 14-1 of Appendix I).
6.3.1.3
Non-enzyme inducing anti-epileptic drugs
Non-enzyme inducing anti-epileptic medication (Non-EIAED) is allowed.
6.3.1.4
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 LDK378 therapy, as determined by the Investigator may undergo 


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radiotherapy and/or surgical resection as palliative localized therapy to treat metastatic lesions. 
LDK378 should be held for at least 4 days prior to radiotherapy and at least 1 day prior to any 
surgery. LDK378 may be resumed ≥3 days after completing radiotherapy or minor surgery, 
and ≥2 weeks after major surgery.
6.3.1.5
Gastric protection agents
The use of gastric protection agents including antacids, H2-antagonists, and proton pump 
inhibitors (PPIs; Table 14-2 of Appendix I) 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).
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 and palliative surgery as described in Section 6.3.1.4], 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.
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
Warfarin sodium or any other coumarin-derivative anticoagulants are not permitted. LDK378 
is an inhibitor of 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 (EIAED)
Use of EIAEDs is not permitted. Refer to Table 14-3 of Appendix I 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.


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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 14-3 of Appendix I 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 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 14-3 of Appendix I for a list of these medications. 
Please note that this list may not be comprehensive.
6.3.2.7
Herbal medications
Herbal preparations/medications are not allowed throughout the study, as a potential drug-
drug interaction is always possible. These herbal medications include, but are not limited to: 
St. John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng.
Patients should stop using herbal medications at least 7 days prior to first dose of study 
treatment.
6.3.2.8
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. 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 LDK378 
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 ms and 10 patients (3.3%) had an increase from 
baseline QTc >60 ms. A central tendency analysis of the QTc data at average steady-state 
concentrations demonstrated that the upper bound of the 2-sided 90% CI for QTc was 16 ms 
at LDK378 750 mg. A pharmacokinetic/pharmacodynamic analysis suggested concentration-
dependent QTc interval prolongation.
Concomitant use of LDK378 and any medication included in Appendix 1, Table 14-4 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.


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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 identified for pre-screening and is retained as the primary identifier 
for the patient throughout the 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 subject is numbered uniquely across the entire 
database. Upon signing the Informed Consent Form (ICF), the patient is assigned to the next 
sequential Subject No. available to the investigator through the Oracle Clinical RDC interface. 
Once assigned, the Subject No. must not be reused for any other subject.
If the patient fails to start treatment for any reason, the reason will be entered into the 
Screening Disposition eCRF page.
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. At the C1D1 visit, before the patient receives the 
first dose, the IRT system must again be contacted to enroll the patient in the study. 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
 
 
 
 
 


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6.5.1
Study drug packaging and labeling
 
 
 
 
 
6.5.2
Drug supply and storage
 
 
 
 
6.5.3
Study drug compliance and accountability
6.5.3.1
Study drug compliance
 
 
 
6.5.3.2
Study drug accountability
 
 
 
 
 
 
 
6.5.3.3
Handling of other study treatment
Not applicable.


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6.5.4
Disposal and destruction
 
 
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 patient’s source 
documentation. eCRF will not be used as a source document. The table indicates which 
assessments produce data to be entered into the database (D) or remain in the source 
documents only (S).


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Table 7-1
Visit evaluation schedule
Category
Protocol 
section
Screening Phase
Treatment Phase
Post treatment 
efficacy/ follow up 
phase
Survival 
follow-
up 
phase
Cycle 1
(28 d)
Subsequent 
cycles
(28 d)
End of 
study 
treatment 
(EOT)
Visit name
Molecular 
pre-screen
Screening 
Visit
(Day -28 
to Day -1)
Cycle 1 
Day 1
Cycle 1 
Day 15
Cycle 2 Day 
1; Cycle 3 
Day 1; etc.
End of 
treatment 
visit
Tumor 
follow-up
Study 
phase 
completion
Survival 
follow-
up
Obtain pre-screening 
informed consent
D
X
Obtain Main Informed 
Consent
D
11.3.
X
Confirmation of ALK status 
by central laboratory
D
7.1.1.
New 
biopsy 
preferred 
and/or 
archival 
tissue & 
pathology 
report
End of Phase Disposition 
Page
D
7.1.
X
X
X
Patient history
Demography
D
7.1.2.3.
X
Inclusion/ exclusion criteria
D
5.2.
5.3.
X
Eligibility check
S
7.1.2.1.
X
Relevant medical history/ 
current medical conditions
D
7.1.2.3.
X


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Category
Protocol 
section
Screening Phase
Treatment Phase
Post treatment 
efficacy/ follow up 
phase
Survival 
follow-
up 
phase
Cycle 1
(28 d)
Subsequent 
cycles
(28 d)
End of 
study 
treatment 
(EOT)
Visit name
Molecular 
pre-screen
Screening 
Visit
(Day -28 
to Day -1)
Cycle 1 
Day 1
Cycle 1 
Day 15
Cycle 2 Day 
1; Cycle 3 
Day 1; etc.
End of 
treatment 
visit
Tumor 
follow-up
Study 
phase 
completion
Survival 
follow-
up
Diagnosis and extent of 
cancer
D
7.1.2.3.
X
Prior antineoplastic 
therapies (meds, surgery, 
radiation)
D
7.1.2.3.
X
Prior and concomitant 
medications
D
6.3.
Continuous
Physical examination
S
7.2.2.1.
X
X
X
X
X
Performance status (WHO)
D
7.2.2.4.
X
X
X
X
Height
D
7.2.2.3.
X
Weight
D
7.2.2.3.
X
X
X
X
Vital signs
D
7.2.2.2.
X
X
X
X
X
Laboratory assessments
Hematology
D
7.2.2.5.1.
X
X
X
X
X
Blood chemistry
D
7.2.2.5.2.
X
X
X
X
X
Urinalysis (dipstick) with 
micro-analysis
D
7.2.2.5.3.
X
Pregnancy test
D
7.2.2.5.4.
X
X
X
X
Testosterone, LH, FSH, 
sex hormone binding 
globulin (SHBG) (males 
only)
D
7.2.2.5.5.
X
X
X
Coagulation
D
7.2.2.5.6.
X


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Category
Protocol 
section
Screening Phase
Treatment Phase
Post treatment 
efficacy/ follow up 
phase
Survival 
follow-
up 
phase
Cycle 1
(28 d)
Subsequent 
cycles
(28 d)
End of 
study 
treatment 
(EOT)
Visit name
Molecular 
pre-screen
Screening 
Visit
(Day -28 
to Day -1)
Cycle 1 
Day 1
Cycle 1 
Day 15
Cycle 2 Day 
1; Cycle 3 
Day 1; etc.
End of 
treatment 
visit
Tumor 
follow-up
Study 
phase 
completion
Survival 
follow-
up
Imaging
CT scan or MRI of chest 
and abdomen
D
7.2.1.
X
Cycle 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
CT scan or MRI of brain
D
7.2.1.
X
Cycle 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)


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Category
Protocol 
section
Screening Phase
Treatment Phase
Post treatment 
efficacy/ follow up 
phase
Survival 
follow-
up 
phase
Cycle 1
(28 d)
Subsequent 
cycles
(28 d)
End of 
study 
treatment 
(EOT)
Visit name
Molecular 
pre-screen
Screening 
Visit
(Day -28 
to Day -1)
Cycle 1 
Day 1
Cycle 1 
Day 15
Cycle 2 Day 
1; Cycle 3 
Day 1; etc.
End of 
treatment 
visit
Tumor 
follow-up
Study 
phase 
completion
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)
Cycle 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)
Study drug administration
LDK378 dosing
D
6.1.
Continuous
Safety
Adverse events
D
8.1.
Continuous
ECG
D
7.2.2.6.1.
X
X
X
X
X


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Category
Protocol 
section
Screening Phase
Treatment Phase
Post treatment 
efficacy/ follow up 
phase
Survival 
follow-
up 
phase
Cycle 1
(28 d)
Subsequent 
cycles
(28 d)
End of 
study 
treatment 
(EOT)
Visit name
Molecular 
pre-screen
Screening 
Visit
(Day -28 
to Day -1)
Cycle 1 
Day 1
Cycle 1 
Day 15
Cycle 2 Day 
1; Cycle 3 
Day 1; etc.
End of 
treatment 
visit
Tumor 
follow-up
Study 
phase 
completion
Survival 
follow-
up
Biomarker studies
Survival follow-up
Antineoplastic therapies 
since discontinuation of 
study treatment
D
7.1.4.1.
X
X
Survival assessment
7.1.4.1.
X


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7.1.1
Pre-screening
Prescreening will involve all activities until the determination of ALK status by the central 
laboratory.
Patients will be consented for a pre-screening visit. If a patient is being treated with 
chemotherapy for their NSCLC, pre-screening may be performed during the chemotherapy 
treatment. However, if a patient is determined to be ALK positive, the patient must only be 
screened when progression of disease on chemotherapy treatment (if such treatment is being 
used) is confirmed.
Preferably, a newly obtained tumor biopsy should be submitted for all patients to determine 
ALK status and trial entry eligibility. If the new biopsy cannot be obtained, a formalin-fixed 
paraffin-embedded (FFPE) tumor sample(s) from archival material obtained at the time of 
diagnosis of NSCLC or any time since must be submitted for central analysis. Analysis 
material must be sent immediately upon the patient entering molecular pre-screening. If 
unstained slides cannot be prepared, paraffin blocks can be submitted. Sections will be cut 
from paraffin block and the remaining material will be returned to the site upon request. The 
translocation analysis to confirm ALK rearrangement will be the FDA-approved FISH test 
(Abbott Molecular Inc) using Vysis break-apart probes.
ALK status must be determined centrally prior to screening assessments being performed. 
Instructions for tumor sampling, preparation and packing are described in a separate 
laboratory manual. Molecular pre-screening samples must consist of tumor tissue (which may 
include fine-needle aspirates) but cannot consist of a cytology sample obtained from fluid 
collections (e.g. pleural, pericardial or ascitic effusions), as the FDA-approved FISH test is 
not validated on such samples.
Results of the assay will be sent to the site. If delays are experienced in processing the sample, 
the pre-screening site will be informed. Results of the ALK rearrangement status must be 
received before the patient is permitted to attend the screening visit.
7.1.2
Screening
Screening assessments to confirm eligibility should be performed as per the schedule of 
assessments. Written informed consent must be obtained before any study specific procedure 
is performed.
Re-screening of patients will not be allowed, but laboratory parameters which do not meet the 
inclusion criteria may be re-tested within the 28 day screening window.
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.


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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

NSCLC diagnosis and extent of disease, including:

Date of diagnosis and stage of NSCLC

ALK status documentation using the FDA-approved Vysis ALK break-apart FISH 
assay. ALK status must be confirmed using the FDA-approved Vysis ALK break-
apart FISH test via a central laboratory using the new biopsy obtained prior to study 
entry (if biopsy was taken) or, if a new biopsy is not available, using the required 
archival tumor tissue.

Site of active disease

Characteristics of disease

Prior antineoplastic therapies (medications, radiation, surgeries)

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
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 as assessed by the investigator), LDK378 administration may be 
stopped, or may be continued if the patient is continuing to derive clinical benefit in the 
opinion of the investigator (see Section 6.1.3).
Patients will be assessed as per visit schedule in Table 7-1.


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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 timepoints.
7.1.4
Discontinuation of study treatment
7.1.4.1
Patients discontinuing LDK378 
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 discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator must make every 
effort (e.g. telephone, e-mail, letter) to determine the primary reason for this decision and 
record this information in the patient’s chart and on the appropriate 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.
Study treatment must be discontinued under the following circumstances:

Emergence of adverse events, as described in Section 6.3

Laboratory abnormalities, as described in Section 6.3

Pregnancy

Deviations from the prescribed dose regimen, as described in Section 6.2.3

Use of prohibited treatment, as described in Appendix 1 for LDK378

Any other protocol deviation that results in a significant risk to the patient’s safety

Study Terminated by Sponsor

Patient/guardian decision

Physician decision

Lost to follow-up

Death
Patients who discontinue study treatment should NOT be considered withdrawn from the 
study. They should return for the assessments indicated in Section 7.2.1 and enter the survival 
follow-up period or continue tumor assessments as appropriate. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, email, letter) should be made 
to contact them as specified in Section 7.1.6.
End of treatment visit
Patients who discontinue LDK378 should be scheduled for a visit as soon as possible and 
within 7 days of the last dose of LDK378, 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 


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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. As a 
minimum, all patients who discontinue LDK378, including those who refuse to return for a 
final visit, will be contacted for safety evaluations at least 30 days after the last dose of 
LDK378. The investigator should inquire about any AE observed/concomitant medication 
taken during this 30-day period. This 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 LDK378.
7.1.4.2
Withdrawal of consent
 
 
 
 
 
 
 
 
 
 
7.1.5
Follow-up period 
7.1.5.1
Post-treatment efficacy follow-up
If a patient discontinues study treatment in the absence of confirmed PD, tumor assessments 
every 8 weeks should continue to be performed from the EOT visit until PD is assessed by the 
investigator (see Section 7.2.1.2); however, safety assessments do not need to continue to be 
performed. .Antineoplastic therapies since discontinuation of study treatment will continue to 
be collected.
Once the patient ceases tumor follow-up, the reason for completion should be recorded on the 
Study Phase Completion Disposition eCRF page.
7.1.5.2
Survival follow-up
Following the end of tumor follow-up for efficacy (i.e. after the time of confirmed PD), the 
patient will be contacted every 3 months to determine survival status and antineoplastic 
therapies since discontinuation of study treatment.
7.1.6
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 


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the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Tumor evaluation will be determined locally according to the Novartis guideline (Appendix II)
on the Response Evaluation Criteria in Solid Tumors (RECIST), based on RECIST Version 
1.1 (Eisenhauer et al 2009). The investigator’s assessment will be used for the primary 
endpoint analysis and for patient’s treatment decision making.
Imaging data will be centrally collected and checked for quality by an imaging Clinical 
Research Organization (CRO) designated by Novartis. It will undergo review by a blinded 
independent review committee (BIRC) according to the Novartis guideline (Appendix II) on 
the Response Evaluation Criteria in Solid Tumors (RECIST), based on RECIST Version 1.1.
Full details of the central reading process are included in the BIRC Charter.
7.2.1.1
Baseline assessments
Details of imaging requirements and logistics can be found in the separate Imaging Manual.
Tumor evaluation will be performed at baseline within 28 days of, and prior to, enrollment. 
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 1.1 (Appendix II). Measurable 
lesions include lytic or mixed (lytic + blastic) bone lesions with an identifiable soft tissue 
component that meets the measurability criteria per RECIST 1.1 (Appendix II).

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.


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Required image assessments for tumor assessment at baseline
The following assessments will be performed:

Computed Tomography (CT) with IV contrast or Magnetic Resonance Imaging (MRI) of 
chest and upper abdomen.

The preferred radiologic technique is CT with intravenous (IV) 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 upper abdomen 
should be performed.

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)).

After screening, scans need not be repeated, unless clinically indicated. If indicated, 
the same methodology as at screening should be used.

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).

After screening, scans need not be repeated, unless clinically indicated. If indicated, 
the same methodology as at screening should be used.

Brain CT with IV contrast or MRI scan.

After screening, scans need not be repeated, unless clinically indicated. If indicated, 
the same methodology as at screening should be used.

Color photographs (with a metric ruler) if skin lesions are present.

After screening, scans need not be repeated, unless clinically indicated. If indicated, 
the same methodology as at screening should be used.

CT or MRI of any other site of disease not captured by any of the above listed images (e.g., 
pelvis, neck).

After screening, scans need not be repeated, unless clinically indicated. If indicated, 
the same methodology as at screening should be used.
Any imaging assessments already completed during the regular work-up of the patient within 
6 weeks prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study.
Chest x-ray or ultrasound must 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.


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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 upper 
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 upper abdomen CT/MRI (and pelvis CT/MRI if 
applicable). Whole body bone scans need not be repeated after baseline unless clinically 
indicated.

Brain CT with IV contrast 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 and the BIRC review promptly after acquisition. The 
activities of the imaging CRO and the BIRC will be described in the Imaging Charter.
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 II).
Imaging evaluations will 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.
Imaging assessment by the BIRC
All radiological assessments will be read locally and should be submitted promptly after 
acquisition to the imaging CRO designated by Novartis. The process at the imaging CRO will 
ensure that the BIRC remains blinded to the results of the local assessment (and other 
unblinding information). The decision regarding patient management will remain with the 
local investigator.


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Rapid image transmission to the BIRC may be accomplished by uploading all digital images 
acquired by the investigator in a secured website.
The results of the BIRC assessment will not be communicated to sites.
All timepoints will be read on an ongoing basis (rolling reads) as detailed in the imaging 
charter to be provided by the designated imaging CRO.
Duration of post-baseline tumor assessments
Tumor assessments will continue until one of the following events:

The patient experiences RECIST-defined PD as determined by the investigator AND 
treatment with LDK378 ceases. If treatment with LDK378 continues beyond RECIST-
defined PD, imaging assessments must continue every 8 weeks until LDK378 treatment 
ceases

If a patient discontinues study treatment in the absence of PD, tumor assessments will 
continue to be performed every 8 weeks until the patient experiences a RECIST-defined 
PD as determined by the investigator

Death

Lost to follow-up, or

Patient decision involving withdrawal of consent (see Section 7.1.4.1).
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.
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 
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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 medication 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 as safety monitoring. All unscheduled blood testing 
will be performed locally. Dipstick urinalysis will be performed locally, except in the case of 
any out of range parameter on scheduled local urine analysis, when a urine sample will be 
sent to central laboratory for further analysis. Details on the collection, shipment of blood, 
urine and tumor samples and reporting of results by the central laboratory are provided to 
investigators in a separate [Laboratory Manual]. The time windows granted for laboratory 
evaluations are identical to the corresponding visit time windows for each visit (refer to 
Section 7.1).
Laboratory values obtained at the screening visit will be used to assess eligibility to meet 
inclusion criteria 7. In addition, eligible patients must have baseline laboratory assessments 
performed on Cycle 1 Day 1 / Run-in Day 1 or within 24 hours prior to dosing. The results of 
centrally-analyzed laboratory assessments performed at Cycle 1 Day 1 do not need to be 
received by the site prior to initiation of dosing.


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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), 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, GGT, lipase
Urinalysis
Macroscopic panel (dipstick) (bilirubin, blood, glucose, ketones, WBC, pH, protein, 
specific gravity)
Microscopic panel (RBC, WBC, casts)
Hormones (males only)
Testosterone, LH, FSH, sex hormone binding globulin (SHBG)
Coagulation
INR and pro-thrombin time (PT) or Quick Test
Details on the collections, shipment of samples and reporting of results by the central 
laboratory are provided to investigators in the [Laboratory Manual].
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 Blood 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
All women of childbearing potential must complete a serum pregnancy test at the screening 
visit, at Cycle 1 Day 1, at every cycle throughout the study and at End of Treatment. Central 
laboratories will be used for the analysis of serum pregnancy tests.
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 bilateral oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of child bearing potential (such testing is not 
covered as part of the study assessments).


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The time windows granted for pregnancy testing are identical to the corresponding visit time 
windows for each visit. Refer to Table 7-1.
7.2.2.5.5 Hormones
Testosterone, LH, FSH and sex 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
INR and pro-thrombin 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

At the screening visit, in triplicate.

At Cycle 1 Day 1, in triplicate, pre-dose, and in triplicate 6 hours (+/- 30 minutes) after 
dosing. 

At Cycle 1 Day 15 and at Cycle 2 Day 1 in triplicate, pre-dose.
 
 

At other defined timepoints (Day 1 of subsequent cycles) (see Table 7-1) as single ECGs, 
pre-dose.
ECGs will be performed in supine position. All ECGs recorded for each time point 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.
Interpretation of the tracing must be made by a qualified physician. 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. Clinically significant abnormalities 
present when the patient signed informed consent should be reported on the Medical History 
eCRF page. Clinically significant findings must be discussed with Novartis prior to enrolling 
the patient in the study. New or worsened clinically significant findings occurring after 
informed consent must be recorded on the Adverse Events eCRF page. When triplicate ECGs 
are taken, for the purposes of inclusion criteria and dose level management, mean parameter 
values should be used.


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7.2.5
Resource utilization
Not applicable.


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8
Safety monitoring and reporting
8.1
Adverse events (AEs)
8.1.1
Definitions and reporting
An AE 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.
Abnormal laboratory values or test results occurring after informed consent constitute AEs 
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).
AEs that begin or worsen after informed consent has been obtained should be recorded in the 
Adverse Events eCRF. Conditions that were already present at the time of informed consent 
should be recorded in the Medical History page of the patient’s eCRF. AE monitoring should 
be continued for at least 30 days following the last dose of study treatment. AEs (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 AE.
AEs 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 AE, 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. The occurrence of AEs should be sought by non-
directive questioning of the patient during the screening process after signing informed 
consent and at each visit during the study. AEs also may be detected when they are 
volunteered by the patient during the screening process or between visits, or through physical 
examination, laboratory test, or other assessments. As far as possible, each AE should be 
evaluated to determine:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates)


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3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)
7. Whether it is serious, where a serious AE (SAE) is defined as in Section 8.2.1.
All AEs should be treated appropriately. If a concomitant medication or non-drug therapy is 
given, this action should be recorded on the Adverse Event eCRF.
Once an AE 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), should not be reported as a 
SAE.
AEs 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 AE 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 eCRF. 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 AEs 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 AE should not be reported as 
AEs. A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate an SAE 
unless it meets the definition of seriousness below and/or at the investigator’s discretion. A 
dose hold or medication for the laboratory abnormality may be required by the protocol in 
which case the laboratory abnormality would, by definition, be an AE and must be reported as 
such (see Section 6.2).


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8.1.3
Adverse events of special interest
Adverse events of special interest to be monitored for LDK378 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).
Details regarding these adverse events are provided in the Investigator’s Brochure for 
LDK378. Potential emergent new AEs will be monitored during the course of the study.
8.2
Serious adverse events
8.2.1
Definitions
An SAE is defined an AE characterized by 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

Protocol exempt SAEs: Progression of malignancy (including fatal outcomes), if 
documented by use of appropriate method (RECIST criteria), should not be reported as 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 SAE 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 


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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 submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each siteFollow-up information is submitted in the 
same way as the original SAE Report Each re-occurrence, complication, or progression of the 
original event should be reported as a follow-up to that event regardless of when it occurs. 
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, 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 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 (EC) 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
Patients who become pregnant during the trial will be withdrawn from the study. 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed until 3 months following delivery 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.
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 


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Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee (DMC)
An independent Data Monitoring Committee (DMC) will be constituted and will be 
responsible for monitoring and reviewing the clinical study data for efficacy and safety during 
the study prior to the final data analysis. Efficacy data will be reviewed periodically during 
Stage 1 to advise on whether the trial should proceed to Stage 2 and full enrolment. DMC 
review for the purpose of advising on the transition of the trial from Stage 1 to Stage 2 will be 
based primarily on local investigator assessment of response. However, the DMC may request 
data on assessment of response by the BIRC if deemed necessary. Responsibilities of the 
DMC, communication flow between DMC, Steering Committee and Novartis, and timing of 
data safety and efficacy reviews, will be included in the DMC charter document.
It is envisioned that the DMC may make four types of recommendations, namely:
1. Transition into Stage 2 of the trial or stopping enrollment after stage 1 for futility
2. No safety or ethical issues, ethical to continue the trial as planned
3. Serious safety concerns precluding further study treatment, regardless of efficacy
4. Ethical to continue the study but recommend an amendment to the protocol (e.g. 
incorporate a safety analysis).
8.7
Steering Committee (SC)
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 DMC, SC and Novartis will be 
included in the SC charter document.
9
Data collection and management


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9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria 
and documentation of SAEs. Additional checks of the consistency of the source data with the 
eCRFs are performed according to the study-specific monitoring plan.


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10
Statistical methods and data analysis
The data from all participating centers in this protocol will be combined. The primary analysis 
of study data will be conducted at the time when all patients have either completed at least six 
cycles of treatment or discontinued treatment. These data will be summarized in the primary 
Clinical Study Report (CSR). The final analysis of study data will be conducted at the end of 
the study (see Section 4.3). All available data from all patients up to this cutoff date will be 
analyzed. Additional data from patients continuing to receive study treatment after this time 
will be captured by a separate protocol. Efficacy and safety reports will be reviewed by a 
DMC regularly during the conduct of the study (see Section 8.6 for details).
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) will include all patients who receive at least one dose of 
LDK378. Patients who are screened but never started treatment will be listed.
The FAS will be used for all listings of raw data. Unless otherwise specified the FAS will be 
the default analysis set used for all analyses, including the primary analysis.
10.1.2
Safety Set
The Safety Set will include 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 will include 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).


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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, 25th and 75th
percentiles, minimum, and maximum will be presented.
10.3
Treatments (study treatment, concomitant therapies, compliance)
The actual dose and duration in days of 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 intensity), will be listed and summarized for all 
patients.
Dose reductions and dose interruptions (including the reasons for these) will be listed and 
summarized.
The safety set will be used.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized for all patients.
10.4
Primary objective
The primary objective is to evaluate the anti-tumor activity of LDK378.
10.4.1
Variable
The variable used to evaluate the anti-tumor activity of LDK378 is the overall response rate 
(ORR), 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 (Appendix II).
10.4.2
Statistical hypothesis, model, and method of analysis
The primary analysis will be performed on the FAS.
The study targets an ORR of 50%. A response rate of 35% or less is considered as insufficient 
level of activity for the proposed patient population. Therefore, a null hypothesis of ORR ≤ 
35% vs. an alternative hypothesis of ORR>35% will be tested using a one-sided test with 
alpha of 0.05 based on a Simon’s optimal two-stage design (Simon 1989). If 45 or more 
responses are seen in 105 total patients (estimated ORR of 42.9%), then the null hypothesis 
will be rejected and the trial declared positive.
Stage 1 will enroll 43 patients. If the study is terminated early at the end of Stage 1 (16 or 
fewer responses among 43 patients enrolled to Stage 1), then the study will be considered to 
have failed to reject the null hypothesis. See Section 10.7 for further details of the stopping 


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criteria for futility. Stage 2 will include an additional 62 patients. The primary analysis will 
occur when all 105 patients have completed 6 cycles of treatment or discontinued treatment 
earlier.
The ORR will be estimated and the 90% exact confidence interval (CI) will be provided. The 
uniformly minimum variance unbiased estimator (UMVUE) and the 90% two-stage CI 
(Atkinson and Brown 1985) will also be presented.
10.4.3
Handling of missing values/censoring/discontinuations
Confirmed partial or complete responses reported prior to any additional anticancer therapy 
will be considered as responses in the calculation of the ORR irrespective of the number of 
missed assessments before response.
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.
10.4.4
Supportive analyses
The primary analysis on the FAS will be repeated on the PPS.
ORR, per RECIST 1.1, as assessed by the BIRC, will also be estimated and CIs will be 
provided based on the FAS as described in Section 10.4.2.
10.5
Secondary objectives
All secondary efficacy assessments (DOR, TTR, DCR, PFS, and OIRR) will be analyzed as 
per investigator assessment and as per the BIRC. Confirmation of response is required for all 
response endpoints, as per RECIST 1.1.
All secondary analyses will be performed based on the FAS, unless otherwise specified.
No adjustment for multiple testing will be made.
10.5.1
Key secondary objective(s)
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 
may be described using Kaplan-Meier curves and relevant statistics if appropriate. Censoring 
rules for DOR are described in the Appendix II.
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 


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1.1. TTR will be described using Kaplan-Meier methods and appropriate summary statistics. 
The TTR analysis will be conducted with censoring rules as described in the Appendix II.
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 90% CI provided. DCR 
will be estimated.
10.5.2
Other secondary efficacy objectives
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 
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 and the BIRC 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 and by BIRC.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the Safety Set will be used. All listings and tables will be presented for 
all patients.
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1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. Post-treatment period: starting at day 31 after last dose of study medication.
10.5.3.2 Adverse events (AEs)
Summary tables for AEs will include only AEs that started or worsened 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 post-treatment period 
will be flagged.
The incidence of AEs will be summarized by system organ class and/or preferred term, 
maximum severity (based on Common Terminology Criteria for Adverse Events [CTCAE] 
grades version 4.03), and relation to study drug.
Clinically notable adverse events (CNAEs) 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 CNAE, number and percentage of patients with at least one event in 
each CNAE category will be reported.
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.
A listing of laboratory values will be provided by laboratory test, patient, and study day. A 
separate listing will display notable laboratory abnormalities (i.e., newly occurring CTCAE 
grade 3 or 4 laboratory abnormalities).
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.


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Listing of all laboratory data with values flagged to show the corresponding CTCAE grades 
and the classifications relative to the laboratory normal ranges will be generated.
 
 
 
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 for baseline to worst on-treatment result based on notable parameter categories

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
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10.7
Interim analysis
In order to inform the recommendation to proceed to Stage 2 of the study, the DMC will 
periodically review response data during Stage 1, based on local investigator assessment, as 
defined in the DMC charter (see Section 8.6). The DMC may request data of assessment of 
response by the BIRC if deemed necessary to provide its recommendation. As per Simon’s 
optimal two-stage design, the trial will be stopped at Stage 1 for futility if 16 or fewer 
responses are observed in the 43 patients enrolled to Stage 1. According to this rule, the DMC 
will make the recommendation to transition into the Stage 2 of the study. If at the time that the 
last patient is enrolled to Stage 1 a minimum of 17 responses have not yet been observed, 
accrual may be temporarily suspended until either the minimum number of 17 responses are 
observed or all 43 patients have been followed for at least 6 cycles of LDK378 or 
discontinued treatment.


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Safety will be reviewed by a DMC regularly during the conduct of the study, as outlined in 
the DMC charter document (see Section 8.6).
10.8
Sample size calculation
Based on Simon’s (1989) optimal two-stage design, if the true ORR is 50% (under the 
alternative hypothesis), approximately 105 total patients are required to reject the null 
hypothesis of ORR ≤ 35% with a one-sided alpha of 0.05 and 90% power. If at least 17 
confirmed responses are observed among 43 patients enrolled into Stage 1, an additional 62 
patients will be enrolled into Stage 2. If 45 or more confirmed responses are observed among 
105 total patients, the trial will be declared positive.
The operating characteristics of the design are described in Table 10-1.
Table 10-1
Operating characteristics of Simon’s optimal two-stage design
True ORR
35%
(null hypothesis)
40%
45%
50% (alternative 
hypothesis)
Probability stop for futility at Stage 1 
(16 or fewer responses out of 43 
patients enrolled at Stage 1)
0.683
0.418
0.192
0.063
Probability trial is success (45 or more 
responses out of 105 total patients)
0.049
0.268
0.642
0.900
10.9
Power for analysis of key secondary variables
Not applicable.
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 
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.


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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 4.2.
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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11.8
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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13
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Gettinger S, Lynch T (2011) A decade of advances in treatment for advanced non-small cell 
lung cancer. Clin Chest Med; 32(4):839-51.
Hollen PJ, Gralla RJ, Kris MG, et al (1993) Quality of life assessment in individuals with lung 
cancer: testing the Lung Cancer Symptom Scale (LCSS). Eur J Cancer; 29A Suppl 1:S51-8.
Hollen PJ, Gralla RJ, Kris MG, et al (1994) Measurement of quality of life in patients with 
lung cancer in multicenter trials of new therapies. Psychometric assessment of the Lung 
Cancer Symptom Scale. Cancer; 73(8):2087-98.
Hollen PJ, Gralla RJ, Kris MG, et al (2005) A comparison of visual analogue and numerical 
rating scale formats for the Lung Cancer Symptom Scale (LCSS): does format affect patient 
ratings of symptoms and quality of life? Qual Life Res; 14(3):837-47.
Kiura K, Seto T, Yamamoto N, et al (2012) A first-in-human phase I/II study of ALK 
inhibitors CH5424802 in patients with ALK-positive NSCLC [abstract]. J Clin Oncol 30, 
(suppl; 7602A).
Kwak EL, Bang YJ, Camidge DR (2010) Anaplastic lymphoma kinase inhibition in non-
small-cell lung cancer. N Engl J Med; 363(18):1693-703.  Malvezzi M, Bertuccio P, Levi F, 
et al (2012) European cancer mortality predictions for the year 2012. Ann Oncol; 23(4):1044-
52.
Mehra R, Camidge DR, Sharma S, et al (2012) First-in-human phase I study of the ALK 
inhibitor LDK378 in advanced solid tumors [abstract]. J Clin Oncol 30, 2012 (suppl; 3007A).


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National Cancer Institute: PDQ® Non-Small Cell Lung Cancer Treatment. Bethesda, MD: 
National Cancer Institute. Date last modified < 02/10/2012>. Available 
at: .cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofessional. Accessed 
<07/29/2012>.
National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology 
Non-Small Cell Lung Cancer (Version 3.2012). Available at .nccn.org Accessed 
<07/29/2012>.
Nguyen KS, Sanford RA, Huberman MS, et al (2012) Patterns of care for non-small-cell lung 
cancer at an academic institution affiliated with a national cancer institute-designated cancer 
center. J Oncol Prac; 8(1):57-62.
Ou SH (2011) Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for 
the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and 
beyond. Drug Des Devel Ther; 5:471-485.
Scagliotti G, Stahel RA, Rosell R, et al (2012) ALK translocation and crizotinib in non-small 
cell lung cancer: An evolving paradigm in oncology drug development. Eur J Cancer; 
48(7):961-73.
Shaw AT, Yeap BY, Mino-Kenudson M, et al (2009) Clinical features and outcome of 
patients with non-small-cell lung cancer who harbor EML4- ALK. J Clin Oncol; 27:4247-
4253.
Shaw AT, Yeap BY, Solomon BJ, et al (2011) Effect of crizotinib on overall survival in 
patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a 
retrospective analysis. Lancet Oncol; 12(11):1004-12.
Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, 
Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, 
Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus chemotherapy in 
advanced ALK-positive lung cancer. N Engl J Med. 2013 Jun 20;368(25):2385-94. doi: 
10.1056/NEJMoa1214886. Epub 2013 Jun 1.
Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin; 62(1):10-
29.
Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials; 
10(1):1-10.
Soda M, Choi YL, Enomoto M (2007) Identification of the transforming EML4-ALK fusion 
gene in non-small-cell lung cancer. Nature; 448(7153):561-6.
Takeuchi K, Choi YL, Togashi Y, et al (2009) KIF5B-ALK, a novel fusion oncokinase 
identified by an immunohistochemistry-based diagnostic system for ALK-positive lung 
cancer. Clin Cancer Res; 15(9):3143-9.
Weickhardt AJ, Rothman MS, Salian-Mehta S, et al (2012): Rapid-onset hypogonadism 
secondary to crizotinib use in men with metastatic nonsmall cell lung cancer. Cancer [Apr 4 
Epub ahead of print].


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Appendices
Appendix I: List of prohibited concomitant medications and concomitant 
medications requiring caution for LDK378
Appendix II: Harmonization of efficacy analysis of solid tumor studies 
(RECIST 1.1)


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Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
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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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.

SAP_001.pdf: 
CONFIDENTIAL • For Business Use Only 
 
l') N OVARTI s 
 
 
 
 
Clinical Development 
 
 
LDK378 
 
 
LDK378A2203 / NCT01685138 
 
 
A phase II, multicenter, single-arm study of oral LDK378 in 
crizotinib na..-ve adult patients with ALK-activated non-small cell 
lung cancer 
 
 
Statistical Analysis Plan (SAP) for Final Analysis 
 
 
 
 
Author: 
 
Document type: 
 RAP Documentaiot n 
Document status: 
Final 1.0 
Release date: 
12-April-2018 
Number of pages: 
40 
 
 
 
Property of Novartis 
Confidential 
May not be used, divulged, published or otheiw ise disclosed 
without the consent of Novartis 


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Document History • Changes compared to previous version 
 
Version 
Date 
Changes 
1.0 
12-April-2018 
N/A; First version 
 
 
 
 


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- 
 
 
Table of contents 
Table of contents....................................................................................................................... 3 
List of tables .............................................................................................................................. 5 
I 
Introduction ............................................................................................................................... 6 
1.1 
Study design .................................................................................................................. 6 
1.2 
Objectives ..................................................................................................................... 6 
1.2.1 
Primary objective ........................................................................................ 6 
1.2.2 
Secondary objectives .................................................................................. 6 
7 
2 
Statistical methods ......................................................................................................................... 7 
2.1 
Data analysis. ................................................................................................................ 7 
2.2 
Analysis sets ...................................................................... 
2.3 
Patient demographics and other baseline characteristics... 
.............8 
.............9 
2.4 
Protocol deviations ....................................................................................................... 0 
2.5 
Patient disposition ....................................................................................................... 10 
2.6 
Treatments (study drng, concomitant therapies, compliance) ............................. 11 
2.7 
Anal ysis of the prima1y variable ............................................................................... 13 
2.7.1 
Variable...................................................................................................... 13 
2.7.2 
Statistical hypothesis, model, and method of analysis ............................ 13 
2.7.3 
Handling of missing values/censo1ing/discontinua.tions ........................... 14 
2.7.4 
Supportive analyses .................................................................................. 14 
2.8 
Analysis of seconda1y  va1iables ................................................................................ 14 
2.8.1 
Efficacy ...................................................................................................... 14 
2.8.2 
Safety ..................................................................................................... 18 
- 
24 
24 
-  2.8.5 
Phannacogenetics/phannacogenomics ..............................................24 
24 
24 
2.9 
Samp le size calculation ............................................................................................. 24 
2.10 
Power for analysis of key secondary variables .......................................................... 25 
2.11 
Inte1i111 anal y s is ............................................................................................................... 25 
3 
Ch  anges  to protocol specified analyses .................................................................................. 25 
4 
Additional details on implementation of statistical methodology ......................................... 27 
4.1 
Data included in the analyses .............................................................................27 


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■ 
 
4.2 
Patient Classification into Analysis Sets  .................................................................. 2. 7 
4.3 
Last contact date................................................................................................. 28 
4.4 
Month derivation ........................................................................................................ 28 
4.5 
Dose inten11ptions and dose changes ......................................................................... 28 
4.6 
Efficacy endpoints ...................................................................................................... 29 
4.6.1 
Implementation of RECIST Guidelines ................................................... 29 
4.6.2 
Sources for overall lesions response ................................................... 33 
4.6.3 
Kaplan-Meier estimates ............................................................................ 33 
4.6.4 
Confidence inte,val and p-value for response rate. ............................. 34 
4.7 
Safety evaluations ...................................................................................................... 35 
4.7.1 
Multiple assessments within post-baseline visits .................................... 35 
4.7.2 
Baseline ............................................................................................. 35 
4.8 
Handling of missing or paitial dates ......................................................................... 36 
4.8.1 
AE date imputation ................................................................................... 36 
4.8.2 
hlcomplete date of initial diagnosis of cancer, da.te of most recent 
recmTence and date of anti-neoplastic therapies ....................................... 38 
4.8.3 
Incompl ete assess ment dates for tumor assessment. .............................. 38 
4.8.4 
Incomplete date for death ....................................................................... 39 
39 
5 
Reference ................................................................................................................................. 40 


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List of tables 
Table 2-1 
Table 2-2 
Table 2-3 
Table 3-1 
Table 4-1 
Table 4-2 
Table 4-3 
Table 4-4 
Table 4-5 
Table 4-6 
Table 4-7 
Outcome and event dates for DOR and PFS analyses ............................. 16 
ECOGpe1fo1mance scale ..................................................................................23 
Operating characteristics of Simon's optimal two-stage design ............ 25 
Changes to protocolspecified analysis or descriptions and rationale ... 25 
Patient classification rnles ..................................................................... 27 
hlclusion/exclusion of assessments used in waterfall graph ............... 32 
SOlu·ces  for overall lesion response ................................................................ 33 
AE/treatment date abbreviations .................................................................... 37 
AE pa1tial date imputation algo1i tlun .............................................. 37 
AE/treatment date relationship and imputationlegend ........................... 38 
AE imputation example scenarios ................................................................ 38 


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1 
Introduction 
This SAP desc1ibes the planned statistical methods for the final analysis for study 
LDK378A2203. 
1.1 
Study design 
This is a prospective, multi-center, open-label, single am1, phase II study with a Simon two- 
stage design to evaluate the efficacy and safety of single-agent LDK378 in patients with ALK-
reammged NSCLC not previously treated with crizotinib. Patients must have received 
cytotoxic chemotherapy (1 to 3 p1ior lines of which I must be a platinum doublet), and must 
have progressed during the most recent chemotherapy prior to emollment in the trial. Patients 
will receive treatment with LDK378 750 mg administered orally on a once-daily dosing 
schedule. Treatment with LDK378 750 mg once daily will continue until the patient 
experiences unacceptable toxicity that precludes ftuther treatment, discontinues treatment  at 
the discretion of the investigator or at patient's request, starts a  new anticancer therapy, or 
dies. LDK378 may be continued beyond RECIST-defined disease progression (PD) as 
assessed  by  the investigator  if,  in  the  judgment  of  the  inves tigator, there is  evidence of 
continued  clinical  benefit.  In  these  patients  tumor  assessment  should  continue  as  per the 
schedule of assessments until treatment with LDK378 is pennanently discontinued. Patients 
who discontinue study drng in the absence of progression will continue to be followed for 
tumor assessments until the time of PD as assessed by the investigator. 
1.2 
Objectvi es 
1.2.1 
Primary objective 
The prinia1y object ive is to demonstrate the anti-tumor activity of LDK378, as measmed by 
overall response rate (ORR), by investigator assessment per RECIST 1.1. 
1.2.2 
Secondary objectives 
Toe  key seconda1y  objectives are to evaluate response related endpoints as assessed by  both 
investigator and Blinded Independent Review Committee (BIRC), tmless otherwise specified, 
asperRECIST 1.1: 
• 
duration ofresponse (DOR) 
• 
disease control rate (DCR) 
• 
tin1e to response (TTR) 
and to assess 
• 
ORR by BIRC assessment. 
Other secondary obje.ctives are to evaluate: 
• 
the safety profile ofLDK378 
• 
progression-freesurvival (PFS) as assessed by both investigator and BIRC 
• 
Overall smv ival (OS). 


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2 
Statistical methods 
This section and its subsections will be imported to section 9.7 of the CSR after the analyses 
have been conducted. This section of the RAP follows the CSR template stmcture of Section 
9.7 as of the release date of this document. 
The text will be changed to the past tense when impo1ted into the CSR; references to Section 
4, where additional details are provided for programming implementation, may be removed in 
the CSR. 
In what follows, study drng refers to LDK378/Cerit:inib. 
2.1 
Data analysis 
Data will be analyzed by Novartis Oncology Biostatistics and programming personnel 
according to the data analysis section 10 of the LDK378A2203 protocol. hnpo11ant 
infom1ation is given in the following sections and details are provided, as applicable, in 
Section 4 from which Appendix 16.1.9 of the CSR will be extracted. 
SAS® version 9.4 (or later version if available at time of database lock) will be used in all 
analyses. 
Data from all patients who signed informed consent in centers that participate in this study 
will be used in the analysis; due to expected small size of emolhnent at individualcenters, no 
center effect will be assessed. Each analysis will use all data in the database up to the analysis 
cutoff date, determined prior to database lock. 


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As described in Section 1.1 this study has a Simon two-stage design. If the study stops at the 
end of Stage 1 (see Section 2.11), the data available will be smnmarized in an  abbreviated 
CSR. Otherwise, the analysis cut-off date for the primary analysis of sn1dy da.ta will be 
established  once all patients have either completed  at  least six  treatment cycles, i.e.,  168 days 
(1 cycle = 28 days), or discontinued study dmg earlier. The data will be summarized in the 
primary CSR. Following the primary analysis time point, the study will remain open. Patients 
still being followed on the study will continue as per the schedule of assessments. 
The analysis cutoff date for the final analysis of study data will be 22-Jan-2018 con-espondi.ng 
to last patient last visit date. 
Section 4.1 provides futther details regarding data to be included in the analyses. 
 
General presentation of descriptive summaries 
Qualitativ e data (e.g., gender, race) will be su!lllnat·ized by frequency co1mts an d percen tages. 
Percentages will be calculated using the number of patients in the relevant populaiton or 
subgroup as the denominator. 
Continuous da.ta (e.g. , age, body weight) will be su!lllnat·ized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximtnn). 
 
2.2 
Ana l ysi s sets 
A patient is considered to be enrolled into the sn1dy if they have signed informed consent. 
Only patients who have signedinfom1ed consent will be included in the analysis data sets. 
 
Full Analysis Set 
Tue Full Analysis Set (FAS) consists of all patients who received at least one dose of study 
drng. All efficacy endpoints will be analyzed using FAS. 
Tue FAS will be used for all listings. Unless othenvise specified the FAS will be the default 
analysis set used for all analyses. 
 
Safety Set 
The Safety Set consists of all patients who received at least one dose of study drng. All safety 
data will be analyzed using the SafetySet. 
The FAS and Safety Set in this study are identical. 
Per-Protocol Set 
For the definition refer to CLDK378A2203 RAP Module 3 Amendment 1. No analyses will 
be pe1fonned based on patients in this analysis set in this CSR. 
 
 


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2.3 
Patient demographics and other baseline characteristics 
Tue 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 smumarized and listed. 
Categorical data (e.g. gender, race, ethnicity, WHO perfonnance status) will be summarized 
by frequency count and percentages. Continuous data (i.e. age) will be summarized by 
desc1pi tivestatistics (as defined in Section 2.1) including quartiles. 
 
Diagnosis and extent of cancer 
Descriptive statistics and frequency counts and percentages will be tabulated, as approp1iate, 
for diagnosis and extent of cancer based on the data collected on the electronic Case Report 
Fonn (eCRF) including primary site of cancer, details of tumor histology/cytology, 
histological grade, time since initial diagnosis of primary site, stage at initial diagnosis, time 
from initial diagnosis to first recunence/progression, time since most recent 
relapse/progression, metastatic sites, and (based on the <la.ta collected on the RECIST eCRFs 
on the individual target and non-target lesion codes) presence/absenceof target and non-target 
lesions. 
Time since initial diagnosis, time since most recent relapse/progression and time since initial 
diagnosis to first recwTence/ progression will be swnmarized in months. 
Medical history 
Medic.al histo1yand ongoing conditions, including cancer-related conditions and symptoms 
will be summarized and listed. Separate sm111uaries will be presented for ongoing and 
histo1ical medical conditions. The summa1ies will be presented by prima1y system organ 
class and preferred tenu. Medical history and current medical conditions are coded using the 
Medical Dictionaiy for Regnlato1yActivities (MedDRA) tenninology . 
 
Prior anti-cancer therapy 
Prior  anti-neoplastic (anti-cancer)  therapy  will  be  listed  in  three  separate  catego1ei s:  1. 
medications,2. radiotherapy, and 3. sm·gery. 
Tue nwnber and percentage of patients who received ai1y prior anti-neoplastic medications, 
prior anti-neoplasticradiotherapy or prior anti-neoplasitc stll'gery will be stll11lnarized. 
Prior anti-neoplastic medications will be stmnuaiized by chemotherapy(medication) setting, 
other therapy (medication) setting, munber of p1ior regimens of chemothe rapy, prior 
anticancer medications  including cisplatin, cai·boplati,npemetrexed, docetaxel, gemcitabine, 
bevacizumab,   erlotinib   and   gefitinib.   Prior   ai1tineoplastic   medications   will   also   be 
summarized by ATC class, and prefell'ed tenn. 


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Screen failures 
Screen failures will comprise patients wbo have been enrolled and have failed to meet 
inclusion or exclusion criteria.. These patients are not treated with study drug. Frequency 
counts and percentages will be tabulated for all enrolled patients as follows: 
• 
Number (%) of patients who completed screening phase (based on the presence of srudy 
phase completion date and the 'Next phase entered' is 'Treatment' in the 'Screening Phase 
Disposition' page); 
• Number (%) of patients who discontinued dtni.ng screening phase ( bas ed on thepresence 
of date of discontinuation and discontinuation/ "subjectstatus" reason entered and ' Will 
the subject continue into the next phase of the tiial' is ' No' in the 'Screening Phase 
Disposition' page) ; 
• 
Reasons for screening phase discontinuation(based on reasons recorded in Screening 
Phase Disposition' page). 
All screen failure patients with reasons for screen failure will be listed. Violations of 
inclusion/ exclusion criteria leading to screen failures will be smnma.rized by criteria. 
2.4 
Protocol deviations 
Frequency counts and percentages of patients in the FAS with any protocol deviations 
(inclusion/exclusioncriteria not met, patient not withdrawn as per protocol, key procedures 
not perfo1med as per protocol, treatment deviation, prohibited concomitant medication, Good 
Clinical Practice (GCP) deviation) will be tabulated by the deviation catego1y Major protocol 
deviations will be tabulated separately. Toe full list of protocol deviations are documented in 
the data handling plan. 
Protocol deviations will be listed. 
 
2.5 
Patient disposition 
The FAS will be used for the patient disposition summary tables and listings. The following 
will be tabulated: 
• Number (%) of patients who are still on-treatment (based on the absence of the ' End of 
Treatment Phase Completion' page); 
• Number(%) of patients who discontinued treatment (based on completion of the ' End of 
Treatment Phase Completion' page with date of discontinuation  and reason of 
discontinuation/ ' Subject Status' entered); 
• Number (%) of patients who entered post treatment efficacy follow-up (based on 'Next 
Phase Entered'  is ' Post-treatmentfollow-up' on the ' End of Treatment Phase Completion' 
page for patients who discontinued t1·e a.tme nt); 
• Number(%) of patients who entered stnvival follow-up (based on ' Next Phase Entered' is 
'Survival follow-up' on the 'End of Treatment Phase Completion' page for patients who 
discontinued treatment); 
• Number (%) of patients who discontinued from study (based on 'Will subject continue 
into the next phase of the trial' is 'No' as entered on the 'End of Treatment Phase 
Completion' page for patients who discontinued treatment;) 


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• Primaiy reasons for srudy treatment discontinuation (based ou discoutiuuatiou reasons 
entered under ' Subject S tatus' in the ' End of Treatment Phase Completion' page); 
• Number (%) of patients who are still in the post-treatment srudy phase (based on presence 
of 'End of Treatment Phase Completion' and absence of 'Sn1dy Phase Completion' page); 
• Number (%) of patients who discontinued from the post-treatment efficacy follow-up 
(based ou completion of 'Study Phase Completion' page with date of discontinuation and 
discontinuation reasons entered under 'Subject Status'); 
• Ntunber (%) of patients who entered stuvival follow-up (based on completion of 'Study 
Phase Completion' page with date of discontinuation and discontinuation reasons entered 
under 'Subject Status' and 'Next Phase Entered' is 'Smvival follow-up' for patients who 
discontinuedfrom the post-treatment efficacy follow-up); 
• Number (%) of patients who discontinued from study (based on completion of 'Study 
Phase Completion' page with date of discontinuation and discontinuation reasons entered 
tmder 'Subject Stanis' and 'Will subject continue into the next phase of the ttial' is 'No ', 
for patients who discontinued from the post-treatment efficacy follow-up); 
• P1ima1y reasons for discontinuation from the post-treatment efficacy follow-up (based on 
discontinuation reasons entered under 'Subject Status' in the 'Study Phase Completion' 
page). 
 
2.6 
Treatments (study drug, concomitant therapies, compliance) 
The Safety Set will be used for all medication data sumrna1ies ai1d listings unless othe1wise 
speci fied. 
Study drug and study treatment 
Sn1dy drng and study treatmentboth refer to LDK378 and will be used interchangeably. 
 
Date of first/last administrationof studydrug 
The date of first administration of study chug is defined as the first date when a non-zero dose 
of study ch11g was achninisteredand recorded on the Dosage Administration Record (DAR) 
eCRF. For the sake of simplicity, the date of first administration of study ch11g will also be 
refe1Ted as start date of srudy chug. 
The date of last administration of study ch11g is defined as the last date when a non-zero dose 
of studydrng was administered and recorded on DAR eCRF. This date will also be refen-ed as 
last da.te of study dmg. 
 
Study day 
The study day for all assessments (e.g. tumor assessment, death, disease progression, tumor 
response,  pe1fonnance status,  adverse event onset,  laboratory abnonnality occunen,ce vital 
sign measm·emeut, dose intem1ption) will be calculated using the sta11 date of srudy drug as 
the origin. For assessments occuning after or on the sta1t date of srudy ch11g, s tud y day will be 
calculated as: 
Study Day =Event date - sta1t date of study chug + I . 


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The first day of study drng 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) occuning p1io r to the sta11 of the sn1dy chug, study day will be 
negative and will be calculated as: 
Study Day= Event date• staJ1date of study ch11g. 
Tue stu dy day will be displayed in the data listings. 
 
Dose exposure and intensity 
Definitions of duration of exposure, cumulative dose, average daily dose, acn1al dose intensity 
(DD, relat ive dose intensity (RDD, as well as intermediate calculations, include: 
• 
Duration of exposure (days): last date of study clrng - first date of study dmg + 1 
(periods of inte1rnption are not excluded) 
• 
Ctunulative dose (mg): 
• 
Number of dosing days(days): 
• 
Average daily dose (mg/day): 
• 
DI (mg/day): 
• 
RD!(%): 
total dose of study ch11g taken by a patient in the study 
duration of expostu·e - number of zero dose days 
cmuulative dose (mg)/ nmuberof dosing days (days) 
ctunulative dose (mg)/  duration  of  exposure  (days) 
100 x [DI (mg/day)/ plalllled dose (750 mg)] 
Note: given the plaiilled LDK378 dose of 750mg/day, the plaiilled dose intensity can be 
calculated as PDI (mg/day) = cumulative planned dose (mg)/Dura.tion of expostu-e (days), 
where Clllllulative plalllled dose (mg) = Protocol plam1ed dose of 750 (mg)* Duration of 
exposme. RDI (%) which is calculated as I00*DI/PDI can be simplified as shown above. 
Dm-ation of srudy exposme to srudy ch11g, cumulativ e dose , average daily dose, DI and RDI 
will be sununarized. In addition, the dmation of exposure to study chug will be categorized 
into time inte1vals; frequency counts and percentages of patients with exposure in each time 
interval will be presented. Frequency counts and percentages of patients who have dose 
chaJ1ges, reduc tions or intenu ptions , and the con-esponding reasons, will be stlllllnarized. 
Listings of all doses of the sn1dy ch11g along with dose change/intenup tion reasons will be 
produced. 
Section 4.5 provides futther details on the definition of dose changes and inte1n1ptions. 
 
Concomitant therapy 
Concomitant therapies are defined as any medica tions (excluding study chug, p1ior 
antineoplastic treatments and blood transfosions), surgeries or procedures (including physical 
therapy) administered in the sn1dy and are recorded in the Prior and Concomitant Medications 
and the Surgical and Medical Procedures eCRF, respectively. 
These therapies will be coded using the WHO Drng Reference Listing (WHO DRL) 
dictiona1y that employs the WHO Anatomical Therapeutic Chemical (\VHO ATC) 
classification system. All stunma1ies will be tabulated using frequency counts and percentages. 
Concomitant therapies will be smnmarized by ATC class and prefen-ed term. These 
smmuaries will include 1) medications sta1t ing on or after the sta1t of study dmg but sta1ting 


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no later than 30 days after last dose of study drng and 2) medications start ing prior to the start 
of study drng but continuing after the start of study drng. 
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the s tart of study drng or starting more than 30 days after the last date of study drng will be 
flagged in the listing. 
Antineopal stic therapy after discontinuation of study drug 
The FAS will be used for all listings and summa1ies of antineoplastic therapies initiated after 
discontinuation of srudy chug. All stuumaries will be tabulated using frequency counts and 
percentages. 
Antineoplastic medications initiated after discontinuation of study drng will be smumarized 
and listed by Anatomical Therapeutic Chemical (ATC) class and prefen-ed tenu . 
Antineoplastic radiotherapy since discontinuation of study treatment will be stUD1ua1ized and 
listed by setting. 
Anti.neoplastic smgery since discontinuation of srudy treatment will be stuumarized and listed 
by procedm·e. 
2.7 
Analysis of the primary variable 
The pri mar y objective is to demonstrate the antitumor activity of LDK378, as measured by 
ORR by investigator assessment. 
 
2.7.1 
Variable 
The pri mary endpoint used to evaluate the anti-tumor activity of LDK378 is the overall 
response rate (ORR), defined as the propo1tion of patients with a best overall confinned 
complete response (CR) or partial response (PR), as assessed per RECIST 1.I by the 
investigator. 
2.7.2 
Statistical hypothesis, model, and method of analysis 
The primary efficacy analysis will be performed on the FAS. 
The study targets an ORR of 50%. A response rate of 35% or Jess is considered as insufficient 
level of activity for the proposed patient population. Therefore, 
Ho: ORR .:'o 35% will be tested vs H1: ORR > 50% 
using a one-sided test with o.=0.05 based on Simon's optimal t\vo-stage design (Simon 1989). 
If 45 or more responses are seen in 105 total patients (estimated ORR of 42.9%), then Ho will 
be rejected and the ttial declared positive. 
Stage 1 will enroll 43 patients. If the sn1dy is terminated early at the end of Stage l (16 or 
fewer responses among 43 patients enrolled to Stage 1), then the study will be considered to 
have failed to reject Ho See Section 2.11 for fi.uther details of the stopping criteria for fotility. 
Stage 2 will include an additional 62 patients. The prim ar y analysis will occur when all l 05 
patients have completed 6 cycles of treatment or discontinued treatment earlier. 


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The ORR will be estimated and the 90% and 95% Clopper-Pearson (Clopper and Pearson 
1934) confidence inte1vals (Cls) will be provided. The uniformly minimum variance tmbiased 
estimator (UMVUE) and the 90% two-stage CI (Atkinson and Brown 1985) will also be 
presented. Refer to Section 4.6.4 for additional details. 
Clopper-Pearson confidence inte,vaJs will be used since the confidence limits based  on  the 
nonnaJ approximation are not bounded by the [O,  1]  interval  ,  meaning that for rates close to 0 
or I, the upper limit of the  nonuaJ approximation inte,val for the  proportion  could exceed  I  or 
the lower limit could  be  negative.  The  90%  two-stage  CI  will be  presented  to conespond  to 
the Simon two-stage p-value. 
2.7.3 
Handling of missing values/censoring/discontinuations 
Confirmed PR or CR repo11ed prior to any additional anticancer therapy will be considered as 
responses in the calculation of the ORR in espective of the number of missed assessments 
before response. 
Patients with a best overall response (BOR) of 'Unknown' or 'Not Assessed'  per RECIST I.I 
will be considered as non-responders when estimating ORR. 
Patients who have disease progression and continue to receive study drng after progression 
will qualify for PD at the time of progression and will be co1mted as PD in the de1ivation of 
ORR and any other efficacy endpoints. 
2.7.4 
Supporitve analyses 
Listings of calculated overall lesion response based on raw measurements repo11ed by the 
investigator (Source 2 in Table 4-3) will be generated. Waterfall plots representing the best 
percentage change from baseline in the smn of the longest tumor diameters for target lesions 
will be produced. 
 
2.8 
Analysis of secondary variables 
2.8.1 
Efficacy 
All tlllllor response related endpoints tmder the secondary efficacy objectives (DOR, TTR, 
DCR, PFS) will be analyzed as per investigator assessment and as per the BIRC. 
Confirmation of response is required for all response endpoints, as per RECIST 1.1. 
All secondary endpoint analyses will be performed based on the FAS, unless otherwise 
specified. 
No adjustment for multiple testing will be made. 
The key secondary effic cy endpoints are 
• 
ORR byBIRC 
• 
DOR by investigator assessment and by BIRC 
• 
DCR by investigator assessment and by BIRC 
• 
TTR by investigator assessment and by BIRC 


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Other secondary efficacy endpoints are 
• PFS by investigator assessment and by BIRC 
• OS 
The definitions and details on the derivation of the secondary endpoints are given in the 
LDK378A2203 protocol. Fmther details and mies needed for programmatic implementation 
of RECIST 1.I guidelines are provided in Section 4.6.1. 
Overall Response Rate 
ORR as assessed by the BIRC, per RECIST  1.1,  will be estimated and  Cls  will  be provided 
per all methods desc1ibed in Section 2.7.2. 
Bestoverall response 
The BOR will be assessed based on reported lesion responses at different evaluation time 
points. Both CR and PR require confinnation at least 4 weeks after its initial obse1vation. 
Only tumor assessments pe1fonned before the start of any finther anti-neoplastic therapies (i.e. 
any additional seconda1y anti-neoplastic therapy or anti-cancersurgery) will be considered in 
the assessment of BOR. If a patient receives any further anti-neoplastic therapy while on 
study, any subsequent assessments will be excluded from the BOR detem1ination. Further 
anti-neoplastic therapies will be identified via protocol deviations or from the data collected 
on ' Anti-neoplastic therapies since last date of study dmg' as appropriate. Clinical 
dete1ioration will  not  be considered  as  documented disease progression.  Patients  with BOR 
' unknown' will be summarized by reason for having unknown status. The following reasons 
will be used: 
• 
No valid post-baseline assessment 
• 
All post-baseline assessments have overall responseUNK 
• 
New anti-neoplastictherapy staited before first post-baseline assessment 
• 
Stable disease (SD) too early (<= 6 weeks after start date of study dmg) 
• 
PD too late (> 12 weeks after start date of study drng) 
Special (and rare) cases where BOR is 'unknown' due to both early SD and late PD will be 
classifiedas 'SD too early'. 
Duration of response 
Among patients with a confumed response (PR or CR), DOR is defined as the time from first 
documented response (PR or CR) to the date of first doclllllented PD or death due to 
underlying cancer. If a patient has not had an event, DOR is censored at the date of last 
adequate trnnor assessment. 
The censoring and event date options to be considered for the main anal ysis are presented in 
Table 2-1. 


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Table 2-1 
Outcome and event dates for DOR and PFS analyses 
Situation 
Date 
Outcome 
A 
No baseline assessment 
 
B 
Progression at or before next scheduled 
Assessment 
C1 
 Progression or death after exactly one 
missing assessment 
C2 
 Progression or death after two or more 
missing assessments 
D 
No progression 
 
E 
Treatment discontinuation due to 'Disease 
progression' without documented 
progression, i.e. clinical progression 
based on investigator claim 
F 
New anticancer therapy given 
 
G 
Deaths due to reason other than 
deterioration of 'Study indication' 
Date of first dose of 
study drug• 
Date ofprogresison 
 
Date ofprogresison (or 
death) 
Date oflastadequate 
assessmen•t 
Date of last adequate 
assessment • 
N/A 
 
 
 
Date of l ast adequate 
assessment • 
Date of last adequate 
assessment • 
Censored 
Progressed 
Progressed 
Censored 
Censored 
Information ignored. 
Outcome derived 
based on radiology 
data only. 
Censored 
 
Censored (only 
applicable to DOR) 
• The rare excepiton to this is tt thepatient dies no later than the time of the second scheduled assessment as 
definedin the protocol in whichcase this is a PFS event at the dateof death 
• After the last adequate rumor assessment. "Date of next scheduled assessment" is defined in Section 3.2.7 of 
Section 14 (Appendix II) of the LDK378A2203 protocol 
DOR will be described in tabular and graphical fom1at using Ka plan-Meier methods including 
estimated median  (in  months)  with 95% CI,  25th  and  75th  percentiles  (Brookmeyer  and 
Crowley 1982, Klein and Moeschberger 2005) and Kaplan-Meier estimated   probabilities  with 
co1Tes p ondin g 9 5 % C ls (K albfleisch and Prentice 2002) at several time points (including at 
least 4, 8, 12, 15, 18 months). 
These analyses will be pe1formed se parately based on investigator assessment and based on 
BIRC assessment. 
Refer to Section 4.6.3 for ftuther details regarding derivation of Kaplan - Meier estimates. 
 
Diseasecontrol rate 
DCR, defined as the propo1tion of patients with BOR of CR,  PR, SD, or Non-CR/Non-PD, 
per RECIST 1.1, will be estimated and the exact binomial 95% CI provided. 
These analyses will be perform ed separately based on investigator assessment and based on 
BIRC assessment. 


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Time to response 
Time to overall response of CR or PR (TTR) is defined as the time from sta1t of study drng to 
first documented response (CR or PR, which must be confumed st1bsequently). Patients who 
did not achieve a response (i.e. confumed response) will be censored as follows: 
• 
At maximum follow-up (i.e. FPFV to LPLV used for the analysis), for patients who ha.d 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; 
• 
At last adequate ttuuor assessment date, otherwise. In this case the patient has not yet 
progressed so he/she theoretically still has a.cha.nee of responding. 
TTR will be summarized by frequency counts using descriptive statistics for patients with 
confinued CR or PR. These analyses will be pe1fonned separntely based on investigator 
assessment and based on BIRC assessment. 
Progression-freesurvival 
PFS is defmed as the time from the slart date of study drng to the date of the fust 
radiologicaly doclllllented PD 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 ftuther anticancer therapy, PFS will be censored at the date of the last 
adequate tumor evaluation before the cut-off date or before the sta11 of the new anticancer 
therapy date, whichever is earlier. Clinical deterioration will not be considered as a qualifying 
event for progression. Refer to Table 2-1 for censoring and event date options and outcomes 
forPFS. 
In particular, PFS will be censored at the last adequate tumor assessment: if one of the 
following occurs: absence of event; the event occuffed after a new anticancer therapy is given; 
the event occuned after two or more missing tumor assessments (see Section 4.6.1). See also 
Section 4.6.1 describing the special case of a missing baseline tlllllor assessment. 
PFS will be described in tabular and graphical fonna.t using Kaplan-Meier methods as 
desc1ibed for DOR, including estimated median (in months) with 95% CI, 25 th and 75th 
percentiles and Kaplan-Meier estimated probabilities with con-esponding 95% Cls at several 
time points (including a.t least 4, 8, 12, 15 and 18 months). Censo1ing reason s will also be 
summarized. 
These analyses will be performed separately based on investigator assessment and based on 
BIRC assessment. 
Overall  survival 
OS is defined as the time from the stan date of snidy drng to the date of death due to any 
cause. lf the patient is alive at the date of the anal ysis cut-off or lost to follow-up, then OS 
will be censored a.t the last contact date p1ior to data. cutoff date (see Section 4.3 for funher 
details on derivation of last contact date). 
OS will be described in tabular and graphical fonnat using Kaplan-Meier methods as 
desc1ibed for DOR, including estimated median (in months) with 95% CI, 25 th and 75th 


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percentiles and Kaplan-Meier estimated probabilities with co1responding95% Cls at several 
time points (including at least 4, 8, 12, 18 and 24 months).Censoring reasons will also be 
sununa1ized. 
 
Duration of Follow-up and Gap Analyses 
The duration of treatment pe1iod will be reported: 
Treatmeut period=Last patient last date of ti-eatment- Firstpatient sta1tdate of treatment+1 
In addition, descriptive statistics including qua1tiles will be tabulated for the duration of 
follow-up in the study: 
• Duration between sta1t date of study drng and cut-off da.te = (Cut-off date - Start date of 
study drng + I)). 
• 
Follow-up time for PFS/OS= (Date of event or censoring - Stait date of sn1dy drug + 1).. 
All stmnnarieswill be reported in months (see Sec tion 4.4). The calculations for PFS will be 
based on the investigator and BIRC assessments. Date of censoring is the same as the one 
defined for thePFS and OS analyses. 
 
2.8.2 
Safety 
All safety analyses will be pe1formed based on the Safety Set. 
 
Baseline 
Baseline is the result of an investigation desc1ibing the " trne" mlinfluenced state of the pa.tient. 
The las t available assessment before or on the startdate of study drng is defined as "baseline" 
value or" baseline" assessmen.t If an assessment is planned to be perfonned prior to the first 
dose of study drng in the protocol and the assessment is perfonned on the same day as the first 
administration of srudy drng, it will be assmned that it was perfonned prior to study drng 
administration, if assessment time point is not collected or is missing. If assessment time 
points are collected, the obse1ved time point will be used to dete1mine pre-dose on studyday 
I for baseline calculation. Unscheduled assessments will be used in the detennination of 
baseline. See Section 4.7.2 for forther details on derivation of baseline for laborato1y data and 
ECGs. 
Patients who stait treatment and discontinue from the study on the same day may have 2 
different sets of data collected on study day 1, one being reported to the cycle 1 day 1 visit, 
the other reponed to the end of treatment (EOT) visit. Data reported at the EOT visit are not 
eligible for baselineselection. 
 
Grouping for the analyses 
The overall observation period will be divided into three mutually exclusivesegments: 
• 
Pre-treatment period: from day of patient' s infonned consent to the day before first dose 
of study drng 
• 
On-treatment pe1iod: 


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o For discontinued patients, from dayof first dose of study drng to 30 days after last 
dose ofsrudy drug 
o For ongoing patients, from day of first dose of study chug to the data cut-off date 
• Post-treatmentperiod:starting at day 31 after last dose of study drug 
The safety SUllllllary tables will include only assessments collected no later than 30 days after 
study ch11g discontinuationand assessments prior to the data cut-off date for on-going patients, 
unless otherwise specified. 
For select items, shift tables or change from baseline summaries generated for laboratory, 
ECG, vital signs and change score generation may use data from pre-treatment period for 
baseline calculations. 
All data, regardless of obse,vation period, will be listed and assessments collected in the pre- 
treatment and post-treatment period will be flagged in all I.be listings . 
 
Adver se e vent s (AE s) 
AEs will be coded using the MedDRA 20.1 corresponding to the latest version available prior 
to planned date of clinical database lock (in case, the setting is changed, SAP will need to be 
amended) 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 
coll'espondingto I.be se ve1ity 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 I.be "End of Treatment Phase completion", "Study Phase Completion" or "Death" 
eCRFpages. 
All AE smrnnaries will be smnmarized (frequency com1ts and percentages) by system orgar1 
class and/or prefe!1'ed term, and maxi.mum severity grades, except where otherwise noted. A 
patient with multiple CTC grades for an AE will be summarized under the maximum CTC 
grade recorded for the event. 
The following AE summaries will beproduced: 
• AEs regardless of study dJug relationship 
• AEs suspected to be sn1dy chug related 
• On-treatment deaths, by primary system organ class and prefened te1m 
• SAEs regardlessof study dJug relationship 
• SAEs suspected to be study drng related 
• AEs leading to discontinuationof study chug 
• AEs requiringdose adjustment 
• AEs requiring study ch11g inten11ption 
• AEs requiring dose adjustment or study chug interruption 
• AEs requiringsignificant additional therapy 


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Adverse events of specialinterest 
Adverse events of special interest (AESis) are defined as AEs within the following categories/ 
groupings of prefen-ed terms: 
• 
Hepatotoxicity 
• 
Interstitial Jung disease/Pneumonitis 
• 
QT inte1val prolongation 
• 
Bradycardia 
• 
Hyperglycemia 
• 
Gastrointestinal toxicity (nausea, vomiting and dianhea) 
• 
Pancreatitis (including lipase and amylase elevations) 
 
The AESI defmitions will be based on the electronic case retii eval strategy (eCRS) for 
LDK378 program based on MedDRA 20.1- 
In case, the setting is changed, SAP will need to be amended. 
These AESis will be summarized for each grouping, by prefened tem1, as follows: 
• AllAESis 
• CTC grade 3/4 AESis 
• 
AESis suspected to be study drug related 
• 
CTC grade 3/4 AESis suspected to be study drng related 
• Serious AESis 
• 
AESis leading to study drng discontinuation 
• 
AESis requiringdose adjustment 
• 
AESis requiling study drng intenuption 
• 
AESis leading to dose adjustlnentor study drng intenuption 
Laboratory data 
For laboratory data assessments, data from all sources (central and local laboratories) will be 
combined. The summa1ies will include all laboratory assessments collected no later than 30 
days after study drng discontinuation. All Jaborato1y assessments will be listed and those 
collected later than 30 days after study drng discontinuation will be flagged in the listings. 
Laboratory data will be classified (by Novartis Oncology CORR) into CTC grades according 
to the NCI CTCAE v4.03. For all repo1ts, CTC grade is always obtai11ed on the converted 


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measurement in SI unit. A seve1ity grade of 0 will be assigned when the val ue is  within 
nonnal limits. Grade 5 will not be used. 
The following sulllJlia1ies will be produced for the hematology and biochem.islly labo ratory 
data (by laboratory parameter): 
• Shift tables using CTC grades to compare baseline to the worst post-baseline value for 
laborato1y parameters with CIC grades 
• Shift tables using low, nonnal, 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 notdefined. 
The following lab parameters will be summarized: 
• 
Hematology: absoh1te lymphocytes (decreased), absolute neutrophils (decreased), 
hemoglobin (anemia) (decreased), WBC (decreased); platelet counts (decreased) 
• Biochemist1y: alkaline phosphatase (APT) (increased), SGPT (ALT) (increased), SGOT 
(AST) (increased), total bilirnbin (increased), amylase (increased), potassium (hyper and 
hypo), sodium (hyper and hypo), creatinine (increased), glucose (hyper and hypo), 
phosphate (hypo) 
The following laboratory parameters will be presented in listings and will not be smnmarized: 
absolute  basophils,  absolute  eosinophils,  absolute  monocytes,  RBC,   albumin, calcium, 
magnesium,  creatinine clearance, direct bilirnb,in blood  urea nitrogen (BUN) or urea, GGT, 
urinalysis macroscopic panel (dipstick) (bilirubin, blood, glucose, ketones, WBC, pH, protein, 
specific gravity), Urinalysis Microscopic  panel (RB,C WB,C casts), Honnones (males only) 
Testosterone, LH, FSH, sex hormone binding globulin (SHBG), coagulation INR, pro- 
tlu·ombinti.me (PT) or Quick Test. 
The following listings will be produced for the laborato1ydata for all laborato1yparameters 
where CTC grades are defined: 
• 
Listing of patients with laborato1y abno1malities of CIC grade 3 or 4 
• Listing of all laboratory data with values flagged to show the conesponding CTC grades 
and the classifications relative to the laboratory reference ranges. 
Liver function tests (LFTs) of interest for LDK378 are total bilirubin (TBILn, ALT, AST and 
ALP. In what follows, AT refers to ALT or AST values. LFTs will be smnmarized as follows: 
• Shift tables of baseline vs. worst post-baselineon-treatment values for the categories: 
o TBILI$ 2xULN, TBILI > 2xULN and missing TBILI 
o ALT$ 3xULN, ALT > 3xULN and missing ALT 
o AST$ 3xULN, AST > 3xULN and missing AST 
o ALP:;; 2x ULN, ALP > 2xULN and missing ALP 
• 
Frequency counts and percentages of patients with worst post-baselineon-treatment 
values in the categories: 
o ALT > 3xULN, ALT> SxULN, ALT> IOxULN, ALT> 20xULN 
o AST > 3xULN, AST > SxULN, AST> I0xULN, AST> 20xULN 
o AT> 3xULN, AT> 5xULN, AT > I0xULN, AT > 20xULN 


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o TBILI > 2xULN 
o ConcmTent ALT > 3xULN and TBILI > 2xULN 
o ConcmTent AST > 3xULN and TBILI > 2xULN 
o ConcmTent AT > 3xULN and TBILI > 2xULN 
o ConcmTent AT > 3xULN and TBILI > 2xULN and ALP :;; l .5xULN 
o ConcmTent AT > 3xULN and TBILI > 2xULN and ALP >= 2xULN 
ConctUTen t mea surements 
are those occmTing on the same date. 
In addition , a listing of all TBILI, ALT, AST and ALP values for patients wilh a post-baseline 
TBILI > 2xULN, ALT> 3xULN or AST > 3xULN will be provided. 
 
ECGs 
ECG data will be analysed based on central laboratory reported results. The smmuaries will 
include all ECG assessments perfonued no later than 30 days after lhe last da.te of stud y drug. 
All ECG assessments will be listed, and those collected later than 30 days after study drug 
discontiima.tion will be flagged in the listing. 
The following analyses will be perfonned for each applicable ECG parameters (RR, PR, QRS, 
QT, ventricular rate, QTcB QTcF, and QTcP) as noted. 
• 
For each of lhe QTcF, QTcB, QTcP, and QT iI1te1v als ,  desctiptive statistics a.t b aseline, a.t 
eac h post-baseline tiine poiI1t and changes from baseline at each post-baseline tin1e point 
• 
For each of lhe QTcF, QTcB, QTcP, and QT iI1te1v als , shift tables based on notable 
parameter categories (g50, >450•g 
80, >480•$500, >500ms) at baseline and the worst 
post-baseline value obse1ved 
• 
Frequency cotmts and percentages of patients having notable ECG values according to lhe 
following categories: 
o QT parameter (QT, QTcF, QTcB, QTcP) increase from baseliI1e >30 ms, >60 ms 
o Newly occm1111g post-baseliI1e QT parameter > 450 ms, > 480 ms, > 500 ms 
o HR increase from baseline> 25% and value> I00 bpm 
o HR decrease from baseline > 25% and value < 50 bpm 
o PR increase from baseliI1e > 25% and value > 200 ms 
o Newly occm1111g post-baseliI1e PR > 200 ms, > 220 ms 
o QRS increase from baseliI1e > 25% and value> 110 ms 
o Newly occun111g post -base liI1e QRS > 110 ms, > 120 ms 
The denominator to calcula.te pe rc e n tages for each category is lhe number of pa.tients with 
both a baseline and a post-baseline evaluation. A newly occur1111g post-baseline ECG 
notable value is defined as a post-baseline value that meets the criterion post-baseline but 
did not meet the c1ite1ion at baseliI1e 
• 
Frequency counts and percentages of patients with newly occtm111g post-baselme 
qualitative ECG abnormalities (mo1pbology) will be smnmarized. The denominator to 
calcula.te percen tages is the number of patients with botha baseline and a post-baseline 
evaluation. A newly occtm-ing post-baseliI1equalitative ECG abnonnality is defined as a 
post-baseline abnonual finding which was not present a.t baseline 


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Patients with notable ECG interval values and newly occuning qualitative ECG abnonnalities 
will be listed and the coffesponding notable values and abnonuality findings will be included 
in the listings. 
Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point. However, they will be used in the 
analysis of notable ECG changes and the shift table analysis of notable QT parameters. 
 
Vital signs 
Vital sign assessments will be perfonued in order to characterize basic body function. Tue 
parameters collected are weight (kg), body temperan·ue (°C), pulse ra.te (beats per  minute), 
systolic and diastolic blood pressure (nmtllg), and respiration rate (breaths per minute). 
Clinically notable elevated values are defined as: 
• 
Systolic BP: 2. 160 nunHg and an increase 2. 20 nunHg from baseline 
• 
Diastolic BP: 2. 100 mmHg and an increase 2. 15 nmtllg from baseline. 
• 
Body temperan·ue: 2. 39.1°C 
• 
Weight: increase from baseline of 2. 10% 
• 
Pulse rate: 2. 120 bpm with increase from baseline of 2.l S bpm 
Clinically notable below nomial values are defined as: 
• Sys tolic BP: ,s; 90 nunHg and a decrease 2. 20 nnnHg from baseline 
• 
Diastolic BP: ,s; 50 mmHg and a decrease 2. 1S mmHg from baseline 
• 
Body temperan·ue: s:35 ° C 
• 
Weight: decrease from baseline of 2. 10% 
• 
Pulse rate: s: 50 bpm with decrease from baseline of 2. 15 bpm 
Vital signs shift table based on values classified as notable low, 1101mal, notable high or 
notable (high and low) at baseline and worst post-baseline will be produced for pulse rate, 
diastolic BP and systolic BP. 
Descriptive statistics will be tabulated for baseline and change from baseline to worst post- 
baseline value for each vital sign measure. 
Patients with clinically notable vital sign ab1101malities will be listed. All vital sign 
assessmentswill be listed by patient and vilal sign parameter. 
In the listings, clinically notable values will also be flagged. 
 
ECOG performance status 
ECOG Perfonnance Scale is provided in Table 2-2 and is used to assess physical health of 
patients, ranging from O (most active) to 5 (dead): 
 
Table 2-2 
ECOG performance scale 
Score Description 
 
0 
Fully active, able to carry on all pre-disease performance without restriction 


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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-carebut 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 ECOG pe1fonnance status at baseline to worst post-baseline ECOG status by 
score. ECOG pe1fo1mance stan1s at each time point will be listed. 
 
2.8.5 
Pharmacogenetics/pharmacogenomics 
Not applicable. 
 
2.9 
Sample size calculation 
Based on Simon's (1989) optimal two-stage design, approximately 105 total patients are 
required to test a null hypothesis of ORR .:'o 35% vs. an altemative hypothesis of ORR of 50% 
or more with a one-sided cr=0.05 and 90% power. If at least 17 confnmed responses are 


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observed among 43 patients enrolled into Stage 1, an additional 62 patients will be enrolled 
into Stage 2. If 45 or more confirmed responses are obse1ved among I05 total patients, the 
nial will bedeclared positive. 
The operating characteristics of the design are desc1ibed in Tab le 2-3. 
 
Table 2-3 
Operating char acteri stics of Simo n' s optimal tw o-stage de sign 
  
True O RR 
 
 
35% 
(null hypothes is) 
40% 
45% 
50% (alternative 
hypothesis) 
Probabilrty stop for futility at Stage 
0.683 
0.418 
0.192 
0.063 
1 (16 or fewer responses out of 
43 patients enrolled at Stage 1) 
Probabilrty trial is success (45 or 
0.049 
more responses out of 105 total 
0.268 
0.642 
0.900 
   patients) 
 
 
2.10 
Power for analysis of key secondary variables 
Not applicable. 
 
2.11 
Interim analysis 
In order to info1m the recommendation to proceed to Stage 2 of the study, a data monitoring 
committee (DMC) will periodically review response data during Stage I, based on local 
investigator assessment, as defined in the DMC cha111er. The DMC may request data of 
assessment of response by the BIRC if deemed necessary to provide its recommendation. As 
per Simon's optimal two-stage design, the nial will be stopped at Stage 1 for futility if 16 or 
fewer responses are obse1ved in the 43 patienst enrolled to Stage 1. According to this rnle, the 
DMC will make the reco1mnendaiton to transition into the Stage 2 of the study. If at the time 
that the last patient is enrolled to Stage 1 a minimmn of 17 responses have not yet been 
obse1ved, accrnal may be temporarily suspended until either the minimmn number of 17 
responses are obse1ved or all 43 patients have been followed for at least 6 cycles of LDK378 
or discontinued treatment. 
Safety will be reviewed by the DMC regularly during the conduct of the study. 
 
3 
Changes to protocol specified analyses 
This section contains to protocol-specified analyses and associated rationale for inclusion in 
Appendix 16.1.9 (Docmnentaiton of statistical methods) of the CSR. 
Table 3-1 
Changes to protocol s pe c ified analysis or des c riptions and rationale 
Protocol Section  Protocol Description 
Change 
Ra.tionale 
Section 10.1.2 - 
Safety Set 
The Safety Set will 
include all patients 
who receive at least 
one dose ofLDK378 
Changed to "The 
Safety Set consists 
of all patients who 
received at least one 
This change from the 
protocol wording for and 
has been introduced in 
Section 2.2 of lhe RAP for 


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LDK378A2203 
 
 
 
 
Protocol Section 
 Protocol Descrietion 
Change 
Rationale 
and have at least one 
dose of srudy dmg" 
progranumng 
valid post-baseline 
cla1ific.ation/simplification. 
safety assessment. 
It does not constitute a de 
The statement that a 
facto change given that the 
patient has no AE (on 
DAR eCRF where the 
the Adverse Event 
infonnation on dosing is 
eCRF) constitutes a 
collected will also collect 
valid safety 
the reason for why the 
assessment. 
dmg was discontinued 
which in itself constitutes 
a safety assessment 
 
Section 10.1.3 - 
The PPS will include 
Changed to"The 
This change was made to 
Per Protocol Set 
patients who have an 
PPS will include 
take into consideration the 
adequate tumor 
patients who have 
+/-1 week window 
assessment at 
au adequate rumor 
associated with rumor 
baseline, a follow-up 
assessment at 
assessments 
tumor assessment >8 
 baseline, a follow- 
weeks after starting 
up tumor 
treatment (unless 
assessment >7 
disease progression is weeks after starting 
observed before that 
treatment (unless 
time),  and no major 
disease progression 
protocol deviation"s 
is obse1ved before 
that time), and no 
major protocol 
deviations" 
 
 
Section 10.5.3.3 
Frequency tables for 
Deleted 
One of the proposed 
- Laborato1y 
newlyoccuning on- 
analysis desc1ibed in 
abno1malities 
treatmentgrades 3 or 
Section 2.8.2 of the RAP 
4 will be provided 
tmder Laborato1y 
separately for 
Abnonnalities, is a shift 
hematology and 
table usingCTC grades to 
biochemistty 
compare baseline to the 
laboratory tests 
 worst post-baselinevalue 
on treatment. The 
info1ma.tion that would be 
contained in the tabulation 
described in the protocol is 
similar to that contained 
  
within this shift table 
 
Section l O.4 - 
Reference is made to 
The analysis for the 
This change is ma.de given 


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Protocol Section 
Protocol Description 
Change 
Rationale 
Primary 
Objective; 
Section 10.5.1 - 
Key Secondary 
Objective(s) 
the calculation of 
90% Cls given that 
the primary endpoint 
is tested at one-sided 
5% significance level 
primary endpoint 
will show the 90% 
CI as per protocol as 
well as 95% nai:ve 
Cls. For other 
secondary endpoints 
only 95% Cls will 
that across the LDK378 
program, all efficacy 
endpoints are surmnarized 
using 95% Cls 
  
be dis  la ed 
 
 
4 
Additional details on implementation of statistical 
methodology 
Tue sec tions below contain additional details on statistical methodology that will be included 
in Appendix 16.1.9 (Documentation of statistical methods) of the CSR as well as rules details 
on programing mies that will be followed to in1plement the analyses desc1ibed in Section 2. 
4.1 
Data included in the analyses 
This section provides additional details to those included in Section 2.1. 
Final analysis of study data at the end of the study will include the data with an assessment 
date or event start date (e.g. vital sign assessment date or sta1t date of an adverse event) prior 
to or on the cut-off date. For example, if the cut-off date is 30DEC2008, an AE starting on 
28DEC2008 will be reported, whereas an adverse event starting on 31DEC2008 will not be 
repo1et d. 
4.2 
Patient Classification into Analysis Sets 
This section provides additional details to those included in Sec tion 2.2. 
Patients are excluded from the analysis populations based on the protocol deviations entered 
in the data.base and/or on specific patient classification mies as shown in Table 4-1 below. No 
analyses based on  Per Protocol Set 
are planned in this final 
CSR. 
Table 4-1 
Patient classification rules 
Anal ysis Population 
Protocol deviation 
severity codes 
Additional patient classification mies leading to 
exclusion 
leading to exclusion 
 
Full Ana lysis Set 
1, 3, 511 
Not applicable 
Safety Set 
2, 3, 511 
Not applicable 
Per Protocol Set 
4,511 
Protocol deviations that will lead to removal of 
pa.tients from Per Protocol Set (defined in 
Section 2.2) 


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Severity code: 0= Include in everything, 1= Exclude from FAS, 2= Exclude from safety, 3= Exclude 
from FAS and safety, 4= Exclude from per-protocol, 511=exclude from all analysis 
 
4.3 
Last contact date 
Tue last contact date is used for censoring in OS analyses and will be derived for patients not 
known to have died at the analysis cut-off using the latest complete date among lhe following: 
• 
All patient assessment dates (e.g. blood draws, vital signs, perfomiance status, patient 
reported outcomes, ECG, ttuuor assessments, etc) 
• 
Concomitant medication stait and end dates 
• 
Start and end dates of antineoplastic therapies administered after stt1dy drng 
discontinuation. 
• 
AE sta1t and end dates 
• 
Last known date patient alive collected on lhe ' Su1vival info1mation' eCRF 
• 
Study drng start ai1d end dates 
• 
Dateof discontinuation on the ' End of treatment phase completion' and/or the ' Srudy 
phase completion' eCRFs. 
If the last contact date as derived above is after the cut-off date then the cut-off date will be 
used. Only dates associated with patient visits or acttial examinations of the pa.tient will be  
used in the de1ivation. Dates associated with a technical operation unrelated to patient status 
such as the date a blood sample was processed will not be used. 
4.4 
Month derivation 
For all derivations, a  month will be calculated as (365.25 I 12 } = 30.4375  days . If  duration is 
to be repotted in months, dmation in days will be divided by 30.4375. 
 
4.5 
Dose interruptions and dose changes 
This section provides additional details to those included in Section 2.6. 
All calculations of dose iutenupt ious and dose changes are based on the dose actually taken 
by lhe patient. 
An intem1ption is defined as a  O mg  dose taken on one  or  more days. What follows defines  
how dose intenuptions will be co unted in the case of multiple dose inte111ptions . 
• If an intenu ption occurs consecutively for at least two days due to the saine reason,  then  it 
will be counted only once (example: If the actual dose on days 1-3 is 750 111g and  actual 
dose 011 days 4-5 is O mg and dose i11te r n1pfio11 on days 4-5 is due to AE, then the total 
number of dose interruptions is J). 


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• 
If an intenu ption occurs consecutively for at least two days due to different reasons, then 
it will be cotmted for each reason (example: If the actual dose on days 1-3 is 750 mg and 
actual dose 011 days 4-5 is 0 mg and dose interruption 011 day 4 is due to AE and dose 
interr11ption on day 5 i.s due to dosing error, then the total number of dose interruptions is 
2). 
• 
If an intenuption 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 
inte1111ption will be counted as a different occunence (example: if the actual dose on days 
1, 3 and 5, is 750 mg and acfllal dose 011 days 2 and 4 is 0mg, and dose interruptions on 
day 2 and 4 m·e borh due to dosing error, the toral number of dose inrerruprions is 2). 
A dose change is defined as a change to a lower or higher dose than the protocol planned dose 
e.g. 600 mg or 450 mg or 300 mg (reduction may be preceded by a O mg due to an 
inte1111ption) in the daily administered dose, with an associated reason for dose change 
documented in the DAR sununa1y eCRF page. For example, in the sequence 750 mg - 0 mg - 
600 mg, the 600 mg dose will be co11nted as a dose change, preceded by a 0 mg due ro 
interruption (with reason documented) and 600 111g due to change (with reason documented). 
A dose inten11ption will not be counted as a dose change. 
If a patient moves from a higher than protocol planned dose down  to the planned dose then 
this will not be counted as a dose change, however if they move directly from a higher than 
planned dose down to a lower than protocol planned dose, then lhis will be cotmted as a dose 
change (with reason documented). 
Dose reductions are a subset of dose changes where dose changes to higher tlian protocol 
plam1ed dose are excluded. 
 
4.6 
Efficacy endpoints 
For further details on efficacyendpoints, 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 I. I. 
Response and progression evaluation will be perfonned according to the Nova1tis RECIST 
1.1 guidelines, included in Section 14 (Appendix II) of the LDK378A2203 protocol. 
The text below gives more detailed instrnctions and mies needed for programming of the 
analyses desc1ibed in Sections 2.7 and 2.8.1. 
4.6.1 
Implementation of RECIST Guidelines 
Disease progression 
PD should only be assigned if it is confumed by an objective assessment metl1od as per 
RECIST I.I (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'). 


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In particu lar, discontinuation due to disease progression or death due to progressive disease, 
without suppo1t ing objective evidence (as defined above), will not be considered as PD in the 
determination ofBOR, 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 teclmique (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. 
However, a response assessment other than the Nova1tis calculated UNK response may be 
accepted from the investigator or BIRC if a definitive response assessment can be jt1stified 
based on the available infonnation. Potential discrepancies between the modality used and 
overall lesion response repo1ted by the investigator (e.g. change in modality but investigator 
assessment of response is different from UNK) will be que1ied dming the data validation 
process. 
Determination of missing adequate tumor assessments 
For the computation of ORR, patients without any radiological assessment after the sta1t date 
of study drng will be counted as failme. 
Pa11iaJ or complete responses repo1t ed prior to any additional anticancer therapy will be 
considered for ORR computation in espective 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 refe1rnd as ' miss ing assessment'. 
As detailed in Section 14 (Appendix II)  of  the  LDK378A2203  protocol,  the  PFS  censo1ing 
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 i11 the 
analysis of PFS at the last adequate tumor assessment before the event date. 
An exact rnle to dete1mine whether there is none, one or two missing assessments is therefore 
needed. This rnle will be based on the distance benveen 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 tmuor assessments plus the protocol allowed window around the 
assessments. Similarly, the tlu-esho ld D2 is defined as nvo times the protocol specified interval 
between the tumor assessments plus the protocol allowed window aro1md the assessments. In 
tl1is study, the protocol defined schedule of tumor assessment is eve1y 8 weeks and each 
assessment is expected to be perf01med 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 tl1an D2 = (2*8) + 2 = 18 weeks means two missing 
assessments. 


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The same definition of D2 will be used to determine the PFS censoring reason. If the distance 
between the last adequate tumor assessment date and one of the following dates is s; D 2: 
I. Analysis cut-off date 
2. Start date of farther anti-neoplastic therapy 
3. Visit date of study treatment discontinuation due to consent withdrawal 
4. Visit date of study treatment discontinuation due to loss to follow-up 
then the associated censoring reason will be 
l. Ongoing 
2. New cancer therapy 
3. Withdrew consent 
4. Loss to follow-up 
However, if this distance is larger than D2, then the censoring reason will be ' Adequate 
assessment no longer available'. 
Non-measurable diseaseat baseline 
As specified in Section 14 (Appendix II) of the LDK378A2203 protocol, the RECIST l. l 
criteria imply that only patients with measurable disease at baseline should be included in the 
study. If a patient without measurable disease is em·olled, the intent-to-treat (ITT) p1inciple 
requires including these patients in the anal yses. Hence, analyses will be based on FAS 
including patients with either measurable or non-measurable disease. Therefore, a mle  needs  
to be specified on how to handle these cases. 
As specified in Table 3-1 of Section 14 (Appendix II) of the LDK378A2203 p rotocol, overall 
lesion response can be derived for patients without measurable disease at baseline. 
Target lesion response will always be UNK due to missing baseline measurements. Therefore, 
a CR, PR or SD can never be assigned as an overall lesion response. However, a PD can still 
be determined from non-target lesions or from new lesions. 
As a result, the overall lesion responses will always be UNK until PD occms. The BOR will 
either be UNK or PD depending on the tuning of PD (if PD is obse1ved > 17 weeks , it will be 
considered as UNK). The PFS censoring and event date options will depend on how many 
UNK.s precede the PD. 
Missing baseline tumor assessment 
As specified in Section 14 (Appendix II) of the protocol  (see Table 4-1},  since the tuning of 
PD cannot be detennined for patients with missing baseline tmnor assessment, these patients 
are censored iJ1 the PFS analysis at the start date of treatment. This mle, however, only applies 
to the ' PD component' of the PFS or DOR assessment. 
Patients without baseline tumor assessment who die within D2 distance from start date of 
treatment will be counted as having an event in  the prinla1y  analysis of  PFS.  All dea.ths will 
be counted in the OS analysis regardless of presence or absence of the baseline tumor 
assessment. 
Construction of waterfall graphs 


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The wate1fall graphs will be used to depict the anti-tumor activity. These plots will display the 
best percentage change from baseline in the smu of the longest diameter of all target  lesions 
for each patient. The proportions of patients with va1ious degrees of tumor shtinkage or growth 
can then represent a useful efficacy meuic. 
However, caution needs to be paid to the assessments, where an occmTence of a new lesion or 
worsening in non-target lesions (resulting in PD as an overall lesion response at given 
assessment) contradicts the measmements obtained on target lesions. These assessments  will 
not be displayed as bars in the graph. If such a " contradicting" assessment represents lhe only 
post-baseline assessment for a patient, then the patient will be represented by a special symbol 
(e.g. *) in the wate1fall 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 tmnor shrinkage and 
nunor growth. Footnote will explain the reason for excluding some patients (due to absence 
of any valid assessment). 
All possible assessment scenarios are desc111bedin Table 4-2. 
 
Table 4-2 
Inclusion/exclusion of assessments used in waterfall graph 
Criteria for inclusion/exclusion 
Possible 
source 
of 
conu·adictions 
Target response 
Overall 
lesion 
resoonse 
Include in waterfaJJ 
Non-target 
resoonse 
New lesion? 
CR/PR/SD 
PD 
Yes but as* onlv 
PD 
anv 
CR/PR/SD 
PD 
Yes but as* onlv 
anv 
Yes 
UNK 
UNKorPD 
No 
anv 
anv 
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 
Tue following algorithm will be used to consu11ct the graph: 
I. 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 overaJJ 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 


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1.3 Check target response. If it's 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 I and find the 
assessment with best % change from baseline in target lesions. The "best" means best for 
the patient, i.e. the largest shrinkage or if a patient only has  assessments  with  tumor 
growth take the assessment where the growth is minimal. (Example1: Patient I has the 
following% changes from baseline at assessments 1, 2, 3, 4 and S,  respectively: -10%;  - 
25%; -13%; -4% and +6%. His/her best % change is then -25%. Exa111ple 2: Patient 2 has 
the following % changes from baseline at assessments I , 2 and 3, respectively: +5%; 
+18% and +35%. His/her best% change is then +5%. 
3. Constnict the wate1fall graph displaying the best% change from baseline for each patient. 
Patients having only * flagged assessment(s) will bedisplayed separately. 
Both investigatorassessment and BIRC will beused in the construction of wate1fall plot. 
The recommended way of the display from left to1ight is: 
l. Bars under the ho1izontal axis representingnunor slu·inkage 
2. Bars above the ho1izontaJ axis representing nunor growth 
3. "Zero" bars with* symbol representing patients with contradiction 
4.6.2 
Sources for overall lesionsresponse 
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 providedfrom different som·ces as illustrated in Table 4-3. 
 
Table 4-3 
Sources for overall lesion response 
Sow-ce 1 
Investigator (local radiolo2v) reported overall lesion response 
Source2 
Calculated overall lesion response based on raw (i.e. individual lesion) 
measurements from Investigator (local radiolo2v) 
Source 3 
BIRC (Blinded Independent review co1111nittee) repor tedoverall lesion 
response 
In this study, Source 1 will be used for the prinuuy endpoint derivation and other secondary 
endpoint calculations based on investigator assessment (ORR, DCR, DOR, TTR and PFS) and 
Sow-ce 2 will be listed against Somce 1 and discrepancies between calculated and reported 
responses assigned by investigator will be identified. Source 3 will be used to calculate ORR, 
DCR, DOR, TTR and PFS by BIRC. 
 
4.6.3 
Kaplan-Meier estimates 
To analyze time to event variables (DOR, TTR, OS and PFS) an estimate of the smvival 
function will be constnicted using Kaplan-Meier (product -limit) method as iniplemented 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 90% or 95% two-sided Cls derived based on the complementa1y log-log 


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transfonnation. This will be conducted via the SAS procedure LIFETEST. The TIME 
statement will include a variable with survival times (survti111e in the example below) and a 
(iight) censo1ing va1iable (censor in the example below) with a va1t1e of 1, representing 
censoring (example code below for constmction of 90% Cls): 
 
PROC LIFETEST data = dataset 
METHOD = KM 
ALPHA = 0. 1 
ALPHAQT = 0 .1 
CONFTY PE=LOGLOG ; 
T IME s urvtime*censor(l); 
RUN; 
I* survtime represents variable containing event/censor times; 
censor represents censoiing variable (I = censored, 0 = event); */ 
Kaplan-Meier sUtv iv aJ and failure ftmction estimates from this procedure will be used to 
construct the Kaplan-Meier figures 
Median smvival will be obtained along with 2-sided 90% or 95% Cls calculated from PROC 
LIFETEST output using the method ofBrookmeyer & Crowley, 1982. 
Kaplan-Meier estimates with 2-sided 90% or 95% Cis a.t sp ecific tim e points will be 
summarized. The time points can be expressed in weeks or in months depending on the time- to-
event va1iable. The Cis will be constmcted using Greenwood's fo1mula [Collet , 1994 , p.23] 
for the standard enor of the Kaplan-Meier estimate. 
The Kaplan-Meier graphs will be constrncted usingSAS software. 
 
4.6.4 
Confidence interval and p-value for response rate 
ORR will be sununa1ized in te1ms of percentage rates with 90% and 95% Cis. An exact 
binomial confidence interval (implemented using SAS procedure FREQ with EXACT 
statement for one-way tables) will be calculated (Clopper and Pearson 1934). 
SAS proced1u·e FREQ will be used to estimate tlle proportion of responders (bina1y outcome = 
1 or "Yes"), along with the associated 90% or 95% (=100 x (1 - two-sided alpha level)) two- 
sided Pearson-Clopper CI and exact one-sided p-value for tlle hypothesis test of the null 
proporrion (0.35). These estiniates are obtained as follows: 
 
proc freq data= dataset; 
table binary event I 
b i nomi a l ( 
p = null propor t i on 
level = " Yes " ) 
alpha= two-sided alpha le vel; 
exact binomial; 
When there are no responders, SAS does not produce a CI by default. To obtain a CI in this 
situation,  PROC FREQ is used as  specified  above except changing Jeve l="No". From the 


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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%· UCL1EVEL="No" (%) 
UCLLEVEL="Yes" (%) = I00% • LCLLEVEL=''No" (%) 
4.7 
Safety evaluations 
Tue text below gives more detailed instrnctions and mies needed for programming of the 
analyses desc1ibed in Section 2.8.2. 
 
4.7.1 
Multiple assessments within post-baseline visits 
For all analyses regarding abnomial assessments or analyses based on worst post-baseline 
value (laboratory, ECGs, vital signs, ECOG perfonnance status), all post-baseline values will 
be included (scheduled, unscheduled, repeat). All unscheduled and repeat measw·ements will 
be included in listings. 
Laboratory data 
For laboratory data, assessments can be collected from both local and central laboratory on 
the same date. For shift tables using CTC grades to compare baseline to the worst post- 
baseline value, the assessment with worst post-baseline value is used for analyses i.nespective 
of the source. For LFT sunnnaries, where concunent 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 laborato1ies. 
 
ECGs 
For all patients, 3 ECGs are targeted to be measured at the protocol-defmed (nominal) ti.me- 
po ints. If a patient bas more than one measurement at a specific time point, the average of all 
available measurements associated with the nominal ti.me point will be used for the analyses. 
 
4.7.2 
Baseline 
As defined in Section 2.8.2, the last available assessment before or on the date of sta1t of 
study dmg is defined as " baseline" value or "baseline" assessment. 
Laboratory data 
If both central and local laboratory assessments were pe1formed  on  the  same  date  and 
co1Tespond ing to the baseline assessment date, then the central laboratory assessment will be 
used for the calculation of baseline. 


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ECGs 
Baseline for ECG analysis is defined as the average of all available ECG measmements 
associated with the baseline assessment date. Study day 1 scheduled pre-dose ECGs will be 
consideredto have been obtained prior to study drng administration if dosing time is missing. 
If a scheduled pre-dose measurement acmally occwTed post-dose, then the c01Tesponding 
measurement will be treated and anal yzedsimilar to an unscheduled post-dose measurement. 
4.8 
Handling of missing or partial dates 
For patients not known to have died prior to the cut-off date: 
• All events with start date before or on the cut-off date, and with end date missing or after 
the cut-off date will be repo11ed as "co ntinuingat the cut-off date". 
• This approach applies, in particular, to AEs and concomitantmedication repo1ts. For these 
events, theend date will not be imputed and therefore will not appear in the listings. 
For patients known to have died p1ior to or on the cut-off date: 
• All events with sta1t date before or on the cut-off date, and with end date missing or after 
the cut-off date will have the end da.te imputed to the death date. 
• This approach applies, in particular, to AEs and concomitant medication repolts. 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 dtug after the cut-off date), the end date will 
be imputed to the cut-off date for the ptupose of calculating dm11tion of exposme to study 
drng and dose intensity. Tue imputed date will bedisplayed and flagged in the listings. 
4.8.1 
AE date imputation 
Date imputation is the creation of a new, complete date from a partial one according to an 
agreed and acceptable algo1ithm. Missing date for AE will be handled according to mies 
specified below. A pa1t ial date is simply an incomplete date e.g. DDOCT2001:  the days are 
missingfrom this DDMMMYYYY date. 
Paitial AE sta1t dates, ifleft pai1ial, would ultimately mean the following 
It would not be possible to place the AE in time. 
Therefore the treatment/dosageat the time of the event would be unknown. 
Therefore theevent could not be repo1etd/sunnnarizedappropriately -  if at all. 
Therefore it is impoltant to pe1fon11 date imputation to ensme that as many data events are 
represented as co1Tectly as possible. Of course pa1tial 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 sta1t dates 
• AE sta111 dates missing the year 


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• 
Pa11ial/missing AE end date s 
The following Table 4-4 explains the abbreviations used. 
 
Table 4-4 
AE/treatment date abbreviations 
Day 
Month 
Year 
 
Partial Adverse Event 
Start Date 
Treatment Start Date 
<not used> 
AEM 
AEY 
 
<not used> 
TRTM 
TRTY 
    TRTSTD 
 
Tue following matrix Table 4-5 describes the possible combinations and their associated 
imputations. hl the light grey boxes the upper_ text indicates the imputation and the lower text 
the relationship of the AEstai1date to the treatment start date (TRTSTD). 
Tab le 4-5 
AE partial date imputation algo rithm 
 
AEMMISSING 
AEM < TRTM 
AEM=TRTM 
AEM > TRTM 
AEYMISSING 
NC 
NC 
NC 
NC 
Uncertain 
Unce1tain 
Uncertain 
Unce1atin 
AEY < TRTY 
(D) 
(C} 
(C) 
(C) 
Before 1R TSTD 
Before 1RTSTD Before 1RTSTD Before TRTSTD
AEY=TRTY 
(B) 
(C} 
(B) 
(A) 
Uncertain 
Before 1RTSTD 
Uncertain 
After 1RTSTD 
AEY> TRTY 
(E) 
(A) 
(A) 
(A) 
  
After 1RTSTD 
After 1RTSTD 
After 1RTSTD 
After 1RTSTD  


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The following Table 4-6 is the legend to the above table. 
Table 4-6 
AE/treatme nt date relationship and imputation legend 
Relationship 
Before TRTSTD 
After TRTSTD 
Uncertain 
Imputation Calculation 
NC / Blank 
(A) 
(B) 
(C) 
(D) 
(E)  
The following Table 4-7 gives a few examples. 
Indicates AE sta1t date prior to Treatment 
Sta11 Date 
h1dica.tes AE sta1t date after Treatment Sta1t 
Date 
htsufficient to determine the relationship of 
AE start date to Treaunent Sta1t Date 
 
No convention/imputation 
0lMONYYYY 
TRTSTD+l 
15MONYYYY 
OlJULYYYY 
0lJANYYYY 
 
Tab le 4-7 
AE imputatio n example scenarios 
 
Calcula tion 
 
 
 
 
 
 
 
 
 
4.8.2 
Incompletedate of initial diagnosis of cancer, date of most recent 
recurrence and date of anti-neoplastictherapies 
Missing day is defaulted to the 151h of the month and missing month and day is defaulted to 
01-Jan. 
 
4.8.3 
Incomplete assessment dates for tumor assessment 
All investigation dates(e.g. X-r,ay CT sca.n) 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 co1tsidered 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 
Partia l 
AE start date 
Treatment 
start date 
Relationship 
Imputation 
Imputed Date 
12mmyyyy 
20OCT2001 
Unce rtain 
NC 
<blan k> 
ddmmm2000 
20OCT2001 
Before 
( D) 
01JUL2000 
ddmmm2002 
20OCT2001 
After 
( E) 
01JAN2002 
ddmmm2001 
20OCT2001 
Unce rtain 
( B) 
21OCT2001 
ddSEP2001 
20OCT2001 
Before 
( C) 
15SEP2001 
ddOCT2001 
20OCT2001 
Unce rtain 
( B) 
21OCT2010 
ddNOV2001 
20OCT2001 
After 
(A)  
01 NOV2001 


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overall lesion response at that assessment is CR/PR/SD/UNK. Otherwise, if overall lesion 
response is PD, the assessment date is calcnlated as the earliest date of all investigation  dates 
at that evaluation number. If all measurement dates have no day recorded, the l st  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. 
4.8.4 
Incomplete date for death 
All dates must be completed with day, month and year. 
If the day or montl1 is miss ing, death will be imputed to the maxinuuu of tl1e last coutact date 
(excluding the date of death) and the following: 
• 
Missing day: 
Ist day of the month and year of death 
• 
Missing day and month: July 1st of the year of deatll 
 


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5 
Reference 
 
Atkinson, E. N, & Brown, B. W. (I 985). Confidence limits for probability of response in 
multistage phase II clinical tiials. Biometrics, 741-744. 
Simon, R. (1989). Optimal hvo-stage designs for phase II clinical trials. Conremporary 
Clinical Trials, 10(1), I-JO. 
Klein, J. P., & Moeschberger, M. L. (2005). Survival analysis: techniques/or censored and 
truncated data.Sp1inger Science & Business Media. 
Brookmeyer, R., & Crowley, J. (1982).A confidence inte1val for the median stnvival time. 
Biometrics, 29-41. 
Clopper, C. J., & Pearson, E. S. (1934). The use of confidence or fiducial limits ilh1strated in 
the case of the binomial. Biometrika , 26(4 ), 404-413. 
Collet D (1994). Modelling smvival data in medical research. London, Chapman & Hall. 
FDA (2007). Guidance for Industly Clinical Trial Endpoints for the Approval of Cancer 
Dmgs and Biologics, US Department of Health and Human Seiv ices. 
 
Kalbfleisch JD, Prentice RL. (2002) The Statistical Analysis of Failure Time Da.ta. Wiley 
Se1ies in Probability and Statistics.