Clinical trial NCT02450903
Conditions: Non-Small-Cell Lung Cancer
Keywords: Non-Small-Cell Lung Cancer NSCLC ALK LDK378 alectinib Non-small cell lung carcinoma (NSCLC) lung cancer lung adenocarcinoma Non small cell lung carcinoma Non small cell lung cancer Non-small cell lung cancer
Sponsor: Novartis Pharmaceuticals
Start date: 2015-08-21; Completion date: 2018-05-24
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This was a single-arm, open-label, multicenter, phase II study to evaluate the efficacy and safety of the ALK inhibitor LDK378 when used as single agent in patients with ALK-rearranged stage IIIB or IV NSCLC previously treated with alectinib. Treatment with LDK378 750 mg qd continued until the patient experienced disease progression as determined by the investigator according to RECIST 1.1, unacceptable toxicity that precluded further treatment, pregnancy, start of a new anticancer therapy, discontinued treatment at the discretion of the patient or investigator, lost to follow-up, death, or study was terminated by Sponsor.

Detailed description:
Study completed as per protocol. 'Switched to commercial drug' implies that after the primary and secondary objectives were achieved, one patient continued the study treatment as they did not meet the progression disease or AE to be discontinued from the treatment. But after the regulatory approval, Novartis decided to close the study, the 1 patient switched to commercially available drug.

Arms: arm 1: Participants who received LDK378 750mg once daily on a 28 day cycle.
Interventions: intervention 1: LDK378
Intervention descriptions: intervention 1: Oral LDK378 750mg once daily

Protocol documents:
Prot_001.pdf: 
 
Clinical Development 
LDK378 
Protocol CLDK378A1201 / NCT02450903
A phase II, multi-center, open-label, single-arm study to 
evaluate the efficacy and safety of oral LDK378 treatment 
for patients with ALK-positive non-small cell lung cancer 
previously treated with alectinib 
Authors 
 
Document type 
Amended Protocol Version 
EUDRACT number 
Not applicable 
Version number 
04 (Clean) 
Development phase 
II 
Document status 
Final 
Release date 
28-Jul-2016
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Template version 02-Dec-2013 


 
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Table of contents 
Table of contents ................................................................................................................. 2 
List of appendices ................................................................................................................ 7 
List of figures ....................................................................................................................... 7 
List of tables ........................................................................................................................ 7 
List of abbreviations ............................................................................................................ 9 
Glossary of terms ............................................................................................................... 12 
Amendment 4 (28-Jul-2016) ............................................................................................. 13 
Amendment 3 (30-Mar-2016) ........................................................................................... 15 
Amendment 2 .................................................................................................................... 17 
Amendment 1 .................................................................................................................... 18 
Protocol summary .............................................................................................................. 20 
1 
Background ........................................................................................................................ 23 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 23 
1.1.1 
Locally advanced or metastatic non-small cell lung cancer 
(NSCLC) ............................................................................................... 23 
1.1.2 
Targeted therapies in NSCLC ............................................................... 23 
1.1.3 
ALK positive NSCLC ........................................................................... 24 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 25 
1.2.1 
Overview of LDK378............................................................................ 25 
2 
Rationale ............................................................................................................................ 35 
2.1 
Study rationale and purpose ................................................................................... 35 
2.2 
Rationale for the study design ............................................................................... 36 
2.3 
Rationale for dose and regimen selection .............................................................. 36 
2.4 
Rationale for choice of combination drugs ............................................................ 37 
2.5 
Rationale for choice of comparators drugs ............................................................ 37 
3 
Objectives and endpoints ................................................................................................... 37 
4 
Study design....................................................................................................................... 40 
4.1 
Description of study design ................................................................................... 40 
4.1.1 
Screening ............................................................................................... 40 
4.1.2 
Treatment duration ................................................................................ 41 
4.1.3 
Follow-up period ................................................................................... 41 
4.2 
Timing of interim analyses and design adaptations ............................................... 42 
4.3 
Definition of end of the study ................................................................................ 42 
4.4 
Early study termination .......................................................................................... 42 
5 
Population .......................................................................................................................... 42 


 
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5.1 
Patient population .................................................................................................. 42 
5.2 
Inclusion criteria .................................................................................................... 42 
5.3 
Exclusion criteria ................................................................................................... 44 
6 
Treatment ........................................................................................................................... 47 
6.1 
Study treatment ...................................................................................................... 47 
6.1.1 
Dosing regimen ..................................................................................... 47 
6.1.2 
Guidelines for continuation of treatment .............................................. 48 
6.1.3 
Treatment duration ................................................................................ 48 
6.1.4 
Definition of treatment cycle................................................................. 48 
6.2 
Dose escalation guidelines ..................................................................................... 48 
6.3 
Dose modifications ................................................................................................ 49 
6.3.1 
Dose modification and dose delay ........................................................ 49 
6.3.2 
Treatment interruption and treatment discontinuation .......................... 49 
6.3.3 
Criteria for LDK378 dose modifications .............................................. 50 
6.3.4 
Follow-up for toxicities ......................................................................... 57 
6.3.5 
Anticipated risks and safety concerns of the study treatment ............... 61 
6.4 
Concomitant medications ...................................................................................... 61 
6.4.1 
Permitted concomitant therapy.............................................................. 62 
6.4.2 
Prohibited concomitant therapy ............................................................ 63 
6.5 
Patient numbering, treatment assignment or randomization ................................. 65 
6.5.1 
Patient numbering ................................................................................. 65 
6.5.2 
Treatment assignment ........................................................................... 65 
6.5.3 
Treatment blinding ................................................................................ 65 
6.6 
Study drug preparation and dispensation ............................................................... 66 
6.6.1 
Study drug packaging and labeling ....................................................... 66 
6.6.2 
Drug supply and storage ........................................................................ 66 
6.6.3 
Study drug compliance and accountability ........................................... 66 
6.6.4 
Disposal and destruction ....................................................................... 67 
7 
Visit schedule and assessments ......................................................................................... 67 
7.1 
Study flow and visit schedule ................................................................................ 67 
7.1.1 
Screening ............................................................................................... 72 
7.1.2 
Treatment period ................................................................................... 73 
7.1.3 
Discontinuation of study treatment ....................................................... 73 
7.1.4 
Withdrawal of consent .......................................................................... 75 
7.1.5 
Follow up period ................................................................................... 75 
7.2 
Assessment types ................................................................................................... 76 


 
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7.2.1 
Efficacy assessments ............................................................................. 76 
7.2.2 
Safety and tolerability assessments ....................................................... 78 
 
 82 
 
 82 
7.2.5 
Resource utilization ............................................................................... 84 
7.2.6 
Patient reported outcomes ..................................................................... 85 
8 
Safety monitoring and reporting ........................................................................................ 85 
8.1 
Adverse events ....................................................................................................... 85 
8.1.1 
Definitions and reporting ...................................................................... 85 
8.1.2 
Laboratory test abnormalities ................................................................ 86 
8.1.3 
Adverse events of special interest ......................................................... 87 
8.2 
Serious adverse events ........................................................................................... 87 
8.2.1 
Definitions ............................................................................................. 87 
8.2.2 
Reporting ............................................................................................... 87 
8.3 
Emergency unblinding of treatment assignment ................................................... 88 
8.4 
Pregnancies ............................................................................................................ 88 
8.5 
Warnings and precautions ...................................................................................... 89 
8.6 
Data Monitoring Committee .................................................................................. 89 
8.7 
Steering Committee (SC) ....................................................................................... 89 
9 
Data collection and management ....................................................................................... 89 
9.1 
Data confidentiality ............................................................................................... 89 
9.2 
Site monitoring ...................................................................................................... 90 
9.3 
Data collection ....................................................................................................... 90 
9.4 
Database management and quality control ............................................................ 91 
10 Statistical methods and data analysis ................................................................................. 91 
10.1 
Analysis sets .......................................................................................................... 92 
10.1.1 
Full Analysis Set ................................................................................... 92 
10.1.2 
Safety Set ............................................................................................... 92 
10.1.3 
Per-Protocol Set..................................................................................... 92 
10.1.4 
Dose-determining analysis set ............................................................... 92 
 
 92 
10.2 
Patient demographics/other baseline characteristics .............................................. 92 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 92 
10.4 
Primary objective ................................................................................................... 92 
10.4.1 
Variable ................................................................................................. 93 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 93 


 
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10.4.3 
Handling of missing values/censoring/discontinuations ....................... 93 
10.4.4 
Supportive analyses ............................................................................... 93 
10.5 
Secondary objectives ............................................................................................. 93 
10.5.1 
Key secondary objective(s) ................................................................... 93 
10.5.2 
Other secondary efficacy objectives ..................................................... 94 
10.5.3 
Safety objectives ................................................................................... 95 
 
 96 
 
 96 
 
 97 
10.7 
Interim analysis ...................................................................................................... 98 
10.8 
Sample size calculation .......................................................................................... 98 
10.9 
Power for analysis of key secondary variables ...................................................... 98 
11 Ethical considerations and administrative procedures ....................................................... 98 
11.1 
Regulatory and ethical compliance ........................................................................ 98 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 98 
11.3 
Informed consent procedures ................................................................................. 99 
11.4 
Discontinuation of the study .................................................................................. 99 
11.5 
Publication of study protocol and results ............................................................... 99 
11.6 
Study documentation, record keeping and retention of documents ....................... 99 
11.7 
Confidentiality of study documents and patient records ...................................... 100 
11.8 
Audits and inspections ......................................................................................... 100 
11.9 
Financial disclosures ............................................................................................ 100 
12 Protocol adherence .......................................................................................................... 101 
12.1 
Amendments to the protocol ................................................................................ 101 
13 References (available upon request) ................................................................................ 102 
14 Appendices: ..................................................................................................................... 104 
14.1 
Appendix 1: List of prohibited concomitant medications and concomitant 
medications requiring caution for LDK378 ......................................................... 104 
15 Appendices ...................................................................................................................... 107 
15.1 
Appendix 2: Harmonization of efficacy analysis of solid tumor studies 
(RECIST 1.1) ....................................................................................................... 107 
15.1.1 
Introduction ......................................................................................... 109 
15.1.2 
Efficacy assessments ........................................................................... 109 
15.1.3 
Definitions ........................................................................................... 109 
15.1.4 
Disease measurability .......................................................................... 109 
15.1.5 
Eligibility based on measurable disease .............................................. 110 
15.1.6 
Methods of tumor measurement - general guidelines ......................... 110 


 
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15.1.7 
Baseline documentation of target and non-target lesions .................... 112 
15.1.8 
Follow-up evaluation of target and non-target lesions ........................ 112 
15.1.9 
Follow-up and recording of lesions ..................................................... 113 
15.1.10 
Non-nodal lesions ................................................................................ 113 
15.1.11 
Nodal lesions ....................................................................................... 113 
15.1.12 
Determination of target lesion response .............................................. 114 
15.1.13 
Determination of non-target lesion response ...................................... 116 
15.1.14 
New lesions ......................................................................................... 116 
15.1.15 
Evaluation of overall lesion response.................................................. 117 
15.1.16 
Efficacy definitions ............................................................................. 118 
15.1.17 
Best overall response ........................................................................... 118 
15.1.18 
Time to event variables ....................................................................... 120 
15.1.19 
Progression-free survival..................................................................... 120 
15.1.20 
Overall survival ................................................................................... 120 
15.1.21 
Time to progression ............................................................................. 121 
15.1.22 
Time to treatment failure ..................................................................... 121 
15.1.23 
Duration of response ........................................................................... 121 
15.1.24 
Time to response ................................................................................. 122 
15.1.25 
Definition of start and end dates for time to event variables ............... 123 
15.1.26 
Handling of patients with non-measurable disease only at baseline ... 124 
15.1.27 
Sensitivity analyses ............................................................................. 125 
15.1.28 
Data handling and programming rules ................................................ 127 
15.1.29 
Study/project specific decisions .......................................................... 127 
15.1.30 
End of treatment phase completion ..................................................... 127 
15.1.31 
End of post-treatment follow-up (study phase completion) ................ 128 
15.1.32 
Medical validation of programmed overall lesion response ............... 128 
15.1.33 
Programming rules .............................................................................. 129 
15.1.34 
Calculation of ‘time to event’ variables .............................................. 129 
15.1.35 
Incomplete assessment dates ............................................................... 129 
15.1.36 
Incomplete dates for last known date patient alive or death ............... 129 
15.1.37 
Non-target lesion response .................................................................. 130 
15.1.38 
Study/project specific programming ................................................... 130 
15.1.39 
Censoring reason ................................................................................. 130 
15.1.40 
References (available upon request) ................................................... 131 


 
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List of appendices 
Appendix 1: List of prohibited concomitant medications and concomitant medications 
requiring caution 
Appendix 2: Harmonization of efficacy analysis of solid tumor studies (RECIST 1.1) 
 
 
List of figures 
Figure 4-1 
Study design .......................................................................................... 40 
 
 
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 (Safety Set) (Data cut-off: 14-April-2014) ...... 30 
Table 1-2 
Summary of best overall response based on investigator assessment 
in NSCLC patients in the 750 mg dose group, by prior ALK 
inhibitor status (Full Analysis Set – NSCLC 750 mg) (Data cut-off: 
14-April-2014) ...................................................................................... 32 
Table 1-3 
Analysis of duration of response based on investigator assessment 
in NSCLC patients in the 750 mg dose group using Kaplan-Meier 
method, by prior ALK inhibitor status (Full Analysis Set – NSCLC 
750 mg– Confirmed CR or PR) (Data cut-off: 14-Apr-2014) ............... 32 
Table 1-4 
Analysis of PFS based on investigator assessment in NSCLC 
patients in the 750 mg dose group, by prior ALK inhibitor status 
(Full Analysis Set – NSCLC 750 mg) (Data cut-off : 14-Apr-2014) .... 33 
Table 3-1 
Objectives and related endpoints ........................................................... 38 
Table 6-1 
Dose and treatment schedule ................................................................. 48 
Table 6-2 
Dose reduction steps for LDK378 ......................................................... 50 
Table 6-3 
Criteria for interruption and re-initiation of LDK378 treatment ........... 51 
Table 6-4 
Follow-up evaluations for selected toxicities ........................................ 61 
Table 7-1 
Visit evaluation schedule ...................................................................... 68 
Table 7-2 
Imaging assessment collection plan ...................................................... 78 
Table 7-3 
WHO performance status scale ............................................................. 79 
Table 7-4 
Local clinical laboratory parameters collection plan ............................ 80 
Table 7-5 
Local ECG collection plan .................................................................... 81 
 
 84 
Table 10-1 
Operating characteristics for various ORRs when N=20 patients ......... 98 
Table 14-1 
Prohibited medications that are strong inducers or inhibitors of 
CYP3A, or CYP3A substrates with narrow therapeutic index, or 
sensitive CYP2C9 substrates with narrow therapeutic index** .......... 104 


 
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Table 14-2 
List of medications to be used with caution ........................................ 105 
Table 14-3 
List of prohibited enzyme-inducing anti-epileptic drugs .................... 105 
Table 14-4 
List of prohibited QT prolonging drugs .............................................. 106 
Table 15-1 
Response criteria for target lesions ..................................................... 114 
Table 15-2 
Response criteria for non-target lesions .............................................. 116 
Table 15-3 
Overall lesion response at each assessment ........................................ 117 
Table 15-4 
Overall lesion response at each assessment: patients with non- 
target disease only ............................................................................... 124 
Table 15-5 
Options for event dates used in PFS, TTP, duration of response ........ 126 


 
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List of abbreviations 
AE 
Adverse event 
ALCL 
Anaplastic large cell lymphoma 
ALK 
Anaplastic lymphoma kinase 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC 
Area under the plasma (serum, or blood) concentration versus time curve 
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 
BLRM 
Bayesian logistic regression model 
BUN 
Blood Urea Nitrogen 
CI 
Confidence interval 
CL/F 
Apparent clearance 
Cmax 
Maximum (peak) concentration of in plasma 
Cmin 
Minimum (trough) concentration of drug in plasma 
CNS 
Central nervous system 
CR 
Complete response 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
DCR 
Disease control rate 
D 
Entered into database 
DILI 
Drug-induced liver injury 
DLT 
Dose limiting toxicity 
DOR 
Duration of response 
DS&E 
Safety & Epidemiology 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EGFR 
Epidermal growth factor receptor 
EML4-ALK 
Echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase 
EOS 
End of study 
EOT 
End of treatment 


 
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FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FISH 
Fluorescent in situ hybridization 
FSH 
Follicle-stimulating hormone 
GGT 
Gamma-glutamyl transpeptidase 
GCP 
Good Clinical Practice 
hCG 
human chorionic gonadotropin 
IB 
Investigator’s brochure 
IC50 
Half maximal (50%) inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IGF1R 
Insulin-like Growth Factor 1 Receptor 
INR 
International normalized ration 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
IV 
Intravenous(ly) 
LFT 
Liver function test 
LH 
Luteinizing hormone 
LLOQ 
lower limit of quantification 
MedDRA 
Medical dictionary for regulatory activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
N/A 
Not applicable 
NSAIDs 
Non-steroidal, anti-inflammatory drugs 
NSCLC 
Non-small cell lung cancer 
OIRR 
Overall intracranial response rate 
ORR 
Overall response rate 
OS 
Overall survival 
 
 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PR 
Partial response 
PS 
Performance Status 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval using Fridericia formula 
QD 
quaque diem/once daily 
RAP 
Report and Analysis Plan 
RBC 
Red blood count 


 
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RD 
Recommended dose 
RECIST 
Response Evaluation Criteria In Solid Tumors 
R Value 
ALT/ALP in x ULN 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SD 
Stable disease 
SEC 
Safety event categories 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SHBG 
Sex hormone binding globulin 
SUSARs 
Suspected unexpected serious adverse reactions 
TKIs 
Tyrosine kinase inhibitors 
TTIR 
Time to intracranial response 
TTR 
Time to response 
ULN 
Upper limit of normal 
VATS 
Video-assisted thoracic surgery 
VEGF-A 
Vascular endothelial growth factor-A 
WBC 
White blood cells 
WHO 
World Health Organization 


 
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Glossary of terms 
Assessment 
A procedure used to generate data required by the study. 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject or study patient. 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q 21 days). 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.). 
Enrollment 
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e., before starting any of the study procedures described in 
the protocol). 
Investigational drug 
The drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug”. 
Investigational 
treatment 
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are 
tested in a fixed combination. Investigational treatment generally does not 
include other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used in within approved 
indication/dosage. 
Medication number 
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study. 
Patient number 
A unique identifier number (consisting of the center number and a patient- 
specific number) assigned to each patient who enrolls in the study. 
Period 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has 
spread from the original site to other parts of the body. 
Stop study 
participation 
Point/time at which the patient came in for a final evaluation visit or when study 
drug was discontinued whichever is later. 
Study treatment 
Any drug administered to the patient as part of the required study procedures; 
includes investigational drug and any combination or control drug(s). 
Study treatment 
discontinuation 
Point/time when a patient permanently discontinues study treatment for any 
reason. 
Treatment group 
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are 
enrolled. 
Variable 
A quantity subject to variation of values used in the data analysis; derived 
directly or indirectly from data collected using specified assessments at 
specified time points. 
Withdrawal of 
Consent 
Withdrawal of consent occurs only when a patient does not want to participate 
in the study any longer, and does not want any further visits or assessments, 
and does not want any further study related contact. 


 
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Amendment 4 (28-Jul-2016) 
Amendment rationale 
As of 27-June-2016, 9 patients have been enrolled. 
 
 
 
 
 
In addition, blood sample can be collected in the event that a patient experiences an AE which 
requires either dose modification or termination from the study medication, QT interval 
prolongation or hepatotoxicity, as needed. 
 
Changes to the protocol 
 
 
 
. 
 
 
 
 
. 
 
 
 
• Section 6.4.2.1: update the immunotherapy in the section of Other anticancer therapy in 
Prohibited concomitant therapy. 
 
 
 
 
 
 
 
 
 
 
• Section 7.2.4.1: correct the language. 
 
 
 
 


 
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IRB/IEC/REB Approval 
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 3 (30-Mar-2016) 
Amendment rationale 
As of 25-Mar-2016, 6 patients have been enrolled. 
The purpose of this amendment is to extend the enrollment also to the patients who received 
prior crizotinib in addition to alectinib. In addition it is clarified that alectinib doesn’t need t o 
be the last therapy prior to study enrollment, and no specific sequence of prior alectinib and 
crizotinib is required for enrollment. 
The reason for this change is that despite alectinib recent approval in Japan as 1 st line therapy 
for ALK-positive NSCLC, the vast majority of patients in Japan have received crizotinib as 1st 
line therapy and alectinib as next line. Therefore, this amendment has been released in order 
to improve the feasibility of the study. 
As shown in Section 1.2.1.2.2, in study CLDK378X2101 five patients previously treated with 
both crizotinib and alectinib, received LDK378; a confirmed PR was observed in two out of 
the five patients. 
 
Changes to the protocol 
• Section 1.2.1: update the ZYKADIA approval status. 
• Section 1.2.1.2.2: update the additional clinical data. 
• Section 2.1: update the additional clinical data. 
• Section 2.2: update the information. 
• Section 4.1.1: update to allow the enrollment of patients pre-treated with crizotinib as 
prior ALK inhibitor therapy in addition to alectinib. 
• Section 4.3: update the language to clarify the definition of end of the study 
• Section 5.1: update the language to clarify the patient population. 
• Section 5.2 Inclusion criteria #4: inclusion criteria #4 has been replaced by inclusion 
criteria #4a to update the crizotinib as prior allowed therapy. 
• Section 5.2 Inclusion criteria #5: inclusion criteria #5 has been replaced by inclusion 
criteria #5a to update the crizotinib as prior allowed therapy. 
• Section 5.2 Inclusion criteria #12: inclusion criteria #12 has been replaced by inclusion 
criteria #12a to update the performance status. 
• Section 5.3 Exclusion criteria #3: exclusion criteria #3 has been replaced by exclusion 
criteria #3a to update the crizotinib as prior allowed therapy. 
• Section 5.3 Exclusion criteria #4: exclusion criteria #4 has been replaced by exclusion 
criteria #4a to update the crizotinib as prior allowed therapy. 
• Section 8.2.2: update the language of SAE reporting. 


 
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IRB/IEC/REB Approval 
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 2 
Amendment rationale 
As of the release date of this amendment, 4 patients have been enrolled. 
The amendment provides follow up evaluations for hepatic toxicities and work -up guidelines 
for potential Drug Induced Liver Injury (DILI) cases. For consistency with other Novartis 
sponsored clinical studies, other changes were implemented in this amendment: 
Exclusion criteria for contraception use is being updated 
Dose guidance modification for QTcF text was updated to provide clarification on monitoring 
procedure. 
 
Changes to the protocol 
• Section 5.3 Exclusion criterion # 18 (contraception): updated the definition of highly 
effective contraception 
• Table 6-3: updated criteria for interruption and re-initiation of LDK378 treatment for AST 
or ALT and concurrent total bilirubin elevation and electrocardiogram QT corrected 
(QTcF) interval prolonged. 
• Section 6.3.4.2: updated to include information for identifying potential drug-induced liver 
injury. 
• Table 14-4: Added medication to reflect updated List of prohibited medication causing 
QTc prolongation. 
 
IRB/IEC/REB Approval 
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 
 
 
 
 
In addition, this amendment has been implemented to provide updated safety information as 
well as clarification of sections of the protocol where additional guidance was required. 
 
Changes to the protocol 
• Section 1.1: updated for editorial change. 
• Section 1.2.1: updated the status of marketing authorization application (MAA) 
submission to health authorities. 
• Section 1.2.1.2: editorial change to “adverse events of special interest” to ensure 
consistency between this section and Section 8.1.3. 
• Section 1.2.1.2.2: editorial change. 
 
 
• Section 5.1: corrected typographical error “rescreening of patients during the screening 
period will not be allowed”. 
• Section 5.2 Inclusion criterion # 10 (serum amylase): updated serum amylase criterion. 
• Section 5.3 Exclusion criterion #10 (pancreatitis): added the pancreatic disease criterion. 
• Section 6.3: updated to clarify the dose modification depending on the AE grade and 
changed period for LDK378 treatment interruption. 
• Table 6-3 : updated criteria for interruption and re-initiation of LDK378 treatment. 
• Section 6.3.4.8: added guidelines for laboratory assessment of pancreatic abnormalities. 
• Table 6-4 (pancreatic): added follow-up evaluations for selected toxicities 
• Section 6.4.1.1: clarified dose modification guidelines for corticosteroids and treatment 
interruption guidelines for LDK378. 
• Section 6.4.1.2: modified the guidelines for bisphosphonates treatment during the study. 
• Section 6.4.1.5: clarified guidelines for interruption and re-initiation of LDK378 treatment 
before and after radiotherapy/surgery. 
• Section 6.4.2.6: clarified that CYP2C9 and CYP3A4/5 substrates with narrow therapeutic 
index are not permitted for concomitant use with LDK378. 
• Section 6.5.1: removed the sentence related to the central enrollment system which is not 
used in this study. 
 
 
• Section 7.1.1.3: removed the “FDA-approved”. 
• Section 7.1.5.2: removed the phrase “start of new anti-cancer therapy”. 


 
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• Section 7.2.2.6.1: clarified ECG instructions and specified ECG reader qualification 
requirements. 
• Table 7-7 (Plasma): clarified the time point. 
• Section 8.1.3: updated for editorial change. 
• Section 13: updated 2 references, “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” and “Fusion of EML4 and ALK 
is associated with development of lung adenocarcinomas lacking EGFR and KRAS 
mutations and is correlated with ALK expression. Mol Cancer”. 
 
IRB/IEC/REB Approval 
A copy of this amended protocol will be s ent 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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Protocol summary: 
Protocol number 
CLDK378A1201 
Title 
A phase II, Multi-center, Open-label, Single-Arm Study to Evaluate the Efficacy 
and Safety of Oral LDK378 Treatment for Patients with ALK-Positive Non- 
Small Cell Lung Cancer previously treated with alectinib. 
Brief title 
To evaluate efficacy and safety of LDK378 in patients with ALK positive 
NSCLC previously treated with alectinib. 
Sponsor and 
Clinical Phase 
Novartis, Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
Alectinib was approved in Jul 2014 in Japan and it has been used widely as a 
first-line ALK-TKI therapy. However clinical experience of LDK378 in patients 
who failed alectinib therapy remains very limited. Therefore we will evaluate 
the antitumor activity and safety profile of LDK378 when used as a single 
agent in patients with ALK-rearranged locally advanced or metastatic NSCLC 
who have been pretreated with alectinib. 
Primary 
Objective(s) and 
Key Secondary 
Objective 
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: disease control rate (DCR), time to response (TTR), 
duration of response (DOR). 
Secondary 
Objectives 
• 
To evaluate progression-free survival (PFS). 
• 
To evaluate overall survival (OS). 
• 
To evaluate overall intracranial response rate (OIRR). 
• 
To evaluate the safety profile of LDK378. 
Study design 
This is a single-arm, open-label, multicenter, phase II study to evaluate the 
efficacy and safety of the ALK inhibitor LDK378 when used as single agent in 
patients with ALK-rearranged stage IIIB or IV NSCLC previously treated with 
alectinib. A total of approximately 20 patients will be enrolled into the study to 
receive oral LDK378. Treatment with LDK378 750 mg qd will continue until the 
patient experiences disease progression as determined by the investigator 
according to RECIST 1.1, unacceptable toxicity that precludes further 
treatment, pregnancy, start of a new anticancer therapy, discontinues 
treatment at the discretion of the patient or investigator, lost to follow-up, 
death, or study is terminated by Sponsor. 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. 
Population 
This study will be conducted in adult male or female patients, with ALK- 
rearranged (as determined by Vysis ALK Break Apart FISH Probe kit [Abbott 
Molecular Inc.]), advanced (stage IIIB or IV) NSCLC who have progressed 
since prior therapy with alectinib. Prior crizotinib and/or up to one regimen of 
cytotoxic chemotherapy are allowed. 


 
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Main Inclusion 
criteria 
• 
Histologically or cytologically confirmed diagnosis of Stage IIIb or IV 
NSCLC that carries an ALK rearrangement as determined locally by Vysis 
ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test. If 
documentation of ALK rearrangement is not available as described above, 
a test to confirm ALK rearrangement must be performed locally by Vysis 
ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) prior to study. 
• 
Patients must have NSCLC that has progressed at study enrollment. 
• 
Patients must have received previous treatment with alectinib for treatment 
of locally advanced or metastatic NSCLC. Prior therapy with crizotinib as 
ALK inhibitor therapy in addition to alectinib is allowed. Alectinib doesn’t 
need to be the last therapy prior to study enrollment. No particular 
sequence of prior alectinib and crizotinib is required for enrollment. 
• 
A minimum of 21 days of treatment with alectinib will be required to qualify 
as one prior course of alectinib (unless alectinib was discontinued due to 
PD after a shorter treatment course). 
• 
Patients may have discontinued alectinib therapy for disease progression, 
intolerance or other reason. 
• 
Patients must be chemotherapy-naïve or have received only one line of 
prior cytotoxic chemotherapy. If patients received chemotherapy, such 
patients must have progressed during or after the last chemotherapy 
regimen received prior to the first dose of LDK378. 
• 
Age 18 years or older at the time of informed consent. 
• 
Patients must have a tumor tissue sample available, as an archival sample 
(collected either at the time of diagnosis of NSCLC or any time since) 
 
 
• 
Patients must have recovered from all toxicities related to prior anticancer 
therapies to grade ≤ 1 (CTCAE v 4.03). Patients with grade ≤ 2 peripheral 
neuropathy or any grade of alopecia, fatigue, nail changes or skin changes 
are allowed to enter the study. 
Main Exclusion 
criteria 
• 
Patients with known hypersensitivity to any of the excipients of 
LDK378. 
• 
Prior therapy with other ALK inhibitor investigational agents except 
crizotinib and alectinib. 
• 
Prior systemic anti-cancer (including investigational) therapy aside from 
alectinib, crizotinib and one regimen of previous cytotoxic chemotherapy 
for locally advanced or metastatic NSCLC. 
• 
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. 
• 
Patient has history of interstitial lung disease or interstitial pneumonitis, 
including clinically significant radiation pneumonitis. 
• 
Corrected QT (QTcF) > 470 msec using Fridericia’s correction on the 
screening ECG (as mean of triplicate ECGs). 
Investigational and 
reference therapy 
LDK378 
Efficacy 
assessments 
Tumor assessment by RECIST 1.1 as evaluated by investigator. 


 
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Safety 
assessments 
• 
Hematology, chemistry, urinalysis, coagulation, pregnancy test and 
hormones (males only) 
• 
ECG 
• 
Performance status 
• 
Vital signs 
• 
Physical examination 
• 
Adverse events 
Data analysis 
The study does not include formal statistical hypothesis testing and the sample 
size is not derived based on power considerations. With a sample size of 20 
patients, there is an approximately 58.4% chance that the exact 95% 
confidence interval (CI) will exclude an insufficient response rate of 10% when 
the true ORR is 30%. For an observed response rate of 30.0% (6 responders 
in 20 patients), the exact 95% CI is (11.9%, 54.3%). 
The ORR will be estimated and reported along with the exact 95% CI. No 
statistical hypothesis testing is planned. DCR and OIRR will be analyzed in a 
similar way to the ORR. DOR, PFS and OS will be described using Kaplan- 
Meier methods and relevant summary statistics. TTR will be summarized using 
descriptive statistics for patients with a confirmed response. 
Adverse events, laboratory abnormalities and notable ECGs will be tabulated. 
Key words 
ALK, NSCLC, LDK378 


 
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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 
Worldwide, lung cancer occurred in approximately 1.8 million patients in 2012 and caused an 
estimated 1.6 million deaths. (Brambilla et al 2014). In 2012, approximately 160,000 deaths 
due to lung cancer were expected in the United S tates (US; Siegel et al 2012) and 262,000 in 
the European Union (EU; Malvezzi et al 2012) and about 70,000 in Japan (MHLW- 
Population survey report 2013). 
The World Health Organization (WHO) divides lung cancer into 2 major classes: NSCLC and 
small cell lung cancer. NSCLC accounts for more than 85% of all lung cancer cases and 
includes 2 major types: (1) non-squamous carcinoma (including adenocarcinoma, large-cell 
carcinoma, other cell types); and (2) squamous cell (epidermoid) carcinoma. Adenocarcinoma 
(40% of lung cancers) is the most common type of lung cancer seen in the US and is also the 
most frequently occurring cell type in nonsmokers (NCCN Guidelines v13 2014) 
Cigarette smoking remains the most important risk factor for lung cancer, although 
approximately 15% of all lung cancers are diagnosed in patients who never smoked. 
The high mortality rate of lung cancer could be explained in an advanced stage for most cases; 
only 25-30% of new NSCLC cases are diagnosed with localized disease that is potentially 
curable with surgery (Nguyen et al 2012). The majority of patients are diagnosed with locally 
advanced or metastatic disease, for which surgery is not indicated and which do not fit 
indications for surgery. 
As summarized in the current National Comprehensive Cancer Network (NCCN) Guidelines 
for NSCLC, platinum-based combination chemotherapy is superior to best supportive care for 
patients with advanced, incurable disease (NCCN Guidelines® v13 2014). Platinum-doublets 
chemotherapy (cisplatin or carboplatin in combination with other chemotherapy agents, with 
or without bevacizumab) is standard firstline treatment of locally advanced or metastatic 
NSCLC, unless a patient has a known “druggable” gene mutation or aberration, and is 
therefore a candidate for a targeted therapy (as discussed below). 
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). In particular, the prognosis for patients presenting with 
advanced, incurable disease is dismal, with a 5-year OS rate of 3.7% (Howlader et al 2009). 
 
1.1.2 
Targeted therapies in NSCLC 
During the last few years, improvement in the knowledge of NSCLC biology has led to the 
identification of molecular events crucial for malignant transformation and cancer cell 
survival. These aberrant molecular events serve as critical oncogenic drivers for these cancers 


 
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and, therefore represent potential therapeutic targets (Gettinger and Lynch 2011). As a result, 
new targeted treatment options for these patients are evolving. Bevacizumab, a monoclonal 
antibody directed against vascular endothelial growth factor-A (VEGF-A), and erlotinib an 
epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), have been 
approved for the treatment of NSCLC (Gettinger and Lynch 2011). 
The case of EGFR TKIs illustrates a new paradigm in the treatment of NSCLC. There is 
increasing evidence that activating mutations of EGFR define a small subset of patients with 
NSCLC who have sensitivity to EGFR TKIs ( Ettinger et al 2010). Six randomized trials have 
demonstrated that patients harboring activating EGFR mutations benefit more from EGFR 
TKIs than from standard chemotherapy in terms of response rate, progression free survival, 
toxicity profile, and quality of life. In particular, the success of EGFR TKIs highlights the 
importance of identifying specific molecular drivers of NSCLC to appropriately direct 
targeted agents in specific patient populations. 
 
1.1.3 
ALK positive NSCLC 
Another clinically relevant molecular subset of NSCLC is driven by recently the newly 
discovered echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic 
lymphoma kinase (ALK) translocation. 
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 rare event; it is 
present in approximately 2-8% of tumors tested (Scagliotti et al 2012; Takeuchi et al 2009; 
Soda et al 2007). 
Patients with ALK-rearranged NSCLC are similar to those with EGFR mutations (i.e., 
adenocarcinoma, nonsmokers or former smokers), up to 30% of smokers or former smokers 
has been included in the pivotal phase 3 study evaluating crizotinib after first line of treatment 
for ALK-rearranged NSCLC (Shaw et al 2013) except they are often younger. In addition, 
ALK rearrangements are found in patients with adenocarcinoma but not usually found in 
squamous cell or large cell carcinoma (Shaw et al 2009). ALK rearrangements and other 
oncogenic drivers such as mutant EGFR and oncogenic RAS are generally mutually exclusive, 
consistent with the notion that ALK rearrangement defines a unique molecular subset of 
NSCLC (Gainor et al 2013). In patients with adenocarcinoma lacking EGFR and KRAS 
mutations, the prevalence of EML4-ALK translocation could be as high as 42.8 % ( Zhang 
2010). In these patients, ALK rearrangements serve as a key strong oncogenic driver for 
NSCLC and represent a critical therapeutic target susceptible to targeted ALK kinase 
inhibition. 
Crizotinib, an orally available small-molecule inhibitor of ALK and MET tyrosine kinases, is 
the first tyrosine kinase inhibitor to target ALK to have demonstrated a clinical activity . The 


 
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first evidence that ALK-positive NSCLC responds to ALK inhibitors was seen with crizotinib, 
an ALK and MET inhibitor, which in single-arm trials was shown to induce durable responses 
in 50-61% of patients. Based on these data, crizotinib received accelerated approval under the 
trade name Xalkori® in the US and conditional marketing authorization in the EU ( Ou 2011). 
Subsequently, crizotinib received approval in Switzerland, Japan, China, Canada, as well as 
other countries worldwide. Advanced or metastatic ALK-positive NSCLC patients, after 
failure to a prior platinum-based chemotherapy, experienced a higher response rate (RR) to 
crizotinib (RR=65%; 95%CI:58-72) compared to chemotherapy (RR=20%; 95CI:14-26) and a 
longer progression free survival (PFS) if treated with crizotinib compared with second -line 
chemotherapy (7.7 months versus 3.0 months, HR=0.49; 95% CI, 0.37 – 0.64) (Shaw et al 
2013). In addition, crizotinib showed a higher RR compared to chemotherapy (ORR= 74% 
versus 45%; P<0.0001) and a longer PFS (Median 10.9 months versus 7.0 months; HR: 0.454; 
95% CI: 0.346–0.596) in treatment naive advanced non-squamous ALK-positive NSCLC 
patients (Mok et al 2014). 
Alectinib, an orally available small-molecule inhibitor of ALK tyrosine kinases, has been 
approved in ALK-TKI naïve patients with advanced NSCLC in Japan in 2014. The results 
from Alectinib phase I/II study (CH5424802/RO5424802, [Chugai/Roche]) in ALK-TKI 
treatment naïve ALK-positive NSCLC were published (Seto et al 2013). In the phase I portion, 
24 patients were treated at doses of 20-300 mg twice daily and no dose limiting toxicities 
(DLTs) were observed. In the phase 2 portion, 46 patients were treated with the recommended 
dose, 300 mg twice daily, of whom 43 (93.5%) achieved an objective response including two 
complete responses. Adverse events were reported in all 46 patients with main toxicities as 
follows: dysgeusia, increased aspartate aminotransferase (AST), increased blood bilirubin and 
increased blood creatinine. Grade 3 adverse events were reported in 17 (37%) patients, but no 
grade 4 adverse events or deaths were reported. The drug was generally well tolerated with 
manageable adverse events. 
While crizotinib and alectinib has impressive activity in patients with ALK rearranged 
NSCLC and ALK-positive patients will receive crizotinib or alectinib, however these cancers 
invariably progress, with the development of resistance to crizotinib and alectinib. For the se 
patients there is limited alternative ALK-targeted therapy. Therefore, the development of 
ALK TKIs with clinical activity against ALK-positive NSCLC resistant to prior ALK-TKI is 
crucial. 
 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of LDK378 
LDK378 
[5-Chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl) 
phenyl]-N4-[2 
(isopropylsulfonyl) phenyl]-2,4-pyrimidinediamine] is an orally available ALK inhibitor. 
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 (as 
described below), and the efficacy seen in the ongoing Phase I clinical trial in patients (wi th 


 
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and without previous crizotinib therapy) led to the approval of LDK378 (ceritinib) by the 
FDA under the trade name ZYKADIA™ on 29-Apr-2014 for the following indication: 
• ‘ZYKADIA is indicated for the treatment of patients with ALK-positive metastatic 
NSCLC who have progressed on or are intolerant to crizotinib’ 
This indication is approved under accelerated approval based on tumor response rate and 
duration of response. An improvement in survival or disease-related symptoms has not been 
established. Continued approval for this indication may be contingent upon verification and 
description of clinical benefit in confirmatory trials. 
In the European Union, the trade name ZYKADIA™ was approved on 6-May-2015 for the 
following indication: 
• “ZYKADIA is indicated for the treatment of adult patients with anaplastic lymphoma 
kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated 
with crizotinib” 
In Japan, the trade name ZYKADIA® was approved on 28-Mar-2016 for the following 
indication: 
• “Unresectable advanced and/or recurrent anaplastic lymphoma kinase (ALK) fusion gene- 
positive non-small cell lung cancer with resistance or intolerance to crizotinib” 
Submissions to other health authorities worldwide have been completed in some countries and 
are underway in others. 
 
1.2.1.1 
Non-clinical experience 
 
1.2.1.1.1 Pharmacology 
LDK378 inhibits ALK and ALK-mediated signaling pathways in a dose-dependent manner. It 
inhibits autophosphorylation of ALK, ALK-mediated phosphorylation of downstream 
signaling proteins, and proliferation of ALK-dependent cancer cells both in vitro and in vivo. 
LDK378 is approximately 20-fold more potent than crizotinib in enzymatic inhibition assays 
of ALK kinase activity (Half maximal (50%) inhibitory concentration (IC 50) of 0.15 nM for 
LDK378 and 3 nM for crizotinib). In a kinase panel of 36 enzymes, LDK 378 demonstrated a 
high degree of selectivity for ALK inhibition by inhibiting only 2 other kinases (INSR and 
IGF1R) but with approximately 50-fold less potency than ALK inhibition. 
Preclinical data showed inhibition of the kinase activity of the NPM-ALK fusion oncogene (in 
Karpas299 human ALCL cells) and of the EML4-ALK fusion oncogene (in H2228 human 
NSCLC cells) with LDK378, which led to inhibition of cancer cell proliferation in vitro. 
Inhibition of the downstream signaling pathway by LDK378 correlated with inhibition of the 
proliferation. In addition, inhibition of fusion oncogenes NPM-ALK and EML4-ALK in 
mouse and rat xenograft models resulted in inhibition of tumor growth and tumor regression 
in vivo. LDK378 was also active in the cell lines with ALK amplification or expression of 
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1.2.1.1.2 Antitumor activity in xenograft models 
LDK378 is highly active in mouse and rat xenograft models of lung cancer and ALCL that 
carry an ALK rearrangement. In murine xenograft models of H2228 NSCLC a nd Karpas299 
ALCL cells, LDK378 dosed at 25 mg/kg daily, a dose below the maximum tolerated dose 
(MTD) in clinical studies defined in good laboratory practice (GLP) toxicity studies (30 
mg/kg in monkey and 30 mg/kg in rat), resulted in regression of establ ished tumors. When 
dosed at 50 mg/kg daily for 14 days in the H2228 NSCLC model in mice, LDK378 resulted in 
complete and prolonged tumor regression (lasting for more than 4.5 months after treatment 
was discontinued). In the same experiments, crizotinib dosed at 100 mg/kg daily for 14 days 
resulted in complete tumor regression, but tumors relapsed within 2 weeks after stopping 
treatment. 
LDK378 also has potent antitumor activity against crizotinib-resistant H2228 NSCLC cell 
lines, including resistant variants carrying I1171T or C1156Y mutations in the ALK kinase 
domain. These data support the hypothesis that LDK378 may be clinically active in ALK - 
rearranged NSCLCs in multiple treatment settings. 
 
1.2.1.1.3 Nonclinical pharmacokinetics (PKs) and metabolism 
In general, LDK378 was moderately absorbed in rats (37%) and monkeys ( ≥40%). Oral 
bioavailability was complete in fed dogs, suggesting the possible existence of a positive food 
effect. The formulation used in these bioavailability determinations was a 0.5% 
methylcellulose suspension except for in the mouse where a solution formulation was used. 
LDK378 is highly bound to plasma protein (>94%) in all species. Following oral 
administration of [14C] LDK378 to LEH male rats, radioactivity was widely distributed. The 
highest tissue exposures were found in intestine wall, uveal tract, pituitary gland, bile, adrenal 
cortex, harderian gland, liver, spleen, lymph node, lung, kidney, thyroid, bone marrow, 
adrenal medulla and pancreas (25- to 710-fold higher exposure relative to blood). Although 
the brain to blood concentration ratio of drug-related radioactivity was low compared to these 
other tissues brain-to-blood exposure (AUCinf) ratio of approximately 15%, it was higher 
than the 3% background associated with brain vasculature at all monitored time points. This 
indicates that drug-related radioactivity crossed the blood-brain barrier. Unchanged LDK378 
was the major component in feces and bile of intact and bile duct -cannulated rats. In the rat, 
LDK378 underwent oxidation leading to the formation of four oxygenated metabolites 
(designated as M23.6, M30.6, M35.8, and M33.4). In addition, LDK378 underwent sulfation 
leading to M36.8 and oxidation followed by sulfation, resulting in the presence of M29.5. 
LDK378 also underwent glucuronidation leading to M26.8 and M27.6. The major metabolite 
in feces was designated M33.4 (oxygenation) accounting for approximately 7% of the dose. 
All other metabolites in feces and bile were minor (< 5% of the dose). In rats dosed with 
[14C]-LDK378, LDK378-derived radioactivity was excreted predominantly via the fecal route 
(>99%), and renal excretion was a minor pathway for excretion (< 1%). Fecal excretion was 
the result of biliary excretion (69%) and gastrointestinal (GI) secretion (31%). Since parent 
drug was the major component in bile and feces after intravenous (i.v.) administration, 
enterohepatic circulation may occur. 
CYP3A4/5 is the major hepatic enzyme metabolizing LDK378 in a human in vitro system. 
The metabolic drug-drug interaction (DDI) potential of LDK378 as an inhibitor was evaluated 


 
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using pooled human liver microsomes. Based on the assessment of clinical significance of in 
vitro results using the appropriate DDI decision tree described in FDA draft DDI guidance 
(2012) “Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and 
Labeling Recommendations” and in EMA DDI guideline (2012) “Guideline on the 
Investigation of Drug Interactions”, at clinically relevant concentrations, LDK378 is unlikely 
to inhibit CYP1A2, 2B6, 2C8, 2C19 or 2D6. Only CYP2A6, 3A4, 2C9 and possibly CYP2E1 
need to be considered as possible victims of in vivo inhibition by LDK378. LDK378 is also a 
time-dependent CYP3A inhibitor (Ki: 1.47 µM and Kinact: 0.0642 min-1), but shows no 
apparent time-dependent inhibition of CYP1A2, 2C9 or 2D6 at LDK378 concentrations of up 
to 50 µM. 
LDK378 is likely a P-gp, but not BCRP or MRP2 substrate. It does not inhibit P-gp, BCRP or 
MRP2 up to 1.5 μM in vitro. 
 
1.2.1.1.4 Safety pharmacology and toxicology 
LDK378 has moderately potent activity on the hERG channel with an IC 50 of 0.4 μM. In a 
GLP implanted telemetry study in monkeys LDK378 at oral doses of 0, 10, 30 and 100 mg/kg 
in a cross-over design had no effects on blood pressure, heart rate, body temperature, or ECG 
intervals (PR, RR or QRS), and did not produce any arrhythmias. Apparent QT/QTc 
prolongation was noted in one animal between approximately 10 and 19 hours (ranged from 
14.25 to 43.52 msec above pre-dose baseline value) post-dose after receiving the 100 mg/kg 
dose. No changes were noted in the central nervous system (CNS) and no effects on the 
respiratory system were observed in rats at single high doses (100 mg/kg). 
LDK378 was evaluated for safety in repeated dose studies up to 26 weeks and 13 weeks in 
rats and monkeys, respectively. The principal toxicity related to LDK378 administration was 
inflammation of the extra hepatic ducts, pancreas, and/or duodenum. Gastrointestinal toxicity 
was observed in both species characterized by body weight loss, decreased food consumption, 
emesis (monkey), diarrhea, and at high doses, by histopathologic lesions including erosion, 
mucosal inflammation, and foamy macrophages in the duodenal crypts and submucosa of rats 
and monkeys. The liver (bile duct) was also affected in both species only at the highest dose 
levels studied (100 mg/kg/day in the 2-week studies for both rat and monkeys, and 50 and 30 
mg/kg/day in the 4-weeks studies in rat and monkeys, respectively), and included 
hepatocellular nectrosis (rat only), minimal increases in  liver transaminases and vacuolation 
of the bile duct epithelium, as well as inflammatory cell infiltrate. The pancre as was a target 
organ in the rat, but not the monkey, with acinar cell atrophy and mixed cell inflammation 
noted at mid and high doses in the 4-week study. The pancreas was not affected in the 13- and 
26-week studies. Alveolar foamy macrophages (confirmed phospholipidosis) were seen in the 
lungs of rats, but not in monkeys, and the lymph nodes of rats and monkeys had macrophage 
aggregates. Lymphoid depletion in the thymus was seen in monkey at overtly high doses 
Target organ effects showed partial to complete recovery during the non-dosing period. 
In embryo-fetal toxicity studies in rats and rabbits, there was no evidence of embryolethality, 
fetotoxicity or teratogenicity at the maternal toxicity dose. However, the exposure at NOAEL 
for maternal toxicity and embryo-fetal development was lower than the clinical exposure in 
patients given 750 mg qd. 


 
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Preclinical studies (in vitro 3T3 NRU assay) indicated a low risk of phototoxicity with use of 
LDK378.However, a confirmatory assay from an in vivo ultraviolet local lymph node assay 
(UV LLNA) demonstrated no phototoxic potential with LDK378. 
 
1.2.1.2 
Clinical experience 
 
1.2.1.2.1 Clinical safety and tolerability 
LDK378 is generally associated with a manageable safety profile. 
In CLDK378X2101, as of the 14-April-2014 cut-off date, total of 255 ALK positive patients 
were enrolled 246 NSCLC (98.4%) and 9 Non-NSCLC (3.6%). For the 246 patients with 
ALK positive NSCLC treated at the recommended dose of 750 mg in this ongoing study, the 
median duration of exposure was 38.6 weeks (range 0.4 to 105.9). At least one dose 
reductions due to adverse events occurred in 61.8% of patients treated with LDK378 at the 
750 mg dose. In 255 ALK positive patients, the most common adverse events regardless of 
study drug relationship (incidence ≥25%) were diarrhea, nausea, vomiting, alanine 
aminotransferase (ALT) increased, fatigue, abdominal pain, decreased appetite, aspartate 
aminotransferase (AST) increased, constipation, and cough. The frequently occurred grade 3- 
4 Adverse events (AEs) (>5%), regardless of study drug relationship were ALT (Alanine 
aminotransferase) increased (29.8%), AST increased (9.8%), lipase increased (6.3%), diarrhea 
(5.9%), nausea (5.9%), hyperglycemia (5.9%), fatigue (5.1%), anaemia (5.1%) and blood 
alkaline phosphatase increased (5.1%) (Table 1-1). 


 
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Table 1-1 
All grades (at least 10%) and grade 3-4 adverse events, regardless of 
study drug relationship, by preferred term in patients treated in the 
750 mg dose group (Safety Set) (Data cut-off: 14-April-2014) 
 
LDK378 
750 mg 
N=255 
All Grades 
Grade ¾ 
Preferred term 
n (%) 
n (%) 
Total 
255 (100.0) 
206 (80.8) 
Diarrhea 
221 (86.7) 
15 (5.9) 
Nausea 
211 (82.7) 
15 (5.9) 
Vomiting 
157 (61.6) 
12 (4.7) 
Alanine Aminotransferase Increased 
112 (43.9) 
76 (29.8) 
Fatigue 
109 (42.7) 
13 (5.1) 
Abdominal Pain 
98 (38.4) 
3 (1.2) 
Decreased Appetite 
95 (37.3) 
4 (1.6) 
Aspartate Aminotransferase Increased 
83 (32.5) 
25 (9.8) 
Constipation 
79 (31.0) 
0 
Cough 
73 (28.6) 
0 
Dyspnea 
63 (24.7) 
11 (4.3) 
Abdominal Pain Upper 
60 (23.5) 
2 (0.8) 
Asthenia 
50 (19.6) 
2 (0.8) 
Back Pain 
50 (19.6) 
1 (0.4) 
Headache 
51 (20.0) 
4 (1.6) 
Weight Decreased 
46 (18.0) 
5 (2.0) 
Blood Alkaline Phosphatase Increased 
45 (17.6) 
13 (5.1) 
Blood Creatinine Increased 
43 (16.9) 
0 
Pyrexia 
42 (16.5) 
0 
Insomnia 
39 (15.3) 
0 
Musculoskeletal Pain 
37 (14.5) 
0 
Rash 
34 (13.3) 
0 
Dyspepsia 
32 (12.5) 
1 (0.4) 
Anemia 
31 (12.2) 
13 (5.1) 
Dizziness 
31 (12.2) 
0 
Hypokalemia 
29 (11.4) 
11 (4.3) 
Edema Peripheral 
27 (10.6) 
0 
Musculoskeletal Chest Pain 
27 (10.6) 
0 
Non-Cardiac Chest Pain 
26 (10.2) 
2 (0.8) 
Arthralgia 
26 (10.2) 
0 
The most frequent AEs requiring dose adjustments or interruptions reported in ≥5% of the 
patients were: ALT increased, nausea, diarrhea, AST increased, vomiting, fatigue, abdominal 
pain, decreased appetite and lipase increased. AEs leading to study drug discontinuations 
occurred in 10.2% of patients treated with LDK378 at the 750 mg dose. The most frequent 
AEs (which occurred in two or more patients) leading to study drug discontinuations were 


 
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pneumonia, ALP increased, decreased appetite, general physical health deterioration, 
pneumonitis, and respiratory failure 
Serious adverse events (SAEs) reported in 47.5 % of the 255 patients treated at the 
recommended dose of 750 mg were pneumonia, interstitial lung disease (ILD)/pneumonitis, 
convulsion, dyspnea, nausea, hyperglycemia, pericardial effusion and respiratory failure 
(incidence ≥2%). On treatment death except death due to the cancer occurred in 14 patients, 
consisting of: pneumonia and respiratory failure in 3 patients and acute respiratory failure, 
cardiac tamponade, gastric haemorrhage, ILD, pneumothorax, pulmonary tuberculosis, 
respiratory failure sepsis and septic shock (1 patient each). 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). For additional details, refer to [Investigator’s Brochure]. 
In Japanese phase I study with expansion phase, CLDK378X1101, total of 20 patients with 
ALK-rearranged tumor patients, 19 (95%) with NSCLC and 1 (5%) inflammatory 
myofibroblastic tumor were enrolled as of the 4-Jul-2014 cut-off date. The median duration of 
exposure was 32.1 weeks (range 0.1 to 86.7). In dose escalation phase, tolerability up to 750 
mg/day was confirmed. All patients experienced ≥1 AE regardless of study drug relationship. 
The most common AEs were nausea (95%), diarrhea (75%) and vomiting (75%). Grade 3 or 4 
AEs regardless of study drug relationship were reported in 16 patients. The most frequent 
grade 3 or 4 AEs were ALT increased and tumor pain, each of which occurred in two patients 
(10%) (Murakami et al 2014). 
 
1.2.1.2.2 Clinical efficacy 
In CLDK378X2101, as of the 14-April-2014 cut-off date, this Study demonstrated a high rate 
of rapid and durable responses with LDK378 in 246 ALK-positive NSCLC patients treated in 
the 750 mg dose group (the RD). LDK378 showed this level of high anti -cancer activity 
regardless of prior ALK inhibitor status (i.e., whether or not the patient received previous 
treatment with an ALK inhibitor). A high ORR of 56.4% and 72.3% was observed in patients 
treated with a prior ALK inhibitor and in ALK inhibitor naïve patients respectively, by 
investigator assessment (Table 1-2). The median duration of response (DOR) was  8.25 
months (95% CI: 6.80, 9.69) and 17.02 months (95% CI: 11.27, non-estimable) in patients 
treated with a prior ALK inhibitor and ALK inhibitor naïve patients respectively (Table 1-3). 
Median time to response was 6.1 weeks (range: 4.6 to 24.1) and 6.1 weeks (3.0 to 42.1) in 
patients treated with a prior ALK inhibitor and the ALK inhibitor naïve patients with 
confirmed complete response (CR) or PR respectively. Based on the investigator assessment 
146 PFS events (123 progressions and 23 deaths) were observed with 40.7% of the patients 
censored. The median PFS was 6.93 months (95% CI: 5.55, 8.67) and 18.4 months (95% CI: 
11.10, non-estimable) in patients treated with a prior ALK inhibitor and the ALK inhibitor 
naïve patients respectively (Table 1-4) (Felip et al 2014). 
There were 5 patients who were previously treated with alectinib and crizotinib. LDK378 
achieved confirmed PR in two, PD in one as best response and unknown in two of five 
patients. 


 
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Table 1-2 
Summary of best overall response based on investigator assessment 
in NSCLC patients in the 750 mg dose group, by prior ALK inhibitor 
status (Full Analysis Set – NSCLC 750 mg) (Data cut-off: 14-April-2014) 
 
NSCLC with prior ALK inhibitor 
N=163 
n (%) 
NSCLC ALK inhibitor naïve 
N=83 
n (%) 
Best overall response 
Complete response (CR) 
3 (1.8) 
1 (1.2) 
Partial response (PR) 
89 (54.6) 
59 (71.1) 
Stable disease (SD) 
29 (17.8) 
14 (16.9) 
Progressive disease (PD) 
16 (9.8) 
0 
Unknown 
26 (16.0) 
9 (10.8) 
Overall response rate (ORR) 
(CR or PR), n (%) 
92 (56.4) 
60 (72.3) 
95% CI 
(48.5-64.2) 
(61.4-81.6) 
Best overall response is based on investigator’s assessment of disease status using RECIST 1.0 
criteria. 
CR and PR are confirmed by repeat assessments performed not less than 4 weeks after the criteria 
for response are first met. 
Exact binomial 95% Confidence Interval. 
 
 
Table 1-3 
Analysis of duration of response based on investigator assessment in 
NSCLC patients in the 750 mg dose group using Kaplan-Meier method, 
by prior ALK inhibitor status (Full Analysis Set – NSCLC 750 mg– 
Confirmed CR or PR) (Data cut-off: 14-Apr-2014) 
 
NSCLC with prior ALK inhibitor 
N=92 
NSCLC ALK inhibitor naïve 
N=60 
No. of events, n (%) 
62 (67.4) 
21 (35.0) 
Progression 
61 (66.3) 
19 (31.7) 
Death 
1 (1.1) 
2 (3.3) 
No. of patients censored 
30 (32.6%) 
39 (65.0%) 
Median DOR (month) [95%CI] 
8.25 
17.02 
[6.80, 9.69] 
[11.27, NE] 
Median with 95% CI is calculated from PROC LIFETEST output using method of Brookmeyer and 
Crowley (1982). 
 


 
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Table 1-4 
Analysis of PFS based on investigator assessment in NSCLC patients 
in the 750 mg dose group, by prior ALK inhibitor status (Full Analysis 
Set – NSCLC 750 mg) (Data cut-off : 14-Apr-2014) 
 
NSCLC with prior ALK inhibitor 
NSCLC 
ALK inhibitor naïve 
N=163 
N=83 
Number of PFS events, n (%) 
113 ( 69.3) 
33 ( 39.8) 
Progression 
96 ( 58.9) 
27 ( 32.5) 
Death 
17 ( 10.4) 
6 ( 7.2) 
Number of patients Censored 
50 ( 30.7%) 
50 ( 60.2%) 
Median PFS (month) [95% CI] 
6.93 
18.40 
[5.55, 8.67] 
[11.10, NE] 
Median with 95% CI is calculated from PROC LIFETEST output using method of Brookmeyer and 
Crowley (1982). 
 
In CLDK378X1101, as of the 4-Jul-2014 cut-off date, 19 ALK positive NSCLC patients were 
enrolled. The majority (16/20; 80%) of patients had received prior ALK -TKI therapy. 
Objective responses (all PR) were documented for 10 (53%) of the 19 patients with NS CLC, 
with SD observed in three patients (16%), yielding a disease control rate (DCR) of 68%. 
Responses were observed regardless of the type of prior ALK inhibitor administered 
(crizotinib, alectinib or ASP3026). LDK378 achieved PR in two of the five patients pretreated 
with alectinib, with SD observed in a further patient. Durable clinical benefit was afforded in 
these three patients out of five patients resistant to alectinib, with response extending up to 10 
months (Murakami et al 2014). In addition, after the above reported cut-off date, two patients 
who received prior alectinib were enrolled into the study. The best overall responses of two 
patients were SD and PR respectively. Therefore, in [CLDK378X1101] study, a total of seven 
patients pretreated with alectinib were enrolled and three of them achieved a PR as best 
overall response. 
 
1.2.1.2.3 Clinical pharmacodynamics 
Data are not available. 
 


 
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2 
Rationale 
2.1 
Study rationale and purpose 
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 been pretreated with alectinib. This study is 
conducted in Japan. 
ALK rearrangement is a relatively rare 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. Crizotinib and  alectinib 
have been approved for ALK positive NSCLC in Japan. While crizotinib and alectinib have 
impressive activity in patients with ALK rearranged NSCLC, as described above,  these 
cancers will invariably progress, with the development of resistance to crizotinib and alectinib. 
For these patients there is limited alternative ALK-targeted therapy. Therefore, the 
development of ALK TKIs with clinical activity against ALK -positive NSCLC resistant to 
prior ALK-TKI therapy is crucial. 
LDK378 could be a therapeutic option for those who fail prior therapy with a ALK inhibitor, 
including alectinib. Recently, it was reported that LDK378 markedly inhibited cell 
proliferation of MGH056-1 cells, which was derived from a NSCLC patient who developed 
resistance to alectinib harboring I1171T mutation in ALK. The IC50 values of LDK378, 
alectinib and crizotinib were 4.3, 80 and 236 nM, respectively. In consistent with this result, 
treatment of this patient with LDK378 led to significant tumor regression with a confirmed 
partial response lasting over 7 months. In addition, LDK378 inhibited the growth of H3122 
CHR-A1 NSCLC cell line, in which alectinib resistance were experimentally induced with the 
V1180L mutation in ALK, while alectinib and crizotinib showed less activity. These 
evidences suggest that LDK378 demonstrates the benefit in patients who relapsed by 
secondary mutations in ALK such as I1171T after treatment with alectinib ( Katayama et al 
2014). 
In study CLDK378X2101, LDK378 has demonstrated potent antitumor activity in patients 
who failed crizotinib therapy mainly. Ongoing clinical phase II and III studies are 
investigating the activity of LDK378 in crizotinib-treated patients. The clinical experience of 
LDK378 in patients who failed alectinib therapy remains very limited. In study 


 
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CLDK378X1101, three out of seven NSCLC patients who had progressed on prior alectinib 
therapy and in study CLDK378X2101, two out of five NSCLC patients who had received 
crizotinib and alectinib therapy demonstrated a PR with durable response. 
These preliminary pre-clinical and clinical data of LDK378 indicate the possibility of 
expanding therapeutic options for patients with ALK-rearranged NSCLC who failed prior 
alectinib. Alectinib was approved in Jul 2014 in Japan and it has been used widely as first line 
and second-line after crizotinib therapy. Additional efficacy data of LDK378 after alectinib 
will be clinically important. 
Therefore this study will evaluate the efficacy and safety of LDK378 in patients with ALK - 
positive NSCLC that may have received prior crizotinib and/or up to one-line of 
chemotherapy, and that has progressed after alectinib therapy. 
 
2.2 
Rationale for the study design 
This is a prospective, multi-center, open-label, single arm, non-randomized phase II study to 
evaluate the efficacy and safety of single-agent LDK378 in patients with ALK-rearranged 
NSCLC previously treated with alectinib. As mentioned above, clinical experien ce in this 
population is very limited, although a high unmet medical need exists. The target population 
for this study is similar to the ALK positive NSCLC population included in CLDK378X1101 
and CLDK378X2101 as described above, where substantial anti-tumor activity of LDK378 
has been observed. 
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. Response rate is an appropriate primary endpoint 
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 that has progressed during alectinib 
therapy. The study will also assess DOR, DCR, time to first tumor response (TTR), 
progression-free survival (PFS), overall survival (OS). These endpoints are considered to be 
important supportive endpoints to better assess the potential clinical benefit of LDK378 in this 
patient population. 
 
2.3 
Rationale for dose and regimen selection 
In the dose-escalation phase I study [Study CLDK378X2101], 59 patients were treated at dose 
levels of 50 to 750 mg. Eight Dose Limiting Toxicities (DLTs) at Cycle 1 were observed in 6 
patients. Based on the Bayesian logistic regression model used to guide dose escalation, the 
probability of overdose (>25% probability that the DLT rate ≥ 33%) at Cycle 1 was 3.3% at 
the 750 mg dose level. However, during the dose-escalation discussion between the 
investigators and the sponsor, further dose escalation was considered to be medically 
inappropriate due to the increasing frequency of persistent grade 1 -2 nausea, vomiting and 
diarrhea, and the occasional occurrence of grade 3-4 ALT and AST increases with prolonged 
treatment. Further confirmation of the 750 mg dose as the appropriate MTD came from the 
incidence of DLTs in Cycle 1 in the first 10 patients treated at this dose in the expansion 
phase of the study. There were no first-cycle DLTs in these 10 patients, thus confirming the 
750 mg dose as a safe MTD and RD. 


 
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In the dose-escalation phase I study in Japanese patients [CLDK378X1101], tolerability up to 
750 mg /day was confirmed. 
 
2.4 
Rationale for choice of combination drugs 
Not applicable 
 
2.5 
Rationale for choice of comparators drugs 
Not applicable 
 
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 
The primary endpoints is: 
Refer to Section 10.4. 
To demonstrate the antitumor activity of LDK378, as 
measured by overall response rate (ORR) to LDK378 
by investigator assessment per RECIST 1.1 
Overall response rate (ORR), defined as the proportion of patients 
with a best overall confirmed response of CR or PR in the whole 
body as assessed per RECIST 1.1 by the investigator. 
Key secondary 
Refer to Section 10.5.1. 
To evaluate response related endpoints as assessed 
by investigator. 
1. To evaluate disease control rate (DCR) 
2. To evaluate time to tumor response (TTR) 
3. Duration of response (DOR) 
The following endpoints will be evaluated by investigator per 
RECIST 1.1: 
1. DCR, calculated as the proportion of patients with best overall 
response of CR, PR, or SD 
2. TTR, calculated as the time from first dose of LDK378 to first 
documented response (CR or PR) for patients with confirmed 
CR or PR 
3. DOR, calculated as the time from the date of the first 
documented response (CR or PR) to the first documented 
disease progression or death due to any cause for patients with 
confirmed CR or PR 
Other secondary 
Refer to Section 10.5.2, 
1. To evaluate progression free survival (PFS) 
2. To evaluate overall survival (OS) 
3. To evaluate overall intracranial response rate 
(OIRR) 
4. To evaluate the safety profile 
1. PFS, calculated as the time from first dose of LDK378 to date of 
first documented disease progression (per RECIST 1.1) or date 
of death due to any cause 
2. OS, calculated as the time from first dose of LDK378 to death 
from any cause 
3. OIRR, calculated as the proportion of patients with a best overall 
confirmed response of CR or PR in the brain assessments for 
patients having measurable brain metastases at baseline 
4. AEs, ECGs and laboratory abnormalities 
Section 10.5.3. 


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4 
Study design 
4.1 
Description of study design 
This is a single-arm, open-label, multicenter, phase II study to evaluate the efficacy and safety 
of the ALK inhibitor LDK378 when used as a single agent in patients with ALK-rearranged, 
stage IIIB or IV NSCLC previously treated with alectinib. A total of approximately 20 
patients will be enrolled into the study. Treatment with LDK378 will continue until the patient 
experiences disease progression as determined by the investigator according to RECIST 1.1, 
unacceptable toxicity that precludes further treatment, pregnancy, start of a new anticancer 
therapy, discontinuation of treatment at the discretion of the patient or investigator, lost to 
follow-up, death, or termination of the study by Sponsor. LDK378 may be continued beyond 
RECIST-defined progressive disease (PD) as assessed by the investigator if, in the judgment 
of the investigator, there may be clinical benefit with continued treatment. In these patients, 
tumor assessments 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 with tumor assessments until the time of 
PD as assessed by the investigator. 
 
Figure 4-1 
Study design 
4.1.1 
Screening 
All patients must sign an Informed Consent Form (ICF) prior to any screening procedures and 
prior to determination of eligibility criteria. 
Patients must have been treated with Alectinib. With respect to the chemotherapy, patients 
must be chemotherapy-naïve or have received 1 lines of prior cytotoxic chemotherapy to treat 
their stage IIIb or IV NSCLC. Patients must have been treated with the alectinib treatment 
andprior therapy with crizotinib as ALK inhibitor therapy in addition to alectinib is allowed. 
Alectinib doesn’t need to be the last therapy prior to study enrollment. No particular sequence 
of prior alectinib and crizotinib is required for enrollment. 
Eligibility assessment will be conducted within 28 days prior to starting the study drug. 
Approximately 20 patients will be enrolled. 


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4.1.2 
Treatment duration 
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. 
Treatment with LDK378 will continue until the patient experiences disease progression as 
determined by the investigator according to RECIST 1.1, unacceptable toxicity that precludes 
further treatment, pregnancy, start of a new anticancer therapy, discontinuation of treatment at 
the discretion of the patient or investigator, lost to follow-up, death or termination of the study 
by Sponsor. 
 
4.1.2.1 
Tumor assessments during study conduct 
Tumor response will be evaluated starting from the first day of treatment with LDK378, every 
8 weeks, until the time of disease progression according to RECIST 1.1 as determined by 
investigator, withdrawal of consent for further follow-up, loss to follow-up or death. This 
schedule of tumor assessment must continue regardless of dose interruptions. 
 
4.1.2.2 
End of Treatment (EOT) 
When the patient discontinues from study treatment, End of Treatment (EOT) visit must be 
performed as soon as possible and within 7 days of the last dose of LDK378. Patients will be 
contacted for the safety follow-up 30 days after their last dose of LDK378 to determine if they 
have experienced any new AEs and/or to follow resolution of ongoing AEs. 
Following the cessation of tumor follow-up assessments, patients will be contacted every 3 
months to assess patient survival status and/or whether the patient started any other 
antineoplastic therapies since discontinuing study treatment. Patients do not need to visit the 
clinic during the survival follow-up. 
4.1.3 
Follow-up period 
Safety follow-up 
All patients will be followed for AEs and SAEs for at least 30 days following the last dose of 
study treatment at the end of treatment phase. 
 
Post-treatment follow-up 
All patients who discontinued treatment during the treatment phase for reasons other than 
death, lost to follow-up, pregnancy or PD (radiological as assessed by investigator) (Section 
7.1.3) will continue tumor assessments thereafter until PD (radiological as assessed by 
investigator), or withdrawal of consent or death. 
 
Survival follow-up 
All patients who had PD as per investigator assessment and/or withdrew consent from further 
study assessments will subsequently be followed for survival information every 3 months  
until death, lost to follow-up or withdrawal of consent for survival follow-up. 


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4.2 
Timing of interim analyses and design adaptations 
There are no interim analyses and design adaptations planned in this study. 
 
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. 
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 study will end once at least approximately 75% of patients have died or are lost to follow- 
up. The final analysis of study data will be conducted at the end of the study. All available 
data from all patients up to this cutoff date will be analyzed. These data will be summarized in 
the Clinical Study Report (CSR). 
 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 for a discontinued or withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial. 
 
5 
Population 
5.1 
Patient population 
This study will be conducted in adult male or female patients, with ALK-rearranged (as 
determined by Vysis ALK Break Apart FISH Probe kit [Abbott Molecular Inc.]), advanced 
(stage IIIB or IV) NSCLC who have progressed since prior therapy with alectinib. Prior 
crizotinib and/or one regimen or less of cytotoxic chemotherapy are allowed. 
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study. 
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies while on treatment. Patients must meet the eligibility 
criteria outlined in Section 5.2 and Section 5.3 to be enrolled in this study. Rescreening of 
patients during the screening period will not be allowed, but laboratory parameters may be 
retested within the 28-day screening period for an individual patient if such parameters meet 
an exclusion criterion when initially tested. 
 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Histologically or cytologically confirmed diagnosis of NSCLC that carries an ALK 
rearrangement as determined locally by Vysis ALK Break Apart FISH Probe Kit (Abbott 
Molecular Inc.) test. If documentation of ALK rearrangement is not available as described 


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above, a test to confirm ALK rearrangement must be performed locally by Vysis ALK 
Break Apart FISH Probe Kit (Abbott Molecular Inc.) prior to study. It is preferable to use 
a new tumor biopsy obtained prior to the first LDK378 dose or, if not available, in 
archival tumor obtained at or since the time of diagnosis. 
2. Stage IIIb or IV NSCLC 
3. 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. 
4a Patients must have NSCLC that has progressed at study enrollment. 
5a Patients must have received previous treatment with alectinib for treatment of locally 
advanced or metastatic NSCLC. Prior therapy with crizotinib as ALK inhibitor therapy in 
addition to alectinib is allowed. Alectinib doesn’t need to be the last therapy prior to study 
enrollment. No particular sequence of prior alectinib and crizotinib is required for 
enrollment. 
• A minimum of 21 days of treatment with alectinib will be required to qualify as one 
prior course of alectinib (unless alectinib was discontinued due to PD after a shorter 
treatment course). 
• Patients may have discontinued alectinib therapy for disease progression, intolerance 
or other reason. 
6. Patients must be chemotherapy-naïve or have received only one line of prior cytotoxic 
chemotherapy. 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 therapy with bevacizumab will be allowed if it was a component of the previous 
platinum-based regimen. 
• Prior maintenance therapy (e.g., bevacizumab, pemetrexed) will be allowed if it was a 
component of the previous platinum-based regimen. 
• For chemotherapy regimens given every 21 or 28 days, Minimum of two cycles will 
be required to qualify as a prior chemotherapy regimen (unless chemotherapy was 
discontinued due to progressive disease after one cycle). If chemotherapy were 
discontinued for a reason other than disease progression after only one cycle, then this 
regimen does not count as a prior line of chemotherapy. 
• Neoadjuvant or adjuvant cytotoxic chemotherapy will count as one prior treatment 
regimen, if relapse occurred within 12 months from the end of the neoadjuvant or 
adjuvant cytotoxic chemotherapy, respectively. 
7. Patients must have recovered from all toxicities related to prior anticancer therapies to 
grade ≤ 1 (CTCAE v 4.03). Patients with grade ≤ 2 peripheral neuropathy or any grade of 
alopecia, fatigue, nail changes or skin changes are allowed to enter the study. 
8. Age 18 years or older at the time of informed consent. 
9. Patients must have a tumor tissue sample available, as an archival sample (collected either 
at the time of diagnosis of NSCLC or any time since) 
 
 
10. Patients must meet the following laboratory values at the screening visit: 
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 


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• Platelets ≥ 75 x 109/L 
• Hemoglobin ≥ 8 g/dL 
• Serum creatinine <1.5 mg/dL 
• 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 
• Alkaline phosphatase (ALP) ≤ 5 x ULN 
• Serum amylase ≤ 2 x ULN 
• Serum lipase ≤ ULN 
• Fasting plasma glucose ≤ 175 mg/dL (≤ 9.8 mmol/L) 
11. Patients must have the following laboratory values within the laboratory normal limits or 
corrected to within normal limits with supplements before the first dose of LDK378 
• Potassium 
• Magnesium 
• Phosphorus 
• Total calcium (corrected for serum albumin) 
12a. World Health Organization (WHO) performance status 0-1. 
13. Written informed consent 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. 
14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests 
and other study procedures. 
 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patients with known hypersensitivity to any of the excipients of LDK378 (microcrystalline 
cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate). 
2. History of carcinomatous meningitis. 
3a Prior therapy with other ALK inhibitor investigational agents except crizotinib and 
alectinib. 
4a Prior systemic anti-cancer (including investigational) therapy aside from alectinib, 
crizotinib and one regimen of previous cytotoxic chemotherapy for locally advanced or 
metastatic NSCLC. 
5. Patients with symptomatic CNS metastases who is neurologically unstable or has required 
increasing doses of steroids within the 2 weeks prior to study entry to manage CNS 
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6. Patient has history of interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis (i.e., affecting activities of daily living or 
requiring therapeutic intervention). 
7. Patient who has received thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting 
the study treatment or patients who have not recovered from radiotherapy-related 
toxicities. For all other anatomic sites (including radiotherapy to thoracic vertebrae and 
ribs) radiotherapy ≤ 2 weeks prior to starting the study treatment or has not recovered 
from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks 
prior to the first dose of study drug is allowed. 
8. Patient has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 
4 weeks prior (2 weeks for resection of brain metastases) to the first dose of study drug or 
has not recovered from side effects of such procedure. Video-assisted thoracic surgery 
(VATS) and mediastinoscopy will not be counted as major surgery and patients can 
receive study treatment ≥1 week after the procedure. 
9. Patient with a concurrent malignancy or history of a malignant disease other than NSCLC 
that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this 
exclusion include the following: completely resected basal cell and squamous cell skin 
cancers, and completely resected carcinoma in situ of any type. 
10. Patient has a history of pancreatitis or history of increased amylase or lipase that was due 
to pancreatic disease. 
11. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event 
(within 6 months), such as: 
• Unstable angina within 6 months prior to screening. 
• Myocardial infarction within 6 months prior to screening. 
• History of documented congestive heart failure (New York Heart Association 
functional classification III-IV). 
• Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without anti- 
hypertensive medication. Initiation or adjustment of antihypertensive medication (s) is 
allowed prior to screening. 
• Ventricular arrhythmias. 
• Supraventricular and nodal arrhythmias not controlled with medication. 
• Other cardiac arrhythmia not controlled with medication. 
• Corrected QT (QTcF) > 470 msec using Fridericia’s correction on the screening ECG 
(as mean of triplicate ECGs). 
12. Patient receiving treatment with medications that meet one of the following criteria and 
that cannot be discontinued at least 1 week prior to the start of treatment with LDK378 
and for the duration of the study (Appendix 1): 
• Strong inhibitors or strong inducers of CYP3A4/5. 
• Medications with a low therapeutic index that are primarily metabolized by 
CYP3A4/5 and/or CYP2C9. 


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• Medications with a known risk of prolonging the QT interval or inducing Torsades de 
Pointes. 
13. Patient has 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). 
14. Patient is currently receiving treatment with warfarin sodium (Coumadin®) or any other 
coumarin-derivative anticoagulants. 
15. Patient is receiving unstable or increasing doses of corticosteroids. If patients are on 
corticosteroids for endocrine deficiencies or tumor-associated symptoms (non-CNS), dose 
must have been stabilized (or decreasing) for at least 5 days before first dose of study 
treatment. Note: Dose of steroids must be stable for 5 days before the baseline brain MRI. 
16. Patient is receiving treatment with any enzyme-inducing anticonvulsant (Appendix 1) that 
cannot be discontinued at least 1 week before first dose of study treatment, and for the 
duration of the study. Patients on non enzyme-inducing anticonvulsants are eligible. 
17. Patient is pregnant or nursing (lactating) woman, 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. 
18. Patient is a woman of child-bearing potential, defined as a woman physiologically capable 
of becoming pregnant, unless they are using highly effective contraception during dosing 
and for 3 months after stopping LDK378 treatment. 
Highly effective contraception is defined as any of: 
• Total abstinence: when this is in line with the preferred and usual lifestyle of the 
patient. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception]. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy,or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment. 
• Male partner sterilization (at least 6 months prior to screening). The vasectomized 
male partner should be the sole partner for that patient. 
• Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to 
screening. In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment is she considered not 
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19. Sexually active males unless they use a condom during intercourse while taking the drug 
and for 3 months after the last dose of LDK378 treatment. Male patients should not father 
a child for 3 months after the last dose of LDK378 treatment. A condom is required to be 
used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. 
20. Patient has other severe, acute, or chronic medical conditions including uncontrolled 
diabetes mellitus or psychiatric conditions or laboratory abnormalities that in the opinion 
of the investigator may increase the risk associated with study participation, or that may 
interfere with the interpretation of study results. 
 
6 
Treatment 
6.1 
Study treatment 
For this study, the term “investigational” refers to LDK378. All dosages prescribed and 
dispensed to the patient and all dose changes during the study must be recorded on the Dosage 
Administration Record eCRF. 
LDK378 will be provided and supplied by Novartis. LDK378 is supplied as 150 mg hard 
gelatin capsules as individual open label patient supply. LDK378 will be dosed on a flat scale 
of 750 mg/day and not be adjusted to body weight or body surface area. 
A complete cycle of treatment is defined as 28 days of once daily treatment of LDK378. 
 
6.1.1 
Dosing regimen 
LDK378 will be administered orally once daily at a dose of 750 mg (five 150 mg capsules) on 
a continuous dosing schedule. The treatment period will start on Cycle 1 Day 1. 
Each study site will be supplied with LDK378 by Novartis. LDK378 is supplied as 150 mg 
hard gelatin capsules as individual patient supply, packaged in bottles. Medication labels will 
comply with legal regulation and be printed in local language. The storage conditions for the 
study treatment will be described on the medication label. LDK378 will be dispensed by the 
pharmacist or designee at the investigator’s institution. 
LDK378 will be administered orally once daily at a dose of 750 mg (five 150 mg capsules) on 
a continuous dosing schedule. The investigator must instruct the patient to take the study drug 
exactly as prescribed. 
The general dose and treatment schedule of the study treatments are listed in Table 6-1. 
• Patients should take LDK378 once daily at approximately the same time each day in the 
morning, afternoon, or evening. 
• 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. 


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• 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 
Pharmaceutical form and 
 
 
Frequency and/or 
Study treatments 
route of administration 
Dose 
Regimen 
LDK378 
Gelatin capsule for oral use 
750 mg (5 x 150 mg / 
capsule) 
Once daily (28 day / 
cycle) 
 
 
 
6.1.2 
Guidelines for continuation of treatment 
For guidelines for dose modification of treatment, refer to Section 6.3. 
 
6.1.3 
Treatment duration 
Patients will continue LDK378 until they experience any of the following: 
• Disease progression (radiologically documented according to RECIST 1.1 by the 
investigator). LDK378 therapy will continue until progressive disease if clinically 
acceptable. However, LDK378 may be continued beyond RECIST-defined progressive 
disease (PD) as assessed by the investigator, if in the judgment of the investigator, there 
may be clinical benefit with continued treatment. 
• Unacceptable toxicity that precludes further treatment 
• Start of a new anti-cancer therapy 
• Pregnancy 
• Treatment is discontinued at the discretion of the investigator or patient 
• Lost to follow-up 
• Death 
• Study terminated by Sponsor 
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. 
 
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 escalation guidelines 
Not applicable to this study 


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6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patients to continue the study treatment. Any changes in 
LDK378 must be recorded on the Dosage Administration Record eCRF. 
General guidelines for dose modifications for toxicities other than those listed in Table 6-3. 
For grade 1 and tolerable grade 2 treatment-related toxicities, patients are encouraged to 
continue at the current dose of study treatment. For intolerable grade 2 treatment-related 
toxicities, dosing should be interrupted until resolution to grade 1 or lower followed by dose 
reduction to the next dose level. For grade 3 or grade 4 treatment-related toxicity that is not 
considered by the investigator to be life-threatening, patients should interrupt study treatment 
until resolution to grade 1 or lower; then study treatment may continue following a dose 
reduction to the next dose level, if in the opinion of the Investigator, the patient continues to 
experience clinical benefit and after discussion with the Sponsor. For any grade 3 or 4 
treatment-related toxicity that is considered by the investigator to be life-threatening, 
permanently discontinue study treatment. 
More detailed LDK378 modification guidelines are described in Section 6.3.3 and Table 6-3 
selected toxicities. 
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. 
Patients whose treatment is interrupted or permanently discontinued due to an AE must be 
followed until resolution or stabilization of the event. Patients requiring interruptions greater 
than 28 consecutive days will be discontinued from study treatment. In certain cases, if the 
Investigator and the Sponsor conclude that a patient, who has experienced a treatment 
interruption greater than 28 consecutive days, could benefit from additional treatment, 
continuation may be allowed. 
 
6.3.2 
Treatment interruption and treatment discontinuation 
If the administration of LDK378 is temporarily interrupted for reasons other than toxicity, 
then treatment with LDK378 may be resumed at the same dose. The same applies if the 
patient experiences an unacceptable toxicity not specifically described in Table 6-3, provided 
this toxicity resolved to ≤ CTCAE grade 1. 
If the treatment with LDK378 is withheld due to toxicity, scheduled visits and all assessments 
should continue to be performed (with the exception of the dosing of the withheld study drug), 
as described in Table 7-1. 
If the treatment with LDK378 dosing is withheld for more than 28 consecutive days 
consecutive days (counting from the first day when a dose was missed), due to treatment- 
related 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. 


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Detailed guidelines for follow-up of study drug related AE or an abnormal laboratory value 
must be followed as described in Section 6.3.4. 
All patients will be followed for safety until 30 days after the last dose of LDK378. Patients 
whose treatment is temporarily interrupted or permanently discontinued due to an AE or 
abnormal laboratory value must be followed until resolution or stabilization of the event, 
whichever comes first, including all study assessments appropriate to monitor the event. 
 
6.3.3 
Criteria for LDK378 dose modifications 
LDK378 dose reduction will follow the dose reduction steps described in Table 6-2. For each 
patient, a maximum of 3 dose modifications is allowed after which the patient must be 
discontinued from treatment with LDK378. Once the dose of LDK378 has been reduced, it 
cannot be re-escalated. If a patient continues treatment with LDK378 after RECIST-defined 
PD as determined by the investigator, the criteria for dose modification will also apply. 
 
Table 6-2 
Dose reduction steps for LDK378 
LDK378 dose levels 
Dose* and schedule 
 
Starting dose level 
750 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 interruptions and re-initiation of LDK378 treatment (with or without dose 
reduction) are described in Table 6-3. 


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Table 6-3 
Criteria for interruption and re-initiation of LDK378 treatment 
 
Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for LDK378 
HEMATOLOGICAL 
Neutropenia (ANC: Absolute neutrophil count) 
Grade 1 (ANC < LLN - 1.5 x 109/L) 
Grade 2 (ANC < 1.5 and ≥ 1.0 x 109/L) 
Grade 3 (ANC < 1.0 and ≥0.5 x 109/L) 
Maintain dose level 
Grade 4 (ANC < 0.5 x 109/L) 
Omit dose until resolved to ≤ Grade 2, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then ↓ 1 dose level 
Febrile neutropenia 
(ANC < 1.0 x 109/L, with a single temperature of ≥ 38.3 °C or a 
sustained temperature of ≥ 38 °C for more than one hour ) 
Omit dose until clinically resolved and neutropenia ≤ Grade 2, then ↓ 1 dose level 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75 x 109/L) 
Grade 2 (PLT < 75 and ≥ 50 x 109/L) 
Maintain dose level 
Grade 3 (PLT < 50 and ≥ 25 x 109/L) 
Omit dose until resolved to ≤ Grade 2, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (PLT < 25 x 109/L) 
Omit dose until resolved to ≤ Grade 2, then ↓ 1 dose level 
HEPATIC 
Alkaline phosphatase and/or Gamma-glutamyl transpeptidase (GGT) 
Isolated elevations of any grade 
Maintain dose level 
Total Bilirubin** 
(for patients with Gilbert Syndrome these dose modifications apply to changes in direct [conjugated] bilirubin only) 
Grade 1 (> ULN and ≤ 1.5 x ULN) 
Maintain dose level with liver function test (LFTs)*** monitored as per protocol 


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Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for LDK378 
Grade 2 (> 1.5 and ≤ 3.0 x ULN) with ALT or AST ≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then ↓ 1 dose level 
Grade 3 (> 3.0 and ≤ 10.0 x ULN) with ALT or AST ≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, ↓ 1 dose level 
If resolved in > 7 days discontinue patient from LDK378 
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 > 
2.0 x ULN 
Maintain dose level with LFTs*** monitored per protocol 
Grade 3 (> 5.0 and ≤ 20.0 x ULN) without total bilirubin elevation to 
> 2.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level 
Grade 4 (> 20.0 x ULN) without total bilirubin elevation to > 2.0 x 
ULN 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level 
AST or ALT and concurrent total bilirubin 
AST or ALT > 3.0 x ULN with total bilirubin > 2.0 x ULN in the 
absence of cholestasis or hemolysis 
Permanently discontinue patient from LDK378 Refer to Section 6.3.4.2 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. 


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Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for LDK378 
RENAL 
Serum creatinine 
Grade 1 (>1 and ≤ 1.5 x baseline; > ULN and ≤1.5 x ULN ) 
Maintain dose level 
Grade 2 (> 1.5 and ≤ 3 x baseline; >1.5 and ≤3.0 x ULN) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then ↓ 1 dose level 
Grade 3 (> 3.0 x baseline ; >3.0 and ≤6.0 x ULN) 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level 
Grade 4 (> 6.0 x ULN) 
Permanently discontinue patient from LDK378 
GASTROINTESTINAL 
Diarrhea**** 
Grade 1 
Maintain dose level but adjust anti-diarrhea treatment 
Grade 2 (despite maximal anti-diarrheal medication) 
Omit dose until resolved to ≤ Grade 1, then maintain dose level. 
If diarrhea returns as ≥ Grade 2, then omit dose until resolved to ≤ Grade 1, then ↓ 
1 dose level 
Grade 3 (despite maximal anti-diarrheal medication) 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level 
Grade 4 (despite maximal anti-diarrheal medication) 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level 
Nausea***** 
Grade 1 or 2 
Maintain dose level but adjust anti-emetic treatment 
Grade 3 (despite standard anti-emetics) 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level 
Vomiting***** 
Grade 1 
Maintain dose level but adjust anti-emetic treatment 
Grade 2 (despite standard anti-emetics) 
Omit dose until resolved to ≤ Grade 1, then maintain dose level. 
If vomiting returns as ≥ Grade 2, then suspend dose until resolved to ≤ Grade 1, 
then ↓ 1 dose level. 
Grade 3 (despite standard anti-emetics) 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level 
Grade 4 (despite standard anti-emetics) 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose level 


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Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for LDK378 
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 
PULMONARY 
Notes: 
• 
Withhold LDK378 for acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever and during diagnostic 
workup for pneumonitis/ILD. 
• 
During evaluation of potential grade 2, 3, and 4 pneumonitis, if an infectious etiology is confirmed (i.e., pneumonia) and pneumonitis is excluded, 
then consider resuming LDK378 at current dose level after the pneumonia resolves. 
PNEUMONITIS 
Any Grade treatment-related ILD/pneumonitis 
Permanently discontinue patient from LDK378 
CARDIAC 
Electrocardiogram QT corrected (QTcF) interval prolonged 
Grade 1 (QTcF 450-480 ms) 
Grade 2 (QTcF 481-500 ms) 
Maintain dose level 


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Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for LDK378 
Grade 3 (QTcF ≥ 501 ms on at least two separate ECGs) 
Omit dose until QTc is less than < 481 ms, then ↓ 1 dose level 
- Assess the quality of the ECG recording and the QT value and repeat if needed 
- Repeat ECG in 24 hours, or less, as clinically indicated; continue monitoring as 
clinically indicated until QTc < 481 ms 
In addition:-Determine the serum electrolyte levels (in particular hypokalemia, 
hypomagnesemia). If abnormal, correct abnormalities before resuming study drug 
treatment 
- Review concomitant medication use for drugs with the potential to increase the 
risk of drug exposure related to QT prolongation 
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 (QTcF ≥ 501 or > 60 ms change from baseline and 
Torsades de pointes or polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia) 
Permanently discontinue patient from LDK378 
BRADYCARDIA 
Grade 1 or Grade 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 patient from LDK378 


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Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for LDK378 
* Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. All dose modifications should be based on the worst preceding toxicity. 
** If Grade 3 or 4 hyperbilirubinemia is due to the indirect (non-conjugated) component only, and hemolysis as the etiology has been ruled out as per 
institutional guidelines (e.g.,review of peripheral blood smear and haptoglobin determination), then ↓ 1 dose level and continue treatment at the discretion 
of the Investigator. 
***LFTs include albumin, ALT, AST, total bilirubin, alkaline phosphatase and GGT. 
**** Dose modifications apply to patients who experience diarrhea despite appropriate antidiarrheal medication. This medication should be started at the 
first sign of abdominal cramping, loose stools or overt diarrhea (see Section 6.3.4.6). 
***** Dose modifications apply to patients who experience nausea and/or vomiting despite appropriate antiemetic medication. This medication should be 
started at the first sign of nausea and/or vomiting (see Section 6.3.4.5). 


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


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• For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 
3.0 x ULN combined with TBIL > 2.0 x ULN 
• For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 
2 x baseline AND > 2.0 x ULN] 
• Medical review needs to ensure that liver test elevations are not caused by cholestasis, 
defined as: ALP elevation > 2.0 x ULN with R value (ALT/ALP in x ULN) < 2 in patients 
without bone metastasis, or elevation of ALP liver fraction in patients with bone 
metastasis. 
• Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the 
ULN for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to 
cholestatic or hepatocellular liver injury). 
• In the absence of cholestasis, these patients should be immediately discontinued from 
study drug treatment, and repeat LFT testing as soon as possible, preferably within 48 
hours from the awareness of the abnormal results. The evaluation should include 
laboratory tests, detailed history, physical assessment and the possibility of liver 
metastasis or new liver lesions, obstructions/compressions, etc. 
• Laboratory tests should include ALT, AST, albumin, creatinine kinase, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline 
phosphatase. 
• A detailed history, including relevant information, such as review of ethanol, 
concomitant medications, herbal remedies, supplement consumption, history of any 
pre-existing liver conditions or risk factors, should be collected. 
• Further testing for acute hepatitis A, B, C or E infection and liver imaging (eg, biliary 
tract) may be warranted. 
• Blood sample can be collected as close as possible to last dose of study drug in the 
event that a patient experiences hepatotoxicity, as needed. 
• Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or 
after consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented. 
 
6.3.4.3 
Guidelines for the follow-up of renal laboratory 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. 


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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. 
 
6.3.4.4 
Guidelines for monitoring pneumonitis 
Monitor patients for pulmonary symptoms indicative of pneumonitis. In addition, withhold 
LDK378 for acute onset of new or progressive unexplained pulmonary symptoms, such as 
dyspnea, cough and fever and during diagnostic workup for pneumonitis/ILD. 
See also dose modification guidelines described in Table 6-3. 
 
6.3.4.5 
Guidelines for the treatment of study drug induced nausea and 
vomiting 
Nausea and vomiting are among the most frequently reported AEs following treatment with 
LDK378 and patients must therefore be closely monitored for the appearance of these AEs. 
The investigator should consider/investigate potential concomitant medication, food or 
comorbidity driven causes of nausea and/or vomiting and remedy these causes if possible (e.g. 
discontinuation of concomitant medication, dietary modification, treatment of comorbidity). 
Individualized supportive and anti-emetic treatment should be initiated, as appropriate, at the 
first signs and/or symptoms of these AEs. In patients with vomiting, the patient should be 
monitored for signs of dehydration and instructed to take preventive measures against 
dehydration. 
Concomitant medication for the treatment of nausea and/or vomiting should follow local 
practice and the investigator’s best judgment. For moderate emetogenic drugs, such as 
LDK378, International Guidelines for anti-emetic treatment recommend early treatment with 
5-HT3-receptor antagonists (5-HT3RAs). 
Dose adaptation of LDK378 in case of treatment related nausea and/or vomiting must follow 
the guidelines presented above in Table 6-3. 
 
6.3.4.6 
Guidelines for the treatment of study drug induced diarrhea 
Diarrhea is among the most frequently reported AEs following treatment with LDK378, and 
patients must therefore be closely monitored for the appearance of this AE. 
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: 


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• 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 orally, then 2 mg 
every 2-4 hours, maximum of 16 mg/day), along with oral hydration, and dietetic 
measures should be considered. Note: complicating signs or symptoms include: moderate 
to severe cramping, decreased performance status, fever, neutropenia, frank bleeding or 
dehydration. 
• For complicated diarrhea (all grade 3 or 4, grade 1-2 with complicating signs or 
symptoms), management should involve intravenous (IV) fluids, and consider treatment 
with octreotide (at starting dose of 100 to 150 µg SC tid or 25 to 50 µg IV) and antibiotics 
(e.g. fluoroquinolone) should be given. 
Dose adaptation of LDK378 in case of treatment related diarrhea must follow the guidelines 
presented above in Table 6-3. 
 
6.3.4.7 
Guidelines for treatment of hypophosphatemia 
In the phase I study [CLDK378X2101], as of 31-Oct-2013, 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 a grade 3 hypophosphatemia that resolved after dose adjustment or 
interruption; in the remaining 8 cases, patients were able to continue therapy without dose 
modification. Hypophosphatemia was a commonly reported AE (6.3%), regardless of 
relationship to 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. 
 
6.3.4.8 
Guidelines for the follow-up of laboratory pancreatic abnormalities 
In case of any occurrence of lipase or amylase increase to grade 3 or 4, both lipase and 
amylase must be monitored weekly (or more frequently if clinically indicated) until the event 
resolves to ≤ grade 1 (or to baseline). 
After resumption of dosing, monitoring must be continued weekly (or more frequently if 
clinically indicated) for one additional cycle (i.e. 4 weeks). If there is no recurrence of ≥ grade 
2 amylase or lipase elevations during this period, subsequent monitoring must be performed 
every 4 weeks. 
Patients who discontinue study treatment due to pancreatic toxicity must be monitored weekly 
(or more frequently if clinically indicated) until the event resolves to ≤ grade 1 or stabilization 
occurs (no CTCAE grade change over 4 weeks). Refer to Table 6-4. 
If amylase and/or lipase elevations are accompanied by new or progressive unexplained 
abdominal symptoms such as severe pain or vomiting, withhold LDK378, 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. 


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Table 6-4 
Follow-up evaluations for selected toxicities 
 
Toxicity 
Follow-up evaluation* 
Investigations 
(hematologic) 
Febrile neutropenia, neutropenia or thrombocytopenia ≥ CTCAE Grade 3 
Test weekly (or more frequently) until ≤ Grade 2 
Subsequent monitoring must be performed every 4 weeks 
Investigations 
(hepatic) 
Total bilirubin/ALT/AST Grade 2: (patients with liver metastasis and grade 2 
AST/ALT at baseline, increased monitoring required for grade 3 ALT/AST. 
Follow guidelines for grade 3 or 4 AST/ALT 
Test weekly (or more frequently) until ≤ Grade 1 
Thereafter, continue to test every 2 weeks (or more frequently) for 8 weeks. 
If no recurrence of ≥ Grade 2 event, continue monitoring every 4 weeks 
Total bilirubin/ALT/AST ≥ Grade 3: 
Test weekly (or more frequently) until ≤ Grade 1 
Thereafter, continue to test every 2 weeks (or more frequently) for 16 weeks. 
If no recurrence of ≥ Grade 2 event, continue monitoring every 4 weeks 
Discontinuation due to liver toxicity: 
Test weekly (or more frequently) until ≤ Grade 1 or stabilization 
Investigations 
(renal) 
Serum creatinine Grade 2: 
Test weekly (or more frequently) until Grade 1 
Thereafter, test every cycle (4 weeks) 
Serum creatinine ≥ Grade 3: 
Test twice weekly (or more frequently) 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 only. Refer to Table 6-3 for dose modifications 
required for applicable toxicities 
 
6.3.5 
Anticipated risks and safety concerns of the study treatment 
Appropriate eligibility criteria and specific dose modification and stopping rules are included 
in this protocol. Recommended guidelines for prophylactic or supportive treatment for 
expected toxicities, including management of study-drug induced AEs, e.g., diarrhea are 
provided in Section 6.3.4. Refer to preclinical toxicity and or clinical data found in the 
Investigator’s brochure (IB). 
 
6.4 
Concomitant medications 
In general, the use of any concomitant medication/therapy deemed necessary for the care of 
the patient (e.g. such as anti-emetics, anti-diarrhea) is permitted (see Section 6.4.1), except 
when specifically prohibited (see Section 6.4.2). 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications including herbal/natural medications 
(excluding study treatment and prior antineoplastic treatments and blood transfusions), 
surgeries and procedures (including physical therapy) administered within 28 days prior to the 


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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 6.4.2.7), food and or 
vitamin supplements. 
 
6.4.1 
Permitted concomitant therapy 
 
6.4.1.1 
Corticosteroids 
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to induce 
CYP3A enzymes, thereby increasing the risk of reducing 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 or prednisone (e.g., for 
tumor associated symptoms) are permitted during the course of the study. If increasing 
doses of corticosteroids are required during the study treatment, LDK378 must be held 
and the corticosteroid dose must have been stabilized (or decreasing) for at least 5 days 
before LDK378 is resumed. 
 
6.4.1.2 
Bisphosphonates 
The use of bisphosphonates is allowed regardless of indication provided patients have been on 
stable doses optimally for at least 4 weeks prior to the start of treatment. Patients requiring 
initiation of bisphosphonate treatment during the course of the study should be evaluated for 
progressive disease and the result of the evaluation should be clearly documented in the 
patients’ source documentation. 
No drug-drug interaction is expected between LDK378 and bisphosphonates as the two drugs 
are eliminated through different elimination pathways. Bisphosphonates are not inhibitors of 
human CYP450 enzymes involved in the metabolism of LDK378 and do not undergo 
metabolism in vivo. 
The same guidelines apply to the use of denosumab for the treatment of bone metastatic 
disease. 
 
6.4.1.3 
Drugs that are metabolized by CYP450 enzymes 
In vitro drug metabolism studies show that the metabolism of LDK378 is mediated by 
CYP3A4/5. LDK378 is a time-dependent CYP3A4/5 inhibitor and is also a potent reversible 
inhibitor of CYP2A6, 2E1, 2C9 and 3A4/5 and may consequently increase exposure to drugs 
metabolized by these enzymes at clinically relevant concentrations. Clinical studies have not 
yet been performed to confirm the potential effect of LDK378 on substrate drugs metabolized 
by these enzymes in patients. The risk for CYP2A6 and CYP2E1 is largely mitigated by the 
low potential for drugs metabolized by these enzymes to be co-administered with LDK378. 


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Concomitant treatment of LDK378 with weak inhibitors or inducers of CYP3A4/5 is 
permitted. Caution is advised when LDK378 is co-administered with drugs that are moderate 
inhibitors or inducers of CYP3A4/5 (Table 14-2 of Appendix 1). Duration of concomitant 
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 and inducers of CYP3A4/5 is prohibited (refer to Section 
6.4.2.5). 
Concomitant treatment of LDK378 with medications known to be metabolized by CYP2C9 
and CYP3A4is allowed with caution (Table 14-2 of Appendix 1), except for drugs which have 
narrow therapeutic index/sensitive substrates for these CYP isoforms (Section 6.4.2.6 and 
Table 14-1 of Appendix 1). 
 
6.4.1.4 
Non-enzyme inducing anti-epileptic drugs 
Non-enzyme inducing anti-epileptic medication (Non-EIAED) is allowed. 
 
6.4.1.5 
Palliative radiotherapy and surgery 
Local radiotherapy for isolated brain progression, 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 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. 
 
6.4.1.6 
Gastric protection agents 
The use of gastric protection agents including antacids, H2-antagonists, and proton pump 
inhibitors (PPIs) is allowed Table 14-2 of Appendix 1). 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). 
 
6.4.2 
Prohibited concomitant therapy 
 
6.4.2.1 
Other anticancer therapy 
Anticancer therapy (chemotherapy, targeted therapy, biologic therapy or radiation therapy 
[except palliative radiotherapy as described in Section 6.4.1.5], anti-cancer surgery and 


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immunotherapy) 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. 
 
6.4.2.2 
Other investigational therapies 
Other investigational therapies must not be used while the patient is on the study. 
 
6.4.2.3 
Warfarin and coumarin derivatives 
Warfarin sodium or any other coumarin-derivative anticoagulant are not permitted. LDK378 
is an inhibitor of CYP2C9, the major metabolizing enzyme of warfarin. A clinically relevant 
increase in warfarin exposure is possible. 
 
6.4.2.4 
Enzyme inducing anti-epileptic drug 
Use of EIAEDs is not permitted. Refer to Table 14-3 of Appendix 1 for a list of prohibited 
EIAED. 
If a patient is currently taking an EIAED, he/she must have discontinued the EIAED therapy 
for at least 1 week prior to starting study drug. 
If a patient was previously on a non-EIAED and needs to permanently change anticonvulsant 
agent but cannot change to another non-EIAED, the patient will be taken off LDK378. 
 
6.4.2.5 
Strong CYP3A inhibitors and inducers 
In vitro metabolism studies suggest that oxidative metabolism of LDK378 is predominantly 
mediated by CYP3A4/5. 
Strong inhibitors or inducers of CYP3A4/5 are prohibited. Patients receiving concomitant 
medications known to strongly inhibit and/or induce CYP3A4/5 that are deemed medically 
necessary should be excluded from the study. Refer to Table 14-1 of Appendix 1 for a list of 
these medications. Please note that this list may not be comprehensive. 
 
6.4.2.6 
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 concomitant medications  
known to be metabolized by these enzymes and that have a narrow therapeutic index is not 
permitted concomitantly with LDK378. Refer to Table 14-1 of Appendix 1 for a list of these 
medications. Please note that this list may not be comprehensive. 
 
6.4.2.7 
Herbal medications 
Herbal preparations/medications are not allowed throughout the study, as a potential drug- 
drug interaction is always possible. These herbal medications include, but are not limited to: 
St. John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng. 


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Patients should stop using herbal medications at least 7 days prior to first dose of study 
treatment. 
 
6.4.2.8 
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. However there 
were no LDK378-related effects in vivo in monkeys at doses as high as 100 mg/kg (human 
equivalent dose [HED] of 1950 mg). 
Serial ECGs were collected following a single dose and at steady-state to evaluate the effect  
of LDK378 on the QT interval in an open-label, dose-escalation, and expansion study 
([CLDK378X2101]). A total of 304 patients were treated with LDK 378 doses ranging from 
50 to 750 mg with 255 patients treated with LDK378 750 mg. One of 304 patients (<1%) was 
found to have a QTc >500 msec and 10 patients (3.3%) had an increase from  baseline       
QTc >60 msec. A central tendency analysis of the QTc data at average steady-state 
concentrations demonstrated that the upper bound of the 2-sided 90% CI for QTc was 16  
msec at LDK378 750 mg. A pharmacokinetic/pharmacodynamic analysis suggested 
concentration-dependent QTc interval prolongation. 
Concomitant administration of LDK378 with drugs known to have a high risk of increasing 
the QTc interval, and drugs known to increase the QTc interval that are also primarily 
metabolized by CYP3A4/5 should be avoided. Concomitant use of LDK378 and any 
medication included in Table 14-4 of Appendix 1 titled “List of prohibited QT prolonging 
drugs” (i.e., drugs that are generally accepted by the Qtdrugs.org Advisory Board of the 
Arizona CERT to have a known risk of causing Torsades de Pointes) is not permitted. 
 
6.5 
Patient numbering, treatment assignment or randomization 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned 
when the patient is first enrolled for screening and is retained as the primary identifier for the 
patient throughout his/her entire participation in the trial. The Subject No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 
sequential patient number suffixed to it, so that each patient is numbered uniquely across the 
entire database. Upon signing the informed consent form, the patient is assigned to the next 
sequential Patient No. Once assigned, the Patient No. must not be reused for any other patient 
and the Subject No. 
 
6.5.2 
Treatment assignment 
Not applicable since this study consists of a single arm and no randomization. 
 
6.5.3 
Treatment blinding 
Not applicable 


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6.6 
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF. 
The site pharmacy will receive open label medication containing LDK378 capsules. 
Medication will be dispensed based on the appropriate dose with instructions from the 
investigator on how to take the medication. 
 
6.6.1 
Study drug packaging and labeling 
Medication labels will be in the local language and comply with the legal requirements of 
country. They will include storage conditions for the drug but no information about the patient. 
 
6.6.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study treatment should be stored 
according to the instructions specified on the drug labels and in the [Investigator’s Brochure]. 
 
6.6.3 
Study drug compliance and accountability 
 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit. 
Compliance will be assured by administrations of the study treatment under the supervision of 
investigator or his/her designee. 
Site personnel will add the patient number on the label. Immediately before dispensing the 
package to the patient, site personnel will detach the outer part of the label from the packaging 
and affix it to the source document (Drug Label Form) for that patient’s unique patient 
number. 
 
6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of LDK378 study treatment in a drug accountability log. Drug accountability will be noted by 
the field monitor during site visits and at the completion of the study. Patients will be asked to 
return all unused LDK378 study treatment and packaging on a regular basis, at the end of the 
study or at the time of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 


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completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. 
 
6.6.3.3 
Handling of other study treatment 
Not applicable 
 
6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. 
 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 lists all of the assessments and indicates with an “X” the visits when they are 
performed. Each treatment cycle is 28 days (the 28 days cycle length is fixed regardless of 
whether the dose of LDK378 is withheld). All visits are to be scheduled according to the 
appropriate number of calendar days from Cycle 1 Day 1 of study drug administration. A visit 
window of +/- 1 day in Cycle 1 and +/- 3 days in Cycle 2 onwards is allowed. Imaging 
evaluations may be performed +/-7 days of the due date of the assessment. 
Note: If treatment with LDK378 is withheld at any time during the study, all study visits, 
safety and efficacy assessments should continue according to the appropriate number of 
calendar days from Cycle 1 Day 1 as per the schedule of assessments. 
All data obtained from these assessments must be supported in the patients’ source 
documentation. No eCRF will be used as a source document. The table indicates which 
assessments produce data to be entered into the database (D) or remain in the source 
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Table 7-1 
Visit evaluation schedule 
 
Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Post treatment 
follow up phase 
Survival 
follow-up 
phase 
Cycle 1 (28 d) Subsequent 
cycles (28 d) 
End of study 
Treatment (EOT) 
Visit name 
Screening Visit 
(Day -28 to Day - 
1) 
Cycle 
1 Day 
1 
Cycle 
1 Day 
15 
Day 1 
End of treatment 
visit 
30-day 
safety 
follow- 
up 
Tumor 
follow- up 
if no PD 
at the 
EOT 
Study 
phase 
completion 
Survival 
follow-up 
Obtain Main Informed Consent 
D 
7.1.1. 
X 
Collection of documentation of ALK 
rearrangement OR 
confirmation of ALK status 
D 
7.1.1.3. 
Archival tissue 
and/or new 
biopsy & 
pathology report 
End of Phase Disposition Page 
D 
7.1.3. 
X 
Screening Phase 
Disposition 
(eCRF) 
X 
End of Treatment 
Phase 
Completion 
(eCRF) 
X 
End of post 
treatment 
phase 
disposition 
Demography 
D 
7.1.1.3. 
X 
Inclusion/ exclusion criteria 
D 
5.2, 5.3. 
X 
Eligibility check 
S 
7.1.1.1. 
X 
Relevant medical history/current 
medical conditions 
D 
7.1.1.3. 
X 
Smoking history 
D 
7.1.1.3. 
X 
Diagnosis and extent of cancer 
D 
7.1.1.3. 
X 
Prior antineoplastic therapies (meds, 
surgery, radiation) 
D 
7.1.1.3. 
X 
Prior and concomitant medications 
D 
7.1.1.3. 
X 
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 


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Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Post treatment 
follow up phase 
Survival 
follow-up 
phase 
Cycle 1 (28 d) Subsequent 
cycles (28 d) 
End of study 
Treatment (EOT) 
Visit name 
Screening Visit 
(Day -28 to Day - 
1) 
Cycle 
1 Day 
1 
Cycle 
1 Day 
15 
Day 1 
End of treatment 
visit 
30-day 
safety 
follow- 
up 
Tumor 
follow- up 
if no PD 
at the 
EOT 
Study 
phase 
completion 
Survival 
follow-up 
Weight 
D 
7.2.2.3. 
X 
X 
X 
X 
Vital signs 
D 
7.2.2.2. 
X 
X 
X 
X 
X 
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 
Serum Pregnancy test 
D 
7.2.2.5.4. X 
Urine Pregnancy test (Prior to dosing) D 
7.2.2.5.4. 
X 
X 
X 
Testosterone, LH, FSH 
D 
7.2.2.5.5. X 
X 
X 
X 
X 
Coagulation 
D 
7.2.2.5.6. X 
ECG 
D 
7.2.2.6.1. X 
X 
X 
X 
X 
CT scan or MRI of chest and 
abdomen 
D 
7.2.1. 
X 
X Cycle 3 
then every 
2nd cycle (i.e. 
every 8 
weeks) 
X 
X Every 8 
weeks 
following 
EOT until 
PD if no 
PD at the 
EOT 
Whole body bone scan 
D 
7.2.1. 
X 
If clinically indicated 


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Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Post treatment 
follow up phase 
Survival 
follow-up 
phase 
Cycle 1 (28 d) Subsequent 
cycles (28 d) 
End of study 
Treatment (EOT) 
Visit name 
Screening Visit 
(Day -28 to Day - 
1) 
Cycle 
1 Day 
1 
Cycle 
1 Day 
15 
Day 1 
End of treatment 
visit 
30-day 
safety 
follow- 
up 
Tumor 
follow- up 
if no PD 
at the 
EOT 
Study 
phase 
completion 
Survival 
follow-up 
CT scan or MRI of brain 
D 
7.2.1. 
X 
X Cycle 3 
then every 
2nd cycle (i.e. 
every 8 
weeks): only if 
clinically 
indicated or 
positive at 
baseline 
X 
Only if clinically 
indicated or 
positive at 
baseline 
X Every 8 
weeks 
following 
EOT until 
PD (only if 
clinically 
indicated 
or positive 
at 
baseline) 
• 
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) 
X Cycle 3 
then every 2 
cycle (i.e. 
every 8 
weeks): only if 
positive at 
baseline or 
clinically 
indicated 
X 
Only if positive at 
baseline or 
clinically indicated 
X Every 8 
weeks 
following 
EOT until 
PD (only if 
positive at 
baseline 
or 
clinically 
indicated) 
LDK378 dosing 
D 
6.1.1. 
Continuous 
Adverse events 
D 
8.1. 
Continuous 


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Category 
Protocol 
Section 
Screening 
Phase 
Treatment Phase 
Post treatment 
follow up phase 
Survival 
follow-up 
phase 
Cycle 1 (28 d) Subsequent 
cycles (28 d) 
End of study 
Treatment (EOT) 
Visit name 
Screening Visit 
(Day -28 to Day - 
1) 
Cycle 
1 Day 
1 
Cycle 
1 Day 
15 
Day 1 
End of treatment 
visit 
30-day 
safety 
follow- 
up 
Tumor 
follow- up 
if no PD 
at the 
EOT 
Study 
phase 
completion 
Survival 
follow-up 
Antineoplastic therapies since 
discontinuation of study treatment 
D 
7.1.5.3. 
X 
X 
X 
Every 12 
weeks 
Survival assessment 
D 
7.1.5.3. 
X 
Every 12 
weeks 


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7.1.1 
Screening 
Written informed consent must be obtained before any study specific procedure is performed. 
Screening assessments to confirm eligibility into the main study should be performed as per 
the schedule of assessments. Re-screening of patients will not be allowed, but laboratory 
parameters which do not meet the inclusion criteria may be re-tested within the screening 
window (Day -28 to Day -1). 
 
7.1.1.1 
Eligibility screening 
After the patient has signed the consent form to participate in the study, a registration sheet 
will be completed and faxed or emailed to the Novartis for approval and acknowledgement of 
entry of the patient onto the study. Details on the enrollment process are provided to 
investigators as the instruction. 
 
7.1.1.2 
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 
• Death 
• Withdrawal of consent 
7.1.1.3 
Patient demographics and other baseline characteristics 
Data to be collected on patient characteristics at screening include: 
• Demography (including: date of birth, age, patient initials, gender, childbearing potential, 
race and ethnicity, or as allowed by local regulations) 
• Relevant medical history 
• History of smoking 
• NSCLC diagnosis and extent of disease, including: 
• Date of diagnosis of NSCLC 
• ALK status documentation using the Vysis ALK break-apart FISH assay. If such 
documentation is not available, ALK status must be confirmed using the Vysis ALK 
break-apart FISH test in site locally (preferably using a new tumor biopsy obtained 
prior to the first LDK378 dose or, if not available, in archival tumor obtained at or 
since the time of diagnosis) prior to study entry. 
• Site of active disease 
• Characteristics of disease 


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• Concomitant molecular alteration when available (and results of all the tests 
performed even if wild type) 
• Prior antineoplastic therapies (medications, radiation, surgeries) 
• Prior and Concomitant Medications, surgical and medical procedures 
• Neurological examination and use of steroids to control CNS symptoms (only for patients 
with symptomatic CNS metastases) 
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. 
 
7.1.2 
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. 
Patients will be assessed as per visit schedule in Table 7-1. 
Visit windows of ± 1 calendar day will be applicable to scheduled study assessments during 
Cycle 1. Visit windows of ± 3 days from scheduled study assessments will apply during and 
beyond Cycle 2. The only exception is imaging assessments, which have a ± 7 day window at 
all scheduled time points. 
 
7.1.3 
Discontinuation of study treatment 
A patient will be defined as on the study if they are continuing to have any study data 
collected, i.e. if the patient is being treated with LDK378, is in efficacy follow-up after 
discontinuing LDK378, or is in survival follow-up. 
Patients may voluntarily withdraw from study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator must make every 
effort (e.g., telephone, e-mail, letter) to determine the primary reason for this decision and 
record this information in the patient’s chart and on the appropriate eCRF pages. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. 
The investigator should discontinue study treatment for a given patient if, he/she believes that 
continuation would be detrimental to the patient’s well-being. 
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 6.1.1. 


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• 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 may permanently stop the study treatment for one of the following reasons: 
• Progression of disease (radiological assessment by investigator) 
• Technical Problems 
• Protocol deviation 
Patients who discontinue study treatment should NOT be considered withdrawn from the 
study. They should return for the assessments indicated in Table 7-1. If they fail to return for 
unknown reasons, every effort (e.g., telephone, email, letter) should be made to contact them 
as specified in Section 7.1.5.4. 
Patients who become pregnant during the trial must be withdrawn (Section 8.4). Patients who 
become pregnant must cease all tumor assessments regardless of whether or not they 
developed Progressive Disease. 
Patients who discontinue study treatment during the treatment phase should be scheduled for a 
visit as soon as possible and within 7 days after the last dose of study treatment, at which time 
all of the assessments listed for the EOT visit will be performed. If a patient withdraws from 
treatment at a study visit, EOT assessments do not need to be repeated. An End of Treatment 
Phase Disposition eCRF page should be completed, giving the date and reason for stopping 
LDK378 treatment. 
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following 
the last dose of study treatment. 
If patients refuse to return for these visits or are unable to do so, every effort should be made 
to contact them or a knowledgeable informant by telephone to determine the survival status. 
Patients who discontinue study treatment should be considered withdrawn from the study after 
the final visit assessments are performed or when it is clear that the patient will not return for 
these assessments. 
If a patient discontinues study treatment, but continues study assessments, (e.g. during post 
treatment follow up phase as detailed in Table 7-1), the patient remains on study until such 
time as he/she completes protocol criteria for ending study assessments. At that time, the 
reason for study completion should be recorded on the End of Post Treatment Phase 
Disposition (Study Phase Completion) eCRF page. 
Patients who discontinue study treatment should enter the survival follow-up period or 
continue tumor assessments when appropriate. Tumor assessments will continue until 


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progression of disease (radiological as assessed by investigator), patient withdraws consent 
from tumor assessments, patient is lost to follow-up, death or study terminated by Sponsor. 
 
7.1.3.1 
Replacement policy 
Patients lost to follow-up or withdrawing consent from the study without observed events for 
efficacy endpoints (e.g. PFS) will be censored for the data analysis and will not be replaced. 
 
7.1.4 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any 
further study related contact. 
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations). 
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information. 
Study treatment must be discontinued and no further assessments conducted. 
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up. 
 
7.1.5 
Follow up period 
 
7.1.5.1 
Safety follow up 
All patients will be followed for AEs and SAEs for at least 30 days following the last dose of 
study treatment at the end of treatment phase. 
At the end of this period, the investigator should assess and discuss with the patient any AE 
observed/concomitant medication taken since discontinuation of study treatment. 
Patients whose treatment is permanently discontinued due to an AE (clinical or based on 
abnormal laboratory value) must be followed until resolution or stabilization of the event, 
whichever comes first. In case of an abnormal laboratory value, blood tests should be repeated 
until resolution or stabilization. Data collected should be added to the Adverse Events CRF 
and the Concomitant Medications CRF. 
 
7.1.5.2 
Post-treatment follow-up 
All patients who discontinued treatment during the treatment phase for reasons other than 
death, lost to follow-up, pregnancy or PD (radiological as assessed by investigator) (Section 
7.1.3) will continue tumor assessments as per Table 7-1 (every 8 weeks) thereafter until PD 
(radiological as assessed by investigator), withdrawal of consent from tumor assessment, lost 
to follow-up or death. Once the patient ceases tumor follow-up, the reason for completion 
should be recorded on the End of Post Treatment Phase Disposition eCRF page. 


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7.1.5.3 
Survival follow-up 
All patients who had PD as per investigator assessment, have started a new anti-neoplastic 
therapy, and/or withdrew consent from further study assessments will subsequently be 
followed for survival information every 12 weeks until death, lost to follow-up or withdrawal 
of consent for survival follow-up. The investigator or his designee will collect this survival 
information and any new anti-neoplastic therapies for all patients until the final survival 
analysis. 
Follow-up can be done via a phone contact. Antineoplastic therapies will be captured on the 
'Antineoplastic therapies since discontinuation of study treatment' eCRF page following the 
last dose of the study treatment. 
 
7.1.5.4 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF. 
 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Tumor response will be assessed locally according to the Novartis guideline version 3.1 
(Appendix 2) based on RECIST 1.1 (Eisenhauer et al 2009). 
The imaging assessment collection plan is presented in Table 7-2. 
 
7.2.1.1 
Baseline imaging (+/- photography) assessment 
Imaging assessments will be performed at screening/baseline Day -28 to Day -1 prior to Cycle 
1 Day 1. 
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study. 
Any imaging assessments obtained after first dose of study drug cannot be considered  
baseline images. The following assessments are required at screening/baseline: 
• CT with IV contrast or MRI of chest and abdomen 
• Whole body bone scan 
• Brain CT with IV contrast or MRI scan 
• Additional CT scan or MRI of other metastatic sites (e.g., neck, pelvis, etc.) 
• Localized bone CT scan, MRI or x-ray (for any lesions identified on whole body bone 
scan not visible on chest/abdomen (and pelvis if applicable) CT scan or MRI) 


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• Photography (for any skin lesions) if clinically significant 
If a patient is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts, however if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen 
and pelvis (as applicable) should be performed. 
A whole body bone scan should be performed per institutional standard of care for all patients 
to detect any skeletal metastases present [e.g., Tc-99 bone scan, whole body bone MRI, FDG- 
PET or sodium fluoride positron emission tomography (NaF PET)]. Localized CT, MRI or X- 
rays should be acquired for all skeletal lesions identified on the screening bone scan, which 
are not visible on the chest, abdomen and pelvis CT/MRI. 
If clinically indicated, CT or MRI of other areas (neck, pelvis) of disease as appropriate 
should be performed. 
Color photography, including a metric ruler to estimate the size of the lesion, must be 
acquired for all skin lesions present per instructions provided in the photography manual from 
the designated vendor. 
Chest x-ray and ultrasound should not be used for lesion evaluation in this study. 
 
7.2.1.2 
Subsequent imaging for response assessment 
Tumor evaluations as described in Table 7-2 should be performed using the same imaging 
modality used at baseline, irrespective of study treatment interruption or actual dosing (see 
Table 7-1). 
Tumor assessment for response determination will be made every 8 weeks starting from Day  
1 of Cycle 3 (+/- 7 days window). The 8 weeks interval should be respected regardless of 
whether treatment with LDK378 is temporarily withheld. 
Clinical suspicion of disease progression at any time requires a physical examination and 
radiological confirmation to be performed promptly rather than waiting for the next scheduled 
radiological assessment. 
Each lesion that is measured at baseline must be measured by the same method (either same 
radiological method or by photography, including a metric ruler) and when possible, the same 
local radiologist/physician throughout the study so that the comparison is consistent. If an off- 
schedule imaging assessment is performed because progression is suspected, subsequent 
imaging assessments should be performed in accordance with the original imaging schedule. 
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of oral and IV contrast media. At the 
discretion of the Investigators, FDG-PET scans may be performed to document PD per 
RECIST 1.1 (Appendix 2). 


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Table 7-2 
Imaging assessment collection plan 
 
Procedure 
Screening/Baseline 
During Treatment/Follow-up 
CT or MRI (Chest, Abdomen) 
Mandated 
every 8 weeks 
Whole bone scan 
Mandated 
If clinically indicated 
Brain CT or MRI 
Mandated 
Cycle 3 then every 2 cycle (i.e. every 
8 weeks): only if positive at baseline 
or clinically indicated only if positive 
at baseline or clinically indicated. 
• 
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) 
if clinically indicated 
Cycle 3 then every 2 cycle (i.e. every 
8 weeks): only if positive at baseline 
or clinically indicated only if positive 
at baseline or clinically indicated. 
 
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. All safety assessments at Cycle 1 Day1 have to be 
conducted prior to start of the first dose of LDK378, unless otherwise specified. 
 
7.2.2.1 
Physical examination 
Physical examinations will include an examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes and 
extremities. Information about the physical examination must be present in the source 
documentation at the study center. For the assessment schedule refer to Table 7-1. 
Significant findings that were present prior to the signing of informed consent must be 
included in the Medical History page on the patient’s eCRF. Significant new findings that 
begin or worsen after informed consent must be recorded on the Adverse Event page of the 
patient’s eCRF. 
 
7.2.2.2 
Vital signs 
Vital signs include body temperature, blood pressure and pulse measurements. Blood pressure 
(systolic and diastolic) and pulse should be measured after the patient has been sitting for five 
minutes. 
For the assessment schedule refer to Table 7-1. 


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7.2.2.3 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured. Height will be measured at screening only. For 
the assessment schedule for weight refer to Table 7-1. 
 
7.2.2.4 
Performance status 
WHO performance status will be assessed as per the assessment schedule (refer to Table 7-1). 
Assessment of WHO performance status (Table 7-3) will be performed within the time 
windows described above of the scheduled assessment, even if study treatment is being held. 
More frequent examinations may be performed at the investigator’s discretion, if medically 
indicated. 
 
Table 7-3 
WHO performance status scale 
Score 
Performance Status 
 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g. light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
 
7.2.2.5 
Laboratory evaluations 
Local laboratories will be used for the analysis of scheduled hematology, biochemistry and 
other blood specimens collected as part of safety monitoring (as detailed in Table 7-1). 
Dipstick urinalysis will also be performed locally. Laboratory values obtained during the 
Screening phase will be used to assess patient’s eligibility. The time windows granted for 
laboratory evaluations are identical to the corresponding visit time windows for each visit 
(refer to Section 7.1). 


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Table 7-4 
Local clinical laboratory parameters collection plan 
 
Test Category 
Test Name 
Hematology 
Hemoglobin, Platelets, Red blood cells, White blood cells with Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils in percentage or 
absolute) 
Chemistry 
Albumin, ALT (SGPT), AST (SGOT), calcium, creatinine, creatinine clearance, total 
bilirubin, direct bilirubin (only if total bilirubin is ≥ grade 2), blood urea nitrogen 
(BUN) or urea, magnesium, potassium, sodium, fasting glucose, 
phosphate(inorganic phosphorus), alkaline phosphatase, amylase, lipase, GGT 
Urinalysis 
Macroscopic Panel (Dipstick) (Color, bilirubin, Blood, Glucose, Ketones, pH, protein, 
specific gravity, urobilinogen) 
Microscopic panel (RBC, WBC, casts, crystals, bacteria, epithelial cells) 
Coagulation 
Pro-thrombin time (PT) and International normalized ratio (INR) or Quick Test 
Pregnancy 
At screening visit, serum pregnancy test 
At subsequent cycles, urinary pregnancy test. 
Hormones 
(males only) 
Testosterone (total and free), LH, Follicle-stimulating hormone (FSH) 
 
7.2.2.5.1 Hematology 
Hematology assessments of the parameters listed in Table 7-4 will be tested as per the 
schedule of assessments (Table 7-1). 
 
7.2.2.5.2 Clinical chemistry 
Blood chemistry assessments of the parameters listed in Table 7-4 will be tested as per the 
schedule of assessments (Table 7-1). 
 
7.2.2.5.3 Urinalysis 
Dipstick measurements will be performed as per Table 7-4 and according to the schedule of 
assessments. Any significant findings on dipstick will be followed up with microscopic 
evaluation as per Table 7-4. 
 
7.2.2.5.4 Pregnancy and assessments of fertility 
During screening, a serum pregnancy test will be completed (Day -28 to Day -1). On Cycle 1 
Day 1 prior to dosing and at subsequent cycles and at EOT, urinary pregnancy test (dipstick) 
will be performed. The time windows granted for pregnancy testing are identical to the 
corresponding visit time windows for each visit. Refer to Table 7-1. 
Women who are determined not to be of child bearing potential before the study will only be 
tested at screening. When non-child bearing potential status is determined during the study, 
further pregnancy testing will not be continued. Women are considered post-menopausal if 
they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms), and otherwise not of child 
bearing potential if they have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone,  
only when the reproductive status of the woman has been confirmed by follow up hormone 
level assessment is she considered not of child bearing potential (such testing is not covered 


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as part of the study assessments). If local requirements dictate otherwise, local regulations 
should be followed. 
The time windows granted for pregnancy testing are identical to the corresponding visit time 
windows for each visit. Refer to Table 7-1. 
If a positive pregnancy test is performed in between study visits, the patients must 
immediately notify the investigator. 
 
7.2.2.5.5 Hormones 
Testosterone (total and free), LH, FSH will be tested in male patients only and as per the 
schedule of assessments (Table 7-1). 
 
7.2.2.5.6 Coagulation 
International normalized ratio (INR) and prothrombin time (PT) or Quick Test will be 
measured at screening only. 
 
7.2.2.6 
Cardiac assessments 
 
7.2.2.6.1 Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed as described in Table 7-5. 
Baseline is defined as the pre-dose assessment on Cycle 1 Day 1 before study drug 
administration. 
The triplicate ECGs should be taken approximately 2-4 minutes apart. 
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG CRF page. An ECG may be repeated at the discretion of the investigator at any time 
during the study and as clinically indicated. Each ECG tracing should be labeled with the 
study number, patient initials (where regulations permit), patient number, date, and kept in the 
source documents at the study site. 
 
Table 7-5 
Local ECG collection plan 
 
Cycle 
Day 
Time 
ECG Type 
Screening 
-28 to -1 
Anytime 
12 Lead 
1 
1 
Pre-dose 
12 Lead 
1 
15 
Pre-dose 
12 Lead 
2 
1 
Pre-dose 
12 Lead 
3 
1 
Pre-dose 
12 Lead 
Subsequent cycles and EOT 
1 
Pre-dose 
12 Lead 
Clinically significant abnormalities present when the patient signed informed consent should 
be reported on the Medical History eCRF page. Clinically significant findings must be 
discussed with Novartis prior to enrolling the patient in the study. New or worsened clinically 
significant findings occurring after informed consent must be recorded on the Adverse Events 
eCRF page. 


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7.2.5 
Resource utilization 
Not applicable 


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7.2.6 
Patient reported outcomes 
Not applicable 
 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose 
of study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected though a Death eCRF 
Abnormal laboratory values or test results occurring after signing the ICF constitute adverse 
events only if they induce clinical signs and symptoms, or require therapy, (e.g., any 
hematologic abnormality that requires transfusion of hematological stem cell support) or 
changes in medication(s) are considered clinical significant and should be recorded on the 
Adverse Event eCRF under signs, symptoms or diagnosis associated with them. In addition, 
isolated abnormal laboratory values that are considered clinical significant (e.g. cause study 
discontinuation or constitute in and of itself a Serious Adverse Event) should be recorded on 
the Adverse Events eCRF. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE Grade 1-4) 


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2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
4. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
5. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) 
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is  
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines 
for hematological malignancies), should not be reported as a serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
 
8.1.2 
Laboratory test abnormalities 
 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such. 


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8.1.3 
Adverse events of special interest 
The 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, pancreatitis (including lipase and amylase elevations); and GI 
toxicity (nausea, vomiting and diarrhea). 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 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 


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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, and send 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 to each site. 
Follow-up information is submitted in the same way as the original SAE Report. Each re- 
occurrence, complication, or progression of the original event should be reported as a follow- 
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
 
8.3 
Emergency unblinding of treatment assignment 
Not applicable. This is an open-label study. 
 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up from the estimated date of delivery plus 3 months to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the Novartis Drug Safety and Epidemiology Department (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 any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
Women of childbearing potential should be advised to use highly effective contraception 
methods while they are receiving study treatment and up to 3 months after treatment has been 
stopped. 


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If a pregnancy occurs while on study treatment, the newborn will be followed for at least 3 
months. 
 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure (IB). Additional safety information collected between IB updates will be 
communicated in the form of Investigator Notifications. This information will be included in 
the patient informed consent and should be discussed with the patient during the study as 
needed. 
 
8.6 
Data Monitoring Committee 
Not applicable 
 
8.7 
Steering Committee (SC) 
A SC, comprised of Investigators in NSCLC management from the study will be formed. 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 
the SC and Novartis will be included in the SC charter document. 
 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
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Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results. 
 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan. 
 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and, allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 


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9.4 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 
 
 
The occurrence of any protocol violations will be determined. After these actions have been 
completed and the data has been verified to be complete and accurate, the database will be 
declared locked and made available for data analysis. Authorization is required prior to 
making any database changes to locked data, by joint written agreement between the Global 
Head of Biostatistics and Data Management and the Global Head of Clinical Development. 
After database lock, the investigator will receive a CD-ROM or paper copies of the patient 
data for archiving at the investigational site. 
 
10 
Statistical methods and data analysis 
The data from all participating centers in this protocol will be combined. The primary analysis 
of study data will be conducted at the time when all patients have either completed at least 6 
cycles of treatment or discontinued earlier. All available data from all patients up to this cutoff 
date will be analyzed. The final analysis of study data will be conducted at the end of the 
study (Section 4.3). These data will be summarized in the CSR. 


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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. The FAS will be used for summaries of baseline characteristics and all efficacy 
analyses, unless otherwise specified. 
 
10.1.2 
Safety Set 
The Safety Set will include all patients who receive at least one dose of LDK378. All safety 
data will be analyzed using the safety set. In this non-randomized study the FAS and safety  
set are identical. 
 
10.1.3 
Per-Protocol Set 
Not applicable 
 
10.1.4 
Dose-determining analysis set 
Not applicable 
 
 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for the FAS. Categorical data will be presented as frequencies and percentages. 
For continuous data, mean, standard deviation, median, minimum, and maximum will be 
presented. 
 
10.3 
Treatments (study treatment, concomitant therapies, compliance) 
The safety set will be used for the analyses below. 
The actual dose and duration 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. Dose 
reductions and dose delays (including the reasons for these) will be listed and summarized. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized. 
 
10.4 
Primary objective 
The primary objective is to demonstrate the antitumor activity of LDK378 in patients with 
ALK-positive non-small cell lung cancer (NSCLC) previously treated with alectinib. 


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10.4.1 
Variable 
The primary variable is the overall response rate (ORR), which is defined as the proportion of 
patients with a best overall confirmed response of CR or PR, as assessed per RECIST 1.1 
(Appendix 2) by the investigator. 
 
10.4.2 
Statistical hypothesis, model, and method of analysis 
The primary analysis will be performed on the FAS. The primary efficacy endpoint ORR will 
be estimated and reported along with the exact (Clopper-Pearson) 95% confidence interval 
(CI). No statistical hypothesis testing is planned. 
 
10.4.3 
Handling of missing values/censoring/discontinuations 
Confirmed partial or complete responses reported prior to any additional anticancer therapy 
will be considered as responses in the calculation of ORR, irrespective of the number of 
missed assessments before response. 
Patients with a best overall response of “Unknown” per RECIST 1.1 will be considered as 
non-responders in estimating the ORR. 
Patients who have disease progression and continue to receive the study treatment after 
progression will qualify for progressive disease at the time of first documented progression. 
Tumor assessments performed after the first documented progression will not be considered 
for ORR. This will apply to secondary efficacy endpoints as well. 
 
10.4.4 
Supportive analyses 
The best overall response will be listed by patient and summarized along with the ORR. 
 
10.5 
Secondary objectives 
All secondary efficacy analyses will be performed on the FAS, unless otherwise specified. 
10.5.1 
Key secondary objective(s) 
Disease control rate 
Disease control rate (DCR) is defined as the proportion of patients with a best overall 
response of CR, PR or SD, as assessed per RECIST 1.1 by the investigator. DCR will be 
estimated and reported along with the exact 95% CI. 
 
Duration of response 
Among patients with a confirmed response (PR or CR) per RECIST 1.1 by the investigator, 
the 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 will be described using Kaplan-Meier methods and relevant summary 
statistics such as median DOR and the 95% CI. Censoring rules for DOR follow those for PFS. 


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Time to response 
Among patients with a confirmed response (PR or CR) per RECIST 1.1 by the investigator, 
the time to response (TTR) is defined as the time from the date of the first dose of LDK378 to 
first documented response (PR or CR). TTR will be listed by patient and will be summarized 
using descriptive statistics for patients with a confirmed response. 
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 for any reason is 
documented after one single missing tumor evaluation, the actual event date of disease 
progression/death will be used for the PFS event date. If disease progression or death for any 
reason is documented after two or more missing tumor evaluations, the PFS time of these 
patients will be censored at the date of the last adequate tumor evaluation without PD. 
Censoring rules will be detailed in the RAP. PFS will be listed by patient and will be 
described using Kaplan-Meier methods and relevant summary statistics such as median PFS 
and the 95% CI. 
 
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 listed by patient and will 
be described using Kaplan-Meier methods and relevant summary statistics such as median OS 
and the 95% CI. 
 
Overall intracranial response rate 
Overall intracranial response rate (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, non-target and new 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. OIRR will be estimated 
and reported along with the exact 95% CI. The best overall intracranial response will be listed 
by patient and will be summarized along with the OIRR. These analyses will be conducted for 
patients with measurable brain metastases at baseline. 


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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. 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
2. On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
3. Post-treatment period: starting at day 31 after last dose of study medication. 
The safety summary tables will include only data collected during the on-treatment period. 
However, all safety data will be listed with data collected during the pre-treatment and post- 
treatment period flagged. 
 
10.5.3.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs observed during the on- 
treatment period. However, all safety data (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. 
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and/or preferred term, severity (based on CTCAE grades), 
type of AE, and relation to study treatment. Deaths will also be listed by patient and tabulated. 
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment. For each specified category, the 
number and percentage of patients with at least one event per category will be summarized. 
 
10.5.3.3 Laboratory abnormalities 
For laboratory tests covered by the CTCAE version 4.03, the study’s biostatistical and 
reporting team will grade laboratory data accordingly. For laboratory tests covered by 
CTCAE, a Grade 0 will be assigned for all non-missing values not graded as 1 or higher. In 
the unlikely case when a local laboratory normal range overlaps into the higher (i.e. non-zero) 
CTC grade, the laboratory value will still be taken as within normal limits and assigned a  
CTC grade of zero. Grade 5 will not be used. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
The following summaries will be generated separately for hematology and biochemistry 
laboratory tests: 
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• for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) 
Listing of all laboratory data with values flagged to show the corresponding CTCAE grades 
and the classifications relative to the laboratory normal ranges will be generated. 
A separate listing will display notable laboratory abnormalities (i.e., newly occurring CTCAE 
grade 3 or 4 laboratory toxicities). 
In addition to the above mentioned tables and listings, other 
 analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the RAP. 
 
10.5.3.4 Other safety data 
Data from other tests (including ECGs and vital signs) will be summarized and listed, notable 
values will be flagged, and any other information collected will be listed as appropriate. 
Definitions of notably abnormal results will be provided in the RAP. 
 
10.5.3.5 Tolerability 
Tolerability will be evaluated in terms of dose reductions or drug interruptions due to an AE. 
 
 


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10.7 
Interim analysis 
No interim analysis is planned in this study. 
 
10.8 
Sample size calculation 
The study does not include formal statistical hypothesis testing and the sample size (N=20) is 
not derived based on power considerations. 
A response rate of 10% or less is considered as an insufficient level of  activity  for  the 
proposed patient population. With a sample size of 20 patients, there is an approximately 58.4% 
chance that the exact 95% CI will exclude an insufficient response rate of 10% when the true 
ORR is 30%. The probability increases to 75.5% and 87.4%, when the true ORRs are 35%     
and 40%, respectively. For an observed response rate of 30.0% (6 responders in 20 patients),  
the exact 95% CI is (11.9%, 54.3%). The operating characteristics of this study  are  
summarized in Table 10-1. 
 
Table 10-1 
Operating characteristics for various ORRs when N=20 patients 
 
True ORR 
Probability that exact 95% CI 
excludes an insufficient level of 10%* 
Expected number 
of responders 
Observed ORR and 
exact 95% CI 
30% 
58.4% 
6 
30.0% (11.9%, 54.3%) 
35% 
75.5% 
7 
35.0% (15.4%, 59.2%) 
40% 
87.4% 
8 
40.0% (19.1%, 63.9%) 
*Of 20 patients at least 6 responders are required to meet the criteria (i.e., exact 95% CI excludes an 
insufficient level of 10%), thus it is calculated as a binomial probability that ≥6/20 responders are 
observed given the true ORR. 
 
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, 


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Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in Section 
4.4. 
 
11.5 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study  
safety and progress. 


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Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or  
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. 
Data reported on the CRF, that are derived from source documents, should be consistent with 
the source documents or the discrepancies should be explained. All data requested on the CRF 
must be recorded. Any missing data must be explained. Any change or correction to a paper 
CRF should be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. For electronic CRFs an audit trail will be maintained by the system. The 
investigator should retain records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site. 
 
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. 


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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 
References (available upon request) 
[Beson Al, Ajani JA, Catalano RB, et al. (2004)] Recommended Guidelines for the Treatment 
of Cancer Treatment-Induced Diarrhea, J Clin Oncol 22:2918-26 
[Brambilla, et al. (2014)] World Cancer Report, Stewart BW, Wild CP (Eds), World Health 
Organization, Lyon 2014 
[Brookmeyer R, Crowley J (1982)] A Confidence Interval for the Median Survival Time, 
Biometrics 38: 29-41 
[Eisenhauer, et al. (2009)] New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). European Journal of Cancer; 45; 228–47 
[EMA Guideline on the Investigation of Drug Interactions (2012)] 
[Ettinger DS, Akerley W, Bepler G, et al. (2010)] NCCN Non-Small Cell Lung Cancer Panel 
Members. J Natl Compr Canc Netw. 2010 Jul;8(7):740-801. Review. No abstract available 
[FDA draft guidance (2012)] Drug interaction studies: study design, data analysis, 
implications for dosing, and labeling recommendations. 
[Felip E, Kim DW, Mehra R, et al. (2014)] Efficacy and Safety of Ceritinib in Patients with 
Advanced Anaplastic Lymphoma Kinase (ALK)-rearranged (ALK+) Non-small Cell Lung 
Cancer (NSCLC): An Update of ASCEND-1 (Internet) Available from: < 
oncologypro.esmo.org/Meeting-Resources/ESMO-2014/NSCLC-Metastatic/Evaluation-of- 
ceritinib-treated-patients-pts-with-anaplastic-lymphoma-kinase-rearranged-ALK-non-small- 
cell-lung-cancer-NSCLC-and-brain-metastases-in-the-ASCEND-1-study> (Accessed 08 Dec 
2014) 
[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 
[Howlader N, Noone AM, Krapcho M, et al. (eds) (2009)] National Cancer Institute SEER 
cancer statistics review 1975-2009 (Vintage 2009 populations) (Internet) Available from: < 
seer.cancer.gov/csr/1975_2009_pops09/> (Accessed 22 February 2013) 
[Katayama R, Friboulet L, Koike S, et al. (2014)] Two Novel ALK Mutations Mediate 
Acquired Resistance to the Next-Generation ALK Inhibitor Alectinib. Clin Cancer Res; 
20(22): 1–11 
[Malvezzi M, Bertuccio P, Levi F, et al. (2012)] European cancer mortality predictions for the 
year 2012. Ann Oncol; 23(4):1044-52 
[Ministry of Health, Labour and Welfare Population Survey Report (2013)] (Internet) 
Available from: < http://www.mhlw.go.jp/toukei/saikin/hw/jinkou/geppo/nengai13/dl/h6.pdf 
> (last accessed on 26-Sep-2014) 
[Mok T, Kim DW, Wu YL, et al. (2014)] First-line crizotinib versus pemetrexed–cisplatin or 
pemetrexed–carboplatin in patients (pts) with advanced ALKpositive non-squamous non-small 
cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014). J Clin Oncol 32:5s, 
2014 (suppl; abstr 8002) 
[Murakami H, Seto T, Takahashi T, et al. (2014)] Phase I Study for Ceritinib (LDK378) in 
Japanese Patients with ALK Genetic Alterations (Internet) Available from: < 


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oncologypro.esmo.org/Meeting-Resources/ESMO-2014/NSCLC-Metastatic/Phase-I-study- 
for-ceritinib-LDK378-in-Japanese-patients-with-ALK-genetic-alterations> (Accessed 08 Dec 
2014) 
[National Comprehensive Cancer Network] NCCN Clinical Practice Guidelines in Oncology 
Non-Small Cell Lung Cancer (Version 3. 2012) (Internet) Available from 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; 5:471-85 
[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 
[Seto T, Kiura K, Nishio M, et al. (2013)] CH5424802 (RO5424802) for patients with ALK- 
rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, 
phase 1–2 study. Lancet Oncol 2013;14:590–8 
[Shaw AT, Mehra R, Kim D-W, et al. (2013)] Clinical activity of the ALK inhibitor LDK378 
in advanced, ALK-positive NSCLC [abstract]. J Clin Oncol 31 (suppl); 8010A 
[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; 27:4247-53 
[Siegel R, Naishadham D, Jemal A (2012)] Cancer statistics, 2012. CA Cancer J Clin; 
62(1):10-29 
[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 
[Zhang X, Zhang S, Wu YL, et al. (2010)] Fusion of EML4 and ALK is associated with 
development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated 
with ALK expression. Mol Cancer. 2010 Jul 13;9:188. doi: 10.1186/1476-4598-9-188 


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


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


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


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15 
Appendices 
15.1 
Appendix 2: Harmonization of efficacy analysis of solid tumor 
studies (RECIST 1.1) 
Guidelines for Response, Duration of Overall Response, TTF, TTP, 
Progression-Free Survival and Overall Survival (based on RECIST 1.1) 
 
Document type: 
TA Specific Guideline 
Document status: 
Version 3.1: 29-Nov-2011 
Version 3:0:  19-Oct-2009 
Version 2:0:  18-Jan-2007 
Version 1:0:  13-Dec-2002 
 
Release date: 
29-Nov-2011 
 
Authors (Version 3.1): 
 
 
Authors (Version 3): 
 
 
 
Authors (Version 2): 
 
 
Authors (Version 1): 
 


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Glossary 
CR 
Complete response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DFS 
Disease-free survival 
eCRF 
Electronic Case Report Form 
FPFV 
First patient first visit 
GBM 
Glioblastoma multiforme 
MRI 
Magnetic resonance imaging 
LPLV 
Last patient last visit 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
Stable disease 
SOD 
Sum of Diameter 
TTF 
Time to treatment failure 
TTP 
Time to progression 
UNK 
Unknown 


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15.1.1 
Introduction 
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This 
document is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the 
revised RECIST 1.1 guidelines (Eisenhauer et al 2009). 
The efficacy assessments described in Section 15.1.2 and the definition of best response in 
Section 15.1.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 15.1.18 is summarizing the “time to 
event” variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 15.1.28  
of this guideline describes data handling and programming rules. This section is to be referred 
to in the RAP (Reporting and Analysis Plan) to provide further details needed for 
programming. 
 
15.1.2 
Efficacy assessments 
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) 
European Journal of Cancer; 45:228-247. 
 
15.1.3 
Definitions 
 
15.1.4 
Disease measurability 
In order to evaluate tumors throughout a study, definitions of measurability are required in 
order to classify lesions appropriately at baseline. In defining measurability, a distinction also 
needs to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions. 
• Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
For patients without measurable disease see Section 15.1.26. 
Measurable lesions (both nodal and non-nodal) 
• Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability. 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes ≥15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring ≥10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease. 


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• Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
• Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with ≥ 
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
 
15.1.5 
Eligibility based on measurable disease 
If no measurable lesions are identified at baseline, the patient may be allowed to enter the 
study in some situations (e.g. in Phase III studies where PFS is the primary endpoint). 
However, it is recommended that patients be excluded from trials where the main focus is on 
the Overall Response Rate (ORR). Guidance on how patients with just non-measurable 
disease at baseline will be evaluated for response and also handled in the statistical analyses is 
given in Section 15.1.26. 
 
15.1.6 
Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (i.v) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow- 
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
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• A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. However, another 
response assessment than the Novartis calculated UNK response may be accepted from 
the investigator or the central blinded reviewer if a definitive response assessment can be 
justified, based on the available information. 
• FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• No FDG-PET at baseline with a positive FDG-PET at follow-up: 
• If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 
• If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan). 
• If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
• Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination. 
• Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained. 
• Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 
PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be 
integrated as non-target disease. If markers are initially above the upper normal limit they 
must normalize for a patient to be considered in complete clinical response when all 
lesions have disappeared. 
• Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 


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and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed). 
• Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 
15.1.7 
Baseline documentation of target and non-target lesions 
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions: 
• Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ). 
 
Minimum target lesion size at baseline 
• Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 15.1.4. 
• Nodal target: See Section 15.1.4. 
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. 
Each target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
• Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
 
15.1.8 
Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 


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for the target (Table 15-1) and non-target lesions (Table 15-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target 
and non-target lesions together (Table 15-3) as well as the presence or absence of new lesions. 
 
15.1.9 
Follow-up and recording of lesions 
At each visit and for each lesion the actual date of the scan or procedure which was used for 
the evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate 
lesion evaluation data are examined by the investigator in order to derive the overall visit 
response. Therefore all such data applicable to a particular visit should be associated with the 
same assessment number. 
 
15.1.10 Non-nodal lesions 
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance 
of the cut from the longest diameter; such lesions may appear to have responded or progressed 
on subsequent examinations, when, in fact, they remain the same size). 
If the lesion has completely disappeared, the lesion size should be reported as 0 mm. 
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval. 
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated. 
 
15.1.11 Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are 
not expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination. 


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15.1.12 Determination of target lesion response 
 
Table 15-1 
Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
 
Complete Response (CR): 
Disappearance of all non-nodal target lesions. In addition, any 
pathological lymph nodes assigned as target lesions must have a 
reduction in short axis to < 10 mm.1 
 
Partial Response (PR): 
At least a 30% decrease in the sum of diameter of all target lesions, 
taking as reference the baseline sum of diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameter of all measured target 
lesions, taking as reference the smallest sum of diameter of all target 
lesions recorded at or after baseline. In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm.2 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR or CR nor an increase in 
lesions which would qualify for PD. 
 
Unknown (UNK) 
Progression has not been documented and one or more target lesions 
have not been assessed or have been assessed using a different 
method than baseline.3 
 
1. SOD for CR may not be zero when nodal lesions are part of target lesions 
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present 
and all nodal lesions are <10 mm in size. In this case, the target lesion response is CR 
3. Methodology change See Section 15.1.6. 
 
 
Notes on target lesion response 
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance 
(i.e., the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually 
present and/or not visualized for technical reasons in this previous assessment. If it is not 
possible to change the 0 value, then the investigator/radiologist has to decide between the 
following three possibilities: 
• The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease 
• The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 15-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at 
or after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section. 
• For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD. 
• Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 


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


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15.1.13 Determination of non-target lesion response 
 
Table 15-2 
Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions. In addition, all lymph nodes 
assigned a non-target lesions must be non-pathological in size (< 10 mm 
short axis) 
 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions.1 
Non-CR/Non-PD: 
Neither CR nor PD 
Unknown (UNK) 
Progression has not been documented and one or more non-target 
lesions have not been assessed or have been assessed using a different 
method than baseline. 
 
1. Although a clear progression of non-target lesions only is exceptional, in such circumstances, the 
opinion of the treating physician does prevail and the progression status should be confirmed later on 
by the review panel (or study chair). 
 
 
Notes on non-target lesion response 
• The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. ≥ 10 mm) the response can only be ‘Non- 
CR/Non-PD’ unless any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD). 
• Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 15.1.12 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied. 
 
15.1.14 New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page. 
• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 


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there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion. 
• If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 15.1.15). 
• A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to ≥ 10 mm for the first time in the study plus 5 
mm absolute increase. 
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 15.1.6. 
 
15.1.15 Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target 
lesion response, non-target lesion response and presence of new lesions as shown below in 
Table 15-3. 
 
Table 15-3 
Overall lesion response at each assessment 
Target lesions 
Non-target lesions 
New Lesions 
Overall lesion response 
 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD1, 2 
 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. This overall lesion response also applies when there are no non-target lesions identified at baseline. 
2. Once confirmed PR was achieved, all these assessments are considered PR. 
3. As defined in Section 15.1.8. 
 
If there are no baseline scans available at all, then the overall lesion response at each 
assessment should be considered Unknown (UNK). 
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 


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15.1.16 Efficacy definitions 
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 15.1.26 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts. 
 
15.1.17 Best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the 
protocol should specifically describe if these will be included in the determination of best 
overall response and/or whether these additional assessments will be required for sensitivity  
or supportive analyses. As a default, any assessments taken more than 30 days after the last 
dose of study treatment will not be included in the best overall response derivation. If any 
alternative cancer therapy is taken while on study any subsequent assessments would 
ordinarily be excluded from the best overall response determination. If response assessments 
taken after withdrawal from study treatment and/or alternative therapy are to be included in 
the main endpoint determination, then this should be described and justified in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
• -For non-randomized trials where response is the primary endpoint, confirmation is 
needed. 
• -For trials intended to support accelerated approval, confirmation is needed 
• For all other trials, confirmation of response may be considered optional. 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required 
• SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR). 


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• PD = progression ≤ 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD). 
• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks) 
Overall lesion responses of CR must stay the same until progression sets in, with the 
exception of a UNK status. A patient who had a CR cannot subsequently have a lower status 
other than a PD, e.g. PR or SD, as this would imply a progression based on one or more 
lesions reappearing, in which case the status would become a PD. 
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (≥30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not ≥20% increase from previous smallest sum), the objective 
status at that assessment should be SD. Once a confirmed PR was seen, the overall lesion 
response should be considered PR (or UNK) until progression is documented or the lesions 
totally disappear in which case a CR assignment is applicable. In studies where confirmation 
of response is not required after a single PR the overall lesion response should still be 
considered PR (or UNK) until progression is documented or the lesion totally disappears in 
which case a CR assignment is applicable. 
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the 
subsequent visits. Assuming that non-target lesions did not progress, the overall lesion 
response would be PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the 
PR for this patient. All subsequent assessments are considered PR even if tumor 
measurements decrease only by 20% compared to baseline (200 mm to 160 mm) at the 
following assessments. 
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response. 
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates. 
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources: 
• Investigator overall lesion response 
• Central Blinded Review overall lesion response 
• Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review) 
The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses. 


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Based on the patients’ best overall response during the study, the following rates are then 
calculated: 
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications. 
Disease control rate (DCR) is the proportion of patients with a best overall response of CR 
or PR or SD. 
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used: 
Early progression rate  (EPR) is the proportion of patients with progressive disease within  
8 weeks of the start of treatment. 
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be 
at 8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with 
an unknown (UNK) assessment at that time point and no PD before, will not be counted as 
early progressors in the analysis but may be included in the denominator of the EPR rate, 
depending on the analysis population used. Similarly when examining overall response and 
disease control, patients with a best overall response assessment of unknown (UNK) will not 
be regarded as “responders” but may be included in the denominator for ORR and DCR 
calculation depending on the analysis population (e.g. populations based on an ITT approach). 
 
15.1.18 Time to event variables 
The protocol should state which of the following variables is used in that study. 
 
15.1.19 Progression-free survival 
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint. 
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment. 
 
15.1.20 Overall survival 
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date 
the patient was last seen alive / last known date patient alive, the date of death and the reason 
of death (“Study indication” or “Other”). 


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Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be 
censored at the date of last known date patient alive. 
 
15.1.21 Time to progression 
Some studies might consider only death related to underlying cancer as an event which 
indicates progression. In this case the variable “Time to progression” might be used. TTP is 
defined as PFS except for death unrelated to underlying cancer. 
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate 
tumor assessment. 
 
15.1.22 Time to treatment failure 
This endpoint is often appropriate in studies of advanced disease where early discontinuation 
is typically related to intolerance of the study drug. In some protocols, time to treatment 
failure may be considered as a sensitivity analysis for time to progression. The list of 
discontinuation reasons to be considered or not as treatment failure may be adapted according 
to the specificities of the study or the disease. 
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation 
due to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to 
treatment failure for patients who did not experience treatment failure will be censored at last 
adequate tumor assessment. 
 
15.1.23 Duration of response 
The analysis of the following variables should be performed with much caution when 
restricted to responders since treatment bias could have been introduced. There have been 
reports where a treatment with a significantly higher response rate had a significantly shorter 
duration of response but where this probably primarily reflected selection bias which is 
explained as follows: It is postulated that there are two groups of patients: a good risk group 
and a poor risk group. Good risk patients tend to get into response readily (and relatively 
quickly) and tend to remain in response after they have a response. Poor risk patients tend to 
be difficult to achieve a response, may have a longer time to respond, and tend to relapse 
quickly when they do respond. Potent agents induce a response in both good risk and poor  
risk patients. Less potent agents induce a response mainly in good risk patients only. This is 
described in more detail by Morgan (1988). 
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then 
interpreted with caution by evaluating the results in the context of the observed response rates. 
If an inferential comparison between treatments is required this should only be performed on 
all patients (i.e. not restricting to “responders” only) using appropriate statistical methods such 


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as the techniques described in Ellis et al (2008). It should also be stated in the protocol if 
duration of response is to be calculated in addition for unconfirmed response. 
For summary statistics on “responders” only the following definitions are appropriate. 
(Specific definitions for an all-patient analysis of these endpoints are not appropriate since the 
status of patients throughout the study is usually taken into account in the analysis). 
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression. 
The following two durations might be calculated in addition for a large Phase III study in 
which a reasonable number of responders is seen. 
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression. 
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to 
be confirmed) or SD the start and end date as well as censoring is defined the same as that for 
time to progression. 
 
15.1.24 Time to response 
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be 
confirmed depending on the type of study and its importance. Where the response needs to be 
confirmed then time to response is the time to the first CR or PR observed. 
Although an analysis on the full population is preferred a descriptive analysis may be 
performed on the “responders” subset only, in which case the results should be interpreted 
with caution and in the context of the overall response rates, since the same kind of selection 
bias may be introduced as described for duration of response in Section 15.1.23. It is 
recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. Where an 
inferential statistical comparison is required, then all patients should definitely be included in 
the analysis to ensure the statistical test is valid. For analysis including all patients, patients 
who did not achieve a response (which may have to be a confirmed response) will be censored 
using one of the following options. 
• at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV) 
• at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding 


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Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
15.1.25 Definition of start and end dates for time to event variables 
Assessment date 
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest 
of all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that 
assessment is CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the 
assessment date is calculated as the earliest date of all measurement dates at that evaluation 
number. 
 
Start dates 
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date. 
For the calculation of duration of response the following start date should be used: 
• Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed. 
 
End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
• Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page). 
• Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease. 
• Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post- 
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used. 
• Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 15.1.26). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
Date of discontinuation is the date of the end of treatment visit. 


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• Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
 
15.1.26 Handling of patients with non-measurable disease only at baseline 
It is possible that patients with only non-measurable disease present at baseline are entered 
into the study, either because of a protocol violation or by design (e.g. in Phase III studies 
with PFS as the primary endpoint). In such cases the handling of the response data requires 
special consideration with respect to inclusion in any analysis of endpoints based on the 
overall response evaluations. 
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints. 
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 15-4. 
 
Table 15-4 
Overall lesion response at each assessment: patients with non-target 
disease only 
 
Non-target lesions 
New Lesions 
Overall lesion response 
CR 
No 
CR 
Non-CR/Non-PD1 
No 
Non-CR/non-PD 
UNK 
No 
UNK 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
1 As defined in Section 15.1.8. 
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category. 
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account. 
For ORR it is recommended that the main (ITT) analysis includes data from patients with 
only non-measurable disease at baseline, handling patients with a best response of CR as 
“responders” with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses 


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which exclude these particular patients. Endpoints such as PFS which are reliant on the 
determination and/or timing of progression can incorporate data from patients with only non- 
measurable disease. 
 
15.1.27 Sensitivity analyses 
This section outlines the possible event and censoring dates for progression, as well as 
addresses the issues of missing tumor assessments during the study. For instance, if one or 
more assessment visits are missed prior to the progression event, to what date should the 
progression event be assigned? And should progression event be ignored if it occurred after a 
long period of a patient being lost to follow-up? It is important that the protocol and RAP 
specify the primary analysis in detail with respect to the definition of event and censoring 
dates and also include a description of one or more sensitivity analyses to be performed. 
Based on definitions outlined in Section 15.1.25, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics-April 
2005) as a reference, the following analyses can be considered: 


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Table 15-5 
Options for event dates used in PFS, TTP, duration of response 
 
Situation 
Options for end-date (progression or 
censoring)1 
(1) = default unless specified differently 
in the protocol or RAP 
Outcome 
A 
No baseline assessment 
(1) Date of randomization/start of treatment3 
Censored 
B 
Progression at or before next 
scheduled assessment 
(1) Date of progression 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C1 
Progression or death after exactly 
one missing assessment 
(1) Date of progression (or death) 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C2 
Progression or death after two or 
more missing assessments 
(1) Date of last adequate assessment2 
(2) Date of next scheduled assessment2 
(3) Date of progression (or death) 
Censored 
Progressed 
Progressed 
D 
No progression 
(1) Date of last adequate assessment 
Censored 
E 
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. 
clinical progression based on 
investigator claim 
(1) N/A 
(2) Date of discontinuation (visit date at 
which clinical progression was determined) 
Ignored 
Progressed 
F 
New anticancer therapy given 
(1) Date of last adequate assessment 
(2) Date of secondary anti-cancer therapy 
(3) Date of secondary anti-cancer therapy 
(4) N/A 
Censored 
Censored 
Event 
Ignored 
G 
Deaths due to reason other than 
deterioration of ‘Study indication’ 
(1) Date of last adequate assessment 
Censored 
(only TTP 
and 
duration of 
response) 
1.=Definitions can be found in Section 15.1.25. 
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 15.1.25. 
3.=The rare exception to this is if the patient dies no later than the time of the second scheduled 
assessment as defined in the protocol in which case this is a PFS event at the date of death. 
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F. 
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e. 
• (C1) taking the actual progression or death date, in the case of only one missing 
assessment. 
• (C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments. 
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2. 


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Situation E: Treatment discontinuation due to ‘Disease progression’ without 
documented progression: By default, option (1) is used for situation E as patients without 
documented PD should be followed for progression after discontinuation of treatment. 
However, option (2) may be used as sensitivity analysis. If progression is claimed based on 
clinical deterioration instead of tumor assessment by e.g. CT-scan, option (2) may be used for 
indications with high early progression rate or difficulties to assess the tumor due to clinical 
deterioration. 
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case. 
 
Additional suggestions for sensitivity analyses 
Other suggestions for additional sensitivity analyses may include analyses to check for 
potential bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for 
censoring and events only at scheduled visit dates. The latter could be handled by replacing in 
Table 15-5 the “Date of last adequate assessment” by the “Date of previous scheduled 
assessment (from baseline)”, with the following definition: 
• Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment. 
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on 
the individual requirements for the specific study and disease area and have to be specified in 
the protocol or RAP documentation. 
 
15.1.28 Data handling and programming rules 
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates). 
 
15.1.29 Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation. 
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock). 
 
15.1.30 End of treatment phase completion 
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow- 
up, the investigator or designee should show "due diligence" by documenting in the source 


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documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 
The end of treatment visit and its associated assessments should occur within 7 days of the  
last study treatment. 
Patients may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Death 
• Progressive disease 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 
• Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given) 
 
15.1.31 End of post-treatment follow-up (study phase completion) 
End of post-treatment follow-up visit will be completed after discontinuation of study 
treatment and post-treatment evaluations but prior to collecting survival follow-up. 
Patients may provide study phase completion information for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Death 
• New therapy for study indication 
• Progressive disease 
• Study terminated by the sponsor 
15.1.32 Medical validation of programmed overall lesion response 
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) 


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and not available evaluations (i.e. if any target or non-target lesion was not evaluated the 
whole overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 
assessments may be re-evaluated by clinicians at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on 
RECIST criteria. This may be queried for clarification. However, the investigator or central 
reader’s response assessment will never be overruled. 
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion 
response at that specific assessment is to be kept in a dataset. This must be clearly 
documented in the RAP documentation and agreed before database lock. This dataset should 
be created and stored as part of the ‘raw’ data. 
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation. 
 
15.1.33 Programming rules 
The following should be used for programming of efficacy results: 
 
15.1.34 Calculation of ‘time to event’ variables 
Time to event = end date - start date + 1 (in days) 
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative. 
 
15.1.35 Incomplete assessment dates 
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year. 
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 15.1.25). If all measurement dates have no 
day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 
 
15.1.36 Incomplete dates for last known date patient alive or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 


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15.1.37 Non-target lesion response 
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’. 
 
15.1.38 Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
 
15.1.39 Censoring reason 
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page. 
For survival the following censoring reasons are possible: 
• Alive 
• Lost to follow-up 
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible: 
• Ongoing without event 
• Lost to follow-up 
• Withdrew consent 
• Adequate assessment no longer available* 
• Event documented after two or more missing tumor assessments (optional, see Table 15-5) 
• Death due to reason other than underlying cancer (only used for TTP and duration of 
response) 
• Initiation of new anti-cancer therapy 
*Adequate assessment is defined in Section 15.1.25. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason 
should also be noted: 
• This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off). 
• The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti- 
cancer therapy) has occurred more than the specified period following the last adequate 
assessment. 
• This reason will also be used to censor in case of no baseline assessment. 


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15.1.40 References (available upon request) 
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791 
Eisenhauer E, et al. (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47 
Ellis S, et al. (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465 
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005 
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007 
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18 
Therasse P, Arbuck S, Eisenhauer E, et al. (2000) New Guidelines to Evaluate the Response 
to Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16 

SAP_000.pdf: 
Clinical Development
LDK378
CLDK378A1201 / NCT02450903
A phase II, multi-center, open-label, single-arm study to 
evaluate the efficacy and safety of oral LDK378 treatment 
for patients with ALK-positive non-small cell lung cancer 
previously treated with alectinib
RAP Module 3 – Detailed Statistical Methodology
Author:
 Trial Statistician
Document type:
RAP Documentation
Document status:
Amendment 1
Release date:
13-Jun-2017
Number of pages:
46
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes
1.0
29-Oct-2015
N/A; First version.
Amendment 1
13-Jun-2017
Section 1.2 Objectives:
 
Section 2.1 Data analysis: 
Reporting strategy was clarified.
Subgroup analysis of key efficacy endpoints by prior ALK inhibitor
(alectinib only, alectinib and crizotinib) was added since a patient 
previously treated with crizotinib (in addition to alectinib) was 
allowed to enroll in the study as per protocol amendment 3. In 
addition, subgroup by best response to prior alectinib (CR/PR, 
SD/PD/UNK) was newly defined.
Section 2.3 Patient demographics and other baseline 
characteristics: 
Analysis of prior antineoplastic therapy was updated to include prior 
crizotinib therapy as per protocol amendment 3. 
Section 2.8.1 Efficacy:
Protocol deviation code was specified to identify further 
antineoplastic therapies.
Section 2.8.2 Safety: 
Summary of treatment-related serious AESIs was added.
AE analysis for clinical trial safety disclosure was updated 
according to the current guidance/standards.
Laboratory parameters for summaries were modified to align with 
other LDK378 studies.
Drug-induced liver injury was added as part of safety assessments 
based on protocol amendment 2. 
Section 4.6 Dose interruptions and dose changes:
Specification for reporting of dose interruption/change was clarified 
to support programming.


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Objectives ................................................................................................................6
2
Statistical methods...............................................................................................................7
2.1
Data analysis............................................................................................................8
2.2
Analysis sets ............................................................................................................9
2.3
Patient demographics and other baseline characteristics.........................................9
2.4
Protocol deviations ................................................................................................11
2.5
Patient disposition..................................................................................................12
2.6
Treatments (study drug, concomitant therapies, compliance)...............................13
2.7
Analysis of the primary variable............................................................................15
2.7.1
Variable.................................................................................................15
2.7.2
Statistical hypothesis, model, and method of analysis..........................15
2.7.3
Handling of missing values/censoring/discontinuations.......................16
2.7.4
Supportive analyses...............................................................................16
2.8
Analysis of secondary variables ............................................................................16
2.8.1
Efficacy .................................................................................................16
2.8.2
Safety.....................................................................................................21
29
29
2.9
Sample size calculation..........................................................................................30
2.10
Power for analysis of key secondary variables......................................................30
2.11
Interim analysis......................................................................................................30
3
Changes to protocol specified analyses.............................................................................30
4
Additional details on implementation of statistical methodology.....................................31
4.1
Data included in the analyses ................................................................................31
4.2
Patient classification into analysis sets..................................................................31
4.3
Last contact date ....................................................................................................31
4.4
Month derivation ...................................................................................................32
4.6
Dose interruptions and dose changes.....................................................................32
4.7
Efficacy endpoints .................................................................................................33
4.7.1
Implementation of RECIST guidelines.................................................33
4.7.2
Sources for overall lesion response.......................................................37


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4.7.3
BOIR calculations in patients with measurable brain metastases at 
baseline..................................................................................................37
4.7.4
Kaplan-Meier estimates ........................................................................38
4.7.5
Confidence interval for response rate ...................................................39
4.8
Safety evaluations..................................................................................................39
4.8.1
Multiple assessments within post-baseline visits..................................39
4.8.2
Baseline.................................................................................................40
4.8.3
Laboratory parameters ..........................................................................40
4.9
Handling of missing or partial dates......................................................................41
4.9.1
AE date imputation ...............................................................................42
4.9.2
Incomplete dates of initial diagnosis, first recurrence/progression 
and most recent relapse/progression .....................................................43
4.9.3
Incomplete date for anti-neoplastic therapies .......................................43
4.9.4
Incomplete assessment dates for tumor assessment..............................44
4.9.5
Incomplete date for death or last contact ..............................................44
4.9.6
Incomplete date for disease progression on alectinib prior to the 
start of study drug..................................................................................44
4.9.7
Incomplete date for last dose of study drug ..........................................45
46
5
Reference:..........................................................................................................................46


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List of tables
Document History – Changes compared to previous version of RAP module 3. ......................2
Table 1-1
Objectives and related endpoints ............................................................6
Table 2-1
Study drug exposure variables ..............................................................14
Table 2-2
Outcome and event dates for DOR and PFS analyses ..........................18
Table 2-3
Laboratory parameters for summaries ..................................................24
Table 2-4
ECOG (WHO) performance status scale ..............................................28
Table 2-5
Operating characteristics for various ORRs when N=20 patients ........30
Table 4-1
Patient classification rules.....................................................................31
Table 4-2
Overall lesion response at each assessment: patients with non-
target disease only.................................................................................35
Table 4-3
Inclusion/exclusion of assessments used in waterfall graph.................36
Table 4-4
AE/treatment date abbreviations...........................................................42
Table 4-5
AE partial date imputation algorithm....................................................42
Table 4-6
AE/treatment date relationship and imputation legend.........................43
Table 4-7
AE imputation example scenarios.........................................................43


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1
Introduction
This Reporting and Analysis Plan (RAP) module describes the planned statistical methods for 
all safety, efficacy,
analyses for study CLDK378A1201.
1.1
Study design
This is a single-arm, open-label, multi-center, phase II study to evaluate the efficacy and 
safety of the ALK inhibitor LDK378 when used as a single agent in patients with ALK-
rearranged, stage IIIB or IV NSCLC previously treated with alectinib. A total of 
approximately 20 patients will be enrolled into the study. Treatment with LDK378 will 
continue until the patient experiences disease progression as determined by the investigator 
according to RECIST 1.1, unacceptable toxicity that precludes further treatment, pregnancy, 
start of a new anticancer therapy, discontinuation of treatment at the discretion of the patient 
or investigator, lost to follow-up, death, or termination of the study by Sponsor. LDK378 may 
be continued beyond RECIST-defined progressive disease (PD) as assessed by the 
investigator if, in the judgment of the investigator, there may be clinical benefit with 
continued treatment. In these patients, tumor assessments 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 
with tumor assessments until the time of PD as assessed by the investigator.
1.2
Objectives
The objectives and related endpoints are listed in Table 1-1.
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Primary
To demonstrate the antitumor activity of 
LDK378, as measured by overall response 
rate (ORR) to LDK378 by investigator 
assessment per RECIST 1.1.
ORR, defined as the proportion of patients 
with a best overall confirmed response of 
CR or PR in the whole body as assessed 
per RECIST 1.1 by the investigator.
Key 
secondary
To evaluate disease control rate (DCR).
DCR, calculated as the proportion of 
patients with best overall response of CR, 
PR, or SD.
To evaluate time to tumor response (TTR).
TTR, calculated as the time from first dose 
of LDK378 to first documented response 
(CR or PR) for patients with confirmed CR 
or PR.
To evaluate duration of response (DOR).
DOR, calculated as the time from the date 
of the first documented response (CR or 
PR) to the first documented disease 
progression or death due to any cause for 
patients with confirmed CR or PR.


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Objective
Endpoint
Other 
secondary
To evaluate progression free survival 
(PFS).
PFS, calculated as the time from first dose 
of LDK378 to date of first documented 
disease progression (per RECIST 1.1) or 
date of death due to any cause.
To evaluate overall survival (OS).
OS, calculated as the time from first dose 
of LDK378 to death from any cause.
To evaluate overall intracranial response 
rate (OIRR).
OIRR, calculated as the proportion of 
patients with a best overall confirmed 
response of CR or PR in the brain 
assessments for patients having 
measurable brain metastases at baseline.
To evaluate the safety profile.
AEs, ECGs and laboratory abnormalities.
All tumor-response related endpoints will be evaluated using tumor responses assessed by 
investigator according to RECIST 1.1.
2
Statistical methods
This section and its subsections will be imported to Section 9.7 of the Clinical Study Report 
(CSR) after the analyses have been conducted. This section of the RAP follows the CSR 
template structure of Section 9.7 as of the release date of this document.
The text will be changed to the past tense when imported into the CSR; references to Section 
4 of the RAP, where additional details are provided for programming implementation, may be 
removed in the CSR. 
In what follows, study drug refers to LDK378.


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2.1
Data analysis
Data will be analyzed by Novartis Oncology Biostatistics and Statistical Programming 
personnel according to the data analysis section 10 of the CLDK378A1201 protocol, which 
will be available in Appendix 16.1.1 of the CSR. Important information is given in the 
following sections and details are provided, as applicable, in Section 4 from which Appendix 
16.1.9 of the CSR will be extracted.
SAS® version 9.4 (or later version if available at time of database lock) will be used in all 
analyses.
Data from all patients who signed informed consent in centers that participate in this study 
will be combined and used in the analysis. Data collected after withdrawal of informed 
consent will not be reported. Due to expected small size of enrollment at individual centers, 
no center effect will be assessed. Each analysis will use all data in the database up to the 
analysis cut-off date, determined prior to database lock. 
The analysis cut-off date for the primary analysis of study data will be around 168 days after 
the first dose of study drug for the last patient enrolled corresponding to when all patients 
have either completed at least 6 cycles of treatment, i.e., 168 days (1 cycle = 28 days), or 
discontinued earlier. The results from primary analysis will be reported in the primary 
(interim) 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 cut-off date for the final analysis of study data will be established at the end of the 
study when at least 75% of deaths have occurred. The results from final analysis will be 
reported in the final CSR. Note that the analysis cut-off date and reporting strategy may be 
changed according to the development and/or NDA submission status of LDK378.    
Section 4.1 provides further details regarding data to be included in the analyses. 
General presentation of descriptive summaries
Qualitative data (e.g., gender, race) will be summarized by frequency counts and percentages. 
Percentages will be calculated using the number of patients in the relevant population or 
subgroup as the denominator.
Continuous data (e.g., age, body weight) will be summarized by appropriate descriptive 
statistics (i.e., mean, standard deviation, median, minimum, and maximum).
Subgroup analysis
Key efficacy endpoints (best overall response, ORR, and DCR) will be summarized for the 
following subgroups:

Brain metastases at baseline: (presence, absence)
Note: for the subgrouping the brain metastases are defined as measurable or non-
measurable disease in the brain at baseline. List of lesion locations considered to be brain 
metastases is provided in Section 4.7.3.

Prior ALK inhibitor: (alectinib only, alectinib and crizotinib)

Best response to prior alectinib: (CR/PR, SD/PD/UNK)


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2.2
Analysis sets
A patient is considered to be enrolled into the study if they have signed informed consent.
Only patients who have signed informed consent will be included in the analysis sets.
Full Analysis Set
The Full Analysis Set (FAS) will include all patients who receive at least one dose of 
LDK378. The FAS will be used for summaries of baseline characteristics and all efficacy 
analyses, unless otherwise specified.
Safety Set
The Safety Set will include all patients who receive at least one dose of LDK378. All safety 
data will be analyzed using the Safety Set. In this non-randomized study the FAS and Safety 
Set are identical.
Frequency counts and percentages (using FAS as denominator) of patients in each of the 
above defined analysis sets will be summarized. In addition, a listing of patients included in
each of the analysis sets will be provided. 
Section 4.2 provides further details regarding the derivation the analysis sets.
2.3
Patient demographics and other baseline characteristics
The FAS will be used for all patient demographic and baseline characteristic summaries and 
listings with the exception of screen failures.


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Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed.
Categorical data (e.g. gender, age category; <65 and ≥65 years, race, ethnicity, WHO 
performance status, smoking history) will be summarized by frequency count and percentages. 
Continuous data (e.g. age, weight, height, body mass index) will be summarized by 
descriptive statistics (as defined in Section 2.1).
Diagnosis and extent of cancer
Descriptive statistics and frequency counts and percentages will be tabulated, as appropriate, 
for diagnosis and extent of cancer based on the data collected on the electronic Case Report 
Form (eCRF) including diagnosis of disease, predominant histology/cytology, histological 
grade, time (in months) since initial diagnosis to start date of study drug, stage at initial 
diagnosis, stage at time of study entry, time (in months) from initial diagnosis to first 
recurrence/progression, time (in months) since most recent relapse/progression to start date of 
study drug, current extent of disease (metastatic sites), number of metastatic sites at baseline, 
types of lesions (target and non-target lesions) at baseline, number of target lesions at baseline, 
and disease burden at baseline for target lesion (based on the data collected on the RECIST 
eCRF page). A listing will also be provided including the information such as the ones above.
ALK status
ALK status at screening, collected on the [ALK Translocation status] eCRF page, will be 
listed.
Medical history
Medical history and current medical conditions will be summarized and listed. Separate 
summaries will be presented for medical history and current medical conditions. The 
summaries will be presented by primary system organ class and preferred term. 
A medical condition that is not active at the study entry (i.e., ‘Ongoing’ is ‘No’ on the 
[Medical History] eCRF page) is classified as medical history (historical medical conditions). 
A medical condition that is active at the study entry (i.e., ‘Ongoing’ is ‘Yes’ on the [Medical 
History] eCRF page) is classified as current medical conditions. Medical history and current 
medical conditions are coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology.
Prior antineoplastic therapy
Prior antineoplastic (anticancer) therapy will be listed in three separate categories: (i) 
medications, (ii) radiotherapy, and (iii) surgery. 
The number and percentage of patients who received any prior antineoplastic therapy 
(including medication, radiotherapy or surgery), prior antineoplastic medication, prior 
antineoplastic radiotherapy or prior antineoplastic surgery will be summarized. 
All patients must have received alectinib for inclusion in the study; reason for alectinib
discontinuation, best response on alectinib, duration of best response, and time from start of 


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last alectinib treatment to progression (date of progression on alectinib – start date of last 
alectinib treatment + 1) will be summarized. Prior crizotinib therapy will be summarized in a 
similar way to alectinib for patients previously treated with crizotinib.
Prior antineoplastic medications will be summarized by chemotherapy (medication) setting, 
other therapy (medication) setting, number of prior regimens, prior anticancer medications
(including alectinib, crizotinib, cisplatin, carboplatin, pemetrexed, docetaxel, gemcitabine, 
bevacizumab, erlotinib, vinorelbine, gefitinib, paclitaxel, and others), therapy type at last 
treatment, and setting at last treatment. Prior antineoplastic medications will also be 
summarized by ATC class and preferred term.
Prior antineoplastic radiotherapy will be summarized by locations, setting at last radiotherapy, 
and time since end of last radiotherapy to start date of study drug (by category).
Prior antineoplastic surgery will be summarized by procedure at last surgery and time since
last surgery to start date of study drug (by category).
Screen failures
Screen failures are patients who have been enrolled and have failed to meet inclusion and/or 
exclusion criteria. These patients are not treated with study drug. Frequency counts and 
percentages will be tabulated for all enrolled (screened) patients as follows:

Number (%) of patients who completed screening phase (based on the presence of ‘Date 
of study phase completion’ and ‘Next phase entered’ is ‘Treatment’ (or ‘Will the subject 
continue into the next phase of the trial?’ is ‘Yes’) on the [End of Screening Phase 
Disposition] eCRF page); 

Number (%) of patients who discontinued during screening phase (based on the presence 
of ‘Date of discontinuation’, ‘Subject status (i.e., reason for discontinuation)’ entered, and
‘Will the subject continue into the next phase of the trial?’ is ‘No’ on the [End of 
Screening Phase Disposition] eCRF page);

Primary reasons for screening phase discontinuation (based on the ‘Subject status (i.e., 
reason for discontinuation)’ recorded on the [End of Screening Phase Disposition]
eCRF page for patients who discontinued during screening phase).
All screen failures (i.e., patients who discontinued during screening phase) will be listed along 
with the relevant information such as reason(s) for screening phase discontinuation and the 
inclusion/exclusion criteria leading to screen failure. The eCRF data reported in screen 
failures will not be included in any data analyses, but it will be presented in separate listings
as needed.
2.4
Protocol deviations
Frequency counts and percentages of patients in the FAS with any CSR-reportable protocol 
deviations (related to study inclusion/exclusion criteria, conduct of the trial, patient 
management or patient assessment) will be tabulated by the deviation category. All protocol 
deviations will be listed for the FAS. 


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The full list of potential CSR-reportable protocol deviations is documented separately in the 
Study Specification Document (SSD). All protocol deviations will be reviewed during the 
study and finalized before database lock.
2.5
Patient disposition
The FAS will be used for the patient disposition summary tables and listings. The following 
will be tabulated:
Treatment phase:

Number (%) of patients who are still on-treatment (based on the absence of [End of 
Treatment Phase Disposition] eCRF page); 

Number (%) of patients who discontinued study treatment (based on the completion of
[End of Treatment Phase Disposition] eCRF page with the ‘Date of discontinuation’ and 
‘Subject status (i.e., reason for discontinuation)’ entered);

Number (%) of patients who entered post-treatment efficacy follow-up (based on the
‘Next phase entered’ is ‘Post-treatment follow-up’ (or ‘Will the subject continue into 
the next phase of the trial?’ is ‘Yes’) on the [End of Treatment Phase Disposition] 
eCRF page for patients who discontinued study treatment);

Number (%) of patients who entered survival follow-up (based on the ‘Will the 
subject continue into the next phase of the trial?’ is ‘No’ and ‘Will the subject be 
followed for survival?’ is ‘Yes’ on the [End of Treatment Phase Disposition] eCRF
page for patients who discontinued study treatment);

Number (%) of patients who discontinued from study (based on the ‘Will the subject 
continue into the next phase of the trial?’ is ‘No’ and ‘Will the subject be followed for 
survival?’ is ‘No’ on the [End of Treatment Phase Disposition] eCRF page for 
patients who discontinued study treatment);

Primary reasons for study treatment discontinuation (based on the ‘Subject status (i.e., 
reason for discontinuation)’ recorded on the [End of Treatment Phase Disposition] eCRF
page for patients who discontinued study treatment);
Post-treatment efficacy follow-up phase:

Number (%) of patients who are still in the post-treatment efficacy follow-up phase (based 
on the presence of [End of Treatment Phase Disposition] eCRF page and the absence of 
[End of Post Treatment Phase Disposition] eCRF page for patients who entered post-
treatment efficacy follow-up);

Number (%) of patients who discontinued from the post-treatment efficacy follow-up 
(based on the completion of [End of Post Treatment Phase Disposition] eCRF page with
the ‘Date of discontinuation’ and ‘Subject status (i.e., reason for discontinuation)’ entered
for patients who entered post-treatment efficacy follow-up);

Number (%) of patients who entered survival follow-up (based on the ‘Will the 
subject be followed for survival?’ is ‘Yes’ on the [End of Post Treatment Phase 
Disposition] eCRF page for patients who discontinued from the post-treatment 
efficacy follow-up);


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
Number (%) of patients who discontinued from study (based on the ‘Will the subject 
be followed for survival?’ is ‘No’ on the [End of Post Treatment Phase Disposition] 
eCRF page for patients who discontinued from the post-treatment efficacy follow-up);

Primary reasons for discontinuation from the post-treatment efficacy follow-up (based on
the ‘Subject status (i.e., reason for discontinuation)’ recorded on the [End of Post 
Treatment Phase Disposition] eCRF page).
The patient disposition will be listed for the FAS. The informed consent data will be listed for 
the screen failures as well as the FAS.
2.6
Treatments (study drug, concomitant therapies, compliance)
The Safety Set will be used for all medication data summaries and listings unless otherwise 
specified.
Study drug and study treatment
Study drug and study treatment both refer to LDK378 and will be used interchangeably.
Date of first/last administration of study drug
The date of first administration of study drug is defined as the first date when a non-zero dose 
of study drug was administered and recorded on the [Dosage Administration Record (DAR)]
eCRF page. For the sake of simplicity, the date of first administration of study drug will also 
be referred to as start date of study drug.
The date of last administration of study drug is defined as the last date when a non-zero dose 
of study drug was administered and recorded on the DAR eCRF page. This date will also be 
referred to as last date of study drug.
Study day
The study day for all assessments (e.g., tumor assessment, death, disease progression, tumor 
response, performance status, adverse event onset, laboratory abnormality occurrence, vital 
sign measurement, and dose interruption) will be calculated using the start date of study drug 
as the origin. For assessments occurring after or on the start date of study drug, study day will 
be calculated as:
Study day = Event date – Start date of study drug + 1.
The first day of study drug is therefore study day 1. 
For any assessment or events such as baseline disease characteristics or medical history (e.g., 
time since diagnosis of disease) occurring prior to the start of the study drug, study day will be 
negative and will be calculated as:
Study day = Event date – Start date of study drug.
The study day will be displayed in the relevant data listings.


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Dose exposure and intensity
Definitions of study drug exposure variables, as well as intermediate calculations, are 
provided in Table 2-1.
Table 2-1
Study drug exposure variables
Variable
Definition
Duration of exposure (days):
Last date of study drug − Start date of study drug + 1
(Periods of interruption are not excluded.)
Cumulative dose (mg):
Total dose of study drug taken by a patient in the study
Number of dosing days (days):
Duration of exposure (days) − Number of zero dose days
% of actual days dosed (%):
100 x Number of dosing days / Duration of exposure (days)
% of days received full dose (%):
100 x Number of days received full (planned) dose / Duration of 
exposure (days)
Average daily dose (mg/day):
Cumulative dose (mg) / Number of dosing days
Dose intensity; DI (mg/day):
Cumulative dose (mg) / Duration of exposure (days)
Relative dose intensity; RDI (%):
100 x DI (mg/day) / Planned dose (i.e., 750 mg/day)
Note:
Given the planned dose of 750 mg/day, the planned dose intensity (PDI) can be calculated as:
   PDI (mg/day) = Cumulative planned dose (mg) / Duration of exposure (days),
where 
   Cumulative planned dose (mg) = Planned dose of 750 (mg) x Duration of exposure (days).
Then, RDI (%) which is calculated as (100 x DI / PDI) can be simplified as shown above.
Duration of exposure to study drug, cumulative dose, average daily dose, DI and RDI will be 
summarized. In addition, the duration of exposure to study drug and RDI will be categorized 
and the frequency counts and percentages of patients in each category will also be presented. 
Frequency counts and percentages of patients who have dose changes, reductions or 
interruptions, and the corresponding reasons, will be summarized. In addition, descriptive 
statistics will also be presented for the % of actual days dosed, % of days received full dose, 
number of dose changes, and number of dose interruptions.
Time to first dose reduction, defined as the time from the first dose of study drug to the first 
reduction of study drug, will be summarized in 2 month-intervals. Summary statistics of time 
to first dose reduction will also be presented. Time to first dose interruption, defined as the 
time from the first dose of study drug to the first interruption of study drug, will be 
summarized in a similar way.
Listings of all doses of the study drug along with dose change and dose interruption reasons 
will be produced. The derived exposure variables will also be listed by patient.
Section 4.6 provides further details on the definition of dose changes and interruptions.
Concomitant therapy
Concomitant therapies are defined as any medications (excluding study drug, prior 
antineoplastic treatments and blood transfusions), surgeries or procedures (including physical 


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therapy) administered in the study and are recorded in the [Prior and Concomitant 
Medications] and the [Surgical and Medical Procedures] eCRF pages, respectively.
Concomitant medications will be coded using the WHO Drug Reference List (WHO DRL) 
dictionary that employs the WHO Anatomical Therapeutic Chemical (WHO ATC) 
classification system. Surgeries or procedures will be coded using the MedDRA terminology. 
All summaries will be tabulated using frequency counts and percentages. Concomitant 
medications will be summarized by ATC class and preferred term. These summaries will 
include: 1) medications starting on or after the start of study drug and starting no later than 30 
days after last dose of study drug and 2) medications starting prior to the start of study drug 
and continuing after the start of study drug. Surgeries or procedures will be summarized by 
primary system organ class and preferred term in a similar way.
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start date of study drug or starting more than 30 days after the last date of study drug 
will be flagged in the listings. 
Note patients who receive the prohibited concomitant therapies will be reported as a protocol 
deviation.
Antineoplastic therapy after discontinuation of study drug
The FAS will be used for all listings and summaries of antineoplastic therapies initiated after 
discontinuation of study drug.
Antineoplastic therapies initiated after discontinuation of study drug will be listed in three 
separate categories: (i) medications, (ii) radiotherapy, and (iii) surgery.
All summaries will be tabulated using frequency counts and percentages. Antineoplastic 
medications initiated after discontinuation of study drug will be summarized by ATC class 
and preferred term.
2.7
Analysis of the primary variable
The primary objective is to demonstrate the antitumor activity of LDK378, as measured by 
ORR by investigator assessment per RECIST 1.1, in patients with ALK-positive NSCLC
previously treated with alectinib.
2.7.1
Variable
The primary efficacy endpoint is the ORR which is defined as the proportion of patients with 
a best overall confirmed response of CR or PR, as assessed per RECIST 1.1 by the 
investigator.
2.7.2
Statistical hypothesis, model, and method of analysis
The primary efficacy analysis will be performed on the FAS. 
The primary efficacy endpoint ORR, as assessed per RECIST 1.1 by the investigator, will be 
estimated and the exact 95% confidence interval (CI) will be provided (Clopper and Pearson, 
1934). Exact CIs will be used since the confidence limits based on the normal approximation 


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are not bounded by the [0, 1] interval, meaning that for rates close to 0 or 1, the upper limit of 
the normal approximation interval for the proportion could exceed 1 or the lower limit could 
be negative. Refer to Section 4.7.5 for additional details of CI calculation.
No statistical hypothesis testing is planned in this study.
2.7.3
Handling of missing values/censoring/discontinuations
Confirmed PR or CR reported prior to any additional anticancer therapy will be considered as 
responses in the calculation of ORR, irrespective of the number of missed assessments before 
response.
Patients with a best overall response of ‘Unknown’ per RECIST 1.1 will be considered as 
non-responders in estimating the ORR.
Patients who have disease progression and continue to receive the study treatment after 
progression will qualify for PD at the time of first documented progression. Tumor 
assessments performed after the first documented progression will not be considered for ORR. 
This will apply to secondary efficacy endpoints as well.
2.7.4
Supportive analyses
Best overall response will be listed by patient and summarized along with the ORR.
ORR will be summarized by subgroup (as defined in Section 2.1).
Waterfall plots representing the best percentage change from baseline in the sum of the tumor
measured diameters for target lesions will be produced. Refer to Section 4.7.1 for additional 
details.
2.8
Analysis of secondary variables
2.8.1
Efficacy
The key secondary and other secondary efficacy endpoints are provided in Table 1-1. All
tumor response related endpoints under the secondary efficacy objectives (DCR, TTR, DOR, 
PFS, and OIRR), as well as the primary efficacy endpoint ORR, will be analyzed based on the 
investigator assessments as per RECIST 1.1. Confirmation of response is required for all 
response endpoints, as per RECIST 1.1.
The definitions and details on the derivation of the efficacy endpoints are given in Section 15
(Appendix 2) of the CLDK378A1201 protocol. Further details and rules needed for 
programmatic implementation of RECIST 1.1 guidelines are provided in Section 4.7.1.
All secondary efficacy endpoint analyses will be performed based on the FAS, unless 
otherwise specified. All efficacy data, such as tumor assessments and respective efficacy 
endpoints, will be listed by patient.
Best overall response and DCR will be summarized by subgroup (as defined in Section 2.1) as 
well as the primary efficacy endpoint ORR.


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Best overall response
Best overall response (BOR) will be assessed based on reported lesion responses at different 
evaluation time points. Both CR and PR must be confirmed by repeat assessments performed 
not less than 4 weeks after the criteria for response are first met. The next scheduled 
assessment may be used for purposes of confirmation of response. If there is only one 
confirmatory assessment available which has been performed earlier, the status PR or CR will 
not be assigned. Unconfirmed PR and unconfirmed CR are considered as SD if >6 weeks after 
start of study drug, otherwise considered as UNK. BOR for each patient is determined from 
the sequence of overall (lesion) responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression.

PR = at least two determinations of PR or better at least 4 weeks apart before progression
(and not qualifying for a CR).

SD = at least one SD assessment (or better) >6 weeks after start of study drug (and not 
qualifying for CR or PR).

PD = progression ≤12 weeks after start of study drug (and not qualifying for CR, PR or 
SD).

UNK = all other cases (i.e., not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or progression within the first 12 weeks)
Only tumor assessments performed before the start of any further antineoplastic therapies (i.e.,
any additional secondary antineoplastic therapy or anticancer surgery) will be considered in 
the assessment of BOR. If a patient receives any further antineoplastic therapy while on study, 
any subsequent tumor assessments will be excluded from the BOR determination. Further 
antineoplastic therapies will be identified via protocol deviations (deviation code: COMDxx 
for use of prohibited concomitant therapy including other anticancer therapy, where xx is a 
serial number, e.g. COMD01, COMD02) or from the data collected on the [Antineoplastic 
Therapy Since Discontinuation of Study Treatment] eCRF pages, as appropriate. Clinical 
deterioration will not be considered as documented disease progression.
For patients with BOR of UNK, the reason for having unknown status will be listed. The 
following reasons will be used:

No valid post-baseline assessment

All post-baseline assessments have overall response UNK

New antineoplastic therapy started before first post-baseline assessment

SD too early (≤6 weeks after start date of study drug)

PD too late (>12 weeks after start date of study drug)
Special (and rare) cases where BOR is ‘Unknown’ due to both early SD and late PD will be 
classified as ‘SD too early’.
Frequency counts and percentages of patients with each BOR will be reported along with
ORR and DCR.


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Disease control rate
Disease control rate (DCR) is defined as the proportion of patients with a best overall 
response of CR, PR or SD, as assessed per RECIST 1.1 by the investigator. 
DCR will be estimated and the exact 95% CI will be provided.
Time to response
Time to response (TTR) is defined as the time from the start date of study drug to the date of 
first documented response (PR or CR, which must be confirmed subsequently) for patients 
with a confirmed response (PR or CR) as assessed per RECIST 1.1 by the investigator. 
TTR will be summarized using descriptive statistics for patients with a confirmed response
(PR or CR). In addition, TTR will be summarized in 2-month intervals.
Duration of response
Duration of response (DOR) is defined as the time from the date of first documented response 
(PR or CR) to the date of first documented disease progression (PD) or death due to any cause 
among patients with a confirmed response (PR or CR) as assessed per RECIST 1.1 by the 
investigator.
If a patient has not progressed or is not known to have died at the date of analysis cut-off or 
has received any further anticancer therapy in the absence of disease progression, DOR will 
be censored at the date of last adequate tumor assessment before the earlier of the cut-off date
or the start date of new anticancer therapy. Clinical deterioration will not be considered as a 
qualifying event for progression. The censoring and event date options to be considered for 
the main analysis are presented in Table 2-2.
Table 2-2
Outcome and event dates for DOR and PFS analyses
Situation
Date
Outcome
A
No baseline assessment
Date of first dose of 
study drug [a]
Censored
B
Progression at or before next scheduled
assessment
Date of progression
Progressed
C1
Progression or death after exactly one
missing assessment
Date of progression (or 
death)
Progressed
C2
Progression or death after two or more
missing assessments
Date of last adequate 
assessment
Censored
D
No progression
Date of last adequate 
assessment
Censored
E
Treatment discontinuation due to ‘Disease
progression’ without documented
progression, i.e. clinical progression
based on investigator claim
N/A
Information ignored. 
Outcome derived 
based on radiology 
data only.
F
New anticancer therapy given
Date of last adequate 
assessment
Censored


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Situation
Date
Outcome
[a] The rare exception to this is if the patient dies no later than the time of the second scheduled 
assessment as defined in the protocol in which case this is a PFS event at the date of death.
DOR will be described in tabular and graphical format using Kaplan-Meier methods. The 
Kaplan-Meier estimate of the distribution function will be constructed. The number of 
patients at risk at certain time points will be shown on the plot. The estimated median (in 
months) along with 95% CIs, as well as 25th and 75th percentiles, will be reported. 
(Brookmeyer and Crowley, 1982; Klein and Moeschberger, 1997). In addition, Kaplan-Meier 
estimated probabilities with corresponding 95% CIs (Kalbfleisch and Prentice, 2002) at 
several time points (including at least 4, 8, 12, 15, 18 months) will be summarized. 
Refer to Section 4.7.4 for further details regarding derivation of Kaplan-Meier estimates.
Progression-free survival
Progression-free survival (PFS) is defined as the time from the start date of study drug to the 
date of first documented disease progression (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 further anticancer therapy in the absence of disease progression, PFS will be 
censored at the date of last adequate tumor assessment before the earlier of the cut-off date or 
the start date of new anticancer therapy. Clinical deterioration will not be considered as a
qualifying event for progression. Refer to Table 2-2 for censoring and event date options and 
outcomes for PFS.
In particular, PFS will be censored at the last adequate tumor assessment if one of the 
following occurs: absence of event; the event occurred after a new anticancer therapy is given; 
the event occurred after two or more missing tumor assessments (see Section 4.7.1). See also 
Section 4.6.1 describing the special case of a missing baseline tumor assessment.
PFS will be described in tabular and graphical format using Kaplan-Meier methods as 
described for DOR, including estimated median (in months) with 95% CI, 25th and 75th
percentiles with 95% CIs, and Kaplan-Meier estimated probabilities with corresponding 95% 
CIs at several time points (including at least 4, 8, 12, 15 and 18 months). Censoring reasons 
will also be summarized.
In addition, the supportive analysis of PFS with censoring rule modified by ignoring further 
anticancer therapy (‘F’ in Table 2-2) will be considered when the percentage of patients
censored due to the initiation of new anticancer therapy in the main analysis (for censoring 
reason classification, see Section 4.7.1) is equal to or more than 25% of the FAS (i.e., ≥5 out 
of 20 patients). In this supportive analysis, data from tumor assessments performed after the 
start of further anticancer therapy will also contribute to the determination of censoring and 
event date for PFS. Except for further anticancer therapy, the same censoring rule used for the 
main analysis will be followed. PFS will be described in a similar way, as needed.
Overall survival
Overall survival (OS) is defined as the time from the start date of study drug to the date of 
death due to any cause. If a patient is alive at the date of the analysis cut-off or lost to follow-


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up, OS will be censored at the last contact date prior to the cut-off date (see Section 4.3 for 
further details on derivation of last contact date).
OS will be described in tabular and graphical format using Kaplan-Meier methods as 
described for DOR, including estimated median (in months) with 95% CI, 25th and 75th
percentiles with 95% CIs, and Kaplan-Meier estimated probabilities with corresponding 95% 
CIs at several time points (including at least 4, 8, 12, 15 and 18 months). Censoring reasons 
will also be summarized. 
Overall intracranial response rate
Overall intracranial response rate (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, non-target and new 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. Refer to Section 4.7.3
for additional details.
OIRR will be estimated and the exact 95% CI will be provided. In addition, best overall 
intracranial response and intracranial disease control rate (i.e., BOR and DCR based on target, 
non-target and new lesions in the brain) will be summarized. These analyses will be 
conducted for patients with measurable brain metastases at baseline.
Duration of Follow-up and Gap Analyses
Follow-up in the study will be summarized using the following methods to provide a 
comprehensive assessment of follow-up for all patients. 
Summary of duration between the start date of study drug and the cut-off date, and follow-up 
times for PFS/OS, are defined as follows:

Duration between the start date of study drug and the cut-off date = (Cut-off date – Start 
date of study drug + 1) / 30.4375 (months).

Follow-up time = (Date of event or censoring – Start date of study drug + 1) / 30.4375 
(months), regardless of outcome (event or censoring). Date of censoring is defined as the 
date of last adequate tumor assessment for PFS or the last contact date (when the patient is 
known as alive) for OS. 
Descriptive statistics (including 25th and 75th percentiles) will be tabulated for the duration 
and the follow-up times for PFS/OS.
Summaries will also be tabulated for the gap time for PFS/OS follow-up compared to the cut-
off date. Gap analysis is the summary of gap time (months) for PFS/OS follow-up as 
compared to the cut-off date. Gap time for PFS/OS is defined as follows

For patients who are censored regardless of follow-up status, 
Gap time = (Cut-off date – Censoring date) / 30.4375 (months).

For patients who completed study phase or prematurely discontinued from the study due 
to certain reasons, e.g., withdraw consent and lost to follow-up, 


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Gap time = (min(Cut-off date, Study termination date) – Censoring date) / 30.4375
(months).

For patients who are censored but still in follow-up,
Gap time = (Cut-off date – Censoring date) / 30.4375 (months).
Median, 25th and 75th percentiles, minimum and maximum, as well as the frequency counts
and percentages of patients in each of <4, 4-<8, 8-<12, 12-<18, ≥18 months, will be reported 
for PFS and OS gap times for patients who were censored. 
All summaries will be reported in months (see Section 4.4). Date of censoring is the same as 
defined for the PFS and OS analysis. 
2.8.2
Safety
All safety analyses will be performed based on the Safety Set. All listings and tables will be 
presented for all patients, unless otherwise specified.
Baseline
Baseline is the result of an investigation describing the “true” uninfluenced state of the patient. 
The last available assessment before or on the start date of study drug is defined as “baseline” 
value or “baseline” assessment. If an assessment is planned to be performed prior to the first
dose of study drug in the protocol and the assessment is performed on the same day as the first 
administration of study drug, it will be assumed that it was performed prior to study drug 
administration, if assessment time or first dose time is not collected or is missing. If 
assessment time and first dose time are collected, the observed time point will be used to 
determine pre-dose on study day 1 for baseline calculation. Unscheduled assessments before 
the start date of study drug will be used in the determination of baseline. See Section 4.8.2 for 
further details on derivation of baseline for laboratory data and ECGs.
Patients who start study 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 reported to the end of treatment (EOT) visit. Data reported at the EOT visit are not 
eligible for baseline selection.
Grouping for the analyses
The overall observation period will be divided into three mutually exclusive segments:

Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study drug.

On-treatment period: from day of first dose of study drug to 30 days after last dose of 
study drug (Note: for ongoing patients, from day of first dose of study drug to the data cut-
off date).

Post-treatment period: starting at day 31 after last dose of study drug.
The safety summary tables will include only assessments collected during the on-treatment 
period, i.e., assessments collected no later than 30 days after last dose of study drug and 
assessments collected before or on the data cut-off date for ongoing patients, unless otherwise 
specified. 


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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 safety data, regardless of observation period, will be listed and assessments collected in 
the pre-treatment and post-treatment period will be flagged in the listings.
Adverse events
Adverse events (AEs) will be coded using the latest version of MedDRA available prior to 
clinical database lock and will be graded using Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an AE, grades 1, 2, 3, or 
4 corresponding to the severity of mild, moderate, severe, and life-threatening, respectively,
will be used. CTCAE grade 5 (death) will not be used in this study; rather, this information 
will be collected on the [Death] eCRF page.
As described previously, AE summary tables will include only AEs observed during the on-
treatment period (i.e., treatment-emergent AEs). All AE summaries will be tabulated
(frequency counts and percentages) by primary system organ class and/or preferred term, and 
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 summary tables will be produced:

AEs, regardless of study drug relationship

AEs, suspected to be study drug related

Deaths (on-treatment deaths, all deaths during the study)

Serious AEs, regardless of study drug relationship

Serious AEs, suspected to be study drug related

AEs leading to study drug discontinuation, regardless of study drug relationship

AEs requiring dose adjustment, regardless of study drug relationship

AEs requiring dose interruption, regardless of study drug relationship

AEs requiring dose adjustment or interruption, regardless of study drug relationship

AEs requiring additional therapy, regardless of study drug relationship
All AEs will be listed along with any other information (e.g., start/end dates, duration, 
severity, causality, action taken and outcome) as appropriate. Additional listings will be 
produced separately for deaths, serious AEs, AEs leading to study drug discontinuation, AEs 
requiring dose adjustment, AEs requiring dose interruption, AEs requiring dose adjustment or 
interruption, and AEs requiring significant additional therapy.
Adverse events of special interest
Adverse events of special interest (AESIs) are defined as AEs within the following categories/ 
groupings of preferred terms:

Hepatic toxicity

Interstitial lung disease/pneumonitis

QTc prolongation


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
Hyperglycemia

Bradycardia 

Pancreatitis

Gastrointestinal toxicity (nausea, vomiting and diarrhea)
AESIs are defined at the project level and may be updated based on emergent data to reflect 
new AESIs at the time of analysis. The AESIs listed above will be identified based on a list of 
preferred terms. The list of preferred terms will be finalized in a separate document (i.e., case 
retrieval strategy). These AESIs will be summarized for each grouping, by preferred term, as 
follows:

AESIs, regardless of study drug relationship

CTC grade 3/4 AESIs, regardless of study drug relationship

AESIs, suspected to be study drug related

Serious AESIs, regardless of study drug relationship

Serious AESIs, suspected to be study drug related

AESIs leading to study drug discontinuation, regardless of study drug relationship

AESIs requiring dose adjustment, regardless of study drug relationship

AESIs requiring dose interruption, regardless of study drug relationship

AESIs requiring dose adjustment or interruption, regardless of study drug relationship
AESIs will be listed by grouping.
Clinical trial safety disclosure
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on on-
treatment AEs (i.e., treatment-emergent AEs) which are not serious AEs with an incidence 
greater than 5% and on on-treatment serious AEs and serious AEs suspected to be related to 
study treatment will be provided by primary system organ class and preferred term.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same system organ class and preferred term:

a single occurrence will be counted if there is ≤1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one serious AE / serious AE suspected to be related to 
study treatment / non-serious AE has to be checked in a block e.g., among AE's in a ≤ 1 day 
gap block, if at least one serious AE is occurring, then one occurrence is calculated for that 
serious AE.
The number of deaths resulting from serious AEs suspected to be related to study treatment 
and serious AEs irrespective of study treatment relationship will be provided by primary 
system organ class and preferred term.


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Laboratory data
Local laboratories will be used for laboratory evaluations in this study. Laboratory data will 
be classified (by Novartis Oncology Statistical Programming personnel) into CTC grades 
according to the CTCAE version 4.03. For all reports, CTC grade is always obtained on the 
converted measurement in SI unit. Grade 5 will not be used. The CTC grade 0 will be 
assigned as below in different scenarios:  
1. For laboratory parameters defined by criteria based on normal range only, a CTC grade of 
0 will be assigned when the value is within normal limits.   
2. For laboratory parameters whose grade is defined by criteria based on normal range and 
absolute values (e.g., platelet count decrease). A CTC grade of 0 will be assigned when 
the value is within normal limits. 
3. For laboratory parameters whose grade is defined by criteria based on normal range and 
the change from baseline value with no other associated clinical criteria such as 
concomitant medication (e.g., creatinine increased), the following will be applied. For the 
grading of baseline value and for the grading of post-baseline values with missing baseline 
value, the grade will be derived using the criteria based only on the normal range as per 
CTCAE version 4.03. A CTC grade of 0 will be assigned when the post-baseline value is 
≤ULN (for hyper) or ≥LLN (for hypo).
Laboratory parameters for which a grading does not exist will be classified into 
low/normal/high group by means of laboratory normal ranges.
As described previously, laboratory summary tables will include only laboratory assessments 
collected during the on-treatment period. Shift tables may use data from pre-treatment period 
for baseline calculations. The following summaries will be produced separately for the 
hematology and biochemistry (including hormones) laboratory data (by laboratory parameter):

Shift tables using CTC grades to compare baseline to the worst post-baseline value for 
laboratory parameters with CTC grades.

Shift tables using low, normal, high (as well as low and high combined) classifications to 
compare baseline to the worst post-baseline value for laboratory parameters where CTC 
grades are not defined.
The laboratory parameters listed in Table 2-3 will be summarized as above stated. For bi-
directional parameters, both hyper and hypo summaries will be presented.
Table 2-3
Laboratory parameters for summaries
Category
Parameter with CTC grades
Parameter without CTC grades
Hematology
absolute lymphocytes [hyper, hypo]
basophils
absolute neutrophils [hypo]
eosinophils
hemoglobin [hypo]
monocytes
platelet counts [hypo]
RBC
WBC [hyper, hypo]
Biochemistry
albumin [hypo]
blood urea nitrogen (BUN) or urea
alkaline phosphatase [hyper]
direct bilirubin
ALT (SGPT) [hyper]


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Category
Parameter with CTC grades
Parameter without CTC grades
amylase [hyper]
AST (SGOT) [hyper]
corrected calcium* [hyper, hypo]
creatinine [hyper]
creatinine clearance [hypo]
GGT [hyper]
glucose [hyper, hypo]
lipase [hyper]
magnesium [hyper, hypo]
phosphate (inorganic phosphorus) [hypo]
potassium [hyper, hypo]
sodium [hyper, hypo]
total bilirubin [hyper]
Hormones
(males only)
follicle stimulating hormone (FSH)
luteinizing hormone (LH)
testosterone, free
testosterone, total (free and bound)
*Corrected for albumin. See Section 4.8.3 for details on calculation of parameter.
Laboratory parameters for urinalysis, coagulation and pregnancy listed below will be 
presented in listings and will not be summarized.

Urinalysis: macroscopic panel (dipstick) (color, bilirubin, blood, glucose, ketones, pH, 
protein, specific gravity, urobilinogen), microscopic panel (RBC, WBC, casts, crystals, 
bacteria, epithelial cells).

Coagulation: international normalized ratio (INR), pro-thrombin time (PT) or quick test.

Pregnancy: serum pregnancy test, urinary pregnancy test.
The following listings will be produced for the laboratory data for all laboratory parameters.

Listing of patients with laboratory abnormalities of CTC grade 3 or 4 (for laboratory 
parameters where CTC grades are defined)

Listing of all laboratory data with values flagged to show the corresponding CTC grades 
and the classifications relative to the laboratory normal ranges.
In addition, laboratory normal ranges will be listed by laboratory identification number and 
laboratory category.
Box plot of laboratory data by time point (scheduled visit) will be produced for each of all 
laboratory parameters with the exception of qualitative data such as urine dipstick glucose.
Liver function tests
Liver function tests (LFTs) of interest for LDK378 are total bilirubin (TBILI), ALT, AST and 
alkaline phosphatase (ALP). In what follows, AT refers to ALT or AST values. LFTs will be 
summarized as follows:

Shift tables of baseline vs. worst post-baseline values for the categories:


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
TBILI ≤2xULN, TBILI > 2xULN and missing TBILI

ALT ≤ 3xULN, ALT > 3xULN and missing ALT

AST ≤ 3xULN, AST > 3xULN and missing AST

ALP < 2xULN, ALP ≥ 2xULN and missing ALP

Frequency counts and percentages of patients with worst post-baseline values in the 
categories:

ALT > 3xULN, ALT > 5xULN, ALT > 10xULN, ALT > 20xULN

AST > 3xULN, AST > 5xULN, AST > 10xULN, AST > 20xULN

AT > 3xULN, AT > 5xULN, AT > 10xULN, AT > 20xULN

TBILI > 2xULN

Concurrent ALT > 3xULN and TBILI > 2xULN

Concurrent AST > 3xULN and TBILI > 2xULN

Concurrent AT > 3xULN and TBILI > 2xULN 

Concurrent AT > 3xULN and TBILI > 2xULN and ALP < 2xULN

Concurrent AT > 3xULN and TBILI > 2xULN and ALP ≥ 2xULN
Note the concurrent measurements are those occurring on the same date.

Scatter plot of maximum post-baseline TBILI/ULN-normalized values vs. maximum post-
baseline AT/ULN-normalized values.
Listing of all TBILI, ALT, AST and ALP values for patients with a post-baseline TBILI > 
2xULN, ALT> 3xULN or AST > 3xULN will be provided. Individual patient profiles with 
ULN-normalized LFT values for patients with a post-baseline TBILI > 2xULN, ALT > 
3xULN or AST > 3xULN will be described graphically.
ECGs
ECG data will be analyzed based on local laboratory reported results. At each scheduled time-
point, the triplicate ECGs will be taken as per protocol and the summary (mean) of their
values for each ECG parameter will be collected in the [12 Lead ECG Evaluation – Local 
Analysis] eCRF page.
The analysis of QT data is complicated by the fact that the QT interval is highly correlated 
with heart rate. Because of this correlation, formulas are routinely used to obtain a corrected 
value, denoted QTc, which is independent of heart rate. This QTc interval is intended to 
represent the QT interval at a standardized heart rate. For this analysis, the Bazett’s correction 
formula defined as QTcB = QT/SquareRoot(RR) and the Fridericia’s correction formula
defined as QTcF = QT/CubeRoot(RR), where RR (in seconds) = 60/HR, will be used for QT 
correction.
As described previously, ECG summary tables will include only ECG assessments collected 
during the on-treatment period. Shift tables, change from baseline summaries, and change 
score generation may use data from pre-treatment period for baseline calculations. The 
following summaries will be produced for each applicable ECG parameters.


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
For each of ECG parameters (HR, and QT, QTcB, QTcF, QRS, PR intervals), descriptive 
statistics at baseline, at each post-baseline time point and changes from baseline at each 
post-baseline time point.

For each of QT/QTc intervals (QT, QTcB, QTcF), shift tables based on notable parameter 
categories (≤450, >450 – ≤480, >480 – ≤500, >500 ms) at baseline and the worst post-
baseline value observed.

Frequency counts and percentages of patients having notable ECG values according to the 
following categories:           

QT/QTcB/QTcF increase from baseline >30 ms,  >60 ms

Newly occurring post-baseline QT/QTcB/QTcF >450 ms, >480 ms, >500 ms

HR increase from baseline >25% and value >100 bpm

HR decrease from baseline >25% and value <50 bpm

PR increase from baseline >25% and value >200 ms

Newly occurring post-baseline PR >200 ms and ≤220 ms, >220 ms

QRS increase from baseline >25% and value >110 ms

Newly occurring post-baseline QRS >110 ms and ≤120ms, >120 ms
Note the denominator to calculate percentages for each category is the number of patients 
with both a baseline and a post-baseline evaluation. A newly occurring post-baseline ECG 
notable value is defined as a post-baseline value that meets the criterion post-baseline but 
did not meet the criterion at baseline.
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 shift 
table analysis of notable QT/QTc intervals and the analysis of notable ECG changes.
All ECG parameters will be listed and the notable values will be flagged in the listing. In 
addition, patients with notable ECG values will be listed separately. 
Vital signs
Vital sign assessments will be performed in order to characterize basic body function. The 
parameters collected are weight (kg), body temperature (°C), pulse rate (beats per minute), 
systolic and diastolic blood pressure (mmHg). 
As described previously, vital sign summary tables will include only vital sign assessments 
collected during the on-treatment period. Shift tables, change from baseline summaries, and 
change score generation may use data from pre-treatment period for baseline calculations. The 
following summaries will be produced for each of vital sign parameters (weight, body 
temperature, pulse rate, systolic and diastolic blood pressure).

Descriptive statistics at baseline, at each post-baseline time point and changes from 
baseline at each post-baseline time point.

Shift table based on values classified as notable low, normal, notable high, or notable 
(high and low) at baseline and the worst post-baseline value observed.
Clinically notable elevated values are defined as:


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
Systolic BP: 160 mmHg and an increase 20 mmHg from baseline

Diastolic BP: 100 mmHg and an increase 15 mmHg from baseline

Body temperature: 39.1°C

Weight: increase from baseline of 10%

Pulse rate: 120 bpm with increase from baseline of 15 bpm
Clinically notable below normal values are defined as:

Systolic BP: 90 mmHg and a decrease 20 mmHg from baseline

Diastolic BP: 50 mmHg and a decrease 15 mmHg from baseline

Body temperature: 35°C

Weight: decrease from baseline of 10%

Pulse rate: 50 bpm with decrease from baseline of 15 bpm
All vital sign parameters (including height and BMI at screening) will be listed and the 
notable values will be flagged in the listing. In addition, patients with notable vital sign values
will be listed separately.
ECOG (WHO) performance status
The ECOG (WHO) performance assessment allows patients to be classified as to their 
functional impairment, the definition of scores in relation to their performance status is 
provided in Table 2-4, ranging from 0 (most active) to 5 (dead):
Table 2-4
ECOG (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 house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than  50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
The following summaries will be produced for the FAS.

Shift table of ECOG performance status at baseline to worst post-baseline status by score

Shift table of ECOG performance status at baseline to best post-baseline status by score
ECOG performance status will be listed for the FAS.
Drug-induced liver injury
For patients meeting the potential drug-induced liver injury (DILI) criteria specified in the 
protocol, further follow-up and data collection related to liver events (e.g., detailed history, 
medication, laboratory test, liver exams/tests) will be required by using the [Liver Events]
eCRF pages as appropriate. All DILI-related data will be listed if available.      


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2.9
Sample size calculation
The study does not include formal statistical hypothesis testing and the sample size (N=20) is 
not derived based on power considerations. 
A response rate of 10% or less is considered as an insufficient level of activity for the
proposed patient population. With a sample size of 20 patients, there is an approximately 
58.4% chance that the exact 95% CI will exclude an insufficient response rate of 10% when 
the true ORR is 30%. The probability increases to 75.5% and 87.4%, when the true ORRs are 
35% and 40%, respectively. For an observed response rate of 30.0% (6 responders in 20 
patients), the exact 95% CI is (11.9%, 54.3%). The operating characteristics of this study are 
summarized in Table 2-5.
Table 2-5
Operating characteristics for various ORRs when N=20 patients
True 
ORR
Probability that exact 95% CI excludes 
an insufficient level of 10% *
Expected number 
of responders
Observed ORR and 
exact 95% CI
30%
58.4%
6
30.0% (11.9%, 54.3%)
35%
75.5%
7
35.0% (15.4%, 59.2%)
40%
87.4%
8
40.0% (19.1%, 63.9%)
*Of 20 patients at least 6 responders are required to meet the criteria (i.e., exact 95% CI excludes an 
insufficient level of 10%), thus it is calculated as a binomial probability that ≥6/20 responders are 
observed given the true ORR.
2.10
Power for analysis of key secondary variables
Not applicable.
2.11
Interim analysis
No interim analysis is planned in this study.
3
Changes to protocol specified analyses
No changes are made.


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4
Additional details on implementation of statistical 
methodology
The sections below contain additional details on statistical methodology that will be included 
in Appendix 16.1.9 (Documentation of Statistical Methods) of the CSR as well as rules details 
on programing rules that will be followed to implement the analyses described in Section 2.
4.1
Data included in the analyses
This section provides additional details to those included in Section 2.1.
Each analysis (primary analysis of study data after all patients have either completed at least 6 
cycles of treatment or discontinued earlier; final analysis of study data once at least 75% of 
patients have died) will include the data with an assessment date or event start date (e.g., vital 
sign assessment date or start date of an AE) prior to or on the analysis cut-off date. For 
example, if the cut-off date is 30DEC2008, an AE starting on 28DEC2008 will be reported, 
whereas an AE starting on 31DEC2008 will not be reported.
4.2
Patient classification into analysis sets
This section provides additional details to those included in Section 2.2.
Patients are excluded from the analysis sets based on the protocol deviations entered in the 
database and/or on specific patient classification rules as shown in Table 4-1 below.
Table 4-1
Patient classification rules 
Analysis set
Protocol deviation ID* leading to 
exclusion
Additional patient classification 
rules leading to exclusion
Full Analysis Set
INCL13 (Patients who do not provide 
the written informed consent prior to 
any screening procedures), 
TRT02 (Patients who do not receive at 
least one dose of study drug without 
the withdrawal of informed consent 
after continuing into the treatment 
phase)
Safety Set
INCL13, 
TRT02
*Protocol deviation IDs are from the ‘PD Specs and Edit Checks’ sheet of Study Specification 
Document (SSD) final version 1.0. If the SSD (protocol deviation IDs) is updated during the study, refer 
to the corresponding IDs provided in the latest SSD at the time of analysis.
4.3
Last contact date
The 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 date using the latest complete date among the 
following:


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
All patient assessment dates (e.g., blood draws, vital signs, performance status, ECG, 
tumor assessments).

Start and end dates of antineoplastic therapies administered after study drug
discontinuation.

AE start and end dates.

From the [Survival information] eCRF page,

Last known date subject alive if answer to question ‘Is subject alive?’ is ‘Lost to
follow-up’;

Date of assessment if answer to question ‘Is subject alive?’ is Yes;

Note: If answer to question ‘Is subject alive?’ is ‘Unknown’, neither last known date 
subject alive nor date of assessment is used.

Study drug start and end dates.

Date of discontinuation collected on the [End of Treatment Phase Disposition] and/or the 
[End of Post Treatment Phase Disposition] eCRF pages.
Only dates associated with patient visits or actual examinations of the patient will be used in 
the derivation. Dates associated with a technical operation unrelated to patient status such as 
the date a blood sample was processed will not be used. Assessment dates after the analysis 
cut-off date will not be applied to the last contact date. 
4.4
Month derivation
For all derivations, a month will be calculated as (365.25 / 12) = 30.4375 days. If duration is 
to be reported in months, duration in days will be divided by 30.4375.
4.5
Age derivation
Age will be calculated based on the date when the patient signed the main study informed 
consent from the date of birth.
4.6
Dose interruptions and dose changes
This section provides additional details to those included in Section 2.6.
All reporting of dose interruptions and dose changes are based on the dose actually taken by 
the patient and flags for dose interruption/change recorded on the [DAR] eCRF page.
An interruption is defined as a 0 mg dose taken on one or more days. What follows defines
how dose interruptions will be counted in the case of multiple dose interruptions.

If an interruption occurs consecutively for at least two days due to the same reason, then it 
will be counted only once (example: If the actual dose on days 1-3 is 750 mg and actual 
dose on days 4-5 is 0 mg and dose interruption on days 4-5 is due to AE, then the total 
number of dose interruptions is 1). 
A dose change is defined as a change in dosing from one record to the next; however a dose 
interruption will not be counted as a dose change.


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Dose reductions are a subset of dose changes where dose changes to higher than protocol
planned dose are excluded.
4.7
Efficacy endpoints 
For further details on efficacy endpoints, see Section 15
(Appendix 2) of the
CLDK378A1201 protocol. For the evaluation of tumor-response related endpoints, response 
is assessed by investigator according to RECIST 1.1.
Response and progression evaluation will be performed according to the Novartis RECIST 
1.1 guidelines, included in Section 15 (Appendix 2) of the protocol.
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Sections 2.7 and 2.8.1.
4.7.1
Implementation of RECIST guidelines
Disease progression
PD should only be assigned if it is confirmed by an objective assessment method as per 
RECIST 1.1 (e.g., radiologic scan, histology for bronchoscopy, photos for skin lesions). If a 
new lesion is detected using an objective assessment method other than radiologic scan, it 
should be entered on the [RECIST New Lesion] eCRF page with appropriate method (or 
method=‘Other’). 
In particular, discontinuation due to disease progression or death due to progressive disease, 
without supporting objective evidence (as defined above), will not be considered as PD in the 
determination of BOR, the derivation of any efficacy endpoint or efficacy analysis.
Change in imaging modality
Per RECIST 1.1, a change in methodology can be defined as either a change in contrast use 
(e.g., keeping the same technique, like CT, but switching from with to without contrast use or 
vice-versa, regardless of the justification for the change) or a change in technique (e.g., from 
CT to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT and vice versa while keeping same contrast use (e.g., switching 
from spiral CT with contrast to CT with contrast) is not considered a change in imaging 
modality. A change in methodology will result by default in an UNK (unknown) overall 
lesion response assessment. However, a response assessment other than the Novartis 
calculated UNK response may be accepted from the investigator if a definitive response 
assessment can be justified based on the available information. Potential discrepancies 
between the modality used and overall lesion response reported by the investigator (e.g.,
change in modality but investigator assessment of response is different from UNK) will be 
queried during the data review process.
Determination of missing adequate tumor assessments
For the computation of ORR, patients without any radiological assessment after the start date 
of study drug will be counted as failure.


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Partial or complete responses reported prior to any additional anticancer therapy will be 
considered for ORR computation irrespective of the number of missed assessments before 
response. In this section, the ‘missing adequate assessment’ is defined as assessment not done 
or assessment with overall lesion response equal to UNK. For the sake of simplicity, the 
‘missing adequate assessment’ will also be referred as ‘missing assessment’.
As detailed in Section 15 (Appendix 2) of the protocol, the PFS censoring and event date 
options depend on the presence and the number of missing tumor assessments. For example, 
an event occurring after two or more missing assessments is censored in the analysis of PFS 
at the last adequate tumor assessment before the event date.
An exact rule to determine whether there is none, one or two missing assessments is therefore 
needed. This rule will be based on the distance between the last adequate tumor assessment 
date and the event date.
If the distance is larger than threshold D1 or D2 then the analysis will assume one or two 
missing assessments, respectively. The threshold D1 will be defined as the protocol specified 
interval between the tumor assessments plus the protocol allowed window around the 
assessments. Similarly, the threshold D2 is defined as two times the protocol specified interval 
between the tumor assessments plus the protocol allowed window around the assessments. In 
this study, the protocol defined schedule of tumor assessment is every 8 weeks and each 
assessment is expected to be performed at the scheduled time point plus or minus 1 week, i.e.,
the window is 2 weeks, then any distance larger than D1 = 8 + 2 = 10 weeks means one 
missing assessment and any distance larger than D2 = (8 x 2) + 2 = 18 weeks means two 
missing assessments.
The same definition of D2 will be used to determine the PFS censoring reason. 
Possible censoring reasons for PFS are:
1. Ongoing without event
2. Lost to follow-up
3. Withdrew consent
4. Adequate assessment no longer available
5. New cancer therapy added prior to disease progression
6. Event after ≥2 missing tumor assessments
PFS censoring reason is then derived by the following sequence of rules.

If patient is considered to have a PFS event then PFS censoring reason is set to missing.

Else if patient has had no baseline tumor assessment then PFS censoring reason = 4.

Else if start date of new anti-neoplastic therapy is before any PFS event which is less than 
D2 distance after date of last adequate tumor assessment (LATA), i.e., if (PFS event date –
LATA date ≤D2), then PFS censoring reason = 5.

Else if patient has a PFS event after two or more missing assessments, i.e., if (PFS event 
date – LATA date > D2) and PFS event is before min date, then PFS censoring reason = 6.

Else if min date = date of withdrawal of consent and (date of withdrawal of consent –
LATA date ≤D2) then PFS censoring reason = 3.


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
Else if min date = date of treatment discontinuation and (date of treatment discontinuation 
– LATA date ≤D2) and date of discontinuation reason in the [End of Treatment Phase 
Disposition] eCRF page = ‘Lost to follow-up’ then PFS censoring reason = 2.

Else if min date = analysis cut-off date and (analysis cut-off date – LATA date ≤D2) then 
PFS censoring reason = 1.

Else PFS censoring reason = 4.
where min date = minimum of non-missing (analysis cut-off date, start date of further anti-
neoplastic therapy, date of withdrawal of consent, date of discontinuation due to loss to 
follow-up).
Non-measurable disease at baseline
As specified in Section 15 (Appendix 2) of the protocol, the RECIST 1.1 criteria imply that 
only patients with measurable disease at baseline should be included in the study. If a patient 
without measurable disease is enrolled, the intent-to-treat (ITT) principle requires including 
these patients in the analyses. Hence, analyses will be based on the FAS including patients 
with either measurable or non-measurable disease. Therefore, a rule needs to be specified on 
how to handle these cases.
As specified in Section 15 (Appendix 2) of the protocol, overall lesion response can be 
derived for patients without measurable disease at baseline as follows (Table 4-2).
Table 4-2
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD *
No
Non-CR/Non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
* In general, the Non-CR/Non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination.
Missing baseline tumor assessment
As specified in Section 15 (Appendix 2) of the protocol, since the timing of PD cannot be 
determined for patients with missing baseline tumor assessment, these patients are censored in 
the PFS analysis at the start date of study drug. This rule, however, only applies to the ‘PD 
component’ of the PFS or DOR assessment.  
Patients without baseline tumor assessment who die within D2 distance from start date of 
study drug will be counted as having an event in the primary analysis of PFS. All deaths will 
be counted in the OS analysis regardless of presence or absence of the baseline tumor 
assessment.


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Construction of waterfall graphs
The waterfall graphs will be used to depict the anti-tumor activity. These plots will display the 
best percentage change from baseline in the sum of the measured diameters of all target 
lesions for each patient. The proportions of patients with various degrees of tumor shrinkage 
or growth can then represent a useful efficacy metric.
However, caution needs to be paid to the assessments, where an occurrence of a new lesion or 
worsening in non-target lesions (resulting in PD as an overall lesion response at given 
assessment) contradicts the measurements obtained on target lesions. These assessments will 
not be displayed as bars in the graph. If such a ‘contradicting’ assessment represents the only 
post-baseline assessment for a patient, then the patient will be represented by a special symbol 
(e.g., *) in the waterfall graph.
The assessments with unknown target response and also assessments with unknown overall
lesion response will be excluded. Patients without any valid assessments will be completely 
excluded from the graphs.
The total number of patients displayed in the graph needs to be shown and this number will be 
used as a denominator when calculating the percentages of patients with tumor shrinkage and 
tumor growth. Footnote will explain the reason for excluding some patients (due to absence of 
any valid assessment) as needed.
All possible assessment scenarios are described in Table 4-3.
Table 4-3
Inclusion/exclusion of assessments used in waterfall graph
Criteria for inclusion/exclusion
Possible source of contradictions
Target response
Overall lesion 
response
Include in 
waterfall
Non-target 
response
New lesion?
CR/PR/SD
PD
Yes but as * only
PD
Any
CR/PR/SD
PD
Yes but as * only
Any
Yes
UNK
UNK or PD
No
Any
Any
CR/PR/SD
UNK
No
UNK
No
CR/PR/SD
CR/PR/SD
Yes as a bar
Non-CR/Non-PD
No
PD
PD
Yes as a bar
Any
Any
The following algorithm will be used to construct the graph:
1. Select ‘valid’ post-baseline assessments to be included, i.e., for each patient and each 
assessment repeat the following four steps:
a. Check the target lesion response and overall lesion response at each assessment. If at 
least one of them is UNK then exclude the whole assessment. Otherwise, go to step b.    
b. Check the overall lesion response. If PD, then go to step c. Otherwise, go to step d.
c. Check target response. If PD, then go to step d. Otherwise flag the assessment *.
d. Calculate the % change from baseline in target lesions. 
2. For each patient, go through all valid assessments identified in step 1 and find the 
assessment with best % change from baseline in target lesions. The ‘best’ means best for 
the patient, i.e., the largest shrinkage or if a patient only has assessments with tumor 


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growth take the assessment where the growth is minimal. (Example 1: Patient 1 has the 
following % changes from baseline at assessments 1, 2, 3, 4 and 5, respectively: -10%; -
25%; -13%; -4% and +6%. His/her best % change is then -25%. Example 2: Patient 2 has 
the following % changes from baseline at assessments 1, 2 and 3, respectively: +5%; 
+18% and +35%. His/her best % change is then +5%.
3. Construct the waterfall graph displaying the best % change from baseline for each patient. 
Patients having only * flagged assessment(s) will be displayed separately. 
Investigator assessment will be used in the construction of waterfall plot.
The recommended way of the display from left to right is:
1. Bars above the horizontal axis representing tumor growth.
2. Bars under the horizontal axis representing tumor shrinkage.
3. ‘Zero’ bars with * symbol representing patients with contradiction.
In addition, patients with a PFS event will be represented by the flag ‘#’ below or above the 
vertical bars.
4.7.2
Sources for overall lesion response
The tumor-response related endpoints derivation is based on the sequence of overall lesion 
responses at each assessment/time point. In this study, the overall lesion response at a given 
assessment/time point will be provided from single source, i.e., investigator (local radiology) 
reported overall lesion responses. No blinded independent review committee (BIRC) is 
established for independent tumor assessments. Therefore the evaluation of tumor-response 
related endpoints will be based only on investigator assessments in this study.
4.7.3
BOIR calculations in patients with measurable brain metastases at 
baseline
A patient with measurable brain metastases at baseline is defined as a patient having at least 
one target lesion in the brain. Inclusion of response assessments based on lesion locations in 
the brain for each assessment, including baseline to identify whether patients have measurable 
brain metastases, uses the following list of terms collected based on investigator reported 
tumor data (‘Lesion Location’ collected on the [RECIST] eCRF pages):

Brain

CNS: Infratentorial

CNS: Supratentorial

Cerebral cortex

Meninges

Spinal cord

CNS - not otherwise specified

Leptomeningeal

Cerebellum
For all lesion locations above, ‘Lesion Type’ should be ‘Non-nodal’ for the inclusion of 
response assessments. This list may be updated based on actual data of the lesion locations


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(and the description of lesion) at the time of analysis, as per scientific judgment of the medical
expert. Especially when the lesion location is ‘Other’, the description of lesion will be 
considered.  
The following steps will be taken to calculate the best overall intracranial response (BOIR) for 
patients with measurable brain metastases at baseline:
1. If only target lesion in brain and no non-target lesions in brain are identified at baseline, 
calculate the sum of the measured diameters from all target lesions in the brain (selected 
from list above), and use new lesions in brain (if any, based on the list) to derive responses 
per assessment. Non-target lesion response status is not considered since no non-target 
lesions were identified in the brain at baseline. 
2. If both target and non-target lesions in the brain are identified at baseline, calculate the 
sum of the measured diameters from all target lesions in the brain (selected from list 
above), use all non-target lesion response status in the brain (selected from list above) and 
new lesions in the brain (if any, based on the list) to derive responses per assessment. 
3. For each assessment, derive overall intracranial response. 
4. For the whole set of derived overall intracranial responses, calculate BOIR. 
For this subset of patients, calculate the OIRR.
4.7.4
Kaplan-Meier estimates
To analyze time-to-event endpoints (DOR, PFS and OS) an estimate of the survival function
will be constructed using Kaplan-Meier (product-limit) method as implemented in PROC 
LIFETEST with METHOD=KM option (see example below). The median time to event and 
estimated event rates at different time points will be estimated, along with associated 95% 
two-sided CIs derived based on the complementary log-log transformation. This will be 
conducted via the SAS procedure LIFETEST. The TIME statement will include a variable 
with survival times (survtime in the example below) and a (right) censoring variable (censor
in the example below) with a value of 1, representing censoring:
PROC LIFETEST DATA=dataset METHOD=KM CONFTYPE=LOGLOG;
    TIME survtime*censor(1);
RUN;
/* survtime represents variable containing event/censor times;
censor represents censoring variable (1=censored, 0=event); */
Kaplan-Meier survival and failure function estimates from this procedure will be used to 
construct the Kaplan-Meier figures.
Median time to event will be obtained along with two-sided 95% CIs calculated from PROC 
LIFETEST output using the method of Brookmeyer and Crowley, 1982.
Kaplan-Meier estimates with two-sided 95% CIs at specific time points will be summarized.  
The time points can be expressed in weeks or in months depending on the time-to-event 
endpoint. The CIs will be constructed using Greenwood’s formula (Collet, 1994, p.23) for the 
standard error of the Kaplan-Meier estimate.
The Kaplan-Meier graphs will be constructed using SAS software.


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4.7.5
Confidence interval for response rate
ORR, DCR and OIRR will be summarized in terms of percentage rates with 95% CIs. An 
exact binomial confidence interval (implemented using SAS procedure FREQ with EXACT 
statement for one-way tables) will be calculated (Clopper and Pearson, 1934).
SAS procedure FREQ will be used to estimate the proportion of responders (binary outcome = 
1 or ‘Yes’), along with the associated 95% (= 100 x (1 – two-sided alpha level of 0.05)) two-
sided Pearson-Clopper CI. These estimates are obtained as follows:
PROC FREQ DATA=dataset;
    TABLE binary-event / BINOMIAL(LEVEL=’Yes’) ALPHA=0.05;
    EXACT BINOMIAL;
RUN;
When there are no responders, SAS does not produce a CI by default. To obtain a CI in this 
situation, PROC FREQ is used as specified above except changing LEVEL=’No’. From the 
results of this modified procedure, the values in percent of the lower confidence limit (LCL)
and the upper confidence limit (UCL) of a 0% response rate are calculated as follows:
LCLLEVEL=’Yes’ (%) = 100% - UCLLEVEL=’No’ (%),
UCLLEVEL=’Yes’ (%) = 100% - LCLLEVEL=’No’ (%)
4.8
Safety evaluations
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Section 2.8.2.
4.8.1
Multiple assessments within post-baseline visits
For all analyses regarding abnormal assessments or analyses based on worst or best post-
baseline value (e.g., laboratory, ECGs, vital signs, ECOG performance status), all post-
baseline values will be included (scheduled, unscheduled, repeat) unless otherwise specified.
All unscheduled and repeat measurements will be included in listings.
Laboratory Data
Local laboratories will be used for laboratory evaluations in this study. However, if laboratory 
assessments are collected from both local and central laboratories on the same date, analyses 
are as follows. For shift tables using CTC grades to compare baseline to the worst post-
baseline value, the assessment with worst post-baseline value is used for analyses irrespective 
of the source. For LFT summaries, where concurrent measurements are used in the calculation 
of number and percentage of patients with worst post-baseline values, the assessment with 
worst post-baseline value is used (since worst values are based on the largest ratio of lab value 
to its ULN for each patient) although the worst values for the different parameters may be 
coming from different laboratories.


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ECGs
ECG data will be analyzed based on local laboratory reported results. At each scheduled time-
pint, the triplicate ECGs will be taken as per protocol and the summary (mean) of their 
measurements for each ECG parameter will be collected in the [12 Lead ECG Evaluation –
Local Analysis] eCRF page. Thus the mean of measurements associated with the scheduled
time point will be used for the analyses.
4.8.2
Baseline
As defined in Section 2.8.2, the last available assessment before or on the start date of study 
drug is defined as ‘baseline’ value or ‘baseline’ assessment.
Laboratory data 
Local laboratories will be used for laboratory evaluations in this study. However, if both local 
and central laboratory assessments are performed on the same date and corresponding to the 
baseline assessment date, then the central laboratory assessment will be used for the 
calculation of baseline.
ECGs 
Baseline for ECG measurement is the mean of the pre-dose replicate measurements on the
baseline day. For the calculation of the mean, unscheduled assessments will not be combined 
with scheduled assessments. The mean will be calculated separately for scheduled and 
unscheduled. Note in this study the mean of replicate measurements at each time point is 
collected on the [12 Lead ECG Evaluation – Local Analysis] eCRF page and thus individual 
measurements are not entered in the database.
Study day 1 scheduled pre-dose ECGs will be considered to have been obtained prior to study 
drug administration. If a scheduled pre-dose measurement actually occurred post-dose, then 
the corresponding measurement will be treated and analyzed similar to an unscheduled post-
dose measurement. Unscheduled assessments on study day 1 will be considered as post-
baseline.
4.8.3
Laboratory parameters
This section provides further detail on the analysis of laboratory parameters that will be listed 
and summarized as described in Section 2.8.2. 
Handling of test values below LLOQ and above HLOQ
For numeric laboratory parameters, test values below the lower limit of quantification 
(LLOQ) and above the higher limit of quantification (HLOQ) may show ‘<n’ (or ‘<=n’) and 
‘>n’ (or ‘>=n’) in the database respectively, where n can be any number. The classification of 
the CTC grades and the low/normal/high groups will follow a data handling rule: a value 
which shows ‘<n’ (or ‘<=n’) will be handled as zero; a value which shows ‘>n’ (or ‘>=n’) 
will be handled as n. These values will be presented in the listing as it is.


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Hematology
Hematologic tests include hemoglobin, platelets, white blood cells (WBC), red blood cells 
(RBC), and differential counts (basophils, eosinophils, lymphocytes, monocytes, neutrophils 
(% or absolute).
The following rules will be applied to derive the WBC differential counts when only 
percentages are available (this is mainly for neutrophils and lymphocytes, because CTC 
grading is based on the absolute counts). 
The method to convert the value is straightforward: for each patient, the original lab value (%) 
is divided by 100 and multiplied by WBC count, e.g., for neutrophils (NEU):
NEU count = (WBC count) x (NEU%value / 100)
In order to derive the corresponding absolute normal range, the rule to be applied depends on 
the availability of the % range and the absolute range for the differential:

If absolute range is NOT missing (% range is or is not missing), then use the absolute 
range provided by the site.

If % range is NOT missing and absolute range is missing, then the % normal limits (i.e., 
LLN and ULN) are divided by 100 and multiplied by the corresponding normal limits of 
WBC count, e.g., for neutrophils (NEU):
LLN for NEU count = (LLN for WBC count) x (LLN for NEU%value / 100),
ULN for NEU count = (ULN for WBC count) x (ULN for NEU%value / 100)
Biochemistry
The following calculation will be applied for corrected calcium (Ca) in SI unit:
Corrected Ca [mmol/L] = measured total Ca [mmol/L] + 0.02 x (40 – serum albumin [g/L]),
where 40 represents the average albumin level in g/L.
The normal limits (LLN and ULN) for corrected Ca will also be derived using the above
formula with the corresponding normal limits for total Ca and serum albumin.
4.9
Handling of missing or partial dates
For patients not known to have died prior to the analysis cut-off date:

All events with start date before or on the cut-off date, and with end date missing or after 
the cut-off date or after the date of withdrawal of informed consent will be reported as 
‘Continuing’. 

This approach applies, in particular, to AEs and concomitant medication reports. For these 
events, the end date will not be imputed and therefore will not appear in the listings.  
If imputation of an end date is required for a specific analysis (e.g., for a dose administration 
record with missing end date or last date of study drug after the cut-off date), the end date will 
be imputed to the min (analysis cut-off date, death date, withdrawal of informed consent date) 
for the purpose of calculating duration of exposure to study drug and dose intensity. The 
imputed date will be displayed and flagged in the listings.


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4.9.1
AE date imputation
Date imputation is the creation of a new, complete date from a partial one according to an 
agreed and acceptable algorithm. Missing date for AE will be handled according to rules 
specified below. A partial date is simply an incomplete date, e.g., DDOCT2001: the days are 
missing from this DDMMMYYYY date.
Partial AE start dates, if left partial, would ultimately mean the following
It would not be possible to place the AE in time.
Therefore the treatment/dosage at the time of the event would be unknown.
Therefore the event could not be reported/summarized appropriately – if at all.
Therefore it is important to perform date imputation to ensure that as many data events are 
represented as correctly as possible. Of course partial and/or missing dates should also be 
caught as edit checks and passed back to the investigator for resolution.
There will be no attempt to impute the following:

Missing AE start dates

AE start dates missing the year

Partial/missing AE end dates
The following Table 4-4 explains the abbreviations used.
Table 4-4
AE/treatment date abbreviations 
Day
Month
Year
Partial Adverse Event 
Start Date
<not used>
AEM
AEY
Treatment Start Date 
(TRTSTD)
<not used>
TRTM
TRTY
The following matrix Table 4-5 describes the possible combinations and their associated 
imputations. In the boxes the upper text indicates the imputation and the lower text the 
relationship of the AE start date to the treatment start date (TRTSTD).
Table 4-5
AE partial date imputation algorithm
AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY MISSING
NC
Uncertain
NC
Uncertain
NC
Uncertain
NC
Uncertain
AEY < TRTY
( D )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
AEY = TRTY
( B )
Uncertain
( C )
Before TRTSTD
( B )
Uncertain
( A )
After TRTSTD
AEY > TRTY
( E )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
The following Table 4-6 is the legend to the above table.


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Table 4-6
AE/treatment date relationship and imputation legend
Relationship
Before TRTSTD
Indicates AE start date prior to Treatment start date
After TRTSTD
Indicates AE start date after Treatment start date
Uncertain
Insufficient to determine the relationship of AE start date to 
Treatment start date
Imputation calculation
NC / Blank
No convention/imputation
( A )
01MONYYYY
( B )
TRTSTD+1
( C )
15MONYYYY
( D )
01JULYYYY
( E )
01JANYYYY
The following Table 4-7 gives a few examples.
Table 4-7
AE imputation example scenarios
Partial AE start 
date
Treatment start 
date
Relationship
Imputation
calculation
Imputed date
12mmyyyy
20OCT2001
Uncertain
NC
<blank>
ddmmm2000
20OCT2001
Before
( D )
01JUL2000
ddmmm2002
20OCT2001
After
( E )
01JAN2002
ddmmm2001
20OCT2001
Uncertain
( B )
21OCT2001
ddSEP2001
20OCT2001
Before
( C )
15SEP2001
ddOCT2001
20OCT2001
Uncertain
( B )
21OCT2001
ddNOV2001
20OCT2001
After
( A )
01NOV2001
4.9.2
Incomplete dates of initial diagnosis, first recurrence/progression and 
most recent relapse/progression
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 
01-Jan. 
4.9.3
Incomplete date for anti-neoplastic therapies
Prior therapies
Start date: 
The same rule which is applied to the imputation of AE/concomitant medication start date will 
be used with the exception that for scenario (B) will be replaced to be ‘start date of study drug 
-1’.
End date:
Imputed date = min (start date of study drug, last day of the month), if day is missing;
Imputed date = min (start date of study drug, 31DEC), if month and day are missing.


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If the end date is not missing and the imputed start date is after the end date, use the end date 
as the imputed start date.
If both the start date and the end date are imputed and if the imputed start date is after the 
imputed end date, use the imputed end date as the imputation for the start date.
Post therapies
Start date:
Imputed date = max (last date of study drug + 1, first day of the month), if day is missing;
Imputed date = max (last date of study drug + 1, 01JAN), if day and month are missing. 
End date: 
No imputation. 
4.9.4
Incomplete assessment dates for tumor assessment
All investigation dates (e.g., X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
the incomplete date(s) are not considered for calculation of the assessment date and 
assessment date is calculated as the latest of all investigation dates (e.g., X-ray, CT-scan) if 
the overall lesion response at that assessment is CR/PR/SD/UNK. Otherwise, if overall lesion 
response is PD, the assessment date is calculated as the earliest date of all investigation dates 
at that evaluation number. If all measurement dates have no day recorded, the 1st of the month 
is used. 
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between the previous and the following 
assessment. If both a previous and following assessments are not available, this assessment 
will not be used for any calculations. 
4.9.5
Incomplete date for death or last contact
All dates must be completed with day, month and year.
If the day or month is missing, death will be imputed to the maximum of the full (non-
imputed) last contact date (excluding the date of death) and the following:

Missing day:
15th day of the month and year of death

Missing day and month:
July 1st of the year of death
If the day is missing from the date of last contact, it will be imputed to the 15th day of the 
month and year of last contact only if derived from the survival page. 
4.9.6
Incomplete date for disease progression on alectinib prior to the start 
of study drug. 
If day of progression associated with the [Prior Antineoplastic Therapy – Alectinib] eCRF
page is missing then the imputed PD date is:


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= min (midpoint between the end date of the prior alectinib medication and the end of the 
month, start date of LDK), if end date of prior alectinib medication is in the same month 
as the PD date. 
= min (15th of the month of the PD date, start date of LDK), if end date of prior alectinib 
medication is in a month prior to the PD date. 
= 15th of the month of the PD date, if end date of alectinib medication is in a month after 
the PD date. 
If both day and month of progression associated with the [Prior Antineoplastic Therapy –
Alectinib] eCRF page is missing then the imputed PD date is:
= min (midpoint between the end date of the prior alectinib medication and the end of the 
year, start date of LDK), if end date of prior alectinib medication is in same year as the PD 
date.
= min (July 1 of the year of the PD date, start date of LDK), if end date of prior alectinib 
medication is in a year prior to the PD date. 
= July 1 of the year of the PD date, if end date of prior alectinib medication is in a year 
after the PD date. 
Completely missing PD dates will not be imputed. For the midpoint calculation, if odd days in 
between (e.g., last dose of alectinib is 27 June 2012, and end of the month is 30 June 2012), 
then use the next day from the midpoint calculation (e.g., midpoint is 29 June 2013). 
4.9.7
Incomplete date for last dose of study drug
Scenario 1 
If the last date of study drug is after the analysis cut-off date or is completely missing and 
there is no [End of Treatment Phase Disposition] eCRF page and no death date, the patient 
should be considered to be on-going and use the cut-off date for the analysis as the last dosing 
date.
Scenario 2 
If the last date of study drug is completely or partially missing and there is EITHER an [End 
of Treatment Phase Disposition] eCRF page OR a death date available then imputed last dose 
date:
= 31DECYYYY, if only Year is available and Year < Year of min (EOT visit date, death 
date).
= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT visit date, death date) and Month < the month of min (EOT visit date, death date)
= min (EOT visit date, death date), for all other cases
The imputed date will be compared with start date of study drug. If the imputed date < start 
date of study drug, then last date of study drug is set to start date of study drug; otherwise, use 
the imputed date.


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