Clinical trial NCT01742286
Conditions: ALK-activated Tumors
Keywords: LDK378 Ceritinib pediatric malignancies anaplastic lymphoma kinase ALK ALK-activated tumors neuroblastoma rhabdomyosarcoma anaplastic large-cell lymphoma inflammatory myofibroblastic tumor
Sponsor: Novartis Pharmaceuticals
Start date: 2013-08-28; Completion date: 2019-04-26
Enrollment: 83 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to estimate the maximum tolerated dose and/or recommended dose for expansion of LDK378 as a single agent, assess safety, tolerability and anti-tumor activity and characterize single and multiple-dose pharmacokinetics when administered orally to pediatric patients with ALK-activated tumors, with and without food.

Detailed description:
LDK378 is a novel inhibitor of ALK that is active in a broad range of ALK-activated tumor models, including models driven by mutated versions of ALK known to be resistant to crizotinib, and by ALK gene amplification.

The primary purpose of this study was to determine the maximum tolerated dose and/or recommended dose for expansion in pediatric patients, and to delineate a clinical dose to be used in any future pediatric studies, with and without food. This study also assessed the safety, tolerability, PK and preliminary evidence of antitumor activity of LDK378 in pediatric patients with neuroblastoma, and other ALK-activated tumors.

Fasted cohort: each daily dose of LDK378 (including days which involved PK blood sampling) was taken at least 2 hours after last meal \& subjects did not eat until 1 hour after LDK378 was taken. Each daily dose of LDK378 was taken with 1-2 tablespoons (15-30 mL) of an appropriate food (such as applesauce or non-fat yogurt) \& a glass of water

Fed cohort: each daily dose of LDK378 (including days which involved PK blood sampling) was taken with, or within 30 minutes after finishing a low-fat light snack containing 100-300 calories \& 1.5-2 grams of fat.

Arms: arm 1: All participants were administered a single-agent LDK378 (Ceritinib) orally, once daily, continuously in fasted or fed conditions.
Interventions: intervention 1: Ceritinib
Intervention descriptions: intervention 1: LDK378 is a capsule taken by mouth, contents can be mixed with food for pediatric patients or mixed with water and given via nasogastric/gastric (NG/G) tube. For patients in fasted group: 1-2 tablespoons (15-30 mL) of an appropriate food such as apple sauce or non-fat yogurt and a glass of water were allowed.

For patients in the fed cohort: LDK378 was taken with, or within 30 minutes after finishing a low-fat light snack containing 100-300 calories and 1.5-2 grams of fat.

Protocol documents:
Prot_000.pdf: 
Clinical Development
LDK378 (ceritinib)
Protocol CLDK378X2103 / NCT01742286
A Phase I, open-label, dose escalation study of LDK378 in 
pediatric patients with malignancies that have a genetic 
alteration in anaplastic lymphoma kinase (ALK)
Authors
Document type
Amended Protocol Version
EUDRACT number
2012-002074-31
Version number
08 (Clean)
Development phase
I
Document status
Final
Release date
18-May-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
 


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................7
List of tables ........................................................................................................................7
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................12
Amendment 8 (18-May-2018)...........................................................................................13
Amendment 7 (24-Jan-2017).............................................................................................15
Amendment 6 ....................................................................................................................17
Amendment 5 ....................................................................................................................18
Summary of previous amendments ...................................................................................21
Protocol summary..............................................................................................................31
1
Background........................................................................................................................35
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............35
1.2
Introduction to investigational treatment(s) and other study treatment(s).............36
1.2.1
Overview of LDK378 ...........................................................................36
2
Rationale............................................................................................................................43
2.1
Study rationale and purpose...................................................................................43
2.2
Rationale for the study design ...............................................................................44
2.3
Rationale for dose and regimen selection..............................................................45
2.4
Rationale for choice of combination drugs............................................................46
2.5
Rationale for choice of comparators......................................................................46
2.6
Risks and benefits..................................................................................................46
3
Objectives and endpoints...................................................................................................49
4
Study design ......................................................................................................................52
4.1
Description of study design ...................................................................................52
4.2
Timing of interim analyses and design adaptations...............................................54
4.3
Definition of end of the study................................................................................54
4.4
Early study termination..........................................................................................54
5
Population..........................................................................................................................54
5.1
Patient population..................................................................................................54
5.2
Inclusion criteria ....................................................................................................55
5.3
Exclusion criteria...................................................................................................55
6
Treatment...........................................................................................................................58
6.1
Study treatment......................................................................................................58
6.1.1
Dosing regimen.....................................................................................58
 


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6.1.2
LDK378 administration ........................................................................58
6.1.3
Treatment duration................................................................................59
6.2
Dose escalation guidelines.....................................................................................59
6.2.1
Starting dose rationale...........................................................................60
6.2.2
Provisional dose levels..........................................................................60
6.2.3
Guidelines for dose escalation and determination of (MTD/RDE) ......61
6.2.4
Definitions of dose limiting toxicities (DLTs)......................................63
6.3
Dose modifications................................................................................................64
6.3.1
Dose modification and dose delay ........................................................64
6.3.2
Follow-up for toxicities.........................................................................73
6.4
Concomitant medications ......................................................................................78
6.4.1
Permitted concomitant therapy .............................................................78
6.4.2
Prohibited concomitant therapy ............................................................79
6.5
Patient numbering, treatment assignment or randomization .................................81
6.5.1
Patient numbering .................................................................................81
6.5.2
Treatment assignment or randomization...............................................81
6.6
Study drug preparation and dispensation...............................................................81
81
6.6.2
Drug supply and storage........................................................................82
6.6.3
Study drug compliance and accountability ...........................................82
6.6.4
Disposal and destruction .......................................................................82
7
Visit schedule and assessments .........................................................................................82
7.1
Study flow and visit schedule................................................................................82
7.1.1
Molecular pre-screening and screening examination............................88
7.1.2
Treatment period...................................................................................89
7.1.3
End of treatment visit............................................................................89
7.1.4
Follow-up period...................................................................................92
7.1.5
Lost to follow-up...................................................................................92
7.2
Assessment types...................................................................................................92
7.2.1
Efficacy .................................................................................................92
7.2.2
Safety and tolerability ...........................................................................93
7.3
Pharmacokinetics...................................................................................................98
7.3.1
Pharmacokinetic blood sample collection and handling.......................98
100
100
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Safety monitoring and reporting......................................................................................101
8.1
Adverse events.....................................................................................................101
8.1.1
Definitions and reporting ....................................................................101
8.1.2
Laboratory test abnormalities..............................................................103
8.1.3
Adverse events of special interest.......................................................103
8.2
Serious adverse events.........................................................................................103
8.2.1
Definitions...........................................................................................103
8.3
Data Monitoring Committee................................................................................105
8.4
Steering Committee .............................................................................................105
9
Data collection and management.....................................................................................106
106
9.2
Site monitoring ....................................................................................................106
9.3
Data collection.....................................................................................................107
9.4
Database management and quality control..........................................................107
10 Statistical methods and data analysis ..............................................................................107
10.1
Analysis sets ........................................................................................................108
10.1.1
Full analysis set...................................................................................108
10.1.2
Safety set .............................................................................................108
10.1.3
Per-protocol set ...................................................................................108
10.1.4
Dose-determining analysis set.............................................................108
10.1.5
Pharmacokinetic analysis set...............................................................108
109
10.2
Patient demographics/other baseline characteristics ...........................................109
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................109
10.3.1
Study treatment ...................................................................................109
10.3.2
Concomitant therapies.........................................................................109
109
10.4
Primary objective.................................................................................................109
10.4.1
Variable...............................................................................................109
10.4.2
Statistical hypothesis, model, and method of analysis........................110
10.5
Handling of missing values/censoring/discontinuations .....................................111
10.6
Supportive analyses .............................................................................................112
10.7
Secondary objectives ...........................................................................................112
10.7.1
Safety objectives .................................................................................112
10.7.2
Pharmacokinetics ................................................................................113
10.7.3
Efficacy ...............................................................................................114
 


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116
116
116
116
10.9
Interim analysis....................................................................................................117
10.10 Sample size calculation........................................................................................117
10.10.1
Dose Escalation...................................................................................117
10.10.2
Dose Expansion...................................................................................117
10.11 Power for analysis of key secondary variables....................................................118
11 Ethical considerations and administrative procedures ....................................................118
11.1
Regulatory and ethical compliance......................................................................118
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................118
11.3
Informed consent procedures...............................................................................118
11.4
Discontinuation of the study................................................................................119
11.5
Publication of study protocol and results.............................................................119
11.6
Study documentation, record keeping and retention of documents.....................119
11.7
Confidentiality of study documents and patient records .....................................120
11.8
Audits and inspections.........................................................................................120
11.9
Financial disclosures............................................................................................120
12 Protocol adherence ..........................................................................................................120
12.1
Amendments to the protocol................................................................................120
13 References (available upon request)................................................................................122
14 Appendices ......................................................................................................................125
125
125
125
127
128
131
134
135
14.3
Appendix 3: Karnofsky Performance Status Scale (for patients greater than 
12 years old) ........................................................................................................138
14.4
Appendix 4: Lansky score (for patients less than or equal to 12 years old)........139
 


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14.5
Appendix 5: Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
Harmonization of Efficacy Analysis of Solid Tumor Studies.............................140
14.6
Appendix 6: Guidelines for efficacy evaluation in lymphoma studies (based 
on Cheson response criteria). International Working Group guidelines for 
hematological malignancies.................................................................................165
Appendix A: Definition of index nodal lesion, non-index nodal lesion, index 
extranodal lesion, non-index extranodal lesion ...................................................184
Appendix B: Calculation of the response for index lesions ............................................186
Appendix C: Calculation of the response for non-index lesions.....................................188
Appendix D: Calculation of the overall disease response...............................................190
Appendix E: Adaptation for use in maintenance/adjuvant settings.................................192
 


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List of figures
Figure 4-1
Overview of study design......................................................................53
Figure 14-1
Dose-DLT scenarios tested .................................................................129
List of tables
Table 1-1
All grades (at least 10%) and associated grade 3-4 adverse events, 
regardless of study drug relationship, by preferred term in patients 
treated in the 750 mg dose group (Data cut-off date: 
).....39
Table 1-2
Summary of best overall response based on investigator assessment 
in NSCLC patients in the 750 mg dose group, by prior ALK 
inhibitor status (Full Analysis Set NSCLC 750 mg) (Cut-off date: 
).........................................................................................42
Table 3-1
Objectives and related endpoints ..........................................................50
Table 6-1
Provisional dose levels for fasted pediatric dose escalationa ................60
Table 6-2
Criteria for defining dose-limiting toxicities.........................................63
Table 6-3
Dose reduction steps for LDK378 at RDE (fasted and fed states)........65
Table 6-4
Criteria for interruption and re-initiation of LDK378 treatment...........67
Table 6-5
Follow up evaluations for selected toxicities........................................77
Table 7-1
Visit evaluation schedule ......................................................................84
Table 7-2
Maximum blood volumes .....................................................................95
Table 7-3
Local clinical laboratory parameters collection plan ............................96
Table 7-4
Central ECG collection plan .................................................................98
Table 7-5
Pharmacokinetic blood collection log – dose escalation (fasted and 
fed) ........................................................................................................99
Table 7-6
Pharmacokinetic blood collection log – dose expansion (fasted and 
fed) ......................................................................................................100
101
Table 10-1
Noncompartmental pharmacokinetic parameters................................114
 
126
127
127
129
130
131
133
 


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135
136
136
137
Table 14-12
Table radiological status based on SPD calculation for all index 
lesions..................................................................................................171
Table 14-13
Radiological response criteria for index extranodal lesions in case 
of CR in index nodal lesions...............................................................171
Table 14-14
Radiological response for index lesions..............................................172
Table 14-15
Response criteria for non-index lesions (nodal, splenic and/or 
hepatic nodules and other extranodal lesions) ....................................173
Table 14-16
Overall radiological response at each assessment...............................174
Table 14-17
Censoring reasons ...............................................................................180
Table 14-18
Options for event dates used in PFS, TTP, duration of response........181
 


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List of abbreviations
AE
Adverse event
ALCL
Anaplastic large cell lymphoma
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
ATC
Anatomic therapeutic chemical
AUC
Area under the plasma (serum, or blood) concentration versus time curve
AUClast
Area under the concentration-time curve from time zero to the last measureable 
concentration time
AUCtau
Area under the plasma (serum, or blood) concentration versus time curve from time zero 
to end of dosing period
BCRP
Breast cancer resistance protein
BLRM
Bayesian logistic regression model
BOR
Best overall response
BSA
Body surface area
BUN
Blood urea nitrogen
CDP
Clinical development plan
CI
Confidence interval
CL
Clearance
Cmax
Maximum (peak) concentration of drug
Cmin
Minimum (trough) concentration of drug
CMV
Cytomegalovirus
CNS
Central nervous system
CR
Complete response
CRO
Contract Research Organization
CRP
C-reactive protein
CSF
Cerebrospinal fluid
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DAR
Dosage Administration Record (DAR)
DDS
Dose-determining set
DILI
Drug Induced Liver Toxicity
DLT
Dose limiting toxicity
DM
Data manager/data management
DOR
Duration of response
DS & E
Drug safety and epidemiology
EBV
Epstein-Barr virus
EC
Ethics committee
ECG
Electrocardiogram
 


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eCRF
Electronic Case Report Form
EDC
Electronic data capture
EMEA
European Medicines Agency
EML4-ALK
Echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase
EOT
End of treatment
EWOC
Escalation with overdose control
F
Bioavailability
FAS
Full analysis set
FCBP
Females of childbearing potential
FDA
Food and Drug Administration
FISH
Fluorescent in situ hybridization
FSH
Follicle-stimulating hormone
G
Gastric
GCP
Good Clinical Practice
GI
Gastrointestinal
HA
Health Authorities
HED
Human equivalent dose
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
HSV
Herpes simplex virus 
IC50
Half maximal (50%) inhibitory concentration
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease
IMT
Inflammatory myofibroblastic tumor
IRB
Institutional Review Board
IV
Intravenous(ly)
Ki
Inhibition constant
LDH
Lactate dehydrogenase
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MIBG
Metaiodobenzylguanidine
MRI
Magnetic resonance imaging
MRP2
Multidrug resistance protein 2
MTD
Maximum tolerated dose
N/A
Not applicable
NCI
National Cancer Institutes
NG
Naso-gastric
NPM
Nucleophosmin
NPM-ALK
Nucleophosmin-anaplastic lymphoma kinase
NSCLC
Non-small cell lung cancer
ORR
Overall response rate
 


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PAS
Pharmacokinetic Analysis Set
PD
Progressive disease
PFS
Progression-free survival
PHI
Protected health information
PI
Principal investigator
PK
Pharmacokinetics
PR
Partial response
PRBC
Packed red blood cells
qd
quaque diem/once daily
QTc
Corrected QT interval
QTcF
Corrected QT interval using Fridericia formula
R Value
ALT/ALP in X ULN
Racc
Accumulation ratio
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence 
of preplanned analysis
RDE
Recommended dose for expansion
REB
Research Ethics Board
RECIST
Response Evaluation Criteria In Solid Tumors
RP2D
Recommended phase two dose
SAE
Serious adverse event
SD
Stable disease
SEC
Study evaluation completion
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
STAT3
Signal transducer and activator of transcription 3
SUSARs
Suspected unexpected serious adverse reactions
T1/2
Half-life
T1/2,acc
Effective half-life calculated from Racc
TBIL
Total bilirubin
TI
Therapeutic index
TKD
Tyrosine kinase domain
Tmax
The time to reach maximum plasma concentration
ULN
Upper limit of normal
USPI
United States Package Insert
Vss
Steady state volume of distribution
WBC
White blood count
 


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biological Samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. obtained from a study subject or study 
patient
Cohort
A group of patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., 21 days)
Enrollment
Point/time of patient entry into the study; the point at which molecular 
pre-screening or main informed consent must be obtained (i.e., before 
starting any of the study procedures described in the protocol)
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.
Personal Data
Patient information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
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
LDK378 discontinuation
Point/time when patient permanently stops taking LDK378 for any 
reason; 
Variable
A quantity subject to variation of values used in the data analysis; 
derived directly or indirectly from data collected using specified 
assessments at specified time points
Withdrawal of Consent
Withdrawal of consent from the study occurs only when a patient does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data
 


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Amendment 8 (18-May-2018)
Amendment rationale
Interim safety, efficacy and pharmacokinetics data for this study have been presented 
previously for both the fasted (n=22 patients) and fed (n=22 patients) cohorts, and no 
particular safety concerns have been identified (Geoerger et al, 2015, Fischer et al, 2016). 
Recruitment of all planned patients was completed in October 31, 2017; eighty-three patients 
have been enrolled in total and treated in both escalation and expansion phases. As of release 
of this amendment (18-May-2018), the study has been ongoing for approximately 5 years and 
3 months and twelve patients are still on treatment and currently ongoing.
The main purpose of this global amendment is to allow patients who are still deriving clinical 
benefit from study treatment as per the investigator to be transitioned to a separate rollover 
study or another option for continued treatment with LDK378 (i.e. managed access program), 
as soon as they become available. The end of study will occur once: 

All patients have discontinued study treatment and completed the required Study 
Evaluation Completion (SEC) follow-up visit, or 

All patients have died, been lost to follow-up, have withdrawn consent, or the last patient 
has been enrolled into a separate rollover study (or other option for continued study 
treatment), whichever comes first  
As per original protocol, a primary analysis and clinical study report (CSR) were to prepared 
after all patients have completed at least 6 cycles of treatment or discontinued the study. 
Given interim data have been presented previously, and at the time of this amendment all 
patients already have completed at least 6 cycles of treatment and will be allowed to be 
transitioned into a separate rollover study (or other options for continued study treatment 
access), a single final analysis/CSR will be conducted once the end of study criteria are met. 
In addition, format and grammatical corrections are made throughout the protocol to improve 
flow and consistency.
Changes to the protocol

Glossary of terms has been updated to align with the new Withdrawal of Consent 
language 

Section 4.3: Text has been updated to allow patients’ transition to the rollover study or 
other options for continued treatment. It has been clarified that a CSR will be prepared at 
the end of the study. 

Table 6-4: Text has been updated to remove the PK sample collection in case of QTc 
prolongation Grade 3

Section 6.3.2.2: Text has been updated to remove the PK sample collection in case of liver 
laboratory abnormalities

Section 7.1.3.2: Text has been updated to align with the new Withdrawal of Consent 
language 
 


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
Section 10: Text has been clarified that analysis and CSR will be prepared at the end of 
the study.
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. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
 


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Amendment 7 (24-Jan-2017)
As of release of this amendment (4-Jan-2017), the recruitment is still ongoing. In total, sixty-
six patients have been enrolled and treated in both escalation and expansion phases. The 
escalation phase is now closed to enrollment and the expansion phase is currently recruiting. 
Eighteen patients are currently ongoing.
The primary purpose of this amendment is to address 
 concerns regarding 
the cardiac safety monitoring conducted until Cycle 6 only and not afterwards for patient who 
remain on treatment, and the recent changes at Cycle 1 Day 1 (ECG monitoring at 4 and 6 
hours post first dose of study drug) for the patients to be treated in the expansion phase of the 
study. Novartis decided to strengthen the cardiac safety monitoring:   all patients will be 
monitored with an ECG at Cycle 1 Day 1 (4-h post dose and 6-h post dose), and at each first 
day of every cycle of treatment. The ECG collection is expanded throughout the entire 
treatment duration. This is done in alignment with the ceritinib cardiovascular safety 
monitoring recommendations. 
In addition, guidelines for dose modification in case of Grade 3 transaminases elevation are 
clarified, allowing patients to stay in the study in case of a re-occurrence of Grade 3 ALT or 
AST elevation after a dose reduction as allowed across the ceritinib development program in 
adults patients. This is to avoid unnecessary withdrawal of patients who may continue to 
derive clinical benefit from ceritinib.
The guidelines in relation to concomitant medications use are also clarified to optimize the 
patient’s safety.
Moreover, ALK status inclusion criterion is clarified and it is specified that 15% threshold for 
rearrangement is applicable only when assessed by FISH. Furthermore the ALK tyrosine 
kinase domain (TKD) mutation inclusion criterion is simplified.
At last, editorial changes and text corrections were made for clarification, where required.
Changes to the specific section of the protocol are shown in the track changes version of the 
protocol using red strike through font for deletions and red underlined font for insertions.
The following sections were updated:

List of abbreviations: updated.

Amendment 6 IRB/IEC/REB Approval: the wording was revised.

Section 5.2: updated to clarify ALK status inclusion criteria in case of rearrangement and 
simplify description of ALK TKD mutation accepted for inclusion.

Section 6.1.3: wording revised to bring more clarity.

Table 6-4 Criteria for interruption and re-initiation of LDK378 treatment: revised to delete 
the criteria of permanent discontinuation of the patients from LDK378 in case a Grade 3 
AST/ALT reoccurs after dose reduction.

Section 6.4.1.5: Permitted concomitant medication-Palliative radiotherapy and surgery: 
modified to align with other ceritinib protocols.

Table 7-1: ECG collection schedule modified to include assessments at each on-site visit.
 


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
Table 7-4: revised to capture collection of ECG at all visits (including 4h and 6h post dose 
at C1D1 in the expansion phase) up to Cycle 16, then at each on-site visit (even number 
cycles post cycle 18) and up to End Of Treatment included.

Appendix 2: Aligned Lists of prohibited concomitant medications (Table 14-8), 
concomitant medications requiring caution with LDK378 (Table 14-9) and prohibited 
enzyme-inducing anti-epileptic drugs (Table 14-10) to align with the ceritinib protocol
language.
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. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
 


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Amendment 6
The dose escalation phase of this study has been completed and 40 patients have been 
enrolled and treated (25 fasted and 15 fed). Similar recommended LDK378 doses (RDE) were
established for both fasted state (510 mg/m2 once daily, declared on 4 Dec 2014), and fed 
state (500 mg/m2 once daily, declared on 12 April 2016). As fed state is more convenient for 
pediatric patients, it has been decided to complete the recruitment of the expansion phase 
using this preferred regimen only. The expansion phase, to confirm the dose, is currently 
recruiting and as of 22 September 16, 20 patients have been enrolled (7 fasted and 13 fed). 
Overall, 19 patients are currently ongoing in total (6 recruited in escalation phase and 13 in 
the expansion phase).
The primary purpose of this amendment is to revise the dose reduction steps for LDK378. 
Considering the recommended doses established for fed and fasted state are similar, the dose 
reduction schedule has been revised to be applicable for both states.
In addition, the schedule of assessments has been revised to reduce frequency of on-site visits 
after cycle 16: on-site visits on day 1 of odd numbered cycles are replaced by phone calls and 
local laboratory tests for safety assessments. 
Moreover, the pre-dose PK sample and the post-dose ECGs collection at Cycle 1 Day 1 have 
been removed in the expansion phase as they were no longer required at this time point as no 
correlation is planned in the expansion.
At last, editorial changes and text corrections were made for clarification, where required.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using red strike through font for deletions and red underlined font for insertions.
The following sections were updated:

Section 6.3.1: Table 6-3 dose reduction steps for LDK378 was revised based on the 
recommended dose for expansion

Table 7-1: revised to include telephone call and local laboratory tests  instead of on-site 
visits on day 1 of odd numbered cycles from Cycle 17 

Section 7.2.2: revised to include information about monitoring of patients’ safety by 
phone call

Section 7.2.2.5.4, Table 7-4: Cycle 1 Day1 4-hour and 6-hour post-dose ECG collections 
have been specified as not needed in the expansion phase as no longer required

Section 7.3.1, Table 7-6: Expansion Cycle 1 Day1 pre-dose PK sample has been removed 
as no longer required

Section  8.1.1: revised to capture collection of downgrading Adverse Events in the CRF
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.
 


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Amendment 5
Amendment rationale
The study was initiated in February 2013. The dose escalation phase of this study for the 
fasted state has been completed and the recommended LDK378 dose was established at 510 
mg/m2 administered orally once daily. The dose escalation phase for the fed state is still 
ongoing. As of 17 February 2016, 40 patients were treated in the dose escalation phase of the 
study (fed and fasted) and 5 in the expansion phase (fasted). Of the 45 patients who entered 
the treatment phase, 34 patients discontinued treatment.
The primary purpose of this amendment is to clarify the LDK378 dose modification 
recommendations, the guidelines for follow up of toxicities to LDK378 (including follow up 
evaluations for hepatic toxicities and work up guidelines for potential DILI cases) and the use 
of concomitant medications in order to optimize the patient safety. Furthermore, this 
amendment provides updated parameters for study visits for patients who are on study drug 
for more than 14 cycles. This was done in an effort to decrease the burden on the patient after 
a set number of cycles on study drug.
 
 
In addition, the definition of highly effective contraception and the time period for using it 
have been updated, as well as the reporting period for pregnancy that has been revised to 3 
months.
At last, editorial changes and text corrections were made for clarification, where required.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using red strike through font for deletions and red underlined font for insertions.
The following sections were updated:

List of abbreviations: updated

Glossary of terms: updated

Protocol Summary: updated to match exclusion criteria list from section5.3

Section 1.2.1: Inclusion of FDA approval of LDK378 (ceritinib) under trade name of 
Zykadia

Section 1.2.1.2: Clinical experience updated from data available from ongoing clinical 
studies
 

Figure 4-1: number of patients for fed escalation corrected

Section 5.3 Exclusion criteria: time period for using highly effective contraception and 
highly effective contraception methods have been revised

Section 6.1.3 Treatment duration: Modified to allow patients who have disease 
progression, but who have evidence of continued clinical benefit from LDK378, to 
 


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continue receiving the study treatment. General rules for dose interruption and 
discontinuation were clarified.

Section 6.2.4 : dose modification recommendations related to Dose Limiting Toxicities 
(DLTs) were moved from section 6.3 to this section

Table 6-2: Reference to table 6-5 for additional follow up of toxicities was added

Section 6.3.1: Dose modification and dose delay were aligned to match with other 
LDK378 protocols. In particular, addition of dose reduction steps for LDK378 fasted state 
(Table 6-3) and criteria for the interruption and re-initiation of LDK378 treatment based 
on updated safety information (Table 6-4), including addition of follow up guidance for 
AST or ALT and concurrent total bilirubin elevation, and for Electrocardiogram QT 
corrected (QTc) interval prolonged.

Section 6.3.2- Follow-up for toxicities: modified to align with other LDK378 protocols. 
Table 6-3 replaced by the following sections:

Section 6.3.2.1: Guidelines for the follow-up of laboratory hematologic abnormalities, 
including addition of guidance for concomitant use of hematopoietic growth factors

Section 6.3.2.2: Guidelines for the follow-up of liver laboratory abnormalities, 
including guidelines for potential drug-induced liver injury

Section 6.3.2.3: Guidelines for the follow-up of renal laboratory abnormalities

Section 6.3.2.4: Guidelines for monitoring pneumonitis

Section 6.3.2.5: Guidelines for the treatment of study treatment-induced diarrhea

Section 6.3.2.6: Guidelines for the treatment of study treatment -induced nausea and 
vomiting

Section 6.3.2.7: Guidelines for the treatment of hypophosphatemia

Section 6.3.2.8: Guidelines for the follow up of laboratory pancreatic abnormalities

Table 6-5 Follow up evaluations for selected toxicities

Section 6.4: Concomitant medications was updated with permitted and prohibited 
therapies

Table 7-1 Reduction of radiological tumor evaluation and MIBG imaging schedule post 
cycle 14. Clarification about collection of Bone marrow bilateral aspirate and biopsy after 
screening evaluation. Clarification of screening ALK testing process and collection of 
tumor sample at screening and end of treatment visits. Addition of meal record (already 
collected in the CRF but not mentioned in Table 7-1).

Section 7.1.1.1.2: Clarification of screening ALK testing process

Section 7.1.3 Clarification for MIBG and bone marrow aspirate protocol requirements; 
End of treatment visit: Modified to allow patients who have disease progression, but who 
have evidence of continued clinical benefit from LDK378, to continue receiving the study 
treatment.

Section 7.1.3.2: Withdrawal consent section added

Section 7.1.5: Lost to follow up section added

Section 7.2.1: the frequency of tumor assessment was reduced post Cycle 14. Clarification 
about collection of Bone marrow bilateral aspirate and biopsy after screening evaluation. 
 


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Addition of the option to stop collecting MIBG scans after screening if it becomes 
negative on 2 consecutive assessments and the concomitant tumor assessments 
demonstrate a complete or partial response.

Section 7.3.1: Updated with capture of meal records

Section 7.4.1: Clarification about sample collection date

Table 7-7: Updated with more precise information about collection timepoint of tumor 
biopsy at End Of Treatement

Section 8.1.3: section created for AEs of special interest

Section 8.2.1: Clarification about the pregnancy which should be followed up from the 
estimated date of delivery plus 3 months

Section 10.1.5: Clarification about the pharmacokinetic analysis set

Section 10.7.2: Clarification about PK analyses

Table 10-1: Alignment with section 10.7.2

Section 11.3: Added the use of highly effective methods of contraception must be carried 
on during dosing and 3 months after stopping dosing to match exclusion criteria.

Appendix 2: Aligned Lists of prohibited concomitant medications (Table 14-1), 
concomitant medications requiring caution with LDK378 (Table 14-2) and prohibited
enzyme-inducing anti-epileptic drugs (Table 14-3) to match with other LDK378 protocols.

Editorial changes and text corrections have been made in the following sections: 
Amendment 1 rationale, 1.1, 4.3, 6.2.4, Table 6-2, 7.1.3, 9.2, 10.7.3, Appendix 5.
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, 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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Summary of previous amendments
Amendment 4
Amendment rationale
Under this amendment, a consistent approach is being implemented across ongoing studies 
with LDK378 to monitor and manage safety signals identified as the clinical experience with 
LDK378 has grown. Specifically, changes are made that address hepatic toxicity, pancreatitis 
and pneumonitis. The protocol has therefore been amended:

to exclude patients with history of pancreatitis or history of increased amylase or lipase 
that was due to pancreatic disease

to include additional dose modification and follow-up monitoring language for patients 
who may experience pancreatic enzyme elevations in the absence of clinical symptoms

to update dose modification language and the guidelines for the management of hepatic 
toxicity

to specify that for patients meeting biochemical criteria for Hy’s law (AST or ALT >3.0 x 
ULN and total bilirubin >2.0 x ULN in the absence of cholestasis or hemolysis), study 
treatment must be permanently discontinued

to update adverse events of special interest including hepatotoxicity, interstitial lung 
disease/pneumonitis, 
QT 
interval 
prolongation, 
bradycardia, 
hyperglycemia, 
gastrointestinal toxicity (nausea, vomiting and diarrhea) and pancreatitis (including lipase 
and amylase elevations).
Hyperglycemia has also been observed in patients treated with LDK378. Patients with 
abnormally high fasting glucose levels are now excluded from participating in this study. For 
consistency across the LDK378 program clinical trials, other changes as outlined below have 
been made to dose modifications for patients who experience toxicity.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using red strike through font for deletions and red underlined font for insertions.
Protocol Summary

Updated exclusion criteria to reflect new pancreatic and hepatic safety parameters
Section 1.2.1.2 Clinical Experience

Updated to delineate overall Adverse Event occurrence and to denote adverse events of 
interest
Section 5.3 Exclusion criteria

Updated exclusionary point 3 with further labs for safety

Added exclusionary point 21 to exclude patients with significant pancreatic history
Section 6.2.4 Definition of Dose Limiting Toxicities

Added clarity around DTLs and how to apply the follow up criteria
 


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Table 6-2 Dose limiting toxicities

Updated safety language for Hematology, hepatic, and pancreatic events
Section 6.3 Dose modifications

Provided additional clarity and parameters for study drug dose modifications, 
discontinuation, with special focus on pneumonitis, hepatic, renal and pancreatic toxicities
Table 6-3 Follow up toxicity guidelines

Updated follow up parameters for Hematology, hepatic, pancreatic and renal events
Section 8.1.1 Safety monitoring and reporting for adverse events, definitions and reporting

Updated with additional information on adverse events of interest
Table 7-3 Local clinical laboratory parameters collection plan

Updated with serum amylase, serum lipase and ALP
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
Amendment rationale
Gastrointestinal symptoms are the most common adverse events seen with LDK378, and 
dosing with food has been shown to improve the GI tolerability of other kinase inhibitors. 
However, a healthy volunteer study has shown that food increases LDK378 exposure. In order 
to evaluate the effect of dosing LDK378 with food in pediatric cancer patients, the protocol 
has been modified to include a fed state (low-fat light snack) dose escalation part following 
the determination of the fasted MTD/RDE. Further expansion at the fed MTD/RDE will be 
allowed if the safety, PK or efficacy suggest that administering LDK378 with food is 
preferred. The age range in the inclusion criteria has been changed to ‘up to 18’ to make it 
clear that patients are eligible until they turn18 years of age.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using red strike through font for deletions and red underlined font for insertions.
Protocol Summary

Updated purpose and rationale, objectives, and study design to reflect planned 
determination of the MTD of LDK378 in both fed and fasted states.

Clarified the nomenclature for inclusion of patients up to their 18th birthday.
Section 1.2.1.2.1 Clinical safety and tolerability

Updated to reflect most recent cardiac safety information
Section 1.2.1.2.3 Clinical pharmacokinetics

Updated to reflect most recent clinical pharmacokinetics data
Section 2.1 Study rational and purpose

Rationale added for a dose escalation arm in the fed state (low-fat snack).
Section 2.2 Rationale for the study design

Clarified the nomenclature for inclusion of patients up to their 18th birthday.
Section 2.3 Rationale for dose and regimen section

Added language describing planned rationale for the starting dose for fed dose escalation 
part.
Table 3-1 Objectives and related endpoints

Clarification added that the primary and secondary objectives and related endpoints will 
be evaluated in both the fed and fasted states.
Section 4.1 Description of study design

Updated to reflect addition of the fed dose escalation part and the addition of fed patients 
enrolled during expansion part.
 


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Figure 4-1: Overview of study design

Updated to reflect addition of the fed dose escalation part and the addition of fed patients 
enrolled during expansion part.
Section 6.1.2 LDK378 administration

Clarification of administration guidance for LDK378 in both the fasted and the fed states 
for patients who are able and unable to swallow capsules.
Section 6.2.2 Provisional dose levels

Language added to describe the plan for initiating a fed-state dose escalation part and 
opening the expansion part.
Section 6.2.3 Guideline for dose escalation and determination of MTD/RDE

Language added to allow for a fed-state dose escalation
Section 6.2.3.3 Change from Fasted to Fed Dosing

Language added to clarify the required parameters prior to allowing a patient enrolled on a 
fasted cohort to change to dosing with a low-fat snack.
Section 6.2.4. Definition of dose limiting toxicities

Clarification that DLTs are attributed during cycle 1
Section 6.4.2. Permitted concomitant therapy requiring caution

Update of medications that should be used with caution if needed during the study because 
of potential drug-drug interactions from LDK378 Investigator’s Brochure edition 7
Table 7-6 Pharmacokinetic blood collection log-dose expansion

Modification of sample collection for patients during dose expansion part
Section 10.4.2 Statistical hypothesis, mode, and method of analysis

Updated to reflect BRLM plan for the fed and fasted states. It will be used to estimate the 
dose-DLT relationships separately for fasted and fed patients.
Section 10.10.1 Dose Escalation

Updated to reflect plan for sample size calculation in the fed and fasted states
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
The following changes were requested 
:

To address the management of QTc prolongation separately from the broader array of 
DLTs a specific approach including a detailed monitoring plan, need for physician 
evaluation, and recommendations for dose reduction or permanent discontinuation have 
been added to Section 6.3.1. and Table 6-3.

Cases of pneumonitis/interstitial lung disease (ILD) have been reported with LDK378 in 
patients treated at the 750 mg dose level. Most cases improved or resolved with 
interruption of LDK378 and treatment with antibiotics and/or steroids. Fatal outcome of 
treatment-related pneumonitis has been reported. Exclusion criteria, the definition of dose 
limiting toxicity, and the guidance for dose modification have been amended to address 
this newly observed risk.
Background safety, efficacy and clinical pharmacology information was updated for 
consistency with the current LDK378 Investigator’s Brochure.
Due to the possibility that a dose level reduction in patients with a low BSA may not actually 
result in a calculated dose reduction due to rounding, the protocol has been modified to 
require a minimum dose reduction of 50mg.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using red strike through font for deletions and red underlined font for insertions.
Protocol Summary

Added exclusion of patients with history of interstitial lung disease or interstitial 
pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting 
activities of daily living or requiring therapeutic intervention).
Section 1.2.1.1.4 Safety pharmacology and toxicology

Omitted line “suggesting that there is no clinical risk for QTc prolongation” describing 
pre-clinical data. There is now clinical evidence for risk of QTc prolongation.
Section 1.2.1.2 Clinical Experience

Updated to reflect the most recent safety, efficacy and clinical pharmacology information 
from LDK378 Investigator’s Brochure edition 4

Language added that cases of pneumonitis/ILD have been reported with LDK378 in 
patients treated at the 750 mg dose level. Most cases improved or resolved with 
interruption of LDK378 and treatment with antibiotics and/or steroids. Fatal outcome of 
treatment-related pneumonitis has been reported.
 


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Section 5.3 Exclusion Criteria

Exclusion criteria added “history of interstitial lung disease or interstitial pneumonitis, 
including clinically significant radiation pneumonitis (i.e., affecting activities of daily 
living or requiring therapeutic intervention).

Exclusion criteria added “Radiotherapy to lungs ≤ 4 weeks prior to starting the study 
treatment or patients who have not recovered from radiotherapy-related toxicities. For all 
other anatomic sites, radiotherapy ≤ 2 weeks prior to starting the study treatment”
Table 6-2

Language added that dose limiting pulmonary toxicity includes pneumonitis or ILD of any 
grade without infectious etiology
Section 6.3.1 Dose modification and dose delay

Clarification that a minimum dose reduction of 50 mg is required following a DLT to 
account for patients with low BSA.

Language added that if pneumonitis/ILD is suspected, LDK378 should be held during the 
evaluation. If pneumonitis/ILD of grade 2 or worse is confirmed, study drug should be 
permanently discontinued. If Grade 1 pneumonitis resolves within 6 weeks LDK378 may 
be resumed reduced by 1 dose level, otherwise it must be discontinued.

Clarification that in the case of a DLT of QTc prolongation (QTc >500 ms) LDK378 
should be held until resolution to grade 1 or less. If LDK378 is resumed, the dose must be 
reduced by at least 1 dose level.

Clarification that in the case of grade 4 QTc prolongation (QTc >500 ms complicated by 
Torsades de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious 
arrhythmia; or >60 ms change from baseline complicated by Torsades de pointes, 
polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia) LDK378 
should be permanently discontinued.
Table 6-3

Language added that in the case of QTc >500 ms blood electrolytes, including calcium, 
magnesium, phosphorus and potassium, should be measured and abnormalities corrected 
and concomitant medications should be reviewed for other potential causes of QTc 
prolongation. An ECG should be repeated daily until the QTc prolongation has resolved to 
grade 1 or less, and the patient should be evaluated by a qualified physician before leaving 
the clinic or treatment facility.
Section 6.4.1 Permitted concomitant therapy

Clarification added that palliative radiotherapy to sites of pre-existing disease that do not 
represent progressive disease is permitted. (Previously only stated in Section 6.4.3.)
7.2.2.5.4 Electrocardiogram (ECG)

Language added that in the event of QTc >500 ms ECGs should be repeated daily until 
resolved to grade 1 or less.
 


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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 1
Amendment rationale
The following changes were requested 
:

In order to clarify the eligibility criteria in the protocol, a detailed definition of “a genetic 
alteration of ALK” has been added to the inclusion criteria.

Due to the observation that LDK378 use is sometimes associated with hypophosphatemia, 
patients with abnormalities of phosphate as well as potassium, calcium or magnesium > 
CTCAE grade 1 are excluded from the study.

The table defining dose-limiting toxicities (Table 6-2) has been reorganized to clarify that 
any adverse event of CTCAE grade 3 or higher is a DLT, except as noted in the table.

Due to the possibility that taking LDK378 mixed with a small amount of food may affect 
its bioavailability, the protocol has been modified to require that all patients take LDK378 
with a small amount of food. If patients can swallow intact capsules, they must eat 1-2 
tablespoons (15-30 mL) of food, such as apple sauce or non-fat yogurt at the time that they 
take LDK378. If patients open the capsules, the contents are mixed with a food carrier, 
such as apple sauce or non-fat yogurt (or other carriers as defined in the separate 
instructions for patients who cannot swallow capsules). This will prevent unexpected 
differences in bioavailability between those patients who swallow intact capsules and 
those who open the capsules.
The amendment summarizes the results of preliminary ECG data from approximately 150 
patients treated at LDK378 doses of 50-750 mg qd. Review of the data indicated that LDK378 
may have an effect on the QT interval; therefore the inclusion/exclusion criteria were also 
updated to exclude patients taking concomitant medications with a known risk of prolonging 
the QT interval or inducing Torsades de Pointes. The list of excluded concomitant 
medications in Section 6.4.3 and in Table 14-8 has been modified accordingly.
Table 7-4 has been clarified to indicate that when an ECG and a PK sample are scheduled 
simultaneously, the ECG should be performed just prior to drawing the PK sample. This is to 
prevent any anxiety associated with PK sampling from affecting the ECG.
The protocol has been updated with additional clinical pharmacokinetic data now available for 
LDK378, both from the ongoing phase 1 study in adults (CLDK378X2101), and the single-
dose food effect study performed in healthy volunteers (CLDK378A2101).
References have been reformatted for consistency throughout the document, and with the list 
of references (Section 13).
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
List of abbreviations

Addition of CSF (Cerebrospinal fluid)
 


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Protocol Summary

Addition of exclusion of patients with potassium, magnesium, calcium or phosphate 
abnormalities > CTCAE grade 1

Patients receiving medications that are a known risk of prolonging the QT interval or 
inducing Torsades de Pointes
Section 1.1 Overview of disease pathogenesis, epidemiology and current treatment

Corrected some references to proper format
Section 1.2.1.2.1 Clinical safety and tolerability

Addition of results from preliminary analysis of ongoing data regarding LDK378 and its 
possible effect on the QT interval.
Section 1.2.1.2.2 Clinical efficacy

Corrected some references to proper format
Section 1.2.1.2.4 Clinical Pharmacology

Additional data was added regarding the CLDK378X2101 first in human study and 
CLDK378A2101 food effect study
Section 2.1 Study rationale and purpose

Corrected some references to proper format
Section 2.2 Rationale for the study design

Corrected some references to proper format
Section 5.2 Inclusion Criteria

Clarified the requirements of various genetic alterations of ALK tumors
Section 5.3 Exclusion Criteria

Addition of exclusion of patients with potassium, magnesium, calcium or phosphate 
abnormalities > CTCAE grade 1

Addition of exclusion of patients taking medications with a known risk of prolonging the 
QT interval or inducing Torsades de Pointes
Section 6.1.2 LDK378 Administration

Addition of instructions for patients able to swallow capsules to take 1-2 tablespoons of an 
appropriate food, such as apple sauce or non-fat yogurt with each dose

Addition of instructions for patients not able to swallow capsules to mix with contents of 
capsules with an appropriate food such as apple sauce or non-fat yogurt and consume the 
mixture within 2 hours

Language added that as additional foods and/or liquids become available (through further 
testing) to mix with capsule contents for consumption, sites will be informed
Table 6-2 Criteria for defining dose-limiting toxicities

Table was changed to outline any adverse event of CTCAE grade 3 or higher is a DLT 
except for those events outlined in the new table
Section 6.4.3 Prohibited concomitant therapy
 


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
Language added prohibiting the use of 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
Table 7-1 Visit evaluation schedule
Corrected table format Table 7-4 Central ECG collection plan

Clarification that ECG does not need to be done within 30 minutes before PK sample but 
should be done any time prior to PK sample
Section 7.3 Pharmacokinetics

Corrected hyperlink
Section 7.3.1 Pharmacokinetic blood sample collection and handling

Corrected hyperlink
Section 13 References

Corrected some references to proper format
Section 14.2 Appendix 2: Guidance on concomitant therapies with CYP3A4/5, CYP2C9 
interactions and/or QTc prolongation potential

Language added prohibiting the use of 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
Table14-8 Prohibited medications that are strong CYP3A4/5 inhibitors or inducers or 
sensitive CYP3A4/5 substrates with narrow therapeutic index or sensitive CYP2C9 substrates 
with narrow TI or causing QTc prolongation or sensitive CYP2C9 substrates with narrow TI

Updated table to expand list of drugs known to have a high risk of 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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Protocol summary
Protocol 
number
LDK378X2103
Title
A Phase I, open-label, dose escalation study of LDK378 in pediatric patients with 
malignancies that have a genetic alteration in anaplastic lymphoma kinase (ALK)
Brief title
Study of safety and efficacy in pediatric patients with ALK-activated tumors
Sponsor and 
Clinical Phase
Novartis;
Phase 1
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
LDK378 is a novel inhibitor of ALK that is active in a broad range of ALK-activated 
tumor models, including models driven by mutated versions of ALK known to be 
resistant to crizotinib, and by ALK gene amplification.
The primary purpose of this study is to determine the maximum tolerated dose 
(MTD) and/or recommended dose for expansion (RDE) in both fed and fasted 
pediatric patients, and to delineate a clinical dose to be used in any future 
pediatric studies. This study will also assess the safety, tolerability, PK and 
preliminary evidence of antitumor activity of LDK378 in pediatric patients with 
neuroblastoma, and other ALK-activated tumors.
Primary 
Objective
Estimate the MTD and/or RDE of LDK378 as a single agent when administered 
orally to pediatric patients with ALK-activated tumors in the fasted and fed state
Secondary 
Objectives
Objective 1: Characterize the safety and tolerability of LDK378 in pediatric 
patients in the fasted and fed state
Objective 2: Characterize single and multiple-dose PK of LDK378 in pediatric 
patients in the fasted and fed state
Objective 3: Assess the anti-tumor activity of LDK378 in the fasted and fed state
Study design
This is a two-part, phase 1 study, with a dose escalation part in both the fasted 
and fed states, followed by an expansion part. The expansion part will start after 
the fasted MTD/RDE has been determined. The expansion part will include 2 
diagnostic groups of patients, one restricted to patients with ALK-activated 
neuroblastoma and the second including patients with all other ALK-activated 
tumors. Enrollment will proceed in parallel. LDK378 will be administered orally, 
once daily, continuously.
Population
Patients, aged 12 months to <18 years, with malignancies carrying a genetic 
alteration of ALK.
 


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Inclusion 
criteria
●
Patients must be diagnosed with a locally advanced or metastatic malignancy 
that has progressed despite standard therapy, or for which no effective standard 
therapy exists
●
Age ≥ 12 months and <18 years
●
The tumor must carry a genetic alteration of ALK, such as a mutation, 
translocation or amplification
●
Patients must have evaluable or measurable disease as defined by one of the 
following criteria: RECIST v1.1 for patients with non-hematologic malignancies; 
MIBG scan for patients with neuroblastoma; International Working Group (IWG) 
criteria for patients with lymphoma
●
Performance status:
●
Karnofsky performance status score ≥ 60% for patients >12 years of age
●
Lansky score ≥ 50% for patients ≤ 12 years of age
Exclusion 
criteria
●
Patients with symptomatic central nervous system (CNS) metastases who are 
neurologically unstable or require increasing doses of steroids or local CNS-
directed therapy (such as radiotherapy, surgery or intrathecal chemotherapy) to 
control their CNS disease.
●
Patients with clinically significant, uncontrolled heart disease or corrected QT 
(QTc) interval > 480 milliseconds, using the Fridericia correction (QTcF).
●
Patients with the following laboratory values during screening:
●
Creatinine > 1.5 x ULN for age.
●
Total bilirubin > 1.5 x ULN for age, except for patients with Gilbert’s 
syndrome, who may be included if total bilirubin is ≤ 3.0 x ULN and direct 
bilirubin is ≤ 1.5 x ULN.
●
Alanine aminotransferase (ALT) > 3 x ULN for age, except for patients 
that have tumor involvement of the liver, who must have a value ≤ 5 x ULN.
●
Serum aspartate aminotransferase (AST) > 3 x ULN for age, except for 
patients that have tumor involvement of the liver, who must have a value ≤ 5 x 
ULN.
●
Absolute neutrophil count (ANC) < 0.75 x 109/L without use of granulocyte 
growth factor for ≥ 14 days.
●
Platelet count < 50 x 109/L.
●
Hemoglobin (Hgb) < 8 g/dL.
●
Alkaline phosphatase (ALP) > 5.0 x ULN
●
Serum amylase > 2 x ULN
●
Serum lipase > ULN
●
Fasting plasma glucose ≥175 mg/dL (≥9.8 mmol/L)
●
Potassium, magnesium, calcium or phosphate abnormality > CTCAE 
grade 1.
●
Body surface area (BSA) < 0.35 m2.
●
Impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of LDK378 (e.g., ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, or malabsorption syndrome).
●
Evidence of active viral hepatitis, including Hepatitis A, B or C (testing for viral 
hepatitis is not mandatory).
●
Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing 
is not mandatory).
●
Presence of ≥ CTCAE grade 2 toxicity (except alopecia, peripheral 
neuropathy, ototoxicity and lymphopenia, which are not excluded if grade 3 or 
less) due to prior cancer therapy.
 


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●
Malignant disease, other than that being treated in this study. Exceptions to 
this exclusion include the following: malignancies that were treated curatively and 
have not recurred within 3 years prior to study entry; completely resected basal 
cell and squamous cell skin cancers; and completely resected carcinoma in situ of 
any type.
●
History of known interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis (i.e., affecting activities of daily living or 
requiring therapeutic intervention).
●
Patients who have received systemic anticancer therapy within 3 weeks of the 
first dose of LDK378. Patients whose immediate prior treatment was an ALK 
inhibitor may start treatment with LDK378 one week after the last dose of the ALK 
inhibitor.
●
Radiotherapy to lungs ≤ 4 weeks prior to starting the study treatment or 
patients who have not recovered from radiotherapy-related toxicities. For all other 
anatomic sites, radiotherapy ≤ 2 weeks prior to starting the study treatment.
●
Major surgery within 2 weeks of the first dose of LDK378. Insertion of a gastric 
feeding tube (G-tube), nasogastric feeding tube (NG-tube), and central venous 
access are not considered major surgery.
●
Patients receiving medications that are known to be strong inhibitors or 
inducers of CYP3A4/5 that cannot be discontinued at least 1 week prior to start of 
treatment with LDK378 and for the duration of the study (Appendix 2).
●
Patients receiving medications that are mainly metabolized by CYP3A4/5 or 
CYP2C9 and have low therapeutic index that cannot be discontinued at least 1 
week prior to start of treatment with LDK378 and for the duration of the study 
(Appendix 2).
●
Medications with a known risk of prolonging the QT interval or inducing 
Torsades de Pointes (Appendix 2).
●
Pregnant or nursing (lactating) females.
●
Females of child-bearing potential, defined as all females physiologically 
capable of becoming pregnant, unless they are using highly effective methods of 
contraception during dosing and for 3 months after stopping dosing. Highly 
effective contraception methods include:
●
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 LDK378. In case of oophorectomy alone, only when the 
reproductive status of the female has been confirmed by follow up hormone 
level assessment.
●
Male sterilization (at least 6 months prior to screening). For female 
patients on the study 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 females should have been stable on the same 
pill for a minimum of 3 months before taking LDK378.
●
Sexually active males, unless they use a condom during intercourse while 
 


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taking LDK378 and for 3 months after stopping LDK378 treatment, and should not 
father a child in this period. A condom is required to be used also by 
vasectomized men in order to prevent delivery of the drug via seminal fluid.
●
Patient has other severe acute or chronic medical or psychiatric condition or 
laboratory abnormality that may interfere with the interpretation of study results, 
and in the judgment of the investigator would make the patient inappropriate for 
the study.
●
Patient has a history of pancreatitis or history of increased amylase or lipase 
that was due to pancreatic disease.
Investigational 
and reference 
therapy
LDK378 (ceritinib)
Efficacy 
assessments
Overall response rate (ORR) and duration of response (DOR), progression-free 
survival (PFS) as per RECIST 1.1 in patients with neuroblastoma and other solid 
tumors, and by International Working Group (IWG) criteria in patients with 
lymphoma. MIBG response in patients with neuroblastoma. Resolution of bone 
marrow disease in patients with neuroblastoma.
Safety 
assessments
Incidence rate of Dose Limiting Toxicities (DLT) during the first cycle of LDK378 
treatment
Adverse events and serious adverse events, changes in laboratory values, 
assessments of physical examinations, vital signs and electrocardiograms
Other 
assessments
Plasma concentration time profiles, PK parameters, including but not limited to 
AUCtau, Cmin, Cmax, Tmax, Racc, and T1/2,acc
 
 
Data analysis
The primary objective of the escalation part is to estimate the MTD/RDE of the 
single agent LDK378 when administered orally on a once daily schedule to fed or 
fasted pediatric patients with ALK-activated tumors. The corresponding primary 
analysis method is an adaptive Bayesian logistic regression model (BLRM) 
guided by the escalation with overdose control (EWOC) principle.
For all safety analyses, the safety set will be used. Unless otherwise specified, all 
listings and tables will be presented by treatment group (regimen [fasted versus 
fed] and dose level) in the clinical study report, with patients classified according 
to treatment received.
Pharmacokinetic parameters will be determined using either non-compartmental 
method(s) or fitting of the actual values to a population PK model.
Anti-tumor activity will be summarized in terms of overall response rate (ORR), 
duration of response (DOR), and progression-free survival (PFS).
 
 
Key words
Phase I, pediatric, open-label, dose escalation, ALK-activated tumors
 


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
The ALK gene was first described in anaplastic large cell lymphoma (ALCL); it was 
identified as the gene on chromosome 2 fused to the NPM gene in the t(2;5)(p23;Q35) 
translocation, and is found in approximately half of patients with ALCL, and a majority of 
pediatric ALCL cases (Gascoyne 1999, McDermott 2008, Savage 2008). ALK activation by 
translocation, amplification, point mutations, or other genetic rearrangements has since been 
identified in other malignancies. About 2-8% of non-small cell lung cancers (NSCLC) carry 
activating translocations of ALK, most commonly an EML4-ALK translocation created by an 
intrachromosomal inversion in chromosome 2 (Soda 2007, Scagliotti 2012, Takeuchi 2009). 
ALK activation is found in approximately 10% of neuroblastomas, but in contrast to ALCL 
and NSCLC, ALK activation in neuroblastoma occurs by point mutation or ALK gene 
amplification (Chen 2008, Azarova 2011). Most pedigrees exhibiting the rare syndrome of 
familial neuroblastoma carry somatic mutations that result in ALK activation, indicating that 
ALK is an important driver in this disease (Mosse 2008). Half of inflammatory 
myofibroblastic tumors (IMT), a rare soft tissue sarcoma most commonly found in children, 
harbor genetic alterations of ALK, including translocations and changes in gene copy number 
(Coffin 2007, Griffin 1999). Increased ALK protein expression and increased ALK gene copy 
number have also been described recently in 50%-80% of rhabdomyosarcomas, more often in 
the alveolar subtype than the embyronal subtype. It is not yet known if ALK is an oncogenic 
driver in this disease (van Gaal 2012). Activating translocations of ALK, including both 
EML4-ALK, commonly found in NSCLC and NPM-ALK, commonly found in ALCL, act as 
dominant oncogenes in murine models; however, the mechanism of oncogenesis is not well 
understood (Chiarle 2003, Soda 2007). Overexpression and activation of ALK mediate many 
downstream effects that may contribute to transformation, increased proliferation, and 
increased survival. For example, ALK activation in ALCL is associated with activation of 
various signal transduction intermediates and pathways implicated in oncogenesis, including 
STAT3, Grb2, mTORC1, PI3K/AKT, and MEK/ERK (Tabbo 2012). Based on these findings, 
activation of ALK appears to be an important mechanism of oncogenesis in subsets of a 
variety of malignancies, several of which typically occur in pediatric patients.
The role of ALK in healthy mammals is not well understood. It is expressed throughout the 
nervous system during embryogenesis in the mouse, most strongly in the brain, and in the 
adult animal ALK expression is much reduced, but still detectable in the brain (Palmer 2009, 
Iwahara 1997). Despite ALK expression in the developing nervous system and in the adult 
mammal brain, available data suggest that inhibiting ALK in children is not a major safety 
concern. Mice with the ALK gene knocked out develop normally without any evident 
developmental abnormalities (Palmer 2009, Bilsland 2008). Behavioral testing suggests that 
ALK knock-out mice have an “anti-depressant” phenotype, but otherwise function and 
reproduce normally (Bilsland 2008). In humans, germline ALK mutations that constitutively 
activate the kinase domain are the likely cause of most cases of familial neuroblastoma, but 
the mutations are not associated with other familial abnormalities (Mosse 2008).
 


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The ALK inhibitor crizotinib was approved by the US FDA in August 2011 “for the treatment 
of patients with locally advanced or metastatic NSCLC that is ALK-positive as detected by an 
FDA-approved test.” Clinical experience with crizotinib indicates that ALK inhibition has 
potent antitumor activity in several malignancies carrying genetic alterations of ALK. The 
response rate to crizotinib in ALK-translocated NSCLC was 50%-60% in the phase 1 study 
(Kwak 2010, Kim 2012). Crizotinib is also active in several ALK-driven pediatric 
malignancies including neuroblastoma, ALCL, and IMT (Mosse 2012, Butrynski 2010). 
Crizotinib has been associated with a high frequency of visual toxicities including changes in
dark-light accommodation and seeing trails of light (Kwak 2010), but these patient-reported 
events have not been associated with abnormalities on ophthalmology exams, or other 
neurological adverse events. The mechanism of these visual toxicities, and the degree that 
crizotinib distributes to the retina is not known; however, based on a single case report 
crizotinib achieves only very low concentrations in the CSF, approximately 0.26% of blood 
(Costa 2011).
It is anticipated that more potent and specific ALK inhibitors, such as LDK378, may be more 
active than crizotinib in ALK-driven diseases, and may also be active in the setting of 
crizotinib-resistant disease.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of LDK378
LDK378 is an orally available ALK inhibitor [5-Chloro-N2-[2-isopropoxy-5-methyl-4-(4-
piperidinyl)phenyl]-N4-[2(isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine]. 
 
,
 
In addition, LDK378 shows potent antitumor activity in crizotinib-resistant models and the 
efficacy seen in the ongoing Phase I clinical trial in patients (with and without previous 
crizotinib therapy) led to the accelerated approval of LDK378 (ceritinib) by the Food and 
Drug Administration (FDA) under the trade name ZYKADIA™ on 29-Apr-2014 for the 
following indication:

ZYKADIA™ is indicated for the treatment of patients with ALK-positive metastatic 
NSCLC who have progressed on or are intolerant to crizotinib.
This indication is approved under accelerated approval based on tumor response rate and 
duration of response. An improvement in survival or disease-related symptoms has not 
been established. Continued approval for this indication may be contingent upon 
verification and description of clinical benefit in confirmatory trials.’
Furthermore, the European Commission approved ZYKADIA on 06-May-2015 for the 
following indications:

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.
 


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Submissions to other health authorities worldwide have been completed in some countries and 
are underway in others. In this protocol we will refer to the investigational treatment as 
LDK378 only.
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 the ALK kinase activity (IC50 of 0.15 nM for LDK378 and 3 nM for crizotinib). In a kinase 
panel of 35 additional enzymes, LDK378 demonstrated a high degree of selectivity for ALK 
inhibition since it inhibited only 2 kinases (INSR and IGF1R) but with approximately 50-fold 
less potency than inhibition for ALK.
Preclinical data showed inhibition of the kinase activity of the NPM-ALK fusion protein (in 
Karpas299 human ALCL cells) and of the EML4-ALK fusion protein (in H2228 human 
NSCLC cells) with LDK378 led to inhibition of cancer cell proliferation in vitro. The 
inhibition of the downstream signaling pathway by LDK378 correlated with the inhibition of 
proliferation. In addition, inhibition of NPM-ALK and EML4-ALK in mouse and rat 
xenograft models resulted in inhibition of tumor growth and tumor regression in vivo. 
LDK378 was also active in cell lines with ALK amplification or expression of activating point 
mutations. A single-dose pharmacodynamic study and multiple-daily dose efficacy study 
performed in Karpas299 and H2228 tumor models indicated that a 70% to 80% reduction in 
the ALK signaling pathway is required to achieve complete tumor regression in rodents.
1.2.1.1.2 Antitumor activity in xenograft models
LDK378 is highly active in mouse and rat xenograft models of lung cancer and ALCL that 
carry an ALK rearrangement. In murine xenograft models of H2228 NSCLC and Karpas299 
ALCL cells, LDK378 dosed at 25 mg/kg daily, less than the MTD in these models, resulted in 
complete regression of established tumors. When dosed at 50 mg/kg daily for 14 days in the 
H2228 NSCLC model, LDK378 resulted in complete and prolonged (lasting for more than 4.5 
months, the observation period) tumor regressions. In the same experiments, crizotinib dosed 
at 100 mg/kg daily for 14 days resulted in complete tumor regression, but tumors re-grew 
within 2 weeks after stopping treatment.
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 that LDK378 may be clinically active in ALK-rearranged 
malignancies that becomes resistant to crizotinib.
1.2.1.1.3 Nonclinical pharmacokinetics (PK) and metabolism
LDK378 showed consistent PK characteristics following intravenous (IV) administration in 
mouse, rat, dog, and monkey. LDK378 showed low to moderate plasma clearance (CL) 
compared to hepatic blood flow (ranging from 9.2 to 27 mL/min/kg). The estimated plasma 
 


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volume of distribution at steady state (Vss) was high across all animal species (9.7 to 19.9 
L/kg). The elimination T1/2 of terminal phase in plasma was long in all species (6.2 to 29 
h).Good oral bioavailability (48%-100%) was observed in various animal species. 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 the 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). 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 five 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 in the feces (> 
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 IV administration, enterohepatic circulation 
may occur.
LDK378 is a potent reversible inhibitor of cytochrome CYP3A4/5, 2B6, 2C8, 2C9 and 2A6 
(half-maximal inhibitory concentration (IC50) ranging from 0.162 to 0.0316 µM) and a weak 
inhibitor of 2C19, 2D6 and 2E1. Time-dependent inhibition of CYP3A4/5 was observed with 
a KI value of 1.47 µM and a Kinact of 0.0642 min-1. These data suggest a potential of drug-
drug interaction between LDK378 and compounds which are metabolized by these CYP 
isoforms if sufficiently high concentrations of LDK378 are achieved. LDK378 was likely a P-
gp, not BCRP or MRP2 substrate. It did not inhibit P-gp, BCRP or MRP2 up to 1.5 µM.
In rats LDK378 crosses the intact blood brain barrier at a low level, with concentrations of 
LDK378 in brain tissue about 10% of that in blood.
1.2.1.1.4 Safety pharmacology and toxicology
LDK378 was evaluated for safety in 2- and 4-week studies in rats and monkeys. The principal 
toxicity induced by LDK378 was a systemic inflammation characterized by increased 
neutrophil counts in the peripheral blood and mixed cell/neutrophilic inflammation of the 
biliopancreatic ducts, pancreas, and/or duodenum. Gastrointestinal toxicity was observed in 
both species, characterized by body weight loss, decreased food consumption, emesis 
(monkey), diarrhea, and at high doses, by histopathologic lesions including erosion, mucosal 
inflammation and foamy macrophages in the duodenal crypts and ampullae of rats and 
monkeys, respectively. 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 species; 50 and 30 
mg/kg/day in the 4-weeks studies in rat and monkey, respectively), and included increases in 
liver transaminases in a few animals at high doses, and mixed cell inflammation, erosion and 
cytoplasmic vacuolation of the bile duct epithelium. The pancreas was a target organ in the rat, 
but not the monkey, with acinar cell atrophy and mixed cell inflammation noted at mid- and 
 


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high doses. Target organ effects showed partial to complete recovery during the 4-week non-
dosing period. No effects in the rat central nervous system or on the respiratory system were 
observed at single, high doses (100 mg/kg).
LDK378 has potent activity on the hERG channel with an IC50 of 0.4 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).
Please refer to the current LDK378 [Investigator’s Brochure] for further information.
1.2.1.2
Clinical experience
1.2.1.2.1 Clinical safety and tolerability
LDK378 is associated with a manageable safety profile (Table 1-1). For the 255 patients 
treated at the recommended dose (RD) of 750 mg in the ongoing study [CLDK378X2101], 
the median duration of exposure as of the 
 was 26.9 weeks (range 0.4 
to 82.3 weeks). The most common adverse events (AE) regardless of study drug relationship 
(incidence ≥25%) were diarrhea, nausea, vomiting, alanine aminotransferase (ALT) increased, 
fatigue, abdominal pain, decreased appetite, aspartate aminotransferase (AST) increased, and 
constipation.
The incidence of grade 3-4 AEs, regardless of study drug relationship was <10% for all AEs 
except ALT increased (26.7%) (Table 1-1). The incidence of grade 3-4 AEs, regardless of 
study drug relationship was <5% for all AEs except AST increased (8.2%), diarrhea (5.9%), 
hyperglycemia (5.5%), lipase increased (5.1%), and blood alkaline phosphatase (ALP) 
increased (5.1%).
Table 1-1
All grades (at least 10%) and associated grade 3-4 adverse events, 
regardless of study drug relationship, by preferred term in patients 
treated in the 750 mg dose group (Data cut-off date: 
)
Preferred term
LDK378
750 mg
N=255
All Grades
Grade 3/4
n (%)
n (%)
Total
255 (100.0)
184 (72.2)
Diarrhea
219 (85.9)
15 (5.9)
Nausea
205 (80.4)
11 (4.3)
Vomiting
153 (60.0)
10 (3.9)
Alanine Aminotransferase 
Increased
110 (43.1)
68 (26.7)
Fatigue
102 (40.0)
10 (3.9)
Abdominal Pain
91 (35.7)
3 (1.2)
Decreased Appetite
87 (34.1)
2 (0.8)
Aspartate Aminotransferase 
Increased
78 (30.6)
21 (8.2)
Constipation
73 (28.6)
0
 


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Preferred term
LDK378
750 mg
N=255
All Grades
Grade 3/4
n (%)
n (%)
Cough
62 (24.3)
0
Abdominal Pain Upper
58 (22.7)
2 (0.8)
Dyspnea
47 (18.4)
8 (3.1)
Asthenia
45 (17.6)
2 (0.8)
Blood Alkaline Phosphatase 
Increased
45 (17.6)
13 (5.1)
Back Pain
43 (16.9)
1 (0.4)
Headache
41 (16.1)
3 (1.2)
Weight Decreased
39 (15.3)
4 (1.6)
Blood Creatinine Increased
39 (15.3)
0
Pyrexia
38 (14.9)
0
Rash
32 (12.5)
0
Insomnia
31 (12.2)
0
Dyspepsia
26 (10.2)
1 (0.4)
Hypokalemia
26 (10.2)
11 (4.3)
Dizziness
26 (10.2)
0
Dose reductions due to adverse events occurred in 58.4% of patients treated with LDK378 at 
the 750 mg dose; 38.8% of patients had only 1 dose reduction. The most frequent AEs 
requiring dose adjustments or interruptions reported in ≥5% of the patients were: ALT 
increased, nausea, AST increased, vomiting, diarrhea, fatigue, and abdominal pain. Adverse 
events (AEs) leading to study drug discontinuations occurred in 10.2% of patients treated with 
LDK378 at the 750 mg dose. The most frequent AEs leading to study drug discontinuations 
were decreased appetite, pneumonia, ALP increased, pneumonitis, and respiratory failure.
Serious adverse events (SAEs) reported in 2% or more of the 255 patients treated at the 
recommended dose of 750 mg were convulsion, pneumonia, interstitial lung disease 
(ILD)/pneumonitis, dyspnea, hyperglycemia, and nausea. Fatal adverse reactions occurred in 
5% of patients, consisting of: pneumonia (4 patients), respiratory failure, ILD/pneumonitis, 
pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary 
tuberculosis, cardiac tamponade, and sepsis (1 patient each). Adverse events of special 
interest to be monitored for LDK378 have also been identified and include: hepatotoxicity, 
interstitial lung disease/pneumonitis, QT interval prolongation, bradycardia, hyperglycemia,
gastrointestinal toxicity (nausea, vomiting and diarrhea) and pancreatitis (including lipase and 
amylase elevations). For additional details, refer to [Investigator’s Brochure].
1.2.1.2.2 Clinical efficacy
 data from the ongoing Study 
demonstrated a high rate 
of rapid and durable responses with LDK378 in 246 ALK-positive NSCLC patients treated in 
the 750 mg dose group (RD). In these patients the ORR was 58.5% (95% CI: 52.1, 64.8) 
based on investigator assessment (Table 1-2). Among the 144 ALK-positive NSCLC patients 
 


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with a confirmed CR or PR based on investigator assessment, 86.1% of those patients 
achieved a response within 12 weeks, with a median time to response of 6.1 weeks (range: 3.0 
to 24.1) . The estimated median duration of response (DOR) based on investigator assessment 
was long at 9.69 months (95% CI: 7.00, 11.40). Based on the investigator assessment, the 
median PFS was 8.21 months (95% CI: 6.70, 10.12) with 53.3% of the patients censored.
Importantly, LDK378 showed this level of high anti-cancer activity regardless of prior ALK 
inhibitor status (i.e., whether or not the patient received previous treatment with an ALK 
inhibitor). A high ORR of 54.6% and 66.3% was observed in patients treated with a prior 
ALK inhibitor and in ALK inhibitor naïve patients, respectively, by investigator assessment 
(Table 1-2). Rapid responses were observed in patients regardless of prior ALK inhibitor 
status, 6.1 weeks (range: 4.6 to 24.1) in patients treated with a prior ALK inhibitor and 
6.1 weeks (range: 3.0 to 24.1) in ALK inhibitor naïve patients. Further, the estimated median 
DOR was 7.39 months (95% CI: 5.42, 10.12) in patients treated with a prior ALK inhibitor 
and, the median DOR was not reached in ALK inhibitor naïve patients. However, the 12-
month DOR rate was 65.2% (95% CI: 46.4, 78.8) for the latter. The estimated median PFS 
was 6.90 months (95% CI: 5.39, 8.41) in patients treated with a prior ALK inhibitor, while the 
median PFS was not reached in ALK inhibitor naïve patients (95% CI: 8.31, NE). Finally, 
LDK378 demonstrated activity in patients with brain metastasis at baseline. Among the 98 
patients with brain metastasis who had received prior ALK-inhibitor treatment, the ORR was 
50.0% (95% CI: 39.7, 60.3), median DOR was 6.9 months (95% CI: 4.8, 8.5), and median 
PFS was 6.7 months (95% CI: 4.9, 8.4). For additional details, refer to the [Investigator’s 
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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) (Cut-off date: 
)
NSCLC with prior 
ALK inhibitor
NSCLC ALK 
inhibitor naïve
All NSCLC
N=163
N=83
N=246
n (%)
n (%)
n (%)
Best overall response
Complete response (CR)
2 (1.2)
1 (1.2)
3 (1.2)
Partial response (PR)
87 (53.4)
54 (65.1)
141 (57.3)
Stable disease (SD)
32 (19.6)
19 (22.9)
51 (20.7)
Progressive disease (PD)
16 (9.8)
0
16 (6.5)
Unknown
26 (16.0)
9 (10.8)
35 (14.2)
Overall response rate (ORR) (CR 
or PR), n (%)
89 (54.6)
55 (66.3)
144 (58.5)
95% CI
(46.6-62.4)
(55.1-76.3)
(52.1-64.8)
This table presents data for all patients with ALK-positive NSCLC in the 750 mg treatment dose group, 
FAS-NSCLC 750 mg group
Best overall response is based on investigator’s assessment of disease status using RECIST 1.0 
criteria
CR and PR are confirmed by repeat assessments performed not less than 4 weeks after the criteria for 
response are first met.
Exact binomial 95% Confidence Interval
1.2.1.2.3 Clinical pharmacodynamics
Data are not yet available from the ongoing clinical studies.
1.2.1.2.4 Clinical pharmacokinetics
In adult patients with tumors characterized by genetic abnormalities in ALK
]
and 
in 
healthy 
volunteers 
 
and 
 the single-dose pharmacokinetics of 
LDK378 in humans has the following features: (1) LDK378 was slowly absorbed, with 
median peak plasma concentration occurring at approximately 4 to 6 h in patients, and 
approximately 6 to 8 h in healthy subjects. Following Cmax, LDK378 concentrations declined 
in a mono-exponential manner. The geometric mean apparent terminal half-life ranged from 
31 to 41 h across the 400 to 750 mg dose groups in patients and 36 to 48 h across the 450 to 
750 mg dose groups in healthy subjects. (2) Cmax and AUClast increased dose-proportionally 
following single oral administration of LDK378 across the 50 to 750 mg dose groups. (3) 
Moderate to high variability in LDK378 PK parameters has been observed in both healthy 
subjects and patients. Following single oral doses of 450 to 750 mg in healthy subjects when 
LDK378 was given alone, the inter-subject variability (geometric mean coefficient of 
variation; CV% range) was 42-74% and 35-72% for AUClast and Cmax, respectively. The 
corresponding values in patients were 93% and 87% following single oral doses of 50 to 
750 mg based on a model developed for dose proportionality analysis.
 


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The multiple-dose PK of LDK378 following repeated daily oral dosing in patients has the 
following features: (1) AUCtau at the maximum tolerated dose and recommended dose of 
750 mg increased from first dose with geometric mean accumulation ratios of 4.7 on Cycle 1 
Day 8 after 1 week of daily dosing and 6.2 on Cycle 2 Day 1 after 3 weeks of daily dosing, 
respectively. Evaluation of trough concentration at 750 mg that steady-state was achieved by 
Cycle 1 Day 15 following 2 weeks of daily dosing. (2) LDK378 demonstrated nonlinear PK 
over time, as indicated by the observed difference in apparent clearance (CL/F) between 
single-dose (88.5 L/h at 750 mg) and steady-state at Cycle 2 Day 1 (33.2 L/h at 750 mg). As 
LDK378 is a substrate as well as a time-dependent inhibitor of CYP3A, it is likely that this 
PK nonlinearity could be attributed to auto inhibition of LDK378. In contrast with single dose 
data, Ctrough on Cycle 2 Day 1 after repeated daily dosing increased with dose in a greater 
than dose-proportional manner.
 
 
 
 
 
CYP3A was identified as the major CYP isozyme responsible for the metabolism of LDK378. 
An inhibition DDI study conducted in healthy volunteers indicated that ketoconazole (200 mg 
bid for 14 days), a strong CYP3A inhibitor, increased the Cmax and AUCinf of a single 
450 mg oral dose of LDK378 by 1.2-fold and 2.9-fold, respectively, compared with LDK378 
alone 
Therefore, concurrent use of strong CYP3A inhibitors should 
be avoided. An induction DDI study conducted in healthy volunteers indicated that rifampin 
(600 mg daily for 14 days), a strong CYP3A inducer, decreased the Cmax and AUCinf of a 
single 750 mg oral dose of LDK378 by 44% and 70%, respectively, compared with LDK378 
alone 
Concurrent use of strong CYP3A inducers should be avoided.
A food effect study was conducted in healthy volunteers 
 Compared to the 
fasted state, a low-fat meal increased Cmax and AUCinf of a single oral dose of LDK378 
500 mg in healthy subjects by 43% and 58%, respectively, whereas a high-fat meal increased 
Cmax and AUCinf by 41% and 73%, respectively.
2
Rationale
2.1
Study rationale and purpose
LDK378 is a novel inhibitor of ALK that in preclinical studies is more potent and specific 
than crizotinib, and is active in a broad range of ALK-activated tumor models, including 
models driven by mutated versions of ALK known to be resistant to crizotinib, and by ALK 
gene amplification.
As described in Section 1.1, genetic alterations of ALK are found in subsets of several 
pediatric cancers, including about 10% of neuroblastomas, the majority of pediatric ALCL, 
and about half of inflammatory myofibroblastic tumors. Both in vitro and in vivo experiments 
have demonstrated that neuroblastoma, ALCL, and NSCLC models carrying ALK alterations 
 


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are frequently dependent on ALK for their growth, and are responsive to treatment with ALK 
inhibitors (Chiarle 2003, Soda 2007, Li 2011, Galkin 2007). Recent clinical data have also 
demonstrated that the ALK inhibitor crizotinib has antitumor activity in children with 
neuroblastoma and ALCL (Mosse 2012).
In the ongoing phase 1 study, [CLDK378X2101], LDK378 has demonstrated substantial 
antitumor activity in adult patients with ALK-rearranged NSCLC. Together, these preclinical 
and clinical data support evaluation of LDK378 in pediatric patients with malignancies 
carrying genetic alterations of ALK.
Safety data from studies in adult patients, as well as the pediatric patients already enrolled in 
this study show a high incidence of GI adverse events (nausea, vomiting, diarrhea, abdominal 
pain). These AE’s seem to be generally low-grade and manageable with prophylactic 
medications. However, GI symptoms are uncomfortable and can affect patients’ general well-
being, as well as drug absorption and dosing compliance, with the latter potentially limiting 
efficacy. Dosing with food has been shown to improve the GI tolerability of other multi-
kinase inhibitors, such as imatinib (Gleevec USPI) and bosutinib (Bosulif USPI). Therefore, a 
separate dose-escalation arm under fed conditions will be explored once the fasting MTD 
and/or RDE is reached.
The primary purpose of this study is to estimate the maximum tolerated dose (MTD) and/or 
recommended dose for expansion (RDE) in pediatric patients, and to delineate a clinical dose 
to be used in any future pediatric studies. The MTD will first be determined in the fasted state, 
then a second dose escalation to determine the MTD in the fed state (low-fat light snack) will 
be conducted. This study will also assess the safety, tolerability, PK and preliminary evidence 
of antitumor activity of LDK378 in children with neuroblastoma, and other ALK-activated 
tumors.
2.2
Rationale for the study design
This is a multi-center, phase 1, open-label, dose escalation study limited to pediatric patients 
with malignancies that have a genetic alteration of ALK. The study includes an expansion part 
at the MTD or RDE in order to better evaluate safety, tolerability, and preliminary evidence of 
antitumor activity in neuroblastoma having a genetic alteration of ALK, and in other 
malignancies having a genetic alteration of ALK.
The current open-label dose escalation study design using a Bayesian logistic regression 
model (BLRM) is a well-established method to estimate the maximum tolerated dose (MTD) 
and/or recommended dose for expansion (RDE) in cancer patients. The adaptive BLRM will 
be guided by the escalation with overdose control (EWOC) principle to control the risk of 
DLT in future patients on study. The use of Bayesian response adaptive models for small 
datasets has been accepted by EMEA (“Guideline on clinical trials in small populations”, 
February 1, 2007) and endorsed by numerous publications (Babb 1998, Neuenschwander 
2008, Neuenschwander 2010), and its development and appropriate use is one aspect of the 
FDA’s Critical Path Initiative.
The study includes patients ranging from 12 months to <18 years of age. Patients must be 
diagnosed with a malignancy that has a genetic alteration of ALK (such as a mutation, 
translocation or amplification) and has progressed following standard therapy or for which no 
 


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standard treatment option exists. The study is limited to malignancies with a genetic alteration 
of ALK because LDK378 is only expected to be active against ALK-activated malignancies.
In order to ensure experience with LDK378 across this age range, at least 3 patients will be 
treated in each of the following age categories: 12 months - < 7 years, 7 - < 12 years, and 12 -
<18 years.
2.3
Rationale for dose and regimen selection
The starting dose for the fasted dose escalation part is 66.7% of the MTD in adults, 
normalized to BSA. Based on the adult MTD of 750 mg qd, and a typical adult BSA of 1.7 m2, 
the pediatric starting dose of LDK378 is 300 mg/m2 ((750 mg x 0.667) /1.7 m2 = 294 mg/m2, 
rounded to 300 mg/m2) dosed once daily by mouth. In adults, LDK378 is dosed once daily by 
mouth, and the half-life of approximately 36 hours supports proceeding with once daily 
dosing in children.
The starting dose of 300 mg/m2 corresponds to an adult dose of approximately 500 mg qd. In 
the ongoing phase 1 study the combined response rate at the 400 mg qd and 500 mg qd dose 
levels was 63% (15/24), including unconfirmed responses only observed on a single 
evaluation as of the Aug 3, 2012 snapshot. In addition, considering that LDK378 is 20-fold 
more potent than crizotinib based on enzymatic inhibition assays of ALK kinase activity and 
at the clinical dose 500 mg qd, the median AUC of LDK378 is approximately 23.3 µM*hr 
(day 8 of cycle 1), which exceeds the steady state exposure of crizotinib of approximately 8.6 
µM*hr, at its MTD (FDA Clin Pharm, Biopharm review of crizotinib, NDA 202570), the 
selected starting dose in the current study should produce anti-tumor activity. The probability 
of overdose at 500 mg qd is estimated to be <0.1% in the adult phase 1 study, based on the 
Bayesian logistic regression model. Thus, the starting dose of 300 mg/m2 is expected to be 
active and well tolerated. The half-life of approximately 36 hours observed in adults supports 
once daily dosing in children.
 
 
 
 
Rodent xenograft experiments in ALK-rearranged tumor models that are resistant to crizotinib 
require higher LDK378 exposures to achieve maximum tumor growth inhibition; therefore, it 
is likely that higher doses of LDK378 will be more active in patients, and it is most 
appropriate to dose LDK378 at the MTD, not to target a minimal efficacious dose.
During the dose escalation parts of the study, dose escalation will be guided by the BLRM, 
but the maximum increase in dose for the fasted dose escalation part will be limited to 50% of 
the last prior dose level before reaching 450mg/m2, and to 25% after reaching 450 mg/m2, 
which is the MTD in adults, as shown in Table 6-1. Dose escalation for the fed dose 
escalation part will be limited to a 25% or smaller increase above the prior fed dose level. 
These restrictions are necessary to prevent excessive escalation, since the starting dose is 
relatively close to the adult MTD.
 


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2.4
Rationale for choice of combination drugs
Not applicable.
2.5
Rationale for choice of comparators
Not applicable.
2.6
Risks and benefits
LDK378 dosed at 750 mg once daily has remarkable anti-tumor activity and induces a high 
rate of rapid and durable responses and prolonged PFS in patients with advanced, ALK-
positive NSCLC, regardless of whether they had been previously treated with an ALK 
inhibitor or were ALK inhibitor naïve. The substantial anti-tumor activity and resulting 
clinical benefit combined with the clinically manageable safety profile of LDK378 strongly 
support a positive benefit/risk balance for ALK-positive NSCLC patients.
Efficacy
Patients with prior ALK inhibitor treatment: ALK-positive NSCLC patients previously treated 
with crizotinib who have progressed and patients intolerant to crizotinib have no effective 
treatment options, have a dismal prognosis, and represent a population with a high unmet 
medical need. In ALK-positive NSCLC patients failing treatment with crizotinib, independent 
from the resistance mechanism involved, ALK translocation is still present and is still the 
oncogenic driver in almost all of the cases. Chemotherapy is not expected to provide a 
meaningful clinical benefit in these patients, as was recently demonstrated in a Phase III study 
(PROFILE 1007) of crizotinib vs. chemotherapy in the second-line setting (Shaw et al 2013).
In ALK-positive NSCLC patients previously treated with an ALK inhibitor and multiple prior 
lines of anti-neoplastic therapy, based on an independent review of tumor assessments, as of 
31-Oct-2013, the response rate was 45.1% (95% CI: 37.1 - 53.3) and the median DOR was 
7.1 months (95% CI: 5.6 – NE). The median PFS was 6.7 months (95% CI: 5.5 - 7.7) in Study 
[CLDK378X2101]. The median PFS is similar (overlapping 95% CIs) to that reported for 
crizotinib in the second-line setting (7.7 months (95% CI: 6.0 - 8.8)) and similar or better than 
that reported for chemotherapy (4.2 months (95% CI: 2.8 - 5.7) with pemetrexed and 2.6 
months (95% CI: 1.6 - 4.0) with docetaxel) in the PROFILE 1007 study (Shaw et al 2013) for 
patients with locally advanced or metastatic ALK-positive NSCLC who had received prior 
treatment with one platinum-containing chemotherapy regimen. Therefore, LDK378 fulfills 
an existing unmet medical need.
The efficacy of LDK378 seen in Study [CLDK378X2101] is highly encouraging in heavily 
pretreated patients with advanced disease, high tumor burden (including a high proportion of 
brain metastases at baseline), limited available therapeutic options, and dismal prognoses 
following prior ALK-targeted therapies, where the only options are chemotherapy and best 
supportive care.
ALK inhibitor naïve patients: As of 31-Oct-2013, based on an independent review of tumor 
assessments, the response rate in ALK inhibitor naïve NSCLC patients was 61.0% (95% CI: 
49.2 - 72.0) in Study [CLDK378X2101]. The median DOR was not evaluable for treatment-
naïve patients. The median PFS for LDK378 in ALK-inhibitor naïve patients was not 
 


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evaluable (95% CI: 13.7 - NE) as the majority of patients were ongoing without an event at 
the time of the data cut-off.
Overall, these data suggest that LDK378 as a first-line ALK inhibitor treatment has 
remarkable anti-tumor activity and induces a consistently high rate of durable responses in 
ALK inhibitor naïve patients.
Safety
The safety profile of LDK378 is manageable (Section 1.2.1.2), with a low rate of AEs leading 
to discontinuation. Furthermore, patients’ perception of their quality of life was maintained or 
slightly improved with LDK378 treatment. The most common AEs were gastrointestinal 
(diarrhea, nausea, vomiting); increases in transaminases, decreased appetite, fatigue; 
abdominal pain, and constipation were also seen in ≥ 25% of patients. These AEs can be 
managed with symptomatic treatment and/or dose reductions or interruptions; only 8.8% of 
patients discontinued study drug due to an AE. No clinically meaningful differences in the 
safety profile were observed between ALK-positive NSCLC patients previously treated with 
an ALK inhibitor and ALK inhibitor naïve patients.
The risks identified with LDK378 treatment include hepatotoxicity, interstitial lung disease 
(ILD)/pneumonitis, QT interval prolongation, bradycardia, hyperglycemia, gastrointestinal 
toxicity (nausea, vomiting and diarrhea) and pancreatitis (including lipase and amylase 
elevations) (Section 8.1.3). These risks can be managed and ameliorated by early diagnosis 
and dose adjustment/interruption, or permanent discontinuation.
Risk management during study conduct
In order to manage the risks associated with LDK378 treatment, specific dose modifications 
and stopping rules during study conduct are described in the protocol. For patients who do not 
tolerate the initial protocol-specified dose, dose adjustments are provided in order to allow the 
patients to continue the study treatment (Section 6.3. and Table 6-3). Patients whose treatment 
is temporarily interrupted or permanently discontinued due to a study drug related AE or an 
abnormal laboratory value must be followed until resolution or stabilization of the event, 
whichever comes first, including all study assessments appropriate to monitor the event.
In addition, a thorough post-treatment safety follow-up is included (Section 7.1.4). Patients 
may voluntarily withdraw from study treatment at any time or on the advice of the 
investigator if he/she believes that continuation would be detrimental to the patient’s well-
being. When the patient discontinues from study treatment, an End of Treatment (EOT) visit 
must be performed as soon as possible and within 7 days of the last dose of LDK378. Patients 
will also be contacted for the safety follow-up 30 days after their last dose of LDK378 to 
determine if they have experienced any new AEs and/or to follow resolution of ongoing AEs.
Detailed information on allowed and prohibited concomitant medications is provided in 
Section 6.4. In vitro drug metabolism studies show that the metabolism of LDK378 is 
mediated by CYP3A4/5. Appendix 2 contains several tables listing medications that are
prohibited, permitted or to be used with caution during treatment with LDK378. Prohibited 
medications should be discontinued at least 1 week prior to the start of treatment with 
LDK378.
 


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Recommended guidelines for prophylactic or supportive treatment for expected toxicities, 
including management of study-drug induced AEs, are extensively described in Section 6.3.
Furthermore, regarding adverse events of special interest (see Section 8.1.3):

Hepatotoxicity: Hepatotoxicity, as defined by TB > 2xULN and ALT and/or AST > 
3xULN and ALP < 2xULN, has been observed in <1% of patients treated with LDK378. 
to grade 3 or 4 ALT elevations were observed in 25% of patients receiving LDK378. 
Concurrent elevations in ALT >3xULN and total bilirubin >2xULN, with normal alkaline 
phosphatase, occurred in less than 1% of patients in clinical studies. The majority of cases 
were manageable with dose interruption and/or dose reduction. Few events required 
discontinuation of LDK378. Patients will be closely monitored by regular laboratory 
testing and related signs and symptoms. Risk to patients will also be minimized by 
restricting study enrollment to subjects with laboratory values for AST, ALT, ALP and 
bilirubin below certain thresholds (see exclusion criteria #3).

Interstitial lung disease/pneumonitis: severe, life-threatening, or fatal interstitial lung 
disease (ILD)/pneumonitis have been observed in patients treated with LDK378 in clinical 
studies. Most cases improved or resolved with interruption of LDK378. Patients will be 
monitored for symptoms such as shortness of breath, cough or fever. Risk to patients will 
be minimized by excluding from study enrollment any patient with a history of interstitial 
lung disease or interstitial pneumonitis, including clinically significant radiation 
pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention) 
(see exclusion criteria #10).

QT interval prolongation: QTc prolongation has been observed in clinical studies in 
patients treated with LDK378, which may lead to an increased risk for ventricular 
tachyarrhythmias (e.g., Torsade de pointes) or sudden death. A pharmacokinetic analysis 
suggested that LDK378 causes concentration-dependent increases in QTc. Repeated ECG 
tracings will be performed throughout the study to closely monitor cardiovascular safety. 
Risk to patients will also be minimized by excluding from study enrollment those patients 
with clinically significant, uncontrolled heart disease and/or a recent cardiac event (within 
6 months), including a corrected QT (QTcF) > 480 ms using Fridericia’s correction on the 
screening ECG (see exclusion criteria #2).

Bradycardia: asymptomatic cases of bradycardia have been observed in patients treated 
with LDK378 in clinical studies. Repeated ECG tracings will be performed throughout the 
study to closely monitor cardiovascular safety. Risk will also be minimized by monitoring 
concomitant use of other agents known to cause bradycardia (e.g., beta-blockers, non-
dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. 
Heart rate and blood pressure will also be monitored regularly during the study.

Hyperglycemia: events of hyperglycemia (all grades) have been reported in less than 10% 
of patients treated with LDK378 in clinical studies; 5% of patients reported a grade 3/4 
event. The risk of hyperglycemia was higher in patients with diabetes mellitus and/or 
concurrent steroid use. Patients will be closely monitored throughout the study for any 
signs and symptoms related to elevated blood glucose levels. Risk will be minimized by 
including subjects with fasting plasma glucose levels < 175 mg/dL (< 9.8mmol/L) at 
screening (see exclusion #3).
 


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
Gastrointestinal toxicity: diarrhea, nausea, and vomiting have been very commonly 
reported; 12.2% of patients reported a grade 3/4 event of diarrhea, nausea, or vomiting. 
Risk to patients will be minimized during the study by closely monitoring symptoms and 
managing patients using standards of care, including anti-diarrheals, anti-emetics, or fluid 
replacement, as indicated.

Pancreatitis (including lipase and amylase elevations): in most cases, pancreatic 
enzyme elevations have been mild to moderate, and have typically reversed with 
interruption of LDK378. Few patients have experienced pancreatitis with severe upper 
abdominal pain. Patients will be monitored closely for any related signs and symptoms. In 
order to minimize the risk to patients during the study, patients with a history of 
pancreatitis or a history of increased lipase or amylase levels that was due to pancreatic 
disease will be excluded. In addition, serum amylase must be ≤2 x ULN and serum lipase 
must be within normal limits at screening.
Conclusion
The outstanding anti-tumor activity and resulting clinical benefit combined with the 
manageable safety profile of LDK378 strongly support a positive benefit-risk balance for 
ALK-positive NSCLC patients, regardless of whether the patients had received prior ALK 
inhibitor treatment or not.
The risk to subjects in this trial will be minimized and managed by compliance with the 
eligibility criteria, close clinical monitoring, dose modifications/interruptions and permanent 
discontinuation as required. There may be unforeseen risks with LDK378 which could be 
serious. Refer to the [Investigator’s Brochure] for additional information regarding the safety 
profile of LDK378.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
 


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4.
Estimate the MTD and/or RDE of LDK378 as a 
single agent when administered orally to 
pediatric patients with ALK-activated tumors in 
fasting and fed states
Incidence rate of Dose Limiting Toxicities (DLT) during the first cycle of 
LDK378 treatment.
Secondary
Refer to Section 10.7.
(1) Characterize the safety and tolerability of 
LDK378 in the pediatric patients in fasting and 
fed states
(2) Characterize single and multiple-dose PK of 
LDK378 in pediatric patients in fasting and fed 
states
(3) Assess the anti-tumor activity of LDK378 in 
fasting and fed states
(1) Adverse events and serious adverse events, changes in laboratory 
values, assessments of physical examinations, vital signs and 
electrocardiograms.
(2) Plasma concentration time profiles, PK parameters, including but not 
limited to, AUCtau, Cmin, Cmax, Tmax, Racc, and T1/2,acc
(3) Overall response rate (ORR) and duration of response (DOR), 
progression-free survival (PFS) as per RECIST 1.1 in patients with 
neuroblastoma and other solid tumors, and by International Working Group 
(IWG) criteria in patients with lymphoma. MIBG response in patients with 
neuroblastoma. 
 


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4
Study design
4.1
Description of study design
This is a two-part, phase 1 study, with a dose escalation part performed in the fasted and fed 
states, and an expansion part performed in the fasted and fed states. Eligible patients must be 
diagnosed with an advanced malignancy carrying a genetic alteration of ALK that has 
progressed following standard therapy, or for which no standard, effective therapy exists. 
LDK378 will be administered orally, once daily, continuously.
Because of the low incidence of cancers with abnormalities in ALK, the study sites will pre-
screen patients for genetic alterations of ALK by sending a tumor sample to a central 
laboratory designated by Novartis. The tumor sample may be a previously obtained archival 
sample, or a sample obtained for the purpose of molecular pre-screening for this study. The 
ALK analysis results will be communicated to the study center within approximately 2 weeks 
of the lab’s receipt of the sample. If the patient has already been identified to have a genetic 
alteration of ALK, he/she can be screened for the study without assessment of ALK at a 
designated laboratory, if Novartis reviews the local laboratory assessment, and agrees that it is 
sufficient for eligibility. The patient/guardian must provide signed informed consent on the 
molecular pre-screening consent form before a pre-screening tumor sample is sent to the 
designated laboratory. Patients found to have a genetic alteration of ALK, such as a mutation, 
translocation or amplification, may be screened for the study, after the patient/guardian 
provides signed informed consent. If the patient fulfills all other inclusion and exclusion 
criteria, the patient can begin treatment.
For the purpose of scheduling assessments, and establishing the MTD/RDE, a cycle is defined 
as 21 days in length, but there is no schedule break in dosing between cycles. It is anticipated 
that approximately 15-36 patients will be treated during the fasted escalation part (3-6 patients 
in approximately 5-6 dose levels, and a minimum of 6 at the MTD dose level). It is 
anticipated that approximately 12-24 patients will be treated during the fed escalation part (3-
6 patients in approximately 3-4 dose levels, and a minimum of 6 at the MTD dose level). 
Patients will be categorized according to one of the age ranges as they enter the study.
The expansion part will start after the fasted MTD has been determined. During the expansion 
part patients will initially be dosed at the fasted MTD, or at a lower RDE, if the available data 
suggest that the MTD is not appropriate for multiple cycles of therapy. Once the fed dose 
escalation part is opened, patients will be enrolled on the open cohort of the fed dose 
escalation part. At times when the fed dose escalation part is closed to enrollment, such as 
during the observation period between cohorts, additional patients may continue to be 
enrolled in the expansion part at the fasted MTD/RDE. After the MTD/RDE is determined for 
the fed state and the available safety, PK and anti-tumor activity data have been reviewed, a 
decision will be made as to whether dosing in the fasted or fed state is preferred. Once this 
decision is made all subsequent patients will be enrolled on that dosing strategy to complete 
the planned expansion part. The expansion part will include 2 groups of patients, one 
restricted to patients with ALK-activated neuroblastoma and the second including all other 
ALK-activated tumors. Enrollment will proceed in parallel. The goals of the expansion part of 
 


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the study are to better characterize the safety, tolerability and PK profile of LDK378, and to 
make a preliminary assessment of antitumor activity. The neuroblastoma group will enroll 
approximately 25 patients on the preferred regimen (fed or fasted), and the mixed tumor 
group will enroll approximately 20 patients. See Section 10.10 for sample size rationale.
Figure 4-1
Overview of study design
 


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4.2
Timing of interim analyses and design adaptations
Not applicable.
4.3
Definition of end of the study
End of study is defined as earliest occurrence of one of the following: 
1. All patients have discontinued study treatment, and all required Study evaluation 
completion (SEC) follow-up visit have been completed, or 
2. All patients have died, have been lost to follow-up or have withdrawn consent to further 
participation in the study, or the last patient on treatment has been enrolled into a separate 
rollover study or other option for continued treatment with LDK378, whichever comes 
first. 
Patients who are still receiving treatment with LDK378 and deriving clinical benefit will be 
offered enrollment into a separate study or other option for continued treatment with LDK378 
that are considered acceptable at the country level such as access to commercially available 
drug or managed access program. In the separate study, Novartis will continue to supply 
LDK378 to patients who may benefit from continued treatment as per the Investigator’s 
opinion. Safety will be monitored and reported to Health Authorities per regulatory 
requirements. Prior to the end of the current study (CLDK378X2103), this separate protocol 
will be submitted to Health Authorities and IRBs involved in the current study. 
The final analysis of study data will be conducted at the end of the study and all available 
safety and efficacy data from all patients will be analyzed. A final clinical study report (CSR) 
will be produced reporting all available data collected.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. This includes early study 
termination if the investigators and Novartis determine that patients are experiencing 
excessive toxicity related to LDK378, and the available data indicate that continuation at a 
lower dose level is not appropriate. Should this be necessary, all patients should be seen as 
soon as possible and the same assessments should be performed as described in Section 7 for 
the EOT and SEC visits. 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 with LDK378 as a single agent will be conducted in patients, aged 12 months to 
less than 18 years, with malignancies carrying a genetic alteration of ALK. Taking into 
account the distribution of ALK abnormalities in pediatric malignancies, it is expected that 
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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.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Patients must be diagnosed with a locally advanced or metastatic malignancy that has 
progressed despite standard therapy, or for which no effective standard therapy exists.
2. Age ≥ 12 months and <18years.
3. The tumor must carry a genetic alteration of ALK including any of the following:

A point mutation, or any other mutation (e.g. insertion or deletion), , which results in 
a change of  the amino acid sequence of the kinase domain of ALK.

An amplification of the ALK gene, defined as ≥ 9 copies per cell, or 4 copies per 
haploid genome. When assessed by FISH, ALK amplification must be observed in 
focal clusters of tumor cells (not only single cells) or in more than one-third of the 
tumor cells.

A rearrangement of the ALK gene (when rearrangement assessed by FISH positivity 
must be detected in ≥ 15% of the tumor cells).

In patients with rhabdomyosarcoma or anaplastic large cell lymphoma, expression of 
ALK protein based on immunohistochemistry is sufficient for eligibility.
4. Patients must have evaluable or measurable disease as defined by one of the following 
criteria: RECIST v1.1 for patients with non-hematologic malignancies (Appendix 5); 
MIBG scan for patients with neuroblastoma, International Working Group (IWG) criteria 
for patients with lymphoma (Appendix 6).
5. Performance status:

Karnofsky performance status score ≥ 60% for patients > 12 years of age.

Lansky score ≥ 50% for patients ≤ 12 years of age.
Note: patients who are unable to walk because of paralysis, but who are mobile in a 
wheelchair, will be considered ambulatory for the purpose of assessing the 
performance score.
6. Written informed consent/assent before any study-specific molecular pre-screening and 
screening procedures. For pediatric patients (as defined by local standards), consent will 
be obtained from parent(s) or legal guardian(s) and the signature of at least 1 parent or 
guardian will be required. Investigators will also obtain assent of patients according to 
local, regional or national guidelines.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patients with symptomatic central nervous system (CNS) metastases who are 
neurologically unstable or require increasing doses of steroids or local CNS-directed 
therapy (such as radiotherapy, surgery or intrathecal chemotherapy) to control their CNS 
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2. Patients with clinically significant, uncontrolled heart disease or corrected QT (QTc) 
interval > 480 milliseconds, using the Fridericia correction (QTcF).
3. Patients with the following laboratory values during screening:

Creatinine > 1.5 x ULN for age.

Total bilirubin > 1.5 x ULN for age, except for patients with Gilbert’s syndrome, who 
may be included if total bilirubin is ≤ 3.0 x ULN and direct bilirubin is ≤ 1.5 x ULN.

Alanine aminotransferase (ALT) > 3 x ULN for age, except for patients that have 
tumor involvement of the liver, who must have a value ≤ 5 x ULN.

Serum aspartate aminotransferase (AST) > 3 x ULN for age, except for patients that 
have tumor involvement of the liver, who must have a value ≤ 5 x ULN.

Absolute neutrophil count (ANC) < 0.75 x 109/L without use of granulocyte growth 
factor for ≥ 14 days.

Platelet count < 50 x 109/L.

Hemoglobin (Hgb) < 8 g/dL.

Alkaline phosphatase (ALP) > 5.0 x ULN

Serum amylase > 2 x ULN

Serum lipase > ULN

Fasting plasma glucose ≥175 mg/dL (≥9.8 mmol/L)

Potassium, magnesium, calcium or phosphate abnormality > CTCAE grade 1.
4. Body surface area (BSA) < 0.35 m2.
5. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of LDK378 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
or malabsorption syndrome).
6. Evidence of active viral hepatitis, including Hepatitis A, B or C (testing for viral hepatitis 
is not mandatory).
7. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not 
mandatory).
8. Presence of ≥ CTCAE grade 2 toxicity (except alopecia, peripheral neuropathy, 
ototoxicity and lymphopenia, which are not excluded if grade 3 or less) due to prior cancer 
therapy.
9. Malignant disease, other than that being treated in this study. Exceptions to this exclusion 
include the following: malignancies that were treated curatively and have not recurred 
within 3 years prior to study entry; completely resected basal cell and squamous cell skin 
cancers; and completely resected carcinoma in situ of any type.
10. History of known interstitial lung disease or interstitial pneumonitis, including clinically 
significant radiation pneumonitis (i.e., affecting activities of daily living or requiring 
therapeutic intervention).
11. Patients who have received systemic anticancer therapy within 3 weeks of the first dose of 
LDK378. Patients whose immediate prior treatment was an ALK inhibitor may start 
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12. Radiotherapy to lungs ≤ 4 weeks prior to starting the study treatment or patients who have 
not recovered from radiotherapy-related toxicities. For all other anatomic sites, 
radiotherapy ≤ 2 weeks prior to starting the study treatment.
13. Major surgery within 2 weeks of the first dose of LDK378. Insertion of a gastric feeding 
tube (G-tube), nasogastric feeding tube (NG-tube), and central venous access are not 
considered major surgery.
14. Patients receiving medications that are known to be strong inhibitors or inducers of 
CYP3A4/5 that cannot be discontinued at least 1 week prior to start of treatment with 
LDK378 and for the duration of the study (Appendix 2).
15. Patients receiving medications that are mainly metabolized by CYP3A4/5 or CYP2C9 and 
have low therapeutic index that cannot be discontinued at least 1 week prior to start of 
treatment with LDK378 and for the duration of the study (Appendix 2).
16. Medications with a known risk of prolonging the QT interval or inducing Torsades de 
Pointes (Appendix 2).
17. Pregnant or nursing (lactating) females.
18. Females of child-bearing potential, defined as all females physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 3 months after stopping dosing. Highly effective contraception 
methods include:

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 
LDK378. In case of oophorectomy alone, only when the reproductive status of the 
female has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female patients on the 
study 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 females should have been stable on the same pill for a 
minimum of 3 months before taking LDK378.
19. Sexually active males, unless they use a condom during intercourse while taking LDK378 
and for 3 months after stopping LDK378 treatment, and should not father a child in this 
period. A condom is required to be used also by vasectomized men in order to prevent 
delivery of the drug via seminal fluid.
20. Patient has other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may interfere with the interpretation of study results, and in the judgment 
of the investigator would make the patient inappropriate for the study.
21. Patient has a history of pancreatitis or history of increased amylase or lipase that was due 
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6
Treatment
6.1
Study treatment
All dosages of LDK378 prescribed and dispensed to the patient and all dose changes during 
the study must be recorded on the Dosage Administration Record (DAR) eCRF.
6.1.1
Dosing regimen
LDK378 dose will be scaled by BSA. The dose will be adjusted to the nearest 50 mg, and the 
minimum dose will be 50 mg. LDK378 will be administered once daily by mouth, or by NG 
tube or G tube. For patients who are not able to swallow the capsules, or who will receive 
LDK378 through a NG tube or G tube, the capsules will be opened, and the contents mixed 
with an appropriate food or liquid. Further detailed instructions regarding capsule opening and 
administration will be provided to all study sites separate from this protocol.
The study site staff will inform each patient of their actual daily dose, and this will be 
recorded on the appropriate eCRF. The actual dose for each patient will be calculated using a 
body surface area (BSA) conversion as follows:

Actual dose in mg = (planned dose level (mg/m2) x BSA) rounded to the nearest 50 mg
Individual patient BSA will be calculated using their height and weight as per standard site 
procedure. The actual dose for Cycle 1 will be based on the BSA calculation at screening. 
Dosage adjustments for changes in BSA in subsequent cycles will be made as per standard 
site practice (e.g., if the BSA changes by ± 10% from the previous dose calculation).
Individual doses will consist of the minimum number of capsules possible given based on the 
available capsule sizes, and will be rounded to the nearest 50 mg.
The investigator should instruct the patient to take the LDK378 exactly as prescribed below. 
All dosages prescribed and dispensed to the patient, and all dose changes during the study 
must be recorded on the appropriate eCRF. Patients/guardians will be asked to complete a 
paper dosing diary starting Cycle 1 Day 1 and will return the paper dosing diary to the study 
site at the beginning of each subsequent cycle (cycle 2 and on). A new diary will be dispensed 
to the patient at the beginning of each new cycle.
6.1.2
LDK378 administration
LDK378 should be taken as follows:

Patients should take LDK378 once daily at approximately the same time each day. On 
days that PK samples are obtained, the patient will take LDK378 during the clinic visit, 
when instructed by the study staff.

For patients enrolled in a fasted cohort each daily dose of LDK378 (including days which 
involve PK blood sampling) should be taken at least 2 hours after the last meal and 
patients should not eat until 1 hour after LDK378 is taken.

Each daily dose of LDK378 should be taken with 1-2 tablespoons (15-30 mL) of an 
appropriate food (such as apple sauce or non-fat yogurt) and a glass of water, and 
consumed over as short a time as possible. Patients should be instructed to swallow 
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
For patients enrolled in a fed cohort each daily dose of LDK378 (including days which 
involve PK blood sampling) should be taken with, or within 30 minutes after finishing a 
low-fat light snack containing 100-300 calories and 1.5-2 grams of fat. Each daily dose of 
LDK378 should be taken with a glass of water, and consumed over as short a time as 
possible. Patients should be instructed to swallow capsules whole.

For patients (including those in fasted cohorts and those in fed cohorts) who have 
difficulty swallowing intact capsule(s), the capsule(s) may be opened and the contents 
may be mixed with an appropriate food (such as apple sauce or non-fat yogurt) and eaten, 
or the contents may be mixed with water and administered via a NG tube or G tube. Once 
LDK378 is mixed with the carrier food or water it should be consumed within 2 hours. 
Further detailed instructions regarding capsule opening and administration will be 
provided to all study sites separate from this protocol. That document will also specify 
other foods and liquids that can be used as a carrier for LDK378, and updated as data 
become available.

If vomiting occurs during the course of treatment, re-dosing is not allowed before the next 
scheduled dose.

Patients should be instructed not to make up missed doses. A missed dose will include 1) 
when a patient forgets to take LDK378 within 12 hours after the approximate time of the 
usual daily dosing, or 2) a patient forgets to take his/her dose for that day. That day’s dose 
should be omitted and the patient should continue treatment with the next scheduled dose.

Patients or guardians should inform the study site staff of any missed or delayed doses.

The investigator should instruct the patient to take the LDK378 exactly as prescribed. All 
dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF. Patients/guardians will be 
asked to complete a paper dosing diary starting Cycle 1 Day 1 and will return the paper 
dosing diary to the study site at the beginning of each subsequent cycle (cycle 2 and on). 
A new diary will be dispensed to the patient at the beginning of each new cycle.
6.1.3
Treatment duration
Patients will continue treatment with the study drug until unacceptable toxicity that precludes 
any further treatment, disease progression, and/or treatment is discontinued at the discretion of 
the investigator or by patient refusal. Patients who have disease progression but who, in the 
opinion of the Investigator, have evidence of continued clinical benefit from LDK378 may 
continue to receive LDK378. A treatment cycle is defined as 21 days for the purposes of 
scheduling procedures and evaluations. There will be no scheduled break between cycles.
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 2 cycles (42 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 2 cycles (42 days), could benefit from additional treatment, 
continuation may be allowed.
6.2
Dose escalation guidelines
 


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6.2.1
Starting dose rationale
The starting dose of LDK378 in this pediatric study is based on the clinical safety data, DLT 
and MTD data from the phase 1 study ([CLDK378X2101]) in adult NSCLC patients. In the 
adult phase 1 study the MTD was 750 mg on a once daily schedule. Based on the Bayesian 
logistic regression model (BLRM), at the 750 mg dose level the probability of unacceptable 
toxicity (DLT rate ≥ 33%) was 3.3% (satisfying the overdose criterion of < 25%), and the 
probability of being within the target toxicity interval (DLT rate ranging from 16% to < 33%) 
was 54%.
The starting dose for the fasted dose escalation, 300 mg/m2, is 66.7% of the adult MTD (0.677 
x 750 mg = 500 mg), scaled by BSA. Assuming an average adult BSA of 1.7 m2, the starting 
dose is 300 mg/m2 (rounded from 294 mg/m2). In the adult phase 1 study most antitumor 
responses occurred at doses ≥ 400 mg qd, with < 0.1% probability of unacceptable toxicity at 
the 500 mg qd dose level, as determined by the BLRM. Thus, a starting dose of 300 mg/m2
offers a high probability of beginning at an active dose, but a low probability of excessive 
toxicity. Additional information supporting the starting dose is provided in Section 2.3.
6.2.2
Provisional dose levels
Table 6-1 describes the starting dose and the dose levels that may be evaluated for the fasted 
dose escalation part during this trial.
Table 6-1
Provisional dose levels for fasted pediatric dose escalationa
Dose Level
Provisional Daily Doseb
Increment from previous dose
-1c
200 mg/m2
33% reduction
1 (starting dose)
300 mg/m2
Starting dose
2
450 mg/m2
50% increase
3
560 mg/m2
25% increase
4
700 mg/m2
25% increase
5
875 mg/m2
25% increase
6
1090 mg/m2
25% increase
a. This table is intended as an example for guidance for the dose escalation part only. Intermediate or 
higher dose levels may be used if the dose-escalation rules presented in this protocol are followed. 
Actual dose levels will be confirmed in writing by Novartis and provided to all participating study sites 
before treatment of patients in a new cohort.
b. All doses will be dosed on a mg/m2 basis, rounded to the nearest 50 mg (refer to Section 6.1.1 for 
details).
c. Dose level -1 may be used if appropriate (e.g., if the starting dose level is not well tolerated).
The fasted dose escalation will continue until the MTD and/or the RDE dose is reached. 
Following completion of the dose escalation part of the study, a dose will be chosen for the 
expansion part of the study. The dose for the expansion part will be opened at either the fasted 
MTD, or a lower dose that is determined to be the RDE.
After the fasted dose escalation has reached the MTD and/or RDE, the fed dose escalation 
will begin. The starting dose for the fed dose escalation part will be approximately 63% of the 
fasted MTD determined in this study. This is based on the data from adult healthy volunteers 
 


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taking LDK378 with a low-fat meal. It is estimated that the steady state exposure of LDK378 
with a low-fat meal will be increased 1.58 fold. Dose escalations during the fed dose 
escalation part of the study will be limited to a 25% or smaller increase above the prior fed 
dose level.
Once the fed dose escalation begins, patients will be preferentially enrolled on the opened fed-
dose escalation cohort; however, patients may continue to be enrolled into the expansion 
cohort at the fasted MTD/RDE if there is no availability on a fed-cohort.
6.2.3
Guidelines for dose escalation and determination of (MTD/RDE)
For the purposes of dose escalation decisions, each cohort will consist of 3 to 6 newly 
enrolled patients who will be treated at the specified dose level. The first fasted cohort will be 
treated with the starting dose of 300 mg/m2. The first fed cohort will be treated with a starting 
dose of approximately 63% of the fasted MTD determined in this study.
Patients must complete a minimum of 1 cycle of treatment with the minimum safety 
evaluation and drug exposure or have had a DLT within the first cycle of treatment to be 
considered evaluable for dose escalation decisions. Dose escalation decisions will occur when 
the cohort of patients has met these criteria.
Dose escalation decisions will be made by Investigators and Novartis study personnel. 
Decisions will be based on a synthesis of all relevant data available from all dose levels 
evaluated in the ongoing study, including safety information, DLTs, all CTCAE Grade ≥ 2 
toxicity data during Cycle 1 and available PK data from evaluable patients. The recommended 
dose for the next cohort of patients will be guided by the Bayesian logistic regression model 
(BLRM) with EWOC principle.
The adaptive Bayesian methodology provides an estimate of all dose levels of LDK378 that 
do not exceed the MTD and incorporates all DLT information at all dose levels for this 
estimation. In general, the next dose will have the highest chance that the DLT rate will fall in 
the target interval (16-33%) and will always satisfy the EWOC principle. In all cases, the dose 
for the next cohort will not exceed a 50% (25% after reaching 450 mg/m2) increase from the 
previous dose. Smaller increases in dose may be recommended by the Investigators and 
Novartis upon consideration of all of the available clinical data.
If the first 2 patients in a cohort experience a DLT, further enrollment to that cohort will stop 
and the BLRM will be updated with this new information. Re-evaluation of the available 
safety and PK data will occur. By incorporating information gained at the preceding dose 
levels, additional patients may be enrolled at this dose level or a lower dose level as agreed by 
Investigators and Novartis personnel and if the BLRM predicts that the risk that this dose 
exceeds the MTD remains below 25% (EWOC).
Dose escalation will continue until identification of the MTD or a suitable lower dose for 
expansion. This will occur when the following conditions are met:
1. at least 6 patients have been treated at this dose.
2. the dose satisfies one of the following conditions:
a. the posterior probability of targeted toxicity at this dose exceeds 50% and is the 
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b. minimum number of patients (15 for the fasted state dose escalation, 12 for the fed 
state dose escalation) have already been treated on the trial.
3. it is the dose recommended for patients, either per the model or by review of all clinical 
data by Novartis and Investigators in a dose-escalation teleconference, see Section 6.2.3.1.
Due to the rarity of pediatric cancers with genetic alterations of ALK and the small number of 
patients evaluated at each dose level, and consistent with the typical approach in phase 1 
pediatric oncology studies, dose escalation decisions will not be based on age categories. 
However, if adequate data become available to indicate that the DLT rate is age-related, the 
protocol may be amended to define different MTDs in different age categories.
To better understand the safety, tolerability and PK of LDK378, additional cohorts of patients 
may be enrolled at preceding dose levels, or to intermediate dose levels before or while 
proceeding with further dose escalation.
If a decision is made to escalate to a higher dose level but one or more additional patient(s) 
treated at the preceding dose level experiences a DLT during the first cycle of treatment, then 
the BLRM will be updated with this new information before any additional patients are 
treated at that higher dose level. Patients ongoing will continue treatment at their assigned 
dose levels.
6.2.3.1
Implementation of dose escalation decisions
To implement dose escalation decisions, the available toxicity information (including adverse 
events and laboratory abnormalities that are not DLTs), the recommendations from the BLRM, 
and the available PK information will all be evaluated by the Investigators and Novartis study 
personnel (including the study physician and statistician) during a dose decision meeting by 
teleconference. Drug administration at the next higher dose level may not proceed until the 
investigator receives written confirmation from Novartis indicating that the results of the 
previous dose level were evaluated and that it is permissible to proceed to a higher dose level.
6.2.3.2
Intra-patient dose escalation
Intra-patient dose escalation is not permitted at any time within the first 4 cycles of treatment. 
After the fourth cycle is completed, individual patients may be considered for treatment at a 
LDK378 dose higher than the dose to which they were initially assigned. In order for a patient 
to be treated at a higher dose of LDK378, he or she must have tolerated the lower dose for at 
least 4 cycles of therapy without any LDK378-related toxicity ≥ CTCAE grade 2. The 
proposed higher dose must be a dose that has completed evaluation and has not exceeded the 
maximum tolerated dose (MTD). Novartis must be consulted prior to an intra-patient dose 
escalation, and agree with the escalation decision. There is no limit to the number of times a 
patient may have his or her dose of LDK378 increased. The dose change must be recorded on 
the DAR eCRF.
Data from the first cycle of treatment at the new dose level will not be formally included in 
the statistical model describing the relationship between dose and occurrence of DLT. 
However, these data will be incorporated into the clinical assessment of safety when 
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6.2.3.3
Changing from Fasted to Fed Dosing
Changing from fasted dosing to fed dosing is allowed after the patient has completed at least 
six cycles of fasted dosing, provided the following:

The MTD/RDE in the fed state has been determined, and dosing with food has been 
chosen for further expansion

The dose level of LDK378 must remain the same, or be reduced to the MTD/RDE in the 
fed state, if that is lower than the patient’s current dose

The patient must have tolerated the fasted dose without any drug-related toxicity ≥ Grade 
3, except for nausea, vomiting, diarrhea or abdominal pain

If a patient on the fasted dosing has had a drug-related toxicity of ≥ Grade 3 other than 
nausea, vomiting, diarrhea or abdominal pain, the patient must have had a dose reduction 
and tolerated the reduced dose without a drug-related toxicity of ≥ Grade 3 for at least two 
cycles before changing from fasting dosing to fed dosing
6.2.4
Definitions of dose limiting toxicities (DLTs)
A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to 
disease, disease progression, inter-current illness, or concomitant therapies that occurs within 
the first 21 days (Cycle 1) of treatment with LDK378 and meets any of the criteria included in 
Table 6-2. Any adverse event is not considered a DLT if it does not happen within the first 21 
days of treatment. However, medically significant events should be followed up as for DLTs. 
NCI CTCAE version 4.03 will be used for all grading. For the purpose of dose-escalation 
decisions, DLTs will be considered and included in the BLRM.
The investigator must notify Novartis immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities. Prior to enrolling patients into a higher dose level, 
CTCAE grade ≥ 2 adverse events will be reviewed for all patients at the current dose level
Table 6-2
Criteria for defining dose-limiting toxicities
Any adverse event of CTCAE grade 3 or higher during cycle 1 is a DLT, with the following 
exceptions
Hematology
●
Neutropenia is a DLT if it is CTCAE grade 4 lasting > 7 days
●
Thromobcytopenia is a DLT if it is CTCAE grade 3 lasting > 7 days 
or CTCAE grade 4 thrombocytopenia at any time 
●
Anemia is a DLT if it is CTCAE grade 4 lasting > 7 days
●
Lymphopenia is a DLT if it is CTCAE grade 4
Renal
●
Serum creatinine > 2 x ULN is a DLT Refer to Table 6-5 for 
additional follow up.
Hepatic
●
AST or ALT increase is a DLT if CTCAE grade 3 or greater
●
Total bilirubin is CTCAE grade 2 with AST or ALT CTCAE grade 1 
in the absence of cholestasis or hemolysis. Refer to Table 6-5 for 
additional follow up.
Pulmonary
●
Pneumonitis or ILD of any grade without infectious etiology is a 
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Any adverse event of CTCAE grade 3 or higher during cycle 1 is a DLT, with the following 
exceptions
Gastrointestinal
●
Nausea and vomiting are DLTs if they are ≥ CTCAE grade 2 
despite optimal anti-emetic therapy
●
Amylase and/or lipase elevation ≥ grade 3 is a DLT. Refer to Table 
6-5 for additional follow up.
●
Diarrhea is a DLT if it is ≥ CTCAE grade 3 despite optimal anti-
diarrhea treatment
Infection
●
Infection or fever in the absence of neutropenia are DLTs if they 
are ≥ CTCAE grade 3 and last > 5 days
Electrolytes
●
Hypophosphatemia is a DLT if it is ≥ CTCAE grade 3 and lasts > 7 
days
Fatigue
●
Fatigue is a DLT if it is ≥ CTCAE grade 3 and lasts > 7 days
Other adverse events
Other unacceptable toxicities may be considered to be DLTs by the 
Investigators and Novartis, even if not CTCAE grade 3 or higher
Any toxicity resulting in an 
excess of missed doses
Inability to deliver ≥ 75% of the planned doses in a treatment cycle 
(i.e. at least 16 doses in a 21 day cycle) because of toxicity at least 
possibly related to LDK378 is a DLT
CTCAE version 4.03 will be used for all grading.
Patients may receive supportive care as per local institutional guidelines.
Optimal therapy for vomiting or diarrhea will be based on institutional guidelines, with consideration of 
the prohibited medications listed in this protocol.
Dose modification related to DLTs
If a patient experiences a DLT, treatment with LDK378 should be held. Following resolution 
of the toxicity to grade 1 or to the patient’s baseline value the patient may resume treatment 
with LDK378. In general patients who resume therapy following a DLT should resume at a 
lower dose level assessed to be safe with a minimum dose reduction of 50 mg. However, 
following recovery of a DLT that was not considered clinically important or can be managed 
if it recurs (e.g., replacement of an electrolyte), the patient may resume therapy without dose 
reduction, if the investigator considers that to be in the best interest of the patient. The dose 
should not be reduced below 150 mg/m2. Provisional dose levels for LDK378 are listed in 
Table 6-1.
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 administration must be recorded on the Dosage Administration Record eCRF.
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 2 cycles (42 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 
 


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interruption greater than 2 cycles (42 days), could benefit from additional treatment, 
continuation may be allowed.
LDK378 dose reduction will follow the dose reduction steps described in Table 6-3. For each 
patient, a maximum of 3 dose modifications will be 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 confirmed by the investigator, the criteria for dose modification will also apply.
Table 6-3
Dose reduction steps for LDK378 at RDE (fasted and fed states)
LDK378 dose levels
Dose* and schedule
Starting dose level
RDE: 500/510  mg/m2 QD continuously
Dose level -1
400 mg/m2 QD continuously
Dose level - 2
300 mg/m2 QD continuously
Dose level -3
200 mg/m2 QD continuously
*Dose reduction should be based on the worst preceding toxicity as per NCI-CTCAE version 4.03
**Dose reduction below 200 mg/m2/day is not allowed. If a dose reduction below 200 mg/m2/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 6-4.
Patients, who discontinue from the study for a study-related adverse event or an abnormal 
laboratory value, must be followed as described in Section 7.1.3.
General guidelines for dose modifications for toxicities other than those listed in
Table 6-4:
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 of that toxicity, to 
grade 1 or lower. Study treatment may be resumed following a dose reduction to the next dose 
level if, in the opinion of the Investigator, the patient continues to experience clinical benefit. 
For any grade 3 or grade 4 treatment-related toxicity that is considered by the Investigator to 
be life-threatening, study treatment must be permanently discontinued.
In the case of a DLT of QTc prolongation (QTc >500 ms) LDK378 must be withheld until 
resolution to grade 1 or less. If LDK378 is resumed, the dose must be reduced by at least 1 
dose level and at least 50 mg. In the case of grade 4 QTc prolongation (QTc >500 ms 
complicated by Torsades de pointes, polymorphic ventricular tachycardia, or signs/symptoms 
of serious arrhythmia; or >60 ms change from baseline complicated by Torsades de pointes, 
polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia) LDK378 
should be permanently discontinued.
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 
 


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than 2 cycles (42 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 2 cycles (42 days), could benefit from additional treatment, 
continuation may be allowed.
 


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


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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 6.3.2.2 for 
additional follow-up.
AST or ALT > 5.0 and ≤ 20.0 x ULN with total bilirubin > 1.5 and ≤ 
3.0 x ULN
Permanently discontinue patient from LDK378 if event reoccurs after dose 
reduction.
PANCREATIC
Amylase and/or lipase evaluations (in absence of clinical symptoms)
Grade 1 (> ULN and ≤1.5 x ULN)
Maintain dose level
Grade 2 (>1.5 - 2.0 x ULN)
Maintain dose level
Grade ≥3 (> 2.0 x ULN)
Omit dose until resolved to ≤ Grade 1, then 1 dose level
Note: Withhold LDK378 for acute onset of new or progressive unexplained abdominal symptoms, such as severe pain or vomiting; perform diagnostic 
procedures (e.g., abdominal CT scan or ultrasound) to exclude pancreatic pathology.
RENAL
 


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Worst toxicity (CTCAE 4.03 Grade)*
Dose Modifications for LDK378
Serum creatinine
Grade 1 (>1 and ≤1.5 x baseline; >ULN and ≤ 1.5 x ULN)
Maintain dose level
Grade 2 (>1.5 and ≤3.0 x baseline; > 1.5 and ≤ 3 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
METABOLIC
Any Grade hypophosphatemia
Treatment with phosphate supplements as clinically indicated and maintain dose 
level
 


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Worst toxicity (CTCAE 4.03 Grade)*
Dose Modifications for LDK378
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.
●
For pneumonitis not treatment related: If pneumonitis/ILD of grade 2 or worse is confirmed, study drug should be permanently discontinued. If Grade 
1 resolves within 6 weeks, LDK378 may be resumed reduced by 1 dose level, otherwise it must be discontinued. If grade 1 pneumonitis recurs after dose 
reduction, then LDK378 must be permanently discontinued.
PNEUMONITIS 
Any Grade treatment-related ILD/pneumonitis
Permanently discontinue patient from LDK378
CARDIAC
Electrocardiogram QT corrected (QTc) interval prolonged
Grade 1 (QTc 450-480 ms)
Grade 2 (QTc 481-500 ms)
Maintain dose level
 


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Worst toxicity (CTCAE 4.03 Grade)*
Dose Modifications for LDK378
Grade 3 (QTc ≥ 501 ms on at least two separate ECGs)
Omit dose until QTc is less than 481 ms , then 1 dose level
- Assess the quality of the ECG recording and the QT value and repeat if needed
Repeat ECG in 24 hours, or less, as clinically indicated; continue monitoring as 
clinically indicated until QTc < 481 ms.
In addition:-Determine the serum electrolyte levels (in particular hypokalemia, 
hypomagnesemia). If abnormal, correct abnormalities before resuming study drug 
treatment
- Review concomitant medication use for drugs with the potential to increase the 
risk of drug exposure related to QT prolongation
After resumption of dosing:
- Repeat ECGs 7 days after dose resumption for all patients who had therapy 
interrupted due to QTc ≥ 501 ms.
Grade 4 (QTc ≥ 501 or > 60 ms change from baseline and 
Torsades de pointes or polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia)
Permanently discontinue patient from LDK378
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
Omit dose until recovery to asymptomatic bradycardia or to a heart rate ≥ 60 bpm
Patient may resume LDK378 at ↓ 1 dose level with frequent monitoring
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 (fractionated if total bilirubin > 2.0 x ULN), alkaline phosphatase 
**** Dose modifications apply to patients who experience diarrhea despite appropriate antidiarrheal medication. This medication should be started at the 
first sign of abdominal cramping, loose stools or overt diarrhea (see Section 6.3.2.5)
***** Dose modifications apply to patients who experience nausea and/or vomiting despite appropriate antiemetic medication. This medication should be 
started at the first sign of nausea and/or vomiting (see Section 6.3.2.6)
 


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6.3.2
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 in (Table 7-1). 
For details and frequency refer to Table 6-5.
6.3.2.1
Guidelines for the follow-up of laboratory hematologic abnormalities
In case of any occurrence of febrile neutropenia, neutropenia ≥ grade 3, anemia grade 4, or 
thrombocytopenia ≥ grade 3, white blood cell count with differential (including neutrophil 
count), platelet count and hemoglobin must be measured after 3 days and then at least once a 
week (or more frequently if clinically indicated) until the event resolves to ≤ grade 2 or 
baseline. Subsequent monitoring must be performed every 3 weeks (21 days).
Hematopoietic growth factors (e.g., erythropoietins, G-CSF, and GM-CSF) are not to be 
administered prophylactically. Use of these drugs should be reserved to patients with severe 
neutropenia and anemia as per the labeling of these agents.
6.3.2.2
Guidelines for the follow-up of liver laboratory abnormalities
In patients with any clinically relevant liver laboratory abnormality, as defined below, hepatic 
toxicity monitoring must include ALL of the following LFTs: albumin, ALT, AST, total 
bilirubin (fractionated if total bilirubin > 1.5x ULN, and any additional evaluation suggested 
by these results should be performed as clinically indicated), ALP. 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 2 weeks (or more frequently if 
clinically indicated) for two additional cycles (e.g. 6 weeks). If there is no recurrence of ≥ 
grade 2 ALT/AST/total bilirubin elevations during this period, subsequent monitoring must be 
performed every 3 weeks. For patients with liver metastasis and grade 2 AST/ALT at baseline, 
increased monitoring is required for grade 3/4 AST/ALT; follow guidelines for grade 3 or 4 
AST/ALT.
In case of any occurrence of ALT/AST/total bilirubin increase to grade 3 or 4, LFTs must be 
monitored weekly (or more frequently if clinically indicated) until the event resolves to ≤ 
grade 1. Thereafter monitoring must be continued every 2 weeks (or more frequently if 
clinically indicated) for four additional cycles (e.g., 12 weeks). If there is no recurrence of ≥ 
grade 2 ALT/AST/total bilirubin elevations during this period, subsequent monitoring must be 
performed every 3 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 3 weeks). Refer to Table 6-5.
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential DILI, and should be considered as clinically important events.
 


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The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: ALP elevation > 2.0 x ULN with R value (ALT/ALP in x ULN) < 2 in patients without 
bone metastasis, or elevation of ALP liver fraction in patients with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to 
cholestatic or hepatocellular liver injury).
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from 
the awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc:

Laboratory tests should include ALT, AST, albumin, creatinine kinase, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.

A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.

Further testing for acute hepatitis A, B, C or E infection and liver imaging (eg, biliary tract) 
may be warranted.

Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
All cases confirmed after repeat testing and meeting the laboratory criteria defined above, 
with no other alternative cause for LFT abnormalities identified should be considered as 
“medically significant”, these cases will meet the definition of SAE (Section 7.2.1) and 
reported as SAE using the term “potential drug-induced liver injury”. All events should be 
followed up with the outcome clearly documented.
6.3.2.3
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 3 weeks.
In case of any occurrence of serum creatinine ≥ grade 3, tests must be performed twice weekly 
(or more frequently if clinically indicated) until the event resolves to ≤ grade 1. Subsequent 
monitoring must be performed every 3 weeks.
 


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6.3.2.4
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. Exclude other 
causes of pneumonitis, and follow dose modification guidelines as described in Table 6-4.
6.3.2.5
Guidelines for the treatment of study treatment-induced diarrhea
The investigator should consider/investigate potential concomitant medication-, food-, or 
comorbidity-driven causes of diarrhea (including infectious causes) and remedy these causes 
if possible (e.g., discontinuation of concomitant medication, dietary modification, treatment of 
comorbidity).
The patient should be actively 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 practices and the Investigator’s best judgment and may follow “the recommended 
guidelines for the treatment of cancer treatment-induced diarrhea” (Benson et al 2004). For 
example:

For uncomplicated diarrhea (grade 1 or 2 without complicating signs or symptoms), 
loperamide given at the usual pediatric dose as per local Label, 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 IV fluids, and consider treatment with 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 6-4.
6.3.2.6
Guidelines for the treatment of study treatment-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 also 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.
 


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Concomitant medication for the treatment of nausea and/or vomiting should follow local 
practices and the Investigator’s best judgment. For moderately 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 6-4.
6.3.2.7
Guidelines for the treatment of hypophosphatemia
In the phase I study [CLDK378X2101] conducted in adult patients, as of 31-Oct-2013, there 
were 9 cases of grade 3 hypophosphatemia observed 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 not among the 
commonly reported AE (6.3%), regardless of relationship to LDK378 treatment.
Therefore, phosphate levels will be checked during treatment. 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.
6.3.2.8
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. 3 weeks). If there is no recurrence of ≥ grade 
2 amylase or lipase elevations during this period, subsequent monitoring must be performed 
every 3 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 3 weeks). Refer to Table 6-5.
If amylase and/or lipase elevations are accompanied by new or progressive unexplained 
abdominal symptoms such as severe pain or vomiting, withhold ceritininb, then perform 
diagnostic procedures (e.g., abdominal CT scan or ultrasound) to exclude pancreatic 
pathology.
See also dose modification guidelines described in Table 6-4.
 


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Table 6-5
Follow up evaluations for selected toxicities
Toxicity
Follow-up evaluation*
Investigations 
(hematologic)
Febrile neutropenia or thrombocytopenia ≥ CTCAE Grade 3 or
Neutropenia or anemia ≥ CTCAE Grade 4
White blood cell count with differential (including neutrophil count), platelet count 
and hemoglobin must be measured after 3 days and then at least once a week until 
resolution to ≤CTCAE grade 2 or baseline.
Neutropenia ≥ CTCAE Grade 3
Test after 3 days and then at least once a week until ≤ Grade 2 or baseline
Subsequent monitoring must be performed every cycle (3 weeks)
Investigations 
(hepatic)
Total bilirubin/AST/ALT 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 2 cycles (6 
weeks)
If no recurrence of ≥ Grade 2 event, continue monitoring every cycle (3 weeks)
Total bilirubin/ALT/AST ≥ Grade 3:
Test weekly (or more frequent) until ≤ Grade 1
Thereafter, continue to test every 2 weeks (or more frequently) for 4 cycles (12 
weeks)
If no recurrence of ≥ grade 2 event, continue monitoring every cycle (3 weeks)
Discontinuation due to liver toxicity:
Test weekly (or more frequent) until ≤ Grade 1 or stabilization
Investigations 
(renal)
Serum creatinine Grade 2:
Test weekly (or more frequent) until Grade 1
Thereafter, test every cycle (3 weeks)
Serum creatinine ≥ Grade 3:
Test twice weekly (or more frequent) until ≤ Grade 1
Thereafter, test every cycle (3 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 (3 weeks). If no reoccurrence of ≥ 
Grade 2 event, continue monitoring every cycle (3 weeks).
Investigations
(gastrointestinal)
Vomiting or diarrhea
Measure blood electrolytes at least once a week until the symptoms have resolved 
to ≤ CTCAE grade 1 or baseline. If nausea occurs in the absence of clinically 
relevant vomiting or diarrhea, the patient must be followed weekly as deemed 
clinically appropriate until resolved to ≤ CTCAE grade 2 or baseline.
*Note: this table refers to the evaluation schedule only. Refer to Table 6-4 for dose modifications 
required for applicable toxicities
 


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6.4
Concomitant medications
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 and prednisone (e.g., for 
tumor associated symptoms) are permitted during the course of the study. The 
corticosteroid dose must have been stabilized (or decreasing) for at least 5 days before 
initiating study therapy
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.
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 (Appendix 2). 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 
 


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dose titration or adjustment. Note that co-administration of LDK378 with strong inhibitors or 
inducers of CYP3A4/5 is prohibited (refer to Section 6.4.2).
Concomitant treatment of LDK378 with medications known to be metabolized by CYP2C9 
and CYP3A4 is allowed with caution (Appendix 2), except for drugs which have narrow 
therapeutic index/sensitive substrates for these CYP isoforms (Appendix 2).
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 analgesic purposes, or for lytic lesions at risk of fracture may be 
carried out if required. If palliative radiotherapy is initiated after start of study treatment, the 
reason for its use must be clearly documented and progression as per RECIST 1.1 must be 
assessed and documented. 
Patients who develop progressive disease but are still deriving clinical benefit from ceritinib 
therapy, as determined by the Investigator may undergo radiotherapy and/or surgical resection 
as palliative localized therapy to treat metastatic lesions. Ceritinib should be held for at least 4 
days prior to radiotherapy and at least 1 day prior to any surgery. Ceritinib may be resumed 
≥3 days after completing radiotherapy or minor surgery, and ≥2 weeks after major surgery.
6.4.1.6
Gastric protection agents
The use of gastric protection agents including antacids, H2-antagonists, and proton pump 
inhibitors (PPIs) is allowed (Appendix 2). 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 and palliative surgery as described in Section 6.4.1.5], and 
anti-cancer surgery), other than the study treatment, must not be given to patients while they 
are enrolled in the treatment portion of the trial. If such agents are required then the patient 
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.
 


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6.4.2.3
Warfarin and coumarin derivatives
Therapeutic doses of warfarin sodium or any other coumarin-derivative anticoagulants are not 
permitted. LDK378 is an inhibitor of CYP2C9, the major metabolizing enzyme of warfarin. A 
clinically relevant increase in warfarin exposure is possible.
6.4.2.4
Enzyme inducing anti-epileptic drug
Use of EIAEDs is not permitted. Refer to Appendix 2 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 Appendix 2 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 medications known to be 
metabolized by these enzymes and that have a narrow therapeutic index is not permitted 
concomitantly with LDK378. Refer to Appendix 2 for a list of these medications. Please note 
that this list may not be comprehensive.
6.4.2.7
Herbal medications
Herbal preparations/medications are not allowed throughout the study, as a potential drug-
drug interaction is always possible. These herbal medications include, but are not limited to: 
St. John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng.
Patients should stop using herbal medications at least 7 days prior to first dose of study 
treatment and may be resumed 9 days (5 ceritinib half life) after study drug discontinuation.
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. 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).
 


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Serial ECGs were collected following a single dose and at steady-state to evaluate the effect 
of LDK378 on the QT interval in an open-label, dose-escalation, and expansion [Study 
CLDK378X2101]. A total of 304 patients were treated with LDK378 doses ranging from 50 
to 750 mg with 255 patients treated with LDK378 750 mg. One of 304 patients (<1%) was 
found to have a QTc >500 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 use of LDK378 and any medication included in Appendix 2, Table 14-11 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 Patient Number (Patient No.), assigned when the 
patient is first pre-screened and is retained as the primary identifier for the patient throughout 
his/her entire participation in the trial. The Patient No. consists of a 4-digit Center Number 
(Center No.) (as assigned by Novartis to the study site) with a sequential 5-digit patient 
number suffixed to it, so that each patient is numbered uniquely across the entire database. 
Upon signing the pre-screening informed consent/assent form (ICF), the patient is assigned to 
the next sequential Patient No. available to the investigator.
6.5.2
Treatment assignment or randomization
The assignment of a patient to a particular cohort will be coordinated by the sponsor.
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient/guardian to 
take/dispense LDK378 as per protocol. LDK378 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 DAR eCRF.
Patients/guardians will be asked to complete a paper dosing diary starting Cycle 1 Day 1 and 
will return the paper dosing diary to the study site at the beginning of each subsequent cycle 
(cycle 2 and on). A new diary will be dispensed to the patient at the beginning of each new 
cycle.
 
 
 
 
 


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6.6.2
Drug supply and storage
LDK378 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, LDK378 should be stored according to the instructions 
specified on the drug labels.
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. Patients/guardians will be asked to complete a paper dosing diary starting Cycle 
1 Day 1 and will return the paper dosing diary to the study site at the beginning of each 
subsequent cycle (cycle 2 and on). A new diary will be dispensed to the patient at the 
beginning of each new cycle.
On days when LDK378 is administered to the patient by the study site staff (e.g. PK sampling 
days), compliance will be assured by administration of the LDK378 under the supervision of 
investigator or his/her designee, and will be verified by determinations of LDK378 in plasma.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of LDK378 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 and packaging on a regular basis, at the end of the study or at the time of 
LDK378 discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused LDK378, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the 
investigator folder at each study site.
6.6.4
Disposal and destruction
LDK378 supply can be destroyed at the local Novartis facility, at the study site 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. All data obtained from these assessments must be supported in the patient’s source 
 


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documentation. No eCRF will be used as a source document. Visit windows can be found for 
procedures starting with Section 7.2.
 


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Table 7-1
Visit evaluation schedule
Category
Protocol Section
Pre-screening
Screening/ Baseline
Treatment Period
End of study 
treatment (EoT)
Study Evaluation 
Completion (SEC)
Cycle 1
Cycle 2
Cycles 3-4
Cycles 5-16
Odd # 
Cycle ≥ 
17 
(teleph
one 
call)
Even # Cycle 
≥ 18 (on site 
visit)
Visit Name
1
2
3
4
5
6
7
8
9
10
11
14+
15+
36
+
37
+
38+
39+
777
778
Day of cycle
-28 
to-1
1
2
8
15 1
2
15
1
15
1
15
1
15
1
15
Last
30-
day 
follo
w-up
Obtain molecular pre-screening 
informed consent
D
7.1.1.
X
Obtain main informed consent
D
7.1.1.
X
Collection of tumor paraffin block or 
slides (archival tumor or tumor collected 
specifically for this study) for ALK 
assessment (only if ALK testing being 
performed at central lab)
D
7.1.1.
X
Patient history
Demography
D
7.1.1.3.
X
X
Inclusion/exclusion criteria
D
5.2/5.3.
X
Medical History
D
7.1.1.3.
X
Diagnosis and extent of cancer
D
7.1.1.3.
X
Prior/concomitant therapies (including 
prior antineoplastic therapies)
D
7.1.1.3.
Continuous
Antineoplastic therapies since 
discontinuation of LDK378
D
7.1.3.
X
 


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Category
Protocol Section
Pre-screening
Screening/ Baseline
Treatment Period
End of study 
treatment (EoT)
Study Evaluation 
Completion (SEC)
Cycle 1
Cycle 2
Cycles 3-4
Cycles 5-16
Odd # 
Cycle ≥ 
17 
(teleph
one 
call)
Even # Cycle 
≥ 18 (on site 
visit)
Visit Name
1
2
3
4
5
6
7
8
9
10
11
14+
15+
36
+
37
+
38+
39+
777
778
Day of cycle
-28 
to-1
1
2
8
15 1
2
15
1
15
1
15
1
15
1
15
Last
30-
day 
follo
w-up
Physical examination, including 
neurological exam
S
7.2.2.1.
X
X
X
X
X
X
X
X
X
Performance status Karnofsky (> 12 
years old) OR Lansky (≤ 12 years old)
D
7.2.2.4.
X
X
X
X
X
X
X
Height
D
7.2.2.3.
X
X
X
X
X
X
Weight
D
7.2.2.3.
X
X
X
X
X
X
BSA
D
7.2.2.3.
X
X
X
X
X
Vital signs
D
7.2.2.2.
X
X
X
X
X
X
X
X
X
Laboratory assessments
Hematology
** done at local laboratory
D
7.2.2.5.1.
X
X
X
X
X
X
X
X
X
X*
*
X
X
Chemistry
** done at local laboratory
D
7.2.2.5.2.
X
X
X
X
X
X
X
X
X
X*
*
X
X
Pregnancy test
** done at local laboratory
D
7.2.2.5.3.
X
X
X
X
X
X*
*
X
X
 


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Category
Protocol Section
Pre-screening
Screening/ Baseline
Treatment Period
End of study 
treatment (EoT)
Study Evaluation 
Completion (SEC)
Cycle 1
Cycle 2
Cycles 3-4
Cycles 5-16
Odd # 
Cycle ≥ 
17 
(teleph
one 
call)
Even # Cycle 
≥ 18 (on site 
visit)
Visit Name
1
2
3
4
5
6
7
8
9
10
11
14+
15+
36
+
37
+
38+
39+
777
778
Day of cycle
-28 
to-1
1
2
8
15 1
2
15
1
15
1
15
1
15
1
15
Last
30-
day 
follo
w-up
Tumor evaluations
Radiological tumor evaluation (± 7 days) 
* post Cycle 14, collect on D15 every six 
cycles: Cycles 20, 26, 32, etc. until off 
study
D
7.2.1.
X
X
C4
C6 
C10
C14
X*
X
MIBG imaging
(neuroblastoma patients only) (± 7 days) 
*post Cycle 14, collect on D15every six 
cycles: Cycles 20, 26, 32, etc. until off 
study
D
7.2.1.
X
If 
positive 
at 
Baseline
If 
positive 
at 
Baseline 
C4
If posit-
ive at 
Base-
line 
C6, 
C10
C14
If positive 
at 
Baseline*
If 
posit-
ive at 
base-
line
Bone marrow bilateral aspirate and 
biopsy (neuroblastoma and lymphoma 
patients only) (±7 days)
D
7.2.1.
X
Optional 
except in 
case of 
radiologi
cal CR 
Optional 
except in 
case of 
radiologi
cal CR
Optional 
except in 
case of 
radiologic
al CR
Optio
nal 
exce
pt in 
case 
of 
radiol
ogical 
CR 
ECG
D
7.2.2.5.4.
X
X
X
X
X
X
X
 


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Category
Protocol Section
Pre-screening
Screening/ Baseline
Treatment Period
End of study 
treatment (EoT)
Study Evaluation 
Completion (SEC)
Cycle 1
Cycle 2
Cycles 3-4
Cycles 5-16
Odd # 
Cycle ≥ 
17 
(teleph
one 
call)
Even # Cycle 
≥ 18 (on site 
visit)
Visit Name
1
2
3
4
5
6
7
8
9
10
11
14+
15+
36
+
37
+
38+
39+
777
778
Day of cycle
-28 
to-1
1
2
8
15 1
2
15
1
15
1
15
1
15
1
15
Last
30-
day 
follo
w-up
Safety
Adverse events
D
8.1.
Continuous
 
 
 
 
LDK378 administration
D
6.1.
Continuous
PK sampling (* indicates during 
Escalation only)
D
7.3.1.
X
*
X*
X* X
X
X
Meal record (* indicates during 
Escalation only)
D
X X*
X X
X*
X
 


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7.1.1
Molecular pre-screening and screening examination
Only patients with tumors carrying a genetic alteration of ALK are eligible for this study. 
Patients will be considered potentially eligible if their tumor carries a mutation (including 
point mutations, insertions and deletions), rearrangement (including translocations and intra-
chromosomal rearrangements), or amplification involving the ALK gene, as long as the 
alteration does not clearly result in inactivation of the kinase activity, such as deletion of the 
kinase domain, or a stop codon preventing translation of the kinase domain.
If the ALK tumor status is unknown when the patient is initially considered for this study, 
patients/guardians will be asked to sign the molecular pre-screening ICF. The study sites will 
pre-screen patients for genetic alterations of ALK by sending a tumor sample to a laboratory 
designated by Novartis. The tumor sample may be a previously obtained archival sample, or a 
sample obtained for the purpose of molecular pre-screening for this study (tumor paraffin 
block or slides). Additionally, a pathology report should be submitted along with the patient’s 
archival tumor block/slides. The ALK analysis results will be communicated to the study 
center within approximately 2 weeks of receipt of the sample. If the patient is already known 
to have a genetic alteration of ALK at pre-screening, the laboratory result may be used for 
eligibility assessment, if Novartis reviews the laboratory assessment and agrees that it is 
sufficient for eligibility.
7.1.1.1
Molecular pre-screening and screening period
 
 
 
 
 
 
 
 
 
 
 


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Patient re-screening is allowed and should be discussed with Novartis on a case by case basis 
before re-screening procedures are performed.
7.1.1.2
Information to be collected on screening failures
Patients who sign the molecular pre-screening ICF but do not meet the pre-screening 
requirements will be considered a screen failure. The reason will be entered on the Screening 
Log eCRF, and each patient’s demographic information will be added to the Demography 
eCRF. No other data will be entered into the clinical database for patients who are screen 
failures.
Patients who meet molecular pre-screening requirements and sign the main ICF but do not 
start treatment for any reason will be considered a screen failure. The reason for not being 
started on treatment will be entered on the Screening Log eCRF, and each patient’s 
demographic information will be added to the Demography eCRF. No other data will be 
entered into the clinical database for patients who are screen failures.
7.1.1.3
Patient demographics and other baseline characteristics
The data that will be collected on patient characteristics at molecular pre-screening and 
baseline include general demographics, relevant medical history, the diagnosis and extent of 
their tumor/s and details regarding anti-neoplastic treatments that they have received in the 
past.
7.1.2
Treatment period
The treatment period commences on the first day of the first cycle (C1D1) of LDK378 and 
ends after the last dose of LDK378.
Patients who enter the study will be treated with continuous once daily dosing of oral 
LDK378 until objective evidence of progression of disease, occurrence of unacceptable 
toxicities, or patient withdrawal.
During the study treatment period, patients will be regularly monitored to assess the safety 
and early anti-tumor activity of the treatment. For the purpose of scheduling and evaluations, 
a treatment cycle will consist of 21 days.
For details of assessments during the treatment period, refer to Table 7-1.
7.1.3
End of treatment visit
At any time, patients may voluntarily withdraw from the study or be removed from it at the 
discretion of the investigator. If withdrawal occurs, or if the patient fails to return for visits, 
effectively withdrawing, the investigator should make a reasonable effort (e,g. telephone, e-
amil, letter) to understand the primary reason for a patient’s premature withdrawal, record this 
information on the End of Treatment eCRF, and notify Novartis. Patients may be withdrawn 
from LDK378for one of the following reasons:
1. Adverse event(s).
2. Disease progression.
3. Protocol violation/deviation.
 


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4. Patient withdrew consent.
5. Lost to follow-up.
6. Death.
Patients who discontinue LDK378 for any of the above reasons (except death) should be 
scheduled for an end of treatment (EOT) visit 14 days (up to 21 days) after discontinuing 
LDK378, at which time all of the assessments listed for the EOT visit will be performed. An 
EOT eCRF will be completed, giving the date and reason for stopping the LDK378.
The EOT completion evaluations include the following:

A physical examination, including an assessment of any tumor lesions; Karnofsky/Lansky 
performance status; height/weight and vital signs; hematology; chemistry; pregnancy test 
for FCBP.

Radiological tumor evaluation of all tumor sites, if not evaluated ≤ 28 days prior to the 
EOT visit, and if objective evidence of disease progression has not previously been 
documented.

For neuroblastoma patients: MIBG imaging, if positive at baseline and not evaluated ≤ 28 
days prior to the EOT visit.

For neuroblastoma and lymphoma patients: If bone marrow bilateral aspirate and biopsies 
were performed and were positive at screening, it will be left to the investigator’s 
discretion to monitor the bone marrow aspirate at each disease evaluation. In order to 
confirm a Complete disease Response (CR), bone marrow biopsy or aspirate may be 
required when a radiological CR has been achieved.

ECG.

Occurrence of new AEs and status of current AEs.

Collection of a fresh tumor biopsy, if medically feasible, and the patient and/or guardian 
agrees.
All patients who discontinue LDK378, including those who refuse to return for a final visit, 
should be contacted 30 days (up to 37 days) after discontinuing LDK378 for safety 
evaluations and a list of concomitant medications, including antineoplastic therapies received 
since discontinuation (Study Evaluation Completion (SEC) visit). See Section 7.1.4. A SEC 
eCRF will then be completed, giving the date and reason for study discontinuation.
For patients who refuse to return for visits or are unable to do so, every effort should be made 
to contact them or a knowledgeable informant by telephone. Patients lost to follow up should 
be recorded as such on the Study Evaluation Completion eCRF. A patient is considered “lost-
to-follow up” if the patient fails to show up for a scheduled follow-up visit and no response 
despite at least 3 documented failed attempts to contact the patient, such as via phone calls 
and / or registered letters. The investigator should show “due diligence” by documenting in 
the source documents steps taken to contact the patient (e.g., dates of telephone calls, 
registered letters, etc).
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 2 cycles (42 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 
 


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interruption greater than 2 cycles (42 days), could benefit from additional treatment, 
continuation may be allowed.
Patients who discontinue from the study for a study-related adverse event will be followed for 
toxicity, as described above. All patients should be followed for adverse events and serious 
adverse events for 30 days (up to 37 days) following the last dose of LDK378 (Study 
Evaluation Completion (SEC) visit).
Patients who discontinue from LDK378 (e.g., due to disease progression) during Cycle 1 
should have all the remaining evaluations for Cycle 1 performed prior to LDK378 completion.
The EOT visit is not considered the end of the study.
7.1.3.1
Patient replacement
Escalation:
Patients will not be replaced on study. However, if a patient is considered as non-evaluable 
for the DDS (Dose Determining Set), enrollment of a new patient to the current cohort will be 
considered if there is less than the required number of evaluable patients. Enrollment of new 
patients may be considered until at least the minimum number (3) or at most the maximum 
number (6) of evaluable patients is achieved within the cohort. Minimum and maximum 
numbers of evaluable patients per cohort are defined in Section 6.2.3.
Expansion:
Patients will not be replaced.
7.1.3.2
Withdrawal of Consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not allow further collection of personal data.
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, 
letter) to understand the primary reason for the subject’s decision to withdraw his/her consent 
and record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. Novartis will continue to keep and use collected study information 
(including any data resulting from the analysis of a subject’s samples until their time of 
withdrawal) according to applicable law. 
 


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All biological samples not yet analyzed at the time of withdrawal will no longer be used, 
unless permitted by applicable law. They will be stored according to applicable legal 
requirements.
7.1.4
Follow-up period
All patients will have a Study Evaluation Completion (SEC) visit 30-days (up to 37 days) 
after the last dose of LDK378. At this time AE, SAE and concomitant medication (including 
subsequent antineoplastic therapy) information during the follow-up period will be recorded 
on the AE eCRF and Novartis will be informed as necessary.
Patients lost to follow-up should have this documented on the appropriate eCRF and attempts 
made to contact the patient to ascertain the reason and required study information, as 
described in Section 7.1.3.
7.1.5
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 
eCRF page.
7.2
Assessment types
7.2.1
Efficacy
Disease will be assessed as per RECIST v1.1 (Appendix 5) in patients with solid tumors, and 
per IWG criteria (Appendix 6) for patients with lymphoma. In addition, patients with 
neuroblastoma will be assessed by MIBG scanning and bone marrow bilateral aspirate and 
biopsy at screening. Disease response and progression will be determined by the local 
investigator. When the revised International Neuroblastoma Response Criteria (INRC) 
currently in development are final they will be incorporated into this protocol.
At screening (within 28 days of the start of LDK378), all patients will undergo CT with i.v. 
contrast or MRI of the brain, chest, abdomen and pelvis. If there is clinical evidence of 
disease in the neck, a CT or MRI of the neck will also be performed. If a patient is intolerant 
of iodine-based contrast agents, CTs may be performed without contrast or MRI may be used. 
Visible skin lesions and easily palpable subcutaneous tumors may be measured by physical 
examination using a ruler or calipers. Ultrasound should not be used to measure sites of 
disease. Patients with neuroblastoma will undergo MIBG scanning, and bone marrow bilateral 
aspirate and biopsy at screening. Patients with lymphoma will undergo bone marrow bilateral 
aspirate and biopsy at screening. MIBG scans should be performed within 28 days of the start
of treatment, and bone marrow bilateral aspirates and biopsies should be performed within 42 
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Subsequent disease evaluations will be performed on Day 15 (±7 days) of cycles 2, 4 and 6. 
After cycle 6, disease evaluations will be performed on Day 15 (±7 days) of every 4th cycle 
(e.g., C10, C14), or sooner if there is clinical evidence of disease progression. Post Cycle 14, 
disease evaluations will be performed every 6 cycles (e.g., C20, C26, C32, etc.) and also 
performed at EOT. If the last prior disease evaluation was within 28 days of EOT or objective 
evidence of progressive disease has already been documented, then evaluations do not need to 
be repeated at EOT.
Disease evaluations after the screening assessment will include evaluation of all sites of 
disease identified at baseline, using the same technique that was used at screening. If there 
was no evidence of disease in a body region at baseline, that region does not need to be 
imaged at subsequent assessments, unless there is clinical concern for a new lesion in that 
body region. Bone marrow bilateral aspirate and biopsies, and MIBG scans are not required 
after screening if they were negative at screening. If bone marrow bilateral aspirate and 
biopsies were performed and were positive at screening, it will be left to the investigator’s 
discretion to monitor the bone marrow aspirate at each disease evaluation. In order to confirm 
a Complete disease Response (CR), bone marrow biopsy or aspirate may be required when a 
radiological CR has been achieved.
MIBG scans if positive at screening will be required at each disease evaluation unless 2 
consecutives MIBG scan post screening were negative and tumor response is a confirmed 
Complete or partial response. MIBG scan will be required if radiological assessment 
demonstrates a progression of the disease.
7.2.2
Safety and tolerability
Safety and tolerability assessments will include adverse event reporting and changes from 
baseline in laboratory measures and vital signs. Tolerability will be assessed by the incidence 
of AEs leading to LDK378 delay or discontinuation.
After cycle 16, for odd numbered cycles, safety assessments can be reduced to a phone call 
and local laboratory tests (see Table 7-1) to assess patient safety. It is left to the investigator’s 
discretion to monitor patient’s safety more closely as suggested for even cycles if judged 
necessary. 
7.2.2.1
Physical examination
A full physical examination (PE) that evaluates all major organ systems will be performed at 
baseline. This should include a brief neurological exam (examination by a neurologist is not 
required). A gynecological exam should be included if clinically indicated. Subsequent PEs 
should be focused on sites of disease, and clinical signs and symptoms.
During the PE the patient’s history related to their diagnosis and extent of cancer should be 
collected. Significant findings that were present prior to the signing of ICF 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.
Note: PE may be performed within 4 days prior to the start of a cycle and ±1 day for other 
visits.
 


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PE to be performed:

Screening/baseline.

Cycle 1 Day 1.

Cycle 1 Day 8 and 15.

Cycle 2 and subsequent cycles Day 1.

End of treatment.
7.2.2.2
Vital signs
Vital signs (heart rate, blood pressure and temperature) will be obtained in the same position, 
as appropriate prior to any blood collection.
Note: Vital signs may be performed within 4 days prior to the start of a cycle and ±1 day for 
other visits.
Vital signs to be obtained:

Screening/baseline.

Cycle 1 Day 1 (pre-dose).

Cycle 1 Day 8 and 15.

Cycle 2 and subsequent cycles Day 1.

End of treatment.
7.2.2.3
Height, weight and body surface area
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes) will be measured. Body surface area (BSA) will be measured 
using the patient’s weight and height, in accordance with local site procedure. The baseline 
BSA will be used to determine the dose at C1D1.
Note: Height, weight and BSA may be performed within 4 days prior to the start of a cycle 
and ±1 day for other visits.
Assessments will be obtained on:

Screening/baseline.

Cycle 2 and subsequent cycles Day 1.

End of treatment (except BSA).
7.2.2.4
Performance status
Performance status will be scored using the Karnofsky or Lansky performance scales, 
depending on the patient’s age (Appendix 3 and Appendix 4).
Note: Performance status may be performed within 4 days prior to the start of a cycle and ±1 
day for other visits.
Performance status to be obtained:

Screening/baseline.

Cycle 1 Day 1.
 


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
Cycle 2 and subsequent cycles Day 1.

End of treatment.
For patients that have their 13th birthday during the study, performance status will continue to 
be assessed by the Lansky scale for the duration the patient is on study. This approach will 
preserve continuity for these patients.
7.2.2.5
Laboratory evaluations
Laboratory tests will be collected and analyzed by the study site’s local laboratory even if 
study medication is being held. More frequent examinations may be performed at the 
investigator’s discretion if medically indicated; results should be recorded on the Unscheduled 
Visit eCRFs.
All efforts should be made to minimize the volume of blood drawn during the course of the 
study. For each test the smallest tube required by the local laboratory should be used, and all 
blood required at a time point, including that for routine safety labs and PK samples should be 
drawn simultaneously to minimize wastage and venipunctures. If a patient has an indwelling 
venous catheter appropriate for drawing blood, it should be used whenever possible to reduce 
venipunctures. The maximum volume of blood that may be drawn over a 24 hour period is 0.8 
mL/kg, and the maximum volume of blood that may be drawn over a 4 week period is 2.4 
mL/kg. The maximum blood volumes required by this protocol over 24 hr and 4 week periods 
are provided in Table 7-2. If the volume of blood requested in the protocol will exceed the 
limit in a particular patient, blood samples exceeding the limit should not be performed, 
unless necessary for the medical care of the patient. If it is anticipated that the volume limit 
will be exceeded, hematology, chemistry and pregnancy test samples should be drawn 
preferentially over PK samples. If PK samples must be skipped, PK samples should be 
prioritized as shown in Table 7-5.
Table 7-2
Maximum blood volumes
Maximum Sample 
Volume
24 hr (Cycle 1 Day 1)
Cycle 1 (4 wk)
No. Samples
Total Volume
No. Samples
Total Volume
Hematology
1 mL
1
1 mL
3
3 mL
Chemistry
1 mL
1
1 mL
3
3 mL
Pregnancy 
testa
1 mL
1
1 mL
2
2 mL
PKb
1 mL
5
5 mL
6
6 mL
Total
8 mL
14 mL
a. Urine test may be performed at all time-points after screening/baseline, and samples are not 
required in females not of child-bearing potential.
b. PK sample volume may be reduced from 1 mL to.5 mL as necessary.
Maximum allowed blood volumes: 0.8 mL/kg over a 24 hr period, 2.4 mL/kg over a 4 week period.
At any time during the study, abnormal laboratory parameters which are clinically relevant 
(e.g., require dose modification and/or interruption of LDK378, lead to clinical signs or 
symptoms, or require therapeutic intervention), whether specifically requested in the protocol 
or not, must be recorded in the AE eCRF.
 


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Novartis will be provided with a copy of the laboratory certification and tabulation of the 
normal ranges for each parameter required. In addition, if at any time a patient has laboratory 
parameters obtained from a different outside laboratory, Novartis must be provided with a 
copy of the certification and a tabulation of the normal ranges for that laboratory.
Note: Laboratory tests may be performed within 4 days prior to the start of a cycle and ±1 day 
for other visits. In order to reduce the volume of blood drawn, tests performed during 
screening/baseline within 4 days of Cycle 1 Day 1 should not be repeated on Cycle 1 Day 1, 
unless repeat testing is considered medically necessary.
For timing of assessments, refer to Table 7-1.
7.2.2.5.1 Hematology
Please refer to Table 7-3 for a list of tests to be performed.
Hematology to be performed:

Screening/baseline.

Cycle 1 Day 1, 8 and 15.

Cycles 2 – 4 Day 1 and 15.

Cycle 5 and subsequent cycles Day 1.

End of treatment.
7.2.2.5.2 Clinical chemistry
Please refer to Table 7-3 for a list of tests to be performed.
Clinical chemistry to be performed:

Screening/baseline.

Cycle 1 Day 1, 8 and 15.

Cycles 2 – 4 Day 1 and 15.

Cycle 5 and subsequent cycles Day 1.

End of treatment.
Table 7-3
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hemoglobin, White blood cells with differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils) and Platelets
Chemistry
Albumin, ALT (SGPT), AST (SGOT), Bicarbonate, Calcium, Chloride, Creatinine, 
Blood Urea Nitrogen (BUN) or Urea, LDH (only required in patients with 
lymphoma), Magnesium, Phosphate, Potassium, Sodium, Total Bilirubin (measure 
direct and indirect bilirubin if total bilirubin elevation ≥ grade 2 occurs), ALP, 
Serum amylase, Serum lipase , plasma glucose
7.2.2.5.3 Pregnancy assessments
All females of childbearing potential should complete a serum β-hCG or urine pregnancy test.
Note: Pregnancy testing should be performed within 1 day prior to Cycle 1 Day 1.
 


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Pregnancy test to be performed:

Screening/baseline (serum).

Cycle 1 Day 1 (urine or serum).

Subsequent cycles Day 1 (urine or serum).

End of treatment (urine or serum).
A positive pregnancy test is cause for immediate withdrawal.
For females to be considered “of non-childbearing potential”, patient should meet one of the 
following:

Pre-menarchal.

Surgically sterile for at least 6 months (hysterectomy with bilateral oophorectomy or tubal 
ligation). Documentation of sterilization method must be provided. The date of 
sterilization will be recorded.
To ensure patient safety, each pregnancy in a patient receiving LDK378 must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
to and including the baby’s date of birth 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 local Novartis Drug Safety and Epidemiology (DS&E) follow-up should be 
recorded on the same form and should include an assessment of the possible relationship to 
LDK378 of any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported on the SAE Report Form.
7.2.2.5.4 Electrocardiogram (ECG)
A standard 12-lead ECG will be performed in accordance with Table 7-4.
Interpretation of the tracing will be made by a central ECG lab. Each ECG tracing should be 
labeled with the study number, patient initials, patient number, date, and kept in the source 
documents at the study site. Only clinically significant abnormalities will be recorded in the 
AE eCRF page. Clinically significant abnormalities at screening/baseline should be recorded 
on the Relevant Medical History/Current Medical Conditions eCRF page. Clinically 
significant findings must be discussed with the Novartis Medical Monitor prior to enrolling 
the patient in the study. In the case of QTc >500 ms an ECG should be repeated daily until the 
QTc prolongation has resolved to grade 1 or less.
 


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Table 7-4
Central ECG collection plan
Cycle
Day
Time
ECG Type
Screening/
Baseline
-28 to -1
Anytime
12 Lead
1
1
Post-dose 4 hours (ECG should be performed just prior to 
drawing PK sample if both are scheduled simultaneously
12 Lead
1
1
Post-dose 6 hours (ECG should be performed just prior to 
drawing PK sample if both are scheduled simultaneously
12 Lead
2
1
Post-dose 4 hours (ECG should be performed just prior to 
drawing PK sample if both are scheduled simultaneously
12 Lead
2
1
Post-dose 6 hours (ECG should be performed just prior to 
drawing PK sample if both are scheduled simultaneously
12 Lead
3
1
Pre-dose (ECG should be performed just prior to drawing PK 
sample if both are scheduled simultaneously
12 Lead
4
1
Pre-dose (ECG should be performed just prior to drawing PK 
sample if both are scheduled simultaneously
12 Lead
5-16
1
Pre-dose
12 Lead
Even # 
cycles ≥18
1
Pre-dose
12 Lead
EOT
1
Within 14 days (up to 21 days) of last dose
12 Lead
7.3
Pharmacokinetics
Blood samples for PK analysis of LDK378 will be collected during the study. Table 10-1 lists 
non-compartmental PK parameters for LDK378 which will be calculated from the individual 
plasma concentration versus time profiles using Phoenix® (Pharsight, Mountain View, CA). 
The individual and mean plasma concentration versus time profiles of LDK378 will be 
displayed graphically. In addition, a population PK model may be developed to characterize 
inter-patient variability and covariate effects on LDK378 by pooling all available data.
 
 
 
 
Blood sampling schedules for PK assessment during the escalation and expansion parts of the 
study can be found in Table 7-5 and Table 7-6, respectively.
7.3.1
Pharmacokinetic blood sample collection and handling
PK blood samples will be collected in the escalation parts (Table 7-5) and the expansion part 
(Table 7-6). For the determination of LDK378 concentrations, 1 mL of whole blood will be 
drawn for each time point. For smaller patients where collection of PK samples may 
compromise local blood volume limits, 0.5 mL of whole blood may be drawn for each PK 
time point, in order to permit all samples to be collected without exceeding the maximum 
blood volume limits (Section 7.2.2.5). If the maximum blood volume limit will be exceeded in 
a particular patient, hematology, chemistry and pregnancy test samples should be drawn 
This document (090095a88d6def99 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 5/23/2018 3:24:29 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by Urban Patrick in Basel at Wed, May 23, 2018 11:27:06 CEST
Approved for report publication by Wang Victor in East Hanover at Wed, 23 May 2018 11:24:08 AM EDT
Approved for report publication by McCulloch Tracey in Basel at Wed, May 23, 2018 10:23:19 CEST


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preferentially over PK samples. If a PK sample needs to be omitted due to blood volume 
limits, the 4 hour samples on Cycle 1 Day 1 and/or Cycle 2 Day 1 should be omitted first.
A total of approximately 13 mL blood will be collected for each patient treated in the dose 
escalation part. The amount of blood for PK analysis required from patients participating in 
the expansion part is approximately 8 mL.
The collection of plasma with exact dates and clock times of drug administration and sample 
collection will be recorded on the appropriate Blood collection eCRF. All blood samples will 
be taken by either direct venipuncture or venous catheter or indwelling cannula inserted in a 
forearm vein. Samples should be processed and labeled as detailed in the [Laboratory Manual]. 
Plasma fractions will be split in 2 aliquots and all samples should be stored frozen at ≤ -70°C 
within 90 minutes of venipuncture at the site until sample shipment.
Meal records, including start and stop times and amount of meal consumed, will be collected 
on PK collection days for patients taking LDK378 with food. Refer to below Table 7-5 and 
Table 7-6. LDK378 administration method, including if the capsule was opened or swallowed 
whole, and type of vehicle, will also be collected on all PK collection days for all patients.
Table 7-5
Pharmacokinetic blood collection log – dose escalation (fasted and 
fed)
Cycle
Day
PK 
collection 
number
Sample 
number
Scheduled time points (hours)
Cycle 1
Day 1
1
1
pre-dose*
Cycle 1
Day 1
1
2
2h post-dose (± 15 min)
Cycle 1
Day 1
1
3
4h post-dose (± 15 min)
(If it is anticipated that the maximum allowed 
blood volume will be exceeded (Section 7.2.2.5) 
sample should be skipped)
Cycle 1
Day 1
1
4
6h post-dose (± 15 min)
Cycle 1
Day 2
2
5
pre-dose* (i.e. 24h post-dose on Cycle 1 day 1)
Cycle 1
Day 15
3
6
pre-dose*
Cycle 2
Day 1
4
7
pre-dose*
Cycle 2
Day 1
4
8
2h post-dose (± 15 min)
Cycle 2
Day 1
4
9
4h post-dose (± 15 min)
(If it is anticipated that the maximum allowed 
blood volume will be exceeded (Section 7.2.2.5) 
sample should be skipped)
Cycle 2
Day 1
4
10
6h post-dose (± 15 min)
Cycle 2
Day 2
5
11
pre-dose* (i.e. 24h post-dose on Cycle 2 day 1)
Cycle 3
Day 1
6
12
pre-dose*
Cycle 4
Day 1
7
13
pre-dose*
Unscheduled
1001+
Anytime
*Take sample immediately prior to LDK378 administration.
 


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Table 7-6
Pharmacokinetic blood collection log – dose expansion (fasted and 
fed)
Cycle
Day
PK collection 
number
Sample 
number
Scheduled time points (hours)
Cycle 2
Day 1
103
203
pre-dose*
Cycle 2
Day 1 
103
206
2h post-dose (± 15 min)
Cycle 2
Day 1
103
207
4h post-dose (± 15 min)
Cycle 2
Day 1
103
208
6h post-dose (± 15 min)
Cycle 2
Day 2
106
209
pre-dose* (i.e. 24 h post dose on 
Cycle 2 Day 1)
Cycle 3
Day 1
104
204
pre-dose*
Cycle 4
Day 1
105
205
pre-dose*
Unscheduled
2001+
Anytime
*Take sample immediately prior to LDK378 administration.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient/guardian 
signed ICF has been obtained.
For patients whose ALK status is unknown and who sign the molecular pre-screening ICF, 
AEs which occur after signature of this consent will only be captured if they meet the 
definition of serious as outlined in Section 8.2 and are reported to be causally related with 
study procedures (e.g. an invasive procedure such as biopsy). Once the main ICF is signed, all 
AEs per the descriptions below will be captured in the Adverse Event eCRF.
Patients whose ALK status is known will sign the main ICF.
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).
Except for screening failures, adverse events that begin or worsen after informed consent 
should be recorded in the Adverse Events eCRF. Conditions that were already present at the 
time of informed consent should be recorded in the Relevant Medical History/Current 
 


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Medical Conditions of the patient’s eCRF. Adverse event monitoring should be continued for 
at least 30 days following the last dose of LDK378. 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 on the EOT or the 
SEC eCRF.
The occurrence of adverse events should be sought by non-directive questioning of the 
patient/guardian during the screening process after 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).
2. Its duration (Start and end dates) or Ongoing at End of Study.
3. Its relationship to LDK378 (Reasonable possibility that AE is related: No, Yes).
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable).
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy).
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1.
If the event worsens the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if 
improvement to a lower grade is determined a new entry for this event should be reported in 
the CRF noting the start date when the event improved from having been Grade 3 or Grade 4.
Any AE that constitutes a DLT should be reported like a grade 3 and 4 adverse event. 
All adverse events should be treated appropriately. If a concomitant therapy is given, this 
action should be recorded on the Adverse Event eCRF.
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 LDK378, 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 1.1 criteria for solid tumors or as per IWG 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 
 


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be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
Adverse events of a 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 the 
Investigator’s Brochure.
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 LDK378), should be recorded on the Adverse Events eCRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for 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 4.03 does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.1.3
Adverse events of special interest
 
 
 
Details regarding these adverse events are provided in the [Investigator’s Brochure] for 
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.
 


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
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.
For patients with unknown ALK status and who sign the molecular pre-screening ICF, SAE 
collection will start upon signing the molecular pre-screening ICF. SAEs will only be reported 
if the event is suspected to be causally related to a study procedure as assessed by the 
investigator (e.g. an invasive procedure such as biopsy). SAEs will be followed until 
resolution or until clinically relevant improvement or stabilization. If the main ICF is not 
signed (molecular screen failure), SAE collection ends 30 days after the last study related 
procedure.
For patients with known ALK status who sign the main ICF, SAE collection starts at time of 
main ICF whether the patient is a screen failure or not.
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has signed the main ICF and until at least 30 days after the patient has stopped 
LDK378 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 LDK378. Recurrent episodes, complications, or 
progression of the initial SAE must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one 
should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to 
LDK378, complete the SAE Report Form in English, and send the completed, signed form by 
fax within 24 hours to the oncology Novartis Drug Safety and Epidemiology (DS&E) 
department.
The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E), specific to the site, are listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site.
 


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Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, 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 LDK378, 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.
To ensure patient safety, each pregnancy occurring while the patient is on LDK378 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 oncology 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 LDK378. 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 
LDK378 in this study up to and including the baby’s date of birth. Consent to report 
information regarding these pregnancy outcomes should be obtained from the mother.
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between [Investigator’s Brochure] updates 
will be communicated in the form of Investigator Notifications. This information will be 
included in the patient ICF and should be discussed with the patient during the study as 
needed.
8.3
Data Monitoring Committee
Not applicable.
8.4
Steering Committee
Not applicable.
 


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9
Data collection and management
 
 
 
 
 
 
 
 
 
 
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that LDK378 is 
being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep all original signed ICFs (a signed copy is given 
to the patient/guardian).
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/assent, 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.
 


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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 the eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.
 
Patient drug diary data will be entered into a paper diary by the patient/guardian. Patient 
diaries will be part of the study source documentation and be kept at the study site.
9.4
Database management and quality control
For studies using eCRFs, 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 study site via the EDC system. Designated study 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. Relevant medical history/current medical conditions and adverse events 
will be coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the study site.
10
Statistical methods and data analysis
The data from this study will be analyzed by Novartis or a designated CRO. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. The data will be summarized 
with respect to demographic and baseline characteristics, efficacy observations and 
measurements, safety observations and measurements, and all relevant PK measurements 
using descriptive statistics (quantitative data) and contingency tables (qualitative data).
The study data will be analyzed and reported based on all patients’ data of both dose 
escalation and safety expansion parts at the end of study, and a final CSR will be written. 
 


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Patients treated with the MTD, or RDE if different, on the regimen (fasted or fed) during the 
dose escalation part, will be pooled with those receiving both the same dose and the same 
regimen during the expansion part. For patients undergoing intra-patient dose escalation to 
doses other than their initially received dose level, their post-escalation data will be listed 
separately. However, only data before the first intra-patient escalation will be used in 
summary statistics. A treatment group is defined by dose level and regimen (fasted versus fed).
10.1
Analysis sets
10.1.1
Full analysis set
The full analysis set (FAS) (Full Analysis Set) includes all patients who received at least one 
dose of LDK378. Patients will be classified according to the planned treatment. The FAS will 
be used for all listings of raw data. Unless otherwise specified, the FAS will be the default 
analysis set used for all analyses.
10.1.2
Safety set
The safety set includes all patients who received at least one dose of LDK378.
On the specified regimen, patients will be classified according to dose level received, where 
dose level received is defined as:
1. The dose level assigned if it was received at least once, or
2. The first dose level received in the study, if the assigned dose level was never received.
10.1.3
Per-protocol set
Not applicable.
10.1.4
Dose-determining analysis set
The dose determining set (DDS) consists of all patients from the safety set who either meet 
the following minimum exposure criterion and have sufficient safety evaluations or 
discontinue earlier due to DLT. A patient is considered to have met the minimum exposure 
criterion if having received at least 16 out of the 21 planned once daily doses of LDK378 in 
the first 21 days of dosing. Patients who do not experience DLT during the first cycle are 
considered to have sufficient safety evaluations if they have been observed for at least 21 days 
following the first dose, and are considered by both the Sponsor and Investigators to have 
sufficient safety data to conclude that a DLT did not occur.
Patients who do not meet these minimum safety evaluation requirements will be regarded as 
ineligible for the DDS.
10.1.5
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who have receive at least one 
dose of LDK378 and have at least one evaluable PK sample. Additional criteria for the PAS 
will be defined in the RAP. The PAS will be used for summaries of PK data (tables and 
figures) as well as for listings of derived parameters. The definition of an evaluable PK blood 
sample will be further specified in the SAP.
 


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10.2
Patient demographics/other baseline characteristics
Demographic and other baseline will be summarized descriptively for all patients in the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.
10.3
Treatments (study treatment, concomitant therapies, compliance)
10.3.1
Study treatment
The actual dose and duration in days of LDK378 treatment, as well as the dose intensity 
(computed as the ratio of actual dose received and actual duration) and the relative dose 
intensity (computed as the ratio of dose intensity and planned dose received/planned duration), 
will be listed and summarized by means of descriptive statistics in the clinical study report. 
The summary data will be presented for each treatment cycle individually, as well as for all 
study days as a single category. The FAS will be used.
10.3.2
Concomitant therapies
Concomitant medications and significant non-drug therapies prior to and after the start of 
LDK378 will be listed by patient, and summarized by ATC term and treatment group by 
means of contingency tables. The FAS will be used.
 
 
10.4
Primary objective
The primary objective of the escalation part is to estimate the MTD/RDE respectively on 
fasted regimen and on fed regimen of the single agent LDK378 when administered orally on a 
once daily schedule to pediatric patients with ALK-activated tumors. The corresponding 
primary analysis method is an adaptive Bayesian logistic regression model (BLRM) guided by 
the escalation with overdose control (EWOC) principle (Neuenschwander et al 2008).
10.4.1
Variable
The primary endpoint is the incidence of dose limiting toxicities (DLTs) in Cycle 1. 
Estimation of the MTD of the treatment will be based upon the estimation of the probability 
of DLT in Cycle 1 for patients in the DDS. This probability is estimated by the model in 
Section 10.4.2.
 


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10.4.2
Statistical hypothesis, model, and method of analysis
Dose escalation
The BLRM with 2 parameters, guided by the EWOC principle, will be used to make dose 
recommendations and estimate the MTD/ RDE during both the fasted escalation part and the 
fed escalation part of the study.
The DLT relationship in the escalation part of the study will be described by the following 
Bayesian logistic regression model:
logit(π(d)) = log(α) + β log(d/d*),
α>0, β>0 
[1]
where logit(π(d))= ln ((d)/(1-(d))), and π(d) is the probability of a DLT at dose d. Doses are 
rescaled as d/d* with reference dose of d* = 400 mg/m2. As a consequence α is equal to the 
odds of toxicity at d*. Note that for a dose equal to zero, the probability of toxicity is zero.
The same 2-parameter form of the BLRM described in equation [1] will be used to estimate 
the dose-DLT relationships separately for fasted and fed patients. The Bayesian approach 
requires the specification of prior distributions for the model parameters. Dose escalation in 
fed patients will begin once the MTD/RDE is determined in fasted patients. Data from fasted 
patients will be utilized to formulate a prior distribution for the BLRM parameters for fed 
patients. The prior distributions and the process of their derivation are provided in the 
statistical appendix (Appendix 1).
Dose recommendation
After each cohort is completed the posterior distributions for the probabilities of DLT at 
different dose levels are obtained. The results of this analysis are summarized in terms of the 
estimated probabilities that the true rate of DLT at each dose-level will lie within each of the 
following intervals:

(0, 0.16) under-dosing.

(0.16, 0.33) targeted toxicity.

(0.33, 1.00) excessive toxicity.
Following the principle of EWOC, after each cohort of patients the recommended dose is the 
one with the highest posterior probability of the DLT rate falling in the target interval (16%, 
33%) among the doses fulfilling EWOC, i.e. it is unlikely (< 25% posterior probability) that 
the DLT rate at the dose falls in the excessive toxicity interval. In addition, the maximum dose 
escalation for the fasted regimen is limited to 50% before reaching 450 mg/m2, and to 25% 
after reaching 450 mg/m2, which correspond to the adult MTD. Dose escalations for the fed 
dose escalation part will be limited to a 25% or smaller increase above the prior fed dose level.
Note that the dose that maximizes the posterior probability of targeted toxicity is the best 
estimate of the MTD, but it may not be an admissible dose according to the overdose criterion 
if the amount of data is insufficient. If vague prior information is used for the probabilities of 
DLT, in the early stages of the study this escalation procedure will reflect a cautious strategy.
 


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The dose recommended by the adaptive Bayesian logistic model may be regarded as guidance 
and information to be integrated with a clinical assessment of the toxicity profiles observed at 
the time of the analysis in determining the next dose level to be investigated.
Details of the criteria for dose escalation and the determination of the MTD are provided in 
Section 6.2.3.
Listing/summary of DLTs
DLTs will be listed and their incidence summarized by primary system organ class, worst 
grade based on the CTCAE version 4.03, type of adverse event, and by treatment. The DDS 
will be used for these summaries.
Dose expansion
Upon completion of the first cycle of treatment for at least 10 patients within the dose 
expansion part, if the observed DLT rate exceeds 33%, the BLRM will be re-run to confirm 
that the estimated MTD/RDE on either regimen still satisfies the overdose criteria of the 
model. If the dose fails to satisfy the criteria a change to the dose under study may be made 
according to the Bayesian model recommendation, after review of the clinical data.
10.5
Handling of missing values/censoring/discontinuations
Patients in the dose-escalation part who are ineligible for the dose-determining set may be 
replaced if necessary. Patients in the safety expansion part will not be replaced.
As of the date of data-cutoff for the final CSR for the purposes of reporting:

Time to event data (i.e. PFS) will be censored if no event is observed before the cut-off 
date or before the start date of a new anti-neoplastic therapy, whichever occurs earlier. 
The censoring date will be the date of last adequate tumor assessment before either of 
these two dates. If a PFS event is documented after two or more missing or non-adequate 
tumor assessments, then the date of PFS will be censored at the date of the last adequate 
tumor assessment. If a PFS event is observed after a single missing or non-adequate tumor 
assessment, the actual date of event will be used.

Continuing events (e.g. adverse events, concomitant therapies, etc.) will be summarized 
using the data cut-off date as the date of completion, with an indication within listings that 
the event is continuing.
For patients who discontinue the study with ongoing events, the discontinuation date will be 
used as the completion date of the event with the appropriate censoring as described in the 
above paragraph.
The reason for discontinuation from study will be summarized and listed, along with dates of 
first and last LDK378, duration of exposure to LDK378 and date of discontinuation for each 
patient.
Other missing data will simply be noted as missing in appropriate tables/listings. The FAS 
will be used.
 


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10.6
Supportive analyses
10.7
Secondary objectives
Refer to Section 3 for secondary objectives.
10.7.1
Safety objectives
10.7.1.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. Unless otherwise specified, all listings and 
tables will be presented by treatment group (regimen (fasted versus fed) and dose level) in the 
clinical study report, with patients classified according to treatment received as described in 
Section 10.1.
Data from patients of the expansion part will be pooled with the patients of the escalation part 
receiving the same dose.
10.7.1.2 Adverse events (AEs)
All AEs recorded during the study will be summarized. The incidence of treatment-emergent 
AEs (new or worsening from baseline) will be summarized by primary system organ class, 
severity based on CTCAE version 4.03, type of adverse event, and relationship to LDK378, 
by treatment group. Deaths reportable as SAEs and non-fatal SAEs will be listed by patient 
and tabulated by primary system organ class, type of adverse event, and treatment group.
Any other information collected (e.g. start/end dates and duration of adverse event, severity or 
relatedness to study medication) will be listed as appropriate.
10.7.1.3 Laboratory abnormalities
All laboratory values will be converted into SI units, as appropriate, and the severity grade 
calculated using CTCAE, version 4.03. Parameters for which a grading does not exist will be 
classified into low/normal/high group by means of laboratory normal ranges.
For each laboratory test (e.g. hematology, biochemistry etc.) a listing of laboratory values will 
be provided by laboratory parameter, patient and treatment group. The frequency of notable 
lab abnormalities (i.e. newly occurring CTCAE grade 3 or 4 laboratory toxicities), will be 
reported by parameter, cycle and treatment group. Similarly, the frequency of all laboratory 
abnormalities will be tabulated by parameter, worst CTCAE v4.03 grade experienced, and 
treatment group. Laboratory data will be summarized by presenting grade shift tables for 
those parameters that can be classified using CTCAE version 4.03. All remaining data will be 
summarized by presenting shift tables based on normal ranges.
Laboratory data will be also be displayed by presenting summary statistics of raw data and 
change from baseline values (means, medians, standard deviations, ranges).
 


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10.7.1.4 Other safety data
ECG

shift table baseline to worst on-treatment result for overall assessments.

listing of ECG evaluations for all patients with at least one abnormality.
Vital signs
Definitions of notably abnormal results will be included in the analysis plans.

shift table baseline to worst on-treatment result.

table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to the post-baseline time points.
Data from other tests will be listed, notable values will be flagged, and any other information 
collected will be listed as appropriate. Any statistical tests performed to explore the data will 
be used only to highlight any interesting comparisons that may warrant further consideration.
10.7.1.5 Supportive analyses for secondary objectives
10.7.1.6 Tolerability
Tolerability of LDK378 will be assessed by summarizing the number of dose interruptions 
and dose reductions. Reasons for dose interruption and dose reductions will be listed by 
patient and summarized. Cumulative dose, dose intensity and relative dose intensity of 
LDK378 will be listed by patient and summarized. Categories for relative dose intensity of 
LDK378 will be specified as < 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1. The 
number and proportion of patients within each category will be presented.
10.7.2
Pharmacokinetics
All PK analyses will be performed based on the PAS unless otherwise specified.
Pharmacokinetic variables:
Pharmacokinetic parameters will be determined using non-compartmental method(s), using 
Phoenix WinNonlin (Pharsight, Mountain View, CA). The PK parameters listed in Table 10-1
will be estimated and reported, as appropriate. PK data generated from this study may be used 
in conjunction with PK data from other adult clinical studies in future meta-analyses for 
population PK assessment. These data will be reported separately.
 


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Table 10-1
Noncompartmental pharmacokinetic parameters
AUCtau
The AUC calculated to the end of the dosing interval, tau.
Cmin
Observed concentration at the end of a dosing interval (taken directly before next 
administration).
Cmax
The maximum observed plasma, blood, serum, or other body fluid drug concentration.
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration.
T1/2,acc
Effective half-life can be calculated from Racc.
CLss/F
Apparent oral total body clearance of drug from the plasma calculated from steady-state 
exposure.
Racc
Accumulation ratio calculated using AUCtau values obtained from a dosing interval at 
steady-state divided by AUCtau at day 1.
10.7.2.1 Data handling principles
Any missing PK parameters will not be imputed. All concentrations of LDK378 below their 
respective LLOQs (lower limits of quantification) or missing data will be labeled as such in 
the concentration data listings. Concentrations below the LLOQ will be treated as zero in 
summary statistics and for the calculation of PK parameters.
10.7.2.2 Data analysis principles
Basic tables, figures and listings
Summary statistics, including n, mean, SD, coefficient of variation CV (%) for mean, 
geometric mean, geometric CV (%), median, minimum and maximum, will be tabulated for 
evaluable PK plasma concentration of LDK378 by treatment group and scheduled time point 
separately for the fasted and fed patients. Graphical representation of individual plasma 
concentration-time profiles will be generated too.
Descriptive statistics will also be provided for all PK parameters by treatment group 
separately for fasted and fed patients. Summaries by age group may be provided as 
appropriate.
Advanced analysis methods
Dose linearity will be assessed by graphic presentation and model-based method with respect 
to AUCtau and Cmax at steady state. To assess the attainment of steady state, median Cmin 
will be plotted by study day and treatment group.
 
 
10.7.3
Efficacy
Anti-tumor activity of LDK378 will be evaluated using investigator-assessed tumor response 
based on RECIST 1.1 for patients with neuroblastoma and other solid tumors, and IWG 
 


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criteria for patients with lymphoma, and summarized in terms of overall response rate (ORR), 
duration of response (DOR), and progression-free survival (PFS). In patients with 
neuroblastoma, disease assessable only by MIBG scans and by bone marrow evaluation at 
screening will be treated as non-target lesions. When the revised International Neuroblastoma 
Response Criteria (INRC) currently in development are final they will be incorporated into 
this protocol.
For analysis by treatment group, patients from the expansion part and patients from the 
escalation treated at the MTD/RDE on the same regimen (either fasted or fed) will be 
combined to be included in the same dose level.
For analysis of patients at the MTD/RDE on one regimen (either fasted or fed), patients from 
the dose escalation part treated at the MTD/RDE on the same regimen will be classified into 
one of the expansion groups.
For patients with neuroblastoma, resolution of disease assessable by MIBG scans will also be 
summarized by treatment group separately from the response assessment by RECIST 1.1.
ORR will be summarized by treatment group and by expansion group, and exact 95% 
confidence intervals will be presented. To assess anti-tumor activity in pediatric patients 
previously treated with an ALK inhibitor, BOR and ORR will be tabulated for this subset of 
patients.
Kaplan Meier analyses of PFS and DOR will be provided overall and by treatment group, if 
sufficient number of patients allow. For MTD/RDE patients, Kaplan Meier analyses of PFS 
and DOR will be done by expansion group, if appropriate.
In addition, for the expansion group patients with ALK activated neuroblastoma, a Bayesian 
approach will be used to estimate the ORR along with a 95% credible intervals based on the 
posterior distributions, using minimally informative unimodal Beta prior distributions. The 
prior clinical assumption for LDK378 in this selected patient population will be used in order 
to derive a minimally informative unimodal Beta prior distribution that reflects the level of 
uncertainty around the ORR before starting the current trial. At completion of the study, this 
prior distribution will be updated with all data available from the expansion group patients 
with ALK activated neuroblastoma (including those treated at the MTD in the dose escalation 
part) in the FAS. Once updated, the posterior probability that the true ORR at the MTD/RDE
for these patients lies in the following categories will be presented:

(0, 10%) insufficient antitumor activity.

(10%, 20%) limited antitumor activity.

(20%, 30%) moderate antitumor activity.

(30%, 100%) substantial antitumor activity.
If the observed ORR is equal to or greater than 30%, then this will be considered as 
preliminary evidence of substantial antitumor activity of LDK378 in ALK activated 
neuroblastoma. If the observed ORR is between 20% and 30% then this will be considered as 
evidence of moderate antitumor activity, and as limited antitumor activity if it is between 10% 
and 20%. If the observed ORR is less than 10% (i.e. ≤ 2 CR or PR out of 25), then insufficient 
antitumor activity will be declared.
 


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Note that for a sample size of n = 25 (see Section 10.8), if the observed ORR is greater than or 
equal to 20% (i.e. ≥ 5 CR or PR), then the true ORR has a posterior risk of less than 10% of 
being in the insufficient antitumor activity category.
A minimally informative unimodal Beta prior distribution of the true ORR is derived as 
follows. A priori it is assumed that the true mean of the ORR equals 20%. A true ORR of 20% 
is the midpoint between limited and moderate antitumor activity and serves as a compromise 
between a skeptical view assuming the treatment has only limited antitumor activity and an 
optimistic view assuming the treatment has moderate antitumor activity. The parameters of 
the minimally informative Beta prior distribution of the ORR are then derived as a=1/4 and 
b=1.
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.9
Interim analysis
No formal interim analyses are planned. However, the dose-escalation design foresees that 
decisions based on the current data are made before the end of the study. More precisely, the 
next dose of LDK378 has to be chosen after each cohort in the dose escalation part, and the 
decision is dependent on the observed data.
10.10
Sample size calculation
10.10.1
Dose Escalation
Cohorts of 3 to 6 evaluable patients will be dosed in the dose-escalation including at least 6 
patients at the MTD/RDE level separately on each regimen, as described in Section 6.2.3. 
Multiple cohorts may be sequentially enrolled to the same dose level. Additional cohorts of 1 
to 6 patients may be enrolled at any dose level below the estimated MTD/RDE for further 
elaboration of safety and pharmacokinetic parameters as required. At least 15 patients for the 
fasted dose escalation and at least 12 patients for the fed dose escalation are respectively 
expected to be treated, for the model to have reasonable operating characteristics relating to its 
MTD recommendation (Appendix 1).
10.10.2
Dose Expansion
During the expansion part, approximately 45 patients will be treated on the preferred regimen 
(including all patients treated at the MTD on that regimen during the dose escalation who are 
eligible for the safety set), approximately 25 patients in group 1 on the preferred regimen, and 
approximately 20 patients in group 2.
Group 1: ALK-activated neuroblastoma
Based on the ORR (per RECIST 1.1) intervals described in Section 10.4.2, it was assessed 
how likely it is to wrongly declare activity as defined by observing at least “moderate 
antitumor activity” (i.e. seeing at least 5 responses out of 25 patients) given the true ORR = 
10%, and how likely it is to correctly declare activity given the true ORR = 30% when 25 
patients are evaluated.

If the true ORR = 10%, the probability to wrongly declare activity is 9.8%.

If the true ORR = 30%, the probability to correctly declare activity is 91.0%.
Given a sample size of 25 in group 1, if 5 responses are seen, the observed ORR is 20% with 
an 80% credible interval of (10.7%, 30.3%). This will be considered as preliminary evidence 
of antitumor activity of LDK378 at the MTD/RDE within this group.
 


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Group 2: other ALK-activated tumors, such as IMT and ALCL
For group 2, sample size estimation is based on safety. A sample size of 20 will result in an 
87.8% probability of detecting an AE with an incidence rate of ≥ 10%.
10.11
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 molecular pre-screening and main ICFs must be reviewed and 
approved by a properly constituted Institutional Review Board/Independent Ethics 
Committee/Research Ethics Board (IRB/IEC/REB) before study start. A signed and dated 
statement that the protocol and ICFs have been approved by the IRB/IEC/REB must be given 
to Novartis before study initiation. Prior to study start, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical 
Quality Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs and 
regulatory authorities as required.
11.3
Informed consent procedures
Patients may only be included in the study after providing written (witnessed, where required 
by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of doing so, 
after such consent has been provided by a legally acceptable representative of the patient. In 
cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written ICF or a 
separate assent form.
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 patient’s informed 
consent was actually obtained will be captured in their eCRFs.
Novartis will provide to investigators, in separate documents, proposed molecular pre-
screening and main ICFs that is considered appropriate for this study and complies with the 
ICH GCP guideline and regulatory requirements. Any changes to these ICFs suggested by the 
 


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investigator must be agreed to by Novartis before submission to the IRB/IEC/REB, and copies 
of the approved versions must be provided to the Novartis monitor after IRB/IEC/REB 
approval.
Females 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 and for 3 months after stopping dosing. 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 patients. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, patients’ 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 patient 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 study staff at the site under the supervision of the 
site Principal Investigator. The electronic case report form (eCRF) is the primary data 
collection instrument for the study. The investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported in the eCRFs and all other required reports. Data 
reported on the eCRF, that are derived from source documents, should be consistent with the 
 


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source documents or the discrepancies should be explained. All data requested on the eCRF 
must be recorded. Any missing data must be explained. Any change or correction to a paper 
eCRF should be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. For electronic eCRFs an audit trail will be maintained by the system.
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 ICFs and patient screening logs must 
be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
 


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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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References (available upon request)
Azaravoa AM, Gautam G, George RE (2011) Emerging importance of ALK in neuroblastoma. 
Sem Cancer Biol, 21: 267-275.
Babb J, Rogatko A, Zacks S (1998) Cancer phase I clinical trials: efficient dose escalation 
with overdose control. Stat Med; 17 (10):1103-1120.
Bilsland JG, Wheeldon A, Mead A, et al (2008) Behavioral and Neurochemical Alterations in 
Mice Deficient in Anaplastic Lymphoma Kinase Suggest Therapeutic Potential for Psychiatric 
Indications. Neuropsychopharmacology; 33: 685-700.
Bosulif United States Package Insert.
Butrynski JE, D’Adamo DR, Hornick JL, et al (2010) Crizotinib in ALK-rearranged 
inflammatory myofibroblastic tumor. N Engl J Med; 363:1727-33.
Center for Drug Evaluation and Research (2011) Pharmacometric Review of Crizotinib, NDA 
202570. Clinical Pharmacology and BioPharmaceutics Review.
Chen Y, Takita J, Choi YL, et al (2008) Oncogenic mutations of ALK kinase in 
neuroblastoma. Nature 455:971-74.
Chiarle R, Gong JZ, Guasparri I, et al (2003) NPM-ALK transgenic mice spontaneously 
develop T-cell lymphomas and plasma cell tumors. Blood; 101: 1919-27.
Chiarle R, Voena C, Ambrogio C, et al (2008) The anaplastic lymphoma kinase in the 
pathogenesis of cancer. Nat Rev Cancer, 8:11-23.
Coffin CM, Hornick JL, Fletcher CDM (2007) Inflammatory myofibroblastic tumor -
Comparison of clinicopathologic, histologic, and immunohistochemical features including 
ALK expression in atypical and aggressive cases. American Journal of Surgical Pathology; 
31:509-520.
Costa DB, Kobayashi S, Pandya S, et al (2011) CSF Concentration of the Anaplastic 
Lymphoma Kinase Inhibitor Crizotinib. J Clin Oncol; 29 (15): 443-445.
Fischer M. et al (2016) Phase 1 study of ceritinib in pediatric patients with malignancies 
harboring activated anaplastic lymphoma kinase (ALK): Safety, pharmacokinetics and 
efficacy results from the fed population European Journal of Cancer, Volume 69 , S49 - S50.
Galkin AV, Melnick JS, Kim S, et al (2007) Identification of NVP-TAE684, a potent, 
selective, and efficacious inhibitor of NPM-ALK. PNAS; 104 (1): 270-275.
Gascoyne RD, Aoun P, Wu D, et al (1999) Prognostic Significance of Anaplastic Lymphoma 
Kinase (ALK) Protein Expression in Adults With Anaplastic Large Cell Lymphoma. Blood; 
93(11): 3913-3921.
Geoerger B. et al (2015) Phase I study of ceritinib in pediatric patients (Pts) with malignancies 
harboring a genetic alteration in ALK (ALK+): Safety, pharmacokinetic (PK), and efficacy 
results. Journal of Clinical Oncology 2015 33:15_suppl, 10005-10005.
Gleevec United States Package Insert.
Griffin CA, Hawkins AL, Dvorak C, et al (1999) Recurrent Involvement of 2p23 in 
Inflammatory Myofibroblastic Tumors. Cancer Research; 59: 2776-80.
 


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Iwahara T, Fujimoto J, Wen D, et al (1997) Molecular characterization of ALK, a receptor 
tyrosine kinase expressed specifically in the nervous system. Oncogene; 14: 439-449.
Kim DW, Ahn MJ, Shi Y, et al (2012) Results of a global phase II study with crizotinib in 
advanced ALK-positive non-small cell lung cancer (NSCLC). J Clin Oncol; 30 (suppl); 
abstract 7533.
Kwak EL, Bang YJ, Camidge DR, et al (2010) Anaplastic lymphoma kinase inhibition in non-
small-cell lung cancer. N Engl J Med; 363(18):1693-703.
Li N, Michellys PY, Kim S, et al (2011) Activity of a potent and selective phase I ALK 
inhibitor LDK378 in naive and crizotinib-resistant preclinical tumor models. Molecular 
Cancer Therapeutics; 10 (11 suppl ); abstract B232.
McDermott U, Iafrate AJ, Gray NS, et al (2008) Genomic alterations of anaplastic lymphoma 
kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer 
Res;68(9):3389-95.
Mehra R, Camidge RD, Sharma S, et al (2012) First-in-human phase I study of the ALK 
inhibitor LDK378 in advanced solid tumors. J Clin Oncol.30 (suppl): abstract 3007.
Mosse YP, Balis FM, Lim MS (2012) Efficacy of crizotinib in children with 
relapsed/refractory ALK-driven tumors including anaplastic large cell lymphoma and 
neuroblastoma: a Children’s Oncology Group phase I consortium study. J Clin Oncol 30 
(suppl: abstract 9500.
Mosse YP, Laudenslager M, Long L, et al (2008) Identification of ALK as a major familial 
neuroblastoma predisposition gene. Nature; 455 (7261): 930-5.
Neuenschwander B, Branson M, Gsponer T (2008) Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med; 27 (13):2420-39.
Neuenschwander B, Capkun-Niggli G, Branson M, et al (2010) Summarizing historical 
information on controls in clinical trials. Clinical Trials; 7:5-18.
Palmer RH, Vernersson E, Grabbe C, et al (2009) Anaplastic lymphoma kinase: signaling in 
development and disease. Biochem J; 420: 345-361.
Savage KJ, Harris NL, Vose JM, et al (2008) ALK- anaplastic large-cell lymphoma is 
clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell 
lymphoma, not otherwise specified: report from the International Peripheral T-Cell 
Lymphoma Project. Blood; 111(12):5496-504.
Scagliotti G, Stahel RA, Rosell R, et al (2012) ALK translocation and crizotinib in non-small 
cell lung cancer: An evolving paradigm in oncology drug development. Eur J Cancer; 
48(7):961-73.
Shaw AT, Mehra R, Kim D-W, et al (2013) Clinical activity of the ALK inhibitor LDK378 in 
advanced, ALK-positive NSCLC; J Clin Oncol; 31 (Suppl; abstr 8010).
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.
Tabbo F, Barreca A, Piva G, et al (2012) ALK signaling and target therapy in anaplastic large 
cell lymphoma. Frontiers in Oncology; 2: 1-12.
 


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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.
van Gaal JC, Flucke UE, Roeffen MHS (2012) Anaplastic lymphoma kinase aberrations in 
rhabdomyosarcoma: clinical and prognostic implications. J Clin Oncol; 30:308-15.
 


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14
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14.3
Appendix 3: Karnofsky Performance Status Scale (for patients 
greater than 12 years old)
Able to carry on normal 
activity and to work; no 
special care needed
100%
Normal no complaints
90%
Able to carry on normal activity; minor signs or symptoms of 
disease.
80%
Normal activity with effort; some signs or symptoms of disease.
Unable to work; able to 
live at home and care 
for most personal 
needs; varying amount 
of assistance needed.
70%
Cares for self; unable to carry on normal activity or to do active 
work.
60%
Requires occasional assistance, but is able to care for most of his 
personal needs.
50%
Requires considerable assistance and frequent medical care.
Unable to care for self; 
requires equivalent of 
institutional or hospital 
care; disease may be 
progressing rapidly.
40%
Disabled; requires special care and assistance
30%
Severely disabled; hospitalization is indicated though death not 
imminent.
20%
Very sick; hospitalization necessary; active supportive treatment 
necessary.
10%
Moribund; fatal processes progressing rapidly.
0
Dead
 


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14.4
Appendix 4: Lansky score (for patients less than or equal to 12 
years old)
100
Fully active, normal
90
Minor restrictions in physically strenuous activity
80
Active, but tires more quickly
70
Both greater restriction of play and less time spent in play activity
60
Up and around, but minimal active play; keeps busy with quieter activities
50
Gets dressed but lies around much of the day; no active play but able to participate in all quiet 
play and activities
40
Mainly in bed; participates in quiet activities
30
Bed-bound; needs assistance even for quiet play
20
Often Sleeping; play entirely limited to very passive activities
10
No play; does not get out of bed
0
Unresponsive
 


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14.5
Appendix 5: Response Evaluation Criteria in Solid Tumors
(RECIST 1.1) Harmonization of Efficacy Analysis of Solid Tumor 
Studies
Harmonization of Efficacy Analysis of Solid Tumor Studies
Guidelines for Response, Duration of Overall Response,
TTF, TTP, Progression-Free Survival and Overall Survival
(based on RECIST 1.1)
Document type:
TA Specific Guideline
Document status:
Version 3.1:
29-Nov-2011
Version 3:0:
19-Oct-2009
Version 2:0:
18-Jan-2007
Version 1:0:
13-Dec-2002
Release date:
29-Nov-2011
List of contributors
Authors (Version 3.1):
 
Authors (Version 3):
 
Authors (Version 2):
 
Authors (Version 1):
 


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


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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 2 and the definition of best response in Section 
3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions and rules for 
determination of best response. Section 3.2 is summarizing the “time to event” variables and 
rules which are mainly derived from internal discussions and regulatory consultations, as the 
RECIST criteria do not define these variables in detail. Section 4 of this guideline describes 
data handling and programming rules. This section is to be referred to in the RAP (Reporting 
and Analysis Plan) to provide further details needed for programming.
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.
2.1
Definitions
2.1.1 Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in 
order to classify lesions appropriately at baseline. In defining measurability, a distinction also 
needs to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 3.2.8.
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease.
 


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
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density (water-like) content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.
2.1.2 Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the 
study in some situations (e.g. in Phase III studies where PFS is the primary endpoint). 
However, it is recommended that patients be excluded from trials where the main focus is on 
the Overall Response Rate (ORR). Guidance on how patients with just non-measurable 
disease at baseline will be evaluated for response and also handled in the statistical analyses is 
given in Section 3.2.8.
2.2
Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
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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.
2.3
Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five
lesions in total (and a maximum of two lesions per organ), representative of all involved
organs should be identified as target lesions and recorded and measured at baseline. Target
lesions should be selected on the basis of their size (lesions with the longest diameter) and
their suitability for accurate repeated measurements (either by imaging techniques or
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice
thickness is not applicable (e.g. clinical examination, photography) should be at least 10
mm in longest diameter. See Section 2.1.1.

Nodal target: See Section 2.1.1.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. 
Each target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.

Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of
non-target lesions should be assessed throughout the study; measurements of these lesions
are not required. Multiple non-target lesions involved in the same organ can be assessed as
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target
lesion identified at baseline must be followed at each subsequent evaluation and
documented on eCRF.
2.4
Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
 


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for the target (Table 2-1) and non-target lesions (Table 2-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target 
and non-target lesions together (Table 2-3) as well as the presence or absence of new lesions.
2.4.1 Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for 
the evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate 
lesion evaluation data are examined by the investigator in order to derive the overall visit 
response. Therefore all such data applicable to a particular visit should be associated with the 
same assessment number.
2.4.1.1
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.
2.4.1.2
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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2.4.2 Determination of target lesion response
Table 2-1
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 mm2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in 
lesions which would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions 
have not been assessed or have been assessed using a different 
method than baseline.3
1.
SOD for CR may not be zero when nodal lesions are part of target lesions
2.
Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present 
and all nodal lesions are <10 mm in size. In this case, the target lesion response is CR
3.
Methodology change See Section 2.2.
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance 
(i.e., the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually 
present and/or not visualized for technical reasons in this previous assessment. If it is not 
possible to change the 0 value, then the investigator/radiologist has to decide between the 
following three possibilities:

The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease.

The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 2-1 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.
 


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


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2.4.3 Determination of non-target lesion response
Table 2-2
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 2.4.2 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
2.4.4 New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
 


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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 2.5).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 2.2.
2.5
Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target 
lesion response, non-target lesion response and presence of new lesions as shown below in 
Table 2-3.
Table 2-3
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 2.4.
If there are no baseline scans available at all, then the overall lesion response at each 
assessment should be considered Unknown (UNK).
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
 


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3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
3.1
Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the 
protocol should specifically describe if these will be included in the determination of best 
overall response and/or whether these additional assessments will be required for sensitivity 
or supportive analyses. As a default, any assessments taken more than 30 days after the last 
dose of study treatment will not be included in the best overall response derivation. If any 
alternative cancer therapy is taken while on study any subsequent assessments would 
ordinarily be excluded from the best overall response determination. If response assessments 
taken after withdrawal from study treatment and/or alternative therapy are to be included in 
the main endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

For non-randomized trials where response is the primary endpoint, confirmation is needed.

For trials intended to support accelerated approval, confirmation is needed.

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required.

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required.

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).
 


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
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.
Based on the patients’ best overall response during the study, the following rates are then 
calculated:
 


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Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR 
or PR or SD.
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 8 
weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be 
at 8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with 
an unknown (UNK) assessment at that time point and no PD before, will not be counted as 
early progressors in the analysis but may be included in the denominator of the EPR rate, 
depending on the analysis population used. Similarly when examining overall response and 
disease control, patients with a best overall response assessment of unknown (UNK) will not 
be regarded as “responders” but may be included in the denominator for ORR and DCR 
calculation depending on the analysis population (e.g. populations based on an ITT approach).
3.2
Time to event variables
The protocol should state which of the following variables is used in that study.
3.2.1 Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
3.2.2 Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date 
the patient was last seen alive / last known date patient alive, the date of death and the reason 
of death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be 
censored at the date of last known date patient alive.
 


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3.2.3 Time to progression
Some studies might consider only death related to underlying cancer as an event which 
indicates progression. In this case the variable “Time to progression” might be used. TTP is 
defined as PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate 
tumor assessment.
3.2.4 Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation 
is typically related to intolerance of the study drug. In some protocols, time to treatment 
failure may be considered as a sensitivity analysis for time to progression. The list of 
discontinuation reasons to be considered or not as treatment failure may be adapted according 
to the specificities of the study or the disease.
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation 
due to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to 
treatment failure for patients who did not experience treatment failure will be censored at last 
adequate tumor assessment.
3.2.5 Duration of response
The analysis of the following variables should be performed with much caution when 
restricted to responders since treatment bias could have been introduced. There have been 
reports where a treatment with a significantly higher response rate had a significantly shorter 
duration of response but where this probably primarily reflected selection bias which is 
explained as follows: It is postulated that there are two groups of patients: a good risk group 
and a poor risk group. Good risk patients tend to get into response readily (and relatively 
quickly) and tend to remain in response after they have a response. Poor risk patients tend to 
be difficult to achieve a response, may have a longer time to respond, and tend to relapse 
quickly when they do respond. Potent agents induce a response in both good risk and poor 
risk patients. Less potent agents induce a response mainly in good risk patients only. This is 
described in more detail by Morgan (1988).
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then 
interpreted with caution by evaluating the results in the context of the observed response rates. 
If an inferential comparison between treatments is required this should only be performed on 
all patients (i.e. not restricting to “responders” only) using appropriate statistical methods such 
as the techniques described in Ellis et al (2008). It should also be stated in the protocol if 
duration of response is to be calculated in addition for unconfirmed response.
 


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For summary statistics on “responders” only the following definitions are appropriate. 
(Specific definitions for an all-patient analysis of these endpoints are not appropriate since the 
status of patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in 
which a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to 
be confirmed) or SD the start and end date as well as censoring is defined the same as that for 
time to progression.
3.2.6 Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be 
confirmed depending on the type of study and its importance. Where the response needs to be 
confirmed then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be 
performed on the “responders” subset only, in which case the results should be interpreted 
with caution and in the context of the overall response rates, since the same kind of selection 
bias may be introduced as described for duration of response in Section 3.2.5. It is 
recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. Where an 
inferential statistical comparison is required, then all patients should definitely be included in 
the analysis to ensure the statistical test is valid. For analysis including all patients, patients 
who did not achieve a response (which may have to be a confirmed response) will be censored 
using one of the following options.

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the
worst possible outcome as it means the patient cannot subsequently respond. Since the
statistical analysis usually makes use of the ranking of times to response it is sufficient to
assign the worst possible censoring time which could be observed in the study which is
equal to the maximum follow-up time (i.e. time from FPFV to LPLV).

at last adequate tumor assessment date otherwise. In this case patients have not yet
progressed so they theoretically still have a chance of responding.
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
 


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3.2.7 Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest 
of all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that 
assessment is CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the 
assessment date is calculated as the earliest date of all measurement dates at that evaluation 
number.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion
response of CR (for duration of overall complete response) or CR / PR (for duration of
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during
follow-up as recorded on the study evaluation completion page or the survival follow-up
page).

Date of progression is the first assessment date at which the overall lesion response was
recorded as progressive disease.

Date of last adequate tumor assessment is the date the last tumor assessment with overall
lesion response of CR, PR or SD which was made before an event or a censoring reason
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus
the protocol specified time interval for assessments. This date may be used if back-dating
is considered when the event occurred beyond the acceptable time window for the next
tumor assessment as per protocol (see Section 3.2.8).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

Date of last contact is defined as the last date the patient was known to be alive. This
corresponds to the latest date for either the visit date, lab sample date or tumor assessment
date. If available, the last known date patient alive from the survival follow-up page is
used. If no survival follow-up is available, the date of discontinuation is used as last
contact date.
 


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
Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
3.2.8 Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered 
into the study, either because of a protocol violation or by design (e.g. in Phase III studies 
with PFS as the primary endpoint). In such cases the handling of the response data requires 
special consideration with respect to inclusion in any analysis of endpoints based on the 
overall response evaluations.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 3-1.
Table 3-1
Overall lesion response at each assessment: patients with non-
target disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 2.4.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with 
only non-measurable disease at baseline, handling patients with a best response of CR as 
“responders” with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses 
which exclude these particular patients. Endpoints such as PFS which are reliant on the 
determination and/or timing of progression can incorporate data from patients with only non-
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3.2.9 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 3.2.7, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 
2005) as a reference, the following analyses can be considered:
Table 3-2
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, 
duration of 
response)
1.
Definitions can be found in Section 3.2.7.
2.
After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in
Section 3.2.7.
3.
The rare exception to this is if the patient dies no later than the time of the second scheduled
assessment as defined in the protocol in which case this is a PFS event at the date of death.
 


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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.
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 3-2 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.
4
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
 


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4.1
Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
4.2
End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc.
The end of treatment visit and its associated assessments should occur within 7 days of the 
last study treatment.
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s).

Lost to follow-up.

Physician decision.

Pregnancy.

Protocol deviation.

Technical problems.

Subject/guardian decision.

Death.

Progressive disease.

Study terminated by the sponsor.

Non-compliant with study treatment.

No longer requires treatment.

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given).
4.3
End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study 
treatment and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event.

Lost to follow-up.

Physician decision.
 


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
Pregnancy.

Protocol deviation.

Technical problems.

Subject/guardian decision.

Death.

New therapy for study indication.

Progressive disease.

Study terminated by the sponsor.
4.4
Medical validation of programmed overall lesion response
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) 
and not available evaluations (i.e. if any target or non-target lesion was not evaluated the 
whole overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 
assessments may be re-evaluated by clinicians at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on 
RECIST criteria. This may be queried for clarification. However, the investigator or central 
reader’s response assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion 
response at that specific assessment is to be kept in a dataset. This must be clearly 
documented in the RAP documentation and agreed before database lock. This dataset should 
be created and stored as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
4.5
Programming rules
The following should be used for programming of efficacy results:
4.5.1 Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days).
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
4.5.2 Incomplete assessment dates
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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 3.2.7). If all measurement dates have no 
day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
4.5.3 Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
4.5.4 Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
4.5.5 Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
4.5.6 Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive.

Lost to follow-up.
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event.

Lost to follow-up.

Withdrew consent.

Adequate assessment no longer available*.

Event documented after two or more missing tumor assessments (optional, see Table 3-2).

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 3.2.7. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
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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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5
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791.
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47.
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465.
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005.
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007.Morgan TM (1988) Analysis of duration of response: a problem of 
oncology trials. Cont Clin Trials; 9: 11-18.
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16.
 


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14.6
Appendix 6: Guidelines for efficacy evaluation in lymphoma 
studies (based on Cheson response criteria). International 
Working Group guidelines for hematological malignancies
Authors:
 
Document type:
TA Specific Guideline
Development phase:
Final Version 1: 17-Nov-2009
 


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1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy in Oncology Lymphoma studies where Cheson 
response criteria apply.
This document is based on the International Working Group response criteria (Cheson et al 
1999), and the International Harmonization Project revised response criteria (Cheson et al 
2007b). Further clarification on these criteria has been published by (Cheson 2007a).
As Positron emission tomography (PET) is not yet widely accepted (Cheson 2009) for 
assessing response to treatment in lymphoma it is not considered for standard use in Novartis 
Oncology Lymphoma studies and therefore it is not considered in this document.
In general, this document is intended for studies where patients currently have measurable 
disease to be assessed, and therefore does not specifically address studies when the eligible 
patient population has no measurable disease (such as studies in patients who achieved 
complete response to first line treatment, or in post-transplantation settings). However, this 
guidance should be readily adaptable to these settings (see Appendix E).
2
Definitions and criteria for normalization
2.1
Definitions
Throughout this document, the following definitions will apply (See also Appendix A).
Nodal vs extranodal lesion
A lesion is categorized based on the location as:

Nodal lesion,

Extranodal lesion, if it is located in organs other than lymph node or nodal mass, but 
including spleen and liver.
Measurability
Throughout this document, a lesion will be called measurable if it can be measured 
accurately in 2 perpendicular dimensions and:

For nodal lesion, if the long axis is > 15 mm, regardless of the length of the short axis,

For extranodal lesion, if the long and short axes are ≥ 10 mm.
Classification of lymph nodes
Lymph nodes are classified according to their size and/or relationship to the disease:

A lymph node meeting the measurability requirement above will constitute a measurable 
nodal lesion.

A lymph node not meeting the measurability requirement but with long axis > 15 mm (e.g. 
short axis cannot be measured accurately) will constitute a non-measurable nodal lesion.
 


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
A lymph node not meeting the measurability criteria but with a size of 11 mm to 15 mm in 
the long axis and > 10 mm in the short axis will be checked for relationship to disease:

If it is thought to be disease related, it will constitute a non-measurable nodal lesion
(referred to as “involved node” in Cheson et al 2007b).

If it is not thought to be disease related, it will constitute an abnormal lymph node
but not a lesion.

All other lymph nodes will be considered normal and will not constitute nodal lesions.
2.2
Criteria for normalization of lesions
The normalization of lesions is defined as follow:

A measurable nodal lesion must become ≤ 15 mm in long axis to be considered 
normalized.

A non-measurable nodal lesion must decrease to ≤ 10 mm in the short axis and be ≤ 15 
mm in long axis to be considered normalized.

An extranodal lesion must disappear completely (assigned a size of 0 mm x 0 mm) to be 
considered normalized.
3
Efficacy assessments
3.1
Eligibility
Studies will be intended to include patients with measurable disease.
Patients should have at least one measurable nodal lesion greater than 20 mm in the long 
axis.
In cases where the patient has no measurable nodal lesions greater than 20 mm in the long 
axis at baseline, then the patient must have at least one measurable extranodal lesion.
3.2
Methods of disease assessment
All radiological measurements should be taken in two perpendicular dimensions and recorded 
in metric notation, using a ruler or calipers.
All baseline evaluations should be performed as closely as possible to the randomization/start 
of treatment (preferably within 7 days) and never more than 3 weeks (21 days) before the 
randomization/start of treatment.
The protocol should state if randomization or start of treatment is used as start date (baseline). 
This is then used in all definitions.
If different window for baseline assessments is allowed in the study this must be justified in 
the Study Protocol.
3.2.1 CT scan (or MRI)
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. 
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5mm 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 be allergic to CT contrast or develops allergy during the trial, the 
following change in imaging modality will be accepted for follow up: a non-contrast CT of 
chest (MRI not recommended due to respiratory artifacts) plus contrast-enhanced MRI of 
abdomen and pelvis.
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 (eg. 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 “Unknown” overall radiological response assessment. However, another 
overall radiological response than the Novartis calculated “Unknown” response may be 
accepted from the investigator or the central blinded reviewer if a definitive overall 
radiological response can be justified to be based on the available information.
In order to calculate the sum of the product of the diameters (SPD) of all index lesions (or 
extranodal lesions), their size must be entered throughout the study.
Actual lesion measurements should be entered on the corresponding CRFs. If, during the 
course of the study, either of the perpendicular diameters of a lesion can not be reliably 
measured because of its small size, it is recommended to enter the minimum limit of detection 
as the diameter size (e.g. 5 mm for spiral CT). In other cases when, during the course of the 
study, the diameter cannot be reliably measured for reasons other than its size (i.e. borders of 
the lesion are confounded by neighboring anatomical structures), no measurement should be 
entered and the lesion cannot be evaluated.
If lesions become confluent over time, it is recommended to measure them as one lesion, 
report the overall diameters to one of the lesions and assign 0 mm x 0 mm to each of the other 
previously measured lesions. If a lesion splits during the study, each sub-lesion should be 
measured separately for all subsequent assessments and all sub-lesions contribute to the SPD.
3.2.2 Bone marrow assessment
Documentation of status of bone marrow involvement by lymphoma based on prior bone 
marrow biopsy or aspirate findings is required at baseline for all patients.
If no such documentation is available then a bone marrow biopsy or aspirate should be 
performed at baseline.
Further collection or confirmation of bone marrow status at baseline beyond the above 
requirement and/or at time of radiological CR may be required for some or all patients 
depending on disease/study/setting basis. A time window should be specified for when the 
biopsy or aspirate date would be expected with respect to the inclusion date (resp. the date of 
radiological CR). Full details should be provided in the Study Protocol.
If bone marrow involvement is assessed by biopsy, the biopsy sample should have a goal of > 
20 mm unilateral core. If the biopsy sample is indeterminate by morphology 
(immunohistochemistry), then flow cytometry may be performed on bone marrow aspirate to 
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3.2.3 Physical examination and assessment of B-symptoms
Skin lesions, if the size is ≥ 20 mm in at least one diameter, must be histologically confirmed 
for lymphoma involvement (the investigational site must document the histological 
confirmation (yes or no) on the corresponding CRF) and photographed including a ruler 
(color photography using digital camera). Tumor assessment will be performed and results 
will be recorded on the corresponding CRF at baseline and at the time of each radiological 
assessment.
B-symptoms are of importance in determining prognosis and should resolve completely in 
patients who have achieved complete response. B-symptoms in lymphoma patients are disease 
related clinical symptoms and are not caused by anticancer therapy (or drug toxicity).
B-symptoms are defined as follows :

Significant unexplained fever (≥ 38°C),

Unexplained, recurrent drenching night sweats,

Unexplained loss of > 10% body weight within the previous 6 months,
as assessed and reported (present vs. absent) by the Investigator.
3.3
Documentation of disease
For the evaluation of disease at baseline and throughout the study, the following are recorded.
Index nodal lesions
Index nodal lesions are selected from the measurable nodal lesions. A minimum of one 
measurable index nodal lesion and maximum of six of the largest dominant nodal lesions 
should be documented at baseline and assessed throughout the study. If a patient has no 
measurable nodal disease at baseline, then it would be acceptable that no index nodal lesions 
be identified. Index nodal lesions should be from disparate regions of the body including 
mediastinal and retroperitoneal areas of disease whenever these sites are involved. Two 
perpendicular dimensions must be recorded on the corresponding CRF at each assessment of a 
measurable lesion selected to be an index lesion.
Non-index nodal lesions
All other nodal lesions (both measurable and non-measurable) are considered as non-index 
lesions.
Non-index lesions should be documented at baseline and assessed throughout the study. 
Measurements of these lesions are not required to be documented on the CRF. Their response 
status will be determined from investigator assessment as described in Section 3.4.2.
Spleen and liver (index and non-index) lesions
The spleen and liver will be assessed by CT scan (or MRI scan).
A maximum four of the largest dominant measurable nodules representing all involved 
anatomic locations should be selected as splenic and hepatic index lesions to be measured at 
 


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baseline and followed up during the treatment. Two perpendicular dimensions will be 
recorded into the CRF at each assessment.
All other splenic or hepatic nodules (both measurable and non-measurable) are considered as
non-index lesions. They should be documented at baseline and assessed throughout the study. 
Measurements of these lesions are not required to be documented on the CRF. Their response 
status will be determined from investigator assessment as described in Section 3.4.2.
Other extranodal (index and non-index) lesions
Organs other than lymph nodes, liver, spleen and bone marrow (such as breast and lung) can 
be occasionally involved by lymphoma. Determination of lymphoma involvement of these 
organs should be confirmed histologically.
If such organs are confirmed to be involved with measurable lesions, then index lesions 
should be selected from those organs. Up to four measurable lesions will be selected as index 
extranodal lesions from disparate regions (other than liver and spleen) at baseline and 
followed during the study.
Additional measurable lesions and all non-measurable extranodal disease will be documented 
at baseline and assessed throughout the study as non-index lesions. Other non-measurable 
disease, such as pleural effusion or bone lesions that are documented to be due to malignant 
disease, will be recorded at baseline as non-index lesions and followed during the study. 
Measurements of these lesions are not required to be documented on the CRF. Their response 
status will be determined from investigator assessment as described in Section 3.4.2.
Enlarged spleen or liver
The presence of enlarged spleen or liver before randomization/start of treatment on the basis 
of CT scan should be recorded on the corresponding CRF at baseline, and reassessed if the 
patient has a radiological CR.
Bone marrow involvement
Status of bone marrow involvement by lymphoma before randomization/start of treatment 
will be collected (see Section 3.2.2).
If specifically required by the Study Protocol, a confirmatory bone marrow biopsy or aspirate 
may be performed at baseline and following a radiological CR, and will be reviewed by 
pathology laboratory to confirm the status of bone marrow involvement of the disease. Report 
will be recorded on the corresponding CRF.
B-symptoms
B-symptoms (unexplained fever ≥ 38°C; unexplained, recurrent drenching night sweats; 
unexplained loss of > 10% body weight within the previous 6 months) will be recorded before 
randomization/start of treatment (baseline) and reevaluated if patients have achieved 
radiological CR as well as at the end of therapy.
 


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3.4
Evaluation of radiological response
For the sake of simplicity, complete remission (as defined in Cheson et al 2007b) and 
complete response will both be referred to as complete response in this document.
To evaluate disease response to treatment, all index and non-index lesions will be followed 
and assessed throughout the study. At each assessment, response is evaluated separately for 
the index lesions (Table 14-14) and non-index lesions (Table 14-15) identified at baseline, 
then a combined overall radiological response is determined (Table 14-16).
3.4.1 Evaluation of index lesions (nodal and extranodal)
3.4.1.1
When index nodal lesions are not in complete response
The response for index lesions is evaluated by calculating the Sum of the Products of 
Diameters (SPD) of all index lesions (see Table 14-12), except when there is a Complete 
Response for index nodal lesions (i.e. complete normalization of all index nodal lesions) (see 
Section 3.4.1.2).
Table 14-12
Table radiological status based on SPD calculation for all index 
lesions
Response Criteria1
Evaluation of index lesions
Complete Response (CR)
See Table 14-14 below (not based on SPD calculation for all index 
lesions)
Partial Response (PR)
At least 50% decrease from baseline in the SPD of all index lesions
Stable Disease (SD)
Failure to attain the criteria needed for CR or PR and failure to fulfill 
the criteria for PD
Progressive Disease (PD)
At least a 50% increase from nadir2 in the SPD of all index lesions
1 At each assessment (if the index nodal lesions are not in CR status), the response status based on 
SPD calculation will be first assessed for meeting PD status criteria, then PR status and SD status.
2 Nadir is defined as the smallest sum of the product of the diameters of all index lesions recorded so 
far, at or after baseline.
3.4.1.2
When index nodal lesions are in complete response
When there is a Complete Response for index nodal lesions (i.e. complete normalization of all 
index nodal lesions as defined in Section 2.2: all index lesion ≤ 15 mm in long axis), the SPD 
for these index nodal lesions may not be equal to zero and therefore a calculation of a SPD for 
all index lesions may be misleading. Therefore, by default, a specific response for extranodal 
index lesions needs to be evaluated, based on the SPD calculation restricted to all index 
extranodal lesions only (see Table 14-13).
Table 14-13
Radiological response criteria for index extranodal lesions in case of 
CR in index nodal lesions
Response Criteria1
Evaluation of index extranodal lesions
Complete Response (CR)
Complete disappearance of all index extranodal lesions
Partial Response (PR)
At least 50% decrease from baseline in the SPD restricted to all index 
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Response Criteria1
Evaluation of index extranodal lesions
Stable Disease (SD)
Failure to attain the criteria needed for CR or PR and failure to fulfill the 
criteria for PD
Progressive Disease (PD)
At least a 50% increase from nadir2 in the SPD restricted to all index 
extranodal lesions
1 At each assessment, response will be first assessed for meeting CR status. If CR status is not met, 
response will be assessed for PD status, then PR status and SD status.
2 Nadir is defined as the smallest sum of the product of the diameters restricted to all index extranodal 
lesions recorded so far, at or after baseline.
The algorithm for evaluating the response integrating index extranodal lesions and the SPD 
calculated on all index lesions (where appropriate) provides an overall response for index 
lesions (see Table 14-14).
3.4.1.3
Evaluation of response for all index lesions
The evaluation of response for all index lesions is based on the combination of the response 
for index nodal lesions (CR or non-CR), the response for index extranodal lesions (as 
calculated in Table 14-13), and the status based on the SPD calculated on all index lesions 
(nodal and extranodal), as described in Table 14-14 and Appendix B.
Table 14-14
Radiological response for index lesions
Response for 
index nodal 
lesions1
Response for 
index extranodal 
lesions1
Status based on SPD 
calculation for all index 
lesions
Response for index 
lesions
CR
CR
Not calculated
CR
CR
SD/ PR
Not calculated
PR
CR
PD
PD
PD
CR
PD
PR
PR
CR
PD
SD
SD
Non-CR
Not evaluated
PD
PD
Non-CR
Not evaluated
PR
PR
Non-CR
Not evaluated
SD
SD
1 If no index nodal lesions are present at baseline, then index lesions response is equal to the index 
extranodal lesions response. A similar rule applied if no index extranodal lesions are present at 
baseline, then index lesions response is equal to the index nodal lesions response.
In case of a missing measurements of any of the index lesions, the radiological response for 
index lesions at that assessment will be “Unknown (UNK)”, unless progression was seen.
All lesions must have been measured with the same method as the one used at baseline, 
otherwise the radiological response for index lesions at that assessment will be “Unknown 
(UNK)”.
 


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3.4.2 Evaluation of non-index lesions (including nodal, splenic and/or hepatic 
nodules and other extranodal lesions)
At each reassessment, a non-index lesion (or a group of non-index lesions) will be given one 
of the following designations:

Normalization (non-index nodal lesion has regressed to normal size; non-index extranodal
lesion is no longer present). Normalization of non-index nodal lesions should be
determined based on their size at baseline as described in Section 2.2.

Improved, stable or worsened, but without unequivocal evidence of disease progression
(non-index lesion is present but there is not sufficient worsening to declare PD based on
the existing non-index lesions).

Unequivocal evidence of disease progression (worsening of existing non-index lesions is
sufficient to declare PD)

Not assessed
Then, this status for each non-index lesion (or group of non-index lesions) will lead to a
global response for non-index lesions (Table 14-15 and Appendix C):
Table 14-15
Response criteria for non-index lesions (nodal, splenic and/or hepatic 
nodules and other extranodal lesions)
Response Criteria
Evaluation of non-index lesions
Complete Response (CR)
Complete normalization of all non-index nodal and extranodal lesions: 
Radiological regression to normal size of all lymph nodes and complete 
disappearance of all extranodal (including splenic and/or hepatic nodules) 
lesions
Stable Disease (SD)
Failure to attain the criteria needed for CR and failure to fulfill the criteria 
for PD
Progressive Disease (PD)
Unequivocal disease progression of any existing non-index lesions (nodal 
or extranodal)
In case of a missing status of any of the non-index lesions, the radiological response for non-
index lesions at that assessment will be “Unknown (UNK)”, unless progression was seen.
All lesions must have been measured with the same method as the one used at baseline, 
otherwise the radiological response for non-index lesions at that assessment will be 
“Unknown (UNK)”.
3.4.3 New lesions
The appearance of

any new nodal lesion >15 mm in any axis. New nodal lesion is defined by:

either a previously normal lymph node becoming > 15 mm in any axis,

or a previously identified abnormal lymph node showing an increase of at least 50%
in the long axis,
as assessed by investigator (or Central Review if applicable).
OR
 


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
any discrete extranodal (including splenic and/or hepatic nodules) lesions reliably 
appearing on CT scan or MRI after baseline,
is always considered as Progressive Disease (PD) and has to be recorded as a new lesion in 
the appropriate module of the CRF. Determination of new lymphoma involvement in organs 
other than lymph nodes or liver or spleen should be confirmed histologically and the site must 
document that in a comment to the corresponding CRF.
3.4.4 Overall radiological response
Overall radiological response is calculated as shown in Table 14-16.
Table 14-16
Overall radiological response at each assessment
Index lesions
Non-index lesions1
New lesions
Overall radiological response
CR
CR
No
CR
CR
SD
No
PR
PR
CR or SD
No
PR
SD
CR or SD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1 If no non-index lesions are present at baseline, then this column is not used in evaluating overall 
radiological response.
If the evaluation of any of the index or non-index lesions identified at baseline could not be 
made during follow-up or if the index or non-index response is “Unknown (UNK)”, the 
overall response status at that assessment must be “Unknown (UNK)” unless progression or a 
new lesion was seen.
3.5
Evaluation of overall disease response
The evaluation of overall disease response at each assessment is a composite of the individual 
radiological responses (index and non-index lesions, new lesions), laboratory test (bone 
marrow) and clinical responses (lymphoma related clinical symptoms).
3.5.1 Bone marrow re-assessment at time of radiological CR
In order to confirm a Complete disease Response (CR), bone marrow biopsy or aspirate may 
be required when a radiological CR has been achieved (see Section 3.2.2). Details are 
provided in the Study Protocol. The infiltrate of lymphoma in bone marrow must have cleared 
on repeat bone marrow biopsy or aspirate. Patients who achieve a CR by other criteria but 
who have persistent morphologic positive or inconclusive bone marrow involvement will be 
considered partial responders. New or recurrent bone marrow involvement anytime during the 
follow up will be considered PD. Bone marrow biopsy or aspirate will be performed after the 
first assessment of CR or when clinically indicated.
The biopsy sample of bone marrow must be adequate (with a goal of > 20 mm unilateral core). 
If the sample is indeterminate by morphology, it should be negative by immunohistochemistry.
 


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3.5.2 Overall disease response
If a patient has an overall radiological response of CR as defined in Table 14-16, then this 
response must be confirmed by bone marrow biopsy or aspirate (if required as per the Study 
Protocol), presence of normal liver and spleen size, and evaluation of lymphoma related B-
symptoms. The patient’s overall response will be calculated as follows (see also Appendix D):
A patient will be deemed to have overall disease response of CR if bone marrow biopsy or 
aspirate becomes negative for tumor involvement (if the bone marrow was involved by 
lymphoma at baseline) and the liver and spleen are normal in size and there are no lymphoma 
related B-symptoms in addition to radiological CR.
If assessments of any of the following: lymphomatous infiltration of bone marrow (If required 
as per the Study Protocol), or evaluation of B-symptoms is not done, unknown or 
indeterminate or B-symptoms are still present when the overall radiological response is 
assessed as CR or the liver or spleen are enlarged, then the overall disease response will be 
assessed as PR until evaluation of these factors have shown normalized results and recorded 
on the corresponding CRF.
For patients whose radiological response is anything other than CR, assessment of bone 
marrow, liver, spleen and B-symptoms will not be required in evaluating overall response and 
overall disease response is the same as radiological response. However any new or recurrent 
bone marrow involvement at any time during follow-up will be considered PD.
Of note, appearance of B-symptoms or enlarged spleen or liver will not in themselves 
constitute documentation of progression. They are however expected to be associated with 
progressive disease. Every effort should be made to document that evidence radiologically 
and report the corresponding tumor assessments. Such tumor assessments are expected to be 
performed within 2 months of appearance of B-symptoms or enlarged spleen or liver.
4
Efficacy analysis definitions
4.1
Best overall disease response
The best overall disease response is the best disease response recorded from 
randomization/start of treatment until progressive disease or start of new anticancer therapy, 
whichever comes first.
A best overall disease response of SD will be declared when at least one SD assessment is 
available at least 6 weeks after randomization/start of treatment (and the patient would not 
qualify for CR or PR).
If a different minimum follow-up period is required to classify for best overall disease 
response= ‘stable disease’, this must be specified in the Study Protocol.
A patient will have a best overall disease response of PD if the progressive disease was 
observed less than 17 weeks after randomization/ start of treatment (and the patient does not 
qualify for CR, PR or SD).
The 17 weeks period corresponds to the time period when two tumor assessments are 
expected (i.e. tumor assessments performed every 8 weeks ± 1 week). If the PD is first 
 


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observed after 2 missing assessments from baseline, the best overall disease response of the 
patient is UNK. If a different follow-up period is considered for PD to lead to a best overall 
disease response= ‘progressive disease’, this must be specified in the Study Protocol.
The best overall disease response for a patient is always calculated, based on the sequence of 
overall disease responses. However, the overall disease response at a given assessment may 
be provided from different sources:

Investigator overall disease response based on local radiological assessments, clinical and 
pathological (bone marrow in patients with CR) response.

Central Blinded Review of radiological response, with or without blinded adjudication 
integrating clinical and pathological (bone marrow in patients with CR) response.

Novartis calculated overall disease response, based on measurements / lesion status from 
either Investigator or Central Review and clinical and pathological (bone marrow in 
patients with CR) response.
The Study Protocol should state which source will be used for the primary analysis.
Based on the patients’ best overall disease response during the study, the following rate is 
then calculated:
Overall response rate (ORR) is the proportion of patients with a best overall disease 
response of CR and PR.
4.2
Time to event variables
Most of the time to event variables are defined in this section according to the International 
Working Group response criteria (Cheson et al 2007b). Further details on dates and censoring 
rules are provided respectively in Section 4.3 and Section 4.4.
4.2.1 Overall survival
Overall survival (OS) is defined as the time from the date of randomization/start of treatment 
to the 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 contact.
4.2.2 Progression-free survival
Progression-free survival (PFS) is defined as the time from the 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 the last adequate assessment.
4.2.3 Time to progression
Time to progression (TTP) is defined as the time from the date of randomization/start of 
treatment to the date of first documented progression or death due to lymphoma. If a patient 
has not had an event, time to progression is censored at the date of the last adequate 
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4.2.4 Duration of response
If the following variables are analyzed, it should be stated that this analysis might introduce a 
bias as it includes only responders. There have been reports where a treatment with a 
significantly higher response rate had a significantly shorter duration of response. The 
analysis of duration of responses should only be used as a descriptive analysis. If they are 
used as inferential comparison between treatments, clear justification must be given in the 
Study Protocol.
Duration of overall response (CR or PR) applies only to patients whose best overall disease 
response was CR or PR. It is defined as the time from the date of first documented disease 
response (CR or PR) to the date of first documented progression or death due to lymphoma. If 
a patient has not had an event, duration of overall response is censored at the date of the last 
adequate assessment.
The following duration might be calculated in addition for a large Phase III study in which a 
reasonable number of responders is seen. Justification must be given in the Study Protocol 
when these endpoints are used for any comparison between treatments.
Duration of overall complete response (CR) applies only to patients whose best overall 
disease response was CR. It is defined as the time from the date of first documented disease 
complete response to the date of first documented progression or death due to lymphoma. If a 
patient has not had an event, duration of overall complete response is censored at the date of 
the last adequate assessment.
4.2.5 Time to response
Time to overall disease response (CR or PR) is defined as the time from the date of 
randomization / start of treatment to the date of first documented disease response (PR or CR). 
This analysis will include all patients/responders. If all patients are included, then patients 
who did not achieve a PR or CR will be censored:

At maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. either progressed or died due to any cause).

At the date of the last adequate assessment otherwise.
Time to overall disease complete response (CR) is defined as the time from the date of 
randomization / start of treatment to the date of first documented disease complete response 
(CR). This analysis will include all patients/responders. If all patients are included, then 
patients who did not achieve a CR will be censored:

At maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. either progressed or died due to any cause)

At the date of the last adequate assessment otherwise.
Indicate whether this analysis should include only the responders (in which case please delete 
‘patients/’ and the sentence on patients who did not respond) or should estimate the time to 
response for the whole study population (in which case please delete ‘/responders’). If both 
methods should be used, please state that in the Study Protocol.
 


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4.2.6 Lymphoma specific survival
Lymphoma specific survival (LSS) is defined as the time from the date of randomization/ 
start of treatment to the date of death documented as a result of lymphoma. If a patient has not 
had an event, lymphoma specific survival will be censored:

at the date of last contact if the patient is not known to have died,

at the date of death if the patient died for other reason than lymphoma.
4.2.7 Event free survival
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.
Event-free survival (Time to treatment failure (TTF)) is defined as the time from the date 
of randomization to the earliest date of any of the following:

death.

progressive disease as overall disease response assessed by the local investigator prior to 
treatment discontinuation.

study treatment discontinuation due to:

disease progression.

adverse event(s).

abnormal laboratory value(s).

abnormal test procedure results.

patient withdrew consent.

lost to follow-up.

death.

new cancer therapy.
Patients who discontinue study treatment for reasons other than those listed above (i.e., as a 
result of protocol violation, administrative problems) are censored at the date of the last 
adequate assessment prior to discontinuation. Patients with neither an event nor study 
treatment discontinuation are censored at the date of the last adequate assessment.
4.3
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 date of all radiological measurement dates (e.g. CT-scan (or MRI), and 
excluding both bone marrow biopsy and B-symptoms assessment), if the overall disease 
response at that assessment is CR/PR/SD/UNK,
 


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
the earliest date of all measurement dates (e.g. CT-scan (or MRI), including bone marrow 
biopsy, but excluding B-symptoms assessments) if the overall disease response at that 
assessment is PD.
Start dates
For all “time to event” variables, other than the duration of responses, the date of 
randomization /start of treatment will be used as the start date.
For the calculation of duration of responses the following start date should be used:

Date of first documented response is the assessment date of the first overall disease 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death as reported on the CRF (on the treatment completion page, the study 
evaluation completion page or survival follow-up page).

Date of last contact is defined as the last date the patient was known to be alive as 
derived from different CRF pages (see details in Section 5).

Date of progression is the first assessment date at which the overall disease response was 
recorded as PD.

Date of last adequate assessment is the date the last assessment with overall disease 
response of CR, PR or SD which was made before an event or a censoring reason occurred. 
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 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 
radiological assessment as per protocol.
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 treatment discontinuation is the last known date subject took study drug.

Date of secondary anti-cancer therapy is defined as the start date of first additional 
(secondary) antineoplastic therapy or surgery (see details in Section 5)
 
 
 
 


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5
Data handling and programming conventions
The following could be used for programming of efficacy results, but should be specified in 
the RAP documentation:
Calculation of ‘time to event’ variables
Time to event = enddate - startdate + 1 (in days).
When no post-baseline assessments are available, the date of randomization/start of treatment 
will be used as enddate (duration = 1 day) when time is to be censored at last assessment, i.e. 
time to event variables can never be negative.
Date of last contact
The date of last contact will be derived for patients alive using the latest complete date among 
the following:

All assessment dates (e.g. vital signs assessment, performance status assessment, and also
assessment date in third-party data such as tumor imaging, central laboratory, ECG etc).

Medication dates including study medication, concomitant medications, antineoplastic
therapies administered after study treatment discontinuation.

Adverse events dates.
 


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
Last contact date collected on the ‘Survival information’ eCRF.

Randomization date.
Date of secondary anti-cancer therapy
The date of secondary anti-cancer therapy is the date of the 1st antineoplastic therapy or 
surgery reported in the concomitant medications page, further antineoplastic therapy page or 
from other sources (e.g. Dosage administration record page).
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 4.3). 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.
Incomplete dates for last contact 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.
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
6
References (available upon request)
Cheson BD (2007a) The international harmonization project for response criteria in 
lymphoma clinical trials. Hematol Oncol Clin N Am 21:841-854.
Cheson BD (2009) The case against heavy PETing. J Clin Oncol 27:1742-1743.
Cheson BD, Horning SJ, Coiffier B, et al (1999) Report of an International Workshop to 
standardize response criteria for non-Hodgkin's lymphomas. J Clin Oncol 17:1244-1253.
Cheson BD, Pfistner B, Juweid ME, et al (2007b) Revised response criteria for malignant 
lymphoma. J Clin Oncol 25:579-586.
FDA Guideline (2005) Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005.
 


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7
Appendices
Appendix A: Definition of index nodal lesion, non-index nodal lesion, 
index extranodal lesion, non-index extranodal lesion
 


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Appendix B: Calculation of the response for index lesions
 


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Appendix C: Calculation of the response for non-index lesions
 


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Appendix D: Calculation of the overall disease response
 


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Protocol No. CLDK378X2103
Appendix E: Adaptation for use in maintenance/adjuvant settings
For settings in which no measurable disease is present at baseline (e.g. maintenance), this 
guideline can be adapted. In such setting, as patients have no more measurable disease at 
baseline, the event of main interest is no more the Progressive Disease but the Relapsed 
Disease and the main endpoint is no more the Progression-free survival but the Disease-free 
survival. The definitions that need to be considered are presented below:
Relapsed disease
The definition of Relapsed Disease can be derived from the definition of New Lesion (see 
Section 3.4.3) and is as follow:
Appearance of the following will always be considered as Relapsed Disease (RD)

any new nodal lesion > 15 mm in any axis (i.e. previously normal lymph node becoming >
15 mm in any axis) on CT scan or MRI after baseline, or

any discrete extranodal lesion (including liver or spleen) reliably appearing on CT scan or
MRI after baseline, or

≥ 50% increase in long axis from baseline of any residual lymph node or mass. A residual
lymph node or mass is defined as a previously lymphoma-involved lymph node or mass
(>10 mm in short axis (without any upper limit)) that was PET scan negative at baseline
and only reliably detected by baseline CT or MRI. Note: If a residual lymph node or mass
at baseline decreases in size during treatment and becomes normal (i.e. complete
disappearance of extranodal mass or ≤ 10 mm in short axis and ≤ 15 mm long axis for
nodal mass), then reappearance of an extranodal lesion at the same site or increase of the
same nodal mass to > 15 mm in the long axis, will be considered as Relapsed Disease and
need to be recorded as a new lesion in the appropriate module of the CRF.
Details on PET scan negative should be provided in the Study Protocol.
Disease-Free Survival
Disease-Free Survival (DFS) is the time from date of randomization/ start of treatment to the 
date of event defined as the first documented relapse of the disease or death due to any cause. 
If a patient has not had an event, disease-free survival is censored at the date of the last 
adequate assessment.
Similar censoring rules and reasons as the ones used for PFS can be applied. Full details 
should be provided in the Study Protocol and in the Report Analysis Plan.
Additional endpoints may be considered for specific lymphoma settings. Full details should 
be provided in the Study Protocol and in the Report Analysis Plan.
 

SAP_001.pdf: 
Clinical Development
LDK378/Ceritinib/Zykadia
LDK378X2103 / NCT01742286
A phase 1, open-label, dose-escalation study of LDK378 in 
pediatric patients with malignancies that have a genetic 
alteration in anaplastic lymphoma kinase (ALK)
Statistical Analysis Plan (SAP)
Author:
Trial Statistician,
 
Document type:
SAP Documentation
Document status:
Amendment 2 
Release date:
30-May-2019
Number of pages:
56
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Version
Date
Changes
1.0
07-MAR-2016
Initial Version
Amendment 1
17-OCT-2016
Front page:

Author changed. 
 is the new trial 
statistician.
Section 2.1

The description of cohort was updated to reflect 
the expanded cohort.

Definition of end of study was updated.
Section 2.2

Rules for treatment classification for FAS was 
added. Table 2-1 was included to illustrate the 
treatment regimen groups.

Method to calculate the actual dose level was 
clarified. Classification rules for safety set was 
updated per protocol terms. 

Definition of evaluable trough PK concentration 
was updated.
Section 2.4

Prior antineoplastic therapy surgery was updated 
to exclude diagnostic biopsies.

List of prohibited concomitant medications was 
added as Table 2.2.
Section 2.6

Criteria for determination of BOR per RECIST 
1.1 were updated.
Section 2.10

Reported primary and secondary PK parameters 
were updated. Table 2-6 was also updated 
accordingly.

PK summaries by age groups was moved from 
“LDK378 concentrations” to “LDK378 PK 
parameters”.

Dose proportionality (DP) analysis was updated 
to clarify which measures are applicable. 
Section 4

Table 4-1 was added to summarize changes to 
protocol specified analysis or descriptions and 
rationale


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Section 5.3

calculations of dose interruptions and dose 
changes were clarified
Section 5.6

Definition of last contact date was added. 
Amendment 2
30-May-2019
Front page:

Author changed. 
 is the new trial 
statistician.
 
List of abbreviations:

Some of the abbreviations were added to the list
Section 1

Updated the version of protocol used in this SAP 
amendment
Section 1.1

Updated the language to clarify the two parts of 
this study
Section 2.1

Updated the text for data analysis general 
information. 

Updated the text to clarify that analysis and CSR 
will be prepared at the end of the study.

Updated the definition of end of study 

Updated the labels for expansion group

Updated the age cut-off used in subgroup analysis 
from 5 years to 7 years

Updated the text to refer to 5.5.2 for further 
details
Section 2.2

Updated the text for the safety set with an 
example to define dosing groups

Updated the specifications for the Dose 
determining set to be in the escalation phase only

Updated the text for an evaluable trough PK 
concentration
Section 2.3

Updated the cut-off for subgroup analysis from 5 
years to 7 years

Updated the text to detail the diagnosis of 
RECIST and Lymphoma separately

Added abbreviations for SOC and PT


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
Updated the section of Prior antineoplastic
therapy

Updated the text for screen failures
Section 2.4

Updated the specifications for dose exposure and 
intensity

Removed prior antineoplastic therapy to baseline 
section and updated specifications for 
concomitant therapy

Deleted table 2.2
Section 2.5

Updated the specifications to specify the 
MTD/RDE 

Updated the specifications for DLT outputs
Section 2.6

Updated the text for ORR.

Updated the specifications for MIBG response 
score output

Updated the specifications for BOR per RECIST 
1.1 and IWG criteria

Updated the specifications for Duration of 
response and time points
Section 2.7 

Updated the specifications for PFS
Section 2.8

Updated the text for safety analyses

Updated the specifications for AE summaries

Updated the source for AESI definition

Updated the text for lab data

Updated the text for ECG

Updated the specifications for Vital Signs
Section 2.10

Updated the PK parameters

Updated table Noncompartmental 
pharmacokinetic parameters

Updated the specifications for Ctrough and 
average Ctrough
Section 5.2

Updated the table for patient classification rules
Section 5.3

Updated the text for dose interruptions and dose 
changes


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Section 5.4

Updated the text for Implementation of RECIST 
and Cheson guidelines
Section 5.6

Updated the text for missing date handling

Updated the text for conmeds date imputation

Updated the text for incomplete assessment dates 
for tumor assessment

Updated the specifications for incomplete date for 
death

Updated the speicifications for last contact date

Updated the specifications for incomplete dates 
for last dose of study drug

Updated the language for incomplete dates for 
disease progression prior to start of study drug


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Table of contents
Table of contents .................................................................................................................6
List of abbreviations............................................................................................................8
1
Introduction .........................................................................................................................9
1.1
Study design.............................................................................................................9
1.2
Study objectives and endpoints .............................................................................12
2
Statistical methods.............................................................................................................13
2.1
Data analysis general information .........................................................................13
2.1.1
General definitions................................................................................16
2.2
Analysis sets ..........................................................................................................17
2.3
Patient disposition, demographics and other baseline characteristics ...................19
2.3.1
Patient disposition.................................................................................21
2.4
Treatments (study treatment, concomitant therapies, compliance) .......................22
2.4.1
Study treatment / compliance................................................................22
2.4.2
Concomitant and post therapies ............................................................23
2.5
Analysis of the primary objective..........................................................................23
2.5.1
Primary endpoint...................................................................................24
2.5.2
Statistical hypothesis, model, and method of analysis..........................24
2.6
Analysis of the secondary objectives.....................................................................26
2.7
Analysis of other secondary efficacy objectives ...................................................28
2.8
Safety analyses.......................................................................................................29
2.8.1
Adverse events (AEs)............................................................................29
2.8.2
Laboratory data .....................................................................................31
2.8.3
Other safety data ...................................................................................32
2.9
Performance status.................................................................................................35
2.10
Pharmacokinetic endpoints....................................................................................36
2.11
Patient-reported outcomes .....................................................................................39
39
2.13
Interim analysis......................................................................................................40
3
Sample size calculation .....................................................................................................40
4
Change to protocol specified analyses ..............................................................................41
5
Appendix ...........................................................................................................................43
5.1
Data included in the analyses ................................................................................43
5.2
Patient classification into analysis sets..................................................................43
5.3
Derivations.............................................................................................................44
5.4
Efficacy endpoints .................................................................................................44


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5.4.1
Implementation of RECIST and Cheson guidelines.............................45
5.4.2
Kaplan-Meier estimates ........................................................................47
5.4.3
Confidence interval for response rate ...................................................48
5.5
Safety evaluations..................................................................................................48
5.5.1
Multiple assessments within post-baseline visits..................................48
5.5.2
Baseline.................................................................................................49
5.5.3
Laboratory Parameters ..........................................................................49
5.6
Handling of missing or partial dates......................................................................50
5.6.1
AE date imputation ...............................................................................51
5.6.2
Concomitant medication date imputation .............................................52
5.6.3
Incomplete date of initial diagnosis of cancer and date of most 
recent recurrence ...................................................................................53
5.6.4
Incomplete date for anti-neoplastic therapies .......................................53
5.6.5
Incomplete assessment dates for tumor assessment..............................53
5.6.6
Incomplete date for death......................................................................54
5.6.7
Last contact date....................................................................................54
5.6.8
Incomplete dates for last dose of study drug.........................................55
5.6.9
Incomplete dates for disease progression prior to start of study drug...55
5.7
PK analyses............................................................................................................56
6
Reference...........................................................................................................................56


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List of abbreviations
AE
ALCL
Adverse event
Anaplastic large cell lymphoma
ATC
Anatomical Therapeutic Classification
AUC
AUCtau
Area Under the Curve
Area under the plasma (serum, or blood) concentration versus time curve from 
time zero to end of dosing period
bid
bis in diem/twice a day
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
IMT
IVR
Inflammatory myofibroblastic tumor
Interactive Voice Response
IWR
Interactive Web Response
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NCI
National Cancer Institute
o.d.
Once Daily
OS
Overall Survival
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
RECIST
Response Evaluation Criteria in Solid Tumors 
SAP
Statistical Analysis Plan
SOC
T1/2
System Organ Class
Half-life
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
The statistical plan (SAP) describes the planned statistical methodology for the analysis of the 
data from study CLDK378X2103, a Phase I, open-label, dose escalation study of LDK378 in 
pediatric patients with malignancies that have a genetic alteration in anaplastic lymphoma 
kinase (ALK). 
The content of this SAP is based on protocol CLDK378X2103 Amendment 8. All decisions 
regarding final analysis, as defined in the SAP document, have been made prior to database 
lock of the study data.
1.1
Study design
This is a multi-center, phase I, open-label, dose escalation study to determine the maximum 
tolerated dose (MTD) and/or the recommended dose for expansion (RDE) of ceritinib 
administered orally on a continuous daily dosing in both fasted (drug should be taken at least 2 
hrs after the last meal and patient should not eat until 1 hr after drug is taken) and fed (drug 
should be taken within 30 minutes after finishing a low-fat light snack containing 100-300 
calories and 1.5-2 grams of fat) pediatric patients with an advanced malignancy carrying a 
genetic alteration of ALK that has progressed following standard therapy, or for which no 
standard therapy exists. 
The study has two parts, one that includes a dose escalation part performed in the fasted and 
fed states, and an expansion part performed at the MTD or RDE on the fasted regimen and on 
the fed regimen separately in order to better evaluate safety, tolerability, and preliminary 
evidence of antitumor activity in 2 groups of patients, one restricted to patients with ALK-
activated neuroblastoma and the second including all other ALK-activated tumors.  
Approximately 15-36 patients will be treated during the fasted escalation part (3-6 patients in 
approximately 5-6 dose levels, and a minimum of 6 at the MTD dose level). Approximately 12-
24 patients will be treated during the fed escalation part (3-6 patients in approximately 3-4 dose 
levels, and a minimum of 6 at the MTD dose level). 


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Figure 1-1
Overview of study design


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Dose-Escalation Phase
The primary objective of the dose escalation phase is to determine the MTD(s) and RDE(s) in 
both fasted and fed states. 
In the fasted dose-escalation, approximately 15 to 36 patients will be enrolled. Successive 
cohorts of patients will receive specified doses of LDK378 until the MTD on fasted regimen is 
determined. Each cohort will consist of 3 to 6 newly enrolled patients. The first cohort will be 
treated with the starting dose of 300 mg/m2.
A two-parameter Bayesian logistic regression model (BLRM) employing the dose-escalation 
with overdose control (EWOC) principle (Babb 1998, Neuenschwander 2008) will be used 
during the fasted dose-escalation for dose level selection and for determination of the MTD on 
fasted regimen.
After the fasted dose escalation has reached the MTD and/or RDE, the fed dose escalation will 
begin. The starting dose for the fed dose escalation part will be approximately 63% of the fasted 
MTD determined in this study. This is based on the data from adult healthy volunteers taking 
LDK378 with a low-fat meal. It is estimated that the steady state exposure of LDK378 with a 
low-fat meal will be increased 1.58 fold. Dose escalations during the fed dose escalation part 
of the study will be limited to a 25% or smaller increase above the prior fed dose level. It is 
anticipated that approximately 12-24 patients will be treated during the fed dose escalation.The 
same 2-parameter form of the BLRM will be used to estimate the dose-DLT relationships 
separately for fed patients. Data from fasted patients will be utilized to formulate a prior 
distribution for the BLRM parameters for fed patients. Details of the statistical model can be 
found in Section 14.1.3 of protocol.
Both fasted and fed dose escalation will continue until identification of the corresponding MTD 
or a suitable lower dose for expansion. This will occur when the following conditions are met:
1. at least 6 patients have been treated at this planned dose (initially assigned dose level 
(mg/m2) on Cycle 1 Day 1).
2. the dose satisfies one of the following conditions:
a. the posterior probability of targeted toxicity at this dose exceeds 50% and is the highest 
among potential doses, or
b. minimum number of patients (15 for the fasted state dose escalation, 12 for the fed state 
dose escalation) have already been treated on the trial.
3. it is the dose recommended for patients, either per the model or by review of all clinical data 
by Novartis and Investigators in a dose-escalation teleconference.
Intra-patient dose escalation is not permitted at any time within the first 4 cycles of treatment. 
After the fourth cycle is completed, individual patients may be considered for treatment at a 
LDK378 dose higher than the dose to which they were initially assigned. In order for a patient 
to be treated at a higher dose of LDK378, he or she must have tolerated the lower dose for at 
least 4 cycles of therapy without any LDK378-related toxicity ≥ CTCAE grade 2. The proposed 
higher dose must be a dose that has completed evaluation and has not exceeded the maximum 
tolerated dose (MTD). There is no limit to the number of times a patient may have his or her 
dose of LDK378 increased. The dose change must be recorded on the DAR eCRF.


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Expansion Phase
The expansion part will start after the fasted MTD has been determined. During the expansion 
part patients will initially be dosed at the fasted MTD, or at a lower RDE, if the available data 
suggest that the MTD is not appropriate for multiple cycles of therapy. Once the fed dose 
escalation part is opened, patients will be enrolled on the open cohort of the fed dose escalation 
part. At times when the fed dose escalation part is closed to enrollment, such as during the 
observation period between cohorts, additional patients may continue to be enrolled in the 
expansion part at the fasted MTD/RDE. After the MTD/RDE is determined for the fed state and 
the available safety, PK and anti-tumor activity data have been reviewed, a decision will be 
made as to whether dosing in the fasted or fed state is preferred. Once this decision is made all 
subsequent patients will be enrolled on that dosing strategy to complete the planned expansion 
part. The expansion part will include 2 groups of patients, one restricted to patients with ALK-
activated neuroblastoma and the second including all other ALK-activated tumors. Enrollment 
will proceed in parallel. The goals of the expansion part of the study are to better characterize 
the safety, tolerability and PK profile of LDK378, and to make a preliminary assessment of 
antitumor activity. The neuroblastoma group will enroll approximately 25 patients on the 
preferred regimen (fed or fasted), and the mixed tumor group will enroll approximately 20 
patients.
No formal interim analyses are planned. However, the dose-escalation design foresees that
decisions based on the current data are made before the end of the study. More precisely, the
next dose of LDK378 has to be chosen after each cohort in the dose escalation part, and the
decision is dependent on the observed data. Additionally, analysis to determine the fed dose 
selected for the expansion phase is also dependent on the observed data.
1.2
Study objectives and endpoints
The primary objective of the study is to estimate the MTD and/or RDE of LDK378 as a single 
agent when administered orally to pediatric patients with ALK-activated tumors in fasting and 
fed states. 
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Primary
Estimate the MTD and/or RDE of 
LDK378 as a single agent when 
administered orally to fed and 
fasted pediatric patients with ALK-
activated tumors for fasted and fed 
regimens
Incidence rate of Dose Limiting Toxicities (DLT) during the first cycle of 
LDK378 treatment.
Secondary


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Objective
Endpoint
(1) Characterize the safety and 
tolerability of LDK378 in the 
pediatric patients in fasting and fed 
states. 
(2) Characterize single and 
multiple-dose PK of LDK378 in 
pediatric patients in fasting and fed 
states. 
(3) Assess the anti-tumor activity 
of LDK378 in fasting and fed 
states. 
(1) Adverse events and serious adverse events, changes in laboratory 
values, assessments of physical examinations, vital signs and 
electrocardiograms.
(2) Plasma concentration time profiles, PK parameters, including but not 
limited to AUCtau, Cmin, Cmax, Tmax, Racc, and T1/2,acc
(3) Overall response rate (ORR) and duration of response (DOR), 
progression-free survival (PFS) as per RECIST 1.1 in patients with 
neuroblastoma and other solid tumors, and by International Working 
Group (IWG) criteria in patients with lymphoma. MIBG response in 
patients with neuroblastoma. 
Abbreviations: area under the concentration-time curve (AUC) from time zero to the last measurable 
concentration sampling time, AUCtau, Area under the plasma (serum, or blood) concentration versus time curve 
from time zero to end of dosing period, Cmax, maximum concentration, Cmin, minimum concentration, MIBG, 
metaiodobenzylguanidine, Racc, accumulation ratio, T1/2acc, effective half-life calculated from Racc, Tmax, time 
to reach maximum plasma concentration.
 
 
 
2
Statistical methods
This section and its subsections will be imported to section 9.7 of the CSR after the analyses 
have been conducted. This section of the SAP follows the CSR template structure of Section
9.7 as of the release date of this document. The text will be changed to past tense when imported 
into the CSR; references to sections of the SAP where additional details are provided for 
programming implementation may be removed in the CSR.
In what follows, study drug refers to LDK378 (certinib).
2.1
Data analysis general information
Data will be analyzed by Novartis Oncology Biostatistics and Statistical Programming
personnel according to the data analysis section 10 of the LDK378X2103 protocol, which will 
be available in Appendix 16.1.1 of the Clinical Study Report (CSR). Important information is 


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given in the following sections and details are provided, from which Appendix 16.1.9 of the 
CSR will be written. 
The data will be analyzed using SAS version 9.4 or later, and for Bayesian modeling, R version 
2.13.2 or later, and WinBUGS version 1.4.3 or later. The Bayesian modeling of the dose-
toxicity relationship used for dose escalation decision making and inference for the MTD is 
performed using internal Novartis R library functions (OncoBayes) created by Novartis’s 
Methodology group and are run using R version 2.13.2 or later in the MODESIM/GPSII 
environment.
Data from patients who signed study informed consent in centers that participate in this study 
will be used in the analysis; due to expected small size of enrollment at individual centers, no 
center effect will be assessed. Each analysis will use all data in the database up to the analysis 
cutoff date, determined prior to database lock. Data collected after patients’ withdrawal of 
informed consent for further participation in the study will not be reported (except for death 
date which might be obtained from public records).
Final CSR
The study data will be analyzed and reported based on all patients’ data of both dose escalation 
and expansion parts at the end of study, and a final CSR will be written. Patients treated with 
the MTD, or RDE if different, on the regimen (fasted or fed) during the dose escalation part, 
will be pooled with those receiving both the same dose and the same regimen during the 
expansion part. For patients undergoing intra-patient dose escalation to doses other than their 
initially received dose level, their post-escalation data will be listed separately. However, only 
data before the first intra-patient escalation will be used in summary statistics. A treatment 
group is defined by dose level and regimen (fasted or fed).
End of study is defined as earliest occurrence of one of the following: 
1. All patients have discontinued study treatment, and all required Study evaluation 
completion (SEC) follow-up visit have been completed, or 
2. All patients have died, have been lost to follow-up or have withdrawn consent to further 
participation in the study, or the last patient on treatment has been enrolled into a separate 
rollover study or other option for continued treatment with LDK378, whichever comes first. 
The final analysis of study data will be conducted at the end of the study and all available safety 
and efficacy data from all patients will be analyzed. A final clinical study report (CSR) will be 
produced reporting all available data collected.
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).


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Summary statistics for PK concentrations and PK parameters will include the following, unless 
otherwise specified: n, mean, SD, CV% mean, geometric mean, CV% of geometric mean, 
median, minimum and maximum.
Data from patients enrolled during the expansion phase in the applicable disease group at the 
MTD/RDE will be pooled with data from patients enrolled in the dose-escalation phase, unless 
otherwise specified (e.g. primary analysis of dose-DLT relationship). 
Unless otherwise specified, analysis of efficacy data will be presented:

by treatment group : A treatment group is defined by both dose level and regimen (fasted or 
fed). Data from patients in the expansion and escalation parts in the same treatment group 
will be combined.    

by expansion group: for patients in the pooled LDK378 MTD/RDE group 
o
patients with ALK-activated neuroblastoma, 
o
patients with ALK-activated IMT.
o
patients with ALK-activated ALCL.
o
patients with all other ALK-activated tumors.
The efficacy data of patients with lymphoma evaluated by IWG (Cheson) response criteria will 
be summarized/listed separately from the efficacy data evaluated by RECIST 1.1.
Unless otherwise specified, all summaries of PK data will be presented by treatment group and 
by expansion group as defined above. 
All listings will be displayed by indication, treatment group, and patient, unless otherwise 
specified.
For safety, PK and all other summaries, data will be presented by treatment group unless 
otherwise specified. 
The safety summary tables will include only assessments collected during the on-treatment 
period unless otherwise specified.  For select items, shift tables or change from baseline 
summaries generated for laboratory, ECG, and vital signs may use data from pre-treatment 
period for baseline calculations. See Section 2.1.1 for key definitions of terms used in this SAP. 
All data, regardless of observation period, will be listed and assessments collected in the pre-
treatment or post-treatment period will be flagged in all the listings.
Subgroup analyses
If the number of patients allows (larger than or equal to 10), in addition to the population 
subgroups described above, efficacy endpoints (ORR) and adverse events (AEs) will also be 
summarized for patients in the LDK378 MTD/RDE group by the following subgroups:

age (1 year to <7 years, 7 years to <12 years, 12 years to <18 years)


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2.1.1
General definitions
Study drug and study treatment
Study drug and study treatment both refer to the Novartis investigational drug, LDK378
(ceritinib) and will be used interchangeably. LDK378 will be provided to investigation sites and 
administered once daily by mouth, or by NG tube or G-tube. 
Date of first/last administration of study drug
The date of first administration of study drug is defined as the first date when a non-zero dose 
of study drug was administered and recorded on the Dosage Administration Record (DAR) 
eCRF. For the sake of simplicity, the date of first administration of study drug will also be 
referred 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 DAR eCRF. This date will also be referred 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, dose interruption etc.) will be calculated using the start date of study drug as the 
origin. For assessments occurring after or on the start date of study drug, study day will be 
calculated as:
Study Day =Date of assessment/Event date - start date of study drug + 1.
The first day of study drug is therefore study day 1. 
For any assessment or events such as baseline disease characteristics or medical history (e.g., 
time since diagnosis of disease) occurring prior to the start of the study drug, study day will be 
negative and will be calculated as:
Study Day = Date of assessment/Event date - start date of study drug.
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.
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, unless otherwise stated. If the 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 and first dose times are collected, the observed time point 
will be used to determine pre-dose on study day 1 for baseline calculation. Unscheduled 
assessments will be used in the determination of baseline. See Section 5.5.2 for further details 
on derivation of baseline for laboratory data and ECGs.


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Patients who start treatment and discontinue from the study on the same day may have two
different sets of data collected on study day 1, one being reported to the cycle 1 day 1 visit, the 
other reported to the end of treatment (EOT) visit. Data reported at the EOT visit are not eligible 
for baseline selection. 
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. treatment group) 
at the same time. There may be more than one cohort at the same dose level. 
Treatment group
Treatment group will generally be determined by the initially planned LDK378 dose level in 
mg/m2 and regimen on Cycle 1 Day 1. For safety analysis, treatment group will be determined 
by dose and regimen received. Further details on the determination of treatment received is 
given in Section 2.2 A treatment group can include several cohorts of patients who have 
received the same dose level and regimen but were recruited at the different point during the 
study. A treatment group may consist of one or more cohorts.
2.2
Analysis sets
A patient is considered to be enrolled into the study if they have signed study informed consent.  
Only patients who have signed study informed consent prior to study procedures will be 
included in the analysis data sets.
Full analysis set
The Full Analysis Set (FAS) includes all patients who received at least one dose of LDK378. 
Patients will be classified according to the intended/planned treatment. The FAS will be used 
for all listings of raw data. Unless otherwise specified, the FAS will be the default analysis set 
used for all analyses.
The planned treatment will be based on the first dosing record. The corresponding fasted/fed 
status will be determined as per Table 2-1 below as per protocol.
Table 2-1
Dose level and fasted/fed status
Dose Levels
Fasted/Fed Status
200 mg/m2
Fasted
300 mg/m2
Fasted
450 mg/m2
Fasted
510 mg/m2
Fasted
560 mg/m2
Fasted
320 mg/m2
Fed
400 mg/m2
Fed
500 mg/m2
Fed
Safety set


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The safety set includes all patients who received at least one dose of LDK378.
The patients will be classified according to treatment received, where treatment received is 
defined as:
1. The actual dose level (mg/m2) is the planned dose level if any actual total daily dose 
administered is equal to the value of “the planned dose levels (Table 2-1) * BSA (m2) rounds 
to the nearest 50 mg”. For 25/75 mg, either rounding up or rounding down is acceptable.
2.  The first actual dose level in the study (converts actual total daily dose administered / BSA 
( m2) and maps to nearest planned dose levels) if the planned dose level was never received.
BSA = The last available BSA measurement on or before dosing date will be used in the 
calculation for actual dose level.
For example, if a patient from 500 mg/ m2 fed group doesn’t meet the first criteria, and the first 
actual dose level in the study is 150 mg. Suppose this patient has BSA=0.45 m2 on/before the 
first dose, then the first actual dose level in the study=actual total daily dose administered / BSA 
(m2)=333 mg/ m2 , which will be rounded to the nearest planned dose level 320 mg/ m2 fed.
Dose determining set
The dose determining analysis set (DDS) consists of all patients from the safety set who either
meet the minimum exposure criterion and have sufficient safety evaluations or discontinue 
earlier due to DLT in the escalation phase.
A patient is considered to have met the minimum exposure criterion if s/he received at least 16 
out of the 21 planned once daily doses of LDK378 in the first 21 days of dosing. Patients who 
do not experience DLT during the first cycle are considered to have sufficient safety evaluations 
if they have been observed for at least 21 days following the first dose, and are considered by 
both the Sponsor and Investigators to have sufficient safety data to conclude that a DLT did not 
occur.
Patients who do not meet these minimum safety evaluation requirements and who did not 
discontinue earlier due to a DLT will be regarded as ineligible for the DDS.
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who received at least one dose 
of LDK378 and have at least one evaluable pharmacokinetic (PK) sample.
Depending on whether the sample is part of a full profile or a trough collection, the specific 
criteria are listed as follows.
An evaluable full PK profile is defined as:
1. On the PK collection day, no vomiting occurred within 4 hours of dosing on the full PK 
sampling day (i.e., no vomiting within 4 hours after Cycle 1 Day 1 dose or after Cycle 
2 Day 1 dose), AND
2. On the PK collection day, the patient takes study drug according to the originally 
assigned dose, AND
3. The patient takes study drug according to the originally assigned dose for at least 5 
consecutive days without interruption or dose modification prior to the PK sampling day 
(except for Cycle 1 Day 1, i.e., only applicable to Cycle 2 Day 1), AND


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4. On the PK collection day, the patient takes study drug under the originally assigned 
prandial condition, AND
5. The patient takes study drug under the originally assigned prandial conditions, i.e., dose 
administered without food for patients in the fasted cohort, or dose administered with 
light snack food for patients in the fed cohort, for at least 5 consecutive days prior to the 
PK sampling day (except for Cycle 1 Day 1, i.e., only applicable to Cycle 2 Day 1), 
AND Additionally, an entire profile can be considered non-evaluable as per scientific 
judgment of the clinical pharmacology expert even if the above criteria are fulfilled. 
Reason will be documented.
An evaluable trough PK concentration (Cmin) is defined as:
1. the patient takes study drug according to the originally assigned dose for at least 5 
consecutive days prior to the PK sampling day (except for Cycle 1 Day 1 in dose 
escalation and expansion phases), AND  no vomiting occurs within 4 hours following 
the last dose intake prior to the PK sample draw,
2. For the pre-dose or 24 hour post-dose sample, draw must occur between 0 to 6 hours 
before the dose that is immediately after, AND
3. The patient takes study drug under the originally assigned prandial conditions, i.e., dose 
administered without food for patients in the fasted cohort, or dose administered with 
light snack food for patients in the fed cohort, for at least 5 consecutive days prior to the 
PK sampling day (except for Cycle 1 Day 1), AND Additionally, a sample can be 
considered non-evaluable as per scientific judgment of the clinical pharmacology expert 
even if the above criteria are fulfilled. Reason will be documented.
A patient belongs to PAS if he/she has either an evaluable full PK profile or an evaluable trough 
PK sample.
Any blood samples missing blood collection date or time, or missing associated study drug 
dosing date or time will be excluded.
Frequency counts and percentages (using FAS as denominator) of patients in each of the above 
defined analysis sets will be summarized. In addition, listings of patients included in each of 
the analysis sets will be provided.
Section 2.3.5 provides further details regarding the derivation of the analysis sets.
2.3
Patient disposition, demographics and other baseline 
characteristics
The FAS will be used for all patient demographic and baseline characteristic summaries and 
listings, unless otherwise specified.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed for all
patients. Categorical data (e.g. gender; age groups: 1 year to <7 years, 7 years to <12 years, 12 
years to <18 years; race; ethnicity; Karnofsky or Lansky performance status) will be 
summarized by frequency count and percentages. Continuous data (i.e. age, weight, height,
body surface area) will be summarized by descriptive statistics (as defined in Section 2.1). 


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All data collected during the baseline evaluation will be listed.
Diagnosis and extent of cancer
Descriptive statistics and frequency counts and percentages will be tabulated, as appropriate, 
for diagnosis and extent of cancer based on the data collected on the eCRF including primary 
site of cancer, time (in months) from initial diagnosis of primary site to start date of study drug,  
time (in months) since most recent recurrence/relapse or progression to start date of study drug, 
current extent of disease (metastatic sites),  types of lesions (target and non-target lesions) at 
baseline, and disease burden at baseline for target lesion. Note: Presence/absence of target and 
non-target lesions will be based on the data collected on RECIST target/non-target lesion 
assessment eCRF pages. Presence/absence of index and non-index lesions will be based on the 
data collected on Lymphoma index/non-index lesion assessment eCRF pages.  Metastatic sites 
will be based on diagnosis page.
ALK status 
If ALK status is not already known, patients will be tested for ALK positive status using a 
Novartis designated central laboratory. ALK status from local and central laboratory results at 
baseline as determined in the retrospective collection of pathological reports will be 
summarized using frequency counts and percentages for patients. The ALK status summary 
includes test result (positive, negative, not evaluable), ALK abnormality type (ALK 
translocation, ALK amplification, ALK point mutation, other), test methodology used (FISH, 
IHC, RT-PCR, sequencing DNA/RNA, other). 
All other ALK data collected during the baseline evaluation will be listed.
Medical history
Medical history and current medical conditions, including cancer-related conditions and 
symptoms will be summarized and listed.  Separate summaries will be presented for ongoing 
and historical medical conditions.  The summaries will be presented by primary system organ 
class (SOC) and preferred term (PT). Medical history and current medical conditions are coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) terminology.
Protocol deviations
Frequency counts and percentages of patients in the FAS with any protocol deviations 
(inclusion/exclusion criteria not met, patient not withdrawn as per protocol, key procedures not 
performed as per protocol, treatment deviation, prohibited concomitant medication, Good 
Clinical Practice (GCP) deviation) will be tabulated by the deviation category. The full list of 
protocol deviations are documented in the Data Handling Plan (DHP). All protocol deviations 
will be listed.
Prior antineoplastic therapy
Prior anti-neoplastic (anti-cancer) 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 anti-neoplastic medications, 
prior anti-neoplastic radiotherapy or prior anti-neoplastic surgery will be summarized. 


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The summary of prior anti-neoplastic medications will include the total number of regimen, 
setting at last medication, the time between end of last medication to start of treatment in days 
(end of last medication is based on end date of last dose, the best response at last medication 
(defined to be the best response during the last treatment regimen recorded), and time (in months) 
from start of last medication to progression. The last medication is defined taking into account 
the end date. Prior antineoplastic medications will also be summarized by ATC class, and 
preferred term.  
The summary of prior anti-neoplastic radiotherapy will include a summary of radiotherapy 
locations, including all locations recorded for each patient. Setting, method, and best response 
at last radiotherapy will also be summarized.
The summary of prior anti-neoplastic surgery (excluding diagnostic biopsies) will include the 
time between the last surgery to start of treatment, procedure at last surgery and residual disease 
at last surgery.
2.3.1
Patient disposition
Screen failures
Screen failures will comprise patients who have been enrolled and signed study ICF, and 
screened to the study and have failed to meet inclusion or exclusion criteria.  These patients are 
not treated with study drug. Frequency counts and percentages will be tabulated for all enrolled 
patients as follows:

Number (%) of patients who completed screening phase (based on the presence of 
‘Screening log’ and ‘Demography’ page); 

Number (%) of patients who discontinued  during screening phase ( based on the presence 
of discontinuation  reason  entered and  ‘Will the subject enter the study’ is ‘No’ in the 
‘Screening log’ page) ;

Reasons for screening phase discontinuation (based on reasons recorded in Screening log’ 
page).
All screen failure patients with reasons for screen failure will be listed.
Patient Disposition
The FAS will be used for the patient disposition summary tables and listings.  The following 
will be tabulated:

Number (%) of patients who are still ongoing-treatment (based on the absence of the ‘End 
of Treatment’ page); 

Number (%) of patients who discontinued  treatment (based on completion of the ‘End of 
Treatment’ page with date of discontinuation and reason of discontinuation entered);

Primary reasons for study treatment discontinuation (based on discontinuation reasons 
entered in the ‘End of Treatment’ page );

Number (%) of patients who discontinued from study (based on completion of ‘Study 
evaluation completion’ page);


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
Number (%) of patients who discontinued treatment but continued to be followed (based on 
completion of ‘End of Treatment’ page and ‘Study evaluation completion’ page not 
completed);

Primary reasons for study evaluation completion (based on primary reason for study 
evaluation completion in the ‘Study evaluation completion’ page).
2.4
Treatments (study treatment, concomitant therapies, 
compliance)
The study drug and the study treatment is LDK378, as in the previous sections, reporting was 
based on FAS. The Safety Set will be used for all medication data summaries and listings unless 
otherwise specified.  
2.4.1
Study treatment / compliance
Dose exposure and intensity
The Safety set will be used for summaries and listings of dose exposure and intensity unless 
otherwise specified.
Definitions of duration of exposure, cumulative dose, average daily dose, actual dose intensity 
(DI), planned dose intensity (PDI), relative dose intensity (RDI), percentage of days dosed, 
percentage of days the planned/intended dose was received, as well as intermediate calculations, 
include:

Duration of exposure (days):
last date of study drug − first date of study drug + 1 
(periods of interruption are not excluded) 

Cumulative dose (mg):
total dose of study drug taken by a patient in the study

Number of dosing days (days):
duration of exposure − number of zero dose days

% Days dosed:
100×number of dosing days/duration of exposure (days)

% Days with planned dose:
100× number of days with planned dose/duration of 
exposure (days)

Average daily dose (mg/day):
cumulative dose (mg) ⁄ number of dosing days (days)

DI (mg/day):
cumulative dose (mg) ⁄ duration of exposure (days)

PDI (mg/day):
cumulative planned dose (mg) / duration of exposure (day)

RDI (%):
100 × DI (mg/day) ⁄ PDI (mg/day)
Duration of exposure to study drug, cumulative dose, and percentage of actual days dosed, 
percentage of days the planned/intended average daily dose was received, DI and RDI will be 
summarized.  In addition, the duration of exposure to study drug will be categorized into time 
intervals); frequency counts and percentages of patients with exposure in each time interval will 
be presented. Frequency counts and percentages of patients who have dose reductions or 
interruptions, and the corresponding reasons, will be provided. The number of dose 
interruptions per patient, and the duration of dose interruptions (days) will be summarized.
Cumulative dose, dose intensity and relative dose intensity of LDK378 will be listed by patient. 
Categories for relative dose intensity of LDK378 will be specified as < 0.5, ≥ 0.5 - < 0.75, ≥ 


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0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1. The number and proportion of patients within each category 
will be presented.
Listings of all doses of the study drug along with dose change/interruption reasons will be 
produced.  
2.4.2
Concomitant and post therapies
The Safety set will be used for the summaries and listings of concomitant and post therapies 
unless otherwise specified.
Concomitant therapy
Concomitant therapies are defined as any medications (excluding study drug, prior 
antineoplastic treatments) and significant non-drug therapies  (including physical therapy and 
blood transfusions) administered in the study and recorded in the Concomitant 
Medications/significant non-drug therapies eCRF.
These therapies will be coded using the WHO Drug Reference Listing (WHO DRL) dictionary 
that employs the WHO Anatomical Therapeutic Chemical (WHO ATC) classification system. 
All summaries will be tabulated using frequency counts and percentages.
Concomitant therapies will be summarized by ATC class and preferred term. These summaries 
will include 1) medications and non-drug therapies starting on or after the start of study drug 
but starting no later than 30 days after last dose of study drug and 2) medications and non-drug 
therapies starting prior to the start of study drug but continuing after the start of study drug.
All therapies will be listed. Any therapies starting and ending prior to the start of study drug or 
starting more than 30 days after the last date of study drug will be flagged in the listing. 
Frequency and percentage of patients using medications known to prolong the QT interval 
concomitantly with study drug will be summarized by ATC class and preferred term.
Antineoplastic therapy after discontinuation of study drug
All summaries will be tabulated using frequency counts and percentages using the FAS.
Antineoplastic therapies, including medications, surgeries, and radiotherapies, initiated after 
discontinuation of study drug will be summarized and listed by Anatomical Therapeutic 
Chemical (ATC) class and preferred term.
2.5
Analysis of the primary objective
The primary objective of the study is to estimate the MTD/RDE separately on a daily dose of
LDK378 when administered orally as a single agent to pediatric patients with an advanced 
malignancy carrying genetic alteration of ALK.  The corresponding primary analysis method is 
an adaptive Bayesian logistic regression model (BLRM) guided by the escalation with overdose 
control (EWOC) principle (Neuenschwander et al 2008). The MTD/RDE is determined to be 
510 mg/m2 for fasted regimen and 500 mg/m2 for fed regimen.


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2.5.1
Primary endpoint
Variable
The primary endpoint is the incidence of dose limiting toxicities (DLTs) in Cycle 1.The MTD 
is defined as the maximum dose for a given schedule that is expected to cause DLTs in no more 
than 33% of patients during the first cycle of treatment. Estimation of the MTD during the dose-
escalation phase of the study will be based upon the estimation of the probability distribution 
of the incidence of DLT in cycle 1 in patients in the dose-determining set.
2.5.2
Statistical hypothesis, model, and method of analysis
An adaptive BLRM with two parameters guided by the EWOC principle will be used to make 
dose recommendations and estimate the MTD separately during the fasted dose escalation and 
the fed dose escalation of the study. 
Statistical model for the fasted dose escalation
The dose-toxicity (DLT) relationship in the fasted dose-escalation phase of the study will be 
described by the following Bayesian logistic regression model:
logit (π(d)) = log(α) + β log(d/d*), 
α>0, β>0 
[1]
where logit(π(d))= ln ((d)/(1-(d))), π(d) is the probability of a DLT at dose d. Doses are rescaled 
as d/d* with reference dose d*= 400 mg/m2 of LDK378. Consequently α is equal to the odds of 
toxicity at d*. Note that for a dose equal to zero, the probability of toxicity is zero. The Bayesian 
approach requires the specification of prior distributions for the model parameters.
See Section 14.1.2 of the protocol for the prior specification for the fasted dose escalation.
Statistical model for the fed dose escalation 
The same 2-parameter form of the BLRM described in equation [1] will be used to estimate the 
dose-DLT relationships separately for fasted and fed patients. Dose escalation in fed patients 
will begin once the MTD/RDE is determined in fasted patients. Data from fasted patients will 
be utilized to formulate a prior distribution for the BLRM parameters for fed patients.
Methodology for updating down-weighting:
Since fed patients will be enrolled after all the patients in dose escalation fasted part will have 
potentially completed cycle 1 (or have experienced DLT), and since it can be assumed that there 
is a certain grade of similarity in dose toxicity relationship between these two regimen, the 
updating of the prior distribution of the BLRM parameters for fed patients will be evidence 
based. In particular, at the time of starting the fed-patients cohort, DLT data from fasting 
patients will be included into the BLRM and discounted (assuming substantial between regimen 
heterogeneity) to account for potential differences between fed and non-fed patients, while 
assuming some degree of similarity.
Specifically, the DLT information from fasted patients will be incorporated through down-
weighting the data directly. The weight “w” (see Neuenschwander et al 2010) that will be 
assigned to each fasted patient included in the DDS is given in the following formula:


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where n is the sample size of historical data (i.e. the number of fasted patients in the DDS), σ is 
the “outcome standard deviation” for one observation and τ is the assumed between regimen 
standard deviation. n*∞can be interpreted as the maximum prior effective sample size under 
infinite historical information. σ was chosen as 2 and τ was set as 2, to correspond to a 
substantial heterogeneity due to the different dosing regimens.
When all patients in the fasted dose escalation have completed at least one cycle, the weights 
will be calculated based on the data available at that time point.
Dose recommendation
After each cohort is completed, the posterior distributions for the probabilities of DLT at
different dose levels are obtained. The results of this analysis are summarized in terms of the 
estimated probabilities that the true rate of DLT at each dose-level will lie within each of the 
following intervals:

(0, 0.16) under-dosing.

(0.16, 0.33) targeted toxicity.

(0.33, 1.00) excessive toxicity.
Following the principle of EWOC, after each cohort of patients the recommended dose is the
one with the highest posterior probability of the DLT rate falling in the target interval (16%, 
33%) among the doses fulfilling EWOC, i.e. it is unlikely (< 25% posterior probability) that the 
DLT rate at the dose falls in the excessive toxicity interval. In addition, the maximum dose 
escalation for the fasted regimen is limited to 50% before reaching 450 mg/m2, and to 25% 
after reaching 450 mg/m2, which correspond to the adult MTD. Dose escalations for the fed 
dose escalation part will be limited to a 25% or smaller increase above the prior fed dose level.
Note that the dose that maximizes the posterior probability of targeted toxicity is the best 
estimate of the MTD, but it may not be an admissible dose according to the overdose criterion 
if the amount of data is insufficient. If vague prior information is used for the probabilities of 
DLT, in the early stages of the study this escalation procedure will reflect a cautious strategy. 
The dose recommended by the adaptive Bayesian logistic model may be regarded as guidance 
and information to be integrated with a clinical assessment of the toxicity profiles observed at 
the time of the analysis in determining the next dose level to be investigated. 
Details of the criteria for dose escalation and the determination of the MTD are provided in 
Section 6.2.3 of the study protocol.
Dose Expansion
Upon completion of the first cycle of treatment for at least 10 patients within the dose expansion
part, if the observed DLT rate exceeds 33%, the BLRM will be re-run to confirm that the 
estimated MTD/RDE on either regimen still satisfies the overdose criteria of the model. If the 
dose fails to satisfy the criteria a change to the dose under study may be made according to the 
Bayesian model recommendation, and review of the clinical data. DLTs will be listed and their 


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incidence summarized by primary system organ class, worst grade based on the CTCAE version 
4.03, type of adverse event, and by treatment. The DDS will be used for these summaries.
2.6
Analysis[SP1] of the secondary objectives
A secondary objective of this study is to assess the anti-tumor activity of LDK378 in fasting 
and fed states. The primary evaluation of the anti-tumor activity of LDK378 will be based on 
investigator assessment of response (Overall Response Rate, Progression-Free Survival, and 
Duration of Response) using the FAS per RECIST 1.1 for patients with neuroblastoma and 
other solid tumors, and IWG criteria for patients with lymphoma. In patients with 
neuroblastoma, disease assessable at screening only by MIBG scans and by bone marrow 
evaluation will be treated as non-target lesions. MIBG response will be listed.
Overall Response rate
ORR is defined as the proportion of patients with a best overall response (BOR) of complete 
response (CR) or partial response (PR) for RECIST. For CHESON: The evaluation of overall 
disease response at each assessment is a composite of the individual radiological responses 
(index and non-index lesions, new lesions), laboratory test (bone marrow) and clinical 
responses (lymphoma related clinical symptoms). ORR will be summarized by indication and 
by treatment group, where the patients are pooled from both the dose escalation and expansion 
phases for MTD / RDE determined for each regimen, and exact 95% confidence intervals will 
be presented. 
In addition, for the expansion group patients with ALK activated neuroblastoma, a Bayesian 
approach will be used to estimate the ORR based on RECIST 1.1 data, along with a 95% 
credible intervals based on the posterior distributions, using minimally informative unimodal 
Beta prior distributions. The prior clinical assumption for LDK378 in this selected patient 
population will be used in order to derive a minimally informative unimodal Beta prior 
distribution that reflects the level of uncertainty around the ORR before starting the current trial. 
At completion of the study, this prior distribution will be updated with all data available from 
the expansion group patients with ALK activated neuroblastoma (including those treated at the 
MTD in the dose escalation part) in the FAS. Once updated, the posterior probability that the 
true ORR at the MTD/RDE for these patients lies in the following categories will be presented:

[0, 10%) insufficient antitumor activity.

[10%, 20%) limited antitumor activity.

[20%, 30%) moderate antitumor activity.

[30%, 100%] substantial antitumor activity.
If the observed ORR is equal to or greater than 30%, then this will be considered as preliminary 
evidence of substantial antitumor activity of LDK378 in ALK activated neuroblastoma. If the 
observed ORR is between 20% and 30% then this will be considered as evidence of moderate 
antitumor activity, and as limited antitumor activity if it is between 10% and 20%. If the 
observed ORR is less than 10% (i.e. ≤ 2 CR or PR out of 25), then insufficient antitumor activity 
will be declared.


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Note that for a sample size of n = 25 (see section 10.8), if the observed ORR is greater than or 
equal to 20% (i.e. ≥ 5 CR or PR), then the true ORR has a posterior risk of less than 10% of 
being in the insufficient antitumor activity category.
A minimally informative unimodal Beta prior distribution of the true ORR is derived as follows. 
A priori it is assumed that the true mean of the ORR equals 20%. A true ORR of 20% is the 
midpoint between limited and moderate antitumor activity and serves as a compromise between 
a skeptical view assuming the treatment has only limited antitumor activity and an optimistic 
view assuming the treatment has moderate antitumor activity. The parameters of the minimally 
informative Beta prior distribution of the ORR are then derived as a=1/4 and b=1.
Best Overall Response 
Best overall response (BOR) is the best response recorded from the start of the treatment until 
disease progression. Patients with a BOR of ‘UNKNOWN’ will be treated as non-responders 
when estimating ORR. If any non-palliative cancer therapy is taken while on study any 
subsequent assessments will be excluded from the BOR determination.  MIBG response score 
per curie criteria will be recorded and listed for patients with neuroblastoma who had MIBG 
scan.
Determination of BOR per RECIST 1.1
ORR is defined as the proportion of patients with a best overall complete response (CR) or 
partial response (PR) per RECIST 1.1.
For patients with the primary diagnosis other than lymphoma, BOR will be based on the overall 
lesion assessment per RECIST 1.1. 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 (for details see Protocol Appendix 5).
The 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)> 29 days after start of treatment (and not 
qualifying for CR or PR).

PD = progression ≤85 days after start of treatment (and not qualifying for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 29 days or early progression within the first 85 days).
Determination of BOR per IWG criteria 
For patients with the primary diagnosis of lymphoma, BOR will be based on the overall lesion 
assessment and disease response assessment per IWG (Cheson) response criteria. See Section 
14.6 of protocol for guideline for efficacy evaluation in lymphoma patients based on IWG 
(Cheson) response criteria.
The BOR for each patient is determined from the sequence of overall radiological responses 
and overall disease responses according to the following rules:


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
CR = at least one overall disease response of CR

PR = at least one overall radiological response or overall disease response of PR (and not 
qualifying for CR)

SD = at least one SD overall radiological response > 29 days after start of treatment (and 
not qualifying for CR or PR)

PD = progression ≤85 days after start of treatment (and not qualifying for CR, PR or SD).

UNK = all other cases.
In general, in the determination of BOR, 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 this assignment must stay the same or 
improve over time until progression sets in, with the exception of an UNK status. 
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
Duration of response
Among patients with a confirmed PR or CR per RECIST 1.1 or with a response (CR or PR) per 
IWG criteria, DOR is defined as the time from first documented response (PR or CR) to the 
date of first documented disease progression (PD) or death due to any cause.
DOR will be described separately by indication and by treatment group, and by expansion group
in tabular and graphical format for patients treated at MTD/RDE by expansion group, using 
Kaplan-Meier methods including estimated median (in months) with 95% CI, 25th and 75th
percentiles (Brookmeyer and Crowley 1982, Klein and Moeschberger 1997and Kaplan-Meier 
estimated probabilities with corresponding 95% CIs (Kalbfleisch and Prentice 1980) at several 
time points (including at least 2, 4, 6, 8, 10, 14 months).
2.7
Analysis of other secondary efficacy objectives
Progression-free survival
PFS is defined as the time from the start date of study drug to the date of the first radiologically 
documented PD or death due to any cause per RECIST 1.1, for patients with solid tumor; and 
from the start date of study drug to the date of the first PD as overall disease response or death 
due to any cause per Cheson, for patients with lymphoma.
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, PFS will be censored at the date of the last adequate 
tumor evaluation before the cut-off date or before the start of the new anticancer therapy date,
whichever is earlier. Clinical deterioration will not be considered as a qualifying event for 
progression. 
In particular, PFS will be censored at the last adequate tumor assessment if one of the 
following occurs: 
1: Ongoing without event
2: Lost to follow-up


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3: Withdrew consent
4: Adequate assessment no longer available
5: Initiation of new cancer therapy prior to progression 
6: Event after >=2 missing tumor assessments
PFS will be described in tabular and graphical format for patients treated at MTD/RDE by 
expansion (disease) group, and also by indication and by treatment group using Kaplan-Meier 
methods as described for DOR, including estimated median (in months) with 95% CI, 25th and 
75th percentiles and Kaplan-Meier estimated probabilities with corresponding 95% CIs at 
several time points (including at least 2, 4, 6, 8, 10, 14 months). Censoring reasons will also be 
summarized. Also duration between treatment start date and cut-off date, and PFS follow-up 
time will be summarized by expansion, and also by indication and by treatment group.
2.8
Safety analyses
The safety set will be used for all safety analyses with the exception of the DLT analyses that
will use the DDS. 
The overall observation period will be divided into three mutually exclusive segments:

Pre-treatment period: from day of patient’s informed consent to the day before first dose of 
study drug

On-treatment period:
o
For discontinued patients, from day of first dose of study drug to 30 days after last dose 
of study drug
o
For ongoing patients, from day of first dose of study drug to the data cut-off date

Post-treatment period: starting at day 31 days after last dose of study drug
The safety summary tables will include only assessments collected no later than 30 days after 
study drug discontinuation and assessments prior to the data cut-off date for on-going patients, 
unless otherwise specified.
For select items, shift tables or change from baseline summaries generated for laboratory, ECG, 
vital signs and change score (including Karnofsky/Lansky) generation may use data from pre-
treatment period for baseline calculations. 
All data, regardless of observation period, will be listed and visits/cycles collected in the pre-
treatment or post-treatment period will be displayed in all the listings.
2.8.1
Adverse events (AEs)
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 criteria exists for an AE, grades 1, 2, 3, or 4 corresponding to the 
severity of mild, moderate, severe, and life threatening, respectively, will be used. CTCAE 
grade 5 (death) will not be used in this study; rather, this information will be collected on the 
“End of Treatment” or “Study evaluation completion” eCRF pages.


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All AE summaries will be summarized (frequency counts and percentages) by system organ 
class and/or preferred term, and maximum severity grades, except where otherwise noted. A 
patient with multiple CTC grades for an AE will be summarized under the maximum CTC grade 
recorded for the event. 
The following AE summaries will be produced:

AEs regardless of study drug relationship 

AEs suspected to be study drug related 

All deaths, by primary SOC and PT

On-treatment deaths, by primary system organ class and preferred term 

SAEs regardless of study drug relationship 

SAEs suspected to be study drug related 

AEs associated with study drug discontinuation 

AEs requiring dose adjustment or interruption 

AEs requiring significant additional therapy

AEs excluding SAEs

In addition, AEs regardless of study drug relationship will be summarized by PT and age 
group for MTD/RDE patients.
2.8.1.1
Adverse events of special interest
Adverse events of special interest (AESIs) are defined as AEs within the following categories/ 
groupings of preferred terms:

Hepatotoxicity

Interstitial lung disease/Pneumonitis

QT prolongation 

Hyperglycemia

Bradycardia

GI toxicity (nausea, diarrhea, vomiting)

Pancreatitis (including Lipase or amylase increases)
AESIs are defined at the project level and may be updated based on emergent data to reflect 
new AESIs of interest 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.
Frequency counts and percentages of patients with DLTs will be tabulated by treatment group 
based on the DDS. DLTs will be listed by treatment group and patient.


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2.8.2
Laboratory data
The summaries will include all laboratory assessments collected no later than 30 days after last 
dose of study drug. All laboratory assessments will be listed and those collected later than 30 
days after study drug discontinuation will be flagged in the listings. For laboratory data 
assessments, data from all sources (central and local laboratories) will be combined.
Laboratory data will be classified (by Novartis Oncology CDRR) into CTC grades according 
to the National Cancer Institute (NCI) CTCAE v4.03.  For all reports, CTC grade is always 
obtained on the converted measurement in SI unit. Grade 5 will not be used. The CTC grade 0 
will be assigned as below in different scenarios:
1. For lab parameters defined by criteria based on normal range only, a severity grade of 0 
will be assigned when the value is within normal limits.
2.
For lab parameters whose grade is defined by criteria based on normal range and 
absolute values (e.g. platelet count decrease). A severity grade of 0 will be assigned 
when the value is within normal limits.
3. For lab parameters whose grade is defined by criteria based on normal range and the
change from baseline value, with no other associated clinical criteria such as concomitant
medication (e.g. creatinine increased) the following will be applied. For the baseline
grading and for the grading of post-baseline laboratory values with missing baseline grading, 
the grade will be derived using the criteria based only on the normal range as per CTCAE
v4.03. A severity grade of 0 will be assigned when the post-baseline value is ≤ ULN (for hyper) 
or ≥ LLN (for hypo).
Parameters for which a grading does not exist will be classified into low/normal/high group by 
means of laboratory normal ranges. 
The following summaries will be produced for 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. 
Liver function tests (LFTs) of interest for LDK378 are total bilirubin (TBILI), ALT, AST and 
ALP.  In what follows, AT refers to ALT or AST values. LFTs will be summarized as follows:

Shift tables of baseline vs. worst post-baseline on-treatment values for the categories:
o
TBILI ≤ 2xULN, TBILI > 2xULN and missing TBILI
o
ALT ≤ 3xULN, ALT > 3xULN and missing ALT
o
AST ≤ 3xULN, AST > 3xULN and missing AST
o
ALP < 2xULN, ALP ≥ 2xULN and missing ALP

Frequency counts and percentages of patients with worst post-baseline on-treatment 
values in the categories:
o
ALT > 3xULN, ALT > 5xULN, ALT > 10xULN, ALT > 20xULN
o
AST > 3xULN, AST > 5xULN, AST > 10xULN, AST > 20xULN
o
AT > 3xULN, AT > 5xULN, AT > 10xULN, AT > 20xULN
o
TBILI > 2xULN


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o
Concurrent ALT > 3xULN and TBILI > 2xULN
o
Concurrent AST > 3xULN and TBILI > 2xULN
o
Concurrent AT > 3xULN and TBILI > 2xULN 
o
Concurrent AT > 3xULN and TBILI > 2xULN and ALP < 2xULN
o
Concurrent AT > 3xULN and TBILI > 2xULN and ALP ≥ 2xULN
Concurrent measurements are those occurring on the same date.
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a post-baseline 
TBILI > 2xULN, ALT> 3xULN or AST > 3xULN will be provided.
The following listings will be produced by laboratory parameter, treatment group, and patient 
for all laboratory parameters where CTC grades are defined:

Listing of patients with laboratory abnormalities of CTC grade 3 or 4

Listing of all laboratory data with values flagged to show the corresponding CTC grades 
and the classifications relative to the laboratory reference ranges.
2.8.3
Other safety data
2.8.3.1
ECG and cardiac imaging data
ECG data will be analysed based on central laboratory reported results. The summaries will 
include all ECG assessments performed no later than 30 days after the last date of study drug.  
All ECG assessments will be listed, and those collected later than 30 days after on treatment 
period will be flagged in the listing. 
Selecting Primary QT Correction for Heart Rate
The analysis of QT data is complicated by the fact that the QT interval is highly correlated with 
heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected value, 
denoted QTc, which is independent of heart rate. This QTc interval is intended to represent the 
QT interval at a standardized heart rate. Several correction formulas have been proposed in the 
literature. For this analysis we will use some of those methods of correction, as described below. 
The QT interval corrected for heart rate by the Bazett’s formula, QTcB, is defined as 
RR
QT
QTcB
,
the QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as 
3 RR
QT
QTcF
,
where RR represents the RR interval of the ECG, in seconds.  
Although Bazett’s correction is the historical standard, it does not perform well when heart rate 
fluctuates. Fridericia’s formula may perform better under these conditions.  An alternate 
correction to achieve the goal of getting uncorrelated QTc and RR is based on linear regression 
methods which yield, theoretically, uncorrelated QTc and RR.


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Linear regression method:

Fit a model QT = a + b * RR to baseline data 

Use the estimated slope,  
^
b, to correct QT

Corrected QT for heart rate will be computed as follows:
QTcP = QT + 
^
b* (1- RR )
Data will be summarized using QTcF and QTcB. However, if these are not appropriate for the 
data set due to an observed large correlation between corrected QT and HR using the baseline 
assessments, the results will also be summarized using QTcP.
ECG Summaries
The following analyses will be performed for each applicable ECG parameters (RR, PR, QRS, 
QT, ventricular rate -denoted as HR in what follows-, and QTc) as noted.

Pearson correlation between QT and RR, QTc (QTcB, QTcF and, if applicable, QTcP) and 
HR using individual (non-averaged) baseline assessments and separately using on-treatment 
assessments 

For each of the ECG parameters (HR, and QTc, QT, QRS and PR intervals) descriptive 
statistics at baseline, at each post-baseline time point and changes from baseline at each 
post-baseline time point 

For each of the QTc and QT intervals, shift tables based on notable parameter categories 
(≤450, >450 - ≤480, >480 - ≤500, >500 ms) at baseline and the worst post-baseline value 
observed
The number and percentage of subjects with notable ECG values will be presented by treatment 
arm. 
o
QT parameter (QT, QTc) increase from baseline >30 ms,  >60 ms
o
Newly occurring post-baseline QT parameter > 450 ms, > 480 ms, > 500 ms
o
HR increase from baseline > 25% and value > 100 bpm
o
HR decrease from baseline > 25% and value < 50 bpm
o
PR increase from baseline > 25% and value > 200 ms
o
Newly occurring post-baseline PR > 200 ms and ≤220 ms, > 220 ms
o
QRS increase from baseline > 25% and value > 110 ms
o
Newly occurring post-baseline QRS > 110 ms and ≤ 120 ms, > 120 ms
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 

Frequency counts and percentages of patients with newly occurring post-baseline 
qualitative ECG abnormalities (morphology) will be summarized. The denominator to 
calculate percentages for any newly occurring ECG abnormality, each abnormality type and 
each individual finding is the number of patients with both a baseline and a post-baseline 


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evaluation, and baseline being normal, i.e. those patients who are at risk of developing this 
abnormality.  A newly occurring post-baseline qualitative ECG abnormality is defined as a 
post-baseline abnormal finding which was not present at baseline
Patients with notable ECG interval values and newly occurring qualitative ECG abnormalities 
will be listed by treatment group, , patient and timepoint, and the corresponding notable values 
and abnormality findings will be included in the listings.
Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point. However, they will be used in the 
analysis of notable ECG changes and the analysis of notable QT parameters.
2.8.3.2
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).
Vital signs shift table based on values classified as notable low, normal, notable high or notable 
(high and low) at baseline and worst post-baseline will be produced for pulse rate. 
Patients with clinically notable vital sign abnormalities will be listed. All vital sign assessments 
will be listed by patient and vital sign parameter. In the listings, clinically notable values will 
also be flagged.
The criteria for clinically notable values are defined in Table 2-2.
Table 2-2 Clinically notable vital sign ranges.
Body temperature (°C)
High
≥39.1°C
Low
≤35.0°C
Weight
High 
Increase from baseline ≥ 10%
Low
Decrease from baseline ≥ 10%
Pulse rate (beats per minute)
High2
12-18 months    
18-24 months
2-3 years
3-4 years
4-6 years
6-8 years
8-12 years
12-15 years
15-18 years
> 140
> 135
> 128
> 123
> 117
> 111
> 103
> 96
> 92
Low2
12-18 months    
18-24 months
2-3 years
3-4 years
4-6 years
6-8 years
< 103
< 98
< 92
< 86
< 81
< 74


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8-12 years
12-15 years
15-18 years
< 67
< 62
< 58
1Systolic and diastolic blood pressure will be listed individually.
2Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and respiratory rate in
children from birth to 18 years of age: a systematic review of observational studies. Lancet 2011;
published online March 15. DOI: 10.1016/S0140-6736(10)62226-X.
2.9
Performance status
Performance status will be assessed using the Karnofsky or Lansky performance scales, 
depending on the patient’s age.  The score, reported on an ordinal scale of 0-100 provides a 
rough measure of the patients’ well-being, including ability to conduct activities of daily living 
and functional capacity. Patients are classified as to their functional impairment status using the 
Karnofsky performance assessment (patients greater than 12years of age) or the Lansky 
performance status (patients 12 years of age and younger). The definition of scores in relation 
to performance based on the Karnofsky performance assessment is given in Table 2-3. The 
definition of scores based on the Lansky performance assessment is given in Table 2-4.
Table 2-3
Karnofsky performance status scale (for patients greater than 12yrs of 
age)
General category
Grade
Karnofsky score interpretation
Able to carry on normal
activity and to work; no
special care needed
100%
Normal no complaints.
90%
Able to carry on normal activity; minor signs or symptoms 
of disease. 
80%
Normal activity with effort; some signs or symptoms of 
disease.
Unable to work; able to
live at home and care
for most personal
needs; varying amount
of assistance needed.
70%
Cares for self; unable to carry on normal activity or to do 
active work.
60%
Requires occasional assistance, but is able to care for most 
of his personal needs.
50%
Requires considerable assistance and frequent medical 
care.
Unable to care for self;
requires equivalent of
institutional or hospital
care; disease may be
progressing rapidly.
40%
Disabled; requires special care and assistance
30%
Severely disabled; hospitalization is indicated though death 
not imminent.
20%
Very sick; hospitalization necessary; active supportive 
treatment necessary.
10%
Moribund; fatal processes progressing rapidly.
0%
Dead
Table 2-4
Lansky score (for patients 12years of age and younger)
General category.
Score
Lansky status
Able to carry on normal
activity and to work; no
special care needed
100
Fully active, normal
90
Minor restrictions in physically strenuous activity
80
Active, but tires more quickly
70
Both greater restriction of play and less time spent in play activity


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General category.
Score
Lansky status
Mild to moderate 
restriction
60
Up and around, but minimal active play; keeps busy with quieter 
activities
50
Gets dressed but lies around much of the day; no active play but 
able to participate in all quiet play and activities
Moderate to severe
restriction/dead
40
Mainly in bed; participates in quiet activities
30
Bed-bound; needs assistance even for quiet play
20
Often Sleeping; play entirely limited to very passive activities
10
No play; does not get out of bed
0
Unresponsive
Performance status will be summarized separately for the Karnofsky and the Lansky score 
based on FAS. Shift tables of scores at baseline to worst post-baseline status by general category 
will summarized.  Performance status at each time point will be listed.
2.10
Pharmacokinetic endpoints
Blood samples for PK analysis of ceritinib are collected during the dose escalation part and 
expansion part of the study as per protocol. All PK analyses will be performed based on the 
PAS unless otherwise specified.
During the dose escalation phase of the study, blood samples for full plasma concentration-time 
profile of ceritinib are collected over 24 hours on Cycle 1 Day 1 and on Cycle 2 Day 1 at the 
following scheduled time points: pre-dose, 2, 4, 6 and 24 hours post-dose. Trough PK samples 
are also collected pre-dose on Day 1 of Cycle 3-4 and Day 15 of Cycle 1. 
During the expansion phase, blood samples for full plasma concentration-time profile of 
ceritinib are collected over 24 hours on Cycle 2 Day 1 at the following scheduled time points: 
pre-dose, 2, 4, 6 and 24 hours post-dose. Trough PK samples will be collected on Day 1 of 
Cycle 1-4 at the MTD and/or RDE.
Only PK plasma concentrations with non-missing sampling data and time, and for which the 
last dose date and time prior to the PK sample draw are non-missing will be included in the PK 
analysis. Unscheduled samples are not included in any analysis, but these samples will be listed 
using PAS and flagged in the corresponding concentration listing.
PK parameters
Pharmacokinetic parameters will be determined using non-compartmental method(s), using 
Phoenix WinNonlin (Pharsight, Mountain View, CA.), The PK parameters listed in Table 2-6
will be estimated and reported, as appropriate. 
Among the parameters, the following are considered primary: AUCtau, Cmin, Cmax, Tmax ; 
and the following are considered secondary: CLss/F, Racc. Those not designated as primary or 
secondary will be listed only. 
Table 2-5
Noncompartmental pharmacokinetic parameters 
AUCtau
The AUC calculated to the end of the dosing interval, tau.


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Cmin
Observed concentration at the end of a dosing interval (taken directly before next 
administration).
Cmax
The maximum observed plasma, blood, serum, or other body fluid drug 
concentration 
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration 
T1/2,acc
Effective half-life can be calculated from Racc.
CLss/F
Apparent oral total body clearance of drug from the plasma calculated from steady-
state exposure 
Racc
Accumulation ratio calculated using AUCtau values obtained from a dosing interval 
at steady-state divided by AUCtau at day 1
Data handling principles
Concentration values below the lower limit of quantitation (LLOQ) (< 1.0 ng/mL) will be 
displayed in listings as zero with a flag and handled as zero in the calculations of summary 
statistics except for geometric means and associated CVs where they will be set to missing Any 
missing PK parameters will not be imputed.
LDK378 concentrations 
Summary statistics, including n, mean, SD, coefficient of variation CV (%) for mean, geometric 
mean, geometric CV (%), median, minimum and maximum, will be presented for evaluable PK 
plasma concentration of LDK378 following the general reporting rule for PK, by treatment and 
scheduled time point for both full PK profile and trough PK concentrations, separately for fasted 
and fed patients and for escalation phase and expansion phase. For patients with full PK profile 
on Cycle 1 Day 1 or Cycle 2 Day 1, corresponding graphical presentations of the plasma 
concentration profiles will be provided by treatment using arithmetic mean (+/- SD) and 
geometric mean values at each scheduled time point. The individual plot will also be provided. 
LDK378 PK parameters
Primary and secondary PK parameters will be summarized using the same reporting approach 
as for LDK378 concentrations, by treatment, separately for Cycle 1 Day 1 and Cycle 2 Day 1 
for fasted and fed patients in the escalation and expansion phase. For Tmax, only median, 
minimum and maximum will be presented. 
All PK parameters and concentration data will be listed by treatment using PAS.
Dose proportionality (DP) analysis
DP analysis at single dose (Cycle 1 Day 1) and steady state (Cycle 2 Day 1): Data from both 
dose-escalation phase and expansion phase will be used. AUC0-24h and Cmax will be analyzed. 
All dose levels will be included. 
DP will be assessed via the following model as well as graphical presentations. 
DP is analyzed by fitting a linear model as described below.
ln(PK) = α + β*ln(actual dose),)


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where PK is the PK parameter, AUC0-24 or Cmax, and actual dose (mg/m2) is defined as dose 
divided by BSA. 
The estimate and its 90% confidence interval (CIs) for β in each case are reported. As an 
informal comparison, the estimates and CIs for βare compared to the target dose-proportionality 
range, calculated by the following formula (Smith, 2000). 
Lower bound of target dose-proportionality range of β: 1 + ln(0.8)/ln(dose range)
Upper bound of target dose-proportionality range of β: 1 + ln(1.25)/ln(dose range)
Dose range is the highest actual dose/lowest actual dose, for which data are used for the dose 
proportionality analysis. The dose range may or may not be the same for all parameters. 
This analysis is not prospectively powered for the result to fall into the target range, and 
therefore the actual result rather than the comparison itself should be emphasized when 
interpreting data. 
Trough concentration (Ctrough)
Trough PK samples will be collected at the following time points:

0 hour pre-dose samples on C1D1, C1D8, C1D15, C2D1-C6D1 in all patients

0 hour pre-dose sample on C1D2 (i.e. 24 hour post-dose samples on C1D1), and C2D2 
(i.e.
24 hour post-dose samples on C2D1) for patients with full PK collection
The trough concentrations obtained throughout the study will be plotted over time by
treatment arm using PAS. Only time points with n ≥ 4 trough observations will be shown on
the figure.
No model-based analyses will be conducted.
Average Ctrough
Average trough concentration will be used in the exposure response analyses. Each patient may 
have one or more Ctrough values. The average Ctrough considering the distribution of PK is 
generally lognormal is defined as:
	ℎ = 	  ( 	ℎ ℎ)
, considering 
the distribution of PK concentration is generally lognormal.
Ceritinib trough concentration included in calculating the average must fulfill the following
rules:

For the pre-dose or 24 hour post-dose sample, draw must occur between 18 to 30 
hours
after the last dose intake (except for Cycle 1 Day 1), AND

For the pre-dose or 24 hour post-dose sample, the draw must occur before the next 
dose
intake, AND

Additionally, a sample can be considered non-evaluable as per scientific judgment of 
the
clinical pharmacology expert even if the above criteria are fulfilled. Reason will be
documented.


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The criteria have been modified over evaluable trough concentration as defined in PAS by
removing the following three rules:

No vomiting occurs within 4 hours following the last dose intake prior to the PK 
sample
draw,

The patient takes study drug according to the originally assigned dose for at least 5
consecutive days without interruption or dose modification prior to the PK sampling day
(except for Cycle 1 Day 1),

The patient takes study drug under the originally assigned prandial conditions, i.e., 
dose
administered without food for patients randomized to the treatment arm of 750 mg fasted,
or dose administered with food for patients randomized to the treatment arm of 450 mg
with low-fat meal or 600 mg with low-fat meal, for at least 5 consecutive days prior to the
PK sampling day (except for Cycle 1 Day 1)
This allows exposure-response analyses to take into account the exposure after study drug
interruption, dose reduction, vomiting or fail to adhere to the assigned prandial condition for
individual patient.
Quartile ranges of Ctrough_avg are defined as:
<Q1: 
<25th percentile
Q1-<Q2: 
≥25th percentile and <50th  percentile
Q2-<Q3: 
≥50th percentile and <75th percentile
≥Q3: 
≥75th percentile
Ctrough_avg and its quartile values will be used in display of AE.
Inter and intra patient variation
The intra-patient and inter-patient variations will be evaluated using data from patients at MTD 
with one or more than one evaluable steady state trough PK measurements. Evaluable trough 
concentration is defined in PAS. For steady state trough concentration, we will only consider 
trough values collected on or after C1D15 (C1D1 sample will not be used in the analysis). The 
intra-patient and inter-patient variations will be estimated using random effects model with 
treatment as a fixed effect and patient as a random effect. See Section 5.7 for more details.
2.11
Patient-reported outcomes
Not applicable
 
 
 
 


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2.13
Interim analysis
No formal interim analyses are planned. However, the dose-escalation design foresees that
decisions based on the current data are made before the end of the study. More precisely, the
next dose of LDK378 has to be chosen after each cohort in the dose escalation part, and the 
decision is dependent on the observed data. 
3
Sample size calculation
Dose escalation part
Respectively for the fasted dose escalation and the fed dose escalation, cohorts of 3 to 6 
evaluable patients will be dosed in the dose-escalation part including at least 6 patients at the 
corresponding MTD/RDE level, as described in Section 6.2.3 of protocol. Multiple cohorts may 
be sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 patients may be 
enrolled at any dose level below the estimated MTD/RDE for further elaboration of safety and 
pharmacokinetic parameters as required. At least 15 patients for the fasted dose escalation  and 
12 for the fed dose escalation are expected to be treated in the dose escalation part, for the model 
to have reasonable operating characteristics relating to its MTD recommendation.
Dose expansion part
During the expansion part, approximately 45 patients will be treated on the preferred regimen 
(including all patients treated at the MTD/RDE on the preferred regimen during the dose 
escalation part who are eligible for the safety set), approximately 25 patients in group 1 on the 
preferred regimen, and approximately 20 patients in group 2.
Group 1: ALK-activated neuroblastoma
Based on the ORR (per RECIST 1.1) intervals described in Section 10.4.2 of protocol, it was 
assessed how likely it is to wrongly declare activity as defined by observing at least “moderate 
antitumor activity” (i.e. seeing at least 5 responses out of 25 patients) given the true ORR = 
10%, and how likely it is to correctly declare activity given the true ORR = 30% when 25 
patients are evaluated.

If the true ORR = 10%, the probability to wrongly declare activity is 9.8%.

If the true ORR = 30%, the probability to correctly declare activity is 91.0%.


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Given a sample size of 25 in-group 1, if five responses are seen, the observed ORR is 20% with 
an 80% credible interval of (10.7%, 30.3%). This will be considered as preliminary evidence of 
antitumor activity of LDK378 at the MTD/RDE within this group.
Group 2: other ALK-activated tumors, such as IMT and ALCL
For group 2, sample size estimation is based on safety. A sample size of 20 will result in an 
87.8% probability of detecting an AE with an incidence rate of ≥ 10%. 
4
Change to protocol specified analyses
Table 4-1 summarizes the changes to protocol-specified analyses and associated rationale for 
inclusion.  


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Table 4-1
Changes to protocol specified analysis or descriptions and rationale 
Protocol Section
Protocol Description
Change 
3.1 Best overall 
response
BOR for each patient will be 
determined based on the following 
rule: 

SD = at least one SD 
assessment (or better) > 
6 weeks after 
randomization (and not 
qualifying for CR or 
PR).

PD = progression ≤ 12 
weeks after 
randomization (and not 
qualifying for CR, PR 
or SD).
BOR for each patient will be 
determined based on the 
following rule: 

SD = at least one SD 
assessment (or better) > 
29 days after 
randomization (and not 
qualifying for CR or 
PR).

PD = progression ≤ 85 
days after randomization 
(and not qualifying for 
CR, PR or SD). 
This update was made to 
account for the +/-1 week 
window for the tumor 
assessment protocol defined 
schedule of 6 weeks. 
Consequently, BOR of 
‘Unknown’ derivations of ‘SD
too early’ and ‘PD too late’ will 
be based on the updated 
calculations:

Stable disease (SD) too early 
(≤ 29 days after 
randomization date)

PD too late (> 85 days after 
randomization date).
See details in section 2.6. 
3.1 Best overall 
response
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.
For the BOR calculation, the 
default option will not be used, 
i.e., assessments taken more 
than the 30 days after the last 
dose of study treatment will be 
included in the best overall 
response derivation for 
consistency with other time to 
event end-points.


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5
Appendix
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.
5.1
Data included in the analyses
This section provides additional details to those included in Section 2.1.
Final analysis of study data once all patients have discontinued treatment, and all required safety 
follow-up has been completed or the patient has died, been lost to follow-up or has withdrawn 
their consent to further participation in the study or the last patient on treatment has been 
enrolled to a separate protocol, whichever comes first, will include the data with an assessment 
date or event start date (e.g. vital sign assessment date or start date of an adverse event) prior to 
or on the cut-off date. For example, if the cut-off date is 30DEC2015, an AE starting on 
28DEC2015 will be reported, whereas an adverse event starting on 31DEC2015 will not be 
reported.
5.2
Patient classification into analysis sets
This section provides additional details to those included in Section 2.2.
Patients are excluded from the analysis populations based on the protocol deviations entered in 
the database and/or on specific patient classification rules as shown in Table 5-1 below. Only 
data from patients having signed informed consent are used in the analyses described below. 
Table 5-1
Patient classification rules 
Analysis Population
Protocol deviation 
ids leading to 
exclusion
Additional patient classification rules leading 
to exclusion
Full Analysis Set
N/A
Patients who did not receive at least one dose 
of study drug
Safety Set
N/A
Patients who did not receive at least one dose 
of study drug.
Dose determining
Set
N/A
Patient did not received at least 16 of the 21 
doses in cycle 1 or did not experience a DLT 
if receiving less than the prescribed number of 
doses.
Pharmacokinetic 
analysis set
N/A
Patients receiving LDK who do not have at 
least one evaluable PK sample as defined in 
Section 2.10


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5.3
Derivations
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.
Dose interruptions and dose changes
This section provides additional details to those included in Section 2.4.
All calculations of dose interruptions and dose changes are based on corresponding CRF check 
box and the dose actually taken by the patient.
An interruption is defined as a 0 mg dose taken on one or more days. What follows defines how 
dose interruptions will be counted in the case of multiple dose interruptions.

If an interruption occurs consecutively for at least two days due to the same reason, then it 
will be counted only once (example: If the actual dose on days 1-3 is 750 mg and actual 
dose on days 4-5 is 0 mg and dose interruption on days 4-5 is due to AE, then the total 
number of dose interruptions is 1).

If an interruption occurs consecutively for at least two days due to different reasons, then it 
will be counted for each reason (example: If the actual dose on days 1-3 is 750 mg and 
actual dose on days 4-5 is 0 mg and dose interruption on day 4 is due to AE and dose 
interruption on day 5 is due to dosing error, then the total number of dose interruptions is 
2). 

If an interruption occurs for more than one day due to the same reason, but the days are not 
consecutive , i.e. there is at least one dosing day in between, then each dose interruption 
will be counted as a different occurrence (example: if the actual dose on days 1, 3 and 5, is 
750 mg and actual dose on days 2 and 4 is 0mg, and dose interruptions on day 2 and 4 are 
both due to dosing error, the total number of dose interruptions is 2). 
A dose change is defined as a change in dosing from one record to the next; however, a dose 
interruption will not be counted as a dose change.
Dose reductions are a subset of dose changes where dose changes to higher than protocol-
planned dose are excluded.
5.4
Efficacy endpoints 
For further details on efficacy endpoints, see Section 14 (Appendix 5 and 6) of the protocol. 
For the evaluation of tumor-response related endpoints, response is assessed by investigator per
RECIST 1.1 and IWG criteria. 
Response and progression evaluation will be performed according to the Novartis RECIST 1.1 
guidelines and the Novartis Cheson criteria guidelines, included in Section 14 (Appendix 5 and 
6) of the LDK378X2103 protocol.
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Sections 2.6 and 2.7


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5.4.1
Implementation of RECIST and Cheson guidelines
Disease progression
PD should only be assigned if it is confirmed by an objective assessment method. If a new 
lesion is detected using an objective assessment method other than radiologic scan, it should be 
entered on the ‘New lesion’ RECIST and Cheson eCRF with appropriate method (or 
method=‘Other’). 
In particular, discontinuation due to disease progression or death due to progressive disease, 
without supporting objective evidence (as defined above), will not be considered as PD in the 
determination of BOR, the derivation of any efficacy endpoint or efficacy analysis. 
Change in imaging modality per RECIST 1.1
Per RECIST 1.1, a change in methodology can be defined as either a change in contrast use (e.g. 
keeping the same technique, like CT, but switching from with to without contrast use or vice-
versa, regardless of the justification for the change) or a change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology will 
result by default in a UNK 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.
Change in imaging modality per Cheson
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 an “Unknown” overall radiological response assessment. However, another overall 
radiological response than the Novartis calculated “Unknown” response might be accepted from 
the investigator or the central blinded reviewer if a definitive overall radiological response can 
be justified to be based on the available information.
Determination of missing adequate tumor assessments
For the computation of ORR, patients without any radiological assessment after the start date 
of study drug will be counted as failure.
Partial or complete responses reported prior to any additional anticancer therapy will be 
considered for ORR computation irrespective of the number of missed assessments before 
response. In this section, the ‘missing adequate assessment’ is defined as assessment not done 
or assessment with overall lesion response equal to UNK.  For the sake of simplicity, the 
‘missing adequate assessment’ will also be referred as ‘missing assessment’.
As detailed in Section 14 (Appendix 5 and 6) of the LDK378X2103 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.


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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. For example, n 
this study, the protocol defined schedule of tumor assessment is every 6 weeks for the first six 
cycles, 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 = 6+2 = 8 weeks 
means one missing assessment and any distance larger than D2 = (2*6) + 2 = 14 weeks means 
two missing assessments. Please see protocol 7.1 for the complete schedules for tumor 
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
6: Event after >=2 missing tumor assessments
New cancer therapy used in RECIST calculations include any anti-cancer therapy as recorded 
in the medication, surgery (diagnostic biopsies are excluded) or radiotherapy CRF pages and
includes LDK378 treatment from the extension-treatment phase.
Eligibility per RECIST 1.1 (Non-measurable disease only at baseline)
As specified in Section 14 (Appendix 5) of the LDK378X2103 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 FAS including 
patients with either measurable or non-measurable disease per RECIST 1.1. Therefore, a rule 
needs to be specified on how to handle these cases.
As specified in Table 14-8 of Section 14 (Appendix 5) of the LDK378X2103 protocol, overall 
lesion response can be derived for patients without measurable disease at baseline as follows 
(Table 5-2).


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Table 5-2
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-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. 
Eligibility per Cheson criteria.
As specified in Section 14 (Appendix 6) of the LDK378X2103 protocol, Cheson criteria imply 
that only patients with measurable disease should be in included in the study. In particular,
patients should have at least one measurable nodal lesions greater than 20mm in the long 
axis.  In cases where the patient has no measurable nodal lesions greater than 20mm in the long 
axis at baseline, then the patient must have at least one measurable extranodal lesion (long and 
short axes are >= 10mm). 
Missing baseline tumor assessment
Since the timing of PD cannot be determined for patients with missing baseline tumor 
assessment, these patients are censored in the PFS analysis at the start date of treatment. This 
rule, however, only applies to the ‘PD component’ of the PFS or DOR assessment.  
Patients without baseline tumor assessment who die within D2 distance from start date of 
treatment will be counted as having an event in the primary analysis of PFS.  
5.4.2
Kaplan-Meier estimates
To analyze time to event variables (DOR and PFS) 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); */


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Kaplan-Meier survival and failure function estimates from this procedure will be used to 
construct the Kaplan-Meier figures
Median survival will be obtained along with 2-sided 95% CIs calculated from PROC 
LIFETEST output using the method of Brookmeyer & Crowley, 1982..
Kaplan-Meier estimates with 2-sided 95% CIs at specific time points will be summarized.  The 
time points can be expressed in weeks or in months depending on the time-to-event variable.  
The CIs will be constructed using Greenwood’s formula [Collet, 1994, p.23] for the standard 
error of the Kaplan-Meier estimate.
The Kaplan-Meier graphs will be constructed using SAS software.
5.4.3
Confidence interval for response rate
ORR will be summarized in terms of percentage rates with 95% CIs. An exact binomial 
confidence interval (implemented using SAS procedure FREQ with EXACT statement for one-
way tables) will be calculated (Clopper & Pearson,1934).
SAS procedure FREQ will be used to estimate the proportion of responders (binary outcome = 
1 or “Yes”), along with the associated 95% (=100 × (1 – two-sided alpha level)) two-sided 
Pearson-Clopper CI for the hypothesis test of the null proportion (0.25). These estimates are 
obtained as follows:
proc freq data = dataset;
table binary event / 
binomial(
level = “Yes”)
alpha = two-sided alpha level;
exact binomial;
When there are no responders, SAS does not produce a CI by default. To obtain a CI in this 
situation, PROC FREQ is used as specified above except changing level=”No”. From the results 
of this modified procedure, the values in percent of the LCL and UCL of a 0% response rate are 
calculated as follows:
LCLLEVEL=”Yes” (%) = 100% - UCLLEVEL=”No” (%)
UCLLEVEL=”Yes” (%) = 100% - LCLLEVEL=”No” (%)
5.5
Safety evaluations
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Section 2.8
5.5.1
Multiple assessments within post-baseline visits
For all analyses regarding abnormal assessments or analyses based on worst or best post-
baseline value (laboratory, ECGs, vital signs, ECOG performance status), all post-baseline 
values will be included (scheduled, unscheduled, repeat).  All unscheduled and repeat 
measurements will be included in listings.
Laboratory Data 


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For laboratory data, assessments can be collected from both local and central laboratory on the 
same date. For shift tables using CTC grades to compare baseline to the worst post-baseline 
value, the assessment with worst post-baseline value is used for analyses irrespective of the 
source. For LFT summaries, where concurrent measurements are used in the calculation of 
number and percentage of patients with worst post-baseline values, the assessment with worst 
post-baseline value is used (since worst values are based on the largest ratio of lab value to its 
ULN for each patient) although the worst values for the different parameters may be coming 
from different laboratories.  
ECGs
For all patients, three ECGs are targeted to be measured at the protocol-defined (nominal) time-
points. If a patient has more than one measurement at a nominal time point, the average of all 
available measurements associated with the nominal time point will be used for the analyses.  
5.5.2
Baseline
As defined in Section 2.1.1, the last available assessment before or on the date of start of study 
drug is defined as “baseline” value or “baseline” assessment.
Laboratory data 
If both central and local laboratory assessments were performed on the same date and 
corresponding to the baseline assessment date, then the central laboratory assessment will be 
used for the calculation of baseline.
ECGs 
Baseline for ECG measurement is the average of all available measurements (unscheduled, if 
applicable) taken prior to dosing on the date associated with the last available ECG 
measurement before or on the date of start of study treatment. To determine whether ECG 
measurement was taken prior to dosing, ECG time will be compared with dosing time, if 
available. Unscheduled assessments will be included in the calculation of the average if ECG 
time is before dosing time. Study day one scheduled pre-dose ECGs will be considered to have 
been obtained prior to study drug administration if dosing time or ECG time is missing.
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement. 
For unscheduled assessments on study day 1, 

if dosing time is non-missing, then the assessment is classified as post-baseline if ECG time 
is later than dosing time. 

if dosing time is missing, the assessment is classified as post-baseline. 
The same ECG assessments will be used for both qualitative and quantitative baseline 
evaluations.
5.5.3
Laboratory Parameters
This section provides further detail on the analysis of laboratory parameters that will be listed 
and summarized as described in Section 2.8.3 .


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Hematology
Hematologic tests include Hemoglobin, platelets, white blood cells (WBC) with differentials
(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 subject, the original lab value (%) 
is divided by 100 and multiplied by WBC count e.g. for neutrophils (NEU):
NEU count = (WBC count) * (NEU%value/100)
In order to derive the corresponding absolute normal range, the rule to be applied depends on 
the availability of the % range and the absolute range for the differential:

If %  absolute range NOT missing (% range is or isn’t missing), then use the absolute range 
provided by the site

If % range NOT missing and absolute range missing, then the % normal limits (i.e. LLN 
and ULN) are divided by 100 and multiplied by the corresponding normal limits of WBC 
count, e.g. for neutrophils NEU):
LLN for NEU count = (LLN for WBC count)* (LLN for NEU%value /100)
ULN for NEU count = (ULN for WBC count)*(ULN for NEU%value/100)
Biochemistry
The following calculation will be applied for corrected calcium in SI unit:
Corrected calcium (mmol/L) =measured total Ca (mmol/L)+0.02 (40-serum 
albumin[g/L]), where 40 represents the average albumin level in g/L.
5.6
Handling of missing or partial dates
For patients not known to have died prior to the cut-off date:

All events with start date before or on the cut-off date, and with end date missing or 
after the cut-off date, or after the date of withdrawal of informed consent, will be 
reported as “continuing”. 

This approach applies, in particular, to AEs and concomitant medication reports. For these 
events, the end date will not be imputed and therefore will not appear in the listings. 
If imputation of an end date is required for a specific analysis (e.g. for a dose administration 
record with missing end date or last date of study drug after the cut-off date), the end date will 
be imputed to the min(cut-off date, death date and withdrawal of informed consent date)for the 
purpose of calculating duration of exposure to study drug and dose intensity. The imputed date 
will be displayed and flagged in the listings.


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5.6.1
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 5-4 explains the abbreviations used.
Table 5-3
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 5-5 describes the possible combinations and their associated 
imputations. In the light grey boxes, the upper text indicates the imputation and the lower text 
the relationship of the AE start date to the treatment start date (TRTSTD).
Table 5-4
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 )
( A )
( A )
( A )


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AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM
After TRTSTD
After TRTSTD
After TRTSTD
After TRTSTD
The following Table 5-6 is the legend to the above table.
Table 5-5
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 5-7 gives a few examples.
Table 5-6
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
5.6.2
Concomitant medication date imputation
The imputation of the start date of concomitant medication will follow the same conventions 
as for AE date. Partial concomitant medication end dates will not be imputed.


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5.6.3
Incomplete date of initial diagnosis of cancer and date of most recent 
recurrence 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
5.6.4
Incomplete date for anti-neoplastic therapies
Prior therapies
Start date: 
The same rule which is applied to the imputation of AE/concomitant medication start date 
will be used with the exception that for scenario (B) will be replaced to be                     ‘start 
date of study drug -1’.
End date:
Imputed date = min (start date of study drug, last day of the month), if day is missing;
Imputed date = min (start date of study drug, 31DEC), if month and day are missing.
If the end date is not missing and the imputed start date is after the end date, use the end 
date as the imputed start date.
If both the start date and the end date are imputed and if the imputed start date is after the 
imputed end date, use the imputed end date as the imputation for the start date.
Post therapies
Start date:
Imputed date = max (last date of study drug + 1, first day of the month), if day is missing;
Imputed date = max (last date of study drug + 1, 01JAN), if day and month are missing. 
End date: No imputation. 
5.6.5
Incomplete assessment dates for tumor assessment
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, the 
incomplete date(s) are not considered for calculation of the assessment date and assessment date 
is calculated as the latest of all investigation dates (e.g. X-ray, CT-scan) if the overall lesion 
response at that assessment is CR/PR/SD/UNK. Otherwise, if overall lesion response is PD, the 
assessment date is calculated as the earliest date of all investigation dates at that evaluation 
number.  If all measurement dates have no day recorded, the first of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date, which is exactly between the previous and the following assessment. 
If both a previous and following assessments are not available, this assessment will not be used 
for any calculations. In case of multiple imaging scans performed within an evaluation, if some 
imaging dates for tumor assessment under the same evaluation for a patient are before as well 
as after cut-off, the entire evaluation will not be included for analyses based on the pre-specified 


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cut-off. Hence, only complete tumor assessments (with all imaging dates on or prior to the cut-
off) for an evaluation will be included for analyses as determined by the pre-specified cut-off.
5.6.6
Incomplete date for death 
All dates must be completed with day, month and year.
Missing month and year will not be imputed. If the day 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:
1st day of the month and year of death
5.6.7
Last contact date
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following:
Table 5-8
Last contact date data sources
Source data
Conditions
Date of Randomization 
No Condition
Last contact date/last date patient was known to 
be alive from Survival Follow-up page 
- Patient status is reported to be alive, lost to 
follow-up or unknown.
Start/End dates from further antineoplastic 
therapy
Non-missing medication/procedure term.
Start/End* dates from drug administration record 
Non-missing dose. Doses of 0 are allowed.
End of treatment date from end of treatment page
No condition.
- Tumor (RECIST) assessment date
- For non-RECIST studies, any specific efficacy 
assessment date if available
Evaluation is marked as ‘done’.
Laboratory/PK collection dates
Sample collection marked as ‘done’. 
Vital signs date
At least one non-missing parameter value
Performance Status date
Non-missing performance status
Start/End dates of AE 
Non-missing verbatim term

The last contact date is defined as the latest complete date from the above list on or before 
the data cut-off date . The cut-off date will not be used for last contact date, unless the
patient was seen or contacted on that date. No date post cut-off date will be used. 
Completely imputed dates (e.g. the analysis cut-off date programmatically imputed to
replace the missing end date of a dose administration record) will not be used to derive the 


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last contact date. Partial date imputation is allowed for event (death)/censoring is coming 
from ‘Survival information’ eCRF. 
5.6.8
Incomplete dates for last dose of study drug
Scenario 1 
If the last date of study drug is after the cut-off date or is completely missing and there is no 
end of treatment eCRF page and no death date the patient should be considered to be on-going 
and use the cutoff date for the analysis as the last dosing date
Scenario 2 
If the last date of study drug is completely or partially missing and there is EITHER an end of
treatment eCRF page OR a death date available then imputed last dose date:
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death date)
= Last day of the month, if both Year and Month are available, and EITHER:
-- Year = Year of min (EOT date, death date) and Month < the month of min (EOT
date, death date) OR,
-- Year < Year of min (EOT date, death date) irrespective of the month
= min (EOT date, death date), for all other cases
5.6.9
Incomplete dates for disease progression prior to start of study drug
If day of PD associated with prior antineoplastic medication is missing then imputed PD date:
= min (midpoint between the end date of the prior antineoplastic medication and the end of
the month, start date of LDK, start date of prior medication from the next regimen), if end
date of prior antineoplastic medication is in the same month as the PD date,
= min (15th of the month of the PD date, start date of LDK, start date of prior medication
from the next regimen), if end date of prior antineoplastic medication is in a month prior to
the PD date
= 15th of the month of the PD date, if end date of prior antineoplastic medication is in a
month after the PD date.
If both day and month of PD associated with prior antineoplastic medication are missing then
imputed PD date:
= min (midpoint between the end date of the prior antineoplastic medication and the end of
the year, start date of LDK, start date of prior medication from the next regimen), if end date
of prior antineoplastic medication is in the same year as the PD date
= min (July 1 of the year of the PD date, start date of LDK, start date of prior medication from
the next regimen), if end date of prior antineoplastic medication is in a year prior to the PD
date
= July 1 of the year of the PD date, if end date of prior antineoplastic medication is in a year
after the PD date
Completely missing PD dates will not be imputed. The start date of medication from the next
regimen is based on the earliest start date of any medication(s) from the next regimen. For the
mid-point calculation, if odd days in between, (e.g. last dose of medication is 27 June 2012,


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and end of the month is 30 June 2012), then use the next day from the midpoint calculation
(e.g. mid-point is 29 June 2012).
5.7
PK analyses
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Section 2.10.
The random effects model with patient as random effect will be used to estimate the intra-patient 
and inter-patient variation. The following SAS code will be used:
PROC MIXED data = pkdataset;
CLASS patient;
MODEL Log_ Ctrough = / solution;
RANDOM patient;
RUN;
/* log_Ctrough refers to log transformed SS Ctrough concentration */
The inter-patient CV% for SS Ctrough will be calculated as:
CV% = sqrt(exp(variance estimate for random patient effect from SS Ctrough model) –1)×100
The intra-patient CV% for SS Ctrough will be calculated as:
CV% = sqrt(exp(residual variance from SS Ctrough model) – 1)×100
6
Reference
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Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time, 
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Clopper CJ, Pearson ES (1934).  The use of confidence or fiducial limits illustrated in the case 
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Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall.
Kalbfleisch JD, Prentice RL. (2002) The Statistical Analysis of Failure Time Data. Wiley 
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Neuenschwander B, Branson M, Gsponer T, et al (2008). Critical aspects of the Bayesian 
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